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Diabetes Care 2020 PDF
Diabetes Care 2020 PDF
Diabetes is a complex, chronic illness re- The ADA strives to improve and update immediate inclusion. More information on
quiring continuous medical care with the Standards of Care to ensure that the “living Standards” can be found on the
multifactorial risk-reduction strategies clinicians, health plans, and policy mak- ADA’s professional website DiabetesPro at
beyond glycemic control. Ongoing dia- ers can continue to rely on it as the professional.diabetes.org/content-page/
betes self-management education and most authoritative source for current living-standards. The Standards of Care
support are critical to preventing acute guidelines for diabetes care. supersedes all previous ADA position
complications and reducing the risk of long- statementsdand the recommendations
ADA STANDARDS, STATEMENTS,
INTRODUCTION
term complications. Significant evidence thereindon clinical topics within the
REPORTS, and REVIEWS purview of the Standards of Care; ADA
exists that supports a range of interven-
tions to improve diabetes outcomes. The ADA has been actively involved in position statements, while still contain-
The American Diabetes Association the development and dissemination of ing valuable analysis, should not be con-
(ADA) “Standards of Medical Care in Di- diabetes care clinical practice recom- sidered the ADA’s current position. The
abetes,” referred to as the Standards of mendations and related documents for Standards of Care receives annual review
30 years. The ADA’s Standards of Medical and approval by the ADA Board of Directors.
Care, is intended to provide clinicians,
Care is viewed as an important resource
patients, researchers, payers, and other ADA Statement
for health care professionals who care for
interested individuals with the compo- An ADA statement is an official
people with diabetes.
nents of diabetes care, general treatment ADA point of view or belief that
goals, and tools to evaluate the quality of Standards of Care does not contain clinical practice
care. The Standards of Care recommen- The annual Standards of Care recommendations and may be issued
dations are not intended to preclude supplement to Diabetes Care contains on advocacy, policy, economic, or
clinical judgment and must be applied official ADA position, is authored by medical issues related to diabetes.
in the context of excellent clinical care, the ADA, and provides all of the ADA statements undergo a formal re-
with adjustments for individual prefer- ADA’s current clinical practice view process, including a review by the
ences, comorbidities, and other patient recommendations. appropriate ADA national committee,
factors. For more detailed information To update the Standards of Care, the ADA science and medicine staff, and
about the management of diabetes, please ADA’s Professional Practice Committee the ADA Board of Directors.
refer to Medical Management of Type 1 (PPC) performs an extensive clinical di-
Diabetes (1) and Medical Management of abetes literature search, supplemented Consensus Report
Type 2 Diabetes (2). with input from ADA staff and the med- A consensus report of a particular
The recommendations in the Stand- ical community at large. The PPC updates topic contains a comprehensive
ards of Care include screening, diagnos- the Standards of Care annually. However, examination and is authored by an
tic, and therapeutic actions that are known the Standards of Care is a “living” docu- expert panel (i.e., consensus panel)
or believed to favorably affect health out- ment, where important updates are pub- and represents the panel’s collective
comes of patients with diabetes. Many lished online should the PPC determine analysis, evaluation, and opinion.
of these interventions have also been that new evidence or regulatory changes The need for a consensus report arises
shown to be cost-effective (3). (e.g., drug approvals, label changes) merit when clinicians, scientists, regulators,
The “Standards of Medical Care in Diabetes” was originally approved in 1988. Most recent review/revision: December 2019.
© 2019 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit,
and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.
S2 Introduction Diabetes Care Volume 43, Supplement 1, January 2020
Table 1—ADA evidence-grading system for “Standards of Medical Care in Diabetes” the evidence in support of the recom-
Level of
mendation. Expert opinion E is a separate
evidence Description category for recommendations in which
there is no evidence from clinical trials,
A Clear evidence from well-conducted, generalizable randomized controlled trials that
are adequately powered, including
clinical trials may be impractical, or there
c Evidence from a well-conducted multicenter trial is conflicting evidence. Recommendations
c Evidence from a meta-analysis that incorporated quality ratings in the analysis with A level evidence are based on large
Compelling nonexperimental evidence, i.e., “all or none” rule developed by the Centre well-designed clinical trials or well-done
for Evidence-Based Medicine at the University of Oxford meta-analyses. Generally, these recom-
Supportive evidence from well-conducted randomized controlled trials that are mendations have the best chance of im-
adequately powered, including
proving outcomes when applied to the
c Evidence from a well-conducted trial at one or more institutions
c Evidence from a meta-analysis that incorporated quality ratings in the analysis
population for which they are appropriate.
B Supportive evidence from well-conducted cohort studies
Recommendations with lower levels of
c Evidence from a well-conducted prospective cohort study or registry evidence may be equally important
c Evidence from a well-conducted meta-analysis of cohort studies but are not as well supported.
Supportive evidence from a well-conducted case-control study Of course, evidence is only one com-
C Supportive evidence from poorly controlled or uncontrolled studies ponent of clinical decision-making. Clini-
c Evidence from randomized clinical trials with one or more major or three or more cians care for patients, not populations;
minor methodological flaws that could invalidate the results guidelines must always be interpreted
c Evidence from observational studies with high potential for bias (such as case
with the individual patient in mind. In-
series with comparison with historical controls)
c Evidence from case series or case reports
dividual circumstances, such as comorbid
Conflicting evidence with the weight of evidence supporting the recommendation and coexisting diseases, age, education,
E Expert consensus or clinical experience disability, and, above all, patients’ values
and preferences, must be considered and
may lead to different treatment targets
and/or policy makers desire guidance Standards of Care. The category may also and strategies. Furthermore, conven-
and/or clarity on a medical or scientific include task force and expert committee tional evidence hierarchies, such as the
issue related to diabetes for which the reports. one adapted by the ADA, may miss
evidence is contradictory, emerging, or nuances important in diabetes care.
incomplete. Consensus reports may also GRADING OF SCIENTIFIC EVIDENCE For example, although there is excellent
highlight gaps in evidence and propose Since the ADA first began publishing evidence from clinical trials supporting
areas of future research to address clinical practice guidelines, there has the importance of achieving multiple risk
these gaps. A consensus report is not been considerable evolution in the eval- factor control, the optimal way to achieve
an ADA position but represents expert uation of scientific evidence and in the this result is less clear. It is difficult to
opinion only and is produced under the development of evidence-based guide- assess each component of such a complex
auspices of the ADA by invited experts. lines. In 2002, the ADA developed a intervention.
A consensus report may be developed af- classification system to grade the quality
ter an ADA Clinical Conference or Re- of scientific evidence supporting ADA rec- References
search Symposium. ommendations. A 2015 analysis of the 1. American Diabetes Association. Medical
Management of Type 1 Diabetes. 7th ed. Wang
evidence cited in the Standards of Care
Scientific Review CC, Shah AC, Eds. Alexandria, VA, American Di-
found steady improvement in quality abetes Association, 2017
A scientific review is a balanced review over the previous 10 years, with the 2. American Diabetes Association. Medical Man-
and analysis of the literature on a 2014 Standards of Care for the first time agement of Type 2 Diabetes. 7th ed. Burant CF,
scientific or medical topic related having the majority of bulleted recom- Young LA, Eds. Alexandria, VA, American Diabetes
Association, 2012
to diabetes. mendations supported by A level or 3. Li R, Zhang P, Barker LE, Chowdhury FM, Zhang
A scientific review is not an ADA position B level evidence (4). A grading system X. Cost-effectiveness of interventions to prevent
and does not contain clinical practice (Table 1) developed by the ADA and and control diabetes mellitus: a systematic
recommendations but is produced un- modeled after existing methods was used to review. Diabetes Care 2010;33:1872–1894
der the auspices of the ADA by invited clarify and codify the evidence that forms 4. Grant RW, Kirkman MS. Trends in the evi-
dence level for the American Diabetes Associa-
experts. The scientific review may pro- the basis for the recommendations. ADA tion’s “Standards of Medical Care in Diabetes”
vide a scientific rationale for clini- recommendations are assigned ratings of from 2005 to 2014. Diabetes Care 2015;38:
cal practice recommendations in the A, B, or C, depending on the quality of 6–8
Diabetes Care Volume 43, Supplement 1, January 2020 S3
The Professional Practice Committee (PPC) and published since 15 October 2018. Hsu, MD; Sally C. Hughes, BA; Scott
of the American Diabetes Association (ADA) Due to limitations associated with pro- Kahan, MD, MPH; Ka Hei Karen Lau,
is responsible for the “Standards of Medical duction timelines, evidence published in MS, RD, LDN, CDE; Jose Leon, MD; Ingrid
Care in Diabetes,” referred to as the Stand- late 2019 was not incorporated into the Libman, MD, PhD; Sarah K. Lyons, MD;
© 2019 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit,
and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.
S4 Diabetes Care Volume 43, Supplement 1, January 2020
GENERAL CHANGES autoimmune diabetes in adults is now Centers for Disease Control (CDC) Diabetes
The field of diabetes care is rapidly chang- acknowledged. Prevention Impact Tool Kit. More infor-
ing as new research, technology, and A new recommendation (2.8) was added mation was added on the risk reduction
treatments that can improve the health regarding testing for prediabetes and/or certain groups experienced with metformin
and well-being of people with diabetes type 2 diabetes for women with over- use, based on 15-year follow-up data
continue to emerge. With annual up- weight or obesity and/or who have one from the Diabetes Prevention Program
dates since 1989, the American Diabetes or more additional risk factors for dia- Outcomes Study.
Association (ADA) has long been a leader betes who are planning a pregnancy.
Additional considerations were added Section 4. Comprehensive Medical
in producing guidelines that capture the
SUMMARY OF REVISIONS
© 2019 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit,
and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.
care.diabetesjournals.org Summary of Revisions S5
Section 5. Facilitating Behavior 2 inhibitors or glucagon-like peptide 1 New evidence and a recommendation
Change and Well-being to Improve (GLP-1) receptor agonists in patients with (9.6) were added on early combination
Health Outcomes cardiovascular disease meeting A1C goals therapy for type 2 diabetes to extend the
(https://doi.org/10.2337/dc20-S005) for cardiovascular benefit. time to treatment failure based on find-
The title of this section was previously A new recommendation (6.11) on ings from the VERIFY trial.
“Lifestyle Management” and was changed screening patients who are taking med- FDA approval of oral semaglutide has
to more appropriately emphasize how ef- ication that can lead to hypoglycemia for been included in the discussion of com-
fective behavior management and psycho- hypoglycemia unawareness was introduced. bination therapies.
logical well-being are foundational to Intranasal glucagon and glucagon so- Figure 9.1 has been revised to include
achieving treatment goals for people lution for subcutaneous injection were the latest trial findings on GLP-1 receptor
with diabetes. included in the section “Hypoglycemia” agonists and SGLT2 inhibitors. It now
The section “Nutrition Therapy” was due to their recent approval by the U.S. suggests that these drugs should be con-
updated to include guidance and evi- Food and Drug Administration (FDA). sidered for patients when atherosclerotic
dence presented in “Nutrition Therapy This section was modified to include a cardiovascular disease (ASCVD), heart
for Adults With Diabetes or Prediabetes: new discussion on the use of continuous failure, or chronic kidney disease pre-
A Consensus Report” (https://doi.org/ glucose monitoring technology in hypo- dominates independent of A1C.
10.2337/dci19-0014), published in May glycemia prevention. Figure 9.2 has been simplified to more
2019. easily guide providers through intensifi-
Because of the emerging evidence from Section 7. Diabetes Technology cation to injectable therapies.
the CDC on deaths related to e-cigarettes, (https://doi.org/10.2337/dc20-S007)
more information was added discourag- This section was reorganized into three Section 10. Cardiovascular Disease
ing their use. broad categories titled “Self-Monitoring of and Risk Management
Recommendations and supporting Blood Glucose,” “Continuous Glucose Mon- (https://doi.org/10.2337/dc20-S010)
evidence on anxiety disorders, depres- itors,” and “Insulin Delivery.” Within these This section is endorsed for the second
sion, disordered eating behavior, and revised sections, emphasis has been made consecutive year by the American Col-
serious mental illness previously found on how there is no “one-size-fits-all” lege of Cardiology.
at the end of Section 4 were moved to approach to technology use in people Blood pressure targets for pregnant
Section 5 and are included under “Psy- with diabetes. Due to the rapidly changing patients with pre-existing hypertension have
chosocial Issues.” More information field of diabetes technology, the recom- been changed in the interest of reducing the
on psychosocial screening for social mendations in each category have been risk for accelerated maternal hypertension
determinants of health and significant revised, and more evidence has been and minimizing fetal growth impairment.
changes in life circumstances was also added to support the recommendations Recommendations for statin treat-
added. throughout. ment (primary and secondary prevention,
10.19–10.28) have been revised to min-
Section 6. Glycemic Targets Section 8. Obesity Management for imize ASCVD risk and to align with the
(https://doi.org/10.2337/dc20-S006) the Treatment of Type 2 Diabetes “2018 AHA/ACC/AACVPR/AAPA/ABC/
Based on the publication “Clinical Tar- (https://doi.org/10.2337/dc20-S008) ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA
gets for Continuous Glucose Monitoring The body mass index (BMI) calculation Guideline on the Management of Blood
Data Interpretation: Recommendations recommendation (8.1) was modified to Cholesterol: Executive Summary: A Report
From the International Consensus on Time recommend annual BMI calculations of the American College of Cardiology/
in Range” (https://doi.org/10.2337/dci19- rather than at every patient encounter. American Heart Association Task Force
0028) published in June 2019, new recom- More discussion was added on how on Clinical Practice Guidelines” (https://
mendations (6.4 and 6.5) were added on providers measure and record patient doi.org/10.1016/j.jacc.2018.11.002),
use of the ambulatory glucose profile (AGP) weight, including recommendations on published in June 2019.
report and time in range (TIR) for assess- how to manage these encounters to Discussion of REDUCE-IT was added to
ment of glycemic management. A discus- maximize patient comfort and engage- the section “Treatment of Other Lipo-
sion of AGP reports, time in range, and ment. Other considerationsdlike access protein Fractions or Targets,” and a new
glucose management indicators follow the to food and individual’s motivation recommendation (10.31) was included
new recommendations. An example of an leveldwere added to the section “Lifestyle on considering icosapent ethyl for re-
AGP report was also added (Fig. 6.1). Interventions.” ducing cardiovascular risk.
Table 6.1 was replaced with a simpli- Recommendations for treatment of
fied estimated average glucose table. Section 9. Pharmacologic Approaches cardiovascular disease (10.43a, 10.43b,
More discussion on the importance of to Glycemic Treatment 10.43c) are now individualized based on
reducing therapeutic inertia in the manage- (https://doi.org/10.2337/dc20-S009) patients’ existing ASCVD, risk of ASCVD,
ment of hyperglycemia and cardiovascular A discussion was added on access to diabetic kidney disease, or heart failure.
disease was included in the section “A1C analog insulins and how there are mul- Discussion of the trials CANVAS, CANVAS-
and Cardiovascular Disease Outcomes.” tiple approaches to insulin treatment, Renal, CREDENCE, DECLARE-TIMI 58,
Also new to “A1C and Cardiovascular with the goal of keeping patients safe REWIND, and CARMELINA were added
Disease Outcomes” is the strategy to and avoiding diabetic ketoacidosis and to the section “Glucose-Lowering Ther-
introduce sodium–glucose cotransporter significant hypo- or hyperglycemia. apies and Cardiovascular Outcomes.”
S6 Summary of Revisions Diabetes Care Volume 43, Supplement 1, January 2020
The cardiovascular outcomes trials of Section 12. Older Adults Section 14. Management of Diabetes
available antihyperglycemic medications (https://doi.org/10.2337/dc20-S012) in Pregnancy
completed after the issuance of FDA 2008 Within the section “Neurocognitive (https://doi.org/10.2337/dc20-S0014)
guidelines table (Table 10.3) has been Function,” more information was added Greater emphasis has been placed
divided into three tables by drug class on the importance of assessment for on preconception care for women
(Table 10.3A on DPP-4 Inhibitors; Table cognitive decline and impairment. with diabetes, and a recommendation
10.3B on GLP-1 receptor agonists; and A new recommendation (12.14) urg- (14.5) focusing on nutrition, diabetes
Table 10.3C on SGLT2 inhibitors). ing providers to consider cost of care education, and screening for diabetes
and insurance coverage when prescrib- related complications was added. A
Section 11. Microvascular Complications ing medications to older adults to reduce new table (Table 14.1) was also added
and Foot Care the risk of cost-related nonadherence on preconception education, medical
(https://doi.org/10.2337/dc20-S011) was added to the section “Pharmacologic assessment, and screening.
The recommendation on screening for Therapy.” The GLP-1 receptor agonist Recommendations (14.9–14.12) on
chronic kidney disease (11.1) has been and SGLT2 inhibitor discussions were use of continuous glucose monitors
modified toincludetwice-yearlyscreenings expanded in this section as well. and measuring glycemia in pregnancy
for certain patients. A treatment recom- A new section titled “Special Con- were added to the section “Glycemic
mendation (11.3) was modified to provide siderations for Older Adults With Targets in Pregnancy” to provide more
more detail on use of SGLT2 inhibitors and Type 1 Diabetes” was added to ad- information on their utility.
GLP-1 receptor agonists in patients with dress the treatment of this growing Further discussion has been added
type 2 diabetes and diabetic kidney disease. population. regarding when insulin may not be
A new recommendation (11.5) was added an option for some women with GDM,
about avoiding discontinuation of RAS Section 13. Children and Adolescents and how oral agents may play a role in
blockade in response to minor increases (https://doi.org/10.2337/dc20-S013) treatment in certain circumstances.
in serum creatinine in the absence of To provide more detail for individual- The section “Postpartum Care” was
volume depletion. izing targets, new A1C goal recommen- expanded to include recommenda-
Additional information on acute kidney dations (13.21–13.24) were added to the tions (14.16–14.22) and supporting
injury was added to the section “Chronic section “Glycemic Control.” evidence on postpartum insulin re-
Kidney Disease,” with information on in- In the section “Management of Cardio- quirements, management of women
creased serum creatinine levels. vascular Risk Factors,” the recommenda- with a history of GDM and risks of
More findings were added from the tions for screening and treatment of type 2 diabetes, and psychosocial
CREDENCE trial. hypertension (13.31–13.35) have been assessment.
Screening for diabetic retinopathy rec- revised and include new criteria for ele-
ommendations (11.16 and 11.17) and vated blood pressure. The dyslipidemia Section 15. Diabetes Care in the
supportive text were revised to include testing recommendation (13.36) was Hospital
consideration of retinal photograph with also modified, and more evidence was (https://doi.org/10.2337/dc20-S0015)
remote reading or use of a validated as- added to the dyslipidemia screening Discussion of new studies supporting
sessment tool as a way to improve screen- section. the use of closed-loop insulin delivery
ing access. The retinopathy screening recommen- with linked pump/sensor devices to
The section “Foot Care” was updated dation for type 1 diabetes (13.46) has been control blood glucose was added to
with more evidence on therapeutic revised based on new evidence supporting the type 1 diabetes section “Transi-
footwear and evaluation for peripheral a lower frequency of eye examinations tioning Intravenous to Subcutaneous
arterial disease. than previously recommended. Insulin.”
Figure 11.1 was introduced (in place of A new recommendation (13.67) was New evidence was also added to
2019 Table 11.1dCKD Stages and Cor- added to the section “Pharmacologic Man- the section “Preventing Admissions and
responding Focus of Kidney-Related agement” for type 2 diabetes due to new Readmissions.”
Care) to show the risk of chronic kidney evidence and FDA approval of liraglutide in
disease progression, frequency of visits, children 10 years of age or older. Section 16. Diabetes Advocacy
and referral to nephrology according to A new recommendation (13.76) on (https://doi.org/10.2337/dc20-S016)
estimated glomerular filtration rate and pharmacologic treatment of hyperten- No changes have been made to this
albuminuria. sion in type 2 diabetes was also added. section.
Diabetes Care Volume 43, Supplement 1, January 2020 S7
whether based on evidence or expert Chronic Care Model diabetes care delivery, including oppor-
opinion, are intended to guide an overall Numerous interventions to improve ad- tunities and challenges (15).
approach to care. The science and art of herence to the recommended standards
Strategies for System-Level Improvement
medicine come together when the clinician have been implemented. However, a
major barrier to optimal care is a delivery Optimal diabetes management requires
is faced with making treatment recommen-
system that is often fragmented, lacks an organized, systematic approach and
dations for a patient who may not meet the
clinical information capabilities, dupli- the involvement of a coordinated team
eligibility criteria used in the studies on
cates services, and is poorly designed of dedicated health care professionals
which guidelines are based. Recognizing
working in an environment where
that one size does not fit all, the standards for the coordinated delivery of chronic
care. The Chronic Care Model (CCM) patient-centered high-quality care is a
presented here provide guidance for when
takes these factors into consideration priority (6,16,17). While many diabetes
and how to adapt recommendations for an
and is an effective framework for im- processes of care have improved nation-
individual.
proving the quality of diabetes care (8). ally in the past decade, the overall quality
of care for patients with diabetes remains
Care Delivery Systems Six Core Elements.The CCM includes six suboptimal (3). Efforts to increase the
The proportion of patients with diabetes core elements to optimize the care of quality of diabetes care include provid-
who achieve recommended A1C, blood patients with chronic disease: ing care that is concordant with evidence-
pressure, and LDL cholesterol levels has
based guidelines (18); expanding the
remained stagnant in recent years (3). In 1. Delivery system design (moving from a role of teams to implement more in-
2013–2016, 64% of adults with diag- reactive to a proactive care delivery tensive disease management strategies
nosed diabetes met individualized A1C system where planned visits are coordi- (6,19,20); tracking medication-taking be-
target levels, 70% achieved recommen- nated through a team-based approach) havior at a systems level (21); redesigning
ded blood pressure control, 57% met the 2. Self-management support the organization of the care process
LDL cholesterol target level, and 85% 3. Decision support (basing care on (22); implementing electronic health record
were nonsmokers (3). Only 23% met evidence-based, effective care guide- tools (23,24); empowering and educating
targets for glycemic, blood pressure, lines) patients (25,26); removing financial bar-
and cholesterol measures while also 4. Clinical information systems (using reg- riers and reducing patient out-of-pocket
avoiding smoking (3). The mean A1C istries that can provide patient-specific costs for diabetes education, eye exams,
nationally among people with diabetes and population-based support to the diabetes technology, and necessary med-
increased slightly from 7.3% in 2005– care team) ications (6); assessing and addressing psy-
2008 to 7.5% in 2013–2016 based on the 5. Community resources and policies chosocial issues (27,28); and identifying,
National Health and Nutrition Examina- (identifying or developing resources developing, and engaging community re-
tion Survey (NHANES), with younger to support healthy lifestyles) sources and public policies that support
adults, women, and non-Hispanic black 6. Health systems (to create a quality- healthy lifestyles (29). The National Di-
individuals less likely to meet treatment oriented culture) abetes Education Program maintains an
targets (3). Certain segments of the pop-
online resource (www.betterdiabetescare
ulation, such as young adults and patients A 5-year effectiveness study of the CCM .nih.gov) to help health care professionals
with complex comorbidities, financial or in 53,436 primary care patients with design and implement more effective
other social hardships, and/or limited type 2 diabetes suggested that the use health care delivery systems for those
English proficiency, face particular chal- of this model of care delivery reduced the with diabetes.
lenges to goal-based care (4–6). Even cumulative incidence of diabetes-related
after adjusting for these patient factors, complications and all-cause mortality (9). Care Teams
the persistent variability in the quality of Patients who were enrolled in the CCM The care team, which centers around the
diabetes care across providers and prac- experienced a reduction in cardiovascu- patient, should avoid therapeutic inertia
tice settings indicates that substantial lar disease (CVD) risk by 56.6%, micro- and prioritize timely and appropriate
system-level improvements are still vascular complications by 11.9%, and intensification of lifestyle and/or phar-
needed. mortality by 66.1% (9). The same study macologic therapy for patients who have
Diabetes poses a significant financial suggested that health care utilization was not achieved the recommended meta-
burden to individuals and society. It is lower in the CCM group, resulting in bolic targets (30–32). Strategies shown to
estimated that the annual cost of diag- health care savings of $7,294 per indi- improve care team behavior and thereby
nosed diabetes in 2017 was $327 billion, vidual over the study period (10). catalyze reductions in A1C, blood pres-
including $237 billion in direct medical Redefining the roles of the health care sure, and/or LDL cholesterol include en-
costs and $90 billion in reduced produc- delivery team and empowering patient gaging in explicit and collaborative goal
tivity. After adjusting for inflation, eco- self-management are fundamental to the setting with patients (33,34); identifying
nomic costs of diabetes increased by 26% successful implementation of the CCM (11). and addressing language, numeracy, or
from 2012 to 2017 (7). This is attributed to Collaborative, multidisciplinary teams are cultural barriers to care (35–37); inte-
the increased prevalence of diabetes and best suited to provide care for people with grating evidence-based guidelines and
the increased cost per person with di- chronic conditions such as diabetes and clinical information tools into the process
abetes. Ongoing population health strat- to facilitate patients’ self-management of care (18,38,39); soliciting performance
egies are needed in order to reduce costs (12–14). There are references to guide feedback, setting reminders, and provid-
and provide optimized care. the implementation of the CCM into ing structured care (e.g., guidelines,
care.diabetesjournals.org Improving Care and Promoting Health S9
formal case management, and patient patients who are prescribed insulin report and the use of accurate, reliable data
education resources) (6); and incorporat- cost-related insulin underuse (47). The cost metrics that include sociodemographic
ing care management teams including of insulin has continued to increase in variables to examine health equity within
nurses, dietitians, pharmacists, and other recent years for reasons that are not and across populations (59).
providers (19,40). Initiatives such as the entirely clear. There are recommenda- In addition to quality improvement
Patient-Centered Medical Home show tions from the ADA Insulin Access efforts, other strategies that simulta-
promise for improving health outcomes and Affordability Working Group for ap- neously improve the quality of care and
by fostering comprehensive primary care proaches to this issue from a systems potentially reduce costs are gaining mo-
and offering new opportunities for team- level. Recommendations including concepts mentum and include reimbursement
based chronic disease management (41). such as cost-sharing for insured people structures that, in contrast to visit-based
with diabetes should be based on the billing, reward the provision of appropriate
Telemedicine
lowest price available, list price for insulins and high-quality care to achieve metabolic
Telemedicine is a growing field that may that closely reflect net price, and health goals (60) and incentives that accommo-
increase access to care for patients with plans that ensure that people with di- date personalized care goals (6,61).
diabetes. Telemedicine is defined as the abetes can access insulin without undue
use of telecommunications to facilitate administrative burden or excessive cost
remote delivery of health-related serv- (48). TAILORING TREATMENT FOR
ices and clinical information (42). A grow- SOCIAL CONTEXT
ing body of evidence suggests that Access to Care and Quality Improvement
Recommendations
various telemedicine modalities may The Affordable Care Act has resulted in
1.5 Providers should assess social con-
be effective at reducing A1C in patients increased access to care for many indi-
text, including potential food in-
with type 2 diabetes compared with viduals with diabetes with an emphasis
security, housing stability, and
usual care or in addition to usual care on the protection of people with preex-
financial barriers, and apply that
(43). For rural populations or those with isting conditions, health promotion, and
information to treatment deci-
limited physical access to health care, disease prevention (49). In fact, health
sions. A
telemedicine has a growing body of insurance coverage increased from 84.7%
1.6 Refer patients to local commu-
evidence for its effectiveness, particu- in 2009 to 90.1% in 2016 for adults with
nity resources when available. B
larly with regard to glycemic control as diabetes aged 18–64 years. Coverage for 1.7 Provide patients with self-
measured by A1C (44–46). Interactive those $65 years remained near universal management support from lay
strategies that facilitate communication (50). Patients who have either private or health coaches, navigators, or
between providers and patients, includ- public insurance coverage are more likely community health workers when
ing the use of web-based portals or text to meet quality indicators for diabetes care available. A
messaging and those that incorporate (51). As mandated by the Affordable Care
medication adjustment, appear more Act,theAgencyfor Healthcare Research and Health inequities related to diabetes and
effective. There is limited data avail- Quality developed a National Quality Strat- its complications are well documented
able on the cost-effectiveness of these egy based on the triple aims that include and are heavily influenced by social de-
strategies. improving the health of a population, terminants of health (62–66). Social de-
overall quality and patient experience of terminants of health are defined as the
Behaviors and Well-being
care, and per capita cost (52,53). As health economic, environmental, political, and
Successful diabetes care also requires
care systems and practices adapt to the social conditions in which people live and
a systematic approach to supporting
changing landscape of health care, it will be are responsible for a major part of health
patients’ behavior change efforts. High-
important to integrate traditional disease- inequality worldwide (67). The ADA rec-
quality diabetes self-management ed-
specific metrics with measures of patient ognizes the association between social
ucation and support (DSMES) has
experience, as well as cost, in assessing the and environmental factors and the pre-
been shown to improve patient self-
quality of diabetes care (54,55). Informa- vention and treatment of diabetes and
management, satisfaction, and glucose
tion and guidance specific to quality im- has issued a call for research that seeks to
outcomes. National DSMES standards
provement and practice transformation for better understand how these social de-
call for an integrated approach that in-
diabetes care is available from the National terminants influence behaviors and how
cludes clinical content and skills, behav-
Diabetes Education Program practice trans- the relationships between these varia-
ioral strategies (goal setting, problem
solving), and engagement with psycho- formation website and the National In- bles might be modified for the preven-
social concerns (28). For more informa- stitute of Diabetes and Digestive and tion and management of diabetes (68).
tion on DSMES, see Section 5 “Facilitating Kidney Diseases report on diabetes care While a comprehensive strategy to re-
Behavior Change and Well-being to Im- and quality (56,57). Using patient registries duce diabetes-related health inequities
prove Health Outcomes” (https://doi and electronic health records, health sys- in populations has not been formally stud-
.org/10.2337/dc20-S005). tems can evaluate the quality of diabetes ied, general recommendations from other
care being delivered and perform inter- chronic disease models can be drawn upon
Cost Considerations vention cycles as part of quality improve- to inform systems-level strategies in di-
The cost of diabetes medications, partic- ment strategies (58). Critical to these abetes. For example, the National Academy
ularly insulin, is an ongoing barrier to efforts is provider adherence to clinical of Medicine has published a framework for
achieving glycemic goals. Up to 25% of practice recommendations (see Table 4.1) educating health care professionals on the
S10 Improving Care and Promoting Health Diabetes Care Volume 43, Supplement 1, January 2020
importance of social determinants of health with low adherence to taking medica- are homeless need secure places to keep
(69). Furthermore, there are resources tions appropriately and recommended their diabetes supplies, as well as re-
available for the inclusion of standardized self-care behaviors, depression, diabetes frigerator access to properly store their
sociodemographic variables in electronic distress, and worse glycemic control insulin and take it on a regular schedule.
medical records to facilitate the measure- when compared with individuals who Risk for homelessness can be ascertained
ment of health inequities as well as the are food secure (78,79). Older adults using a brief risk assessment tool de-
impact of interventions designed to re- with food insecurity are more likely to veloped and validated for use among
duce those inequities (70–72). have emergency department visits and veterans (85). Given the potential chal-
Social determinants of health are not hospitalizations compared with older lenges, providers who care for homeless
always recognized and often go undis- adults who do not report food insecurity individuals should be familiar with re-
cussed in the clinical encounter (65). A (80). Risk for food insecurity can be sources or have access to social workers
studyby Piette et al. (73) found that among assessed with a validated two-item that can facilitate temporary housing for
patients with chronic illnesses, two-thirds screening tool (81) that includes the their patients as a way to improve di-
of those who reported not taking medi- statements: 1) “Within the past12 months abetes care.
cations as prescribed due to cost never we worried whether our food would run
shared this with their physician. In a study out before we got money to buy more” Migrant and Seasonal Agricultural
using data from the National Health In- and 2) “Within the past 12 months the Workers
terview Survey (NHIS), Patel et al. (65) food we bought just didn’t last and we Migrant and seasonal agricultural workers
found that one-half of adults with diabetes didn’t have money to get more.” An may have a higher risk of type 2 diabetes
reported financial stress and one-fifth affirmative response to either statement than the overall population. While mi-
reported food insecurity. One population had a sensitivity of 97% and specificity of grant farmworker-specific data are lack-
in which such issues must be considered is 83%. ing, most agricultural workers in the U.S.
older adults, where social difficulties may are Latino, a population with a high rate of
Treatment Considerations type 2 diabetes. Living in severe poverty
impair the quality of life and increase the
In those with diabetes and food insecu- brings with it food insecurity, high chronic
risk of functional dependency (74) (see
rity, the priority is mitigating the increased stress, and increased risk of diabetes;
Section 12 “Older Adults,” https://doi.org/
risk for uncontrolled hyperglycemia and there is also an association between
10.2337/dc20-S012, for a detailed discus-
severe hypoglycemia. Reasons for the the use of certain pesticides and the
sion of social considerations in older
increased risk of hyperglycemia include incidence of diabetes (85a).
adults). Creating systems-level mecha-
the steady consumption of inexpensive Data from the Department of Labor
nisms to screen for social determinants
carbohydrate-rich processed foods, binge indicates that there are 2.5–3 million
of health may help overcome structural
eating, financial constraints to filling di- agricultural workers in the U.S., and these
barriers and communication gaps be-
abetes medication prescriptions, and agricultural workers travel throughout
tween patients and providers (65,75).
anxiety/depression leading to poor di- the country serving as the backbone
In addition, brief, validated screening
abetes self-care behaviors. Hypoglyce- for a multibillion-dollar agricultural in-
tools for some social determinants of
mia can occur as a result of inadequate dustry. According to 2018 health center
health exist and could facilitate discussion
or erratic carbohydrate consumption data, 174 health centers across the U.S.
around factors that significantly impact
following the administration of sulfony- reported that they provided health care
treatment during the clinical encounter.
lureas or insulin. See Table 9.1 for drug- services to 579,806 adult agricultural
Below is a discussion of assessment and
specific and patient factors, including patients, and 78,332 had encounters
treatment considerations in the context
of food insecurity, homelessness, and lim- cost and risk of hypoglycemia, for the for diabetes (13.5%) (86).
ited English proficiency/low literacy. treatment options for adults with food Migrant farmworkers encounter nu-
insecurity and type 2 diabetes. Providers merous and overlapping barriers to re-
Food Insecurity should consider these factors when mak- ceiving care. Migration, which may occur
Food insecurity is the unreliable avail- ing treatment decisions in people with as frequently as every few weeks for
ability of nutritious food and the inability food insecurity and seek local resources farmworkers, disrupts care. Cultural
to consistently obtain food without re- that might help patients with diabetes and and linguistic barriers, lack of transpor-
sorting to socially unacceptable practi- their family members to more regularly tation and money, lack of available work
ces. Over 18% of the U.S. population obtain nutritious food (82). hours, unfamiliarity with new communi-
reported food insecurity between 2005– ties, lack of access to resources, and other
2014 (76). The rate is higher in some Homelessness barriers prevent migrant farmworkers
racial/ethnic minority groups, including Homelessness often accompanies many from accessing health care. Without reg-
African American and Latino popula- additional barriers to diabetes self- ular care, those with diabetes may suffer
tions, low-income households, and homes management, including food insecurity, severe and often expensive complica-
headed by a single mother. The rate of literacy and numeracy deficiencies, lack tions that affect quality of life.
food insecurity in individuals with dia- of insurance, cognitive dysfunction, Health care providers should be attuned
betes may be up to 20% (77). Addition- and mental health issues (83). The prev- to the working and living conditions of all
ally, the risk for type 2 diabetes is alence of diabetes in the homeless pop- patients. If a migrant farmworker with
increased twofold in those with food ulation is estimated to be around 8% (84). diabetes presents for care, appropriate
insecurity (68) and has been associated Additionally, patients with diabetes who referrals should be initiated to social
care.diabetesjournals.org Improving Care and Promoting Health S11
workers and community resources, as Intern Med. 12 August 2019 [Epub ahead of print] a large-scale hypertension program. JAMA 2013;
available, to assist with removing barriers DOI: 10.1001/jamainternmed.2019.2396 310:699–705
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to care.
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with the specific goals of preventing di- concordance, and glycemic control among in- ogy and definitions of medication adherence and
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care providers can reduce language barriers costs of diabetes in the U.S. in 2017. Diabetes outcomes of patients with diabetes mellitus. Ann
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S14 Diabetes Care Volume 43, Supplement 1, January 2020
CLASSIFICATION
Diabetes can be classified into the following general categories:
This section reviews most common forms of diabetes but is not comprehensive. For
additional information, see the American Diabetes Association (ADA) position
statement “Diagnosis and Classification of Diabetes Mellitus” (1).
Type 1 diabetes and type 2 diabetes are heterogeneous diseases in which clinical Suggested citation: American Diabetes Associa-
presentation and disease progression may vary considerably. Classification is tion. 2. Classification and diagnosis of diabetes:
important for determining therapy, but some individuals cannot be clearly classified Standards of Medical Care in Diabetesd2020.
as having type 1 or type 2 diabetes at the time of diagnosis. The traditional paradigms Diabetes Care 2020;43(Suppl. 1):S14–S31
of type 2 diabetes occurring only in adults and type 1 diabetes only in children are no © 2019 by the American Diabetes Association.
longer accurate, as both diseases occur in both age-groups. Children with type 1 Readers may use this article as long as the work
is properly cited, the use is educational and not
diabetes typically present with the hallmark symptoms of polyuria/polydipsia, and for profit, and the work is not altered. More infor-
approximately one-third present with diabetic ketoacidosis (DKA) (2). The onset of mation is available at http://www.diabetesjournals
type 1 diabetes may be more variable in adults; they may not present with the classic .org/content/license.
care.diabetesjournals.org Classification and Diagnosis of Diabetes S15
symptoms seen in children and may expe- serve as a framework for future research mainly been demonstrated among indi-
rience temporary remission from the need and regulatory decision-making (8,9). There viduals who have impaired glucose tol-
for insulin (3–5). Occasionally, patients is debate as to whether slowly progressive erance (IGT) with or without elevated
with type 2 diabetes may present with autoimmune diabetes with an adult onset fasting glucose, not for individuals with
DKA (6), particularly ethnic minorities (7). should be termed latent autoimmune di- isolated impaired fasting glucose (IFG)
It is important for the provider to realize abetes in adults (LADA) or whether the or for those with prediabetes defined
that classification of diabetes type is not clinical priority is awareness that slow auto- by A1C criteria.
always straightforward at presentation and immune b-cell destruction means there may The same tests may be used to screen
that misdiagnosis is common (e.g., adults be long duration of marginal insulin secre- for and diagnose diabetes and to detect
with type 1 diabetes misdiagnosed as hav- tory capacity. For the purpose of this clas- individuals with prediabetes (Table 2.2
ing type 2 diabetes; individuals with matu- sification, all forms of diabetes mediated by and Table 2.5). Diabetes may be identi-
rity-onset diabetes of the young [MODY] autoimmune b-cell destruction are included fied anywhere along the spectrum of
misdiagnosed as having type 1 diabetes, under the rubric of type 1 diabetes. clinical scenariosdin seemingly low-
etc.). Although difficulties in distinguish- The paths to b-cell demise and dys- risk individuals who happen to have glu-
ing diabetes type may occur in all age- function are less well defined in type 2 cose testing, in individuals tested based on
groups at onset, the diagnosis becomes diabetes, but deficient b-cell insulin se- diabetes risk assessment, and in symp-
more obvious over time. cretion, frequently in the setting of in- tomatic patients.
In both type 1 and type 2 diabetes, sulin resistance, appears to be the
various genetic and environmental fac- common denominator. Characterization Fasting and 2-Hour Plasma Glucose
tors can result in the progressive loss of of subtypes of this heterogeneous dis- The FPG and 2-h PG may be used to
b-cell mass and/or function that mani- order have been developed and vali- diagnose diabetes (Table 2.2). The con-
fests clinically as hyperglycemia. Once dated in Scandinavian and Northern cordance between the FPG and 2-h
hyperglycemia occurs, patients with all European populations but have not PG tests is imperfect, as is the concor-
forms of diabetes are at risk for devel- been confirmed in other ethnic and ra- dance between A1C and either glucose-
oping the same chronic complications, cial groups. Type 2 diabetes is associated based test. Compared with FPG and
although rates of progression may differ. with insulin secretory defects related A1C cut points, the 2-h PG value di-
The identification of individualized ther- to inflammation and metabolic stress agnoses more people with prediabe-
apies for diabetes in the future will re- among other contributors, including tes and diabetes (15).
quire better characterization of the many genetic factors. Future classification
paths to b-cell demise or dysfunction (8). schemes for diabetes will likely focus A1C
Characterization of the underlying path- on the pathophysiology of the underly-
Recommendations
ophysiology is more developed in type 1 ing b-cell dysfunction (8,10,11).
2.1 To avoid misdiagnosis or missed
diabetes than in type 2 diabetes. It is now
diagnosis, the A1C test should be
clear from studies of first-degree relatives DIAGNOSTIC TESTS FOR DIABETES
performed using a method that is
of patients with type 1 diabetes that the Diabetes may be diagnosed based on
certified by the NGSP and stan-
persistent presence of two or more islet plasma glucose criteria, either the fast-
dardized to the Diabetes Control
autoantibodies is an almost certain pre- ing plasma glucose (FPG) value or the
and Complications Trial (DCCT)
dictor of clinical hyperglycemia and diabe- 2-h plasma glucose (2-h PG) value during
assay. B
tes. The rate of progression is dependent on a 75-g oral glucose tolerance test (OGTT),
2.2 Marked discordance between
the age at first detection of autoantibody, or A1C criteria (12) (Table 2.2).
measured A1C and plasma glu-
number ofautoantibodies, autoantibody Generally, FPG, 2-h PG during 75-g
cose levels should raise the pos-
specificity, and autoantibody titer. Glu- OGTT, and A1C are equally appropriate
sibility of A1C assay interference
cose and A1C levels rise well before the for diagnostic screening. It should be
due to hemoglobin variants (i.e.,
clinical onset of diabetes, making diag- noted that the tests do not necessarily
hemoglobinopathies) and con-
nosis feasible well before the onset of detect diabetes in the same individuals.
sideration of using an assay with-
DKA. Three distinct stages of type 1 di- The efficacy of interventions for primary
out interference or plasma blood
abetes can be identified (Table 2.1) and prevention of type 2 diabetes (13,14) has
S16 Classification and Diagnosis of Diabetes Diabetes Care Volume 43, Supplement 1, January 2020
cut point, greater cost, limited availabil- between measured A1C and plasma glu-
glucose criteria to diagnose di-
ity of A1C testing in certain regions of cose levels should prompt consideration
abetes. B
the developing world, and the imperfect that the A1C assay may not be reliable for
2.3 In conditions associated with an
correlation between A1C and average that individual. For patients with a hemo-
altered relationship between A1C
glucose in certain individuals. The A1C globin variant but normal red blood cell
and glycemia, such as sickle cell
test, with a diagnostic threshold of turnover, such as those with the sickle cell
disease, pregnancy (second and
$6.5% (48 mmol/mol), diagnoses only trait, an A1C assay without interference
third trimesters and the postpar-
30% of the diabetes cases identified col- from hemoglobin variants should be used.
tum period), glucose-6-phosphate
lectively using A1C, FPG, or 2-h PG, ac- An updated list of A1C assays with inter-
dehydrogenase deficiency, HIV,
cording to National Health and Nutrition ferences is available at www.ngsp.org/
hemodialysis, recent blood loss
Examination Survey (NHANES) data (16). interf.asp.
or transfusion, or erythropoietin
When using A1C to diagnose diabetes, African Americans heterozygous for
therapy, only plasma blood glu-
it is important to recognize that A1C is the common hemoglobin variant HbS
cose criteria should be used to
an indirect measure of average blood may have, for any given level of mean
diagnose diabetes. B
glucose levels and to take other factors glycemia, lower A1C by about 0.3% than
into consideration that may impact he- those without the trait (20). Another ge-
The A1C test should be performed using
moglobin glycation independently of netic variant, X-linked glucose-6-phosphate
a method that is certified by the NGSP
glycemia, such as hemodialysis, preg- dehydrogenase G202A, carried by 11% of
(www.ngsp.org) and standardized or
nancy, HIV treatment (17,18), age, race/ African Americans, was associated with a
traceable to the Diabetes Control and
ethnicity, pregnancy status, genetic back- decrease in A1C of about 0.8% in homo-
Complications Trial (DCCT) reference as-
ground, and anemia/hemoglobinopathies. zygous men and 0.7% in homozygous
say. Although point-of-care A1C assays
(See OTHER CONDITIONS ALTERING THE RELATION- women compared with those without
may be NGSP certified or U.S. Food and SHIP OF A1C AND GLYCEMIA below for more the variant (21).
Drug Administration approved for diag- information.) Even in the absence of hemoglobin
nosis, proficiency testing is not always variants, A1C levels may vary with race/
mandated for performing the test. There- Age
ethnicity independently of glycemia
fore, point-of-care assays approved for The epidemiological studies that formed
(22–24). For example, African Americans
diagnostic purposes should only be con- the basis for recommending A1C to
may have higher A1C levels than non-
sidered in settings licensed to perform diagnose diabetes included only adult
Hispanic whites with similar fasting and
moderate-to-high complexity tests. As populations (16). However, recent ADA
postglucose load glucose levels (25), and
discussed in Section 6 “Glycemic Targets” clinical guidance concluded that A1C,
A1C levels may be higher for a given mean
(https://doi.org/10.2337/dc20-S006), FPG, or 2-h PG can be used to test for
glucose concentration when measured
point-of-care A1C assays may be more prediabetes or type 2 diabetes in children
with continuous glucose monitoring (26).
generally applied for assessment of gly- and adolescents (see SCREENING AND TESTING
Though conflicting data exists, African
FOR PREDIABETES AND TYPE 2 DIABETES IN CHILDREN
cemic control in the clinic. Americans may also have higher levels of
A1C has several advantages com- AND ADOLESCENTSbelow for additional in-
fructosamine and glycated albumin and
pared with FPG and OGTT, including formation) (19).
lower levels of 1,5-anhydroglucitol, sug-
greater convenience (fasting not re- Race/Ethnicity/Hemoglobinopathies gesting that their glycemic burden (par-
quired), greater preanalytical stability, Hemoglobin variants can interfere ticularly postprandially) may be higher
and less day-to-day perturbations during with the measurement of A1C, al- (27,28). The association of A1C with risk
stress, diet, or illness. However, these though most assays in use in the for complications appears to be similar
advantages may be offset by the lower U.S. are unaffected by the most com- in African Americans and non-Hispanic
sensitivity of A1C at the designated mon variants. Marked discrepancies whites (29,30).
Table 2.2—Criteria for the diagnosis of diabetes Other Conditions Altering the Relationship
FPG $126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 h.* of A1C and Glycemia
OR In conditions associated with increased
2-h PG $200 mg/dL (11.1 mmol/L) during OGTT. The test should be performed as described red blood cell turnover, such as sickle
by the WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose cell disease, pregnancy (second and
dissolved in water.* third trimesters), glucose-6-phosphate
OR dehydrogenase deficiency (31,32), he-
A1C $6.5% (48 mmol/mol). The test should be performed in a laboratory using a method that modialysis, recent blood loss or trans-
is NGSP certified and standardized to the DCCT assay.* fusion, or erythropoietin therapy, only
OR plasma blood glucose criteria should be
In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma used to diagnose diabetes (33). A1C is
glucose $200 mg/dL (11.1 mmol/L). less reliable than blood glucose mea-
DCCT, Diabetes Control and Complications Trial; FPG, fasting plasma glucose; OGTT, oral glucose surement in other conditions such as
tolerance test; WHO, World Health Organization; 2-h PG, 2-h plasma glucose. *In the absence of the postpartum state (34–36), HIV
unequivocal hyperglycemia, diagnosis requires two abnormal test results from the same sample or treated with certain drugs (17), and
in two separate test samples.
iron-deficient anemia (37).
care.diabetesjournals.org Classification and Diagnosis of Diabetes S17
Confirming the Diagnosis knowing the plasma glucose level is modest fasting hyperglycemia that can
Unless there is a clear clinical diagnosis critical because, in addition to confirm- rapidly change to severe hyperglycemia
(e.g., patient in a hyperglycemic crisis or ing that symptoms are due to diabetes, and/or DKA with infection or other stress.
with classic symptoms of hyperglycemia it will inform management decisions. Adults may retain sufficient b-cell func-
and a random plasma glucose $200 Some providers may also want to know tion to prevent DKA for many years; such
mg/dL [11.1 mmol/L]), diagnosis requires the A1C to determine how long a patient individuals may have remission or de-
two abnormal test results from the same has had hyperglycemia. The criteria to creased insulin needs for months or years
sample (38) or in two separate test diagnose diabetes are listed in Table 2.2. and eventually become dependent on
samples. If using two separate test sam- insulin for survival and are at risk for DKA
ples, it is recommended that the second TYPE 1 DIABETES (3–5,39,40). At this latter stage of the
test, which may either be a repeat of the disease, there is little or no insulin se-
Recommendations
initial test or a different test, be per- cretion, as manifested by low or undetect-
2.4 Screening for type 1 diabetes risk
formed without delay. For example, if the able levels of plasma C-peptide. Immune-
with a panel of islet autoanti-
A1C is 7.0% (53 mmol/mol) and a repeat mediated diabetes is the most common
bodies is currently recommended
result is 6.8% (51 mmol/mol), the di- form of diabetes in childhood and ado-
in the setting of a research trial or
agnosis of diabetes is confirmed. If two lescence, but it can occur at any age, even
can be offered as an option for
different tests (such as A1C and FPG) are in the 8th and 9th decades of life.
first-degree family members of a
both above the diagnostic threshold Autoimmune destruction of b-cells
proband with type 1 diabetes. B
when analyzed from the same sample has multiple genetic predispositions
2.5 Persistence of autoantibodies is
or in two different test samples, this also and is also related to environmental
a risk factor for clinical diabetes
confirms the diagnosis. On the other factors that are still poorly defined. Al-
and may serve as an indication for
hand, if a patient has discordant results though patients are not typically obese
intervention in the setting of
from two different tests, then the test when they present with type 1 diabetes,
a clinical trial. B
result that is above the diagnostic cut obesity is increasingly common in the
point should be repeated, with consid- general population and there is evidence
eration of the possibility of A1C assay Immune-Mediated Diabetes that it may also be a risk factor for type 1
interference. The diagnosis is made on This form, previously called “insulin- diabetes. As such, obesity should not
the basis of the confirmed test. For dependent diabetes” or “juvenile-onset preclude the diagnosis. People with
example, if a patient meets the diabetes diabetes,” accounts for 5–10% of diabe- type 1 diabetes are also prone to other
criterion of the A1C (two results $6.5% tes and is due to cellular-mediated au- autoimmune disorders such as Hashi-
[48 mmol/mol]) but not FPG (,126 toimmune destruction of the pancreatic moto thyroiditis, Graves disease, celiac
mg/dL [7.0 mmol/L]), that person should b-cells. Autoimmune markers include disease, Addison disease, vitiligo, auto-
nevertheless be considered to have islet cell autoantibodies and autoanti- immune hepatitis, myasthenia gravis,
diabetes. bodies to GAD (GAD65), insulin, the and pernicious anemia (see Section
All the tests have preanalytic and tyrosine phosphatases IA-2 and IA-2b, 4 “Comprehensive Medical Evaluation
analytic variability, so it is possible and zinc transporter 8 (ZnT8). Numer- and Assessment of Comorbidities,”
that an abnormal result (i.e., above ous clinical studies are being conducted https://doi.org/10.2337/dc20-S004).
the diagnostic threshold), when re- to test various methods of preventing
peated, will produce a value below type 1 diabetes in those with evidence Idiopathic Type 1 Diabetes
the diagnostic cut point. This scenario of islet autoimmunity (www.clinicaltrials Some forms of type 1 diabetes have no
is likely for FPG and 2-h PG if the glucose .gov). Stage 1 of type 1 diabetes is defined known etiologies. These patients have per-
samples remain at room temperature by the presence of two or more of these manent insulinopenia and are prone to DKA
and are not centrifuged promptly. Be- autoimmune markers. The disease has but have no evidence of b-cell autoimmu-
cause of the potential for preanalytic strong HLA associations, with linkage to nity. However, only a minority of patients
variability, it is critical that samples for the DQA and DQB genes. These HLA-DR/ with type 1 diabetes fall into this category.
plasma glucose be spun and separated DQ alleles can be either predisposing or Individuals with autoantibody-negative
immediately after they are drawn. If protective (Table 2.1). There are important type 1 diabetes of African or Asian ancestry
patients have test results near the mar- genetic considerations, as most of the mu- may suffer from episodic DKA and exhibit
gins of the diagnostic threshold, the tations that cause diabetes are dominantly varying degrees of insulin deficiency be-
health care professional should discuss inherited. The importance of genetic testing tween episodes. This form of diabetes is
signs and symptoms with the patient and is in the genetic counseling that follows. strongly inherited and is not HLA associated.
repeat the test in 3–6 months. Some mutations are associated with other An absolute requirement for insulin re-
conditions, which then may prompt addi- placement therapy in affected patients
Diagnosis tional screenings. may be intermittent. Future research is
In a patient with classic symptoms, The rate of b-cell destruction is quite needed to determine the cause of b-cell
measurement of plasma glucose is suf- variable, being rapid in some individuals destruction in this rare clinical scenario.
ficient to diagnose diabetes (symptoms (mainly infants and children) and slow in
of hyperglycemia or hyperglycemic crisis others (mainly adults). Children and ado- Screening for Type 1 Diabetes Risk
plus a random plasma glucose $200 lescents may present with DKA as the first The incidence and prevalence of type 1
mg/dL [11.1 mmol/L]). In these cases, manifestation of the disease. Others have diabetes is increasing (41). Patients with
S18 Classification and Diagnosis of Diabetes Diabetes Care Volume 43, Supplement 1, January 2020
Table 2.4—Risk-based screening for type 2 diabetes or prediabetes in asymptomatic (Fig. 2.1) (diabetes.org/socrisktest). For
children and adolescents in a clinical setting (163) additional background regarding risk fac-
Testing should be considered in youth* who have overweight ($85th percentile) or obesity
tors and screening for prediabetes, see
($95th percentile) A and who have one or more additional risk factors based on the strength SCREENING AND TESTING FOR PREDIABETES AND
of their association with diabetes: TYPE 2 DIABETES IN ASYMPTOMATIC ADULTS and
c Maternal history of diabetes or GDM during the child’s gestation A also SCREENING AND TESTING FOR PREDIABETES
AND TYPE 2 DIABETES IN CHILDREN AND ADOLESCENTS
c Family history of type 2 diabetes in first- or second-degree relative A
below.
c Race/ethnicity (Native American, African American, Latino, Asian American, Pacific
Islander) A
Type 2 Diabetes
c Signsof insulin resistance or conditions associated with insulin resistance (acanthosis
nigricans, hypertension, dyslipidemia, polycystic ovary syndrome, or small-for-gestational-
Type 2 diabetes, previously referred to
age birth weight) B as “noninsulin-dependent diabetes” or
“adult-onset diabetes,” accounts for 90–
GDM, gestational diabetes mellitus. *After the onset of puberty or after 10 years of age, whichever
occurs earlier. If tests are normal, repeat testing at a minimum of 3-year intervals, or more 95% of all diabetes. This form encom-
frequently if BMI is increasing, is recommended. Reports of type 2 diabetes before age 10 years passes individuals who have relative
exist, and this can be considered with numerous risk factors. (rather than absolute) insulin deficiency
and have peripheral insulin resistance. At
least initially, and often throughout their
World Health Organization (WHO) and the high-risk participants in the Diabetes
lifetime, these individuals may not need
numerous other diabetes organizations Prevention Program (DPP) (51), and A1C
insulin treatment to survive.
define the IFG cutoff at 110 mg/dL at baseline was a strong predictor of
There are various causes of type 2
(6.1 mmol/L). the development of glucose-defined di-
diabetes. Although the specific etiologies
As with the glucose measures, several abetes during the DPP and its follow-up
are not known, autoimmune destruction
prospective studies that used A1C to (52). Hence, it is reasonable to consider
of b-cells does not occur and patients do
predict the progression to diabetes as an A1C range of 5.7–6.4% (39–47 mmol/
not have any of the other known causes
defined by A1C criteria demonstrated a mol) as identifying individuals with pre-
of diabetes. Most but not all patients with
strong, continuous association between diabetes. Similar to those with IFG and/or
type 2 diabetes have overweight or obe-
A1C and subsequent diabetes. In a sys- IGT, individuals with A1C of 5.7–6.4%
sity. Excess weight itself causes some
tematic review of 44,203 individuals from (39–47 mmol/mol) should be informed
degree of insulin resistance. Patients who
16 cohort studies with a follow-up in- of their increased risk for diabetes and
do not have obesity or overweight by
terval averaging 5.6 years (range 2.8–12 CVD and counseled about effective strat-
traditional weight criteria may have an
years), those with A1C between 5.5% and egies to lower their risks (see Section
increased percentage of body fat distrib-
6.0% (between 37 and 42 mmol/mol) 3 “Prevention or Delay of Type 2 Di-
uted predominantly in the abdominal
had a substantially increased risk of di- abetes,” https://doi.org/10.2337/dc20-
region.
abetes (5-year incidence from 9% to S003). Similar to glucose measurements,
DKA seldom occurs spontaneously in
25%). Those with an A1C range of 6.0– the continuum of risk is curvilinear, so as
type 2 diabetes; when seen, it usually
6.5% (42–48 mmol/mol) had a 5-year A1C rises, the diabetes risk rises dispro-
arises in association with the stress of
risk of developing diabetes between 25% portionately (49). Aggressive interven-
another illness such as infection or with
and 50% and a relative risk 20 times tions and vigilant follow-up should be
the use of certain drugs (e.g., cortico-
higher compared with A1C of 5.0% pursued for those considered at very
steroids, atypical antipsychotics, and
(31 mmol/mol) (49). In a community- high risk (e.g., those with A1C .6.0%
sodium–glucose cotransporter 2 in-
based study of African American and [42 mmol/mol]).
hibitors) (53,54). Type 2 diabetes fre-
non-Hispanic white adults without dia- Table 2.5 summarizes the categories
quently goes undiagnosed for many
betes, baseline A1C was a stronger pre- of prediabetes and Table 2.3 the cri-
years because hyperglycemia develops
dictor of subsequent diabetes and teria for prediabetes testing. The ADA
gradually and, at earlier stages, is often
cardiovascular events than fasting glucose diabetes risk test is an additional op-
not severe enough for the patient to
(50). Other analyses suggest that A1C of tion for assessment to determine the
notice the classic diabetes symptoms.
5.7% (39 mmol/mol) or higher is associated appropriateness of testing for diabetes
Nevertheless, even undiagnosed pa-
with a diabetes risk similar to that of or prediabetes in asymptomatic adults.
tients are at increased risk of develop-
ing macrovascular and microvascular
Table 2.5—Criteria defining prediabetes* complications.
FPG 100 mg/dL (5.6 mmol/L) to 125 mg/dL (6.9 mmol/L) (IFG) Whereas patients with type 2 diabetes
OR may have insulin levels that appear nor-
2-h PG during 75-g OGTT 140 mg/dL (7.8 mmol/L) to 199 mg/dL (11.0 mmol/L) (IGT) mal or elevated, the higher blood glucose
OR levels in these patients would be expected
A1C 5.7–6.4% (39–47 mmol/mol) to result in even higher insulin values had
FPG, fasting plasma glucose; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; OGTT, their b-cell function been normal. Thus,
oral glucose tolerance test; 2-h PG, 2-h plasma glucose. *For all three tests, risk is continuous, insulin secretion is defective in these
extending below the lower limit of the range and becoming disproportionately greater at the patients and insufficient to compensate
higher end of the range. for insulin resistance. Insulin resistance
S20 Classification and Diagnosis of Diabetes Diabetes Care Volume 43, Supplement 1, January 2020
may improve with weight reduction diabetes are undiagnosed (47,56). Al- BMI and Ethnicity
and/or pharmacologic treatment of hy- though screening of asymptomatic indi- In general, BMI $25 kg/m2 is a risk factor
perglycemia but is seldom restored to viduals to identify those with prediabetes for diabetes. However, data suggest that
normal. or diabetes might seem reasonable, rig- the BMI cut point should be lower for the
The risk of developing type 2 diabetes orous clinical trials to prove the effective- Asian American population (60,61). The
increases with age, obesity, and lack of ness of such screening have not been BMI cut points fall consistently between
physical activity. It occurs more fre- conducted and are unlikely to occur. 23 and 24 kg/m2 (sensitivity of 80%) for
quently in women with prior gestational Based on a population estimate, diabe- nearly all Asian American subgroups
diabetes mellitus (GDM), in those with tes in women of childbearing age is (with levels slightly lower for Japanese
hypertension or dyslipidemia, and in underdiagnosed. Employing a probabi- Americans). This makes a rounded cut
certain racial/ethnic subgroups (African listic model, Peterson et al. (57) dem- point of 23 kg/m2 practical. An argument
American, American Indian, Hispanic/ onstrated cost and health benefits of can be made to push the BMI cut point to
Latino, and Asian American). It is often preconception screening. lower than 23 kg/m2 in favor of increased
associated with a strong genetic predis- A large European randomized con- sensitivity; however, this would lead to
position or family history in first-degree trolled trial compared the impact of an unacceptably low specificity (13.1%).
relatives, more so than type 1 diabetes. screening for diabetes and intensive Data from the WHO also suggests that a
However, the genetics of type 2 diabetes multifactorial intervention with that of BMI of $23 kg/m2 should be used to
is poorly understood. In adults without screening and routine care (55). General define increased risk in Asian Americans
traditional risk factors for type 2 diabetes practice patients between the ages of (62). The finding that one-third to one-
and/or younger age, consider islet auto- 40 and 69 years were screened for di- half of diabetes in Asian Americans is
antibody testing (e.g., GAD65 autoanti- abetes and randomly assigned by prac- undiagnosed suggests that testing is
bodies) to exclude the diagnosis of tice to intensive treatment of multiple not occurring at lower BMI thresholds
type 1 diabetes. risk factors or routine diabetes care. (63,64).
After 5.3 years of follow-up, CVD risk Evidence also suggests that other pop-
Screening and Testing for Prediabetes factors were modestly but significantly ulations may benefit from lower BMI cut
and Type 2 Diabetes in Asymptomatic improved with intensive treatment points. For example, in a large multieth-
Adults compared with routine care, but the nic cohort study, for an equivalent in-
Screening for prediabetes and type 2 incidence of first CVD events or mortal- cidence rate of diabetes, a BMI of 30
diabetes risk through an informal assess- ity was not significantly different be- kg/m2 in non-Hispanic whites was equiv-
ment of risk factors (Table 2.3) or with tween the groups (48). The excellent alent to a BMI of 26 kg/m2 in African
an assessment tool, such as the ADA risk care provided to patients in the routine Americans (65).
test (Fig. 2.1) (online at diabetes.org/ care group and the lack of an un-
Medications
socrisktest), is recommended to guide screened control arm limited the au-
providers on whether performing a di- thors’ ability to determine whether Certain medications, such as glucocor-
agnostic test (Table 2.2) is appropriate. screening and early treatment im- ticoids, thiazide diuretics, some HIV
Prediabetes and type 2 diabetes meet proved outcomes compared with no medications, and atypical antipsy-
criteria for conditions in which early screening and later treatment after chotics (66), are known to increase
detection is appropriate. Both conditions clinical diagnoses. Computer simula- the risk of diabetes and should be
are common and impose significant clin- tion modeling studies suggest that considered when deciding whether
ical and public health burdens. There is major benefits are likely to accrue to screen.
often a long presymptomatic phase be- from the early diagnosis and treat- Testing Interval
fore the diagnosis of type 2 diabetes. ment of hyperglycemia and cardiovas- The appropriate interval between
Simple tests to detect preclinical disease cular risk factors in type 2 diabetes screening tests is not known (67). The
are readily available. The duration of (58); moreover, screening, beginning at rationale for the 3-year interval is
glycemic burden is a strong predictor age 30 or 45 years and independent of that with this interval, the number of
of adverse outcomes. There are effec- risk factors, may be cost-effective false-positive tests that require confir-
tive interventions that prevent progres- (,$11,000 per quality-adjusted life- matory testing will be reduced and
sion from prediabetes to diabetes (see year gained) (59). individuals with false-negative tests
Section 3 “Prevention or Delay of Type 2 Additional considerations regard- will be retested before substantial
Diabetes,” https://doi.org/10.2337/dc20- ing testing for type 2 diabetes and time elapses and complications de-
S003) and reduce the risk of diabetes prediabetes in asymptomatic patients velop (67).
complications (see Section 10 “Cardiovas- include the following.
cular Disease and Risk Management,” Community Screening
https://doi.org/10.2337/dc20-S010, and Age Ideally, testing should be carried out
Section 11 “Microvascular Complications Age is a major risk factor for diabetes. within a health care setting because of
and Foot Care,” https://doi.org/10.2337/ Testing should begin at no later than the need for follow-up and treatment.
dc20-S011). age 45 years for all patients. Screening Community screening outside a health
Approximately one-quarter of people should be considered in adults of any care setting is generally not recom-
with diabetes in the U.S. and nearly half age with overweight or obesity and one mended because people with positive
of Asian and Hispanic Americans with or more risk factors for diabetes. tests may not seek, or have access to,
care.diabetesjournals.org Classification and Diagnosis of Diabetes S21
appropriate follow-up testing and care. diabetes in children with cystic fibrosis or however, recent publications suggest
However, in specific situations where symptoms suggestive of acute onset of that an A1C cut point lower than 5.4%
an adequate referral system is estab- type 1 diabetes and only A1C assays (5.8% in a second study) would detect
lished beforehand for positive tests, without interference are appropriate more than 90% of cases and reduce
community screening may be consid- for children with hemoglobinopathies, patient screening burden (77,78). On-
ered. Community testing may also be the ADA continues to recommend A1C going studies are underway to validate
poorly targeted; i.e., it may fail to for diagnosis of type 2 diabetes in this this approach. Regardless of age, weight
reach the groups most at risk and in- cohort (74,75). loss or failure of expected weight gain
appropriately test those at very low risk is a risk for CFRD and should prompt
or even those who have already been CYSTIC FIBROSIS–RELATED screening (77,78). Continuous glucose
diagnosed (68). DIABETES monitoring or HOMA of b-cell function
(79) may be more sensitive than OGTT to
Screening in Dental Practices Recommendations
detect risk for progression to CFRD;
Because periodontal disease is associated 2.14 Annual screening for cystic
however, evidence linking these results
with diabetes, the utility of screening in a fibrosis–related diabetes (CFRD)
to long-term outcomes is lacking, and
dental setting and referral to primary care with an oral glucose tolerance
these tests are not recommended for
as a means to improve the diagnosis of test should begin by age 10 years
screening (80).
prediabetes and diabetes has been in all patients with cystic fibrosis
CFRD mortality has significantly de-
explored (69–71), with one study es- not previously diagnosed with
creased over time, and the gap in mor-
timating that 30% of patients $30 CFRD. B
tality between cystic fibrosis patients
years of age seen in general dental 2.15 A1C is not recommended as a
with and without diabetes has consid-
practices had dysglycemia (71). Further screening test for cystic fibrosis–
erably narrowed (81). There are limited
research is needed to demonstrate the related diabetes. B
clinical trial data on therapy for CFRD.
feasibility, effectiveness, and cost-effec- 2.16 Patients with cystic fibrosis–
The largest study compared three regi-
tiveness of screening in this setting. related diabetes should be
mens: premeal insulin aspart, repagli-
treated with insulin to attain
Screening and Testing for Prediabetes nide, or oral placebo in cystic fibrosis
individualized glycemic goals. A
and Type 2 Diabetes in Children and patients with diabetes or abnormal glu-
2.17 Beginning 5 years after the di-
Adolescents cose tolerance. Participants all had
agnosis of cystic fibrosis–related
In the last decade, the incidence and weight loss in the year preceding treat-
diabetes, annual monitoring for
prevalence of type 2 diabetes in chil- ment; however, in the insulin-treated
complications of diabetes is rec-
dren and adolescents has increased group, this pattern was reversed, and
ommended. E
dramatically, especially in racial and patients gained 0.39 (60.21) BMI units
ethnic minority populations (41). See (P 5 0.02). The repaglinide-treated
Table 2.4 for recommendations on risk- Cystic fibrosis–related diabetes (CFRD) group had initial weight gain, but this
based screening for type 2 diabetes or is the most common comorbidity in was not sustained by 6 months. The
prediabetes in asymptomatic children people with cystic fibrosis, occurring in placebo group continued to lose weight
and adolescents in a clinical setting about 20% of adolescents and 40–50% of (81). Insulin remains the most widely
(19). See Table 2.2 and Table 2.5 for adults (76). Diabetes in this population, used therapy for CFRD (82).
the criteria for the diagnosis of diabetes compared with individuals with type 1 or Additional resources for the clinical
and prediabetes, respectively, which type 2 diabetes, is associated with worse management of CFRD can be found in
apply to children, adolescents, and nutritional status, more severe inflam- the position statement “Clinical Care
adults. See Section 13 “Children and matory lung disease, and greater mor- Guidelines for Cystic Fibrosis–Related
Adolescents” (https://doi.org/10.2337/ tality. Insulin insufficiency is the primary Diabetes: A Position Statement of the
dc20-S013) for additional information defect in CFRD. Genetically determined American Diabetes Association and a
on type 2 diabetes in children and b-cell function and insulin resistance Clinical Practice Guideline of the Cystic
adolescents. associated with infection and inflamma- Fibrosis Foundation, Endorsed by the
Some studies question the validity of tion may also contribute to the devel- Pediatric Endocrine Society” (83) and
A1C in the pediatric population, espe- opment of CFRD. Milder abnormalities in the International Society for Pedi-
cially among certain ethnicities, and sug- of glucose tolerance are even more com- atric and Adolescent Diabetes’s 2014
gest OGTT or FPG as more suitable mon and occur at earlier ages than CFRD. clinical practice consensus guidelines
diagnostic tests (72). However, many Whether individuals with IGT should be (84).
of these studies do not recognize that treated with insulin replacement has not
diabetes diagnostic criteria are based on currently been determined. Although POSTTRANSPLANTATION
long-term health outcomes, and valida- screening for diabetes before the age DIABETES MELLITUS
tions are not currently available in the of 10 years can identify risk for progres- Recommendations
pediatric population (73). The ADA ac- sion to CFRD in those with abnormal 2.18 Patients should be screened af-
knowledges the limited data supporting glucose tolerance, no benefit has been ter organ transplantation for
A1C for diagnosing type 2 diabetes in established with respect to weight, hyperglycemia, with a formal
children and adolescents. Although A1C height, BMI, or lung function. OGTT diagnosis of posttransplantation
is not recommended for diagnosis of is the recommended screening test;
care.diabetesjournals.org Classification and Diagnosis of Diabetes S23
patients with KATP-related neonatal di- MODY (MODY3), and HNF4A-MODY HNF4A-MODY). Additionally, diagnosis can
abetes will exhibit improved glycemic (MODY1). lead to identification of other affected
control when treated with high-dose For individuals with MODY, the treat- family members. Genetic screening is in-
oral sulfonylureas instead of insulin. ment implications are considerable and creasingly available and cost-effective
Insulin gene (INS) mutations are the warrant genetic testing (104,105). Clin- (104,105).
second most common cause of perma- ically, patients with GCK-MODY exhibit A diagnosis of MODY should be con-
nent neonatal diabetes, and, while mild, stable, fasting hyperglycemia and sidered in individuals who have atypical
intensive insulin management is cur- do not require antihyperglycemic ther- diabetes and multiple family members
rently the preferred treatment strategy, apy except sometimes during pregnancy. with diabetes not characteristic of type
there are important genetic counseling Patients with HNF1A- or HNF4A-MODY 1 or type 2 diabetes, although admit-
considerations, as most of the mutations usually respond well to low doses of tedly “atypical diabetes” is becoming
that cause diabetes are dominantly in- sulfonylureas, which are considered increasingly difficult to precisely define
herited. first-line therapy. Mutations or deletions in the absence of a definitive set of tests
in HNF1B are associated with renal cysts for either type of diabetes (104–110). In
Maturity-Onset Diabetes of the Young and uterine malformations (renal cysts
MODY is frequently characterized by most cases, the presence of autoantibodies
and diabetes [RCAD] syndrome). Other for type 1 diabetes precludes further
onset of hyperglycemia at an early age extremely rare forms of MODY have been
(classically before age 25 years, although testing for monogenic diabetes, but
reported to involve other transcription
diagnosis may occur at older ages). the presence of autoantibodies in pa-
factor genes including PDX1 (IPF1) and
MODY is characterized by impaired in- tients with monogenic diabetes has been
NEUROD1.
sulin secretion with minimal or no de- reported (111). Individuals in whom
fects in insulin action (in the absence of Diagnosis of Monogenic Diabetes monogenic diabetes is suspected should
coexistent obesity). It is inherited in A diagnosis of one of the three most be referred to a specialist for further
an autosomal dominant pattern with common forms of MODY, including GCK- evaluation if available, and consultation
abnormalities in at least 13 genes on MODY, HNF1A-MODY, and HNF4A-MODY, is available from several centers. Readily
different chromosomes identified to allows for more cost-effective therapy available commercial genetic testing fol-
date. The most commonly reported (no therapy for GCK-MODY; sulfonylureas lowing the criteria listed below now
forms are GCK-MODY (MODY2), HNF1A- as first-line therapy for HNF1A-MODY and enables a cost-effective (112), often
care.diabetesjournals.org Classification and Diagnosis of Diabetes S25
cost-saving, genetic diagnosis that is in- pancreoprivic diabetes (1). The diverse Definition
creasingly supported by health insur- set of etiologies includes pancreatitis For many years, GDM was defined as
ance. A biomarker screening pathway (acute and chronic), trauma or pancre- any degree of glucose intolerance that
such as the combination of urinary atectomy, neoplasia, cystic fibrosis (ad- was first recognized during preg-
C-peptide/creatinine ratio and antibody nancy (49), regardless of the degree
dressed elsewhere in this chapter),
screening may aid in determining who of hyperglycemia. This definition facili-
hemochromatosis, fibrocalculous pan-
should get genetic testing for MODY tated a uniform strategy for detection
creatopathy, rare genetic disorders
(113). It is critical to correctly diagnose and classification of GDM, but this defi-
(117), and idiopathic forms (1). A distin- nition has serious limitations (126). First,
one of the monogenic forms of diabetes
because these patients may be incor- guishing feature is concurrent pancreatic the best available evidence reveals that
rectly diagnosed with type 1 or type 2 exocrine insufficiency (according to the many, perhaps most, cases of GDM rep-
diabetes, leading to suboptimal, even monoclonal fecal elastase 1 test or direct resent preexisting hyperglycemia that is
potentially harmful, treatment regimens function tests), pathological pancreatic detected by routine screening in preg-
and delays in diagnosing other family imaging (endoscopic ultrasound, MRI, nancy, as routine screening is not widely
members (114). The correct diagnosis is computed tomography) and absence of performed in nonpregnant women of
especially critical for those with GCK- type 1 diabetes–associated autoimmu- reproductive age. It is the severity of
MODY mutations where multiple studies nity (118–122). There is loss of both hyperglycemia that is clinically important
have shown that no complications ensue insulin and glucagon secretion and often with regard to both short- and long-term
in the absence of glucose-lowering ther- maternal and fetal risks. Universal pre-
higher-than-expected insulin require-
apy (115). Genetic counseling is recom- conception and/or first trimester screen-
ments. Risk for microvascular complica-
mended to ensure that affected ing is hampered by lack of data and
tions is similar to other forms of diabetes. In
individuals understand the patterns of consensus regarding both appropriate
the context of pancreatectomy, islet auto-
inheritance and the importance of a diagnostic thresholds and outcomes. A
transplantation can be done to retain insulin
correct diagnosis. compelling argument for further work in
secretion (123,124). In some cases, this can
The diagnosis of monogenic diabetes this area is the fact that hyperglycemia
lead to insulin independence. In others,
should be considered in children and that would be diagnostic of diabetes
it may decrease insulin requirements
adults diagnosed with diabetes in outside of pregnancy and is present at
(125).
early adulthood with the following the time of conception is associated with
findings: an increased risk of congenital malfor-
GESTATIONAL DIABETES MELLITUS mations that is not seen with lower
c Diabetes diagnosed within the first glucose levels (127,128).
Recommendations
6 months of life (with occasional cases The ongoing epidemic of obesity and
2.24 Test for undiagnosed predia-
presenting later, mostly INS and diabetes has led to more type 2 diabetes
betes and diabetes at the first
ABCC8 mutations) (103,116) in women of reproductive age, with an
prenatal visit in those with risk
c Diabetes without typical features of increase in the number of pregnant
factors using standard diagnos-
type 1 or type 2 diabetes (negative women with undiagnosed type 2 diabe-
tic criteria. B
diabetes-associatedautoantibodies,non- tes in early pregnancy (129–132). Be-
2.25 Test for gestational diabetes
obese, lacking other metabolic features cause of the number of pregnant women
mellitus at 24–28 weeks of ges-
especially with strong family history of with undiagnosed type 2 diabetes, it is
tation in pregnant women not
diabetes) reasonable to test women with risk fac-
previously found to have diabe-
c Stable, mild fasting hyperglycemia tors for type 2 diabetes (133) (Table 2.3)
tes. A
(100–150 mg/dL [5.5–8.5 mmol/L]), at their initial prenatal visit, using stan-
2.26 Test women with gestational
stable A1C between 5.6 and 7.6% dard diagnostic criteria (Table 2.2).
diabetes mellitus for prediabe-
(between 38 and 60 mmol/mol), es- Women found to have diabetes by the
tes or diabetes at 4–12 weeks
pecially if nonobese standard diagnostic criteria used outside
postpartum, using the 75-g oral
of pregnancy should be classified as
glucose tolerance test and clin-
PANCREATIC DIABETES OR having diabetes complicating pregnancy
DIABETES IN THE CONTEXT ically appropriate nonpregnancy
(most often type 2 diabetes, rarely type 1
OF DISEASE OF THE diagnostic criteria. B
diabetes or monogenic diabetes) and
EXOCRINE PANCREAS 2.27 Women with a history of ges-
managed accordingly. Women who
tational diabetes mellitus should
Pancreatic diabetes includes both struc- meet the lower glycemic criteria for
have lifelong screening for the
tural and functional loss of glucose- GDM should be diagnosed with that
development of diabetes or pre-
normalizing insulin secretion in the context condition and managed accordingly.
diabetes at least every 3 years. B
of exocrine pancreatic dysfunction and Other women should be rescreened
2.28 Women with a history of ges-
is commonly misdiagnosed as type 2 for GDM between 24 and 28 weeks of
tational diabetes mellitus found
diabetes. Hyperglycemia due to general gestation (see Section 14 “Management
to have prediabetes should re-
pancreatic dysfunction has been called of Diabetes in Pregnancy,” https://doi
ceive intensive lifestyle inter-
“type 3c diabetes” and, more recently, .org/10.2337/dc20-S014). The Interna-
ventions and/or metformin to
diabetes in the context of disease of tional Association of the Diabetes and
prevent diabetes. A
the exocrine pancreas has been termed Pregnancy Study Groups (IADPSG) GDM
S26 Classification and Diagnosis of Diabetes Diabetes Care Volume 43, Supplement 1, January 2020
diagnostic criteria for the 75-g OGTT as well normal for pregnancy. For most compli- study population. This one-step strategy
as the GDM screening and diagnostic cri- cations, there was no threshold for risk. was anticipated to significantly increase
teria used in the two-step approach were These results have led to careful recon- the incidence of GDM (from 5–6% to 15–
not derived from data in the first half of sideration of the diagnostic criteria for 20%), primarily because only one abnor-
pregnancy, so the diagnosis of GDM in GDM. mal value, not two, became sufficient to
early pregnancy by either FPG or OGTT GDM diagnosis (Table 2.7) can be ac- make the diagnosis (142). Many regional
values is not evidence based (134) and complished with either of two strate- studies have investigated the impact of
further work is needed. gies: adopting IADPSG criteria on prevalence
GDM is often indicative of underly- and have seen a roughly one- to threefold
ing b-cell dysfunction (135), which 1. The “one-step” 75-g OGTT derived increase (143). The anticipated increase
confers marked increased risk for later from the IADPSG criteria or in the incidence of GDM could have a
development of diabetes, generally but 2. The older “two-step” approach with a substantial impact on costs and medical
not always type 2 diabetes, in the mother 50-g (nonfasting) screen followed by infrastructure needs and has the poten-
after delivery (136,137). As effective pre- a 100-g OGTT for those who screen tial to “medicalize” pregnancies previ-
vention interventions are available positive, based on the work of Car- ously categorized as normal. A recent
(138,139), women diagnosed with GDM penter and Coustan’s interpretation follow-up study of women participating
should receive lifelong screening for pre- of the older O’Sullivan (141a) criteria. in a blinded study of pregnancy OGTTs
diabetes to allow interventions to reduce found that 11 years after their pregnan-
diabetes risk and for type 2 diabetes to Different diagnostic criteria will iden- cies, women who would have been di-
allow treatment at the earliest pos- tify different degrees of maternal hyper- agnosed with GDM by the one-step
sible time (140). glycemia and maternal/fetal risk, leading approach, as compared with those
some experts to debate, and disagree on, without, were at 3.4-fold higher risk
Diagnosis optimal strategies for the diagnosis of of developing prediabetes and type 2
GDM carries risks for the mother, fetus, GDM. diabetes and had children with a higher
and neonate. The Hyperglycemia and risk of obesity and increased body fat,
One-Step Strategy
Adverse Pregnancy Outcome (HAPO) suggesting that the larger group of
The IADPSG defined diagnostic cut points
study (141), a large-scale multinational women identified by the one-step ap-
for GDM as the average fasting, 1-h, and 2-h
cohort study completed by more than proach would benefit from increased
23,000 pregnant women, demonstrated PG values during a 75-g OGTT in women at screening for diabetes and prediabetes
that risk of adverse maternal, fetal, and 24–28 weeks of gestation who participated that would accompany a history of GDM
neonatal outcomes continuously in- in the HAPO study at which odds for ad- (144). The ADA recommends the IADPSG
creased as a function of maternal glyce- verse outcomes reached 1.75 times the diagnostic criteria with the intent of
mia at 24–28 weeks of gestation, even estimated odds of these outcomes at the optimizing gestational outcomes be-
within ranges previously considered mean fasting, 1-h, and 2-h PG levels of the cause these criteria were the only
ones based on pregnancy outcomes
rather than end points such as prediction
Table 2.7—Screening for and diagnosis of GDM
One-step strategy
of subsequent maternal diabetes.
Perform a 75-g OGTT, with plasma glucose measurement when patient is fasting and at 1 The expected benefits of using IADPSG to
and 2 h, at 24–28 weeks of gestation in women not previously diagnosed with diabetes. the offspring are inferred from intervention
The OGTT should be performed in the morning after an overnight fast of at least 8 h. trials that focused on women with lower
The diagnosis of GDM is made when any of the following plasma glucose values are met or levels of hyperglycemia than identified
exceeded: using older GDM diagnostic criteria. Those
c Fasting: 92 mg/dL (5.1 mmol/L) trials found modest benefits including re-
c 1 h: 180 mg/dL (10.0 mmol/L) duced rates of large-for-gestational-age
c 2 h: 153 mg/dL (8.5 mmol/L) births and preeclampsia (145,146). It is
Two-step strategy important to note that 80–90% of women
Step 1: Perform a 50-g GLT (nonfasting), with plasma glucose measurement at 1 h, at 24– being treated for mild GDM in these two
28 weeks of gestation in women not previously diagnosed with diabetes. randomized controlled trials could be man-
If the plasma glucose level measured 1 h after the load is $130, 135, or 140 mg/dL (7.2, 7.5, or aged with lifestyle therapy alone. The
7.8 mmol/L, respectively), proceed to a 100-g OGTT.
OGTT glucose cutoffs in these two trials
Step 2: The 100-g OGTT should be performed when the patient is fasting.
overlapped with the thresholds recom-
The diagnosis of GDM is made when at least two* of the following four plasma glucose levels
(measured fasting and at 1, 2, and 3 h during OGTT) are met or exceeded (Carpenter-Coustan mended by the IADPSG, and in one trial
criteria [154]): (146), the 2-h PG threshold (140 mg/dL
c Fasting: 95 mg/dL (5.3 mmol/L) [7.8 mmol/L]) was lower than the cutoff
c 1 h: 180 mg/dL (10.0 mmol/L) recommended by the IADPSG (153 mg/
c 2 h: 155 mg/dL (8.6 mmol/L) dL [8.5 mmol/L]). No randomized con-
c 3 h: 140 mg/dL (7.8 mmol/L)
trolled trials of treating versus not
GDM, gestational diabetes mellitus; GLT, glucose load test; OGTT, oral glucose tolerance test. treating GDM diagnosed by the IADPSG
*American College of Obstetricians and Gynecologists notes that one elevated value can be used criteria but not the Carpenter-Coustan
for diagnosis (150).
criteria have been published to date.
care.diabetesjournals.org Classification and Diagnosis of Diabetes S27
Data are also lacking on how the treat- of neonatal macrosomia, large-for- approaches have been inconsistent to
ment of lower levels of hyperglycemia gestational-age births (153), and shoulder date (159,160). In addition, pregnancies
affects a mother’s future risk for the dystocia, without increasing small-for- complicated by GDM per the IADPSG
development of type 2 diabetes and her gestational-age births. ACOG currently criteria, but not recognized as such,
offspring’s risk for obesity, diabetes, supports the two-step approach but have outcomes comparable to preg-
and other metabolic disorders. Addi- notes that one elevated value, as op- nancies with diagnosed GDM by the
tional well-designed clinical studies are posed to two, may be used for the di- more stringent two-step criteria (161,162).
needed to determine the optimal in- agnosis of GDM (150). If this approach There remains strong consensus that
tensity of monitoring and treatment of is implemented, the incidence of GDM establishing a uniform approach to di-
women with GDM diagnosed by the by the two-step strategy will likely in- agnosing GDM will benefit patients,
one-step strategy (147,148). crease markedly. ACOG recommends caregivers, and policy makers. Longer-
either of two sets of diagnostic thresh- term outcome studies are currently
Two-Step Strategy
olds for the 3-h 100-g OGTTdCarpenter- underway.
In 2013, the National Institutes of Health
(NIH) convened a consensus develop- Coustan or National Diabetes Data References
ment conference to consider diagnostic Group (154,155). Each is based on dif- 1. American Diabetes Association. Diagnosis
criteria for diagnosing GDM (149). The ferent mathematical conversions of the and classification of diabetes mellitus. Diabetes
15-member panel had representatives original recommended thresholds by Care 2014;37(Suppl. 1):S81–S90
O’Sullivan (141a), which used whole 2. Dabelea D, Rewers A, Stafford JM, et al.;
from obstetrics and gynecology, maternal-
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search, biostatistics, and other related glucose determination. A secondary diabetes diagnosis: the SEARCH for Diabetes
fields. The panel recommended a two- analysis of data from a randomized in Youth Study. Pediatrics 2014;133:e938–
step approach to screening that used a clinical trial of identification and treat- e945
ment of mild GDM (156) demonstrated 3. Humphreys A, Bravis V, Kaur A, et al. Individual
1-h 50-g glucose load test (GLT) followed
and diabetes presentation characteristics asso-
by a 3-h 100-g OGTT for those who that treatment was similarly benefi-
ciated with partial remission status in children
screened positive. The American College cial in patients meeting only the lower and adults evaluated up to 12 months following
of Obstetricians and Gynecologists thresholds per Carpenter-Coustan (154) diagnosis of type 1 diabetes: an ADDRESS-2 (After
(ACOG) recommends any of the com- and in those meeting only the higher Diagnosis Diabetes Research Support System-2)
monly used thresholds of 130, 135, or thresholds per National Diabetes Data study analysis. Diabetes Res Clin Pract 2019;155:
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offs of 130 mg/dL (7.2 mmol/L) and nostic thresholds as shown in step 2 in type 2 diabetes. Diabetologia 2019;62:1167–1172
140 mg/dL (7.8 mmol/L) (151). The Table 2.7. 5. Hope SV, Wienand-Barnett S, Shepherd M,
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S32 Diabetes Care Volume 43, Supplement 1, January 2020
includes the ADA’s current clinical practice recommendations and is intended to provide
the components of diabetes care, general treatment goals and guidelines, and tools
to evaluate quality of care. Members of the ADA Professional Practice Committee, a
multidisciplinary expert committee (https://doi.org/10.2337/dc20-SPPC), are re-
sponsible for updating the Standards of Care annually, or more frequently as
warranted. For a detailed description of ADA standards, statements, and reports, as
well as the evidence-grading system for ADA’s clinical practice recommendations,
please refer to the Standards of Care Introduction (https://doi.org/10.2337/
dc20-SINT). Readers who wish to comment on the Standards of Care are invited to
do so at professional.diabetes.org/SOC.
For guidelines related to screening for increased risk for type 2 diabetes (prediabetes),
please refer to Section 2 “Classification and Diagnosis of Diabetes” (https://doi.org/10
.2337/dc20-S002).
Recommendation
3.1 At least annual monitoring for the development of type 2 diabetes in those
with prediabetes is suggested. E
Screening for prediabetes and type 2 diabetes risk through an informal assessment of
risk factors (Table 2.3) or with an assessment tool, such as the American Diabetes
Association risk test (Fig. 2.1), is recommended to guide providers on whether
performing a diagnostic test for prediabetes (Table 2.5) and previously undiagnosed
type 2 diabetes (Table 2.2) is appropriate (see Section 2 “Classification and Diagnosis
of Diabetes,” https://doi.org/10.2337/dc20-S002). Those who are determined to be
at high risk for type 2 diabetes, including people with A1C 5.7–6.4% (39–47
mmol/mol), impaired glucose tolerance, or impaired fasting glucose, are ideal
candidates for diabetes prevention efforts. Using A1C to screen for prediabetes may
be problematic in the presence of certain hemoglobinopathies or conditions that
affect red blood cell turnover. See Section 2 “Classification and Diagnosis of
Diabetes” (https://doi.org/10.2337/dc20-S002) and Section 6 “Glycemic Targets”
(https://doi.org/10.2337/dc20-S006) for additional details on the appropriate
use of the A1C test. Suggested citation: American Diabetes Associa-
tion. 3. Prevention or delay of type 2 diabetes:
LIFESTYLE INTERVENTIONS Standards of Medical Care in Diabetesd2020.
Diabetes Care 2020;43(Suppl. 1):S32–S36
Recommendations
© 2019 by the American Diabetes Association.
3.2 Refer patients with prediabetes to an intensive behavioral lifestyle inter- Readers may use this article as long as the work
vention program modeled on the Diabetes Prevention Program (DPP) to is properly cited, the use is educational and not
achieve and maintain 7% loss of initial body weight and increase moderate- for profit, and the work is not altered. More infor-
intensity physical activity (such as brisk walking) to at least 150 min/week. A mation is available at http://www.diabetesjournals
.org/content/license.
care.diabetesjournals.org Prevention or Delay of Type 2 Diabetes S33
as it is associated with moderately producing weight loss and diabetes risk PHARMACOLOGIC
lower postprandial glucose levels reduction (39–42). The use of community INTERVENTIONS
(24,25). The preventive effects of health workers to support DPP efforts Recommendations
exercise appear to extend to the pre- has been shown to be effective with 3.6 Metformin therapy for preven-
vention of gestational diabetes mellitus cost savings (43,44) (see Section 1 “Im- tion of type 2 diabetes should be
(GDM) (26). proving Care and Promoting Health considered in those with predia-
in Populations,” https://doi.org/10 betes, especially for those with
Tobacco Use .2337/dc20-S001, for more informa- BMI $35 kg/m2, those aged ,60
Smoking may increase the risk of type 2 tion). Given the cost-effectiveness of years, and women with prior
diabetes (27); therefore, evaluation for diabetes prevention, such intervention gestational diabetes mellitus. A
tobacco use and referral for tobacco programs should be covered by third- 3.7 Long-term use of metformin may
cessation, if indicated, should be part party payers. be associated with biochemical
of routine care for those at risk for The CDC coordinates the National Di- vitamin B12 deficiency, and pe-
diabetes. Of note, the years immedi- abetes Prevention Program (National DPP), riodic measurement of vitamin
ately following smoking cessation may a resource designed to bring evidence- B12 levels should be considered
represent a time of increased risk for based lifestyle change programs for pre- in metformin-treated patients,
diabetes (27–29) and patients should venting type 2 diabetes to communities especially in those with anemia
be monitored for diabetes develop- (www.cdc.gov/diabetes/prevention/index or peripheral neuropathy. B
ment and receive evidence-based inter- .htm). This online resource includes loca-
ventions for diabetes prevention as tions of CDC-recognized diabetes preven-
described in this section. See Section tion lifestyle change programs (available Pharmacologic agents including met-
5 “Facilitating Behavior Change and at nccd.cdc.gov/DDT_DPRP/Programs formin, a-glucosidase inhibitors, glu-
Well-being to Improve Health Outcomes” .aspx). To be eligible for this program, cagon-like peptide 1 receptor agonists,
(https://doi.org/10.2337/dc20-S005) for patients must have a BMI in the over- thiazolidinediones, and several agents
more detailed information. weight range and be at risk for diabetes approved for weight loss have been
based on laboratory testing or a posi- shown in research studies to decrease
Technology-Assisted Interventions to tive risk test (available at www.cdc.gov/ the incidence of diabetes to various
Deliver Lifestyle Interventions prediabetes/takethetest/). Results from degrees in those with prediabetes
Technology-assisted interventions may the CDC’s National DPP during the first (1,47–53), though none are approved
effectively deliver the DPP lifestyle 4 years of implementation are promis- by the U.S. Food and Drug Administra-
intervention, reducing weight and, ing (45). The CDC has also developed tion specifically for diabetes preven-
therefore, diabetes risk (30–35). Such the Diabetes Prevention Impact Tool tion. The risk versus benefit of each
technology-assisted interventions may Kit (available at nccd.cdc.gov/toolkit/ medication must be weighed. Metfor-
deliver content through smartphone diabetesimpact) to help organizations min has the strongest evidence base
and web-based applications and tele- assess the economics of providing or (54) and demonstrated long-term
health (30). The Centers for Disease covering the National DPP lifestyle safety as pharmacologic therapy for
Control and Prevention (CDC) Diabetes change program (46). diabetes prevention (52). For other
Prevention Recognition Program (DPRP) drugs, cost, side effects, and durable
(www.cdc.gov/diabetes/prevention/ National Policy efficacy require consideration.
requirements-recognition.htm) certifies In an effort to expand preventive services Metformin was overall less effective
technology-assisted modalities as ef- using a cost-effective model that began than lifestyle modification in the DPP,
fective vehicles for DPP-based inter- in April 2018, the Centers for Medicare though group differences declined over
ventions; such programs must use an & Medicaid Services expanded Medi- time in the DPPOS (7), and metformin
approved curriculum, include interac- care reimbursement coverage for the may be cost-saving over a 10-year
tion with a coach, and attain the DPRP National DPP lifestyle intervention to period (38). During initial follow up
outcomes of participation, physical organizations recognized by the CDC in the DPP, metformin was as effective
activity reporting, and weight loss. that become Medicare suppliers for this as lifestyle modification in participants
The selection of an in-person or virtual service (online at innovation.cms.gov/ with BMI $35 kg/m2 but not signifi-
program should be based on patient initiatives/medicare-diabetes-prevention- cantly better than placebo in those over
preference. program/). The locations of Medicare 60 years of age (1). In the DPP, for
DPPs are available online at innovation women with a history of GDM, met-
Cost-effectiveness .cms.gov/initiatives/medicare-diabetes- formin and intensive lifestyle modifi-
A cost-effectiveness model suggested prevention-program/mdpp-map.html. cation led to an equivalent 50%
that the lifestyle intervention used in To qualify for Medicare coverage, patients reduction in diabetes risk (55), and
the DPP was cost-effective (36,37). Ac- must have a BMI in the overweight both interventions remained highly ef-
tual cost data from the DPP and DPPOS range and laboratory testing consistent fective during a 10-year follow-up pe-
confirmed this (38). Group delivery of with prediabetes in the last year. Med- riod (56). By the time of the 15-year
DPP content in community or primary icaid coverage of the DPP lifestyle follow-up (DPPOS), exploratory analy-
care settings has the potential to re- intervention is also expanding on a ses demonstrated that participants
duce overall program costs while still state-by-state basis. with a higher baseline fasting glucose
care.diabetesjournals.org Prevention or Delay of Type 2 Diabetes S35
($110 mg/dL vs. 95–109 mg/dL) and Change and Well-being to Improve 9. Hamman RF, Wing RR, Edelstein SL, et al.
women with a history of GDM (vs. Health Outcomes,” https://doi.org/10 Effect of weight loss with lifestyle intervention
on risk of diabetes. Diabetes Care 2006;29:2102–
women without a history of GDM) ex- .2337/dc20-S005) can also apply to people 2107
perienced higher risk reductions with with prediabetes. Currently, there are sig- 10. Evert AB, Dennison M, Gardner CD, et al.
metformin (compared with the placebo nificant barriers to the provision of educa- Nutrition therapy for adults with diabetes or
arm) (57). In the Indian Diabetes Pre- tion and support to those with prediabetes. prediabetes: a consensus report. Diabetes Care
vention Program (IDPP-1), metformin and However, the strategies for supporting 2019;42:731–754
11. Salas-Salvadó J, Guasch-Ferré M, Lee C-H,
the lifestyle intervention reduced diabetes successful behavior change and the
Estruch R, Clish CB, Ros E. Protective effects of
risk similarly at 30 months; of note, the healthy behaviors recommended for the Mediterranean diet on type 2 diabetes and
lifestyle intervention in IDPP-1 was less people with prediabetes are compara- metabolic syndrome. J Nutr 2016;146:920S–
intensive than that in the DPP (58). Based ble to those for people with diabetes. 927S
on findings from the DPP, metformin should Although reimbursement remains a bar- 12. Bloomfield HE, Koeller E, Greer N, MacDonald
R, Kane R, Wilt TJ. Effects on health outcomes of a
be recommended as an option for high-risk rier, studies show that providers of di- Mediterranean diet with no restriction on fat
individuals (e.g., those with a history of abetes self-management education and intake: a systematic review and meta-analysis.
GDM or those with BMI $35 kg/m2). support are particularly well equipped to Ann Intern Med 2016;165:491–500
Consider monitoring vitamin B12 levels assist people with prediabetes in develop- 13. Estruch R, Ros E, Salas-Salvadó J, et al.;
in those taking metformin chronically to ing and maintaining behaviors that can PREDIMED Study Investigators. Primary pre-
vention of cardiovascular disease with a Med-
check for possible deficiency (56) (see Sec- prevent or delay the development of di- iterranean diet supplemented with extra-virgin
tion 9 “Pharmacologic Approaches to Gly- abetes (19,63). olive oil or nuts. N Engl J Med 2018;378:e34
cemic Treatment,” https://doi.org/10 14. Department of Health and Human Services
.2337/dc20-S009, for more details). and Department of Agriculture. Dietary Guide-
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Diabetes Care Volume 43, Supplement 1, January 2020 S37
Figure 4.1—Decision cycle for patient-centered glycemic management in type 2 diabetes. Reprinted from Davies et al. (99).
on their individual preferences, values, and “nonadherence” when the outcomes language in diabetes care and education
goals. The management plan should take of self-management are not optimal (8). can help to inform and motivate people,
into account the patient’s age, cognitive The familiar terms “noncompliance” and yet language that shames and judges may
abilities, school/work schedule and con- “nonadherence” denote a passive, obe- undermine this effort. The American Diabe-
ditions, health beliefs, support systems, dient role for a person with diabetes in tes Association (ADA) and the American
eating patterns, physical activity, social “following doctor’s orders” that is at odds Association of Diabetes Educators consen-
situation, financial concerns, cultural fac- with the active role people with diabetes sus report, “The Use of Language in Diabetes
tors, literacy and numeracy (mathematical take in directing the day-to-day decision- Care and Education,” provides the authors’
literacy), diabetes complications and du- making, planning, monitoring, evaluation, expert opinion regarding the use of language
ration of disease, comorbidities, health and problem-solving involved in diabetes by health care professionals when speaking
priorities, other medical conditions, pref- self-management. Using a nonjudgmental or writing about diabetes for people with
erences for care, and life expectancy. Var- approach that normalizes periodic lapses diabetes or for professional audiences (14).
ious strategies and techniques should be in self-management may help minimize Although further research is needed to ad-
used to support patients’ self-management patients’ resistance to reporting problems dress the impact of language on diabetes
efforts, including providing education with self-management. Empathizing and outcomes, the report includes five key
on problem-solving skills for all aspects using active listening techniques, such as consensus recommendations for lan-
of diabetes management. open-ended questions, reflective state- guage use:
Provider communication with patients ments, and summarizing what the patient
and families should acknowledge that said, can help facilitate communication. c Use language that is neutral, nonjudg-
multiple factors impact glycemic manage- Patients’ perceptions about their own mental, and based on facts, actions, or
ment but also emphasize that collabo- ability, or self-efficacy, to self-manage physiology/biology.
ratively developed treatment plans and diabetes are one important psychosocial c Use language free from stigma.
a healthy lifestyle can significantly im- factor related to improved diabetes self- c Use language that is strength based, respect-
prove disease outcomes and well-being management and treatment outcomes in ful, and inclusive and that imparts hope.
(4–7). Thus, the goal of provider-patient diabetes (9–13) and should be a target of c Use language that fosters collabora-
communication is to establish a collaborative ongoing assessment, patient education, tion between patients and providers.
relationship and to assess and address and treatment planning. c Use language that is person centered
self-management barriers without blam- Language has a strong impact on percep- (e.g., “person with diabetes” is pre-
ing patients for “noncompliance” or tions and behavior. The use of empowering ferred over “diabetic”).
care.diabetesjournals.org Comprehensive Medical Evaluation and Assessment of Comorbidities S39
Continued on p. S41
care.diabetesjournals.org Comprehensive Medical Evaluation and Assessment of Comorbidities S41
mortality and morbidity in vulnerable with a mortality rate as high as 50% (19). be due to contact with infected blood or
populations, including youth, older The ADA endorses recommendations from through improper equipment use (glucose
adults, and people with chronic dis- the CDC ACIP that adults age $65 years, monitoring devices or infected needles).
eases. Influenza vaccination in people who are at higher risk for pneumococcal Because of the higher likelihood of trans-
with diabetes has been found to sig- disease, receive an additional 23-valent mission, hepatitis B vaccine is recommen-
nificantly reduce influenza and diabe- pneumococcal polysaccharide vaccine ded for adults with diabetes age ,60 years.
tes-related hospital admissions (18). (PPSV23), regardless of prior pneumococcal Foradultsage$60years, hepatitisBvaccine
vaccination history. See detailed recom- may be administered at the discretion of the
Pneumococcal Pneumonia
mendations at www.cdc.gov/vaccines/hcp/ treating clinician based on the patient’s
Like influenza, pneumococcal pneumo-
acip-recs/vacc-specific/pneumo.html. likelihood of acquiring hepatitis B infection.
nia is a common, preventable disease.
People with diabetes are at increased risk Hepatitis B
for the bacteremic form of pneumococ- Compared with the general population, ASSESSMENT OF COMORBIDITIES
cal infection and have been reported to people with type 1 or type 2 diabetes Besides assessing diabetes-related com-
have a high risk of nosocomial bacteremia, have higher rates of hepatitis B. This may plications, clinicians and their patients
S42 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 43, Supplement 1, January 2020
Table 4.4—Referrals for initial care management mediated, at least in part, by weight loss
c Eye care professional for annual dilated eye exam (53–55).
c Family planning for women of reproductive age
Islet autotransplantation should be twice as prevalent in people with diabetes diabetes. Among patients with HIV
considered for patients requiring total compared with those without, after and diabetes, preventive health care
pancreatectomy for medically refractory adjusting for age and other risk factors using an approach similar to that used
chronic pancreatitis to prevent postsur- for hearing impairment (75). Low HDL, in patients without HIV is critical to
gical diabetes. Approximately one-third coronary heart disease, peripheral neu- reduce the risks of microvascular and
of patients undergoing total pancreatec- ropathy, and general poor health have macrovascular complications.
tomy with islet autotransplantation are been reported as risk factors for hearing For patients with HIV and ARV-associated
insulin free 1 year postoperatively, and impairment for people with diabetes, hyperglycemia, it may be appropriate to
observational studies from different cen- but an association of hearing loss with consider discontinuing the problematic
ters have demonstrated islet graft func- blood glucose levels has not been ARV agents if safe and effective alter-
tion up to a decade after the surgery in consistently observed (76). In the Di- natives are available (82). Before making
some patients (65–69). Both patient and abetes Control and Complications Trial/ ARV substitutions, carefully consider
disease factors should be carefully con- Epidemiology of Diabetes Interventions the possible effect on HIV virological
sidered when deciding the indications and Complications (DCCT/EDIC) cohort, control and the potential adverse ef-
and timing of this surgery. Surgeries time-weighted mean A1C was associated fects of new ARV agents. In some cases,
should be performed in skilled facilities with increased risk of hearing impairment antihyperglycemic agents may still be
that have demonstrated expertise in islet when tested after long-term (.20 years) necessary.
autotransplantation. follow-up (77). Impairment in smell, but
not taste, has also been reported in in- Low Testosterone in Men
Fractures
dividuals with diabetes (78).
Recommendation
Age-specific hip fracture risk is signifi- 4.18 In men with diabetes who have
cantly increased in both people with HIV symptoms or signs of hypogo-
type 1 diabetes (relative risk 6.3) and Recommendation nadism, such as decreased sex-
those with type 2 diabetes (relative risk 4.17 Patients with HIV should be ual desire (libido) or activity, or
1.7) in both sexes (70). Type 1 diabetes is screened for diabetes and pre- erectile dysfunction, consider
associated with osteoporosis, but in type 2 diabetes with a fasting glucose screening with a morning se-
diabetes, an increased risk of hip fracture test before starting antiretroviral rum testosterone level. B
is seen despite higher bone mineral den- therapy, at the time of switching
sity (BMD) (71). In three large observa- antiretroviral therapy, and 3–6 Mean levels of testosterone are lower
tional studies of older adults, femoral neck months after starting or switch- in men with diabetes compared with age-
BMD T score and the World Health ing antiretroviral therapy. If ini- matched men without diabetes, but
Organization Fracture Risk Assessment tial screening results are normal, obesity is a major confounder (83,84).
Tool (FRAX) score were associated with fasting glucose should be checked Treatment in asymptomatic men is con-
hip and nonspine fractures. Fracture annually. E troversial. Testosterone replacement in
risk was higher in participants with
men with symptomatic hypogonadism
diabetes compared with those without Diabetes risk is increased with certain may have benefits including improved
diabetes for a given T score and age or protease inhibitors (PIs) and nucleoside sexual function, well-being, muscle mass
for a given FRAX score (72). Providers reverse transcriptase inhibitors (NRTIs). and strength, and bone density (85). In
should assess fracture history and risk New-onset diabetes is estimated to men with diabetes who have symp-
factors in older patients with diabetes occur in more than 5% of patients toms or signs of low testosterone
and recommend measurement of BMD infected with HIV on PIs, whereas (hypogonadism), a morning total testos-
if appropriate for the patient’s age and more than 15% may have prediabetes terone level should be measured using
sex. Fracture prevention strategies for (79). PIs are associated with insulin an accurate and reliable assay. In men
people with diabetes are the same resistance and may also lead to apo- who have total testosterone levels close
as for the general population and in- ptosis of pancreatic b-cells. NRTIs also to the lower limit, it is reasonable to check
clude vitamin D supplementation. For
affect fat distribution (both lipohyper- sex hormone–binding globulin, as it is
patients with type 2 diabetes with fracture
trophy and lipoatrophy), which is asso- often low in diabetes and associated with
risk factors, thiazolidinediones (73) and
ciated with insulin resistance. lower testosterone levels. Further test-
sodium–glucose cotransporter 2 inhibi-
Individuals with HIV are at higher risk ing (such as luteinizing hormone and
tors (74) should be used with caution.
for developing prediabetes and diabetes follicle-stimulating hormone levels) may
on antiretroviral (ARV) therapies, so a be needed to determine if the patient
Sensory Impairment screening protocol is recommended (80). has hypogonadism. Testosterone re-
Hearing impairment, both in high-frequency The A1C test may underestimate glyce- placement in older men with hypogonad-
and low- to mid-frequency ranges, is more mia in people with HIV; it is not recom- ism has been associated with increased
common in people with diabetes than in mended for diagnosis and may present coronary artery plaque volume and, in
those without, perhaps due to neuropathy challenges for monitoring (81). In those some studies, an increase in cardiovas-
and/or vascular disease. In a National Health with prediabetes, weight loss through cular events, which should be considered
and Nutrition Examination Survey (NHANES) healthy nutrition and physical activity when assessing the risks and benefits of
analysis, hearing impairment was about may reduce the progression toward treatment (86,87).
care.diabetesjournals.org Comprehensive Medical Evaluation and Assessment of Comorbidities S45
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S48 Diabetes Care Volume 43, Supplement 1, January 2020
judgmental words with increased feelings lower A1C (14,16–18), lower self-reported
implementation, medical nutri-
of shame and guilt, providers are encour- weight (19,20), improved quality of life
tion therapy, and well-being: at
aged to consider the impact that language (17,21), reduced all-cause mortality risk
diagnosis, annually, when com-
has on building therapeutic relationships (22), healthy coping (5,23), and reduced
plicating factors arise, and when
and to choose positive, strength-based health care costs (24–26). Better out-
transitions in care occur. E
words and phrases that put people first comes were reported for DSMES inter-
5.3 Clinical outcomes, health status,
(4,10). Patient performance of self-man- ventions that were over 10 h in total
and well-being are key goals of
agement behaviors, as well as psychosocial duration (18), included ongoing support
diabetes self-management edu-
factors with the potential to impact the (12,27), were culturally (28,29) and age
cation and support that should
person’s self-management, should be appropriate (30,31), were tailored to
be measured as part of routine
monitored. Please see Section 4 “Compre- individual needs and preferences, and
care. C
hensive Medical Evaluation and Assess- addressed psychosocial issues and incor-
5.4 Diabetes self-management edu-
ment of Comorbidities”(https://doi.org/ porated behavioral strategies (13,23,32,33).
cation and support should be pa-
10.2337/dc20-S004) for more on use of Individual and group approaches are
tient centered, may be given in
language. effective (20,34,35), with a slight ben-
group or individual settings and/
DSMES and the current national stan- efit realized by those who engage in
or use technology, and should be
dards guiding it (2,11) are based on evi- both (18).
communicated with the entire
dence of benefit. Specifically, DSMES Emerging evidence demonstrates the
diabetes care team. A
helps people with diabetes to identify benefit of internet-based DSMES services
5.5 Because diabetes self-management
and implement effective self-management for diabetes prevention and the man-
educationandsupportcanimprove
strategies and cope with diabetes at four agement of type 2 diabetes (36–38).
outcomes and reduce costs B,
critical time points (see below) (2). On- Technology-enabled diabetes self-man-
reimbursement by third-party
going DSMES helps people with diabetes agement solutions improve A1C most
payers is recommended. C
to maintain effective self-management effectively when there is two-way com-
throughout a lifetime of diabetes as they munication between the patient and the
Diabetes self-management education face new challenges and as advances in health care team, individualized feed-
and support (DSMES) services facilitate treatment become available (12). back, use of patient-generated health
the knowledge, decision-making, and Four critical time points have been data, and education (38). Current re-
skills mastery necessary for optimal dia- defined when the need for DSMES is to search supports nurses, dietitians, and
betes self-care and incorporate the be evaluated by the medical care pro- pharmacists as providers of DSMES who
needs, goals, and life experiences of vider and/or multidisciplinary team, may also tailor curriculum to the person’s
the person with diabetes. The overall with referrals made as needed (2): needs (39–41). Members of the DSMES
objectives of DSMES are to support in- team should have specialized clinical
formed decision-making, self-care be- 1. At diagnosis knowledge in diabetes and behavior
havior, problem-solving, and active 2. Annually for assessment of education, change principles. Certification as a diabetes
collaboration with the health care nutrition, and emotional needs educator (see www.ncbde.org) and/or
team to improve clinical outcomes, 3. When new complicating factors (health board certification in advanced diabetes
health status, and well-being in a cost- conditions, physical limitations, emo- management (see www.diabeteseducator
effective manner (2). Providers are en- tional factors, or basic living needs) .org/education/certification/bc_adm) dem-
couraged to consider the burden of arise that influence self-management onstrates an individual’s specialized training
treatment and the patient’s level of 4. When transitions in care occur in and understanding of diabetes manage-
confidence/self-efficacy for management ment and support. (11). Additionally, there
behaviors as well as the level of social and DSMES focuses on supporting patient is growing evidence for the role of com-
family support when providing DSMES. empowerment by providing people munity health workers (42,43), as well as
Patient performance of self-manage- with diabetes the tools to make informed peer (42–46) and lay leaders (47), in pro-
ment behaviors, including its effect on self-management decisions (13). Diabe- viding ongoing support.
clinical outcomes, health status, and tes care has shifted to an approach that DSMES is associated with an increased
quality of life, as well as the psychosocial places the person with diabetes and his use of primary care and preventive ser-
factors impacting the person’s ability or her family/support system at the center vices (24,48,49) and less frequent use of
to self-manage should be monitored as of the care model, working in collaboration acute care and inpatient hospital services
part of routine clinical care. A randomized with health care professionals. Patient- (19). Patients who participate in DSMES
controlled trial testing a decision-making centered care is respectful of and respon- are more likely to follow best practice
education and skill-building program (8) sive to individual patient preferences, treatment recommendations, particu-
showed that addressing these targets needs, and values. It ensures that patient larly among the Medicare population,
improved health outcomes in a popu- values guide all decision-making (14). and have lower Medicare and insurance
lation in need of health care resources. claim costs (25,48). Despite these bene-
Furthermore, following a DSMES cur- Evidence for the Benefits fits, reports indicate that only 5–7%
riculum improves quality of care (9). Studies have found that DSMES is of individuals eligible for DSMES through
In addition, in response to the grow- associated with improved diabetes Medicare or a private insurance plan
ing literature that associates potentially knowledge and self-care behaviors (14,15), actually receive it (50,51). This low
S50 Facilitating Behavior Change and Well-being to Improve Health Outcomes Diabetes Care Volume 43, Supplement 1, January 2020
participation may be due to lack of with A1C decreases of 1.0–1.9% for peo- team be knowledgeable about nutrition
referral or other identified barriers ple with type 1 diabetes (57) and 0.3– therapy principles for people with all
such as logistical issues (accessibility, 2.0% for people with type 2 diabetes (57). types of diabetes and be supportive of
timing, costs) and the lack of a perceived See Table 5.1 for specific nutrition rec- their implementation. Members of the
benefit (52). Thus, in addition to educat- ommendations. Because of the progres- health care team should complement
ing referring providers about the benefits sive nature of type 2 diabetes, behavior MNT by providing evidence-based guid-
of DSMES and the critical times to refer modification alone may not be adequate ance that helps people with diabetes
(2), alternative and innovative models to maintain euglycemia over time. How- make healthy food choices that meet
of DSMES delivery need to be explored ever, after medication is initiated, nu- their individualized needs and improve
and evaluated. trition therapy continues to be an overall health. A variety of eating pat-
important component and should be terns are acceptable for the management
Reimbursement integrated with the overall treatment of diabetes (41,58,60). Until the evidence
Medicare reimburses DSMES when that plan (55). surrounding comparative benefits of dif-
service meets the national standards ferent eating patterns in specific individ-
(2,11) and is recognized by the Ameri- Goals of Nutrition Therapy for Adults uals strengthens, health care providers
can Diabetes Association (ADA) or other With Diabetes should focus on the key factors that are
approval bodies. DSMES is also covered 1. To promote and support healthful common among the patterns: 1) empha-
by most health insurance plans. Ongoing eating patterns, emphasizing a variety size nonstarchy vegetables, 2) minimize
support has been shown to be instru- of nutrient-dense foods in appropri- added sugars and refined grains, and 3)
mental for improving outcomes when ate portion sizes, to improve overall choose whole foods over highly pro-
it is implemented after the completion health and: cessed foods to the extent possible
of education services. DSMES is fre- c achieve and maintain body weight (41). An individualized eating pattern
quently reimbursed when performed goals also considers the individual’s health
in person. However, although DSMES c attain individualized glycemic, blood status, skills, resources, food preferen-
can also be provided via phone calls pressure, and lipid goals ces, and health goals. Referral to an RD/
and telehealth, these remote versions c delay or prevent the complications RDN is essential to assess the overall
may not always be reimbursed. Changes of diabetes nutrition status of, and to work collab-
in reimbursement policies that increase 2. To address individual nutrition needs oratively with, the patient to create
DSMES access and utilization will result based on personal and cultural pref- a personalized meal plan that coordi-
in a positive impact to beneficiaries’ erences, health literacy and numeracy, nates and aligns with the overall treat-
clinical outcomes, quality of life, health access to healthful foods, willingness ment plan, including physical activity
care utilization, and costs (53,54). and ability to make behavioral changes, and medication use. The Mediterranean-
and existing barriers to change style (61,62), low-carbohydrate (63–
MEDICAL NUTRITION THERAPY 3. To maintain the pleasure of eating by 65), and vegetarian or plant-based
Please refer to the ADA consensus report providing nonjudgmental messages (66,67) eating patterns are all examples
“Nutrition Therapy for Adults With Di- about food choices while limiting of healthful eating patterns that have
abetes or Prediabetes: A Consensus Re- food choices only when indicated shown positive results in research, but
port” for more information on nutrition by scientific evidence individualized meal planning should fo-
therapy (41). For many individuals with 4. To provide an individual with diabe- cus on personal preferences, needs, and
diabetes, the most challenging part of tes the practical tools for developing goals. Reducing overall carbohydrate in-
the treatment plan is determining what healthy eating patterns rather than take for individuals with diabetes has
to eat. There is not a “one-size-fits-all” focusing on individual macronutrients, demonstrated the most evidence for
eating pattern for individuals with diabe- micronutrients, or single foods improving glycemia and may be applied
tes, and meal planning should be individ- in a variety of eating patterns that meet
ualized. Nutrition therapy plays an Eating Patterns, Macronutrient individual needs and preferences. For
integral role in overall diabetes manage- Distribution, and Meal Planning individuals with type 2 diabetes not
ment, and each person with diabetes Evidence suggests that there is not an meeting glycemic targets or for whom
should be actively engaged in education, ideal percentage of calories from carbo- reducing glucose-lowering drugs is a
self-management, and treatment plan- hydrate, protein, and fat for people with priority, reducing overall carbohydrate
ning with his or her health care team, diabetes. Therefore, macronutrient dis- intake with a low- or very-low-carbohy-
including the collaborative development tribution should be based on an individ- drate eating pattern is a viable option
of an individualized eating plan (41,55). ualized assessment of current eating (63–65). As research studies on some
All individuals with diabetes should be patterns, preferences, and metabolic low-carbohydrate eating plans generally
referred for individualized MNT provided goals. Consider personal preferences indicate challenges with long-term sus-
by a registered dietitian nutritionist (RD/ (e.g., tradition, culture, religion, health tainability, it is important to reassess and
RDN) who is knowledgeable and skilled beliefs and goals, economics) as well as individualize meal plan guidance regu-
in providing diabetes-specific MNT (56) metabolic goals when working with in- larly for those interested in this ap-
at diagnosis and as needed throughout dividuals to determine the best eating proach. This eating pattern is not
the life span, similar to DSMES. MNT pattern for them (41,58,59). It is impor- recommended at this time for women
delivered by an RD/RDN is associated tant that each member of the health care who are pregnant or lactating, people
care.diabetesjournals.org Facilitating Behavior Change and Well-being to Improve Health Outcomes S51
with or at risk for disordered eating, or involving both aerobic and resistance importance of providing guidance on
people who have renal disease, and it exercise (73,76,77) and a healthy eating an individualized meal plan containing
should be used with caution in patients plan, such as a Mediterranean-style eating nutrient-dense foods, such as vegeta-
taking sodium–glucose cotransporter pattern (78). bles, fruits, legumes, dairy, lean sources
2 inhibitors due to the potential risk For many individuals with overweight of protein (including plant-based sources
of ketoacidosis (68,69). There is inade- and obesity with type 2 diabetes, 5% as well as lean meats, fish, and poultry),
quate research in type 1 diabetes to weight loss is needed to achieve bene- nuts, seeds, and whole grains, cannot be
support one eating pattern over another ficial outcomes in glycemic control, lipids, overemphasized (92), as well as guidance
at this time. and blood pressure (79). It should be on achieving the desired energy deficit
The diabetes plate method is com- noted, however, that the clinical benefits (93–96). Any approach to meal planning
monly used for providing basic meal of weight loss are progressive, and more should be individualized considering the
planning guidance (70) and provides a intensive weight loss goals (i.e., 15%) may health status, personal preferences, and
visual guide showing how to portion be appropriate to maximize benefit de- ability of the person with diabetes to
calories (featuring a 9-inch plate) and pending on need, feasibility, and safety sustain the recommendations in the plan.
carbohydrates (by limiting them to what (80,81). In select individuals with type 2
fits in one-quarter of the plate) and places diabetes, an overall healthy eating plan Carbohydrates
an emphasis on low-carbohydrate (or non- that results in energy deficit in conjunc- Studies examining the ideal amount
starchy) vegetables. Providing a visual/ tion with weight loss medications and/or of carbohydrate intake for people with
small graphic of the diabetes plate method metabolic surgery should be considered diabetes are inconclusive, although mon-
is preferred, as descriptions of the concept to help achieve weight loss and mainte- itoring carbohydrate intake and con-
can be confusing when unfamiliar. nance goals, lower A1C, and reduce CVD sidering the blood glucose response to
risk (82–84). Overweight and obesity dietary carbohydrate are key for improv-
Weight Management are also increasingly prevalent in people ing postprandial glucose management
Management and reduction of weight with type 1 diabetes and present clinical (97,98). The literature concerning gly-
is important for people with type 1 di- challenges regarding diabetes treatment cemic index and glycemic load in in-
abetes, type 2 diabetes, or prediabetes and CVD risk factors (85,86). Sustaining dividuals with diabetes is complex, often
and overweight or obesity. To support weight loss can be challenging (79,87) but yielding mixed results, though in some
weight loss and improve A1C, cardio- has long-term benefits; maintaining studies lowering the glycemic load of
vascular disease (CVD) risk factors, and weight loss for 5 years is associated consumed carbohydrates has demon-
well-being in adults with overweight/ with sustained improvements in A1C and strated A1C reductions of 0.2% to 0.5%
obesity and prediabetes or diabetes, lipid levels (88). MNT guidance from an (99,100). Studies longer than 12 weeks
MNT and DSMES services should include RD/RDN with expertise in diabetes and report no significant influence of glycemic
an individualized eating plan in a format weight management, throughout the index or glycemic load independent of
that results in an energy deficit in com- course of a structured weight loss plan, weight loss on A1C; however, mixed
bination with enhanced physical activ- is strongly recommended. results have been reported for fasting
ity (41). Lifestyle intervention programs People with diabetes and prediabetes glucose levels and endogenous insulin
should be intensive and have frequent should be screened and evaluated during levels.
follow-up to achieve significant reduc- DSMES and MNT encounters for disor- Reducing overall carbohydrate intake
tions in excess body weight and improve dered eating, and nutrition therapy for individuals with diabetes has dem-
clinical indicators. There is strong and should be individualized to accommo- onstrated evidence for improving gly-
consistent evidence that modest persis- date disorders (41). Disordered eating cemia and may be applied in a variety
tent weight loss can delay the progres- can make following an eating plan chal- of eating patterns that meet individ-
sion from prediabetes to type 2 diabetes lenging, and individuals should be re- ual needs and preferences (41). For
(58,71,72) (see Section 3 “Prevention or ferred to a mental health professional as people with type 2 diabetes or predia-
Delay of Type 2 Diabetes,” https://doi needed. Studies have demonstrated that betes, low-carbohydrate eating plans
.org/10.2337/dc20-S003) and is benefi- a variety of eating plans, varying in mac- show potential to improve glycemia
cial to the management of type 2 diabe- ronutrient composition, can be used and lipid outcomes for up to 1 year
tes (see Section 8 “Obesity Management effectively and safely in the short term (63,65,90,101–104). Part of the chal-
for the Treatment of Type 2 Diabetes,” (1–2 years) to achieve weight loss in lenge in interpreting low-carbohydrate
https://doi.org/10.2337/dc20-S008). people with diabetes. This includes struc- research has been due to the wide range
In prediabetes, the weight loss goal tured low-calorie meal plans with meal of definitions for a low-carbohydrate
is 7–10% for preventing progression to replacements (80,88,89) and the Medit- eating plan (65,100). As research stud-
type 2 diabetes (73). In conjunction erranean-style eating pattern (78), as well ies on low-carbohydrate eating plans
with lifestyle therapy, medication-assisted as low-carbohydrate meal plans (90). generally indicate challenges with long-
weight loss can be considered for peo- However, no single approach has been term sustainability, it is important to
ple at risk for type 2 diabetes when proven to be consistently superior reassess and individualize meal plan
needed to achieve and sustain 7–10% (41,91,92), and more data are needed guidance regularly for those interested
weight loss (74,75). People with predia- to identify and validate those meal plans in this approach. Providers should main-
betes at a healthy weight should also that are optimal with respect to long-term tain consistent medical oversight and
be considered for lifestyle intervention outcomes and patient acceptability. The recognize that certain groups are not
care.diabetesjournals.org Facilitating Behavior Change and Well-being to Improve Health Outcomes S53
appropriate for low-carbohydrate eating and/or high-protein mixed meals is is not an ideal percentage of calories
plans, including women who are preg- recommended to address delayed hy- from fat for people with or at risk for
nant or lactating, children, and people perglycemia that may occur 3 h or more diabetes and that macronutrient distri-
who have renal disease or disordered after eating (41). Checking glucose 3 h bution should be individualized accord-
eating behavior, and these plans should after eating may help to determine if ing to the patient’s eating patterns,
be used with caution in those taking additional insulin adjustments are required preferences, and metabolic goals (41).
sodium–glucose cotransporter 2 inhibitors (112,113). Continuous glucose monitoring The type of fats consumed is more im-
because of the potential risk of ketoacidosis or self-monitoring of blood glucose portant than total amount of fat when
(68,69). There is inadequate research should guide decision making for admin- looking at metabolic goals and CVD
about dietary patterns for type 1 diabe- istration of additional insulin. For indi- risk, and it is recommended that the
tes to support one eating plan over viduals on a fixed daily insulin schedule, percentage of total calories from satu-
another at this time. meal planning should emphasize a rel- rated fats should be limited (78,105,
Most individuals with diabetes re- atively fixed carbohydrate consump- 119–121). Multiple randomized con-
port a moderate intake of carbohydrate tion pattern with respect to both time trolled trials including patients with
(44–46% of total calories) (58). Efforts and amount, while considering insulin type 2 diabetes have reported that a
to modify habitual eating patterns are action time (41). Mediterranean-style eating pattern (78,
often unsuccessful in the long term; 122–127), rich in polyunsaturated and
people generally go back to their usual Protein monounsaturated fats, can improve both
macronutrient distribution (58). Thus, There is no evidence that adjusting the glycemic management and blood lipids.
the recommended approach is to indi- daily level of protein intake (typically 1– However, supplements do not seem to
vidualize meal plans to meet caloric goals 1.5 g/kg body wt/day or 15–20% total have the same effects as their whole-
with a macronutrient distribution that is calories) will improve health in individ- food counterparts. A systematic review
more consistent with the individual’s uals without diabetic kidney disease, and concluded that dietary supplements
usual intake to increase the likelihood research is inconclusive regarding the with n-3 fatty acids did not improve
for long-term maintenance. ideal amount of dietary protein to opti- glycemic management in individuals
As for all individuals in developed mize either glycemic management or with type 2 diabetes (99). Randomized
countries, both children and adults CVD risk (99,114). Therefore, protein controlled trials also do not support
with diabetes are encouraged to mini- intake goals should be individualized recommending n-3 supplements for pri-
mize intake of refined carbohydrates and based on current eating patterns. mary or secondary prevention of CVD
added sugars and instead focus on carbo- Some research has found successful (128–132). People with diabetes should
hydrates from vegetables, legumes, fruits, management of type 2 diabetes with be advised to follow the guidelines for
dairy (milk and yogurt), and whole grains. meal plans including slightly higher levels the general population for the recom-
The consumption of sugar-sweetened of protein (20–30%), which may contrib- mended intakes of saturated fat, die-
beverages (including fruit juices) and pro- ute to increased satiety (115). tary cholesterol, and trans fat (105). In
cessed food products with high amounts Those with diabetic kidney disease general, trans fats should be avoided.
of refined grains and added sugars is (with albuminuria and/or reduced esti- In addition, as saturated fats are progres-
strongly discouraged (105–107). mated glomerular filtration rate) should sively decreased in the diet, they should
Individuals with type 1 or type 2 di- aim to maintain dietary protein at the be replaced with unsaturated fats and not
abetes taking insulin at mealtime should recommended daily allowance of 0.8 g/kg with refined carbohydrates (126).
be offered intensive and ongoing edu- body wt/day. Reducing the amount of
cation on the need to couple insulin dietary protein below the recommended Sodium
administration with carbohydrate intake. daily allowance is not recommended be- As for the general population, people
For people whose meal schedule or car- cause it does not alter glycemic meas- with diabetes are advised to limit their
bohydrate consumption is variable, reg- ures, cardiovascular risk measures, or the sodium consumption to ,2,300 mg/day
ular counseling to help them understand rate at which glomerular filtration rate (41). Restriction below 1,500 mg, even
the complex relationship between car- declines (116,117). for those with hypertension, is generally
bohydrate intake and insulin needs In individuals with type 2 diabetes, not recommended (133–135). Sodium
is important. In addition, education on protein intake may enhance or increase intake recommendations should take
using the insulin-to-carbohydrate ratios the insulin response to dietary carbohy- into account palatability, availability, af-
for meal planning can assist them with drates (118). Therefore, use of carbohy- fordability, and the difficulty of achiev-
effectively modifying insulin dosing from drate sources high in protein (such as ing low-sodium recommendations in a
meal to meal and improving glycemic milk and nuts) to treat or prevent hypo- nutritionally adequate diet (136).
management (58,97,108–111). Results glycemia should be avoided due to the
from recent high-fat and/or high-protein potential concurrent rise in endogenous Micronutrients and Supplements
mixed meals studies continue to support insulin. There continues to be no clear evidence
previous findings that glucose response of benefit from herbal or nonherbal
to mixed meals high in protein and/or fat Fats (i.e., vitamin or mineral) supplemen-
along with carbohydrate differ among The ideal amount of dietary fat for in- tation for people with diabetes without
individuals; therefore, a cautious approach dividuals with diabetes is controver- underlying deficiencies (41). Metformin
to increasing insulin doses for high-fat sial. New evidence suggests that there is associated with vitamin B12 deficiency
S54 Facilitating Behavior Change and Well-being to Improve Health Outcomes Diabetes Care Volume 43, Supplement 1, January 2020
per a report from the Diabetes Preven- reduce overall calorie and carbohydrate
be interrupted every 30 min for
tion Program Outcomes Study (DPPOS), intake (58). Most systematic reviews and
blood glucose benefits. C
suggesting that periodic testing of vita- meta-analyses show benefits for nonnu-
5.28 Flexibility training and balance
min B12 levels should be considered tritive sweetener use in weight loss
training are recommended 2–3
in patients taking metformin, particularly (142,143); however, some research sug-
times/week for older adults with
in those with anemia or peripheral gests an association with weight gain
diabetes. Yoga and tai chi may
neuropathy (137). Routine supplemen- (144). When use of sugar substitutes
be included based on individual
tation with antioxidants, such as vita- is meant to reduce overall caloric and
preferences to increase flexibil-
mins E and C and carotene, is not advised carbohydrate intake, people should be
ity, muscular strength, and bal-
due to lack of evidence of efficacy and counseled to avoid compensating with
ance. C
concern related to long-term safety. In intake of additional calories from other
addition, there is insufficient evidence to food sources (41). Regulatory agencies
support the routine use of herbal supple- set acceptable daily intake levels for each Physical activity is a general term that
ments and micronutrients, such as cin- nonnutritive sweetener, defined as the includes all movement that increases
namon (138), curcumin, vitamin D (139), amount that can be safely consumed energy use and is an important part of
aloe vera, or chromium, to improve gly- over a person’s lifetime (41,145). For the diabetes management plan. Exercise
cemia in people with diabetes (41,140). those who consume sugar-sweetened is a more specific form of physical activ-
However, for special populations, in- beverages regularly, a low-calorie or ity that is structured and designed to
cluding pregnant or lactating women, nonnutritive-sweetened beverage may improve physical fitness. Both physical
older adults, vegetarians, and people serve as a short-term replacement strat- activity and exercise are important. Ex-
following very low-calorie or low-carbo- egy, but overall, people are encour- ercise has been shown to improve blood
hydrate diets, a multivitamin may be aged to decrease both sweetened and glucose control, reduce cardiovascu-
necessary. nonnutritive-sweetened beverages and lar risk factors, contribute to weight
use other alternatives, with an emphasis loss, and improve well-being (147). Phys-
Alcohol on water intake (146). ical activity is as important for those with
Moderate alcohol intake does not have type 1 diabetes as it is for the general
major detrimental effects on long-term population, but its specific role in the
blood glucose management in people PHYSICAL ACTIVITY prevention of diabetes complications
with diabetes. Risks associated with al- Recommendations
and the management of blood glucose
cohol consumption include hypogly- 5.24 Children and adolescents with is not as clear as it is for those with type 2
cemia and/or delayed hypoglycemia type 1 or type 2 diabetes or diabetes. A recent study suggested that
(particularly for those using insulin or prediabetes should engage in the percentage of people with diabetes
insulin secretagogue therapies), weight 60 min/day or more of moder- who achieved the recommended exer-
gain, and hyperglycemia (for those con- ate- or vigorous-intensity aerobic cise level per week (150 min) varied by
suming excessive amounts) (41,140). activity, with vigorous muscle- race. Objective measurement by accel-
People with diabetes should be educated strengthening and bone-strength- erometer showed that 44.2%, 42.6%, and
about these risks and encouraged to ening activities at least 3 days/ 65.1% of whites, African Americans, and
monitor blood glucose frequently after week. C Hispanics, respectively, met the thresh-
drinking alcohol to minimize such risks. 5.25 Most adults with type 1 C and old (148). It is important for diabetes care
People with diabetes can follow the same type 2 B diabetes should engage management teams to understand the
guidelines as those without diabetes if in 150 min or more of moderate- difficulty that many patients have reach-
they choose to drink. For women, no to vigorous-intensity aerobic ac- ing recommended treatment targets and
more than one drink per day, and for tivity per week, spread over at to identify individualized approaches to
men, no more than two drinks per day is least 3 days/week, with no more improve goal achievement.
recommended (one drink is equal to a than 2 consecutive days without Moderate to high volumes of aerobic
12-oz beer, a 5-oz glass of wine, or 1.5 oz activity. Shorter durations (min- activity are associated with substantially
of distilled spirits). imum 75 min/week) of vigorous- lower cardiovascular and overall mortal-
intensity or interval training may ity risks in both type 1 and type 2 diabetes
Nonnutritive Sweeteners be sufficient for younger and (149). A recent prospective observational
For some people with diabetes who more physically fit individuals. study of adults with type 1 diabetes
are accustomed to sugar-sweetened 5.26 Adults with type 1 C and type 2 B suggested that higher amounts of phys-
products, nonnutritive sweeteners (con- diabetes should engage in 2–3 ical activity led to reduced cardiovascular
taining few or no calories) may be an sessions/week of resistance ex- mortality after a mean follow-up time of
acceptable substitute for nutritive sweet- ercise on nonconsecutive days. 11.4 years for patients with and without
eners (those containing calories, such 5.27 All adults, and particularly those chronic kidney disease (150). Addition-
as sugar, honey, and agave syrup) when with type 2 diabetes, should ally, structured exercise interventions of
consumed in moderation. While use decrease the amount of time at least 8 weeks’ duration have been
of nonnutritive sweeteners does not spent in daily sedentary behav- shown to lower A1C by an average of
appear to have a significant effect on ior. B Prolonged sitting should 0.66% in people with type 2 diabetes,
glycemic management (141), they can even without a significant change in BMI
care.diabetesjournals.org Facilitating Behavior Change and Well-being to Improve Health Outcomes S55
(151). There are also considerable data more than 2 days to elapse between resistance training in older adults with
for the health benefits (e.g., increased exercise sessions, is recommended to type 2 diabetes (169) and for an additive
cardiovascular fitness, greater muscle decrease insulin resistance, regardless benefit of combined aerobic and resis-
strength, improved insulin sensitivity, of diabetes type (161,162). Over time, tance exercise in adults with type 2 di-
etc.) of regular exercise for those with activities should progress in intensity, abetes (170). If not contraindicated,
type 1 diabetes (152). A recent study frequency, and/or duration to at least patients with type 2 diabetes should
suggested that exercise training in type 1 150 min/week of moderate-intensity ex- be encouraged to do at least two weekly
diabetes may also improve several im- ercise. Adults able to run at 6 miles/h sessions of resistance exercise (exercise
portant markers such as triglyceride (9.7 km/h) for at least 25 min can benefit with free weights or weight machines),
level, LDL, waist circumference, and sufficiently from shorter-intensity activ- with each session consisting of at least
body mass (153). Higher levels of exercise ity (75 min/week) (156). Many adults, one set (group of consecutive repetitive
intensity are associated with greater including most with type 2 diabetes, exercise motions) of five or more differ-
improvements in A1C and in fitness would be unable or unwilling to partic- ent resistance exercises involving the
(154). Other benefits include slowing ipate in such intense exercise and should large muscle groups (169).
the decline in mobility among over- engage in moderate exercise for the For type 1 diabetes, although exercise
weight patients with diabetes (155). recommended duration. Adults with di- in general is associated with improve-
The ADA position statement “Physical abetes should engage in 2–3 sessions/ ment in disease status, care needs to be
Activity/Exercise and Diabetes” reviews week of resistance exercise on noncon- taken in titrating exercise with respect
the evidence for the benefits of exercise secutive days (163). Although heavier to glycemic management. Each individ-
in people with type 1 and type 2 diabetes resistance training with free weights ual with type 1 diabetes has a variable
and offers specific recommendation (156). and weight machines may improve glycemic response to exercise. This var-
Physical activity and exercise should be glycemic control and strength (164), iability should be taken into consider-
recommended and prescribed to all indi- resistance training of any intensity is ation when recommending the type
viduals with diabetes as part of manage- recommended to improve strength, and duration of exercise for a given in-
ment of glycemia and overall health. balance, and the ability to engage in dividual (171).
Specific recommendations and precau- activities of daily living throughout the Women with preexisting diabetes,
tions will vary by the type of diabetes, life span. Providers and staff should help particularly type 2 diabetes, and those
age, activity done, and presence of di- patients set stepwise goals toward meet- at risk for or presenting with gestational
abetes-related health complications. ing the recommended exercise targets. diabetes mellitus should be advised to
Recommendations should be tailored As persons intensify their exercise pro- engage in regular moderate physical
to meet the specific needs of each in- gram, medical monitoring may be indi- activity prior to and during their preg-
dividual (156). cated to ensure safety and evaluate the nancies as tolerated (156).
effects on glucose management. (See
Exercise and Children the section PHYSICAL ACTIVITY AND GLYCEMIC Pre-exercise Evaluation
All children, including children with di- CONTROL below) As discussed more fully in Section 10
abetes or prediabetes, should be en- Recent evidence supports that all in- “Cardiovascular Disease and Risk Man-
couraged to engage in regular physical dividuals, including those with diabetes, agement” (https://doi.org/10.2337/
activity. Children should engage in at should be encouraged to reduce the dc20-S010), the best protocol for as-
least 60 min of moderate to vigorous amount of time spent being sedentary sessing asymptomatic patients with
aerobic activity every day with muscle- (e.g., working at a computer, watching diabetes for coronary artery disease re-
and bone-strengthening activities at television) by breaking up bouts of sed- mains unclear. The ADA consensus report
least 3 days per week (157). In general, entary activity (.30 min) by briefly “Screening for Coronary Artery Disease in
youth with type 1 diabetes benefit from standing, walking, or performing other Patients With Diabetes” (172) concluded
being physically active, and an active light physical activities (165,166). Avoid- that routine testing is not recommended.
lifestyle should be recommended to ing extended sedentary periods may help However, providers should perform a
all (158). Youth with type 1 diabetes prevent type 2 diabetes for those at risk careful history, assess cardiovascular
who engage in more physical activity and may also aid in glycemic control for risk factors, and be aware of the atypical
may have better health outcomes those with diabetes. presentation of coronary artery disease
and health-related quality of life (159, A wide range of activities, including in patients with diabetes. Certainly, high-
160). yoga, tai chi, and other types, can have risk patients should be encouraged to
significant impacts on A1C, flexibility, start with short periods of low-intensity
Frequency and Type of Physical muscle strength, and balance (147, exercise and slowly increase the inten-
Activity 167,168). Flexibility and balance exercises sity and duration as tolerated. Providers
People with diabetes should perform may be particularly important in older should assess patients for conditions
aerobic and resistance exercise regularly adults with diabetes to maintain range that might contraindicate certain types
(156). Aerobic activity bouts should ide- of motion, strength, and balance (156). of exercise or predispose to injury, such as
ally last at least 10 min, with the goal of uncontrolled hypertension, untreated
;30 min/day or more, most days of the Physical Activity and Glycemic Control proliferative retinopathy, autonomic
week for adults with type 2 diabetes. Clinical trials have provided strong evi- neuropathy, peripheral neuropathy, and
Daily exercise, or at least not allowing dence for the A1C-lowering value of a history of foot ulcers or Charcot foot. The
S56 Facilitating Behavior Change and Well-being to Improve Health Outcomes Diabetes Care Volume 43, Supplement 1, January 2020
patient’s age and previous physical activity an ophthalmologist prior to engaging SMOKING CESSATION: TOBACCO
level should be considered. The provider in an intense exercise regimen may be AND E-CIGARETTES
should customize the exercise regimen appropriate. Recommendations
to the individual’s needs. Those with 5.29 Advise all patients not to use
Peripheral Neuropathy
complications may require a more thorough cigarettes and other tobacco
Decreased pain sensation and a higher
evaluation prior to beginning an exer- products A or e-cigarettes. A
pain threshold in the extremities can
cise program (171). 5.30 After identification of tobacco or
result in an increased risk of skin break-
down, infection, and Charcot joint de- e-cigarette use, include smoking
Hypoglycemia struction with some forms of exercise. cessation counseling and other
In individuals taking insulin and/or insulin forms of treatment as a routine
Therefore, a thorough assessment
secretagogues, physical activity may component of diabetes care. A
should be done to ensure that neurop-
cause hypoglycemia if the medication
athy does not alter kinesthetic or pro-
dose or carbohydrate consumption is Results from epidemiological, case-
not altered. Individuals on these thera- prioceptive sensation during physical control, and cohort studies provide con-
pies may need to ingest some added activity, particularly in those with more vincing evidence to support the causal
carbohydrate if pre-exercise glucose lev- severe neuropathy. Studies have shown link between cigarette smoking and
els are ,90 mg/dL (5.0 mmol/L), depend- that moderate-intensity walking may health risks (178). Recent data show
ing on whether they are able to lower not lead to an increased risk of foot tobacco use is higher among adults
insulin doses during the workout (such ulcers or reulceration in those with with chronic conditions (179) as well as
as with an insulin pump or reduced pre- peripheral neuropathy who use proper in adolescents and young adults with
exercise insulin dosage), the time of day footwear (174). In addition, 150 min/week diabetes (180). Smokers with diabetes
exercise is done, and the intensity and of moderate exercise was reported to (and people with diabetes exposed to
duration of the activity (156,171). In improve outcomes in patients with pre- second-hand smoke) have a height-
some patients, hypoglycemia after diabetic neuropathy (175). All individuals ened risk of CVD, premature death,
exercise may occur and last for several with peripheral neuropathy should wear microvascular complications, and worse
hours due to increased insulin sensitivity. glycemic control when compared with
proper footwear and examine their feet
Hypoglycemia is less common in patients nonsmokers (181–183). Smoking may
daily to detect lesions early. Anyone
with diabetes who are not treated with have a role in the development of type 2
with a foot injury or open sore should
insulin or insulin secretagogues, and no diabetes (184–187).
routine preventive measures for hypo- be restricted to non–weight-bearing
The routine and thorough assessment
glycemia are usually advised in these activities.
of tobacco use is essential to prevent
cases. Intense activities may actually Autonomic Neuropathy smoking or encourage cessation. Numer-
raise blood glucose levels instead of Autonomic neuropathy can increase the ous large randomized clinical trials have
lowering them, especially if pre-exercise risk of exercise-induced injury or ad- demonstrated the efficacy and cost-
glucose levels are elevated (152). Be- verse events through decreased cardiac effectiveness of brief counseling in
cause of the variation in glycemic re- responsiveness to exercise, postural hy- smoking cessation, including the use of
sponse to exercise bouts, patients need potension, impaired thermoregulation, telephone quit lines, in reducing tobacco
to be educated to check blood glucose impaired night vision due to impaired use. Pharmacologic therapy to assist with
levels before and after periods of ex- papillary reaction, and greater suscepti- smoking cessation in people with diabe-
ercise and about the potential pro- bility to hypoglycemia (176). Cardiovas- tes has been shown to be effective (188),
longed effects (depending on intensity and for the patient motivated to quit, the
cular autonomic neuropathy is also an
and duration) (see the section DIABETES addition of pharmacologic therapy to
independent risk factor for cardiovascu-
SELF-MANAGEMENT EDUCATION AND SUPPORT
lar death and silent myocardial ischemia counseling is more effective than either
above).
(177). Therefore, individuals with diabetic treatment alone (189). Special consider-
autonomic neuropathy should undergo ations should include assessment of level
Exercise in the Presence of of nicotine dependence, which is asso-
cardiac investigation before beginning
Microvascular Complications ciated with difficulty in quitting and re-
See Section 11 “Microvascular Compli- physical activity more intense than
that to which they are accustomed. lapse (190). Although some patients may
cations and Foot Care” (https://doi.org/ gain weight in the period shortly after
10.2337/dc20-S011) for more informa- Diabetic Kidney Disease
smoking cessation (191), recent research
tion on these long-term complications. Physical activity can acutely increase has demonstrated that this weight gain
urinary albumin excretion. However, does not diminish the substantial CVD
Retinopathy
If proliferative diabetic retinopathy or there is no evidence that vigorous- benefit realized from smoking cessation
severe nonproliferative diabetic retinop- intensity exercise accelerates the rate (192). One study in smokers with newly
athy is present, then vigorous-intensity of progression of diabetic kidney disease, diagnosed type 2 diabetes found that
aerobic or resistance exercise may be and there appears to be no need for smoking cessation was associated with
contraindicated because of the risk of specific exercise restrictions for people amelioration of metabolic parameters
triggering vitreous hemorrhage or ret- with diabetic kidney disease in general and reduced blood pressure and albu-
inal detachment (173). Consultation with (173). minuria at 1 year (193).
care.diabetesjournals.org Facilitating Behavior Change and Well-being to Improve Health Outcomes S57
In recent years e-cigarettes have multifaceted issues when integrating as feeling overwhelmed or stressed by
gained public awareness and popularity diabetes care into daily life (11). having diabetes (see the section DIABETES
because of perceptions that e-cigarette Emotional well-being is an important DISTRESS below), changes in finances, or
use is less harmful than regular cigarette part of diabetes care and self-management. competing medical demands (e.g., the
smoking (194,195). However, in light of Psychological and social problems can diagnosis of a comorbid condition). In
recent Centers for Disease Control and impair the individual’s (11,197–201) or circumstances where persons other
Prevention evidence (196) of deaths re- family’s (200) ability to carry out di- than the patient are significantly in-
lated to e-cigarette use, no persons abetes care tasks and therefore poten- volved in diabetes management, these
should be advised to use e-cigarettes, tially compromise health status. There issues should be explored with non-
either as a way to stop smoking tobacco are opportunities for the clinician to medical care providers (205). Standard-
or as a recreational drug. routinely assess psychosocial status ized and validated tools for psychosocial
in a timely and efficient manner for monitoring and assessment can also be
PSYCHOSOCIAL ISSUES
referral to appropriate services (202, used by providers (1), with positive
Recommendations 203). A systematic review and meta- findings leading to referral to a mental
5.31 Psychosocial care should be in- analysis showed that psychosocial in- health provider specializing in diabetes
tegrated with a collaborative, terventions modestly but significantly for comprehensive evaluation, diagno-
patient-centered approach and improved A1C (standardized mean dif- sis, and treatment.
provided to all people with di- ference –0.29%) and mental health out-
Diabetes Distress
abetes, with the goals of opti- comes (204). However, there was a
mizing health outcomes and limited association between the effects Recommendation
health-related quality of life. A on A1C and mental health, and no in- 5.35 Routinely monitor people with
5.32 Psychosocial screening and tervention characteristics predicted ben- diabetes for diabetes distress,
follow-up may include, but are efit on both outcomes. particularly when treatment
not limited to, attitudes about targets are not met and/or at
diabetes, expectations for med- Screening the onset of diabetes complica-
ical management and outcomes, Key opportunities for psychosocial screen- tions. B
affect or mood, general and ing occur at diabetes diagnosis, during
diabetes-related quality of life, regularly scheduled management visits, Diabetes distress is very common and is
available resources (financial, during hospitalizations, with new onset distinct from other psychological disor-
social, and emotional), and psy- of complications, during significant tran- ders (207–209). Diabetes distress refers
chiatric history. E sitions in care such as from pediatric to to significant negative psychological re-
5.33 Providers should consider assess- adult care teams (205), or when prob- actions related to emotional burdens and
ment for symptoms of diabetes lems with achieving A1C goals, quality of worries specific to an individual’s expe-
distress, depression, anxiety, dis- life, or self-management are identified rience in having to manage a severe,
ordered eating, and cognitive (2). Patients are likely to exhibit psycho- complicated, and demanding chronic
capacities using appropriate logical vulnerability at diagnosis, when disease such as diabetes (208–210).
standardized and validated tools their medical status changes (e.g., end The constant behavioral demands (med-
at the initial visit, at periodic of the honeymoon period), when the ication dosing, frequency, and titration;
intervals, and when there is a need for intensified treatment is ev- monitoring blood glucose, food intake,
change in disease, treatment, or ident, and when complications are dis- eating patterns, and physical activity) of
life circumstance. Including care- covered. Significant changes in life diabetes self-management and the po-
givers and family members in this circumstances, often called social deter- tential or actuality of disease progression
assessment is recommended. B minants of health, are known to con- are directly associated with reports of
5.34 Consider screening older adults siderably affect a person’s ability to diabetes distress (208). The prevalence
(aged $65 years) with diabetes self-manage their illness. Thus, screen- of diabetes distress is reported to be 18–
for cognitive impairment and ing for social determinants of health 45% with an incidence of 38–48% over
depression. B (e.g., loss of employment, birth of a child, 18 months in persons with type 2 di-
or other family-based stresses) should abetes (210). In the second Diabetes
Please refer to the ADA position state- also be incorporated into routine care Attitudes, Wishes and Needs (DAWN2)
ment “Psychosocial Care for People With (206). study, significant diabetes distress was
Diabetes” for a list of assessment tools Providers can start with informal ver- reported by 45% of the participants, but
and additional details (1). bal inquires, for example, by asking only 24% reported that their health care
Complex environmental, social, be- whether there have been persistent teams asked them how diabetes affected
havioral, and emotional factors, known changes in mood during the past 2 weeks their lives (207). High levels of diabetes
as psychosocial factors, influence living or since the patient’s last visit and distress significantly impact medication-
with diabetes, both type 1 and type 2, whether the person can identify a trig- taking behaviors and are linked to higher
and achieving satisfactory medical out- gering event or change in circumstan- A1C, lower self-efficacy, and poorer
comes and psychological well-being. ces. Providers should also ask whether dietary and exercise behaviors (5,208,210).
Thus, individuals with diabetes and their there are new or different barriers to DSMES has been shown to reduce diabe-
families are challenged with complex, treatment and self-management, such tes distress (5). It may be helpful to
S58 Facilitating Behavior Change and Well-being to Improve Health Outcomes Diabetes Care Volume 43, Supplement 1, January 2020
provide counseling regarding expected ADA Mental Health Provider Directory measures is provided in the ADA position
diabetes-related versus generalized psy- (professional.diabetes.org/mhp_listing). statement “Psychosocial Care for People
chological distress, at diagnosis and when Ideally, psychosocial care providers with Diabetes” (1).
disease state or treatment changes (211). should be embedded in diabetes care
Diabetes distress should be routinely settings. Although the clinician may not Anxiety Disorders
monitored (212) using person-based feel qualified to treat psychological prob- Recommendations
diabetes-specific validated measures (1). lems (214), optimizing the patient-pro- 5.36 Consider screening for anxiety
If diabetes distress is identified, the person vider relationship as a foundation may in people exhibiting anxiety
should be referred for specific diabetes increase the likelihood of the patient or worries regarding diabetes
education to address areas of diabetes accepting referral for other services. complications, insulin admin-
self-care causing the patient distress Collaborative care interventions and a istration, and taking medications,
and impacting clinical management. team approach have demonstrated ef- as well as fear of hypoglyce-
People whose self-care remains im- ficacy in diabetes self-management, out- mia and/or hypoglycemia un-
paired after tailored diabetes education comes of depression, and psychosocial awareness that interferes with
should be referred by their care team to a functioning (5,6). self-management behaviors, and
behavioral health provider for evaluation in those who express fear,
and treatment. Psychosocial/Emotional Distress dread, or irrational thoughts
Other psychosocial issues known to Clinically significant psychopathologic di- and/or show anxiety symp-
affect self-management and health out- agnoses are considerably more preva- toms such as avoidance be-
comes include attitudes about the illness, lent in people with diabetes than in haviors, excessive repetitive
expectations for medical management those without (215,216). Symptoms, behaviors, or social withdrawal.
and outcomes, available resources (fi- both clinical and subclinical, that inter- Refer for treatment if anxiety is
nancial, social, and emotional) (213), and fere with the person’s ability to carry out present. B
psychiatric history. daily diabetes self-management tasks 5.37 People with hypoglycemia un-
must be addressed. In addition to im- awareness, which can co-occur
Referral to a Mental Health Specialist pacting a person’s ability to carry out with fear of hypoglycemia, should
Indications for referral to a mental health self-management, and the association of be treated using blood glucose
specialist familiar with diabetes manage- mental health diagnosis and poorer awareness training (or other ev-
ment may include positive screening for short-term glycemic stability, symptoms idence-based intervention) to
overall stress related to work-life bal- of emotional distress are associated with help re-establish awareness of
ance, diabetes distress, diabetes man- mortality risk (215). Providers should symptoms of hypoglycemia and
agement difficulties, depression, anxiety, consider an assessment of symptoms reduce fear of hypoglycemia. A
disordered eating, and cognitive dysfunc- of depression, anxiety, disordered eat-
tion (see Table 5.2 for a complete list). It ing, and cognitive capacities using ap- Anxiety symptoms and diagnosable dis-
is preferable to incorporate psychosocial propriate standardized/validated tools at orders (e.g., generalized anxiety disorder,
assessment and treatment into routine the initial visit, at periodic intervals when body dysmorphic disorder, obsessive-
care rather than waiting for a specific patient distress is suspected, and when compulsive disorder, specific phobias,
problem or deterioration in metabolic or there is a change in health, treatment, or and posttraumatic stress disorder) are
psychological status to occur (32,207). life circumstance. Inclusion of caregivers common in people with diabetes (217).
Providers should identify behavioral and and family members in this assessment The Behavioral Risk Factor Surveillance
mental health providers, ideally those is recommended. Diabetes distress is ad- System (BRFSS) estimated the lifetime
who are knowledgeable about diabetes dressed as an independent condition (see prevalence of generalized anxiety disorder
treatment and the psychosocial aspects the section DIABETES DISTRESS above), as this to be 19.5% in people with either type 1 or
of diabetes, to whom they can refer pa- state is very common and expected and type 2 diabetes (218). Common diabetes-
tients. The ADA provides a list of mental is distinct from the psychological dis- specific concerns include fears related to
health providers who have received orders discussed below (1). A list of age- hypoglycemia (219,220), not meeting
additional education in diabetes at the appropriate screening and evaluation blood glucose targets (217), and insulin
Table 5.2—Situations that warrant referral of a person with diabetes to a mental health provider for evaluation and treatment
c If self-care remains impaired in a person with diabetes distress after tailored diabetes education
c If a person has a positive screen on a validated screening tool for depressive symptoms
c In the presence of symptoms or suspicions of disordered eating behavior, an eating disorder, or disrupted patterns of eating
c If intentional omission of insulin or oral medication to cause weight loss is identified
c If a person has a positive screen for anxiety or fear of hypoglycemia
c If a serious mental illness is suspected
c In youth and families with behavioral self-care difficulties, repeated hospitalizations for diabetic ketoacidosis, or significant distress
c If a person screens positive for cognitive impairment
c Declining or impaired ability to perform diabetes self-care behaviors
c Before undergoing bariatric or metabolic surgery and after surgery if assessment reveals an ongoing need for adjustment support
care.diabetesjournals.org Facilitating Behavior Change and Well-being to Improve Health Outcomes S59
American Association of Diabetes Educators, of the effect on glycemic control. Patient Educ
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S66 Diabetes Care Volume 43, Supplement 1, January 2020
SPPC), are responsible for updating the Standards of Care annually, or more
frequently as warranted. For a detailed description of ADA standards, statements,
and reports, as well as the evidence-grading system for ADA’s clinical practice
recommendations, please refer to the Standards of Care Introduction (https://doi
.org/10.2337/dc20-SINT). Readers who wish to comment on the Standards of Care
are invited to do so at professional.diabetes.org/SOC.
A1C Testing
Recommendations
6.1 Perform the A1C test at least two times a year in patients who are meeting
treatment goals (and who have stable glycemic control). E
6.2 Perform the A1C test quarterly in patients whose therapy has changed or
who are not meeting glycemic goals. E
6.3 Point-of-care testing for A1C provides the opportunity for more timely
treatment changes. E
A1C reflects average glycemia over approximately 3 months. The performance of Suggested citation: American Diabetes Associa-
the test is generally excellent for National Glycohemoglobin Standardization tion. 6. Glycemic targets: Standards of Medical
Program (NGSP)-certified assays (see www.ngsp.org). The test is the major tool Care in Diabetesd2020. Diabetes Care 2020;
for assessing glycemic control and has strong predictive value for diabetes 43(Suppl. 1):S66–S76
complications (1–3). Thus, A1C testing should be performed routinely in all patients © 2019 by the American Diabetes Association.
with diabetesdat initial assessment and as part of continuing care. Measurement Readers may use this article as long as the work
is properly cited, the use is educational and not
approximately every 3 months determines whether patients’ glycemic targets have for profit, and the work is not altered. More infor-
been reached and maintained. The frequency of A1C testing should depend on mation is available at http://www.diabetesjournals
the clinical situation, the treatment regimen, and the clinician’s judgment. The .org/content/license.
care.diabetesjournals.org Glycemic Targets S67
use of point-of-care A1C testing may also inform the accuracy of the patient’s ethnic groups in the regression lines
provide an opportunity for more timely meter (or the patient’s reported SMBG between A1C and mean glucose, al-
treatment changes during encounters results) and the adequacy of the SMBG though the study was underpowered
between patients and providers. Pa- testing schedule. to detect a difference and there was a
tients with type 2 diabetes with stable trend toward a difference between the
glycemia well within target may do well Correlation Between SMBG and A1C African/African American and non-Hispanic
with A1C testing only twice per year. Table 6.1 shows the correlation between white cohorts, with higher A1C values
Unstable or intensively managed pa- A1C levels and mean glucose levels based observed in Africans/African Americans
tients or people not at goal with treat- on the international A1C-Derived Average compared with non-Hispanic whites
ment adjustments may require testing Glucose (ADAG) study, which assessed the for a given mean glucose. Other studies
more frequently (every 3 months) (4). correlation between A1C and frequent have also demonstrated higher A1C levels
SMBG and CGM in 507 adults (83% non- in African Americans than in whites
A1C Limitations Hispanic whites) with type 1, type 2, and at a given mean glucose concentration
The A1C test is an indirect measure of no diabetes (6), and an empirical study of (8,9).
average glycemia and, as such, is sub- the average blood glucose levels at pre- A1C assays are available that do not
ject to limitations. As with any labo- meal, postmeal, and bedtime associated demonstrate a statistically significant
ratory test, there is variability in the with specified A1C levels using data from difference in individuals with hemoglo-
measurement of A1C. Although such the ADAG trial (7). The American Diabe- bin variants. Other assays have statisti-
variability is less on an intraindividual tes Association (ADA) and the American cally significant interference, but the
basis than that of blood glucose measure- Association for Clinical Chemistry have difference is not clinically significant.
ments, clinicians should exercise judg- determined that the correlation (r 5 Use of an assay with such statistically
ment when using A1C as the sole basis 0.92) in the ADAG trial is strong enough significant interference may explain a
for assessing glycemic control, particu- to justify reporting both the A1C result report that for any level of mean glyce-
larly if the result is close to the threshold and the estimated average glucose (eAG) mia, African Americans heterozygous for
that might prompt a change in medica- result when a clinician orders the A1C the common hemoglobin variant HbS
tion therapy. Conditions that affect red test. Clinicians should note that the had lower A1C by about 0.3 percentage
blood cell turnover (hemolytic and other mean plasma glucose numbers in Table points when compared with those with-
anemias, glucose-6-phosphate dehydro- 6.1 are based on ;2,700 readings per A1C out the trait (10,11). Another genetic
genase deficiency, recent blood trans- in the ADAG trial. In a recent report, mean variant, X-linked glucose-6-phosphate
fusion, use of drugs that stimulate glucose measured with CGM versus cen- dehydrogenase G202A, carried by 11%
erythropoesis, end-stage kidney disease, tral laboratory–measured A1C in 387 of African Americans, was associated
and pregnancy) may result in discrep- participants in three randomized trials with a decrease in A1C of about 0.8%
ancies between the A1C result and the demonstrated that A1C may underesti- in hemizygous men and 0.7% in homo-
patient’s true mean glycemia. Hemoglo- mate or overestimate mean glucose (5). zygous women compared with those
bin variants must be considered, partic- Thus, as suggested, a patient’s CGM pro- without the trait (12).
ularly when the A1C result does not file has considerable potential for opti- A small study comparing A1C to CGM
correlate with the patient’s SMBG levels. mizing his or her glycemic management data in children with type 1 diabetes
However, most assays in use in the U.S. (5). found a highly statistically significant
are accurate in individuals heterozy- correlation between A1C and mean
gous for the most common variants A1C Differences in Ethnic Populations blood glucose, although the correlation
(see www.ngsp.org/interf.asp). Other and Children (r 5 0.7) was significantly lower than in
measures of average glycemia such as In the ADAG study, there were no sig- the ADAG trial (13). Whether there are
fructosamine and 1,5-anhydroglucitol nificant differences among racial and clinically meaningful differences in how
are available, but their translation into
average glucose levels and their prog- Table 6.1—Estimated average glucose (eAG)
nostic significance are not as clear as for
A1C (%) mg/dL* mmol/L
A1C. Though some variability in the re-
lationship between average glucose lev- 5 97 (76–120) 5.4 (4.2–6.7)
els and A1C exists among different 6 126 (100–152) 7.0 (5.5–8.5)
individuals, generally the association be- 7 154 (123–185) 8.6 (6.8–10.3)
tween mean glucose and A1C within an 8 183 (147–217) 10.2 (8.1–12.1)
individual correlates over time (5). 9 212 (170–249) 11.8 (9.4–13.9)
A1C does not provide a measure of 10 240 (193–282) 13.4 (10.7–15.7)
glycemic variability or hypoglycemia. For 11 269 (217–314) 14.9 (12.0–17.5)
patients prone to glycemic variability, 12 298 (240–347) 16.5 (13.3–19.3)
especially patients with type 1 diabetes Data in parentheses are 95% CI. A calculator for converting A1C results into eAG, in either mg/dL or
or type 2 diabetes with severe insulin mmol/L, is available at professional.diabetes.org/eAG. *These estimates are based on ADAG data
deficiency, glycemic control is best of ;2,700 glucose measurements over 3 months per A1C measurement in 507 adults with type 1,
type 2, or no diabetes. The correlation between A1C and average glucose was 0.92 (6,7). Adapted from
evaluated by the combination of results
Nathan et al. (6).
from SMBG or CGM and A1C. A1C may
S68 Glycemic Targets Diabetes Care Volume 43, Supplement 1, January 2020
A1C relates to average glucose in children response to therapy and assess whether providers. Reports can be generated
or in different ethnicities is an area for glycemic targets are being safely achieved. from CGM that will allow the provider
further study (8,14,15). Until further The international consensus on time in to determine time in range (TIR) and to
evidence is available, it seems prudent range provides guidance on standardized assess hypoglycemia, hyperglycemia, and
to establish A1C goals in these popula- CGM metrics (see Table 6.2) and consid- glycemic variability. As discussed in a re-
tions with consideration of both individ- erations for clinical interpretation and cent consensus document, a report for-
ualized SMBG and A1C results. care (17). To make these metrics more matted as shown in Fig. 6.1 can be
actionable, standardized reports with generated (17). Published data sug-
Glucose Assessment visual cues such as the Ambulatory Glu- gest a strong correlation between TIR
cose Profile (see Fig. 6.1) are recommended and A1C, with a goal of 70% TIR aligning
Recommendations
(17) and may help the patient and the with an A1C of ;7% in two prospective
6.4 Standardized, single-page glu-
provider interpret the data and use it to studies (18,19).
cose reports with visual cues
guide treatment decisions. Integrating
such as the Ambulatory Glucose A1C GOALS
SMBG and CGM results into diabetes
Profile (AGP) should be consid-
management can be useful for guiding For glycemic goals in older adults, please
ered as a standard printout for
all CGM devices. E
medical nutrition therapy and physical refer to Section 12 “Older Adults” (https://
activity, preventing hypoglycemia, and doi.org/10.2337/dc20-S012). For glycemic
6.5 Time in range (TIR) is associated
adjusting medications. As recently re- goals in children, please refer to Section
with the risk of microvascular
viewed, while A1C is currently the primary 13 “Children and Adolescents” (https://
complications and should be an
measure guiding glucose management doi.org/10.2337/dc20-S013). For glycemic
acceptable end point for clinical
and a valuable marker of the risk of goals in pregnant women, please refer to
trials and can be used for assess-
ment of glycemic control. Addi-
developing diabetes complications, the Section 14 “Management of Diabetes in
Glucose Management Indicator (GMI) along Pregnancy” (https://doi.org/10.2337/dc20-
tionally, time below target (,70
with the other CGM metrics are suggested S014).
and ,54 mg/dL [3.9 and 3.0
to provide for a much more personalized
mmol/L]) and time above target
diabetes management plan. The incorpo- Recommendations
(.180 mg/dL [10.0 mmol/L]) are
ration of these metrics into clinical prac- 6.6 An A1C goal for many nonpreg-
useful parameters for reevaluation
tice is in evolution, and optimization of nant adults of ,7% (53 mmol/mol)
of the treatment regimen. E
CGM terminology will evolve to suit pa- is appropriate. A
tient and provider needs. The patient’s 6.7 On the basis of provider judge-
For many people with diabetes, glucose specific needs and goals should dictate ment and patient preference,
monitoring is key for the achievement of SMBG frequency and timing or the con- achievement of lower A1C levels
glycemic targets. Major clinical trials of sideration of CGM use. Please refer to (such as ,6.5%) may be accept-
insulin-treated patients have included Section 7 “Diabetes Technology” (https:// able if this can be achieved safely
SMBG as part of multifactorial interven- doi.org/10.2337/dc20-S007) for a fuller without significant hypoglyce-
tions to demonstrate the benefit of in- discussion of the use of SMBG and CGM. mia or other adverse effects of
tensive glycemic control on diabetes treatment. C
complications (16). SMBG is thus an in- Glucose Assessment Using 6.8 Less stringent A1C goals (such as
tegral component of effective therapy of Continuous Glucose Monitoring ,8% [64 mmol/mol]) may be
patients taking insulin. In recent years, With the advent of new technology, CGM appropriate for patients with a
CGM has emerged as a complementary has evolved rapidly in both accuracy and history of severe hypoglycemia,
method for the assessment of glucose affordability. As such, many patients have limited life expectancy, advanced
levels. Glucose monitoring allows pa- these data available to assist with both microvascular or macrovascular
tients to evaluate their individual self-management and assessment by
Table 6.2—Standardized continuous glucose monitoring (CGM) metrics for clinical care
1. Number of days CGM device is worn (recommend 14 days)
2. Percentage of time CGM device is active (recommend 70% of data from 14 days)
3. Mean glucose
4. Glucose management indicator (GMI)
5. Glycemic variability (%CV) target #36%*
6. Time above range (TAR): % of readings and time .250 mg/dL (.13.9 mmol/L) Level 2
7. Time above range (TAR): % of readings and time 181–250 mg/dL (10.1–13.9 mmol/L) Level 1
8. Time in range (TIR): % of readings and time 70–180 mg/dL (3.9–10.0 mmol/L) In range
9. Time below range (TBR): % of readings and time 54–69 mg/dL (3.0–3.8 mmol/L) Level 1
10. Time below range (TBR): % of readings and time ,54 mg/dL (,3.0 mmol/L) Level 2
CGM, continuous glucose monitoring; CV, coefficient of variation. *Some studies suggest that lower %CV targets (,33%) provide additional protection
against hypoglycemia for those receiving insulin or sulfonylureas. Adapted from Battelino et al. (17).
care.diabetesjournals.org Glycemic Targets S69
Figure 6.1—Sample Ambulatory Glucose Profile (AGP) report. Adapted from Battelino et al. (17).
glycemic separation between the treat- low hypoglycemia risk with a long life
complications, extensive comorbid
ment groups diminished and disappeared expectancy.
conditions, or long-standing dia-
during follow-up. Given the substantially increased risk
betes in whom the goal is difficult
The Kumamoto Study (22) and UK of hypoglycemia in type 1 diabetes and
to achieve despite diabetes self-
Prospective Diabetes Study (UKPDS) with polypharmacy in type 2 diabetes,
management education, appropri-
(23,24) confirmed that intensive glyce- the risks of lower glycemic targets may
ate glucose monitoring, and ef-
fective doses of multiple glucose- mic control significantly decreased rates outweigh the potential benefits on
lowering agents including insulin. of microvascular complications in pa- microvascular complications. Three land-
B tients with short-duration type 2 diabe- mark trials (Action to Control Cardiovas-
6.9 Reassess glycemic targets over tes. Long-term follow-up of the UKPDS cular Risk in Diabetes [ACCORD], Action
time based on the criteria in cohorts showed enduring effects of early in Diabetes and Vascular Disease: Pre-
Fig. 6.2 or, in older adults, glycemic control on most microvascular terax and Diamicron MR Controlled Eval-
Table 12.1. E complications (25). uation [ADVANCE], and Veterans Affairs
Therefore, achieving A1C targets Diabetes Trial [VADT]) were conducted
of ,7% (53 mmol/mol) has been shown to test the effects of near normalization
A1C and Microvascular Complications to reduce microvascular complications of blood glucose on cardiovascular out-
Hyperglycemia defines diabetes, and gly- of type 1 and type 2 diabetes when comes in individuals with long-standing
cemic control is fundamental to diabetes instituted early in the course of disease type 2 diabetes and either known car-
management. The Diabetes Control and (26). Epidemiologic analyses of the DCCT diovascular disease (CVD) or high cardio-
Complications Trial (DCCT) (16), a pro- (16) and UKPDS (27) demonstrate a cur- vascular risk. These trials showed that
spective randomized controlled trial of lower A1C levels were associated with
vilinear relationship between A1C and
intensive (mean A1C about 7% [53 reduced onset or progression of some
microvascular complications. Such anal-
mmol/mol]) versus standard (mean A1C microvascular complications (28–30).
yses suggest that, on a population level,
about 9% [75 mmol/mol]) glycemic control The concerning mortality findings in
the greatest number of complications
in patients with type 1 diabetes, showed the ACCORD trial (31), discussed below,
will be averted by taking patients from
definitively that better glycemic control and the relatively intense efforts re-
is associated with 50–76% reductions very poor control to fair/good control. quired to achieve near euglycemia should
in rates of development and progres- These analyses also suggest that further also be considered when setting glycemic
sion of microvascular (retinopathy, neu- loweringofA1Cfrom7%to6%[53mmol/mol targets for individuals with long-standing
ropathy, and diabetic kidney disease) to 42 mmol/mol] is associated with fur- diabetes such as those studied in ACCORD,
complications. Follow-up of the DCCT ther reduction in the risk of microvascular ADVANCE, and VADT. Findings from these
cohorts in the Epidemiology of Diabetes complications, although the absolute risk studies suggest caution is needed in
Interventions and Complications (EDIC) reductions become much smaller. The im- treating diabetes aggressively to near-
study (20,21) demonstrated persistence plication of these findings is that there is no normal A1C goals in people with long-
of these microvascular benefits over need to deintensify therapy for an individ- standing type 2 diabetes with or at
two decades despite the fact that the ual with an A1C between 6% and 7% and significant risk of CVD. However, on the
S70 Glycemic Targets Diabetes Care Volume 43, Supplement 1, January 2020
basis of physician judgment and patient years of observational follow-up, those targets, therapeutic approaches, and
preferences, select patients, especially originally randomized to intensive glyce- population characteristics (41).
those with little comorbidity and long mic control had significant long-term Mortality findings in ACCORD (31) and
life expectancy, may benefit from adopt- reductions in MI (15% with sulfonylurea subgroup analyses of VADT (42) suggest
ing more intensive glycemic targets if or insulin as initial pharmacotherapy, that the potential risks of intensive gly-
they can achieve it safely without hy- 33% with metformin as initial pharma- cemic control may outweigh its benefits
poglycemia or significant therapeutic cotherapy) and in all-cause mortality in higher-risk patients. In all three trials,
burden. (13% and 27%, respectively) (25). severe hypoglycemia was significantly
ACCORD, ADVANCE, and VADT sug- more likely in participants who were
A1C and Cardiovascular Disease gested no significant reduction in CVD randomly assigned to the intensive gly-
Outcomes outcomes with intensive glycemic con- cemic control arm. Those patients with
Cardiovascular Disease and Type 1 Diabetes trol in participants followed for shorter long duration of diabetes, a known history
CVD is a more common cause of death durations (3.5–5.6 years) and who had of hypoglycemia, advanced atherosclero-
than microvascular complications in pop- more advanced type 2 diabetes than sis, or advanced age/frailty may benefit
ulations with diabetes. There is evidence UKPDS participants. All three trials from less aggressive targets (43,44).
for a cardiovascular benefit of intensive were conducted in relatively older par- As discussed further below, severe
glycemic control after long-term follow-up ticipants with longer known duration of hypoglycemia is a potent marker of
of cohorts treated early in the course of diabetes (mean duration 8–11 years) and high absolute risk of cardiovascular
type 1 diabetes. In the DCCT, there was a either CVD or multiple cardiovascular risk events and mortality (45). Providers
trend toward lower risk of CVD events factors. The target A1C among intensive- should be vigilant in preventing hypo-
with intensive control. In the 9-year control subjects was ,6% (42 mmol/mol) glycemia and should not aggressively
post-DCCT follow-up of the EDIC cohort, in ACCORD, ,6.5% (48 mmol/mol) in attempt to achieve near-normal A1C
participants previously randomized to ADVANCE, and a 1.5% reduction in A1C levels in patients in whom such tar-
the intensive arm had a significant 57% compared with control subjects in VADT, gets cannot be safely and reasonably
reduction in the risk of nonfatal myo- with achieved A1C of 6.4% vs. 7.5% achieved. As discussed in Section 9 “Phar-
cardial infarction (MI), stroke, or car- (46 mmol/mol vs. 58 mmol/mol) in macologic Approaches to Glycemic Treat-
diovascular death compared with those ACCORD, 6.5% vs. 7.3% (48 mmol/mol ment” (https://doi.org/10.2337/dc20-S009),
previously randomized to the standard vs. 56 mmol/mol) in ADVANCE, and 6.9% addition of specific sodium–glucose co-
arm (32). The benefit of intensive gly- vs. 8.4% (52 mmol/mol vs. 68 mmol/mol) transporter 2 inhibitors (SGLT2i) or gluca-
cemic control in this cohort with type 1 in VADT. Details of these studies are gon-like peptide 1 receptor agonists (GLP-1
diabetes has been shown to persist for reviewed extensively in “Intensive Gly- RA) that have demonstrated CVD benefit
several decades (33) and to be associ- cemic Control and the Prevention of are recommended for use in patients with
ated with a modest reduction in all- Cardiovascular Events: Implications of established CVD or indicators of high risk.
cause mortality (34). the ACCORD, ADVANCE, and VA Diabetes As outlined in more detail in Section 9
Cardiovascular Disease and Type 2 Diabetes Trials” (38). “Pharmacologic Approaches to Glycemic
In type 2 diabetes, there is evidence The glycemic control comparison in Treatment” (https://doi.org/10.2337/dc20-
that more intensive treatment of glyce- ACCORD was halted early due to an S009) and Section 10 “Cardiovascular Dis-
mia in newly diagnosed patients may increased mortality rate in the intensive ease and Risk Management” (https://doi
reduce long-term CVD rates. In addi- compared with the standard treatment .org/10.2337/dc20-S010), the cardiovas-
tion, data from the Swedish National arm (1.41% vs. 1.14% per year; hazard cular benefits of SGLT2i or GLP-1 RA are
Diabetes Registry and Joint Asia Diabetes ratio 1.22 [95% CI 1.01–1.46]), with a not dependent upon A1C lowering, so
Evaluation (JADE) demonstrate greater similar increase in cardiovascular deaths. initiation can be considered in people with
proportions of people with diabetes be- Analysis of the ACCORD data did not type 2 diabetes and CVD independent of
ing diagnosed at ,40 years of age and a identify a clear explanation for the ex- the current A1C or A1C goal. Based on
demonstrably increased burden of heart cess mortality in the intensive treat- these considerations, the following two
disease and years of life lost in people ment arm (31). strategies are offered (46):
diagnosed at a younger age (35–37). Longer-term follow-up has shown no
Thus, for prevention of both microvas- evidence of cardiovascular benefit or 1. If already on dual therapy or multiple
cular and macrovascular complications harm in the ADVANCE trial (39). The glucose-lowering therapies and not
of diabetes, there is a major call to end-stage renal disease rate was lower on an SGLT2i or GLP-1 RA, consider
overcome therapeutic inertia and treat in the intensive treatment group over switching to one of these agents with
to target for an individual patient (37). follow-up. However, 10-year follow-up of proven cardiovascular benefit.
During the UKPDS, there was a 16% the VADT cohort (40) showed a reduction 2. Introduce SGLT2i or GLP-1 RA in pa-
reduction in CVD events (combined fa- in the risk of cardiovascular events (52.7 tients with CVD at A1C goal for car-
tal or nonfatal MI and sudden death) [control group] vs. 44.1 [intervention diovascular benefit.
in the intensive glycemic control arm group] events per 1,000 person-years) Setting and Modifying A1C Goals
that did not reach statistical signifi- with no benefit in cardiovascular or over- Numerous factors must be considered
cance (P 5 0.052), and there was no all mortality. Heterogeneity of mortal- when setting glycemic targets. The ADA
suggestion of benefit on other CVD out- ity effects across studies was noted, proposes general targets appropriate
comes (e.g., stroke). However, after 10 which may reflect differences in glycemic for many patients but emphasizes the
care.diabetesjournals.org Glycemic Targets S71
but did not affect the definition of hy- Table 6.3—Summary of glycemic recommendations for many nonpregnant adults
poglycemia. with diabetes
A1C ,7.0% (53 mmol/mol)*
HYPOGLYCEMIA Preprandial capillary plasma glucose 80–130 mg/dL* (4.4–7.2 mmol/L)
Recommendations Peak postprandial capillary plasma glucose† ,180 mg/dL* (10.0 mmol/L)
6.10 Individuals at risk for hypogly- *More or less stringent glycemic goals may be appropriate for individual patients. Goals should be
cemia should be asked about individualized based on duration of diabetes, age/life expectancy, comorbid conditions, known
CVD or advanced microvascular complications, hypoglycemia unawareness, and individual patient
symptomatic and asymptom- considerations. †Postprandial glucose may be targeted if A1C goals are not met despite reaching
atic hypoglycemia at each en- preprandial glucose goals. Postprandial glucose measurements should be made 1–2 h after the
counter. C beginning of the meal, generally peak levels in patients with diabetes.
6.11 In patients taking medication
that can lead to hypoglycemia,
investigate, screen, and assess If a patient has level 2 hypoglycemia
at least several weeks in order to
risk for or occurrence of un- without adrenergic or neuroglycopenic
partially reverse hypoglycemia
recognized hypoglycemia, con- symptoms, they likely have hypoglycemia
unawareness and reduce risk of
sidering that patients may unawareness (discussed further below).
future episodes. A
have hypoglycemia unaware- This clinical scenario warrants investiga-
6.16 Ongoing assessment of cogni-
ness. C tion and review of the medical regimen.
tive function is suggested with
6.12 Glucose (15–20 g) is the preferred Lastly, level 3 hypoglycemia is defined as a
increased vigilance for hypogly-
treatment for the conscious in- severe event characterized by altered
cemia by the clinician, patient,
dividual with blood glucose ,70 mental and/or physical functioning
and caregivers if low cognition
mg/dL [3.9 mmol/L]), although that requires assistance from another
or declining cognition is found. B
any form of carbohydrate that person for recovery.
contains glucose may be used. Symptoms of hypoglycemia include,
Fifteen minutes after treatment, Hypoglycemia is the major limiting but are not limited to, shakiness, irrita-
if SMBG shows continued hypo- factor in the glycemic management of bility, confusion, tachycardia, and hun-
glycemia,thetreatmentshouldbe type 1 and type 2 diabetes. Recommen- ger. Hypoglycemia may be inconvenient
repeated. Once SMBG returns to dations regarding the classification of or frightening to patients with diabetes.
normal, the individual should con- hypoglycemia are outlined in Table 6.4 Level 3 hypoglycemia may be recognized
sume a meal or snack to prevent (51–56). Level 1 hypoglycemia is defined or unrecognized and can progress to
recurrence of hypoglycemia. B as a measurable glucose concentration loss of consciousness, seizure, coma,
6.13 Glucagon should be prescribed ,70 mg/dL (3.9 mmol/L) but $54 mg/dL or death. It is reversed by administration
for all individuals at increased risk (3.0 mmol/L). A blood glucose concen- of rapid-acting glucose or glucagon. Hy-
of level 2 hypoglycemia, defined tration of 70 mg/dL (3.9 mmol/L) has poglycemia can cause acute harm to the
as blood glucose ,54 mg/dL been recognized as a threshold for neu- person with diabetes or others, espe-
(3.0 mmol/L), so it is available roendocrine responses to falling glucose cially if it causes falls, motor vehicle
should it be needed. Caregivers, in people without diabetes. Because accidents, or other injury. Recurrent
school personnel, or family mem- many people with diabetes demonstrate level 2 hypoglycemia and/or level 3 hy-
bers of these individuals should impaired counterregulatory responses poglycemia is an urgent medical issue
know where it is and when and to hypoglycemia and/or experience hy- and requires intervention with medical
how to administer it. Glucagon poglycemia unawareness, a measured regimen adjustment, behavioral inter-
administration is not limited to glucose level ,70 mg/dL (3.9 mmol/L) is vention, and, in some cases, use of
health care professionals, partic- considered clinically important, inde- technology to assist with hypoglycemia
ularly with the availability of intra- pendent of the severity of acute hypo- prevention and identification (52,57–60).
nasal and stable soluble glucagon glycemic symptoms. Level 2 hypoglycemia A large cohort study suggested that
available in autoinjector pens. E (defined as a blood glucose concentration among older adults with type 2 diabetes,
6.14 Hypoglycemia unawareness or ,54 mg/dL [3.0 mmol/L]) is the thresh- a history of level 3 hypoglycemia was
one or more episodes of level old at which neuroglycopenic symp- associated with greater risk of dementia
3 hypoglycemia should trigger toms begin to occur and requires immediate (61). Conversely, in a substudy of the
hypoglycemia avoidance edu- action to resolve the hypoglycemic event. ACCORD trial, cognitive impairment at
cation and reevaluation of the
treatment regimen. E
Table 6.4—Classification of hypoglycemia
6.15 Insulin-treated patients with hy-
Glycemic criteria/description
poglycemia unawareness, one
level 3 hypoglycemic event, or Level 1 Glucose ,70 mg/dL (3.9 mmol/L) and $54 mg/dL (3.0 mmol/L)
a pattern of unexplained level 2 Level 2 Glucose ,54 mg/dL (3.0 mmol/L)
hypoglycemia should be advised Level 3 A severe event characterized by altered mental and/or physical status requiring
to raise their glycemic targets to assistance for treatment of hypoglycemia
strictly avoid hypoglycemia for Reprinted from Agiostratidou et al. (51).
care.diabetesjournals.org Glycemic Targets S73
baseline or decline in cognitive function and hypoglycemia unawareness that per- use of glucagon, including where
during the trial was significantly associ- sists despite medical treatment, human the glucagon product is kept and
ated with subsequent episodes of level islet transplantation may be an option, when and how to administer. An in-
3 hypoglycemia (62). Evidence from but the approach remains experimental dividual does not need to be a health
DCCT/EDIC, which involved adolescents (72,73). care professional to safely administer
and younger adults with type 1 diabetes, In 2015, the ADA changed its prepran- glucagon. In addition to traditional glu-
found no association between fre- dial glycemic target from 70–130 mg/dL cagon injection powder that requires
quency of level 3 hypoglycemia and (3.9–7.2 mmol/L) to 80–130 mg/dL (4.4– reconstitution prior to injection, intra-
cognitive decline (63), as discussed in 7.2 mmol/L). This change reflects the nasal glucagon and glucagon solution
Section 13 “Children and Adolescents” results of the ADAG study, which dem- for subcutaneous injection recently re-
(https://doi.org/10.2337/dc20-S013). onstrated that higher glycemic targets ceived U.S. Food and Drug Administra-
Studies of rates of level 3 hypoglycemia corresponded to A1C goals (7). An addi- tion approval. Care should be taken to
that rely on claims data for hospitaliza- tional goal of raising the lower range of ensure that glucagon products are not
tion, emergency department visits, and the glycemic target was to limit over- expired.
ambulance use substantially underesti- treatment and provide a safety margin
mate rates of level 3 hypoglycemia (64) in patients titrating glucose-lowering Hypoglycemia Prevention
yet find high burden of hypoglycemia in drugs such as insulin to glycemic targets. Hypoglycemia prevention is a critical
adults over 60 years of age in the com- component of diabetes management.
munity (65). African Americans are at Hypoglycemia Treatment SMBG and, for some patients, CGM
substantially increased risk of level 3 hy- Providers should continue to counsel are essential tools to assess therapy
poglycemia (65,66). In addition to age patients to treat hypoglycemia with and detect incipient hypoglycemia. Pa-
and race, other important risk factors fast-acting carbohydrates at the hypo- tients should understand situations that
found in a community-based epidemi- glycemia alert value of 70 mg/dL increase their risk of hypoglycemia, such
ologic cohort of older black and white (3.9 mmol/L) or less. This should be as when fasting for tests or procedures,
adults with type 2 diabetes include insulin reviewed at each patient visit. Hypogly- when meals are delayed, during and after
use, poor or moderate versus good gly- cemia treatment requires ingestion of the consumption of alcohol, during and
cemic control, albuminuria, and poor glucose- or carbohydrate-containing foods after intense exercise, and during sleep.
cognitive function (65). Level 3 hypo- (74–76). The acute glycemic response Hypoglycemia may increase the risk of
glycemia was associated with mortal- correlates better with the glucose con- harm to self or others, such as with
ity in participants in both the standard tent of food than with the carbohy- driving. Teaching people with diabetes
and the intensive glycemia arms of the drate content of food. Pure glucose is the to balance insulin use and carbohydrate
ACCORD trial, but the relationships be- preferred treatment, but any form of intake and exercise are necessary, but
tween hypoglycemia, achieved A1C, and carbohydrate that contains glucose will these strategies are not always sufficient
treatment intensity were not straightfor- raise blood glucose. Added fat may retard for prevention.
ward. An association of level 3 hypo- and then prolong the acute glycemic In type 1 diabetes and severely insulin
glycemia with mortality was also found response. In type 2 diabetes, ingested deficient type 2 diabetes, hypoglycemia
in the ADVANCE trial (67). An association protein may increase insulin response unawareness (or hypoglycemia-associated
between self-reported level 3 hypoglyce- without increasing plasma glucose con- autonomic failure) can severely com-
mia and 5-year mortality has also been centrations (77). Therefore, carbohy- promise stringent diabetes control and
reported in clinical practice (68) drate sources high in protein should not quality of life. This syndrome is char-
Young children with type 1 diabetes be used to treat or prevent hypogly- acterized by deficient counterregu-
and the elderly, including those with cemia. Ongoing insulin activity or latory hormone release, especially in
type 1 and type 2 diabetes (61,69), insulin secretagogues may lead to older adults, and a diminished auto-
are noted as particularly vulnerable to recurrent hypoglycemia unless more nomic response, which are both risk
hypoglycemia because of their reduced food is ingested after recovery. Once factors for, and caused by, hypoglyce-
ability to recognize hypoglycemic symp- the glucose returns to normal, the in- mia. A corollary to this “vicious cycle” is
toms and effectively communicate their dividual should be counseled to eat a that several weeks of avoidance of
needs. Individualized glucose targets, meal or snack to prevent recurrent hypoglycemia has been demonstrated
patient education, dietary intervention hypoglycemia. to improve counterregulation and hy-
(e.g., bedtime snack to prevent overnight Glucagon poglycemia awareness in many patients
hypoglycemia when specifically needed The use of glucagon is indicated for (78). Hence, patients with one or more
to treat low blood glucose), exercise the treatment of hypoglycemia in peo- episodes of clinically significant hypo-
management, medication adjustment, ple unable or unwilling to consume glycemia may benefit from at least
glucose monitoring, and routine clinical carbohydrates by mouth. Those in close short-term relaxation of glycemic tar-
surveillance may improve patient out- contact with, or having custodial care gets and availability of glucagon (79).
comes (70). CGM with automated low of, people with hypoglycemia-prone di-
glucose suspend has been shown to be abetes (family members, roommates, Use of CGM Technology in
effective in reducing hypoglycemia in school personnel, childcare providers, Hypoglycemia Prevention
type 1 diabetes (71). For patients with correctional institution staff, or cow- With the advent of CGM and CGM-
type 1 diabetes with level 3 hypoglycemia orkers) should be instructed on the assisted pump therapy, there has been a
S74 Glycemic Targets Diabetes Care Volume 43, Supplement 1, January 2020
promise of alarm-based prevention of hyperglycemia requires temporary ad- 11. Rohlfing C, Hanson S, Little RR. Measure-
hypoglycemia (80,81). To date, there justment of the treatment regimen ment of hemoglobin A1c in patients with sickle
cell trait. JAMA 2017;317:2237
have been six randomized controlled and immediate interaction with the di- 12. Wheeler E, Leong A, Liu C-T, et al.; EPIC-CVD
trials in adults with type 1 diabetes abetes care team. The patient treated Consortium; EPIC-InterAct Consortium; Lifelines
and seven in adults and children with with noninsulin therapies or medical Cohort Study. Impact of common genetic deter-
type 1 diabetes using real-time CGM. nutrition therapy alone may require in- minants of Hemoglobin A1c on type 2 diabetes
These studies had differing A1C at entry sulin. Adequate fluid and caloric intake risk and diagnosis in ancestrally diverse popu-
lations: A transethnic genome-wide meta-
and differing primary end points and thus must be ensured. Infection or dehydra- analysis. PLoS Med 2017;14:e1002383
must be interpreted carefully. Real-time tion is more likely to necessitate hospi- 13. Wilson DM, Kollman; Diabetes Research in
CGM studies can be divided into studies talization of the person with diabetes Children Network (DirecNet) Study Group. Re-
with elevated A1C with the primary end than the person without diabetes. lationship of A1C to glucose concentrations in
point of A1C reduction and studies with A physician with expertise in diabe- children with type 1 diabetes: assessments by
high-frequency glucose determinations by sen-
A1C near target with the primary end tes management should treat the hos- sors. Diabetes Care 2008;31:381–385
point of reduction in hypoglycemia pitalized patient. For further information 14. Buse JB, Kaufman FR, Linder B, Hirst K, El
(81–97). In people with type 1 and on the management of diabetic keto- Ghormli L, Willi S; HEALTHY Study Group. Di-
type 2 diabetes with A1C above target, acidosis and the nonketotic hyperglyce- abetes screening with hemoglobin A1c versus
CGM improved A1C between 0.3% and mic hyperosmolar state, please refer to fasting plasma glucose in a multiethnic middle-
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0.6%. For studies targeting hypoglyce- the ADA consensus report “Hyperglyce- 15. Kamps JL, Hempe JM, Chalew SA. Racial
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Diabetes Care Volume 43, Supplement 1, January 2020 S77
7. DIABETES TECHNOLOGY
Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc20-SPPC),
are responsible for updating the Standards of Care annually, or more frequently as
warranted. For a detailed description of ADA standards, statements, and reports, as well
as the evidence-grading system for ADA’s clinical practice recommendations, please refer
to the Standards of Care Introduction (https://doi.org/10.2337/dc20-SINT). Readers who
wish to comment on the Standards of Care are invited to do so at professional.diabetes
.org/SOC.
Diabetes technology is the term used to describe the hardware, devices, and software
that people with diabetes use to help manage their condition, from lifestyle to blood
glucose levels. Historically, diabetes technology has been divided into two main
categories: insulin administered by syringe, pen, or pump, and blood glucose
monitoring as assessed by meter or continuous glucose monitor. More recently,
diabetes technology has expanded to include hybrid devices that both monitor
glucose and deliver insulin, some automatically, as well as software that serves as a
medical device, providing diabetes self-management support. Diabetes technology,
when coupled with education and follow-up, can improve the lives and health of
people with diabetes; however, the complexity and rapid change of the diabetes
technology landscape can also be a barrier to patient and provider implementation.
OVERALL STATEMENT
Recommendation
7.1 Use of technology should be individualized based on a patient’s needs,
desires, skill level, and availability of devices. Nonprofit websites can offer advice
for providers and patients to determine the suitability of various options. E
glucose monitoring (CGM) has emerged almost 27,000 children and adolescents
self-monitoring of blood glucose
as a method for the assessment of glu- with type 1 diabetes showed that, after
(and/or continuous glucose mon-
cose levels (discussed below). Glucose adjustment for multiple confounders,
itoring) prior to meals and
monitoring allows patients to evaluate increased daily frequency of SMBG was
snacks, at bedtime, prior to ex-
their individual response to therapy and significantly associated with lower A1C
ercise, when they suspect low
assess whether glycemic targets are (–0.2% per additional test per day) and
blood glucose, after treating
being safely achieved. Integrating with fewer acute complications (7).
low blood glucose until they
results into diabetes management can
are normoglycemic, and prior
be a useful tool for guiding medical Patients Using Basal Insulin and/or
to and while performing critical
nutrition therapy and physical activity, Oral Agents
tasks such as driving. B
preventing hypoglycemia, and adjusting The evidence is insufficient regarding
7.3 When prescribed as part of a
medications (particularly prandial insulin when to prescribe SMBG and how often
diabetes self-management edu-
doses). The patient’s specific needs and testing is needed for insulin-treated pa-
cation and support program, self-
goals should dictate SMBG frequency tients who do not use intensive insulin
monitoring of blood glucose may
and timing or the consideration of regimens, such as those with type 2
help to guide treatment decisions
CGM use. diabetes using basal insulin with or with-
and/or self-management for pa-
out oral agents. However, for patients
tients taking less-frequent insulin Optimizing SMBG Monitor Use using basal insulin, assessing fasting glu-
injections. B SMBG accuracy is dependent on the cose with SMBG to inform dose adjust-
7.4 Although self-monitoring of blood instrument and user, so it is important ments to achieve blood glucose targets
glucose in patients on noninsulin to evaluate each patient’s monitoring results in lower A1C (8,9).
therapies has not shown clinically technique, both initially and at regular In people with type 2 diabetes not
significant reductions in A1C, it intervals thereafter. Optimal use of using insulin, routine glucose monitoring
may be helpful when altering SMBG requires proper review and in- may be of limited additional clinical
diet, physical activity, and/or terpretation of the data, by both the benefit. By itself, even when combined
medications (particularly medica- patient and the provider, to ensure that with education, it has showed limited
tions that can cause hypoglyce- data are used in an effective and timely improvement in outcomes (10–13). How-
mia) inconjunctionwithatreatment manner. In patients with type 1 diabetes, ever, for some individuals, glucose mon-
adjustment program. E there is a correlation between greater itoring can provide insight into the
7.5 When prescribing self-monitoring SMBG frequency and lower A1C (3). impact of diet, physical activity, and
of blood glucose, ensure that pa- Among patients who check their blood medication management on glucose lev-
tients receive ongoing instruction glucose at least once daily, many report els. Glucose monitoring may also be
and regular evaluation of techni- taking no action when results are high or useful in assessing hypoglycemia, glu-
que, results, and their ability to use low (4). Patients should be taught how cose levels during intercurrent illness,
data from self-monitoring of blood to use SMBG data to adjust food or discrepancies between measured
glucose to adjust therapy. E intake, exercise, or pharmacologic ther- A1C and glucose levels when there is con-
7.6 Health care providers should be apy to achieve specific goals. The ongoing cern an A1C result may not be reliable
aware of medications and other need for and frequency of SMBG should in specific individuals. It may be useful
factors, such as high-dose vita- be reevaluated at each routine visit to when coupled with a treatment adjust-
min C and hypoxemia, that can avoid overuse, particularly if SMBG is not ment program. In a year-long study of
interfere with glucose meter being used effectively for self-management insulin-naive patients with suboptimal
accuracy and provide clinical (4–6). initial glycemic stability, a group trained
management as indicated. E
Patients on Intensive Insulin Regimens in structured SMBG (a paper tool was
7.7 Providers should be aware of the
SMBG is especially important for insulin- used at least quarterly to collect and
differences in accuracy among
treated patients to monitor for and pre- interpret seven-point SMBG profiles
glucose metersdonly U.S. Food
vent hypoglycemia and hyperglycemia. taken on 3 consecutive days) reduced
and Drug Administration–approved
Most patients using intensive insulin regi- their A1C by 0.3% more than the control
meters should be used with un-
mens (multiple daily injections or insulin group (14). A trial of once-daily SMBG
expired strips, purchased from a
pump therapy) should be encouraged to that included enhanced patient
pharmacy or licensed distributor. E
assess glucose levels using SMBG (and/ feedback through messaging found no
or CGM) prior to meals and snacks, at clinically or statistically significant
Major clinical trials of insulin-treated bedtime, occasionally postprandially, change in A1C at 1 year (13). Meta-
patients have included self-monitoring prior to exercise, when they suspect low analyses have suggested that SMBG can
of blood glucose (SMBG) as part of blood glucose, after treating low blood reduce A1C by 0.25–0.3% at 6 months
multifactorial interventions to demon- glucose until they are normoglycemic, (15–17), but the effect was attenuated at
strate the benefit of intensive glycemic and prior to and while performing critical 12 months in one analysis (15). Reduc-
control on diabetes complications (2). tasks such as driving. For many patients tions in A1C were greater (20.3%) in
SMBG is thus an integral component using SMBG, this will require testing up trials where structured SMBG data were
of effective therapy of patients tak- to 6–10 times daily, although individual used to adjust medications, but A1C was
ing insulin. In recent years, continuous needs may vary. A database study of not changed significantly without such
care.diabetesjournals.org Diabetes Technology S79
Table 7.2—Comparison of ISO 15197:2013 and FDA blood glucose meter accuracy standards
Setting FDA (154,155) ISO 15197:2013 (156)
Home use 95% within 15% for all BG in the usable BG range† 95% within 15% for BG $100 mg/dL
99% within 20% for all BG in the usable BG range† 95% within 15 mg/dL for BG ,100 mg/dL
99% in A or B region of consensus error grid‡
Hospital use 95% within 12% for BG $75 mg/dL
95% within 12 mg/dL for BG ,75 mg/dL
98% within 15% for BG $75 mg/dL
98% within 15 mg/dL for BG ,75 mg/dL
BG, blood glucose; FDA, U.S. Food and Drug Administration; ISO, International Organization for Standardization. To convert mg/dL to mmol/L, see
endmemo.com/medical/unitconvert/Glucose.php. †The range of blood glucose values for which the meter has been proven accurate and will provide
readings (other than low, high, or error). ‡Values outside of the “clinically acceptable” A and B regions are considered “outlier” readings and may be
dangerous to use for therapeutic decisions (157).
Some real-time systems require calibra- Real-time CGM Device Use in Adults
7.16 People who have been using
tion by the user, which varies in frequency With Type 1 Diabetes
continuous glucose monitors
depending on the device. Additionally, for Data exist to support the use of real-time
should have continued access
some CGM systems, the FDA suggests CGM in adults, both those on multiple
across third-party payers. E
SMBG for making treatment decisions. daily injections (MDI) and continuous
Devices that require SMBG confirmation subcutaneons insulin infusion (CSII). In
CGM measures interstitial glucose
(which correlates well with plasma glu- are called “adjunctive,” while those that terms of RCTs in people with type 1
do not are called “nonadjunctive.” An RCT diabetes, there are four studies in adults
cose). There are two basic types of CGM
of 226 adults suggested that a CGM device with A1C as the primary outcome
devices: those that provide unblinded data
could be used safely and effectively with- (28–32), three studies in adults with
to the user and those that are blinded with hypoglycemia as the primary outcome
data available to the patient and their out regular confirmatory SMBG in patients
with well-controlled type 1 diabetes at (33–35), four studies in adults and chil-
health care provider for retrospective anal- dren with A1C as the primary outcome
ysis. Table 7.3 provides the definitions low risk of severe hypoglycemia (23). Two
(36–39), and three studies in adults and
for the types of CGM devices. For devices CGM devices are approved by the FDA
children with hypoglycemia as a primary
that provide patients unblinded data, for making treatment decisions without
outcome (40–42).
SMBG calibration or confirmation (24,25).
most of the published randomized con-
The abundance of data provided by Primary Outcome: A1C Reduction
trolled trials (RCTs) have been performed
CGM offers opportunities to analyze pa- In general, A1C reduction was shown in
using real-time CGM devices that have studies where the baseline A1C was higher.
tient data more granularly than was pre-
alarms and alerts. It is difficult to deter- In two larger studies in adults with type 1
viously possible, providing additional
mine how much impact having these information to aid in achieving glycemic diabetes that assessed the benefit of real-
notices makes in terms of reacting to targets. A variety of metrics have been pro- time CGM in patients on MDI, there were
glucose levels. There is one small study posed (26) and are discussed in Section significant reductions in A1C: –0.6% in one
in patients at risk for hypoglycemia that 6, “Glycemic Targets” (https://doi.org/10 (28,29) and –0.43% in the other (30). No
compares real-time CGM with intermit- .21337/dc20-S006). CGM is essential for reduction in A1C was seen in a small study
tently scanned CGM (isCGM) (22). The creating the ambulatory glucose profile performed in underserved, less well-
study showed improvement in time spent (AGP) and providing data on time in educated adults with type 1 diabetes
in hypoglycemia with real-time CGM com- range, percentage of time spent above (31). In the adult subset of the JDRF CGM
pared with isCGM. and below range, and variability (27). study, there was a significant reduction in
A1C of –0.53% (43) in patients who were
primarily treated with insulin pump ther-
Table 7.3—Continuous glucose monitoring (CGM) devices
apy. Better adherence in wearing the
Real-time CGM CGM systems that measure glucose levels continuously and real-time CGM device resulted in a
provide the user automated alarms and alerts at specific
glucose levels and/or for changing glucose levels.
greater likelihood of an improvement in
glycemic control (32,36).
Intermittently scanned CGM CGM systems that measure glucose levels continuously but
only display glucose values when swiped by a reader or Primary Outcome: Hypoglycemia
a smart phone that reveals the glucose levels. In studies in adults where reduction in
Blinded (professional) CGM CGM devices that measure glucose levels that are not episodes of hypoglycemia was the pri-
displayed to the patient in real time. These devices are mary end point, significant reductions
generally initiated in a clinic, using a reader that is were seen in individuals with type 1
owned by the clinic. They are removed after a period of
time (generally 10–14 days) and analyzed by the patient
diabetes on MDI or CSII (33–35). In
and provider to assess glycemic patterns and trends. one study in patients who were at higher
Unblinded CGM CGM devices that measure glucose levels that are displayed risk for episodes of hypoglycemia (35),
to the patient. there was a reduction in rates of all levels
of hypoglycemia (see Section 6 “Glycemic
care.diabetesjournals.org Diabetes Technology S81
CSII or insulin pumps have been available must be recognized and managed early diabetes, there is insufficient evidence to
in the U.S. for 40 years. These devices (97); lipohypertrophy or, less frequently, make recommendations.
deliver rapid-acting insulin throughout the lipoatrophy (98,99); and pump site in- Commonbarrierstopumptherapyadop-
day to help manage blood glucose levels. fection (100). Discontinuation of pump tion in children and adolescents are con-
Most insulin pumps use tubing to deliver therapy is relatively uncommon today; cerns regarding the physical interference of
insulin through a cannula, while a few the frequency has decreased over the the device, discomfort with idea of having a
attach directly to the skin, without tubing. past few decades, and its causes have device on the body, therapeutic effective-
Most studies comparing MDI with CSII changed (100,101). Current reasons for ness, and financial burden (107,117).
have been relatively small and of short attrition are problems with cost, wear-
duration. However, a recent systematic ability, disliking the pump, suboptimal Insulin Pumps in Patients With Type 2
review and meta-analysis concluded that glycemic control, or mood disorders and Other Types of Diabetes
pump therapy has modest advantages (e.g., anxiety or depression) (102). Certain patients with insulin deficiency,
for lowering A1C (20.30% [95% CI 20.58 for instance those with long standing
to 20.02]) and for reducing severe hypo- Insulin Pumps in Pediatric Patients type 2 diabetes, those who have had a
glycemia rates in children and adults (88). The safety of insulin pumps in youth has pancreatectomy, and/or individuals with
There is no consensus to guide choosing been established for over 15 years (103). cystic fibrosis may benefit from insulin
which form of insulin administration is best Studying the effectiveness of CSII in pump therapy. This is an individual de-
for a given patient, and research to guide lowering A1C has been challenging be- cision and must be tailored to fit patient
this decision-making is needed (89). Thus, cause of the potential selection bias of needs and preferences.
the choice of MDI or an insulin pump is observational studies. Participants on
often based upon the individual character- CSII may have a higher socioeconomic Insulin Pumps in Older Adults
istics of the patient and which is most likely status that may facilitate better glycemic Older individuals with type 1 diabetes
to benefit him or her. Newer systems, such control (104) versus MDI. In addition, the benefit from ongoing insulin pump ther-
as sensor-augmented pumps and auto- fast pace of development of new insulins apy. There is no data to suggest that
matic insulin delivery systems, are dis- and technologies quickly renders com- measurement of C-peptide levels or
cussed elsewhere in this section. parisons obsolete. However, RCTs com- antibodies predicts success with insulin
Adoption of pump therapy in the U.S. paring CSII and MDI with insulin analogs pump therapy (118,119). Additionally,
shows geographical variations, which demonstrate a modest improvement in frequency of follow-up does not influ-
may be related to provider preference A1C in participants on CSII (105,106). ence outcomes. Access to insulin pump
or center characteristics (90,91) and so- Observational studies, registry data, therapy should be allowed/continued in
cioeconomic status, as pump therapy is and meta-analysis have also suggested older adults as it is for younger people.
more common in individuals of higher an improvement of glycemic control in
socioeconomic status as reflected by participants on CSII (107–109). Although Combined Insulin Pump and Sensor
race/ethnicity, private health insurance, hypoglycemia was a major adverse effect Systems
family income, and education (91,92). of intensified insulin regimen in the Di- Recommendations
Given the additional barriers to optimal abetes Control and Complications Trial 7.25 Sensor-augmented pump ther-
diabetes care observed in disadvantaged (DCCT) (110), data suggest that CSII may apy with automatic low glucose
groups (93), addressing the differences reduce the rates of severe hypoglycemia suspend may be considered for
in access to insulin pumps and other compared with MDI (109,111–113). adults and children with type 1
diabetes technology may contribute to There is also evidence that CSII may diabetes to prevent/mitigate
fewer health disparities. reduce DKA risk (109,114) and diabetes episodes of hypoglycemia. B
Pump therapy can be successfully complications, in particular, retinopathy 7.26 Automated insulin delivery systems
started at the time of diagnosis (94,95). and peripheral neuropathy in youth, may be considered in children B
Practical aspects of pump therapy initia- compared with MDI (62). Finally, treat- and adults with type 1 diabetes
tion include assessment of patient and ment satisfaction and quality-of-life to improve glycemic control. A
family readiness (although there is no measures improved on CSII compared 7.27 Individual patients may be using
consensus on which factors to consider with MDI (115,116). Therefore, CSII can systems not approved by the U.S.
in adults [96] or pediatric patients), se- be used safely and effectively in youth Food and Drug Administration
lection of pump type and initial pump with type 1 diabetes to assist with achiev- such as do-it-yourself closed
settings, patient/family education of po- ing targeted glycemic control while re- loop systems and others; providers
tential pump complications (e.g., diabetic ducing the risk of hypoglycemia and DKA, cannot prescribe these systems
ketoacidosis [DKA] with infusion set fail- improving quality of life and preventing but can provide safety informa-
ure), transition from MDI, and introduction long-term complications. Based on pa- tion/troubleshooting/backup
of advanced pump settings (e.g., tem- tient–provider shared decision-making, advice for the individual devices
porary basal rates, extended/square/ insulin pumps may be considered in all to enhance patient safety. E
dual wave bolus). pediatric patients. In particular, pump
Complications of the pump can be therapy may be the preferred mode of
caused by issues with infusion sets (dis- insulin delivery for children under 7 years Sensor-Augmented Pumps
lodgement, occlusion), which place pa- of age (63). Because of a paucity of data Sensor-augmented pumps that suspend
tients at risk for ketosis and DKA and thus in adolescents and youth with type 2 insulin when glucose is low or predicted
S84 Diabetes Technology Diabetes Care Volume 43, Supplement 1, January 2020
to go low within the next 30 min have delivery (139–141). These systems are or less information, such as being part of
been approved by the FDA. The Auto- not approved by the FDA, although there a registry or data repository or not).
mation to Simulate Pancreatic Insulin are efforts underway to obtain regula- There are many online programs that
Response (ASPIRE) trial of 247 patients tory approval for them. The information offer lifestyle counseling to aid with
with type 1 diabetes and documented on how to set up and manage these weight loss and increase physical activity
nocturnal hypoglycemia showed that systems is freely available on the inter- (144). Many of these include a health
sensor-augmented insulin pump therapy net, and there are internet groups where coach and can create small groups of
with a low glucose suspend function people inform each other as to how to set similar patients in social networks. There
significantly reduced nocturnal hypogly- up and use them. Although not pre- are programs that aim to treat predia-
cemia over 3 months without increasing scribed by providers, it is important to betes and prevent progression to diabe-
A1C levels (39). In a different sensor- keep patients who are using these meth- tes, often following the model of the
augmented pump, predictive low glu- ods for automated insulin delivery safe. Diabetes Prevention Program (145,146).
cose suspend reduced time spent with Part of this entails making sure people Others assist in improving diabetes out-
glucose ,70 mg/dL from 3.6% at baseline have a “backup plan” in case of pump comes by remotely monitoring patient
to 2.6% (3.2% with sensor-augmented failure. Additionally, in most DIY systems, clinical data (for instance, wireless mon-
pump therapy without predictive low insulin doses are adjusted based on the itoring of glucose levels, weight, or blood
glucose suspend) without rebound hyper- pump settings for basal rates, carbohy- pressure) and providing feedback and
glycemia during a 6-week randomized drate ratios, correction doses, and insulin coaching (147–149). There are text mes-
crossover trial (120). These devices may activity. Therefore, these settings can be saging approaches that tie into a variety
offer the opportunity to reduce hypogly- evaluated and changed based on the of different types of lifestyle and treat-
cemia for those with a history of nocturnal patient’s insulin requirements. ment programs, which vary in terms of
hypoglycemia. Additional studies have their effectiveness (150,151). For many of
been performed, in adults and children, Digital Health Technology these interventions, there are limited RCT
showing the benefits of this technology Increasingly, people are turning to the data and long-term follow-up is lacking.
(121,122). internet for advice, coaching, connec- But for an individual patient, opting into
Automated insulin delivery systems tion, and health care. Diabetes, in part one of these programs can be helpful and,
increase and decrease insulin delivery because it is both common and numeric, for many, is an attractive option.
based on sensor derived glucose level to lends itself to the development of apps
begin to approximate physiologic insulin and online programs. The FDA approves Inpatient Care
delivery. These systems consist of three and monitors clinically validated, digital, Patients who are comfortable using their
components: an insulin pump, a contin- usually online, health technologies diabetes devices, such as insulin pumps
uous glucose sensor, and an algorithm intended to treat a medical or psycho- and sensors, should be given the chance
that determines insulin delivery. With logical conditiondthese are known as to use them in an inpatient setting if they
these systems, insulin delivery can not digital therapeutics or “digiceuticals” are competent to do so (152,153). Pa-
only be suspended but also increased or (142). Other applications, such as those tients who are familiar with treating their
decreased based on sensor glucose val- that assist in displaying or storing data, own glucose levels can often adjust in-
ues. Emerging evidence suggests such encourage a healthy lifestyle or provide sulin doses more knowledgably than in-
systems may lower the risk of exercise- limited clinical data support. Therefore, it patient staff who do not personally know
related hypoglycemia (123) and may is possible to find apps that have been the patient or their management style.
have psychosocial benefits (124–127). fully reviewed and approved and others However, this should occur based on the
While eventually insulin delivery in designed and promoted by people with hospital’s policies for diabetes manage-
closed-loop systems may be truly auto- relatively little skill or knowledge in the ment, and there should be supervision to
mated, currently meals must be an- clinical treatment of diabetes. be sure that the individual can adjust their
nounced. A so-called hybrid approach, An area of particular importance is that insulin doses in a hospitalized setting
hybrid closed-loop, has been adopted in of online privacy and security. There are where factors such as infection, certain
first-generation closed-loop systems and established cloud-based data collection medications, immobility, changes in diet,
requires users to bolus for meals and programs, such as Tidepool, Glooko, and and other factors can impact insulin sen-
snacks. Multiple studies, utilizing a vari- others, that have been developed with sitivity and the response to insulin.
ety of systems with varying algorithms, appropriate data security features and
pump, and sensors have been performed are HIPAA (U.S. Health Insurance Porta- The Future
in adults and children (128–138). Use of bility and Accountability Act of 1996) The pace of development in diabetes
these systems depends on patient pref- compliant. These programs can be useful technology is extremely rapid. New ap-
erence and selection of patients (and/or for monitoring patients, both by the proaches and tools are available each
caregivers) who are capable of safely and patients themselves as well as their year. It is hard for research to keep up
effectively using the devices. health care team (143). Consumers should with these advances because by the
Some people with type 1 diabetes read the policy regarding data privacy time a study is completed, newer ver-
have been using “do-it-yourself” (DIY) and sharing before providing data into sions of the devices are already on the
systems that combine a pump and a real- an application and learn how they can market. The most important component
time CGM with a controller and an control how their data will be used (some in all of these systems is the patient.
algorithm designed to automate insulin programs offer the ability to share more Technology selection must be appropriate
care.diabetesjournals.org Diabetes Technology S85
for the individual. Simply having a device 12. Simon J, Gray A, Clarke P, Wade A, Neil A, 1 November 2019. Available from https://www.fda
or application does not change outcomes Farmer A; Diabetes Glycaemic Education and .gov/NewsEvents/Newsroom/PressAnnouncements/
Monitoring Trial Group. Cost effectiveness of self ucm577890.htm
unless the human being engages with it monitoring of blood glucose in patients with non- 26. Danne T, Nimri R, Battelino T, et al. In-
to create positive health benefits. This insulin treated type 2 diabetes: economic eval- ternational consensus on use of continuous
underscores the need for the health care uation of data from the DiGEM trial. BMJ 2008; glucose monitoring. Diabetes Care 2017;40:
provider to assist the patient in device/ 336:1177–1180 1631–1640
program selection and to support its use 13. Young LA, Buse JB, Weaver MA, et al.; 27. Battelino T, Danne T, Bergenstal RM, et al.
Monitor Trial Group. Glucose self-monitoring Clinical targets for continuous glucose monitor-
through ongoing education and training. in non-insulin-treated patients with type 2 di- ing data interpretation: recommendations from
Expectations must be tempered by realityd abetes in primary care settings: a randomized the international consensus on time in range.
we do not yet have technology that com- trial. JAMA Intern Med 2017;177:920–929 Diabetes Care 2019;42:1593–1603
pletely eliminates the self-care tasks neces- 14. Polonsky WH, Fisher L, Schikman CH, et al. 28. Beck RW, Riddlesworth T, Ruedy K, et al.;
Structured self-monitoring of blood glucose sig- DIAMOND Study Group. Effect of continuous
sary for treating diabetes, but the tools
nificantly reduces A1C levels in poorly controlled, glucose monitoring on glycemic control in adults
described in this section can make it easier noninsulin-treated type 2 diabetes: results from with type 1 diabetes using insulin injections: the
to manage. the Structured Testing Program study. Diabetes DIAMOND randomized clinical trial. JAMA 2017;
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Pediatr Diabetes 2014;15:564–572 105. Doyle EA, Weinzimer SA, Steffen AT, Ahern reported barriers. Diabetes Technol Ther 2017;
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following diagnosis of type 1 diabetes. Diabetes Diabetes Care 2004;27:1554–1558 cutaneous insulin infusion pump therapy did not
Technol Ther 2013;15:929–934 106. Alemzadeh R, Ellis JN, Holzum MK, Parton improve utilization or medical costs among older
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dren with type 1 diabetes. Pediatrics 2015;135: in type 1 diabetes. Pediatrics 2004;114:e91–e95 OpT2mise Study Group. Improved HbA1c, total
424–434 107. Sherr JL, Hermann JM, Campbell F, et al.; daily insulin dose, and treatment satisfaction
93. Redondo MJ, Libman I, Cheng P, et al.; T1D Exchange Clinic Network, the DPV Initiative, with insulin pump therapy compared to multiple
Pediatric Diabetes Consortium. Racial/ethnic mi- and the National Paediatric Diabetes Audit and daily insulin injections in patients with type 2
nority youth with recent-onset type 1 diabetes the Royal College of Paediatrics and Child Health diabetes irrespective of baseline C-peptide lev-
have poor prognostic factors. Diabetes Care registries. Use of insulin pump therapy in children els. Endocr Pract 2018;24:446–452
2018;41:1017–1024 and adolescents with type 1 diabetes and its 120. Forlenza GP, Li Z, Buckingham BA, et al.
94. Ramchandani N, Ten S, Anhalt H, et al. Insulin impact on metabolic control: comparison of Predictive low-glucose suspend reduces hypo-
pump therapy from the time of diagnosis of results from three large, transatlantic paediatric glycemia in adults, adolescents, and children with
type 1 diabetes. Diabetes Technol Ther 2006;8: registries. Diabetologia 2016;59:87–91 type 1 diabetes in an at-home randomized
663–670 108. Jeitler K, Horvath K, Berghold A, et al. crossover study: results of the PROLOG trial.
95. Berghaeuser MA, Kapellen T, Heidtmann B, Continuous subcutaneous insulin infusion versus Diabetes Care 2018;41:2155–2161
Haberland H, Klinkert C, Holl RW; German work- multiple daily insulin injections in patients with 121. Wood MA, Shulman DI, Forlenza GP, et al.
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atric patients. Continuous subcutaneous insulin analysis. Diabetologia 2008;51:941–951 “suspend before low” feature in children with
S88 Diabetes Technology Diabetes Care Volume 43, Supplement 1, January 2020
type 1 diabetes. Diabetes Technol Ther 2018;20: patients with type 1 diabetes in a supervised 147. Öberg U, Isaksson U, Jutterström L, Orre CJ,
731–737 hotel setting. Diabetes Obes Metab 2019;21: Hörnsten Å. Perceptions of persons with type 2
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743 135. Anderson SM, Buckingham BA, Breton MD, connected glucose meter with certified diabetes
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Diabetes Care Volume 43, Supplement 1, January 2020 S89
There is strong and consistent evidence that obesity management can delay the
progression from prediabetes to type 2 diabetes (1–5) and is beneficial in the
treatment of type 2 diabetes (6–17). In patients with type 2 diabetes who also have
overweight or obesity, modest and sustained weight loss has been shown to improve
glycemic control and to reduce the need for glucose-lowering medications (6–8). Small
studies have demonstrated that in patients with type 2 diabetes and obesity, more
extreme dietary energy restriction with very low-calorie diets can reduce A1C
to ,6.5% (48 mmol/mol) and fasting glucose to ,126 mg/dL (7.0 mmol/L) in
the absence of pharmacologic therapy or ongoing procedures (10,18,19). The goal of
this section is to provide evidence-based recommendations for weight-loss therapy,
including diet, behavioral, pharmacologic, and surgical interventions, for obesity
management as treatment for hyperglycemia in type 2 diabetes.
ASSESSMENT
Recommendations
8.1 Measure height and weight and calculate BMI at annual visits or more
frequently. E Suggested citation: American Diabetes Associa-
8.2 Based on clinical considerations, such as the presence of comorbid heart tion. 8. Obesity management for the treatment
failure or significant unexplained weight gain or loss, weight may need to be of type 2 diabetes: Standards of Medical Care in
Diabetesd2020. Diabetes Care 2020;43(Suppl. 1):
monitored and evaluated more frequently. B If deterioration of medical status S89–S97 (https://doi.org/10.2337/dc20-s008)
is associated with significant weight gain or loss, inpatient evaluation should
© 2019 by the American Diabetes Association.
be considered, specifically focused on the association between medication Readers may use this article as long as the work
use, food intake, and glycemic status. E is properly cited, the use is educational and not
8.3 For patients with a high level of weight-related distress, special accommo- for profit, and the work is not altered. More infor-
dations should be made to ensure privacy during weighing. E mation is available at http://www.diabetesjournals
.org/content/license.
S90 Obesity Management for the Treatment of Type 2 Diabetes Diabetes Care Volume 43, Supplement 1, January 2020
feasibility of achieving and maintaining practitioners, with close patient moni- PHARMACOTHERAPY
long-term weight loss in patients with toring, can be beneficial. Within the in-
Recommendations
type 2 diabetes. In the Look AHEAD tensive lifestyle intervention group of the
8.11 When choosing glucose-lowering
intensive lifestyle intervention group, Look AHEAD trial, for example, use of a
medications for patients with
mean weight loss was 4.7% at 8 years partial meal replacement plan was as-
type 2 diabetes and overweight
(32). Approximately 50% of intensive sociated with improvements in diet
or obesity, consider a medica-
lifestyle intervention participants lost quality (38). The diet choice should be
tion’s effect on weight. B
and maintained $5% of their initial based on the patient’s health status and
8.12 Whenever possible, minimize
body weight, and 27% lost and main- preferences, including a determination
medications for comorbid con-
tained $10% of their initial body weight of food availability and other cultural
ditions that are associated with
at 8 years (32). Participants randomly circumstances that could affect dietary
weight gain. E
assigned to the intensive lifestyle group patterns (39).
8.13 Weight-loss medications are ef-
achieved equivalent risk factor con- Intensive behavioral lifestyle interven-
fective as adjuncts to diet, phys-
trol but required fewer glucose-, blood tions should include $16 sessions in
ical activity, and behavioral
pressure–, and lipid-lowering medica- 6 months and focus on dietary changes,
counseling for selected patients
tions than those randomly assigned physical activity, and behavioral strate-
with type 2 diabetes and
to standard care. Secondary analyses gies to achieve an ;500–750 kcal/day
BMI $27 kg/m2. Potential ben-
of the Look AHEAD trial and other large energy deficit. Interventions should be
efits must be weighed against
cardiovascular outcome studies docu- provided by trained interventionists in
potential risks of medications. A
ment other benefits of weight loss in either individual or group sessions (34).
8.14 If a patient’s response to weight-
patients with type 2 diabetes, includ- Assessing an individual’s motivation level,
loss medications is ,5% weight
ing improvements in mobility, physical life circumstances, and willingness to im-
loss after 3 months or if there
and sexual function, and health-related plement lifestyle changes to achieve weight
are significant safety or tolera-
quality of life (23). A post hoc analysis loss should be considered along with med-
bility issues at any time, the
of the Look AHEAD study suggests ical status when weight-loss interventions
medication should be discon-
that heterogeneous treatment effects are recommended and initiated (27).
tinued and alternative medica-
may have been present. Participants Patients with type 2 diabetes and
tions or treatment approaches
who had moderately or poorly controlled overweight or obesity who have lost
should be considered. A
diabetes (A1C $6.8% [51 mmol/mol]) weight during a 6-month intensive be-
as well as those with well-controlled havioral lifestyle intervention should be
diabetes (A1C ,6.8% [51 mmol/mol]) enrolled in long-term ($1 year) compre- Glucose-Lowering Therapy
and good self-reported health were hensive weight-loss maintenance pro- Agents associated with varying degrees
found to have significantly reduced grams that provide at least monthly of weight loss include metformin,
cardiovascular events with inten- contact with a trained interventionist a-glucosidase inhibitors, sodium–glucose
sive lifestyle intervention during and focus on ongoing monitoring of cotransporter 2 inhibitors, glucagon-like
follow-up (33). body weight (weekly or more frequently) peptide 1 receptor agonists, and amylin
and/or other self-monitoring strategies mimetics. Dipeptidyl peptidase 4 inhibi-
Lifestyle Interventions such as tracking intake, steps, etc.; con- tors are weight neutral. Unlike these
Significant weight loss can be attained tinued consumption of a reduced-calorie agents, insulin secretagogues, thiazolidi-
with lifestyle programs that achieve a diet; and participation in high levels of nediones, and insulin often cause weight
500–750 kcal/day energy deficit, which in physical activity (200–300 min/week) gain (see Section 9 “Pharmacologic Ap-
most cases is approximately 1,200–1,500 (40). Some commercial and proprietary proaches to Glycemic Treatment,” https://
kcal/day for women and 1,500–1,800 weight-loss programs have shown doi.org/10.2337/dc20-s009).
kcal/day for men, adjusted for the indi- promising weight-loss results (41). A meta-analysis of 227 randomized
vidual’s baseline body weight. Weight When provided by trained practi- controlled trials of glucose-lowering
loss of 3–5% is the minimum necessary tioners in medical care settings with treatments in type 2 diabetes found
for clinical benefit (20,34). However, close medical monitoring, short-term that A1C changes were not associated
weight-loss benefits are progressive; (3-month) interventions that use very with baseline BMI, indicating that pa-
more intensive weight-loss goals (.5%, low-calorie diets (defined as #800 tients with obesity can benefit from the
.7%, .15%, etc.) may be pursued if kcal/day) and total meal replacements same types of treatments for diabetes as
needed to achieve a healthy weight may achieve greater short-term weight normal-weight patients (44).
and/or if the patient is more motivated loss (10–15%) than intensive behav-
and more intensive goals can be feasibly ioral lifestyle interventions that typically Concomitant Medications
and safely attained. achieve 5% weight loss. However, weight Providers should carefully review the
Dietary interventions may differ in the regain following the cessation of very patient’s concomitant medications
types of foods they restrict (such as high- low-calorie diets is greater than regain and, whenever possible, minimize or
fat or high-carbohydrate foods) but are following intensive behavioral lifestyle provide alternatives for medications
effective if they create the necessary interventions unless a long-term com- that promote weight gain. Examples of
energy deficit (20,35–37). Use of meal prehensive weight-loss maintenance medications associated with weight gain
replacement plans prescribed by trained program is provided (42,43). include antipsychotics (e.g., clozapine,
S92 Obesity Management for the Treatment of Type 2 Diabetes Diabetes Care Volume 43, Supplement 1, January 2020
All medications are contraindicated in women who are or may become pregnant. Women of reproductive potential must be counseled regarding the use of reliable methods of contraception. Select
safety and side effect information is provided; for a comprehensive discussion of safety considerations, please refer to the prescribing information for each agent. b.i.d., twice daily; BP, blood pressure;
ER, extended release; MEN 2, multiple endocrine neoplasia syndrome type 2; MTC, medullary thyroid carcinoma; OTC, over the counter; PBO, placebo; q.d., daily; Rx, prescription; t.i.d., three times
daily; XR, extended release. *Use lowest effective dose; maximum appropriate dose is 37.5 mg. †Duration of treatment was 28 weeks in a general obese adult population. **Agent has demonstrated cardiovascular
safety in a dedicated cardiovascular outcome trial (118,119). ‡Enrolled participants had normal (79%) or impaired (21%) glucose tolerance. §Maximum dose, depending on response, is 15 mg/92 mg q.d.
| Approximately 68% of enrolled participants had type 2 diabetes or impaired glucose tolerance.
S93
S94 Obesity Management for the Treatment of Type 2 Diabetes Diabetes Care Volume 43, Supplement 1, January 2020
degrees and lengths of remission compared of minimally invasive approaches (lapa- or other mental health conditions should
with other bariatric surgeries (17,70). Avail- roscopic surgery), enhanced training and therefore first be assessed by a mental
able data suggest an erosion of diabetes credentialing, and involvement of multi- health professional with expertise in
remission over time (71): 35–50% or disciplinary teams. Mortality rates with obesity management prior to consider-
more of patients who initially achieve metabolic operations are typically 0.1– ation for surgery (107). Surgery should
remission of diabetes eventually experi- 0.5%, similar to cholecystectomy or hys- be postponed in patients with alcohol
ence recurrence. However, the median terectomy (87–91). Morbidity has also or substance abuse disorders, significant
disease-free period among such individ- dramatically declined with laparoscopic depression, suicidal ideation, or other men-
uals following RYGB is 8.3 years (72,73). approaches. Major complications rates tal health conditions until these condi-
With or without diabetes relapse, the (e.g., venous thromboembolism, need tions have been fully addressed. Individuals
majority of patients who undergo sur- for operative reintervention) are 2–6%, with preoperative psychopathology should
gery maintain substantial improvement with other minor complications in up to be assessed regularly following metabolic
of glycemic control from baseline for 15% (87–96), rates which compare favor- surgery to optimize mental health man-
at least 5 years (74,75) to 15 years ably with those for other commonly per- agement and to ensure that psychiatric
(51,52,73,76–78). formed elective operations (91). Empirical symptoms do not interfere with weight loss
Exceedingly few presurgical predic- data suggest that proficiency of the and lifestyle changes.
tors of success have been identified, operating surgeon is an important
but younger age, shorter duration of factor for determining mortality, com-
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S98 Diabetes Care Volume 43, Supplement 1, January 2020
Insulin Therapy
Because the hallmark of type 1 diabetes is absent or near-absent b-cell function,
insulin treatment is essential for individuals with type 1 diabetes. In addition to
hyperglycemia, insulinopenia can contribute to other metabolic disturbances like
hypertriglyceridemia and ketoacidosis as well as tissue catabolism that can be
life threatening. Severe metabolic decompensation can be, and was, mostly pre-
vented with once or twice daily injections for the six or seven decades after the
discovery of insulin. However, over the past three decades, evidence has accumulated
supporting more intensive insulin replacement, using multiple daily injections of Suggested citation: American Diabetes Associa-
insulin or continuous subcutaneous administration through an insulin pump, as tion. 2. Pharmacologic approaches to glycemic
providing the best combination of effectiveness and safety for people with type 1 treatment: Standards of Medical Care inDiabetesd
diabetes. The Diabetes Control and Complications Trial (DCCT) demonstrated that 2020. Diabetes Care 2020;43(Suppl. 1):S98–S110
intensive therapy with multiple daily injections or continuous subcutaneous insulin © 2019 by the American Diabetes Association.
infusion (CSII) reduced A1C and was associated with improved long-term outcomes Readers may use this article as long as the work
is properly cited, the use is educational and not
(1–3). The study was carried out with short-acting (regular) and intermediate-acting for profit, and the work is not altered. More infor-
(NPH) human insulins. In this landmark trial, lower A1C with intensive control (7%) mation is available at http://www.diabetesjournals
led to ;50% reductions in microvascular complications over 6 years of treatment. .org/content/license.
care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S99
However, intensive therapy was associ- meta-analysis concluded that pump ther- Typical multidose regimens for pa-
ated with a higher rate of severe hypo- apy has modest advantages for lowering tients with type 1 diabetes combine
glycemia than conventional treatment (62 A1C (–0.30% [95% CI –0.58 to –0.02]) and premeal use of shorter-acting insulins
compared with 19 episodes per 100 pa- for reducing severe hypoglycemia rates with a longer-acting formulation, usually
tient-years of therapy). Follow-up of sub- in children and adults (11). However, there at night. The long-acting basal dose is
jects from the DCCT more than 10 years is no consensus to guide the choice of titrated to regulate overnight, fasting
after the active treatment component of injection or pump therapy in a given glucose. Postprandial glucose excur-
the study demonstrated less macrovas- patient, and research to guide this sions are best controlled by a well-timed
cular as well as less microvascular com- decision-making is needed (12). The arrival injection of prandial insulin. The opti-
plications in the group that received of continuous glucose monitors to clinical mal time to administer prandial insulin
intensive treatment. practice has proven beneficial in specific varies, based on the pharmacokinetics
Over the last 25 years, rapid-acting and circumstances. Reduction of nocturnal of the formulation (regular, RAA, in-
long-acting insulin analogs have been hypoglycemia in people with type 1 di- haled), the premeal blood glucose level,
developed that have distinct pharmaco- abetes using insulin pumps with glucose and carbohydrate consumption. Recom-
kinetics compared with recombinant hu- sensors is improved by automatic sus- mendations for prandial insulin dose
man insulins: basal insulin analogs have pension of insulin delivery at a preset administration should therefore be indi-
longer duration of action with flatter, glucose level (12–14). The U.S. Food and vidualized. Physiologic insulin secretion
more constant plasma concentrations Drug Administration (FDA) has also ap- varies with glycemia, meal size, and tissue
and activity profiles than NPH insulin; proved the first hybrid closed-loop pump demands for glucose. To approach this
rapid-acting analogs (RAA) have a quicker system. The safety and efficacy of hybrid variability in people using insulin treat-
onset and peak and shorter duration of closed-loop systems has been supported ment, strategies have evolved to adjust
action than regular human insulin. In in the literature in adolescents and adults prandial doses based on predicted needs.
people with type 1 diabetes, treatment with type 1 diabetes (15,16), and recent Thus, education of patients on how to
with analog insulins is associated with less evidence suggests that a closed-loop adjust prandial insulin to account for
hypoglycemia and weight gain as well as system is superior to sensor-augmented carbohydrate intake, premeal glucose
lower A1C compared with human insu- pump therapy for glycemic control levels, and anticipated activity can be
lins (4–6). More recently, two new insulin and reduction of hypoglycemia over 3 effective and should be offered to most
formulations with enhanced rapid action months of comparison in children and patients (20,21). For individuals in whom
profiles have been introduced. Inhaled adults with type 1 diabetes (17). Intensive carbohydrate counting is effective, esti-
human insulin has a rapid peak and insulin management using a version of CSII mates of the fat and protein content of
shortened duration of action compared and continuous glucose monitoring should meals can be incorporated into their
with RAA and may cause less hypogly- be considered in most patients. See Sec- prandial dosing for added benefit (22).
cemia and weight gain (7), and faster- tion 7 “Diabetes Technology” (https://doi
acting insulin aspart may reduce prandial .org/10.2337/dc20-S007) for a full discus- Insulin Injection Technique
excursions better than RAA (8); further sion of insulin delivery devices. Ensuring that patients and/or caregivers
investigation is needed to establish a clear In general, patients with type 1 di- understand correct insulin injection tech-
place for these agents in diabetes man- abetes require 50% of their daily insulin nique is important to optimize glucose
agement. In addition, new longer-acting as basal and 50% as prandial. Total daily control and insulin use safety. Thus, it is
basal analogs (U-300 glargine or degludec) insulin requirements can be estimated important that insulin be delivered into
may confer a lower hypoglycemia risk based on weight, with typical doses the proper tissue in the right way. Rec-
compared with U-100 glargine in patients ranging from 0.4 to 1.0 units/kg/day. ommendations have been published else-
with type 1 diabetes (9,10). Despite the Higher amounts are required during pu- where outlining best practices for insulin
advantages of insulin analogs in patients berty, pregnancy, and medical illness. injection (23). Proper insulin injection tech-
with type 1 diabetes, for some patients the The American Diabetes Association/ nique includes injecting into appropriate
expense and/or intensity of treatment JDRF Type 1 Diabetes Sourcebook notes body areas, injection site rotation, ap-
required for their use is prohibitive. There 0.5 units/kg/day as a typical starting dose propriate care of injection sites to avoid
are multiple approaches to insulin treat- in patients with type 1 diabetes who are infection or other complications, and avoid-
ment, and the central precept in the metabolically stable, with half adminis- ance of intramuscular (IM) insulin delivery.
management of type 1 diabetes is tered as prandial insulin given to control Exogenous-delivered insulin should be
that some form of insulin be given in blood glucose after meals and the other injected into subcutaneous tissue, not
a planned regimen tailored to the in- half as basal insulin to control glycemia intramuscularly. Recommended sites for
dividual patient to keep them safe, out of in the periods between meal absorption insulin injection include the abdomen,
diabetic ketoacidosis, and avoid signifi- (18); this guideline provides detailed in- thigh, buttock, and upper arm. Because
cant hypoglycemia, with every effort formation on intensification of therapy insulin absorption from IM sites differs
made to reach the patient’s glycemic to meet individualized needs. In addi- according to the activity of the muscle,
targets. tion, the American Diabetes Association inadvertent IM injection can lead to un-
Most studies comparing multiple daily position statement “Type 1 Diabetes predictable insulin absorption and vari-
injections with CSII have been rela- Management Through the Life Span” able effects on glucose, with IM injection
tively small and of short duration. How- provides a thorough overview of type 1 being associated with frequent and unex-
ever, a recent systematic review and diabetes treatment (19). plained hypoglycemia in several reports.
S100 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 43, Supplement 1, January 2020
*For agent-specific dosing recommendations, please refer to the manufacturers’ prescribing information. †FDA approved for CVD benefit. ‡FDA-approved for heart failure indication; §FDA-approved for CKD
indication. CV, cardiovascular; DPP-4, dipeptidyl peptidase 4; DKA, diabetic ketoacidosis; DKD, diabetic kidney disease; GLP-1 RAs, glucagon-like peptide 1 receptor agonists; HF, heart failure; NASH, nonalcoholic
steatohepatitis; SGLT2, sodium–glucose cotransporter 2; SQ, subcutaneous; T2DM, type 2 diabetes.
Pharmacologic Approaches to Glycemic Treatment
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S102 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 43, Supplement 1, January 2020
approach to choosing appropriate phar- very high circulating levels (e.g., as a re- positive and negative effects of new drugs
macologic treatment of blood glucose sult of overdose or acute renal failure) and reduces patient risk and expense (42);
(Fig. 9.1). This includes consideration of have been associated with lactic acidosis. based on these factors, sequential addi-
efficacy and key patient factors: 1) im- However, the occurrence of this compli- tion of oral agents to metformin has been
portant comorbidities such as atheroscle- cation is now known to be very rare, and the standard of care. However, there is
rotic cardiovascular disease (ASCVD) and metformin may be safely used in patients data to support initial combination ther-
indicators of high ASCVD risk, chronic with reduced estimated glomerular filtra- apy for more rapid attainment of glycemic
kidney disease (CKD), and heart failure tion rates (eGFR); the FDA has revised the goals (43,44), and a recent clinical trial
(HF) (see Section 10 “Cardiovascular Dis- label for metformin to reflect its safety in has demonstrated that this approach is
ease and Risk Management,” https://doi patients with eGFR $30 mL/min/1.73 m2 superior to sequential addition of medica-
.org/10.2337/dc20-S010, and Section 11 (37). A recent randomized trial confirmed tions for extending primary and secondary
“Microvascular Complications and Foot previous observations that metformin use failure (45). In the VERIFY trial, partic-
Care,” https://doi.org/10.2337/dc20-S011), is associated with vitamin B12 deficiency ipants receiving the initial combination of
2) hypoglycemia risk, 3) effects on body and worsening of symptoms of neurop- metformin and the dipeptidyl peptidase 4
weight, 4) side effects, 5) cost, and 6) athy (38). This is compatible with a recent (DPP-4) inhibitor vildagliptin had a slower
patient preferences. Lifestyle modifica- report from the Diabetes Prevention Pro- decline of glycemic control compared
tions that improve health (see Section gram Outcomes Study (DPPOS) suggesting with metformin alone and to vildagliptin
5 “Facilitating Behavior Change and periodic testing of vitamin B12 (39). added sequentially to metformin. These
Well-being to Improve Health Outcomes,” In patients with contraindications or results have not been generalized to oral
https://doi.org/10.2337/dc20-S005) should intolerance to metformin, initial therapy agents other than vildagliptin, but they
be emphasized along with any pharma- should be based on patient factors; suggest that more intensive early treat-
cologic therapy. Section 12 “Older Adults” consider a drug from another class de- ment has some benefits and should be
(https://doi.org/10.2337/dc20-S012)andSec- picted in Fig. 9.1. When A1C is $1.5% considered through a shared decision-
tion 13 “Children and Adolescents” (12.5 mmol/mol) above the glycemic making process with patients, as appropriate.
(https://doi.org/10.2337/dc20-S013) target (see Section 6 “Glycemic Targets,” Moreover, since the absolute effectiveness
have recommendations specific for older https://doi.org/10.2337/dc20-S006, for of most oral medications rarely exceeds
adults and for children and adolescents selecting appropriate targets), many pa- 1%, initial combination therapy should be
with type 2 diabetes, respectively; Sec- tients will require dual combination ther- considered in patients presenting with
tion 10 “Cardiovascular Disease and Risk apy to achieve their target A1C level (40). A1C levels 1.5–2.0% above target.
Management” (https://doi.org/10.2337/ Insulin has the advantage of being effec- The choice of medication added to
dc20-S010) and Section 11 “Microvascular tive where other agents are not and should metformin is based on the clinical char-
Complications and Foot Care” (https://doi be considered as part of any combination acteristics of the patient and their pref-
.org/10.2337/dc20-S011) have recommen- regimen when hyperglycemia is severe, erences. Important clinical characteristics
dations for the use of glucose-lowering especially if catabolic features (weight include the presence of established
drugs in the management of cardiovascular loss, hypertriglyceridemia, ketosis) are ASCVD or indicators of high ASCVD risk,
and renal disease, respectively. present. It is common practice to initiate other comorbidities, and risk for specific
insulin therapy for patients who present adverse drug effects, as well as safety,
Initial Therapy with blood glucose levels $300 mg/dL tolerability, and cost. Although there are
Metformin should be started at the time (16.7 mmol/L) or A1C .10% (86 mmol/mol) numerous trials comparing dual therapy
type 2 diabetes is diagnosed unless there or if the patient has symptoms of hy- with metformin alone, there is little ev-
are contraindications; for many patients perglycemia (i.e., polyuria or polydipsia) idence to support one combination over
this will be monotherapy in combination or evidence of catabolism (weight loss) another. A comparative effectiveness
with lifestyle modifications. Metformin (Fig. 9.2). As glucose toxicity resolves, meta-analysis suggests that each new
is effective and safe, is inexpensive, and simplifying the regimen and/or changing class of noninsulin agents added to initial
may reduce risk of cardiovascular events to oral agents is often possible. However, therapy with metformin generally lowers
and death (35). Metformin is available in there is evidence that patients with un- A1C approximately 0.7–1.0% (46,47). If the
an immediate-release form for twice- controlled hyperglycemia associated with A1C target is not achieved after approxi-
daily dosing or as an extended-release type 2 diabetes can also be effectively mately 3 months, metformin can be com-
form that can be given once daily. Com- treated with a sulfonylurea (41). bined with any one of the preferred six
pared with sulfonylureas, metformin as treatment options: sulfonylurea, thiazolidine-
first-line therapy has beneficial effects on Combination Therapy dione, DPP-4 inhibitor, SGLT2 inhibitor, GLP-1
A1C, weight, and cardiovascular mortal- Because type 2 diabetes is a progressive RA, or basal insulin; the choice of which agent
ity (36); there is little systematic data disease in many patients, maintenance of to add is based on drug-specific effects and
available for other oral agents as initial glycemic targets with monotherapy is patient factors (Fig. 9.1 and Table 9.1).
therapy of type 2 diabetes. The principal often possible for only a few years, after For patients with established ASCVD or
side effects of metformin are gastroin- which combination therapy is necessary. indicators of high ASCVD risk (such as
testinal intolerance due to bloating, ab- Current recommendations have been to patients $55 years of age with coronary,
dominal discomfort, and diarrhea; these use stepwise addition of medications carotid, or lower-extremity artery steno-
can be mitigated by gradual dose titration. to metformin to maintain A1C at target. sis .50% or left ventricular hypertro-
The drug is cleared by renal filtration, and This allows a clearer assessment of the phy), established kidney disease, or heart
care.diabetesjournals.org
Figure 9.1—Glucose-lowering medication in type 2 diabetes: overall approach. For appropriate context, see Fig. 4.1. ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; CV, cardiovascular;
CVD, cardiovascular disease; CVOTs, cardiovascular outcomes trials; DPP-4i, dipeptidyl peptidase 4 inhibitor; eGFR, estimated glomerular filtration rate; GLP-1 RA, glucagon-like peptide 1 receptor agonist; HF,
heart failure; SGLT2i, sodium–glucose cotransporter 2 inhibitor; SU, sulfonylurea; TZD, thiazolidinedione. Adapted from Davies and colleagues (33,34).
Pharmacologic Approaches to Glycemic Treatment
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S104 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 43, Supplement 1, January 2020
Figure 9.2—Intensifying to injectable therapies. DSMES, diabetes self-management education and support; FPG, fasting plasma glucose; FRC, fixed-ratio
combination; GLP-1 RA, glucagon-like peptide 1 receptor agonist; max, maximum; PPG, postprandial glucose. Adapted from Davies et al. (33).
care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S105
failure, an SGLT-2 inhibitor or GLP-1 RA with preferred option for patients requiring Insulin Therapy
demonstrated CVD benefit (Table 9.1, the potency of an injectable therapy for Many patients with type 2 diabetes even-
Table 10.3B, Table 10.3C) is recommended glucose control (Fig. 9.2). However, high tually require and benefit from insulin
as part of the glucose-lowering regimen costs and tolerability issues are impor- therapy (Fig. 9.2). See the section INSULIN
independent of A1C and in consideration of tant barriers to the use of GLP-1 RAs. INJECTION TECHNIQUE above, for guidance on
patient-specific factors (Figure 9.1). For Cost for diabetes medicine has in- how to administer insulin safely and
patients without established ASCVD, indi- creased dramatically over the past two effectively. The progressive nature of
cators of high ASCVD risk, HF, or CKD, the decades, and an increasing proportion is type 2 diabetes should be regularly
choice of a second agent to add to met- now passed on to patients and their families and objectively explained to patients,
formin is not yet guided by empiric evi- (53). Table 9.2 provides cost information for and providers should avoid using insulin
dence. Rather, drug choice is based on currently approved noninsulin therapies. Of as a threat or describing it as a sign of
avoidance of side effects, particularly hy- note, prices listed are average wholesale personal failure or punishment. Rather,
poglycemia and weight gain, cost, and prices (AWP) (54) and National Average the utility and importance of insulin to
patient preferences (48). Similar consider- Drug Acquisition Costs (NADAC) (55), sep- maintain glycemic control once progres-
ations are applied in patients who require a arate measures to allow for a comparison of sion of the disease overcomes the effect of
third agent to achieve glycemic goals; there drug prices but do notaccountfor discounts, other agents should be emphasized. Ed-
is very little trial-based evidence to guide rebates, or other price adjustments often ucating and involving patients in insulin
this choice. In all cases, treatment regimens involved in prescription sales that affect the management is beneficial. For example,
need to be continuously reviewed for actual cost incurred by the patient. Med- instruction of patients in self-titration of
efficacy, side effects, and patient burden ication costs can be a major source of stress insulin doses based on self-monitoring of
(Table 9.1). In some instances, patients will for patients with diabetes and contribute to blood glucose improves glycemic control
require medication reduction or discontin- worse adherence with medications (56); in patients with type 2 diabetes initiating
uation. Common reasons for this include cost-reducing strategies may improve ad- insulin (58). Comprehensive education re-
ineffectiveness, intolerable side effects, ex- herence in some cases (57). garding self-monitoring of blood glucose,
pense, or a change in glycemic goals (e.g., in diet, and the avoidance and appropriate
response to development of comorbidities Cardiovascular Outcomes Trials treatment of hypoglycemia are critically
or changes in treatment goals). Section There are now multiple large randomized important in any patient using insulin.
12 “Older Adults”(https://doi.org/10.2337/ controlled trials reporting statistically
dc20-S012) has a full discussion of treat- significant reductions in cardiovascular Basal Insulin
ment considerations in older adults, a events in patients with type 2 diabetes Basal insulin alone is the most convenient
setting where changes of glycemic goals treated with an SGLT2 inhibitor (em- initial insulin regimen and can be added
and de-escalation of therapy is common. pagliflozin, canagliflozin, dapagliflozin) to metformin and other oral agents.
Although most patients prefer oral or GLP-1 RA (liraglutide, semaglutide, Starting doses can be estimated based
medications to drugs that need to be dulaglutide); see Section 10 “Cardiovas- on body weight (0.1–0.2 units/kg/day)
injected, the eventual need for the cular Disease and Risk Management” and the degree of hyperglycemia, with
greater potency of injectable medica- (https://doi.org/10.2337/dc20-S010) for individualized titration over days to weeks
tions is common, particularly in people details. The subjects enrolled in the cardio- as needed. The principal action of basal
with a longer duration of diabetes. The vascular outcome trials using empagliflozin, insulin is to restrain hepatic glucose pro-
addition of basal insulin, either human canagliflozin, liraglutide, and semaglutide duction and limit hyperglycemia overnight
NPH or one of the long-acting insulin had A1C $7%, and more than 70% were and between meals (59,60). Control of
analogs, to oral agent regimens is a well- taking metformin at baseline. Thus, a prac- fasting glucose can be achieved with
established approach that is effective for tical extension of these results to clinical human NPH insulin or a long-acting insulin
many patients. In addition, recent evi- practice is to use these drugs preferen- analog. In clinical trials, long-acting basal
dence supports the utility of GLP-1 RAs in tially in patients with type 2 diabetes and analogs (U-100 glargine or detemir) have
patients not reaching glycemic targets established ASCVD or indicators of high been demonstrated to reduce the risk of
with use of non-GLP-1 RA oral agent ASCVD risk. For these patients, incorpo- symptomatic and nocturnal hypoglycemia
regimens. While most GLP-1 RA products rating one of the SGLT2 inhibitors or compared with NPH insulin (61–66), al-
are injectable, an oral formulation of GLP-1 RAs that have been demonstrated though these advantages are modest and
semaglutide is now commercially avail- to have cardiovascular disease benefit is may not persist (67). Longer-acting basal
able (49). In trials comparing the ad- recommended (Table 9.1). In cardiovascular analogs (U-300 glargine or degludec) may
dition of an injectable GLP-1 RAs or outcomes trials, empagliflozin, canagliflozin, convey a lower hypoglycemia risk com-
insulin in patients needing further glu- dapagliflozin, liraglutide, semaglutide, and pared with U-100 glargine when used in
cose lowering, the efficacy of the two dulaglutide all had beneficial effects on combination with oral agents (68–74).
treatments was similar (50–52). How- indices of CKD. See Section 11 “Microvas- Despite evidence for reduced hypoglyce-
ever, GLP-1 RAs in these trials had a cular Complications and Foot Care” (https:// mia with newer, longer-acting basal in-
lower risk of hypoglycemia and beneficial doi.org/10.2337/dc20-S011) for a detailed sulin analogs in clinical trial settings, in
effects on body weight compared with discussion on how CKD may impact treat- practice these effects may be modest
insulin, albeit with greater gastroin- ment choices. Additional large randomized compared with NPH insulin (75).
testinal side effects. Thus, trial results trials of other agents in these classes are The cost of insulin has been rising
support injectable GLP-1 RAs as the ongoing. steadily over the past two decades, at
S106 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 43, Supplement 1, January 2020
Table 9.2—Median monthly (30-day) cost of maximum approved daily dose of noninsulin glucose-lowering agents in the U.S.
Dosage strength/product Median AWP Median NADAC Maximum approved
Class Compound(s) (if applicable) (min, max)† (min, max)† daily dose*
Biguanides c Metformin 500 mg (IR) $84 ($4, $85) $2 2,000 mg
850 mg (IR) $108 ($6, $109) $3 2,550 mg
1,000 mg (IR) $87 ($4, $88) $2 2,000 mg
500 mg (ER) $89 ($87, $7,412) $5 ($5, $988) 2,000 mg
750 mg (ER) $74 ($65, $74) $4 1,500 mg
1,000 mg (ER) $242 ($242, $7,214) $224 ($224, $910) 2,000 mg
Sulfonylureas (2nd c Glimepiride 4 mg $74 ($71, $198) $4 8 mg
generation) c Glipizide 10 mg (IR) $75 ($67, $97) $5 40 mg (IR)
10 mg (XL) $48 $15 20 mg (XL)
c Glyburide 6 mg (micronized) $50 ($48, $71) $4 12 mg (micronized)
5 mg $93 ($63, $103) $11 20 mg
Thiazolidinediones c Pioglitazone 45 mg $348 ($283, $349) $4 45 mg
c Rosiglitazone 4 mg $407 $330 8 mg
a-Glucosidase c Acarbose 100 mg $106 ($104, $106) $23 300 mg
inhibitors c Miglitol 100 mg $241 $311 300 mg
Meglitinides (glinides) c Nateglinide 120 mg $155 $39 360 mg
c Repaglinide 2 mg $878 ($162, $897) $39 16 mg
DPP-4 inhibitors c Alogliptin 25 mg $234 $168 25 mg
c Saxagliptin 5 mg $505 $403 5 mg
c Linagliptin 5 mg $523 $419 5 mg
c Sitagliptin 100 mg $541 $433 100 mg
SGLT2 inhibitors c Ertugliflozin 15 mg $338 $271 15 mg
c Dapagliflozin 10 mg $591 $473 10 mg
c Empagliflozin 25 mg $591 $473 25 mg
c Canagliflozin 300 mg $593 $475 300 mg
GLP-1 RAs c Exenatide (extended release) 2 mg powder for $840 $672 2 mg**
suspension or pen
c Exenatide 10 mg pen $876 $730 20 mg
c Dulaglutide 1.5/0.5 mL pen $911 $730 1.5 mg**
c Semaglutide 1 mg pen $927 $745 1 mg**
14 mg (tablet) $927 N/A 14 mg
c Liraglutide 18 mg/3 mL pen $1,106 $886 1.8 mg
c Lixisenatide 300 mg/3 mL pen $744 N/A 20 mg
Bile acid sequestrant c Colesevelam 625 mg tabs $712 ($674, $712) $177 3.75 g
3.75 g suspension $675 $415 3.75 g
Dopamine-2 agonist c Bromocriptine 0.8 mg $906 $729 4.8 mg
Amylin mimetic c Pramlintide 120 mg pen $2,623 $2,097 120 mg/injection†††
AWP, average wholesale price; DPP-4, dipeptidyl peptidase 4; ER and XL, extended release; GLP-1 RA, glucagon-like peptide 1 receptor agonist; IR,
immediate release; N/A, data not available; NADAC, National Average Drug Acquisition Cost; SGLT2, sodium–glucose cotransporter 2. †Calculated
for 30-day supply (AWP [54] or NADAC [55] unit price 3 number of doses required to provide maximum approved daily dose 3 30 days); median AWP
or NADAC listed alone when only one product and/or price. *Utilized to calculate median AWP and NADAC (min, max); generic prices used, if
available commercially. **Administered once weekly. †††AWP and NADAC calculated based on 120 mg three times daily.
a pace several fold that of other medical familiar with its use (75). Human regular patient needs (see Figure 9.2). People
expenditures (76). This expense contrib- insulin, NPH, and 70/30 NPH/regular prod- with type 2 diabetes are generally more
utes significant burden to patients as ucts can be purchased for considerably insulin resistant than those with type 1
insulin has become a growing “out-of- less than the AWP and NADAC prices listed diabetes, require higher daily doses (;1
pocket” cost for people with diabetes, in Table 9.3 at select pharmacies. unit/kg), and have lower rates of hypo-
and direct patient costs contribute to glycemia (77). Titration can be based
treatment nonadherence (76). Therefore, Prandial Insulin on home glucose monitoring or A1C.
consideration of cost is an important com- Many individuals with type 2 diabetes With significant additions to the prandial
ponent of effective management. For require doses of insulin before meals, in insulin dose, particularly with the evening
many patients with type 2 diabetes addition to basal insulin, to reach glyce- meal, consideration should be given to
(e.g., individuals with relaxed A1C goals, mic targets. A dose of 4 units or 10% of decreasing basal insulin. Meta-analyses
low rates of hypoglycemia, and prominent the amount of basal insulin at the largest of trials comparing rapid-acting insulin
insulin resistance, as well as those with meal or the meal with the greatest post- analogs with human regular insulin in
cost concerns), human insulin (NPH and prandial excursion is a safe estimate for patients with type 2 diabetes have not
regular) may be the appropriate choice initiating therapy. The prandial insulin reported important differences in A1C
of therapy, and clinicians should be regimen can then be intensified based on or hypoglycemia (78,79).
care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S107
Table 9.3—Median cost of insulin products in the U.S. calculated as AWP (54) and NADAC (55) per 1,000 units of specified dosage
form/product
Insulins Compounds Dosage form/product Median AWP (min, max)* Median NADAC (min, max)*
Rapid-acting c Lispro follow-on U-100 vial $157 $126
product U-100 prefilled pen $202 $162
c Lispro U-100 vial $330 $264
U-100 3 mL cartridges $408 $327
U-100 prefilled pen; U-200 $424 $340
prefilled pen
c Glulisine U-100 vial $341 $273
U-100 prefilled pen $439 $353
c Aspart U-100 vial $347† $278†
U-100 3 mL cartridges $430 $345
U-100 prefilled pen $447† $358†
c Inhaled insulin Inhalation cartridges $924 $606
Short-acting c human regular U-100 vial $165 ($165, $178)†† $134 ($134, $146)††
Intermediate-acting c human NPH U-100 vial $165 ($165, $178)†† $135 ($135, $146)††
U-100 prefilled pen $377 $304
Concentrated human c U-500 human regular U-500 vial $178 $144
regular insulin insulin U-500 prefilled pen $230 $184
Long-acting c Glargine follow-on U-100 prefilled pen $261 $210
product
c Glargine U-100 vial; U-100 prefilled pen $340 $272
U-300 prefilled pen $346 $280
c Detemir U-100 vial; U-100 prefilled pen $370 $295
c Degludec U-100 vial; U-100 prefilled pen; $407 $326
U-200 prefilled pen
Premixed insulin products c NPH/regular 70/30 U-100 vial $165 ($165, $178) $134 ($134, $145)
U-100 prefilled pen $377 $303
c Lispro 50/50 U-100 vial $342 $274
U-100 prefilled pen $424 $338
c Lispro 75/25 U-100 vial $342 $274
U-100 prefilled pen $424 $340
c Aspart 70/30 U-100 vial $360 $289
U-100 prefilled pen $447 $358
Premixed insulin/GLP-1 RA c Glargine/Lixisenatide 100/33 prefilled pen $565 $454
products c Degludec/Liraglutide 100/3.6 prefilled pen $832 $668
AWP, average wholesale price; GLP-1, glucagon-like peptide 1; NADAC, National Average Drug Acquisition Cost. *AWP or NADAC calculated as in
Table 9.2. †Inclusive of both the original and “faster-acting” products. ††AWP and NADAC data presented do not include vials of regular human
insulin and NPH available at Walmart for approximately $25/vial; median listed alone when only one product and/or price.
and GLP-1 RA has potent glucose-lower- in type 1 diabetic participants of the Diabetes 15. Bergenstal RM, Garg S, Weinzimer SA, et al.
ing actions and less weight gain and hypo- Control and Complications Trial/Epidemiology of Safety of a hybrid closed-loop insulin delivery
Diabetes Interventions and Complications (DCCT/ system in patients with type 1 diabetes. JAMA
glycemia compared with intensified insulin EDIC) study. Diabetes 2006;55:3556–3565 2016;316:1407–1408
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over, humaninsulins,separately,self-mixed, scientific review. JAMA 2003;289:2254–2264 patients with type 1 diabetes mellitus: a system-
7. Bode BW, McGill JB, Lorber DL, Gross JL, Chang atic review and meta-analysis. Arch Endocrinol
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these options, as well as recommendations 24-week trial. Diabetes Care 2015;38:2266–2273 glycemic index on postprandial glucose control in
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Fast-acting insulin aspart improves glycemic con- management in the continuous glucose monitor-
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discontinued. In patients with suboptimal 9. Lane W, Bailey TS, Gerety G, et al.; Group 24. Bergenstal RM, Strock ES, Peremislov D,
Information; SWITCH 1. Effect of insulin degludec Gibney MA, Parvu V, Hirsch LJ. Safety and ef-
blood glucose control, especially those re- vs insulin glargine U100 on hypoglycemia in ficacy of insulin therapy delivered via a 4mm pen
quiring large insulin doses, adjunctive use patients with type 1 diabetes: the SWITCH 1 needle in obese patients with diabetes. Mayo
of a thiazolidinedione or an SGLT2 inhibitor randomized clinical trial. JAMA 2017;318:33–44 Clin Proc 2015;90:329–338
may help to improve control and reduce the 10. Home PD, Bergenstal RM, Bolli GB, et al. New 25. Ratner RE, Dickey R, Fineman M, et al. Amylin
amountofinsulin needed, though potential insulin glargine 300 units/mL versus glargine replacement with pramlintide as an adjunct to
100 units/mL in people with type 1 diabetes: insulin therapy improves long-term glycaemic
side effects should be considered. Once a a randomized, phase 3a, open-label clinical and weight control in type 1 diabetes mellitus:
basal/bolus insulin regimen is initiated, trial (EDITION 4). Diabetes Care 2015;38:2217– a 1-year, randomized controlled trial. Diabet Med
dose titration is important, with adjust- 2225 2004;21:1204–1212
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insulins based on the blood glucose levels Comparative effectiveness and safety of meth- placebo-controlled trial assessing pramlintide treat-
ods of insulin delivery and glucose monitoring for ment in the setting of intensive insulin therapy in
and an understanding of the pharma- diabetes mellitus: a systematic review and meta- type 1 diabetes. Diabetes Care 2006;29:2189–2195
codynamic profile of each formulation analysis. Ann Intern Med 2012;157:336–347 27. Meng H, Zhang A, Liang Y, Hao J, Zhang X, Lu J.
(pattern control). As people with type 2 12. Pickup JC. The evidence base for diabetes Effect of metformin on glycaemic control in
diabetes get older, it may become necessary technology: appropriate and inappropriate meta- patients with type 1 diabetes: a meta-analysis
to simplify complex insulin regimens be- analysis. J Diabetes Sci Technol 2013;7:1567–1574 of randomized controlled trials. Diabetes Metab
13. Bergenstal RM, Klonoff DC, Garg SK, et al.; Res Rev 2018;34:e2983
cause of a decline in self-management ASPIRE In-Home Study Group. Threshold-based 28. Petrie JR, Chaturvedi N, Ford I, et al.; RE-
ability (see Section 12 “Older Adults,” insulin-pump interruption for reduction of hy- MOVAL Study Group. Cardiovascular and met-
https://doi.org/10.2337/dc20-S012). poglycemia. N Engl J Med 2013;369:224–232 abolic effects of metformin in patients with
14. Buckingham BA, Raghinaru D, Cameron F, type 1 diabetes (REMOVAL): a double-blind,
et al.; In Home Closed Loop Study Group. Predictive randomised, placebo-controlled trial. Lancet Di-
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Diabetes Care Volume 43, Supplement 1, January 2020 S111
with diabetes. These risk factors in- epidemiology, diagnosis, and treatment
making process that addresses
clude obesity/overweight, hyperten- of hypertension (17).
cardiovascular risk, potential
sion, dyslipidemia, smoking, a family
Screening and Diagnosis adverse effects of antihyper-
history of premature coronary disease,
tensive medications, and pa-
chronic kidney disease, and the pres- Recommendations tient preferences. C
ence of albuminuria. Modifiable abnor- 10.1 Blood pressure should be mea- 10.4 For individuals with diabetes
mal risk factors should be treated as sured at every routine clinical and hypertension at higher car-
described in these guidelines. visit. Patients found to have el- diovascular risk (existing athero-
evated blood pressure ($140/90 sclerotic cardiovascular disease
THE RISK CALCULATOR mmHg) should have blood pres- [ASCVD] or 10-year ASCVD risk
The American College of Cardiology/ sure confirmed using multiple $15%), a blood pressure target
American Heart Association ASCVD risk readings, including measure- of ,130/80 mmHg may be ap-
calculator (Risk Estimator Plus) is generally ments on a separate day, to propriate, if it can be safely
a useful tool to estimate 10-year ASCVD diagnose hypertension. B attained. C
risk (available online at tools.acc.org/ 10.2 All hypertensive patients with 10.5 For individuals with diabetes
ASCVD-Risk-Estimator-Plus). The calcu- diabetes should monitor their and hypertension at lower risk
lator includes diabetes as a risk factor, blood pressure at home. B for cardiovascular disease (10-
since diabetes itself confers increased risk year atherosclerotic cardio-
for ASCVD, although it should be acknowl- Blood pressure should be measured at vascular disease risk ,15%),
edged that these risk calculators do not every routine clinical visit by a trained treat to a blood pressure target
account for the duration of diabetes or the individual and should follow the of ,140/90 mmHg. A
presence of diabetes complications, such guidelines established for the general pop- 10.6 In pregnant patients with dia-
as albuminuria. Although some variability ulation: measurement in the seated posi- betes and preexisting hyperten-
in calibration exists in various subgroups, tion, with feet on the floor and arm sion, a blood pressure target
including by sex, race, and diabetes, the supported at heart level, after 5 min of of #135/85 mmHg is suggested
overall risk prediction does not differ in rest. Cuff size should be appropriate for the in the interest of reducing the
those with or without diabetes (11–14), upper-arm circumference. Elevated values risk for accelerated maternal
validating the use of risk calculators in should be confirmed on a separate day. hypertension A and minimizing
people with diabetes. The 10-year risk of a Postural changes in blood pressure and impaired fetal growth. E
first ASCVD event should be assessed to pulse may be evidence of autonomic neu-
better stratify ASCVD risk and help guide ropathy and therefore require adjustment
therapy, as described below. of blood pressure targets. Orthostatic blood Randomized clinical trials have demon-
Recently, risk scores and other car- pressure measurements should be checked strated unequivocally that treatment of
diovascular biomarkers have been devel- on initial visit and as indicated. hypertension to blood pressure ,140/90
oped for risk stratification of secondary Home blood pressure self-monitoring mmHg reduces cardiovascular events
prevention patients (i.e., those who are and 24-h ambulatory blood pressure as well as microvascular complications
already high risk because they have monitoring may provide evidence of (21–27). Therefore, patients with type 1
ASCVD) but are not yet in widespread white coat hypertension, masked hyper- or type 2 diabetes who have hyperten-
use (15,16). With newer, more expensive tension, or other discrepancies between sion should, at a minimum, be treated
lipid-lowering therapies now available, office and “true” blood pressure (17). In to blood pressure targets of ,140/90
use of these risk assessments may help addition to confirming or refuting a di- mmHg. The benefits and risks of inten-
target these new therapies to “higher agnosis of hypertension, home blood sifying antihypertensive therapy to tar-
risk” ASCVD patients in the future. pressure assessment may be useful to get blood pressures lower than ,140/90
monitor antihypertensive treatment. mmHg (e.g., ,130/80 or ,120/80
Studies of individuals without diabetes mmHg) have been evaluated in large
HYPERTENSION/BLOOD PRESSURE found that home measurements may randomized clinical trials and meta-
CONTROL better correlate with ASCVD risk than analyses of clinical trials. Notably, there
Hypertension, defined as a sustained office measurements (18,19). Moreover, is an absence of high-quality data avail-
blood pressure $140/90 mmHg, is com- home blood pressure monitoring may able to guide blood pressure targets in
mon among patients with either type 1 improve patient medication adherence type 1 diabetes.
or type 2 diabetes. Hypertension is a and thus help reduce cardiovascular
major risk factor for both ASCVD and risk (20). Randomized Controlled Trials of Intensive
microvascular complications. Moreover, Versus Standard Blood Pressure Control
numerous studies have shown that anti- Treatment Goals The Action to Control Cardiovascular Risk
hypertensive therapy reduces ASCVD in Diabetes Blood Pressure (ACCORD BP)
Recommendations
events, heart failure, and microvascular trial provides the strongest direct assess-
10.3 For patients with diabetes and
complications. Please refer to the Amer- ment of the benefits and risks of intensive
hypertension, blood pressure
ican Diabetes Association (ADA) position blood pressure control among people
targets should be individual-
statement “Diabetes and Hyperten- with type 2 diabetes (28). In ACCORD
ized through a shared decision-
sion” for a detailed review of the BP, compared with standard blood
care.diabetesjournals.org Cardiovascular Disease and Risk Management S113
pressure control (target systolic blood relevance of their results to people A number of post hoc analyses have
pressure ,140 mmHg), intensive blood with diabetes is less clear. The Action attempted to explain the apparently
pressure control (target systolic blood in Diabetes and Vascular Disease: Pre- divergent results of ACCORD BP and
pressure ,120 mmHg) did not reduce terax and Diamicron MR Controlled SPRINT. Some investigators have argued
total major atherosclerotic cardiovascu- Evaluation–Blood Pressure (ADVANCE that the divergent results are not due to
lar events but did reduce the risk of BP) trial did not explicitly test blood differences between people with and with-
stroke, at the expense of increased ad- pressure targets (29); the achieved out diabetes but rather are due to differ-
verse events (Table 10.1). The ACCORD blood pressure in the intervention ences in study design or to characteristics
BP results suggest that blood pressure group was higher than that achieved other than diabetes (31–33). Others have
targets more intensive than ,140/90 in the ACCORD BP intensive arm and opined that the divergent results are most
mmHg are not likely to improve car- would be consistent with a target readily explained by the lack of benefit of
diovascular outcomes among most blood pressure of ,140/ 90 mmHg. intensive blood pressure control on cardio-
people with type 2 diabetes but may Notably, ACCORD BP and SPRINT mea- vascular mortality in ACCORD BP, which
be reasonable for patients who may sured blood pressure using automated may be due to differential mechanisms
derive the most benefit and have office blood pressure measurement, underlying cardiovascular disease in type
been educated about added treatment which yields values that are generally 2 diabetes, to chance, or both (34).
burden, side effects, and costs, as dis- lower than typical office blood pres-
cussed below. sure readings by approximately 5–10 Meta-analyses of Trials
Additional studies, such as the Sys- mmHg (30), suggesting that im- To clarify optimal blood pressure targets
tolic Blood Pressure Intervention Trial plementing the ACCORD BP or SPRINT in patients with diabetes, meta-analyses
(SPRINT) and the Hypertension Optimal protocols in an outpatient clinic might have stratified clinical trials by mean
Treatment (HOT) trial, also examined require a systolic blood pressure tar- baseline blood pressure or mean blood
effects of intensive versus standard get higher than ,120 mmHg, such as pressure attained in the intervention (or
control (Table 10.1), though the ,130 mmHg. intensive treatment) arm. Based on these
Table 10.1—Randomized controlled trials of intensive versus standard hypertension treatment strategies
Clinical trial Population Intensive Standard Outcomes
ACCORD BP (28) 4,733 participants with SBP target: SBP target: c No benefit in primary end point: composite
T2D aged 40–79 years ,120 mmHg 130–140 mmHg of nonfatal MI, nonfatal stroke, and CVD
with prior evidence Achieved (mean) Achieved (mean) death
of CVD or multiple SBP/DBP: SBP/DBP: c Stroke risk reduced 41% with intensive
cardiovascular risk 119.3/64.4 mmHg 13.5/70.5 mmHg control, not sustained through follow-up
factors beyond the period of active treatment
c Adverse events more common in intensive
group, particularly elevated serum
creatinine and electrolyte abnormalities
ADVANCE BP (29) 11,140 participants Intervention: a single-pill, Control: placebo c Intervention reduced risk of primary
with T2D aged fixed-dose combination Achieved (mean) composite end point of major
55 years and older of perindopril and SBP/DBP: macrovascular and microvascular events
with prior evidence indapamide 141.6/75.2 mmHg (9%), death from any cause (14%), and
of CVD or multiple Achieved (mean) death from CVD (18%)
cardiovascular risk SBP/DBP: c 6-year observational follow-up found
factors 136/73 mmHg reduction in risk of death in intervention
group attenuated but still significant (174)
HOT (185) 18,790 participants, DBP target: DBP target: c In the overall trial, there was no
including 1,501 #80 mmHg #90 mmHg cardiovascular benefit with more intensive
with diabetes targets
c In the subpopulation with diabetes, an
intensive DBP target was associated with
a significantly reduced risk (51%) of CVD
events
SPRINT (39) 9,361 participants SBP target: SBP target: c Intensive SBP target lowered risk of the
without diabetes ,120 mmHg ,140 mmHg primary composite outcome 25% (MI, ACS,
Achieved (mean): Achieved (mean): stroke, heart failure, and death due to CVD)
121.4 mmHg 136.2 mmHg c Intensive target reduced risk of death 27%
c Intensive therapy increased risks of
electrolyte abnormalities and AKI
ACCORD BP, Action to Control Cardiovascular Risk in Diabetes Blood Pressure trial; ACS, acute coronary syndrome; ADVANCE BP, Action in Diabetes
and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation–Blood Pressure trial; AKI, acute kidney injury; CVD, cardiovascular
disease; DBP, diastolic blood pressure; HOT, Hypertension Optimal Treatment trial; MI, myocardial infarction; SBP, systolic blood pressure; SPRINT,
Systolic Blood Pressure Intervention Trial; T2D, type 2 diabetes. Data from this table can also be found in the ADA position statement “Diabetes and
Hypertension” (17).
S114 Cardiovascular Disease and Risk Management Diabetes Care Volume 43, Supplement 1, January 2020
analyses, antihypertensive treatment ap- syncope, falls, acute kidney injury, and recommends use of antihypertensive
pears to be beneficial when mean base- electrolyte abnormalities) should also be therapy to maintain systolic blood pres-
line blood pressure is $140/90 mmHg or taken into account (28,39–41). Patients sure between 110 and 140 mmHg and
mean attained intensive blood pressure with older age, chronic kidney disease, diastolic blood pressure between 80 and
is $130/80 mmHg (17,21,22,24–26). and frailty have been shown to be at 85 mmHg (44).
Among trials with lower baseline or higher risk of adverse effects of intensive During pregnancy, treatment with ACE
attained blood pressure, antihyperten- blood pressure control (41). In addition, inhibitors, angiotensin receptor blockers
sive treatment reduced the risk of stroke, patients with orthostatic hypotension, (ARBs), and spironolactone are contra-
retinopathy, and albuminuria, but effects substantial comorbidity, functional lim- indicated as they may cause fetal dam-
on other ASCVD outcomes and heart itations, or polypharmacy may be at high age. Antihypertensive drugs known to be
failure were not evident. Taken together, risk of adverse effects, and some patients effective and safe in pregnancy include
these meta-analyses consistently show may prefer higher blood pressure targets methyldopa, labetalol, and long-acting
that treating patients with baseline blood to enhance quality of life. Patients with nifedipine, while hydralzine may be con-
pressure $140 mmHg to targets ,140 low absolute cardiovascular risk (10-year sidered in the acute management of
mmHg is beneficial, while more-intensive ASCVD risk ,15%) or with a history of hypertension in pregnancy or severe
targets may offer additional (though adverse effects of intensive blood pres- preeclampsia (45). Diuretics are not rec-
probably less robust) benefits. sure control or at high risk of such ommended for blood pressure control in
adverse effects should have a higher pregnancy but may be used during late-
Individualization of Treatment Targets blood pressure target. In such patients, stage pregnancy if needed for volume
Patients and clinicians should engage in a blood pressure target of ,140/90 control (45,46). The American College of
a shared decision-making process to de- mmHg is recommended, if it can be safely Obstetricians and Gynecologists also rec-
termine individual blood pressure tar- attained. ommends that postpartum patients with
gets (17). This approach acknowledges gestational hypertension, preeclampsia,
that the benefits and risks of intensive Pregnancy and Antihypertensive and superimposed preeclampsia have
blood pressure targets are uncertain and Medications their blood pressures observed for
may vary across patients and is consis- There are few randomized controlled 72 h in the hospital and for 7–10 days
tent with a patient-focused approach to trials of antihypertensive therapy in preg- postpartum. Long-term follow-up is rec-
care that values patient priorities and nant women with diabetes. A 2014 ommended for these women as they
provider judgment (35). Secondary anal- Cochrane systematic review of antihy- have increased lifetime cardiovascular
yses of ACCORD BP and SPRINT suggest pertensive therapy for mild to moder- risk (47). See Section 14 “Management
that clinical factors can help determine ate chronic hypertension that included of Diabetes in Pregnancy” (https://doi
individuals more likely to benefit and 49 trials and over 4,700 women did not .org/10.2337/dc20-S014) for additional
less likely to be harmed by intensive find any conclusive evidence for or information.
blood pressure control (36). against blood pressure treatment to
Absolute benefit from blood pres- reduce the risk of preeclampsia for Treatment Strategies
sure reduction correlated with absolute the mother or effects on perinatal out- Lifestyle Intervention
baseline cardiovascular risk in SPRINT comes such as preterm birth, small-for-
Recommendation
and in earlier clinical trials conducted gestational-age infants, or fetal death
at higher baseline blood pressure levels (42). The more recent Control of Hyper- 10.7 For patients with blood pressure
(11,37). Extrapolation of these studies tension in Pregnancy Study (CHIPS) (43) .120/80 mmHg, lifestyle inter-
suggests that patients with diabetes enrolled mostly women with chronic vention consists of weight loss if
may also be more likely to benefit hypertension. In CHIPS, targeting a di- overweight or obese, a Dietary
from intensive blood pressure control astolic blood pressure of 85 mmHg dur- Approaches to Stop Hyperten-
when they have high absolute cardio- ing pregnancy was associated with sion (DASH)-style eating pattern
vascular risk. Therefore, it may be rea- reduced likelihood of developing accel- including reducing sodium and
sonable to target blood pressure erated maternal hypertension and no increasing potassium intake,
,130/80 mmHg among patients with demonstrable adverse outcome for in- moderation of alcohol intake,
diabetes and either clinically diag- fants compared with targeting a higher and increased physical activity. A
nosed cardiovascular disease (particu- diastolic blood pressure. The mean sys-
larly stroke, which was significantly tolic blood pressure achieved in the Lifestyle management is an important
reduced in ACCORD BP) or 10-year more intensively treated group was component of hypertension treatment
ASCVD risk $15%, if it can be attained 133.1 6 0.5 mmHg, and the mean di- because it lowers blood pressure, enhan-
safely. This approach is consistent with astolic blood pressure achieved in that ces the effectiveness of some antihyper-
guidelines from the American College of group was 85.3 6 0.3 mmHg. Therefore, tensive medications, promotes other
Cardiology/American Heart Association, current evidence supports controlling aspects of metabolic and vascular health,
which advocate a blood pressure target blood pressure to these levels, with a and generally leads to few adverse effects.
,130/80 mmHg for all patients, with or target of #135/85 mmHg. A similar Lifestyle therapy consists of reducing ex-
without diabetes (38). approach is supported by the Interna- cess body weight through caloric restric-
Potential adverse effects of antihyper- tional Society for the Study of Hyperten- tion, restricting sodium intake (,2,300
tensive therapy (e.g., hypotension, sion in Pregnancy, which specifically mg/day), increasing consumption of fruits
care.diabetesjournals.org Cardiovascular Disease and Risk Management S115
and vegetables (8–10 servings per day) the combination of an ACE inhibitor or
patients with diabetes and uri-
and low-fat dairy products (2–3 servings ARB and a direct renin inhibitor, is not
nary albumin-to-creatinine ra-
per day), avoiding excessive alcohol con- recommended given the lack of added
tio $300 mg/g creatinine A or
sumption (no more than 2 servings per ASCVD benefit and increased rate of
30–299 mg/g creatinine. B If
day in men and no more than 1 serving per adverse eventsdnamely, hyperkalemia,
one class is not tolerated, the
day in women) (48), and increasing ac- syncope, and acute kidney injury (AKI)
other should be substituted. B
tivity levels (49). (60–62). Titration of and/or addition of
10.13 For patients treated with an ACE
These lifestyle interventions are rea- further blood pressure medications
inhibitor, angiotensin receptor
sonable for individuals with diabetes and should be made in a timely fashion to
blocker, or diuretic, serum cre-
mildly elevated blood pressure (systolic overcome clinical inertia in achieving
atinine/estimated glomerular fil-
.120 mmHg or diastolic .80 mmHg) blood pressure targets.
tration rate and serum potassium
and should be initiated along with phar- Bedtime Dosing. Growing evidence sug-
levels should be monitored at
macologic therapy when hypertension is gests that there is an association be-
least annually. B
diagnosed (Fig. 10.1) (49). A lifestyle tween the absence of nocturnal blood
therapy plan should be developed in Initial Number of Antihypertensive pressure dipping and the incidence of
collaboration with the patient and dis- Medications. Initial treatment for people ASCVD. A meta-analysis of randomized
cussed as part of diabetes management. with diabetes depends on the severity clinical trials found a small benefit of
of hypertension (Fig. 10.1). Those with evening versus morning dosing of anti-
Pharmacologic Interventions blood pressure between 140/90 mmHg hypertensive medications with regard to
and 159/99 mmHg may begin with a blood pressure control but had no data
Recommendations
single drug. For patients with blood on clinical effects (63). In two subgroup
10.8 Patients with confirmed office-
based blood pressure $140/ pressure $160/100 mmHg, initial phar- analyses of a single subsequent random-
macologic treatment with two antihy- ized controlled trial, moving at least one
90 mmHg should, in addition
pertensive medications is recommended antihypertensive medication to bedtime
to lifestyle therapy, have prompt
in order to more effectively achieve significantly reduced cardiovascular events,
initiation and timely titration of
adequate blood pressure control (50–52). but results were based on a small num-
pharmacologic therapy to achieve
Single-pill antihypertensive combinations ber of events (64).
blood pressure goals. A Hyperkalemia and Acute Kidney Injury.
10.9 Patients with confirmed office- may improve medication adherence in
some patients (53). Treatment with ACE inhibitors or ARBs
based blood pressure $160/
Classes of Antihypertensive Medications. can cause AKI and hyperkalemia, while
100 mmHg should, in addition
Initial treatment for hypertension should diuretics can cause AKI and either hypo-
to lifestyle therapy, have prompt
include any of the drug classes demon- kalemia or hyperkalemia (depending on
initiation and timely titration of mechanism of action) (65,66). Detection
strated to reduce cardiovascular events
two drugs or a single-pill combi- and management of these abnormalities
in patients with diabetes: ACE inhibitors
nation of drugs demonstrated to is important because AKI and hyperkale-
(54,55), ARBs (54,55), thiazide-like di-
reduce cardiovascular events in mia each increase the risks of cardiovas-
uretics (56), or dihydropyridine calcium
patients with diabetes. A cular events and death (67). Therefore,
channel blockers (57). For patients
10.10 Treatment for hypertension serum creatinine and potassium should
with albuminuria (urine albumin-to-
should include drug classes
creatinine ratio [UACR] $30 mg/g), initial be monitored during treatment with an
demonstrated to reduce cardio-
treatment should include an ACE inhib- ACE inhibitor, ARB, or diuretic, particularly
vascular events in patients with
itor or ARB in order to reduce the risk among patients with reduced glomerular
diabetes (ACE inhibitors, angioten-
of progressive kidney disease (17) (Fig. filtration who are at increased risk of
sin receptor blockers, thiazide-like
10.1). In the absence of albuminuria, hyperkalemia and AKI (65,66,68).
diuretics, or dihydropyridine cal-
risk of progressive kidney disease is
cium channel blockers). A
low, and ACE inhibitors and ARBs have Resistant Hypertension
10.11 Multiple-drug therapy is gener-
not been found to afford superior Recommendation
ally required to achieve blood
cardioprotection when compared with 10.14 Patients with hypertension who
pressure targets. However, com-
thiazide-like diuretics or dihydropyridine are not meeting blood pres-
binations of ACE inhibitors and
calcium channel blockers (58). b-Blockers sure targets on three classes
angiotensin receptor blockers
may be used for the treatment of prior of antihypertensive medica-
and combinations of ACE inhib-
MI, active angina, or heart failure but tions (including a diuretic)
itors or angiotensin receptor
have not been shown to reduce mortality should be considered for min-
blockers with direct renin inhib-
as blood pressure–lowering agents in the eralocorticoid receptor antag-
itors should not be used. A
absence of these conditions (23,59). onist therapy. B
10.12 An ACE inhibitor or angiotensin
Multiple-Drug Therapy. Multiple-drug
receptor blocker, at the maxi-
therapy is often required to achieve Resistant hypertension is defined as
mum tolerated dose indicated
blood pressure targets (Fig. 10.1), par- blood pressure $140/90 mmHg despite
for blood pressure treatment,
ticularly in the setting of diabetic kidney a therapeutic strategy that includes ap-
is the recommended first-line
disease. However, the use of both ACE propriate lifestyle management plus a
treatment for hypertension in
inhibitors and ARBs in combination, or diuretic and two other antihypertensive
S116 Cardiovascular Disease and Risk Management Diabetes Care Volume 43, Supplement 1, January 2020
Figure 10.1—Recommendations for the treatment of confirmed hypertension in people with diabetes. *An ACE inhibitor (ACEi) or angiotensin receptor
blocker (ARB) is suggested to treat hypertension for patients with urine albumin-to-creatinine ratio 30–299 mg/g creatinine and strongly
recommended for patients with urine albumin-to-creatinine ratio $300 mg/g creatinine. **Thiazide-like diuretic; long-acting agents shown to
reduce cardiovascular events, such as chlorthalidone and indapamide, are preferred. ***Dihydropyridine calcium channel blocker (CCB). BP, blood
pressure. Adapted from de Boer et al. (17).
drugs belonging to different classes at medication nonadherence, white coat should be identified and addressed (Fig.
adequate doses. Prior to diagnosing re- hypertension, and secondary hyperten- 10.1). Mineralocorticoid receptor antag-
sistant hypertension, a number of other sion. In general, barriers to medication onists are effective for management of
conditions should be excluded, including adherence (such as cost and side effects) resistant hypertension in patients with
care.diabetesjournals.org Cardiovascular Disease and Risk Management S117
type 2 diabetes when added to existing increasing plant stanols/sterols, n-3 fatty effects occur. There is evidence for ben-
treatment with an ACE inhibitor or ARB, acids, and viscous fiber (such as in oats, efit from even extremely low, less than
thiazide-like diuretic, and dihydropyri- legumes, and citrus) intake (76). Glyce- daily statin doses (78).
dine calcium channel blocker (69). mic control may also beneficially modify
Mineralocorticoid receptor antagonists plasma lipid levels, particularly in pa- STATIN TREATMENT
also reduce albuminuria and have addi- tients with very high triglycerides and Primary Prevention
tional cardiovascular benefits (70–73). poor glycemic control. See Section 5 Recommendations
However, adding a mineralocorticoid re- “Facilitating Behavior Change and Well- 10.19 For patients with diabetes aged
ceptor antagonist to a regimen including being to Improve Health Outcomes” 40–75 years without atheroscle-
an ACE inhibitor or ARB may increase the (https://doi.org/10.2337/dc20-S010) for ad- rotic cardiovascular disease, use
risk for hyperkalemia, emphasizing the ditional nutrition information. moderate-intensity statin ther-
importance of regular monitoring for apy in addition to lifestyle ther-
Ongoing Therapy and Monitoring
serum creatinine and potassium in these apy. A
With Lipid Panel
patients, and long-term outcome studies 10.20 For patients with diabetes
are needed to better evaluate the role of Recommendations aged 20–39 years with addi-
mineralocorticoid receptor antagonists 10.17 In adults not taking statins or tional atherosclerotic cardiovas-
in blood pressure management. other lipid-lowering therapy, it cular disease risk factors, it may be
is reasonable to obtain a lipid reasonable to initiate statin ther-
LIPID MANAGEMENT profile at the time of diabetes apy in addition to lifestyle
Lifestyle Intervention diagnosis, at an initial medical therapy. C
evaluation, and every 5 years 10.21 In patients with diabetes at
Recommendations
thereafter if under the age of higher risk, especially those
10.15 Lifestyle modification focusing
40 years, or more frequently if with multiple atherosclerotic
on weight loss (if indicated);
indicated. E cardiovascular disease risk fac-
application of a Mediterranean
10.18 Obtain a lipid profile at initia- tors or aged 50–70 years, it is
style or Dietary Approaches
tion of statins or other lipid- reasonable to use high-inten-
to Stop Hypertension (DASH)
lowering therapy, 4–12 weeks sity statin therapy. B
eating pattern; reduction of
after initiation or a change 10.22 In adults with diabetes and
saturated fat and trans fat;
in dose, and annually thereaf- 10-year atherosclerotic cardio-
increase of dietary n-3 fatty
ter as it may help to monitor vascular disease risk of 20% or
acids, viscous fiber, and plant
the response to therapy and in- higher, it may be reasonable to
stanols/sterols intake; and in-
form medication adherence. E add ezetimibe to maximally
creased physical activity should
tolerated statin therapy to re-
be recommended to improve In adults with diabetes, it is reasonable duce LDL cholesterol levels by
the lipid profile and reduce the to obtain a lipid profile (total cholesterol, 50% or more. C
risk of developing atheroscle- LDL cholesterol, HDL cholesterol, and tri-
rotic cardiovascular disease in glycerides) at the time of diagnosis, at the
patients with diabetes. A initial medical evaluation, and at least every Secondary Prevention
10.16 Intensify lifestyle therapy and 5 years thereafter in patients under the age
optimize glycemic control for Recommendations
of 40 years. In younger patients with longer
patients with elevated triglyc- 10.23 For patients of all ages with
duration of disease (such as those with
eride levels ($150 mg/dL [1.7 diabetes and atherosclerotic
youth-onset type 1 diabetes), more fre-
mmol/L]) and/or low HDL cho- cardiovascular disease, high-in-
quent lipid profiles may be reasonable. A
lesterol (,40 mg/dL [1.0 tensity statin therapy should be
lipid panel should also be obtained imme-
mmol/L] for men, ,50 mg/dL diately before initiating statin therapy.
added to lifestyle therapy. A
[1.3 mmol/L] for women). C 10.24 For patients with diabetes and
Once a patient is taking a statin, LDL
atherosclerotic cardiovascular
cholesterol levels should be assessed 4–
disease considered very high
Lifestyle intervention, including weight 12 weeks after initiation of statin therapy,
risk using specific criteria, if
loss (74), increased physical activity, and after any change in dose, and on an in-
LDL cholesterol is $70 mg/dL
medical nutrition therapy, allows some dividual basis (e.g., to monitor for medica-
on maximally tolerated statin
patients to reduce ASCVD risk factors. tion adherence and efficacy). If LDL
dose, consider adding additional
Nutrition intervention should be tailored cholesterol levels are not responding in
LDL-lowering therapy (such as
according to each patient’s age, diabetes spite of medication adherence, clinical
ezetimibe or PCSK9 inhibitor).
type, pharmacologic treatment, lipid judgment is recommended to determine
A Ezetimibe may be preferred
levels, and medical conditions. the need for and timing of lipid panels. In
due to lower cost.
Recommendations should focus on individual patients, the highly variable LDL
10.25 For patients who do not toler-
application of a Mediterranean style cholesterol–lowering response seen with
ate the intended intensity, the
diet (75) or Dietary Approaches to Stop statins is poorly understood (77). Clini-
maximally tolerated statin dose
Hypertension (DASH) eating pattern, re- cians should attempt to find a dose or
should be used. E
ducing saturated and trans fat intake and alternative statin that is tolerable if side
S118 Cardiovascular Disease and Risk Management Diabetes Care Volume 43, Supplement 1, January 2020
the only dose of statin that a patient can it may also be reasonable to add ezeti-
10.26 In adults with diabetes aged
tolerate. For patients who do not tolerate mibe to maximally tolerated statin ther-
.75 years already on statin
the intended intensity of statin, the apy if needed to reduce LDL cholesterol
therapy, it is reasonable to
maximally tolerated statin dose should levels by 50% or more (12). The evidence
continue statin treatment. B
be used. is lower for patients aged .75 years;
10.27 In adults with diabetes aged .75
As in those without diabetes, absolute relatively few older patients with diabe-
years, it may be reasonable to
reductions in ASCVD outcomes (CHD tes have been enrolled in primary pre-
initiate statin therapy after dis-
death and nonfatal MI) are greatest in vention trials. However, heterogeneity
cussion of potential benefits and
people with high baseline ASCVD risk by age has not been seen in the relative
risks. C
(known ASCVD and/or very high LDL benefit of lipid-lowering therapy in tri-
10.28 Statin therapy is contraindi-
cholesterol levels), but the overall benefits als that included older participants
cated in pregnancy. B
of statin therapy in people with diabetes (80,87,88), and because older age con-
Initiating Statin Therapy Based on Risk at moderate or even low risk for ASCVD fers higher risk, the absolute benefits are
Patients with type 2 diabetes have an are convincing (89,90). The relative ben- actually greater (80,92). Moderate-in-
increased prevalence of lipid abnormalities, efit of lipid-lowering therapy has been tensity statin therapy is recommended
contributing to their high risk of ASCVD. uniform across most subgroups tested in patients with diabetes who are 75
Multiple clinical trials have demonstrated (80,88), including subgroups that varied years or older. However, the risk-benefit
the beneficial effects of statin therapy on with respect to age and other risk factors. profile should be routinely evaluated in
this population, with downward titra-
ASCVD outcomes in subjects with and Primary Prevention (Patients Without
ASCVD) tion of dose performed as needed. See
without CHD (79,80). Subgroup analyses
For primary prevention, moderate-dose sta- Section 12 “Older Adults” (https://doi
of patients with diabetes in larger trials
tin therapy is recommended for those .org/10.2337/dc20-S012) for more de-
(81–85) and trials in patients with diabetes
40 years and older (82,89,90), though tails on clinical considerations for this
(86,87) showed significant primary and
high-intensity therapy may be consid- population.
secondary prevention of ASCVD events
Age <40 Years and/or Type 1 Diabetes. Very
and CHD death in patients with diabetes. ered on an individual basis in the context
little clinical trial evidence exists for
Meta-analyses, including data from over of additional ASCVD risk factors. The
patients with type 2 diabetes under
18,000 patients with diabetes from 14 ran- evidence is strong for patients with di-
the age of 40 years or for patients
domized trials of statin therapy (mean abetes aged 40–75 years, an age-group
with type 1 diabetes of any age. For
follow-up 4.3 years), demonstrate a 9% well represented in statin trials showing pediatric recommendations, see Section
proportional reduction in all-cause mortal- benefit. Since risk is enhanced in patients 13 “Children and Adolescents” (https://
ity and 13% reduction in vascular mortality with diabetes, as noted above, patients doi.org/10.2337/dc20-S013). In the
for each mmol/L (39 mg/dL) reduction in who also have multiple other coronary Heart Protection Study (lower age limit
LDL cholesterol (88). risk factors have increased risk, equiva- 40 years), the subgroup of ;600 patients
Accordingly, statins are the drugs of lent to that of those with ASCVD. As such, with type 1 diabetes had a proportion-
choice for LDL cholesterol lowering and recent guidelines recommend that in ately similar, although not statistically
cardioprotection. Table 10.2 shows the patients with diabetes who are at higher significant, reduction in risk as patients
two statin dosing intensities that are risk, especially those with multiple with type 2 diabetes (82). Even though
recommended for use in clinical practice: ASCVD risk factors or aged 50–70 years, the data are not definitive, similar statin
high-intensity statin therapy will achieve it is reasonable to prescribe high-intensity treatment approaches should be consid-
approximately a $50% reduction in LDL statin therapy (12,91). Furthermore, for ered for patients with type 1 or type 2
cholesterol, and moderate-intensity sta- patients with diabetes whose ASCVD risk diabetes, particularly in the presence
tin regimens achieve 30–49% reductions is $20%, i.e., an ASCVD risk equivalent, of other cardiovascular risk factors. Pa-
in LDL cholesterol. Low-dose statin ther- the same high-intensity statin therapy is tients below the age of 40 have lower
apy is generally not recommended in recommended as for those with docu- risk of developing a cardiovascular event
patients with diabetes but is sometimes mented ASCVD (12). In those individuals, over a 10-year horizon; however, their
lifetime risk of developing cardiovascu-
lar disease and suffering an MI, stroke,
Table 10.2—High-intensity and moderate-intensity statin therapy* or cardiovascular death is high. For
High-intensity statin therapy Moderate-intensity statin therapy patients who are younger than 40 years
(lowers LDL cholesterol by $50%) (lowers LDL cholesterol by 30–49%) of age and/or have type 1 diabetes
Atorvastatin 40–80 mg Atorvastatin 10–20 mg
with other ASCVD risk factors, it is rec-
Rosuvastatin 20–40 mg Rosuvastatin 5–10 mg ommended that the patient and health
Simvastatin 20–40 mg care provider discuss the relative bene-
Pravastatin 40–80 mg fits and risks and consider the use
Lovastatin 40 mg of moderate-intensity statin therapy.
Fluvastatin XL 80 mg Please refer to “Type 1 Diabetes
Pitavastatin 1–4 mg Mellitus and Cardiovascular Dis-
*Once-daily dosing. XL, extended release.
ease: A Scientific Statement From
the American Heart Association and
care.diabetesjournals.org Cardiovascular Disease and Risk Management S119
American Diabetes Association” (93) Guidelines (12) for recommendations for feature who were receiving their maxi-
for additional discussion. primary and secondary prevention and for mally tolerated statin therapy (two-
statin and combination treatmentin adults thirds were on high-intensity statin)
Secondary Prevention (Patients With with diabetes (97). butwhostill had LDLcholesterol $70mg/dL
ASCVD) or non-HDL cholesterol $100 mg/dL (95).
Because risk is high in patients with Combination Therapy for LDL Patients were randomized to receive sub-
ASCVD, intensive therapy is indicated Cholesterol Lowering cutaneous injections of evolocumab (either
and has been shown to be of benefit Statins and Ezetimibe 140 mg every 2 weeks or 420 mg every
in multiple large randomized cardiovas- The IMProved Reduction of Outcomes: month based on patient preference)
cular outcomes trials (88,92,94,95). High- Vytorin Efficacy International Trial versus placebo. Evolocumab reduced
intensity statin therapy is recommended (IMPROVE-IT) was a randomized controlled LDL cholesterol by 59% from a me-
for all patients with diabetes and ASCVD. trial in 18,144 patients comparing the dian of 92 to 30 mg/dL in the treatment
This recommendation is based on the addition of ezetimibe to simvastatin arm.
Cholesterol Treatment Trialists’ Collab- therapy versus simvastatin alone. Indi- During the median follow-up of 2.2
oration involving 26 statin trials, of viduals were $50 years of age, had years, the composite outcome of cardio-
which 5 compared high-intensity versus experienced a recent acute coronary vascular death, MI, stroke, hospitaliza-
moderate-intensity statins. Together, syndrome (ACS), and were treated for tion for angina, or revascularization
they found reductions in nonfatal car- an average of 6 years. Overall, the ad- occurred in 11.3% vs. 9.8% of the placebo
diovascular events with more intensive dition of ezetimibe led to a 6.4% relative and evolocumab groups, respectively,
therapy, in patients with and without benefit and a 2% absolute reduction in representing a 15% relative risk reduc-
diabetes (80,84,94). major adverse cardiovascular events, tion (P , 0.001). The combined end
Over the past few years, there have with the degree of benefit being directly point of cardiovascular death, MI, or
been multiple large randomized trials proportional to the change in LDL cho- stroke was reduced by 20%, from
investigating the benefits of adding lesterol, which was 70 mg/dL in the statin 7.4% to 5.9% (P , 0.001). Importantly,
nonstatin agents to statin therapy, in- group on average and 54 mg/dL in the similar benefits were seen in a prespe-
cluding those that evaluated further combination group (92). In those with cified subgroup of patients with diabe-
lowering of LDL cholesterol with eze- diabetes (27% of participants), the com- tes, comprising 11,031 patients (40% of
timibe (92,96) and proprotein conver- bination of moderate-intensity simvas- the trial) (100).
tase subtilisin/kexin type 9 (PCSK9) tatin (40 mg) and ezetimibe (10 mg)
inhibitors (95). Each trial found a sig- showed a significant reduction of major Treatment of Other Lipoprotein
nificant benefit in the reduction of adverse cardiovascular events with an Fractions or Targets
ASCVD events that was directly related absolute risk reduction of 5% (40% vs. Recommendations
to the degree of further LDL cholesterol 45% cumulative incidence at 7 years) and 10.29 For patients with fasting tri-
lowering. These large trials included a a relative risk reduction of 14% (hazard glyceride levels $500 mg/dL,
significant number of participants with ratio [HR] 0.86 [95% CI 0.78–0.94]) over evaluate for secondary causes
diabetes. For very high-risk patients moderate-intensity simvastatin (40 mg) of hypertriglyceridemia and con-
with ASCVD who are on high-intensity alone (96). sider medical therapy to reduce
(and maximally tolerated) statin the risk of pancreatitis. C
therapy and have an LDL chole- Statins and PCSK9 Inhibitors 10.30 In adults with moderate hyper-
sterol $70 mg/dL, the addition of Placebo-controlled trials evaluating the triglyceridemia (fasting or non-
nonstatin LDL-lowering therapy can addition of the PCSK9 inhibitors evolo- fasting triglycerides 175–499
be considered following a clinician- cumab and alirocumab to maximally mg/dL), clinicians should ad-
patient discussion about the net ben- tolerated doses of statin therapy in dress and treat lifestyle factors
efit, safety, and cost. Definition of very participants who were at high risk for (obesity and metabolic syn-
high-risk patients with ASCVD includes ASCVD demonstrated an average reduc- drome), secondary factors
the use of specific criteria (major tion in LDL cholesterol ranging from (diabetes, chronic liver or kid-
ASCVD events and high-risk condi- 36% to 59%. These agents have been ney disease and/or nephrotic
tions); refer to the 2018 American Col- approved as adjunctive therapy for syndrome, hypothyroidism),
lege of Cardiology/American Heart patients with ASCVD or familial hyper- and medications that raise tri-
Association multisociety guideline on cholesterolemia who are receiving max- glycerides. C
the management of blood cholesterol imally tolerated statin therapy but
10.31 In patients with atherosclerotic
for further details regarding this def- require additional lowering of LDL cho-
cardiovascular disease or other
inition of risk (12). lesterol (98,99).
cardiovascular risk factors on a
Please see 2018 AHA/ACC/AACVPR/ The effects of PCSK9 inhibition on
statin with controlled LDL cho-
AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/ ASCVD outcomes was investigated in
lesterol but elevated trigly-
NLA/PCNA Guideline on the Manage- the Further Cardiovascular Outcomes
cerides (135–499 mg/dL), the
ment of Blood Cholesterol: Executive Research With PCSK9 Inhibition in Sub-
addition of icosapent ethyl can
Summary: A Report of the American jects With Elevated Risk (FOURIER)
be considered to reduce cardio-
College of Cardiology/American Heart trial, which enrolled 27,564 patients with
vascular risk. A
Association Task Force on Clinical Practice prior ASCVD and an additional high-risk
S120 Cardiovascular Disease and Risk Management Diabetes Care Volume 43, Supplement 1, January 2020
Hypertriglyceridemia should be ad- that for statin therapy (103). In a large [1.3 mmol/L]), and triglyceride levels of
dressed with dietary and lifestyle trial in patients with diabetes, fenofi- 150–400 mg/dL (1.7–4.5 mmol/L) to
changes including weight loss and ab- brate failed to reduce overall cardiovas- statin therapy plus extended-release ni-
stinence from alcohol (101). Severe cular outcomes (104). acin or placebo. The trial was halted early
hypertriglyceridemia (fasting triglycer- due to lack of efficacy on the primary
ides $500 mg/dL and especially .1,000 Other Combination Therapy ASCVD outcome (first event of the com-
mg/dL) may warrant pharmacologic ther- posite of death from CHD, nonfatal MI,
Recommendations
apy (fibric acid derivatives and/or fish ischemic stroke, hospitalization for an
10.32 Statin plus fibrate combination
oil) to reduce the risk of acute pancre- ACS, or symptom-driven coronary or
therapy has not been shown to
atitis. Moderate- or high-intensity statin cerebral revascularization) and a possible
improve atherosclerotic car-
therapy should also be used as indicated increase in ischemic stroke in those on
diovascular disease outcomes
to reduce risk of cardiovascular events combination therapy (108).
and is generally not recom-
(see STATIN TREATMENT ). In patients with The much larger Heart Protection
mended. A
moderate hypertriglyceridemia, lifestyle Study 2–Treatment of HDL to Reduce
10.33 Statin plus niacin combination
interventions, treatment of secondary the Incidence of Vascular Events (HPS2-
therapy has not been shown to
factors, and avoidance of medications THRIVE) trial also failed to show a benefit
provide additional cardiovas-
that might raise triglycerides are recom- of adding niacin to background statin
cular benefit above statin ther-
mended. therapy (109). A total of 25,673 patients
apy alone, may increase the
The Reduction of Cardiovascular with prior vascular disease were random-
risk of stroke with additional
Events with Icosapent Ethyl–Intervention ized to receive 2 g of extended-release
side effects, and is generally
Trial (REDUCE-IT) enrolled 8,179 adults niacin and 40 mg of laropiprant (an
not recommended. A
receiving statin therapy with mod- antagonist of the prostaglandin D2 re-
erately elevated triglycerides (135– ceptor DP1 that has been shown to
499 mg/dL, median baseline of 216 Statin and Fibrate Combination Therapy improve adherence to niacin therapy)
mg/dL) who had either established car- Combination therapy (statin and fibrate) versus a matching placebo daily and
diovascular disease (secondary preven- is associated with an increased risk for followed for a median follow-up period
tion cohort) or diabetes plus at least one abnormal transaminase levels, myositis, of 3.9 years. There was no significant
other cardiovascular risk factor (primary and rhabdomyolysis. The risk of rhabdo- difference in the rate of coronary death,
prevention cohort). Patients were ran- myolysis is more common with higher MI, stroke, or coronary revascularization
domized to icosapent ethyl 4 g/day (2 g doses of statins and renal insufficiency with the addition of niacin–laropiprant
twice daily with food) versus placebo. and appears to be higher when statins versus placebo (13.2% vs. 13.7%; rate
The trial met its primary end point, are combined with gemfibrozil (com- ratio 0.96; P 5 0.29). Niacin–laropiprant
demonstrating a 25% relative risk reduc- pared with fenofibrate) (105). was associated with an increased inci-
tion (P , 0.001) for the primary end point In the ACCORD study, in patients dence of new-onset diabetes (absolute
composite of cardiovascular death, non- with type 2 diabetes who were at high excess, 1.3 percentage points; P , 0.001)
fatal myocardial infarction, nonfatal risk for ASCVD, the combination of fe- and disturbances in diabetes control
stroke, coronary revascularization, or nofibrate and simvastatin did not reduce among those with diabetes. In addition,
unstable angina. The composite of car- the rate of fatal cardiovascular events, there was an increase in serious adverse
diovascular death, nonfatal myocardial nonfatal MI, or nonfatal stroke as com- events associated with the gastrointes-
infarction, or nonfatal stroke was re- pared with simvastatin alone. Prespeci- tinal system, musculoskeletal system,
duced by 26% (P , 0.001). Additional fied subgroup analyses suggested skin, and, unexpectedly, infection and
ischemic end points were significantly heterogeneity in treatment effects bleeding.
lower in the icosapent ethyl group than in with possible benefit for men with Therefore, combination therapy with
the placebo group, including cardiovas- both a triglyceride level $204 mg/dL a statin and niacin is not recommended
cular death, which was reduced by 20% (2.3 mmol/L) and an HDL cholesterol given the lack of efficacy on major
(P 5 0.03). The proportions of patients level #34 mg/dL (0.9 mmol/L) (106). ASCVD outcomes and increased side
experiencing adverse events and serious A prospective trial of a newer fibrate effects.
adverse events were similar between the in this specific population of patients is
active and placebo treatment groups. It ongoing (107). Diabetes Risk With Statin Use
should be noted that data are lacking Statin and Niacin Combination Therapy Several studies have reported a modestly
with other n-3 fatty acids, and results of The Atherothrombosis Intervention in increased risk of incident diabetes with
the REDUCE-IT trial should not be ex- Metabolic Syndrome With Low HDL/ statin use (110,111), which may be lim-
trapolated to other products (102). High Triglycerides: Impact on Global ited to those with diabetes risk factors.
Low levels of HDL cholesterol, often Health Outcomes (AIM-HIGH) trial ran- An analysis of one of the initial studies
associated with elevated triglyceride lev- domized over 3,000 patients (about suggested that although statin use was
els, are the most prevalent pattern of one-third with diabetes) with established associated with diabetes risk, the cardio-
dyslipidemia in individuals with type 2 ASCVD, low LDL cholesterol levels vascular event rate reduction with sta-
diabetes. However, the evidence for the (,180 mg/dL [4.7 mmol/L]), low HDL tins far outweighed the risk of incident
use of drugs that target these lipid frac- cholesterol levels (men ,40 mg/dL diabetes even for patients at highest
tions is substantially less robust than [1.0 mmol/L] and women ,50 mg/dL risk for diabetes (112). The absolute
care.diabetesjournals.org Cardiovascular Disease and Risk Management S121
risk increase was small (over 5 years of outcome was major bleeding (i.e., in-
clopidogrel (75 mg/day) should
follow-up, 1.2% of participants on placebo tracranial hemorrhage, sight-threatening
be used. B
developed diabetes and 1.5% on rosuvas- bleeding in the eye, gastrointestinal bleed-
10.36 Dual antiplatelet therapy (with
tatin developed diabetes) (112). A meta- ing, or other serious bleeding). During a
low-dose aspirin and a P2Y12
analysis of 13 randomized statin trials with mean follow-up of 7.4 years, there was a
inhibitor) is reasonable for a
91,140 participants showed an odds ratio of significant 12% reduction in the primary
year after an acute coronary
1.09 for a new diagnosis of diabetes, so that efficacy end point (8.5% vs. 9.6%; P 5
syndrome A and may have
(on average) treatment of 255 patients with 0.01). In contrast, major bleeding was
benefits beyond this period. B
statins for 4 years resulted in one additional significantly increased from 3.2% to
10.37 Aspirin therapy (75–162 mg/day)
case of diabetes while simultaneously pre- 4.1% in the aspirin group (rate ratio
may be considered as a pri-
venting 5.4 vascular events among those 1.29; P 5 0.003), with most of the excess
mary prevention strategy in
255 patients (111). being gastrointestinal bleeding and other
those with diabetes who are
extracranial bleeding. There were no sig-
at increased cardiovascular
Lipid-Lowering Agents and Cognitive nificant differences by sex, weight, or
risk, after a comprehensive dis-
Function duration of diabetes or other baseline
cussion with the patient on the
Although concerns regarding a potential factors including ASCVD risk score.
benefits versus the comparable
adverse impact of lipid-lowering agents on Two other large randomized trials of
increased risk of bleeding. A
cognitive function have been raised, sev- aspirin for primary prevention, in pa-
eral lines of evidence point against this tients without diabetes (ARRIVE [Aspirin
association, as detailed in a 2018 European Risk Reduction to Reduce Risk of Initial Vascular Events])
Atherosclerosis Society Consensus Panel Aspirin has been shown to be effective in (126) and in the elderly (ASPREE [Aspirin
statement (113). First, there are three large reducing cardiovascular morbidity and in Reducing Events in the Elderly]) (127),
randomized trials of statin versus placebo mortality in high-risk patients with pre- which included 11% with diabetes, found
where specific cognitive tests were per- vious MI or stroke (secondary preven- no benefit of aspirin on the primary efficacy
formed, and no differences were seen tion) and is strongly recommended. In end point and an increased risk of bleeding.
between statin and placebo (114–117). primary prevention, however, among In ARRIVE, with 12,546 patients over a pe-
In addition, no change in cognitive function patients with no previous cardiovascular riod of 60 months follow-up, the primary
has been reported in studies with the events, its net benefit is more contro- end point occurred in 4.29% vs. 4.48% of
addition of ezetimibe (92) or PCSK9 inhib- versial (120,121). patients in the aspirin versus placebo
itors (95,118) to statin therapy, including Previous randomized controlled trials groups (HR 0.96; 95% CI 0.81–1.13; P 5
among patients treated to very low LDL of aspirin specifically in patients with 0.60). Gastrointestinal bleeding events
cholesterol levels. In addition, the most diabetes failed to consistently show a (characterized as mild) occurred in 0.97%
recent systematic review of the U.S. Food significant reduction in overall ASCVD of patients in the aspirin group vs. 0.46% in
and Drug Administration’s (FDA’s) post- end points, raising questions about the the placebo group (HR 2.11; 95% CI 1.36–
marketing surveillance databases, ran- efficacy of aspirin for primary preven- 3.28; P 5 0.0007). In ASPREE, including
domized controlled trials, and cohort, tion in people with diabetes, although 19,114 persons, for the rate of cardiovas-
case-control, and cross-sectional studies some sex differences were suggested cular disease (fatal CHD, MI, stroke, or
evaluating cognition in patients receiving (122–124). hospitalization for heart failure) after a
statins found that published data do not The Antithrombotic Trialists’ Collabo- median of 4.7 years of follow-up, the rates
reveal an adverse effect of statins on ration published an individual patient– per 1,000 person-years were 10.7 vs. 11.3
cognition (119). Therefore, a concern level meta-analysis (120) of the six large events in aspirin vs. placebo groups (HR
that statins or other lipid-lowering agents trials of aspirin for primary prevention 0.95; 95% CI 0.83–1.08). The rate of major
might cause cognitive dysfunction or in the general population. These trials hemorrhage per 1,000 person-years was
dementia is not currently supported collectively enrolled over 95,000 partic- 8.6 events vs. 6.2 events, respectively (HR
by evidence and should not deter their ipants, including almost 4,000 with di- 1.38; 95% CI 1.18–1.62; P , 0.001).
use in individuals with diabetes at high abetes. Overall, they found that aspirin Thus, aspirin appears to have a modest
risk for ASCVD (119). reduced the risk of serious vascular effect on ischemic vascular events, with
events by 12% (relative risk 0.88 [95% the absolute decrease in events depend-
ANTIPLATELET AGENTS CI 0.82–0.94]). The largest reduction was ing on the underlying ASCVD risk. The
for nonfatal MI, with little effect on CHD main adverse effect is an increased risk
Recommendations
death (relative risk 0.95 [95% CI 0.78– of gastrointestinal bleeding. The excess
10.34 Use aspirin therapy (75–162
1.15]) or total stroke.
mg/day) as a secondary pre- risk may be as high as 5 per 1,000 per
Most recently, the ASCEND (A Study of
vention strategy in those with year in real-world settings. However, for
Cardiovascular Events iN Diabetes) trial
diabetes and a history of ath- adults with ASCVD risk .1% per year, the
randomized 15,480 patients with diabe-
erosclerotic cardiovascular number of ASCVD events prevented will
tes but no evident cardiovascular disease
disease. A be similar to the number of episodes
to aspirin 100 mg daily or placebo (125).
10.35 For patients with atheroscle- of bleeding induced, although these com-
The primary efficacy end point was vas-
rotic cardiovascular disease and
cular death, MI, or stroke or transient plications do not have equal effects on
documented aspirin allergy,
ischemic attack. The primary safety long-term health (128).
S122 Cardiovascular Disease and Risk Management Diabetes Care Volume 43, Supplement 1, January 2020
Table 10.3A—Cardiovascular outcomes trials of available antihyperglycemic medications completed after the issuance of the FDA
2008 guidelines: DPP-4 inhibitors
SAVOR-TIMI 53 (181) EXAMINE (186) TECOS (183) CARMELINA (184,187)
(n 5 16,492) (n 5 5,380) (n 5 14,671) (n 5 6,979)
Intervention Saxagliptin/placebo Alogliptin/placebo Sitagliptin/placebo Linagliptin/placebo
Main inclusion criteria Type 2 diabetes and history Type 2 diabetes and ACS Type 2 diabetes Type 2 diabetes and high CV and
of or multiple risk factors within 15–90 days before and preexisting renal risk
for CVD randomization CVD
A1C inclusion criteria (%) $6.5 6.5–11.0 6.5–8.0 6.5–10.0
Age (years)†† 65.1 61.0 65.4 65.8
Race (% white) 75.2 72.7 67.9 80.2
Sex (% male) 66.9 67.9 70.7 62.9
Diabetes duration (years)†† 10.3 7.1 11.6 14.7
Median follow-up (years) 2.1 1.5 3.0 2.2
Statin use (%) 78 91 80 71.8
Metformin use (%) 70 66 82 54.8
Prior CVD/CHF (%) 78/13 100/28 74/18 57/26.8
Mean baseline A1C (%) 8.0 8.0 7.2 7.9
Mean difference in A1C 20.3^ 20.3^ 20.3^ 20.36^
between groups at end of
treatment (%)
Year started/reported 2010/2013 2009/2013 2008/2015 2013/2018
Primary outcome§ 3-point MACE 3-point MACE 4-point MACE 3-point MACE
1.00 (0.89–1.12) 0.96 (95% UL #1.16) 0.98 (0.89–1.08) 1.02 (0.89–1.17)
Key secondary outcome§ Expanded MACE 4-point MACE 3-point MACE Kidney composite (ESRD,
1.02 (0.94–1.11) 0.95 (95% UL #1.14) 0.99 (0.89–1.10) sustained $40% decrease in
eGFR, or renal death)
1.04 (0.89–1.22)
Cardiovascular death§ 1.03 (0.87–1.22) 0.85 (0.66–1.10) 1.03 (0.89–1.19) 0.96 (0.81–1.14)
MI§ 0.95 (0.80–1.12) 1.08 (0.88–1.33) 0.95 (0.81–1.11) 1.12 (0.90–1.40)
Stroke§ 1.11 (0.88–1.39) 0.91 (0.55–1.50) 0.97 (0.79–1.19) 0.91 (0.67–1.23)
HF hospitalization§ 1.27 (1.07–1.51) 1.19 (0.90–1.58) 1.00 (0.83–1.20) 0.90 (0.74–1.08)
Unstable angina 1.19 (0.89–1.60) 0.90 (0.60–1.37) 0.90 (0.70–1.16) 0.87 (0.57–1.31)
hospitalization§
All-cause mortality§ 1.11 (0.96–1.27) 0.88 (0.71–1.09) 1.01 (0.90–1.14) 0.98 (0.84–1.13)
Worsening nephropathy§|| 1.08 (0.88–1.32) d d Kidney composite (see above)
d, not assessed/reported; ACS, acute coronary syndrome; CHF, congestive heart failure; CV, cardiovascular; CVD, cardiovascular disease; DPP-4,
dipeptidyl peptidase 4; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; GLP-1, glucagon-like peptide 1; HF, heart failure;
MACE, major adverse cardiac event; MI, myocardial infarction; UL, upper limit. Data from this table was adapted from Cefalu et al. (188) in
the January 2018 issue of Diabetes Care. ††Age was reported as means in all trials except EXAMINE, which reported medians; diabetes
duration was reported as means in all trials except SAVOR-TIMI 53 and EXAMINE, which reported medians. §Outcomes reported as
hazard ratio (95% CI). ||Worsening nephropathy is defined as as doubling of creatinine level, initiation of dialysis, renal transplantation, or
creatinine .6.0 mg/dL (530 mmol/L) in SAVOR-TIMI 53. Worsening nephropathy was a prespecified exploratory adjudicated outcome in
SAVOR-TIMI 53. ^Significant difference in A1C between groups (P , 0.05).
and cardiovascular death by 14% (abso- assessed 1) the cardiovascular effects of drug (163). Thereafter, the postapproval
lute rate 10.5% vs. 12.1% in the placebo treatment in patients at high risk for CANVAS-Renal (CANVAS-R) trial was
group, HR in the empagliflozin group major adverse cardiovascular events, started in 2014. Combining both of these
0.86; 95% CI 0.74–0.99; P 5 0.04 for and 2) the impact of canagliflozin therapy trials, 10,142 participants with type 2
superiority) and cardiovascular death by on cardiorenal outcomes in patients with diabetes were randomized to canagliflo-
38% (absolute rate 3.7% vs. 5.9%, HR diabetes-related chronic kidney disease zin or placebo and were followed for an
0.62; 95% CI 0.49–0.77; P , 0.001) (8). have been conducted (162). First, the average 3.6 years. The mean age of
The FDA added an indication for empa- Canagliflozin Cardiovascular Assessment patients was 63 years, and 66% had a
gliflozin to reduce the risk of major Study (CANVAS) Program integrated data history of cardiovascular disease. The
adverse cardiovascular death in adults from two trials. The CANVAS trial that combined analysis of the two trials found
with type 2 diabetes and cardiovascular started in 2009 was partially unblinded that canagliflozin significantly reduced
disease. prior to completion because of the the composite outcome of cardiovascu-
Two large outcomes trials of the SGLT2 need to file interim cardiovascular out- lar death, MI, or stroke versus placebo
inhibitor canagliflozin that separately comes data for regulatory approval of the (occurring in 26.9 vs. 31.5 participants
care.diabetesjournals.org Cardiovascular Disease and Risk Management S125
Table 10.3B—Cardiovascular outcomes trials of available antihyperglycemic medications completed after the issuance
of the FDA 2008 guidelines: GLP-1 receptor agonists
Harmony
ELIXA (170) LEADER (165) SUSTAIN-6 (166)* EXSCEL (171) Outcomes (168) REWIND (169)
(n 5 6,068) (n 5 9,340) (n 5 3,297) (n 5 14,752) (n 5 9,463) (n 5 9,901)
Intervention Lixisenatide/ Liraglutide/ Semaglutide/ Exenatide QW/ Albiglutide/ Dulaglutide/
placebo placebo placebo placebo placebo placebo
Main inclusion Type 2 diabetes Type 2 diabetes Type 2 diabetes and Type 2 diabetes Type 2 diabetes Type 2 diabetes
criteria and history of and preexisting preexisting CVD, with or without with preexisting and prior
ACS (,180 days) CVD, CKD, or HF HF, or CKD at preexisting CVD CVD ASCVD event
at $50 years of $50 years of age or risk factors
age or CV risk at or CV risk at $60 for ASCVD
$60 years of years of age
age
A1C inclusion 5.5–11.0 $7.0 $7.0 6.5–10.0 $7.0 #9.5
criteria (%)
Age (years)†† 60.3 64.3 64.6 62 64.1 66.2
Race (% white) 75.2 77.5 83.0 75.8 84.8 75.7
Sex (% male) 69.3 64.3 60.7 62 69.4 53.7
Diabetes duration 9.3 12.8 13.9 12 13.8 10.5
(years)††
Median follow-up 2.1 3.8 2.1 3.2 1.6 5.4
(years)
Statin use (%) 93 72 73 74 84.0 66
Metformin use (%) 66 76 73 77 73.6 81
Prior CVD/CHF (%) 100/22 81/18 60/24 73.1/16.2 100/20.2 32/9
Mean baseline 7.7 8.7 8.7 8.0 8.7 7.4
A1C (%)
Mean difference in 20.3^ 20.4^ 20.7 or – 1.0^† 20.53^ 20.52^ 20.61^
A1C between
groups at end of
treatment (%)
Year started/ 2010/2015 2010/2016 2013/2016 2010/2017 2015/2018 2011/2019
reported
Primary outcome§ 4-point MACE 3-point MACE 3-point MACE 3-point MACE 3-point MACE 3-point MACE
1.02 (0.89–1.17) 0.87 (0.78–0.97) 0.74 (0.58–0.95) 0.91 (0.83–1.00) 0.78 (0.68–0.90) 0.88 (0.79–0.99)
Key secondary Expanded MACE Expanded MACE Expanded MACE Individual Expanded MACE Composite
outcome§ (0.90–1.11) 0.88 (0.81–0.96) 0.74 (0.62–0.89) components of (with urgent microvascular
MACE (see revascularization outcome
below) for unstable (eye or renal
angina) outcome)
0.78 (0.69–0.90) 0.87 (0.79–0.95)
CV death or HF
hospitalization
0.85 (0.70–1.04)
Individual
components of
MACE (see below)
Cardiovascular 0.98 (0.78–1.22) 0.78 (0.66–0.93) 0.98 (0.65–1.48) 0.88 (0.76–1.02) 0.93 (0.73–1.19) 0.91 (0.78–1.06)
death§
MI§ 1.03 (0.87–1.22) 0.86 (0.73–1.00) 0.74 (0.51–1.08) 0.97 (0.85–1.10) 0.75 (0.61–0.90) 0.96 (0.79–1.15)
Stroke§ 1.12 (0.79–1.58) 0.86 (0.71–1.06) 0.61 (0.38–0.99) 0.85 (0.70–1.03) 0.86 (0.66–1.14) 0.76 (0.61–0.95)
HF 0.96 (0.75–1.23) 0.87 (0.73–1.05) 1.11 (0.77–1.61) 0.94 (0.78–1.13) d 0.93 (0.77–1.12)
hospitalization§
Unstable angina 1.11 (0.47–2.62) 0.98 (0.76–1.26) 0.82 (0.47–1.44) 1.05 (0.94–1.18) d 1.14 (0.84–1.54)
hospitalization§
Continued on p. S126
S126 Cardiovascular Disease and Risk Management Diabetes Care Volume 43, Supplement 1, January 2020
Table 10.3B—Continued
Harmony
ELIXA (170) LEADER (165) SUSTAIN-6 (166)* EXSCEL (171) Outcomes (168) REWIND (169)
(n 5 6,068) (n 5 9,340) (n 5 3,297) (n 5 14,752) (n 5 9,463) (n 5 9,901)
All-cause 0.94 (0.78–1.13) 0.85 (0.74–0.97) 1.05 (0.74–1.50) 0.86 (0.77–0.97) 0.95 (0.79–1.16) 0.90 (0.80–1.01)
mortality§
Worsening d 0.78 (0.67–0.92) 0.64 (0.46–0.88) d d 0.85 (0.77–0.93)
nephropathy§||
d, not assessed/reported; ACS, acute coronary syndrome; ASCVD, atherosclerotic cardiovascular disease; CHF, congestive heart failure; CKD, chronic
kidney disease; CV, cardiovascular; CVD, cardiovascular disease; GLP-1, glucagon-like peptide 1; HF, heart failure; MACE, major adverse cardiac event;
MI, myocardial infarction. Data from this table was adapted from Cefalu et al. (188) in the January 2018 issue of Diabetes Care. *Powered to rule out
a hazard ratio of 1.8; superiority hypothesis not prespecified. ††Age was reported as means in all trials; diabetes duration was reported as means in all
trials except EXSCEL, which reported medians. †A1C change of 0.66% with 0.5 mg and 1.05% with 1 mg dose of semaglutide. §Outcomes reported as
hazard ratio (95% CI). ||Worsening nephropathy is defined as the new onset of urine albumin-to-creatinine ratio .300 mg/g creatinine or a doubling of
the serum creatinine level and an estimated glomerular filtration rate of ,45 mL/min/1.73 m2, the need for continuous renal replacement therapy, or
death from renal disease in LEADER and SUSTAIN-6 and as new macroalbuminuria, a sustained decline in estimated glomerular filtration rate of 30% or
more from baseline, or chronic renal replacement therapy in REWIND. Worsening nephropathy was a prespecified exploratory adjudicated outcome in
LEADER, SUSTAIN-6, and REWIND.^Significant difference in A1C between groups (P , 0.05).
per 1,000 patient-years; HR 0.86 [95% CI failure (HR 0.61 [95% CI 0.47–0.80]), and lowerrateofhospitalizationforheartfailure
0.75–0.97]). The specific estimates for of the composite of cardiovascular death (HR 0.73; 95% CI 0.61–0.88). No difference
canagliflozin versus placebo on the or hospitalization for heart failure (HR was seen in cardiovascular death between
primary composite cardiovascular out- 0.69 [95% CI 0.57–0.83]). In terms of groups.
come were HR 0.88 (0.75–1.03) for safety, no significant increase in lower-
the CANVAS trial and 0.82 (0.66–1.01) limb amputations, fractures, acute kidney GLP-1 Receptor Agonist Trials
for CANVAS-R, with no heterogeneity injury, or hyperkalemia was noted for The Liraglutide Effect and Action in Di-
found between trials. Of note, there canagliflozin relative to placebo in CRE- abetes: Evaluation of Cardiovascular
was an increased risk of lower-limb am- DENCE. An increased risk for diabetic Outcome Results (LEADER) trial was a
putation with canagliflozin (6.3 vs. 3.4 ketoacidosis was noted, however, with randomized, double-blind trial that
participants per 1,000 patient-years; HR 2.2 and 0.2 events per 1,000 patient-years assessed the effect of liraglutide, a
1.97 [95% CI 1.41–2.75]) (9). Second, the noted in the canagliflozin and placebo glucagon-like peptide 1 (GLP-1) receptor
Canagliflozin and Renal Events in Dia- groups, respectively (HR 10.80 [95% CI agonist, versus placebo on cardiovascular
betes with Established Nephropathy 1.39–83.65]) (162). outcomes in 9,340 patients with type 2
Clinical Evaluation (CREDENCE) trial ran- The Dapagliflozin Effect on Cardiovascu- diabetes at high risk for cardiovascular
domized 4,401 patients with type 2 lar Events–Thrombosis in Myocardial In- disease or with cardiovascular disease.
diabetes and chronic diabetes-related farction 58 (DECLARE-TIMI 58) trial was Study participants had a mean age of
kidney disease (UACR .300 mg/g and another randomized, double-blind trial that 64 years and a mean duration of diabetes
estimated glomerular filtration rate 30 assessed the effects of dapagliflozin versus of nearly 13 years. Over 80% of study
to ,90 mL/min/1.73 m2) to canagliflozin placebo on cardiovascular and renal out- participants had established cardiovascu-
100 mg daily or placebo (162). The pri- comes in 17,160 patients with type 2 di- lar disease. After a median follow-up of 3.8
mary outcome was a composite of end- abetes and established ASCVD or multiple years, LEADER showed that the primary
stage kidney disease (ESKD), doubling of risk factors for atherosclerotic cardiovascu- composite outcome (MI, stroke, or car-
serum creatinine, or death from renal or lar disease (164). Study participants had a diovascular death) occurred in fewer
cardiovascular causes. The trial was stop- mean age of 64 years, with ;40% of study participants in the treatment group
ped early due to conclusive evidence of participants having established ASCVD at (13.0%) when compared with the pla-
efficacy identified during a prespecified baselineda characteristic of this trial that cebo group (14.9%) (HR 0.87; 95% CI
interim analysis with no unexpected differs from other large cardiovascular trials 0.78–0.97; P , 0.001 for noninferiority;
safety signals. The risk of the primary where a majority of participants had estab- P 5 0.01 for superiority). Deaths from
composite outcome was 30% lower with lished cardiovascular disease. DECLARE- cardiovascular causes were significantly
canagliflozin treatment when compared TIMI 58 met the prespecified criteria for reduced in the liraglutide group (4.7%)
with placebo (HR 0.70 [95% CI 0.59– noninferiority to placebo with respect to compared with the placebo group
0.82]). Moreover, it reduced the prespe- MACE but did not show a lower rate of (6.0%) (HR 0.78; 95% CI 0.66–0.93;
cified end point of ESKD alone by 32% (HR MACE when compared with placebo (8.8% P 5 0.007) (165). The FDA approved
0.68 [95% CI 0.54–0.86]). Canagliflozin in the dapagliflozin group and 9.4% in the the use of liraglutide to reduce the risk of
was additionally found to have a lower placebo group; HR 0.93; 95% CI 0.84–1.03; major adverse cardiovascular events,
risk of the composite of cardiovascular P 5 0.17). A lower rate of cardiovascular including heart attack, stroke, and car-
death, myocardial infarction, or stroke death or hospitalization for heart failure diovascular death, in adults with type 2
(HR 0.80 [95% CI 0.67–0.95]), as well as was noted (4.9% vs. 5.8%; HR 0.83; 95% CI diabetes and established cardiovascu-
lower risk of hospitalizations for heart 0.73–0.95; P 5 0.005), which reflected a lar disease.
care.diabetesjournals.org Cardiovascular Disease and Risk Management S127
Table 10.3C—Cardiovascular outcomes trials of available antihyperglycemic medications completed after the issuance
of the FDA 2008 guidelines: SGLT2 inhibitors
EMPA-REG
CANVAS (9)
OUTCOME (8) DECLARE-TIMI 58 (164)
(n 5 7,020) (n 5 4,330) (n 5 5,812) (n 5 17,160)
Intervention Empagliflozin/ Canagliflozin/ Dapagliflozin/placebo
placebo placebo
Main inclusion criteria Type 2 diabetes Type 2 diabetes Type 2 diabetes and
and and preexisting established ASCVD or
preexisting CVD at $30 multiple risk factors
CVD years of age for ASCVD
or .2 CV risk
factors at $50
years of age
A1C inclusion criteria (%) 7.0–10.0 7.0–10.5 $6.5
Age (years)†† 63.1 63.3 64.0
Race (% white) 72.4 78.3 79.6
Sex (% male) 71.5 64.2 62.6
Diabetes duration (years)†† 57% .10 13.5 11.0
Median follow-up (years) 3.1 5.7 2.1 4.2
Statin use (%) 77 75 75 (statin or ezetimibe use)
Metformin use (%) 74 77 82
Prior CVD/CHF (%) 99/10 65.6/14.4 40/10
Mean baseline A1C (%) 8.1 8.2 8.3
Mean difference in A1C between 20.3^‡ 20.58^ 20.43^
groups at end of treatment (%)
Year started/reported 2010/2015 2009/2017 2013/2018
Primary outcome§ 3-point MACE 3-point MACE Progression to 3-point MACE 0.93 (0.84–
0.86 (0.74–0.99) 0.86 (0.75–0.97)§ albuminuria** 1.03)
0.73 (0.47–0.77) CV death or HF hospitalization
0.83 (0.73–0.95)
Key secondary outcome§ 4-point MACE All-cause and CV 40% reduction in Death from any cause
mortality (see composite 0.93 (0.82–1.04)
below) eGFR, renal Renal composite ($40%
replacement, decrease in eGFR rate to
renal death 0.60 ,60 mL/min/1.73m2, new
(0.47–0.77) ESRD, or death from renal or
CV causes
0.76 (0.67–0.87)
Cardiovascular death§ 0.62 (0.49–0.77) 0.96 (0.77–1.18)¶ 0.98 (0.82–1.17)
0.87 (0.72–1.06)#
MI§ 0.87 (0.70–1.09) 0.85 (0.65–1.11) 0.85 (0.61–1.19) 0.89 (0.77–1.01)
Stroke§ 1.18 (0.89–1.56) 0.97 (0.70–1.35) 0.82 (0.57–1.18) 1.01 (0.84–1.21)
HF hospitalization§ 0.65 (0.50–0.85) 0.77 (0.55–1.08) 0.56 (0.38–0.83) 0.73 (0.61–0.88)
Unstable angina hospitalization§ 0.99 (0.74–1.34) d d
All-cause mortality§ 0.68 (0.57–0.82) 0.87 (0.74–1.01)‡‡ 0.93 (0.82–1.04)
0.90 (0.76–1.07)##
Worsening nephropathy§|| 0.61 (0.53–0.70) 0.60 (0.47–0.77) 0.53 (0.43–0.66)
d, not assessed/reported; CHF, congestive heart failure; CV, cardiovascular; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate;
ESRD, end-stage renal disease; HF, heart failure; MACE, major adverse cardiac event; MI, myocardial infarction; SGLT2, sodium–glucose cotransporter 2.
Data from this table was adapted from Cefalu et al. (188) in the January 2018 issue of Diabetes Care. **On the basis of prespecified outcomes, the renal
outcomes are not viewed as statistically significant. ††Age was reported as means in all trials; diabetes duration was reported as means in all trials except
EMPA-REG OUTCOME, which reported as percentage of population with diabetes duration .10 years, and DECLARE-TIMI 58, which reported median.
‡AlC change of 0.30 in EMPA-REG OUTCOME is based on pooled results for both doses (i.e., 0.24% for 10 mg and 0.36% for 25 mg of empagliflozin).
§Outcomes reported as hazard ratio (95% CI). ||Worsening nephropathy is defined as the new onset of urine albumin-to-creatinine ratio .300 mg/g
creatinine or a doubling of the serum creatinine level and an estimated glomerular filtration rate of ,45 mL/min/1.73 m2, the need for continuous
renal replacement therapy, or death from renal disease in EMPA-REG OUTCOME and as $40% decrease in estimated glomerular filtration rate
to ,60 mL/min/1.73 m2, ESRD, or death from renal cause in DECLARE-TIMI 58. Worsening nephropathy was a prespecified exploratory adjudicated
outcome in DECLARE-TIMI 58 but not in EMPA-REG OUTCOME. ¶Truncated data set (prespecified in treating hierarchy as the principal data set
for analysis for superiority of all-cause mortality and cardiovascular death in the CANVAS Program).^Significant difference in A1C between groups
(P , 0.05). #Nontruncated data set. ‡‡Truncated integrated data set (refers to pooled data from CANVAS after 20 November 2012 plus CANVAS-R;
prespecified in treating hierarchy as the principal data set for analysis for superiority of all-cause mortality and cardiovascular death in the
CANVAS Program). ##Nontruncated integrated data (refers to pooled data from CANVAS, including before 20 November 2012 plus CANVAS-R).
S128 Cardiovascular Disease and Risk Management Diabetes Care Volume 43, Supplement 1, January 2020
Results from a moderate-sized trial of blind, placebo-controlled trial that as- disease) were randomized to receive ex-
another GLP-1 receptor agonist, sema- sessed the effect of the once-weekly tended-release exenatide 2 mg or pla-
glutide, were consistent with the LEADER GLP-1 receptor agonist dulaglutide ver- cebo and followed for a median of 3.2
trial (166). Semaglutide is a once-weekly sus placebo on MACE in ;9,990 patients years. The primary end point of cardio-
GLP-1 receptor agonist approved by the with type 2 diabetes at risk for cardio- vascular death, MI, or stroke occurred in
FDA for the treatment of type 2 diabetes. vascular events or with a history of 839 patients (11.4%; 3.7 events per
The Trial to Evaluate Cardiovascular and cardiovascular disease (169). Study par- 100 person-years) in the exenatide
Other Long-term Outcomes With Sem- ticipants had a mean age of 66 years and a group and in 905 patients (12.2%; 4.0
aglutide in Subjects With Type 2 Diabe- mean duration of diabetes of ;10 years. events per 100 person-years) in the
tes (SUSTAIN-6) was the initial randomized Approximately 32% of participants had placebo group (HR 0.91; 95% CI 0.83–
trial powered to test noninferiority of prior history of atherosclerotic cardio- 1.00; P , 0.001 for noninferiority) but
semaglutide for the purpose of initial vascular events at baseline. After a me- was not superior to placebo with re-
regulatory approval. In this study, 3,297 dian follow-up of 5.4 years, the primary spect to the primary end point (P 5 0.06 for
patients with type 2 diabetes were ran- composite outcome of nonfatal myocar- superiority). However, all-cause mortality
domized to receive once-weekly semaglu- dial infarction, nonfatal stroke, or death was lower in the exenatide group (HR 0.86
tide (0.5 mg or 1.0 mg) or placebo for from cardiovascular causes occurred [95% CI 0.77–0.97]). The incidence of acute
2 years. The primary outcome (the first in 12.0% and 13.4% of participants in pancreatitis, pancreatic cancer, medullary
occurrence of cardiovascular death, non- the dulaglutide and placebo treatment thyroid carcinoma, and serious adverse
fatal MI, or nonfatal stroke) occurred in groups, respectively (HR 0.88; 95% CI events did not differ significantly between
108 patients (6.6%) in the semaglutide 0.79–0.99; P 5 0.026). These findings the two groups.
group vs. 146 patients (8.9%) in the placebo equated to incidence rates of 2.4 and 2.7 In summary, there are now numerous
group (HR 0.74; 95% CI 0.58–0.95; P , events per 100 person-years, respec- large randomized controlled trials re-
0.001). More patients discontinued treat- tively. The results were consistent across porting statistically significant reductions
ment in the semaglutide group because of the subgroups of patients with and with- in cardiovascular events for three of the
adverse events, mainly gastrointestinal. out prior history of CV events. All-cause FDA-approved SGLT2 inhibitors (empa-
The cardiovascular effects of the oral for- mortality did not differ between groups gliflozin, canagliflozin, and dapagliflozin)
mulation of semaglutide compared with (P 5 0.067). and four FDA-approved GLP-1 receptor
placebo have been assessed in Peptide The Evaluation of Lixisenatide in Acute agonists (liraglutide, albiglutide [al-
Innovation for Early Diabetes Treatment Coronary Syndrome (ELIXA) trial studied though that agent was removed from
(PIONEER) 6, a preapproval trial designed the once-daily GLP-1 receptor agonist the market for business reasons], sem-
to rule out an unacceptable increase in in lixisenatide on cardiovascular outcomes aglutide [lower risk of cardiovascular
cardiovascular risk. In this trial of 3,183 in patients with type 2 diabetes who had events in a moderate-sized clinical trial
patients with type 2 diabetes and high had a recent acute coronary event (170). but one not powered as a cardiovascu-
cardiovascular risk followed for a me- A total of 6,068 patients with type 2 lar outcomes trial], and dulaglutide).
dian of 15.9 months, oral semaglutide diabetes with a recent hospitalization for Meta-analyses of the trials reported
was noninferior to placebo for the pri- MI or unstable angina within the previous to date suggest that GLP-1 receptor
mary composite outcome of cardiovas- 180 days were randomized to receive agonists and SGLT2 inhibitors reduce risk
cular death, nonfatal myocardial infarction, lixisenatide or placebo in addition to of atherosclerotic major adverse cardio-
or nonfatal stroke (HR 0.79; 95% CI 0.57– standard care and were followed for a vascular events to a comparable degree
1.11; P , 0.001 for noninferiority) (167). median of ;2.1 years. The primary out- in patients with type 2 diabetes and
The cardiovascular effects of this formu- come of cardiovascular death, MI, stroke, established ASCVD (172). SGLT2 inhib-
lation of semaglutide will be further tested or hospitalization for unstable angina itors also appear to reduce risk of heart
in a large, longer-term outcomes trial. occurred in 406 patients (13.4%) in the failure hospitalization and progression
The Harmony Outcomes trial random- lixisenatide group vs. 399 (13.2%) in the of kidney disease in patients with es-
ized 9,463 patients with type 2 diabetes placebo group (HR 1.2 [95% CI 0.89– tablished ASCVD, multiple risk factors
and cardiovascular disease to once- 1.17]), which demonstrated the noninfer- for ASCVD, or diabetic kidney disease
weekly subcutaneous albiglutide or match- iority of lixisenatide to placebo (P , 0.001) (173). In patients with type 2 diabetes
ing placebo, in addition to their standard but did not show superiority (P 5 0.81). and established ASCVD, multiple ASCVD
care. Over a median duration of 1.6 years, The Exenatide Study of Cardiovascu- risk factors, or diabetic kidney disease,
the GLP-1 receptor agonist reduced the risk lar Event Lowering (EXSCEL) trial also an SGLT2 inhibitor with demonstrated
of cardiovascular death, MI, or stroke to an reported results with the once-weekly cardiovascular benefit is recommended
incidence rate of 4.6 events per 100 per- GLP-1 receptor agonist extended-release to reduce the risk of major adverse
son-years in the albiglutide group vs. 5.9 exenatide and found that major adverse cardiovascular events and heart failure
events in the placebo group (HR ratio 0.78, cardiovascular events were numeri- hospitalization. In patients with type 2
P 5 0.0006 for superiority) (168). This cally lower with use of extended-release diabetes and established ASCVD or mul-
agent is not currently available for clinical exenatide compared with placebo, al- tiple risk factors for ASCVD, a glucagon-
use. though this difference was not statisti- like peptide 1 receptor agonist with
The Researching Cardiovascular Events cally significant (171). A total of 14,752 demonstrated cardiovascular benefit is
With a Weekly Incretin in Diabetes (RE- patients with type 2 diabetes (of whom recommended to reduce the risk of ma-
WIND) trial was a randomized, double- 10,782 [73.1%] had previous cardiovascular jor adverse cardiovascular events. For
care.diabetesjournals.org Cardiovascular Disease and Risk Management S129
many patients, use of either an SGLT2 compared with placebo (Table 10.3B) 5. Cavender MA, Steg PG, Smith SC Jr, et al.;
inhibitor or a GLP-1 receptor agonist to (165,166,169–171). REACH Registry Investigators. Impact of diabetes
mellitus on hospitalization for heart failure,
reduce cardiovascular risk is appropri- Reduced incidence of heart failure has cardiovascular events, and death: outcomes at
ate. It is unknown whether use of both been observed with the use of SGLT2 4 years from the Reduction of Atherothrombosis
classes of drugs will provide an additive inhibitors (162,164). In EMPA-REG OUT- for Continued Health (REACH) registry. Circula-
cardiovascular outcomes benefit. COME, the addition of empagliflozin to tion 2015;132:923–931
standard care led to a significant 35% 6. McAllister DA, Read SH, Kerssens J, et al.
Incidence of hospitalization for heart failure and
Glucose-Lowering Therapies and reduction in hospitalization for heart case-fatality among 3.25 million people with and
Heart Failure failure compared with placebo (8). Al- without diabetes mellitus. Circulation 2018;138:
As many as 50% of patients with type 2 though the majority of patients in the 2774–2786
diabetes may develop heart failure (174). study did not have heart failure at base- 7. Lam CSP, Voors AA, de Boer RA, Solomon SD,
Data on the effects of glucose-lowering line, this benefit was consistent in pa- van Veldhuisen DJ. Heart failure with preserved
ejection fraction: from mechanisms to therapies.
agents on heart failure outcomes have tients with and without a history of heart Eur Heart J 2018;39:2780–2792
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have a strong and consistent relationship DECLARE-TIMI 58, there were 33% and REG OUTCOME Investigators. Empagliflozin, car-
with increased risk of heart failure 27% reductions in hospitalization for diovascular outcomes, and mortality in type 2
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9. Neal B, Perkovic V, Mahaffey KW, et al.;
use should be avoided in patients with inhibitor use versus placebo (9,164). CANVAS Program Collaborative Group. Canagli-
symptomatic heart failure. Restrictions to Additional data from the CREDENCE trial flozin and cardiovascular and renal events in
use of metformin in patients with med- with canagliflozin showed a 39% reduc- type 2 diabetes. N Engl J Med 2017;377:644–657
ically treated heart failure were removed tion in hospitalization for heart failure, 10. Fitchett D, Butler J, van de Borne P, et al.;
by the FDA in 2006 (178). In fact, obser- and 31% reduction in the composite of EMPA-REG OUTCOMEÒ trial investigators. Ef-
fects of empagliflozin on risk for cardiovascu-
vational studies of patients with type 2 cardiovascular death or hospitalization lar death and heart failure hospitalization across
diabetes and heart failure suggest that for heart failure, in a diabetic kidney dis- the spectrum of heart failure risk in the EMPA-
metformin users have better outcomes ease population with albuminuria (UACR REG OUTCOMEÒ trial. Eur Heart J 2018;39:363–
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tomatic Diabetics (DIAD) study. Diabetes Care 77–84 175. Dormandy JA, Charbonnel B, Eckland DJA,
2007;30:2892–2898 161. U.S. Food and Drug Administration. Guid- et al.; PROactive Investigators. Secondary pre-
148. Elkeles RS, Godsland IF, Feher MD, et al.; ance for industry. Diabetes mellitusdevaluating vention of macrovascular events in patients with
PREDICT Study Group. Coronary calcium mea- cardiovascular risk in new antidiabetic thera- type 2 diabetes in the PROactive Study (PRO-
surement improves prediction of cardiovascular pies to treat type 2 diabetes. Silver Spring, spective pioglitAzone Clinical Trial In macroVas-
events in asymptomatic patients with type 2 MD, 2008. Accessed 3 November 2017. Avail- cular Events): a randomised controlled trial.
diabetes: the PREDICT study. Eur Heart J 2008;29: able from http://www.fda.gov/downloads/Drugs/ Lancet 2005;366:1279–1289
2244–2251 GuidanceComplianceRegulatoryInformation/ 176. Singh S, Loke YK, Furberg CD. Long-term risk
149. Raggi P, Shaw LJ, Berman DS, Callister TQ. Guidances/ucm071627.pdf of cardiovascular events with rosiglitazone:
Prognostic value of coronary artery calcium 162. Perkovic V, Jardine MJ, Neal B, et al. Can- a meta-analysis. JAMA 2007;298:1189–1195
screening in subjects with and without diabetes. agliflozin and renal outcomes in type 2 diabetes 177. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE.
J Am Coll Cardiol 2004;43:1663–1669 and nephropathy. N Engl J Med 2019;380:2295– Pioglitazone and risk of cardiovascular events in
150. Anand DV, Lim E, Hopkins D, et al. Risk 2306 patientswithtype2diabetesmellitus:ameta-analysis
stratification in uncomplicated type 2 diabetes: 163. Neal B, Perkovic V, Matthews DR, et al.; of randomized trials. JAMA 2007;298:1180–1188
prospective evaluation of the combined use of CANVAS-R Trial Collaborative Group. Ratio- 178. Inzucchi SE, Masoudi FA, McGuire DK.
coronary artery calcium imaging and selective nale, design and baseline characteristics of Metformin in heart failure. Diabetes Care
myocardial perfusion scintigraphy. Eur Heart J the CANagliflozin cardioVascular Assessment 2007;30:e129–e129
2006;27:713–721 Study-Renal (CANVAS-R): a randomized, placebo- 179. Eurich DT, Majumdar SR, McAlister FA,
151. Young LH, Wackers FJT, Chyun DA, et al.; controlled trial. Diabetes Obes Metab 2017;19: Tsuyuki RT, Johnson JA. Improved clinical out-
DIAD Investigators. Cardiac outcomes after 387–393 comes associated with metformin in patients
screening for asymptomatic coronary artery 164. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, with diabetes and heart failure. Diabetes Care
disease in patients with type 2 diabetes: the Kato ET, Cahn A, et al. Dapagliflozin and cardio- 2005;28:2345–2351
DIAD study: a randomized controlled trial. JAMA vascular outcomes in type 2 diabetes. N Engl J 180. U.S. Food and Drug Administration. FDA
2009;301:1547–1555 Med 2019;380:347–357 drug safety communication: FDA revises warn-
152. Wackers FJT, Young LH, Inzucchi SE, et al.; 165. Marso SP, Daniels GH, Brown-Frandsen K, ings regarding use of the diabetes medicine
Detection of Ischemia in Asymptomatic Diabetics et al.; LEADER Steering Committee; LEADER Trial metformin in certain patients with reduced
Investigators. Detection of silent myocardial ische- Investigators. Liraglutide and cardiovascular out- kidney function, 2016. Accessed 14 October
mia in asymptomatic diabetic subjects: the DIAD comes in type 2 diabetes. N Engl J Med 2016;375: 2016. Available from http://www.fda.gov/
study. Diabetes Care 2004;27:1954–1961 311–322 Drugs/DrugSafety/ucm493244.htm
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181. Scirica BM, Bhatt DL, Braunwald E, et al.; 184. Rosenstock J, Perkovic V, Johansen OE, coronary syndrome in patients with type 2 di-
SAVOR-TIMI 53 Steering Committee and Investiga- et al. Effect of linagliptin vs placebo on major abetes. N Engl J Med 2013;369:1327–1335
tors. Saxagliptin and cardiovascular outcomes in cardiovascular events in adults with type 2 di- 187. Rosenstock J, Perkovic V, Alexander JH,
patients with type 2 diabetes mellitus. N Engl J Med abetes and high cardiovascular and renal risk: the et al. Rationale, design, and baseline character-
2013;369:1317–1326 CARMELINA randomized clinical trial. JAMA istics of the CArdiovascular safety and Renal
182. Zannad F, Cannon CP, Cushman WC, et al.; 2019;321:69–79 Microvascular outcomE study with LINAgliptin
EXAMINE Investigators. Heart failure and mortality 185. Hansson L, Zanchetti A, Carruthers SG, (CARMELINA): a randomized, double-blind, placebo-
outcomes in patients with type 2 diabetes taking et al.; HOT Study Group. Effects of intensive controlled clinical trial in patients with type 2
alogliptinversusplaceboinEXAMINE: amulticentre, blood-pressure lowering and low-dose aspirin diabetes and high cardio-renal risk. Cardiovasc
randomised, double-blind trial. Lancet 2015;385: in patients with hypertension: principal results Diabetol 2018;17:39
2067–2076 of the Hypertension Optimal Treatment (HOT) 188. Cefalu WT, Kaul S, Gerstein HC, et al.
183. Green JB, Bethel MA, Armstrong PW, et al.; randomised trial. Lancet 1998;351:1755– Cardiovascular outcomes trials in type 2 diabe-
TECOS Study Group. Effect of sitagliptin on 1762 tes: where do we go from here? Reflections
cardiovascular outcomes in type 2 diabetes. N 186. White WB, Cannon CP, Heller SR, et al.; from a Diabetes Care Editors’ Expert Forum.
Engl J Med 2015;373:232–242 EXAMINE Investigators. Alogliptin after acute Diabetes Care 2018;41:14–31
Diabetes Care Volume 43, Supplement 1, January 2020 S135
Recommendations
11.1 At least once a year, assess urinary albumin (e.g., spot urinary albumin-to-
creatinine ratio) and estimated glomerular filtration rate (eGFR) in patients
with type 1 diabetes with duration of $5 years and in all patients with type 2
diabetes regardless of treatment. B Patients with urinary albumin .30 mg/g
creatinine and/or an eGFR ,60 mL/min/1.73 m2 should be monitored twice
annually to guide therapy. C
Treatment
Recommendations
11.2 Optimize glucose control to reduce the risk or slow the progression of
chronic kidney disease. A
11.3 For patients with type 2 diabetes and diabetic kidney disease, consider use Suggested citation: American Diabetes Associa-
of a sodium–glucose cotransporter 2 inhibitor in patients with an estimated tion. 11. Microvascular complications and
glomerular filtration rate $30 mL/min/1.73 m2 and urinary albumin .30 foot care: Standards of Medical Care in
Diabetesd2020. Diabetes Care 2020;43(Suppl.
mg/g creatinine, particularly in those with urinary albumin .300 mg/g 1):S135–S151
creatinine, to reduce risk of chronic kidney disease (CKD) progression,
© 2019 by the American Diabetes Association.
cardiovascular events, or both. A In patients with CKD who are at increased Readers may use this article as long as the work
risk for cardiovascular events, use of a glucagon-like peptide 1 receptor is properly cited, the use is educational and
agonist may reduce risk of progression of albuminuria, cardiovascular not for profit, and the work is not altered.
events, or both (Table 9.1). C More information is available at http://www
.diabetesjournals.org/content/license.
S136 Microvascular Complications and Foot Care Diabetes Care Volume 43, Supplement 1, January 2020
Figure 11.1—Risk of chronic kidney disease (CKD) progression, frequency of visits, and referral to nephrology according to glomerular filtration rate
(GFR) and albuminuria. The GFR and albuminuria grid depicts the risk of progression, morbidity, and mortality by color, from best to worst (green, yellow,
orange, red, dark red). The numbers in the boxes are a guide to the frequency of visits (number of times per year). Green can reflect CKD with normal
eGFR and albumin-to-creatinine ratio only in the presence of other markers of kidney damage, such as imaging showing polycystic kidney disease or
kidney biopsy abnormalities, with follow-up measurements annually; yellow requires caution and measurements at least once per year; orange requires
measurements twice per year; red requires measurements three times per year; and dark red requires measurements four times per year. These are
general parameters only, based on expert opinion, and underlying comorbid conditions and disease state as well as the likelihood of impacting a change
in management for any individual patient must be taken into account. “Refer” indicates that nephrology services are recommended. *Referring
clinicians may wish to discuss with their nephrology service, depending on local arrangements regarding treating or referring. Reprinted with permission
from Vassalotti et al. (188).
eGFR $60 mL/min/1.73 m2, while stages progression and other adverse health particularly when combined with diu-
3–5 CKD have been defined by progres- outcomes) and cause of kidney damage retics or other medications that reduce
sively lower ranges of eGFR (17) (Fig. (including possible causes other than glomerular filtration; however, this
11.1). At any eGFR, the degree of albu- diabetes) may also affect these decisions has not been found to be true in ran-
minuria is associated with risk of cardio- (20). domized clinical outcome trials of ad-
vascular disease (CVD), CKD progression, vanced kidney disease (24) or high
and mortality (7). Therefore, Kidney Acute Kidney Injury cardiovascular disease risk with normal
Disease: Improving Global Outcomes Acute kidney injury (AKI) is diagnosed kidney function (25–27). Timely iden-
(KDIGO) recommends a more compre- by a 50% or greater sustained increase tification and treatment of AKI is im-
hensive CKD staging that incorporates in serum creatinine over a short period portant because AKI is associated with
albuminuria at all stages of eGFR; this of time, which is also reflected as a rapid increased risks of progressive CKD and
system is more closely associated with decrease in eGFR (21,22). People with other poor health outcomes (28).
risk but is also more complex and does diabetes are at higher risk of AKI than Small elevations in serum creatinine
not translate directly to treatment deci- those without diabetes (23). Other risk (up to 30% from baseline) with renin-
sions (2). Thus, based on the current factors for AKI include preexisting CKD, angiotensin system blockers (such as
classification system, both eGFR and the use of medications that cause ACE inhibitors and ARBs) must not be
albuminuria must be quantified to guide kidney injury (e.g., nonsteroidal anti- confused with AKI (29). An analysis
treatment decisions. This is also impor- inflammatory drugs), and the use of of the Action to Control Cardiovascu-
tant since eGFR levels are essential to medications that alter renal blood flow lar Risk in Diabetes Blood Pressure
modify drug dosage or restrictions of use and intrarenal hemodynamics. In partic- (ACCORD BP) trial demonstrates that those
(Fig. 11.1) (18,19). The degree of albu- ular, many antihypertensive medications randomized to intensive blood pressure
minuria may influence choice of antihy- (e.g., diuretics, ACE inhibitors, and an- lowering with up to a 30% increase in
pertensive (see Section 10 “Cardiovascular giotensin receptor blockers [ARBs]) can serum creatinine did not have any in-
Disease and Risk Management,” https:// reduce intravascular volume, renal blood crease in mortality or progressive kidney
doi.org.10.2337/dc20-S010) or glucose- flow, and/or glomerular filtration. There disease (30–32). Moreover, a measure of
lowering medications (see below). Ob- was concern that sodium–glucose co- markers for AKI showed no significant
served history of eGFR loss (which transporter 2 (SGLT2) inhibitors may increase of any markers with increased
is also associated with risk of CKD promote AKI through volume depletion, creatinine (32). Accordingly, ACE inhibitors
S138 Microvascular Complications and Foot Care Diabetes Care Volume 43, Supplement 1, January 2020
Table 11.1—Selected complications of chronic kidney disease recommended because it does not alter
Complication Medical and laboratory evaluation
glycemic measures, cardiovascular risk
measures, or the course of GFR decline (39).
Elevated blood pressure .140/90 mmHg Blood pressure, weight
Restriction of dietary sodium (to ,2,300
Volume overload History, physical examination, weight mg/day) may be useful to control blood
Electrolyte abnormalities Serum electrolytes pressure and reduce cardiovascular risk
Metabolic acidosis Serum electrolytes (40,41), and restriction of dietary potas-
Anemia Hemoglobin; iron testing if indicated sium may be necessary to control se-
Metabolic bone disease Serum calcium, phosphate, PTH, vitamin 25(OH)D rum potassium concentration (23,33–35).
Complications of chronic kidney disease (CKD) generally become prevalent when estimated These interventions may be most important
glomerular filtration rate falls below 60 mL/min/1.73 m2 (stage 3 CKD or greater) and become more for patients with reduced eGFR, for whom
common and severe as CKD progresses. Evaluation of elevated blood pressure and volume urinary excretion of sodium and potassium
overload should occur at every clinical contact possible; laboratory evaluations are generally
indicated every 6–12 months for stage 3 CKD, every 3–5 months for stage 4 CKD, and every 1– may be impaired. For patients on dialysis,
3 months for stage 5 CKD, or as indicated to evaluate symptoms or changes in therapy. PTH, higher levels of dietary protein intake should
parathyroid hormone; 25(OH)D, 25-hydroxyvitamin D. be considered, since malnutrition is a major
problem in some dialysis patients (42).
Recommendations for dietary sodium and
and ARBs should not be discontinued for 2 diabetes, reducing albuminuria from potassium intake should be individualized
minor increases in serum creatinine (,30%), levels $300 mg/g Cr has been associated on the basis of comorbid conditions, med-
in the absense of volume depletion. with improved renal and cardiovascular ication use, blood pressure, and labora-
outcomes, leading some to suggest that tory data.
Surveillance medications should be titrated to min-
Albuminuria and eGFR should be mon- imize UACR. However, this approach has Glycemic Targets
itored regularly to enable timely diagno- not been formally evaluated in prospec- Intensive glycemic control with the goal
sis of CKD, monitor progression of CKD, tive trials. In type 1 diabetes, remission of achieving near-normoglycemia has
detect superimposed kidney diseases of albuminuria may occur spontane- been shown in large prospective random-
including AKI, assess risk of CKD compli- ously and cohort studies evaluating ized studies to delay the onset and pro-
cations, dose drugs appropriately, and associations of change in albuminuria gression of albuminuria and reduced
determine whether nephrology referral with clinical outcomes have reported eGFR in patients with type 1 diabetes
is needed. Among people with existing inconsistent results (36,37). (43,44) and type 2 diabetes (1,45–51).
kidney disease, albuminuria and eGFR The prevalence of CKD complications Insulin alone was used to lower blood
may change due to progression of CKD, correlates with eGFR (38). When eGFR glucose in the Diabetes Control and
development of a separate superim- is ,60 mL/min/1.73 m2, screening for Complications Trial (DCCT)/Epidemiol-
posed cause of kidney disease, AKI, or complications of CKD is indicated (Table ogy of Diabetes Interventions and Com-
other effects of medications, as noted 11.1). Early vaccination against hepatitis plications (EDIC) study of type 1 diabetes,
above. Serum potassium should also B virus is indicated in patients likely to while a variety of agents were used in
be monitored for patients treated with progress to ESRD (see Section 4 “Com- clinical trials of type 2 diabetes, support-
ACE inhibitors, ARBs, and diuretics be- prehensive Medical Evaluation and As- ing the conclusion that glycemic control
cause these medications can cause hy- sessment of Comorbidities,” https://doi itself helps prevent CKD and its progres-
perkalemia or hypokalemia, which are .org/10.2337/dc20-S004, for further in- sion. The effects of glucose-lowering
associated with cardiovascular risk and formation on immunization). therapies on CKD have helped define
mortality (33–35). For patients with A1C targets (see Table 6.2).
eGFR ,60 mL/min/1.73 m2, appropriate Interventions The presence of CKD affects the risks
medication dosing should be verified, Nutrition and benefits of intensive glycemic con-
exposure to nephrotoxins (e.g., nonste- For people with nondialysis-dependent trol and a number of specific glucose-
roidal anti-inflammatory drugs and io- CKD, dietary protein intake should be lowering medications. In the Action to
dinated contrast) should be minimized, ;0.8 g/kg body weight per day (the Control Cardiovascular Risk in Diabetes
and potential CKD complications should recommended daily allowance) (1). (ACCORD) trial of type 2 diabetes, ad-
be evaluated (Table 11.1). Compared with higher levels of dietary verse effects of intensive glycemic con-
The need for annual quantitative as- protein intake, this level slowed GFR trol (hypoglycemia and mortality) were
sessment of albumin excretion after di- decline with evidence of a greater effect increased among patients with kidney
agnosis of albuminuria, institution of ACE over time. Higher levels of dietary pro- disease at baseline (52,53). Moreover,
inhibitors or ARB therapy, and achiev- tein intake (.20% of daily calories from there is a lag time of at least 2 years in
ing blood pressure control is a subject protein or .1.3 g/kg/day) have been type 2 diabetes to over 10 years in type 1
of debate. Continued surveillance can associated with increased albuminuria, diabetes for the effects of intensive glu-
assess both response to therapy and more rapid kidney function loss, and cose control to manifest as improved
disease progression and may aid in as- CVD mortality and therefore should be eGFR outcomes (49,54,55). Therefore, in
sessing adherence to ACE inhibitor or avoided. Reducing the amount of di- some patients with prevalent CKD and
ARB therapy. In addition, in clinical trials etary protein below the recommended substantial comorbidity, target A1C levels
of ACE inhibitors or ARB therapy in type daily allowance of 0.8 g/kg/day is not may be less intensive (1,56).
care.diabetesjournals.org Microvascular Complications and Foot Care S139
Direct Renal Effects of Glucose-Lowering constraints, metformin should be con- In addition, subgroup analyses of CANVAS
Medications sidered the first-line treatment for all and LEADER suggested that the renal
Some glucose-lowering medications also patients with type 2 diabetes, including benefits of canagliflozin and liraglutide
have effects on the kidney that are direct, those with CKD. were as great or greater for participants
i.e., not mediated through glycemia. For SGLT2 inhibitors and GLP-1 RAs should with CKD at baseline (27,66) and in CANVAS
example, SGLT2 inhibitors reduce renal be considered for patients with type 2 were similar for participants with or with-
tubular glucose reabsorption, weight, diabetes and CKD who require another out atherosclerotic cardiovascular disease
systemic blood pressure, intraglomerular drug added to metformin to attain target (ASCVD) at baseline (72).
pressure, and albuminuria and slow GFR A1C or cannot use or tolerate metformin. Several large clinical trials of SGLT2
loss through mechanisms that appear SGLT2 inhibitors reduce risks of CKD inhibitors focused on patients with ad-
independent of glycemia (26,57–60). progression, CVD events, and hypogly- vanced CKD, and assessment of primary
Moreover, recent data support the cemia. GLP-1 RAs are suggested because renal outcomes are completed or ongo-
notion that SGLT2 inhibitors reduce ox- they reduce risks of CVD events and ing. Canagliflozin and Renal End points in
idative stress in the kidney by .50% and hypoglycemia and appear to possibly Diabetes with Established Nephropa-
blunt increases in angiotensinogen as slow CKD progression. thy Clinical Evaluation (CREDENCE), a
well as reduce NLRP3 inflammasome A number of large cardiovascular out- placebo-controlled trial of canagliflozin
activity (61–63). Glucagon-like peptide comes trials in patients with type 2 di- among 4,401 adults with type 2 diabetes,
1 receptor agonists (GLP-1 RAs) also have abetes at high risk for CVD or with UACR $300 mg/g Cr, and mean eGFR
direct effects on the kidney and have existing CVD examined kidney effects 56 mL/min/1.73 m2 with a mean albu-
been reported to improve renal out- as secondary outcomes. These trials minuria level of over 900 mg/day, has a
comes compared with placebo (64–67). include EMPA-REG OUTCOME [BI primary composite end point of ESRD,
Renal effects should be considered when 10773 (Empagliflozin) Cardiovascular doubling of serum creatinine, or renal or
selecting antihyperglycemia agents (see Outcome Event Trial in Type 2 Diabetes cardiovascular death (24,73). It was stop-
Section 9 “Pharmacologic Approaches to Mellitus Patients], CANVAS (Canagliflozin ped early due to positive efficacy and
Glycemic Treatment,” https://doi.org/10 Cardiovascular Assessment Study), showed a 32% risk reduction for devel-
.2337/dc20-S009). LEADER (Liraglutide Effect and Action opment of ESRD over control (24).
in Diabetes: Evaluation of Cardiovascular Additionally, the development of the
Selection of Glucose-Lowering Medications Outcome Results), and SUSTAIN-6 (Trial primary end point, which included
for Patients With Chronic Kidney Disease to Evaluate Cardiovascular and Other chronic dialysis for $30 days, kidney
For patients with type 2 diabetes and Long-term Outcomes With Semaglutide transplantation or eGFR ,15 mL/min/
established CKD, special considerations in Subjects With Type 2 Diabetes) 1.73 m2 sustained for $30 days by
for the selection of glucose-lowering med- (59,64,67,71). Specifically, compared central laboratory assessment, doubling
ications include limitations to available with placebo, empagliflozin reduced from the baseline serum creatinine av-
medications when eGFR is diminished the risk of incident or worsening ne- erage sustained for $30 days by central
and a desire to mitigate high risks of phropathy (a composite of progression laboratory assessment, or renal death or
CKD progression, CVD, and hypoglycemia to UACR .300 mg/g Cr, doubling of cardiovascular death, was reduced by
(68,69). Drug dosing may require modifi- serum creatinine, ESRD, or death from 30%. This benefit was on background
cation with eGFR ,60 mL/min/1.73 m2 (1). ESRD) by 39% and the risk of doubling ACE inhibitor or ARB therapy in .99% of
The U.S. Food and Drug Administration of serum creatinine accompanied by the patients (24). Moreover, in this ad-
(FDA) revised its guidance for the use of eGFR #45 mL/min/1.73 m2 by 44%; vanced CKD group, there were clear
metformin in CKD in 2016 (70), recom- canagliflozin reduced the risk of progres- benefits on cardiovascular outcomes
mending use of eGFR instead of serum sion of albuminuria by 27% and the risk demonstrating a 31% reduction in car-
creatinine to guide treatment and ex- of reduction in eGFR, ESRD, or death from diovascular death or heart failure hos-
panding the pool of patients with kidney ESRD by 40%; liraglutide reduced the risk pitalization and a 20% reduction in
disease for whom metformin treatment of new or worsening nephropathy (a cardiovascular death, nonfatal myocar-
should be considered. The revised FDA composite of persistent macroalbumin- dial infarction, or nonfatal stroke (24,74).
guidance states that metformin is uria, doubling of serum creatinine, ESRD, In addition to renal effects, some
contraindicated in patients with an or death from ESRD) by 22%; and sema- SGLT2 inhibitors and GLP-1 RAs have
eGFR ,30 mL/min/1.73 m2; eGFR should glutide reduced the risk of new or wors- demonstrated cardiovascular benefits.
be monitored while taking metformin; ening nephropathy (a composite of Namely, in EMPA-REG OUTCOME, CANVAS,
the benefits and risks of continuing persistent UACR .300 mg/g Cr, doubling and LEADER, empagliflozin, canagliflozin,
treatment should be reassessed when of serum creatinine, or ESRD) by 36% and liraglutide, respectively, each reduced
eGFR falls ,45 mL/min/1.73 m2; met- (each P , 0.01). cardiovascular events, evaluated as primary
formin should not be initiated for These analyses were limited by eval- outcomes, compared with placebo (see
patients with an eGFR ,45 mL/min/ uation of study populations not selected Section 10 “Cardiovascular Disease and
1.73 m2; and metformin should be primarily for CKD and examination of Risk Management,” https://doi.org/10
temporarily discontinued at the time renal effects as secondary outcomes. .2337/dc20-S010 for further discussion).
of or before iodinated contrast imag- However, all of these trials included large While the glucose-lowering effects
ing procedures in patients with eGFR numbers of people with stage 3a (eGFR of SGLT2 inhibitors are blunted with
30–60 mL/min/1.73 m2. Within these 45–59 mL/min/1.73 m2) kidney disease. eGFR ,45 mL/min/1.73 m2, the renal
S140 Microvascular Complications and Foot Care Diabetes Care Volume 43, Supplement 1, January 2020
and cardiovascular benefits were still Cardiovascular Disease and Blood Pressure blockers (92). In a trial of people with
seen down to eGFR levels of 30 mL/ Hypertension is a strong risk factor for type 2 diabetes and normal urine albu-
min/1.73 m2 with no significant change the development and progression of CKD min excretion, an ARB reduced or sup-
in glucose (24,26,43,45,52,56,71). Most (78). Antihypertensive therapy reduces pressed the development of albuminuria
participants with CKD in these trials the risk of albuminuria (79–82), and but increased the rate of cardiovascular
also had diagnosed ASCVD at baseline, among patients with type 1 or 2 diabetes events (93). In a trial of people with type 1
though ;28% of CANVAS participants with established CKD (eGFR ,60 mL/ diabetes exhibiting neither albuminuria
with CKD did not have diagnosed min/1.73 m2 and UACR $300 mg/g Cr), nor hypertension, ACE inhibitors or ARBs
ASCVD (27). ACE inhibitor or ARB therapy reduces the did not prevent the development of
Based on evidence from the CREDENCE risk of progression to ESRD (83–85). diabetic glomerulopathy assessed by kid-
trial and secondary analyses of cardio- Moreover, antihypertensive therapy re- ney biopsy (90) This was further sup-
vascular outcomes trials with SGLT2 duces risks of cardiovascular events (79). ported by a similar trial in patients with
inhibitors, cardiovascular and renal Blood pressure levels ,140/90 mmHg type 2 diabetes (91). Therefore, ACE
events are reduced with SGLT2 inhibitor are generally recommended to reduce inhibitors or ARBs are not recommended
use in patients down to an eGFR of CVD mortality and slow CKD progres- for patients without hypertension to pre-
30 mL/min/1.73 m2 even independent sion among all people with diabetes vent the development of CKD.
of glucose-lowering effects (75). (82). Lower blood pressure targets Two clinical trials studied the combi-
While there is clear cardiovascular risk (e.g., ,130/80 mmHg) should be con- nations of ACE inhibitors and ARBs and
reduction associated with GLP-1 RA use sidered for patients based on individual found no benefits on CVD or CKD, and the
in patients with type 2 diabetes and CKD, anticipated benefits and risks. Patients drug combination had higher adverse
the proof of benefit on renal outcome with CKD are at increased risk of CKD event rates (hyperkalemia and/or AKI)
will come with the results of the ongoing progression (particularly those with al- (94,95). Therefore, the combined use of ACE
FLOW (A Research Study to See How buminuria) and CVD and therefore may inhibitors and ARBs should be avoided.
Semaglutide Works Compared to Pla- be suitable in some cases for lower blood Mineralocorticoid receptor antago-
cebo in People With Type 2 Diabetes pressure targets, especially in those nists (spironolactone, eplerenone, and
and Chronic Kidney Disease) trial with with $300 mg/day albuminuria. finerenone) in combination with ACE
injectable semaglutide (76). As noted ACE inhibitors or ARBs are the pre- inhibitors or ARBs remain an area of
above, published data address a limited ferred first-line agent for blood pressure great interest. Mineralocorticoid recep-
group of CKD patients, mostly with coex- treatment among patients with diabe- tor antagonists are effective for man-
isting ASCVD. Renal events have been tes, hypertension, eGFR ,60 mL/min/ agement of resistant hypertension, have
examined, however, as both primary and 1.73 m2, and UACR $300 mg/g Cr be- been shown to reduce albuminuria in
secondary outcomes in published large cause of their proven benefits for pre- short-term studies of CKD, and may
trials. Also, adverse event profiles of vention of CKD progression (83–86). In have additional cardiovascular benefits
these agents must be considered. Please general, ACE inhibitors and ARBs are (96–98). There has been, however, an
refer to Table 9.1 for drug-specific considered to have similar benefits increase in hyperkalemic episodes in
factors, including adverse event infor- (87,88) and risks. In the setting of lower those on dual therapy, and larger, longer
mation, for these agents. Additional levels of albuminuria (30–299 mg/g Cr), trials with clinical outcomes are needed
clinical trials focusing on CKD and car- ACE inhibitor or ARB therapy has been before recommending such therapy.
diovascular outcomes in CKD patients demonstrated to reduce progression to
Referral to a Nephrologist
are ongoing and will be reported in the more advanced albuminuria ($300 mg/g
next few years. Cr) and cardiovascular events but not Consider referral to a physician experi-
For patients with type 2 diabetes and progression to ESRD (86,89). While ACE enced in the care of kidney disease when
CKD, the selection of specific agents may inhibitors or ARBs are often prescribed there is uncertainty about the etiology
depend on comorbidity and CKD stage. for high albuminuria without hyperten- of kidney disease, for difficult manage-
SGLT2 inhibitors may be more useful for sion, outcome trials have not been per- ment issues (anemia, secondary hyper-
patients at high risk of CKD progression formed in this setting to determine parathyroidism, metabolic bone disease,
(i.e., with albuminuria or a history of whether this improves renal outcomes. resistant hypertension, or electrolyte dis-
documented eGFR loss) (Fig. 9.1) be- Moreover, two long-term, double-blind turbances), or when there is advanced
cause they appear to have large bene- studies demonstrate no renoprotective kidney disease (eGFR ,30 mL/min/
ficial effects on CKD incidence. The SGLT2 effect of either ACE inhibitors or ARBs in 1.73 m2) requiring discussion of renal
inhibitors canagliflozin, empagliflozin, type 1 and type 2 diabetes among those replacement therapy for ESRD (2). The
and dapagliflozin are approved by the who were normotensive with or without threshold for referral may vary depending
FDA for use with eGFR $45 mL/min/ high albuminuria (formerly microalbu- on the frequency with which a provider
1.73 m2 (though pivotal trials for each minuria) (90,91). encounters patients with diabetes and
included participants with eGFR $30 Absent kidney disease, ACE inhibitors kidney disease. Consultation with a ne-
mL/min/1.73 m 2 and demonstrated or ARBs are useful to control blood phrologist when stage 4 CKD develops
benefit in subgroups with low eGFR) pressure but have not proven superior (eGFR ,30 mL/min/1.73 m2) has been
(26,27,77). Some GLP-1 RAs may be used to alternative classes of antihypertensive found to reduce cost, improve quality of
with lower eGFR, but most require dose therapy, including thiazide-like diuretics care, and delay dialysis (99). However,
adjustment. and dihydropyridine calcium channel other specialists and providers should
care.diabetesjournals.org Microvascular Complications and Foot Care S141
also educate their patients about the Diabetic retinopathy is a highly specific
11.18 Women with preexisting type
progressive nature of CKD, the kidney vascular complication of both type 1 and
1 or type 2 diabetes who are
preservation benefits of proactive treat- type 2 diabetes, with prevalence strongly
planning pregnancy or who are
ment of blood pressure and blood glucose, related to both the duration of diabetes
pregnant should be counseled
and the potential need for renal replace- and the level of glycemic control (100).
on the risk of development and/
ment therapy. Diabetic retinopathy is the most frequent
or progression of diabetic reti-
cause of new cases of blindness among
nopathy. B
DIABETIC RETINOPATHY adults aged 20–74 years in developed
11.19 Eye examinations should occur
countries. Glaucoma, cataracts, and other
Recommendations before pregnancy or in the first
disorders of the eye occur earlier and
11.12 Optimize glycemic control to trimester in patients with pre-
more frequently in people with diabetes.
reduce the risk or slow the existing type 1 or type 2 di-
In addition to diabetes duration, fac-
progression of diabetic reti- abetes, and then patients
tors that increase the risk of, or are
nopathy. A should be monitored every tri-
associated with, retinopathy include
11.13 Optimize blood pressure and mester and for 1 year postpar-
chronic hyperglycemia (101), nephropa-
serum lipid control to reduce tum as indicated by the degree
thy (102), hypertension (103), and
the risk or slow the progression of retinopathy. B
dyslipidemia (104). Intensive diabetes
of diabetic retinopathy. A management with the goal of achieving
Treatment near-normoglycemia has been shown in
Screening large prospective randomized studies to
Recommendations
prevent and/or delay the onset and pro-
Recommendations 11.20 Promptly refer patients with
gression of diabetic retinopathy and po-
11.14 Adults with type 1 diabetes any level of macular edema,
tentially improve patient reported visual
should have an initial dilated severe nonproliferative dia-
function (46,105–107).
and comprehensive eye exam- betic retinopathy (a precursor
Several case series and a controlled
ination by an ophthalmologist of proliferative diabetic reti-
prospective study suggest that preg-
or optometrist within 5 years nopathy), or any proliferative
nancy in patients with type 1 diabe-
after the onset of diabetes. B diabetic retinopathy to an oph-
tes may aggravate retinopathy and
11.15 Patients with type 2 diabetes thalmologist who is knowl-
threaten vision, especially when gly-
should have an initial dilated edgeable and experienced in
cemic control is poor at the time of
and comprehensive eye exam- the management of diabetic
conception (108,109). Laser photocoagu-
ination by an ophthalmologist retinopathy. A
lation surgery can minimize the risk of
or optometrist at the time of 11.21 The traditional standard treat-
vision loss (109).
the diabetes diagnosis. B ment, panretinal laser photo-
11.16 If there is no evidence of ret- coagulation therapy, is indicated
Screening
inopathy for one or more an- to reduce the risk of vision loss
The preventive effects of therapy and
nual eye exams and glycemia is in patients with high-risk prolif-
the fact that patients with proliferative
well controlled, then screening erative diabetic retinopathy and,
diabetic retinopathy (PDR) or macular
every 1–2 years may be con- in some cases, severe nonproli-
edema may be asymptomatic provide
sidered. If any level of diabetic ferative diabetic retinopathy. A
strong support for screening to detect
retinopathy is present, subse- 11.22 Intravitreous injections of anti–
diabetic retinopathy.
quent dilated retinal examina- vascular endothelial growth fac-
Diabetic retinopathy screening should
tions should be repeated at least tor ranibizumab are not inferior
be performed using validated ap-
annually by an ophthalmologist to traditional panretinal laser
proaches and methodologies. Youth
or optometrist. If retinopathy is photocoagulation and are also
with type 1 or type 2 diabetes are
progressing or sight-threatening, indicated to reduce the risk of
also at risk for complications and need
then examinations will be re- vision loss in patients with pro-
to be screened for diabetic retinopathy
quired more frequently. B liferative diabetic retinopathy. A
(110). If diabetic retinopathy is evident
11.17 Programs that use retinal pho- 11.23 Intravitreous injections of anti–
on screening, prompt referral to an oph-
tography (with remote reading vascular endothelial growth
thalmologist is recommended. Subse-
or use of a validated assess- factor are indicated for central
quent examinations for patients with
ment tool) to improve access involveddiabeticmacularedema,
type 1 or type 2 diabetes are generally
to diabetic retinopathy screen- which occurs beneath the foveal
repeated annually for patients with min-
ing can be appropriate screen- center and may threaten reading
imal to no retinopathy. Exams every 1–2
ing strategies for diabetic vision. A
years may be cost effective after one or
retinopathy. Such programs 11.24 The presence of retinopathy is
more normal eye exams, and in a pop-
need to provide pathways not a contraindication to aspirin
ulation with well controlled type 2 di-
for timely referral for a com- therapy for cardioprotection, as
abetes, there was essentially no risk of
prehensive eye examination aspirin does not increase the risk
development of significant retinopathy
when indicated. B of retinal hemorrhage. A
with a 3-year interval after a normal
S142 Microvascular Complications and Foot Care Diabetes Care Volume 43, Supplement 1, January 2020
examination (111). Less frequent intervals comprehensive eye examination at the growth factor (anti-VEGF) agent, specif-
have been found in simulated modeling time of diagnosis. ically ranibizumab, resulted in visual acu-
to be potentially effective in screening for Pregnancy
ity outcomes that were not inferior to
diabetic retinopathy in patients without Pregnancy is associated with a rapid those observed in patients treated with
diabetic retinopathy (112). More frequent progression of diabetic retinopathy panretinal laser at 2 years of followup
examinations by the ophthalmologist will (117,118). Women with preexisting (121). In addition, it was observed that
be required if retinopathy is progressing. type 1 or type 2 diabetes who are plan- patients treated with ranibizumab
Retinal photography with remote ning pregnancy or who have become tended to have less peripheral visual
reading by experts has great potential pregnant should be counseled on the field loss, fewer vitrectomy surgeries
to provide screening services in areas risk of development and/or progression for secondary complications from their
where qualified eye care professionals of diabetic retinopathy. In addition, rapid proliferative disease, and a lower risk of
are not readily available (105,106). High implementation of intensive glycemic developing diabetic macular edema.
quality fundus photographs can detect management in the setting of retinopa- However, a potential drawback in using
most clinically significant diabetic reti- thy is associated with early worsening anti-VEGF therapy to manage prolifer-
nopathy. Interpretation of the images of retinopathy (109). Women who de- ative disease is that patients were re-
should be performed by a trained eye velop gestational diabetes mellitus do quired to have a greater number of visits
care provider. Retinal photography may not require eye examinations during and received a greater number of
also enhance efficiency and reduce pregnancy and do not appear to be treatments than is typically required
costs when the expertise of ophthalmol- at increased risk of developing diabetic for management with panretinal laser,
ogists can be used for more complex retinopathy during pregnancy (119). which may not be optimal for some pa-
examinations and for therapy (113,114). tients. Other emerging therapies for
In-person exams are still necessary Treatment retinopathy that may use sustained intra-
when the retinal photos are of unaccept- Two of the main motivations for screen- vitreal delivery of pharmacologic agents
able quality and for follow-up if abnor- ing for diabetic retinopathy are to pre- are currently under investigation. The FDA
malities are detected. Retinal photos are vent loss of vision and to intervene with approved ranibizumab for the treatment
not a substitute for comprehensive eye treatment when vision loss can be pre- of diabetic retinopathy in 2017.
exams, which should be performed at vented or reversed. While the ETDRS (122) established the
least initially and at intervals thereafter benefit of focal laser photocoagulation
Photocoagulation Surgery
as recommended by an eye care pro- surgery in eyes with clinically significant
Two large trials, the Diabetic Retinop-
fessional. Artificial intelligence systems macular edema (defined as retinal edema
athy Study (DRS) in patients with PDR
that detect more than mild diabetic located at or within 500 mm of the center
and the Early Treatment Diabetic Ret-
retinopathy and diabetic macular edema of the macula), current data from well-
inopathy Study (ETDRS) in patients with
authorized for use by the FDA represent designed clinical trials demonstrate that
macular edema, provide the strongest
an alternative to traditional screening intravitreal anti-VEGF agents provide a
support for the therapeutic benefits
approaches (115). However, the bene- more effective treatment regimen for
of photocoagulation surgery. The DRS
fits and optimal utilization of this type central-involved diabetic macular edema
(120) showed in 1978 that panretinal
of screening have yet to be fully de- than monotherapy or even combination
photocoagulation surgery reduced the
termined. Artificial intelligence systems therapy with laser (123,124). There
risk of severe vision loss from PDR from
should not be used for patients with are currently three anti-VEGF agents
15.9% in untreated eyes to 6.4% in
known retinopathy, prior retinopathy commonly used to treat eyes with
treated eyes with the greatest benefit
treatment, or symptoms of vision central-involved diabetic macular
ratio in those with more advanced base-
impairment. Results of eye examina- edemadbevacizumab, ranibizumab,
line disease (disc neovascularization
tions should be documented and trans- and aflibercept (100).
or vitreous hemorrhage). In 1985, the
mitted to the referring health care In both the DRS and the ETDRS, laser
ETDRS also verified the benefits of
professional. photocoagulation surgery was beneficial
panretinal photocoagulation for high-
in reducing the risk of further visual loss
Type 1 Diabetes risk PDR and in older-onset patients
in affected patients but generally not
Because retinopathy is estimated to with severe nonproliferative diabetic
beneficial in reversing already dimin-
take at least 5 years to develop after retinopathy or less-than-high-risk PDR.
ished acuity. Anti-VEGF therapy im-
the onset of hyperglycemia, patients Panretinal laser photocoagulation is still
proves vision and has replaced the
with type 1 diabetes should have an commonly used to manage compli-
need for laser photocoagulation in
initial dilated and comprehensive eye ex- cations of diabetic retinopathy that in-
the vast majority of patients with di-
amination within 5 years after the diagnosis volve retinal neovascularization and its
abetic macular edema (125). Most
of diabetes (116). complications.
patients require near-monthly admin-
Type 2 Diabetes Anti–Vascular Endothelial Growth Factor istration of intravitreal therapy with
Patients with type 2 diabetes who may Treatment anti-VEGF agents during the first 12
have had years of undiagnosed diabetes Recent data from the Diabetic Retinop- months of treatment, with fewer injec-
and have a significant risk of prevalent athy Clinical Research Network and tions needed in subsequent years to
diabetic retinopathy at the time of di- others demonstrate that intravitreal in- maintain remission from central-involved
agnosis should have an initial dilated and jections of anti–vascular endothelial diabetic macular edema.
care.diabetesjournals.org Microvascular Complications and Foot Care S143
.10 mmHg, respectively, upon standing a modest slowing of progression without expensive, although it is not FDA ap-
without an appropriate increase in heart reversal of neuronal loss (48,139). Specific proved for this indication (154).
rate). CAN treatment is generally focused glucose-lowering strategies may have dif- Duloxetine is a selective norepineph-
on alleviating symptoms. ferent effects. In a post hoc analysis, par- rine and serotonin reuptake inhibitor.
Gastrointestinal Neuropathies. Gastroin- ticipants, particularly men, in the Bypass Doses of 60 and 120 mg/day showed
testinal neuropathies may involve any Angioplasty Revascularization Investigation efficacy in the treatment of pain associ-
portion of the gastrointestinal tract with in Type 2 Diabetes (BARI 2D) trial treated ated with DPN in multicenter randomized
manifestations including esophageal with insulin sensitizers had a lower inci- trials, although some of these had
dysmotility, gastroparesis, constipation, dence of distal symmetric polyneuropathy high drop-out rates (143,145,150,152).
diarrhea, and fecal incontinence. Gastro- over4yearsthanthosetreatedwith insulin/ Duloxetine also appeared to improve
paresis should be suspected in individ- sulfonylurea (140). neuropathy-related quality of life (155).
uals with erratic glycemic control or with In longer-term studies, a small increase in
upper gastrointestinal symptoms with- Neuropathic Pain A1C was reported in people with diabetes
out another identified cause. Exclusion of Neuropathic pain can be severe and can treated with duloxetine compared with
organic causes of gastric outlet obstruc- impact quality of life, limit mobility, and placebo (156). Adverse events may be
tion or peptic ulcer disease (with esoph- contribute to depression and social dys- more severe in older people but may be
agogastroduodenoscopy or a barium function (141). No compelling evidence attenuated with lower doses and slower
study of the stomach) is needed before exists in support of glycemic control or titrations of duloxetine.
considering a diagnosis of or specialized lifestyle management as therapies for Tapentadol is a centrally acting opioid
testing for gastroparesis. The diagnostic neuropathic pain in diabetes or predia- analgesic that exerts its analgesic effects
gold standard for gastroparesis is the betes, which leaves only pharmaceutical through both m-opioid receptor agonism
measurement of gastric emptying with interventions (142). and noradrenaline reuptake inhibition.
scintigraphy of digestible solids at Pregabalin and duloxetine have re- Extended-release tapentadol was ap-
15-min intervals for 4 h after food intake. ceived regulatory approval by the FDA, proved by the FDA for the treatment
The use of 13C octanoic acid breath test Health Canada, and the European Med- of neuropathic pain associated with
is emerging as a viable alternative. icines Agency for the treatment of neu- diabetes based on data from two mul-
ropathic pain in diabetes. The opioid ticenter clinical trials in which partici-
Genitourinary Disturbances. Diabetic auto- tapentadol has regulatory approval in pants titrated to an optimal dose of
nomic neuropathy may also cause gen- the U.S. and Canada, but the evidence tapentadol were randomly assigned to
itourinary disturbances, including sexual of its use is weaker (143). Comparative continue that dose or switch to placebo
dysfunction and bladder dysfunction. In effectiveness studies and trials that in- (157,158). However, both used a design
men, diabetic autonomic neuropathy clude quality-of-life outcomes are rare, enriched for patients who responded to
may cause erectile dysfunction and/or so treatment decisions must consider tapentadol and therefore their results are
retrograde ejaculation (130). Female each patient’s presentation and comor- not generalizable. A recent systematic
sexual dysfunction occurs more frequently bidities and often follow a trial-and-error review and meta-analysis by the Special
in those with diabetes and presents as approach. Given the range of partially Interest Group on Neuropathic Pain of the
decreased sexual desire, increased pain effective treatment options, a tailored International Association for the Study of
during intercourse, decreased sexual and stepwise pharmacologic strategy Pain found the evidence supporting the
arousal, and inadequate lubrication with careful attention to relative symp- effectiveness of tapentadol in reducing
(134). Lower urinary tract symptoms tom improvement, medication adher- neuropathic pain to be inconclusive (143).
manifest as urinary incontinence and ence, and medication side effects is Therefore, given the high risk for addiction
bladder dysfunction (nocturia, frequent recommended to achieve pain reduction and safety concerns compared with the
urination, urination urgency, and weak and improve quality of life (144–146). relatively modest pain reduction, the use
urinary stream). Evaluation of bladder Pregabalin, a calcium channel a2-d of extended release tapentadol is not
function should be performed for indi- subunit ligand, is the most extensively
generally recommended as a first- or
viduals with diabetes who have recurrent studied drug for DPN. The majority of
urinary tract infections, pyelonephritis, second-line therapy. The use of any
studies testing pregabalin have reported
incontinence, or a palpable bladder. opioids for management of chronic neu-
favorable effects on the proportion of
ropathic pain carries the risk of addiction
participants with at least 30–50% im-
Treatment
and should be avoided.
provement in pain (143,145,147–150).
Tricyclic antidepressants, venlafaxine,
Glycemic Control However, not all trials with pregabalin
carbamazepine, and topical capsaicin,
Near-normal glycemic control, imple- have been positive (143,145,151,152),
although not approved for the treatment
mented early in the course of diabetes, especially when treating patients with
has been shown to effectively delay or advanced refractory DPN (149). Adverse of painful DPN, may be effective and
prevent the development of DPN and effects may be more severe in older considered for the treatment of painful
CAN in patients with type 1 diabetes patients (153) and may be attenuated DPN (130,143,145).
(135–138). Although the evidence for by lower starting doses and more gradual Orthostatic Hypotension
the benefit of near-normal glycemic titration. The related drug, gabapentin, Treating orthostatic hypotension is chal-
control is not as strong for type 2 di- has also shown efficacy for pain control lenging. The therapeutic goal is to min-
abetes, some studies have demonstrated in diabetic neuropathy and may be less imize postural symptoms rather than
care.diabetesjournals.org Microvascular Complications and Foot Care S145
foot ulcer recurrence or worsening. How- ulcer and peripheral arterial disease consideration and a thorough workup
ever, there is very little evidence for the should be performed: skin perfusion should be performed when patients with
use of interventions to prevent a first foot pressure ($40 mmHg), toe pressure neuropathy present with the acute onset
ulcer or heal ischemic, infected, non- ($30 mmHG), or transcutaneous oxygen of a red, hot, swollen foot or ankle, and
plantar, or proximal foot ulcers (170). pressure (TcPO2 $25 mmHg). Urgent Charcot neuroarthropathy should be ex-
Studies on specific types of footwear vascular imaging and revascularization cluded. Early diagnosis and treatment of
demonstrated that shape and barefoot should be considered in a patient with Charcot neuroarthropathy is the best
plantar pressure–based orthoses were a diabetic foot ulcer and an ankle pres- way to prevent deformities that increase
more effective in reducing submeta- sure (ankle-brachial index) ,50 mmHg, the risk of ulceration and amputation.
tarsal head plantar ulcer recurrence toe pressure ,30 mmHg, or a TcPO2 The routine prescription of therapeutic
than current standard-of-care orthoses ,25 mmHg (130,175). footwear is not generally recommended.
(171). However, patients should be provided
Clinicians are encouraged to review Patient Education adequate information to aid in selection
ADA screening recommendations for fur- All patients with diabetes and partic- of appropriate footwear. General foot-
ther details and practical descriptions of ularly those with high-risk foot condi- wear recommendations include a broad
how to perform components of the com- tions (history of ulcer or amputation, and square toe box, laces with three or
prehensive foot examination (172). deformity, LOPS, or PAD) and their four eyes per side, padded tongue, qual-
families should be provided general ity lightweight materials, and sufficient
Evaluation for Loss of Protective
education about risk factors and ap- size to accommodate a cushioned insole.
Sensation
propriate management (176). Patients Use of custom therapeutic footwear can
All adults with diabetes should undergo a
at risk should understand the implica- help reduce the risk of future foot ulcers
comprehensive foot evaluation at least
tions of foot deformities, LOPS, and in high-risk patients (173,176).
annually. Detailed foot assessments may
PAD; the proper care of the foot, in- Most diabetic foot infections are poly-
occur more frequently in patients with
cluding nail and skin care; and the microbial, with aerobic gram-positive
histories of ulcers or amputations, foot
importance of foot monitoring on a cocci. Staphylococci and streptococci
deformities, insensate feet, and PAD
daily basis. Patients with LOPS should are the most common causative organ-
(173,174). To assess risk, clinicians should
be educated on ways to substitute isms. Wounds without evidence of soft
ask about history of foot ulcers or am-
other sensory modalities (palpation tissue or bone infection do not require
putation, neuropathic and peripheral
or visual inspection using an unbreak- antibiotic therapy. Empiric antibiotic
vascular symptoms, impaired vision, re-
able mirror) for surveillance of early therapy can be narrowly targeted at
nal disease, tobacco use, and foot care
foot problems. gram-positive cocci in many patients
practices. A general inspection of skin
The selection of appropriate footwear with acute infections, but those at risk
integrity and musculoskeletal deform-
and footwear behaviors at home should for infection with antibiotic-resistant
ities should be performed. Vascular as-
also be discussed. Patients’ understand- organisms or with chronic, previously
sessment should include inspection and
ing of these issues and their physical treated, or severe infections require
palpation of pedal pulses.
ability to conduct proper foot surveil- broader-spectrum regimens and should
The neurological exam performed as
lance and care should be assessed. Pa- be referred to specialized care centers
part of the foot examination is designed
tients with visual difficulties, physical (177). Foot ulcers and wound care may
to identify LOPS rather than early neu-
constraints preventing movement, or require care by a podiatrist, orthopedic
ropathy. The 10-g monofilament is the
cognitive problems that impair their abil- or vascular surgeon, or rehabilitation
most useful test to diagnose LOPS.
ity to assess the condition of the foot and specialist experienced in the manage-
Ideally, the 10-g monofilament test
to institute appropriate responses will ment of individuals with diabetes (177).
should be performed with at least
need other people, such as family mem- Hyperbaric oxygen therapy (HBOT) in
one other assessment (pinprick, tem-
bers, to assist with their care. patients with diabetic foot ulcers has
perature or vibration sensation using a
mixed evidence supporting its use as
128-Hz tuning fork, or ankle reflexes).
Treatment an adjunctive treatment to enhance
Absent monofilament sensation sug-
People with neuropathy or evidence of wound healing and prevent amputation
gests LOPS, while at least two normal
increased plantar pressures (e.g., ery- (178–181). A well-conducted random-
tests (and no abnormal test) rules out
thema, warmth, or calluses) may be ized controlled study performed in
LOPS.
adequately managed with well-fitted 103 patients found that HBOT did not
Evaluation for Peripheral Arterial walking shoes or athletic shoes that reduce the indication for amputation or
Disease cushion the feet and redistribute pres- facilitate wound healing compared with
Initial screening for PAD should include a sure. People with bony deformities comprehensive wound care in patients
history of decreased walking speed, leg (e.g., hammertoes, prominent metatar- with chronic diabetic foot ulcers (182).
fatigue, claudication, and an assessment sal heads, bunions) may need extra Moreover, a systematic review by the
of the pedal pulses. Ankle-brachial index wide or deep shoes. People with bony International Working Group on the Di-
testing should be performed in patients deformities, including Charcot foot, who abetic Foot of interventions to improve
with symptoms or signs of PAD. Addi- cannot be accommodated with com- the healing of chronic diabetic foot ulcers
tionally, at least one of the following mercial therapeutic footwear, will re- concluded that analysis of the evidence
tests in a patient with a diabetic foot quire custom-molded shoes. Special continues to present methodological
care.diabetesjournals.org Microvascular Complications and Foot Care S147
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studies remain few, with a majority being 308 flozin and renal outcomes in type 2 diabetes and
9. Groop P-H, Thomas MC, Moran JL, et al.; nephropathy. N Engl J Med 2019;380:2295–2306
of poor quality (179). Thus, HBOT does FinnDiane Study Group. The presence and se- 25. Nadkarni GN, Ferrandino R, Chang A, et al.
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Singleton JR. The diagnostic utility of Sudoscan meta-analysis. Ann Intern Med 2014;161:639–649 statement of the American Autonomic Society,
for distal symmetric peripheral neuropathy. J 146. Ziegler D, Fonseca V. From guideline to European Federation of Autonomic Societies,
Diabetes Complications 2014;28:511–516 patient: a review of recent recommendations and the European Society of Hypertension. J
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163. Parrish CR, Pastors JG. Nutritional manage- ation of Clinical Endocrinologists. Comprehensive 181. Löndahl M, Katzman P, Nilsson A,
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164. Parkman HP, Yates KP, Hasler WL, et al.; American Diabetes Association, with endorsement tients with diabetes. Diabetes Care 2010;33:
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in patients with diabetic or idiopathic gastro- 173. Hingorani A, LaMuraglia GM, Henke P, et al. Hyperbaric oxygen therapy does not reduce
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165. Olausson EA, Störsrud S, Grundin H, collaboration with the American Podiatric Medical limb: a prospective, double-blind, randomized
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Diabetes Care Volume 43, Supplement 1, January 2020 S135
Recommendations
11.1 At least once a year, assess urinary albumin (e.g., spot urinary albumin-to-
creatinine ratio) and estimated glomerular filtration rate (eGFR) in patients
with type 1 diabetes with duration of $5 years and in all patients with type 2
diabetes regardless of treatment. B Patients with urinary albumin .30 mg/g
creatinine and/or an eGFR ,60 mL/min/1.73 m2 should be monitored twice
annually to guide therapy. C
Treatment
Recommendations
11.2 Optimize glucose control to reduce the risk or slow the progression of
chronic kidney disease. A
11.3 For patients with type 2 diabetes and diabetic kidney disease, consider use Suggested citation: American Diabetes Associa-
of a sodium–glucose cotransporter 2 inhibitor in patients with an estimated tion. 11. Microvascular complications and
glomerular filtration rate $30 mL/min/1.73 m2 and urinary albumin .30 foot care: Standards of Medical Care in
Diabetesd2020. Diabetes Care 2020;43(Suppl.
mg/g creatinine, particularly in those with urinary albumin .300 mg/g 1):S135–S151
creatinine, to reduce risk of chronic kidney disease (CKD) progression,
© 2019 by the American Diabetes Association.
cardiovascular events, or both. A In patients with CKD who are at increased Readers may use this article as long as the work
risk for cardiovascular events, use of a glucagon-like peptide 1 receptor is properly cited, the use is educational and
agonist may reduce risk of progression of albuminuria, cardiovascular not for profit, and the work is not altered.
events, or both (Table 9.1). C More information is available at http://www
.diabetesjournals.org/content/license.
S136 Microvascular Complications and Foot Care Diabetes Care Volume 43, Supplement 1, January 2020
Figure 11.1—Risk of chronic kidney disease (CKD) progression, frequency of visits, and referral to nephrology according to glomerular filtration rate
(GFR) and albuminuria. The GFR and albuminuria grid depicts the risk of progression, morbidity, and mortality by color, from best to worst (green, yellow,
orange, red, dark red). The numbers in the boxes are a guide to the frequency of visits (number of times per year). Green can reflect CKD with normal
eGFR and albumin-to-creatinine ratio only in the presence of other markers of kidney damage, such as imaging showing polycystic kidney disease or
kidney biopsy abnormalities, with follow-up measurements annually; yellow requires caution and measurements at least once per year; orange requires
measurements twice per year; red requires measurements three times per year; and dark red requires measurements four times per year. These are
general parameters only, based on expert opinion, and underlying comorbid conditions and disease state as well as the likelihood of impacting a change
in management for any individual patient must be taken into account. “Refer” indicates that nephrology services are recommended. *Referring
clinicians may wish to discuss with their nephrology service, depending on local arrangements regarding treating or referring. Reprinted with permission
from Vassalotti et al. (188).
eGFR $60 mL/min/1.73 m2, while stages progression and other adverse health particularly when combined with diu-
3–5 CKD have been defined by progres- outcomes) and cause of kidney damage retics or other medications that reduce
sively lower ranges of eGFR (17) (Fig. (including possible causes other than glomerular filtration; however, this
11.1). At any eGFR, the degree of albu- diabetes) may also affect these decisions has not been found to be true in ran-
minuria is associated with risk of cardio- (20). domized clinical outcome trials of ad-
vascular disease (CVD), CKD progression, vanced kidney disease (24) or high
and mortality (7). Therefore, Kidney Acute Kidney Injury cardiovascular disease risk with normal
Disease: Improving Global Outcomes Acute kidney injury (AKI) is diagnosed kidney function (25–27). Timely iden-
(KDIGO) recommends a more compre- by a 50% or greater sustained increase tification and treatment of AKI is im-
hensive CKD staging that incorporates in serum creatinine over a short period portant because AKI is associated with
albuminuria at all stages of eGFR; this of time, which is also reflected as a rapid increased risks of progressive CKD and
system is more closely associated with decrease in eGFR (21,22). People with other poor health outcomes (28).
risk but is also more complex and does diabetes are at higher risk of AKI than Small elevations in serum creatinine
not translate directly to treatment deci- those without diabetes (23). Other risk (up to 30% from baseline) with renin-
sions (2). Thus, based on the current factors for AKI include preexisting CKD, angiotensin system blockers (such as
classification system, both eGFR and the use of medications that cause ACE inhibitors and ARBs) must not be
albuminuria must be quantified to guide kidney injury (e.g., nonsteroidal anti- confused with AKI (29). An analysis
treatment decisions. This is also impor- inflammatory drugs), and the use of of the Action to Control Cardiovascu-
tant since eGFR levels are essential to medications that alter renal blood flow lar Risk in Diabetes Blood Pressure
modify drug dosage or restrictions of use and intrarenal hemodynamics. In partic- (ACCORD BP) trial demonstrates that those
(Fig. 11.1) (18,19). The degree of albu- ular, many antihypertensive medications randomized to intensive blood pressure
minuria may influence choice of antihy- (e.g., diuretics, ACE inhibitors, and an- lowering with up to a 30% increase in
pertensive (see Section 10 “Cardiovascular giotensin receptor blockers [ARBs]) can serum creatinine did not have any in-
Disease and Risk Management,” https:// reduce intravascular volume, renal blood crease in mortality or progressive kidney
doi.org.10.2337/dc20-S010) or glucose- flow, and/or glomerular filtration. There disease (30–32). Moreover, a measure of
lowering medications (see below). Ob- was concern that sodium–glucose co- markers for AKI showed no significant
served history of eGFR loss (which transporter 2 (SGLT2) inhibitors may increase of any markers with increased
is also associated with risk of CKD promote AKI through volume depletion, creatinine (32). Accordingly, ACE inhibitors
S138 Microvascular Complications and Foot Care Diabetes Care Volume 43, Supplement 1, January 2020
Table 11.1—Selected complications of chronic kidney disease recommended because it does not alter
Complication Medical and laboratory evaluation
glycemic measures, cardiovascular risk
measures, or the course of GFR decline (39).
Elevated blood pressure .140/90 mmHg Blood pressure, weight
Restriction of dietary sodium (to ,2,300
Volume overload History, physical examination, weight mg/day) may be useful to control blood
Electrolyte abnormalities Serum electrolytes pressure and reduce cardiovascular risk
Metabolic acidosis Serum electrolytes (40,41), and restriction of dietary potas-
Anemia Hemoglobin; iron testing if indicated sium may be necessary to control se-
Metabolic bone disease Serum calcium, phosphate, PTH, vitamin 25(OH)D rum potassium concentration (23,33–35).
Complications of chronic kidney disease (CKD) generally become prevalent when estimated These interventions may be most important
glomerular filtration rate falls below 60 mL/min/1.73 m2 (stage 3 CKD or greater) and become more for patients with reduced eGFR, for whom
common and severe as CKD progresses. Evaluation of elevated blood pressure and volume urinary excretion of sodium and potassium
overload should occur at every clinical contact possible; laboratory evaluations are generally
indicated every 6–12 months for stage 3 CKD, every 3–5 months for stage 4 CKD, and every 1– may be impaired. For patients on dialysis,
3 months for stage 5 CKD, or as indicated to evaluate symptoms or changes in therapy. PTH, higher levels of dietary protein intake should
parathyroid hormone; 25(OH)D, 25-hydroxyvitamin D. be considered, since malnutrition is a major
problem in some dialysis patients (42).
Recommendations for dietary sodium and
and ARBs should not be discontinued for 2 diabetes, reducing albuminuria from potassium intake should be individualized
minor increases in serum creatinine (,30%), levels $300 mg/g Cr has been associated on the basis of comorbid conditions, med-
in the absense of volume depletion. with improved renal and cardiovascular ication use, blood pressure, and labora-
outcomes, leading some to suggest that tory data.
Surveillance medications should be titrated to min-
Albuminuria and eGFR should be mon- imize UACR. However, this approach has Glycemic Targets
itored regularly to enable timely diagno- not been formally evaluated in prospec- Intensive glycemic control with the goal
sis of CKD, monitor progression of CKD, tive trials. In type 1 diabetes, remission of achieving near-normoglycemia has
detect superimposed kidney diseases of albuminuria may occur spontane- been shown in large prospective random-
including AKI, assess risk of CKD compli- ously and cohort studies evaluating ized studies to delay the onset and pro-
cations, dose drugs appropriately, and associations of change in albuminuria gression of albuminuria and reduced
determine whether nephrology referral with clinical outcomes have reported eGFR in patients with type 1 diabetes
is needed. Among people with existing inconsistent results (36,37). (43,44) and type 2 diabetes (1,45–51).
kidney disease, albuminuria and eGFR The prevalence of CKD complications Insulin alone was used to lower blood
may change due to progression of CKD, correlates with eGFR (38). When eGFR glucose in the Diabetes Control and
development of a separate superim- is ,60 mL/min/1.73 m2, screening for Complications Trial (DCCT)/Epidemiol-
posed cause of kidney disease, AKI, or complications of CKD is indicated (Table ogy of Diabetes Interventions and Com-
other effects of medications, as noted 11.1). Early vaccination against hepatitis plications (EDIC) study of type 1 diabetes,
above. Serum potassium should also B virus is indicated in patients likely to while a variety of agents were used in
be monitored for patients treated with progress to ESRD (see Section 4 “Com- clinical trials of type 2 diabetes, support-
ACE inhibitors, ARBs, and diuretics be- prehensive Medical Evaluation and As- ing the conclusion that glycemic control
cause these medications can cause hy- sessment of Comorbidities,” https://doi itself helps prevent CKD and its progres-
perkalemia or hypokalemia, which are .org/10.2337/dc20-S004, for further in- sion. The effects of glucose-lowering
associated with cardiovascular risk and formation on immunization). therapies on CKD have helped define
mortality (33–35). For patients with A1C targets (see Table 6.2).
eGFR ,60 mL/min/1.73 m2, appropriate Interventions The presence of CKD affects the risks
medication dosing should be verified, Nutrition and benefits of intensive glycemic con-
exposure to nephrotoxins (e.g., nonste- For people with nondialysis-dependent trol and a number of specific glucose-
roidal anti-inflammatory drugs and io- CKD, dietary protein intake should be lowering medications. In the Action to
dinated contrast) should be minimized, ;0.8 g/kg body weight per day (the Control Cardiovascular Risk in Diabetes
and potential CKD complications should recommended daily allowance) (1). (ACCORD) trial of type 2 diabetes, ad-
be evaluated (Table 11.1). Compared with higher levels of dietary verse effects of intensive glycemic con-
The need for annual quantitative as- protein intake, this level slowed GFR trol (hypoglycemia and mortality) were
sessment of albumin excretion after di- decline with evidence of a greater effect increased among patients with kidney
agnosis of albuminuria, institution of ACE over time. Higher levels of dietary pro- disease at baseline (52,53). Moreover,
inhibitors or ARB therapy, and achiev- tein intake (.20% of daily calories from there is a lag time of at least 2 years in
ing blood pressure control is a subject protein or .1.3 g/kg/day) have been type 2 diabetes to over 10 years in type 1
of debate. Continued surveillance can associated with increased albuminuria, diabetes for the effects of intensive glu-
assess both response to therapy and more rapid kidney function loss, and cose control to manifest as improved
disease progression and may aid in as- CVD mortality and therefore should be eGFR outcomes (49,54,55). Therefore, in
sessing adherence to ACE inhibitor or avoided. Reducing the amount of di- some patients with prevalent CKD and
ARB therapy. In addition, in clinical trials etary protein below the recommended substantial comorbidity, target A1C levels
of ACE inhibitors or ARB therapy in type daily allowance of 0.8 g/kg/day is not may be less intensive (1,56).
care.diabetesjournals.org Microvascular Complications and Foot Care S139
Direct Renal Effects of Glucose-Lowering constraints, metformin should be con- In addition, subgroup analyses of CANVAS
Medications sidered the first-line treatment for all and LEADER suggested that the renal
Some glucose-lowering medications also patients with type 2 diabetes, including benefits of canagliflozin and liraglutide
have effects on the kidney that are direct, those with CKD. were as great or greater for participants
i.e., not mediated through glycemia. For SGLT2 inhibitors and GLP-1 RAs should with CKD at baseline (27,66) and in CANVAS
example, SGLT2 inhibitors reduce renal be considered for patients with type 2 were similar for participants with or with-
tubular glucose reabsorption, weight, diabetes and CKD who require another out atherosclerotic cardiovascular disease
systemic blood pressure, intraglomerular drug added to metformin to attain target (ASCVD) at baseline (72).
pressure, and albuminuria and slow GFR A1C or cannot use or tolerate metformin. Several large clinical trials of SGLT2
loss through mechanisms that appear SGLT2 inhibitors reduce risks of CKD inhibitors focused on patients with ad-
independent of glycemia (26,57–60). progression, CVD events, and hypogly- vanced CKD, and assessment of primary
Moreover, recent data support the cemia. GLP-1 RAs are suggested because renal outcomes are completed or ongo-
notion that SGLT2 inhibitors reduce ox- they reduce risks of CVD events and ing. Canagliflozin and Renal End points in
idative stress in the kidney by .50% and hypoglycemia and appear to possibly Diabetes with Established Nephropa-
blunt increases in angiotensinogen as slow CKD progression. thy Clinical Evaluation (CREDENCE), a
well as reduce NLRP3 inflammasome A number of large cardiovascular out- placebo-controlled trial of canagliflozin
activity (61–63). Glucagon-like peptide comes trials in patients with type 2 di- among 4,401 adults with type 2 diabetes,
1 receptor agonists (GLP-1 RAs) also have abetes at high risk for CVD or with UACR $300 mg/g Cr, and mean eGFR
direct effects on the kidney and have existing CVD examined kidney effects 56 mL/min/1.73 m2 with a mean albu-
been reported to improve renal out- as secondary outcomes. These trials minuria level of over 900 mg/day, has a
comes compared with placebo (64–67). include EMPA-REG OUTCOME [BI primary composite end point of ESRD,
Renal effects should be considered when 10773 (Empagliflozin) Cardiovascular doubling of serum creatinine, or renal or
selecting antihyperglycemia agents (see Outcome Event Trial in Type 2 Diabetes cardiovascular death (24,73). It was stop-
Section 9 “Pharmacologic Approaches to Mellitus Patients], CANVAS (Canagliflozin ped early due to positive efficacy and
Glycemic Treatment,” https://doi.org/10 Cardiovascular Assessment Study), showed a 32% risk reduction for devel-
.2337/dc20-S009). LEADER (Liraglutide Effect and Action opment of ESRD over control (24).
in Diabetes: Evaluation of Cardiovascular Additionally, the development of the
Selection of Glucose-Lowering Medications Outcome Results), and SUSTAIN-6 (Trial primary end point, which included
for Patients With Chronic Kidney Disease to Evaluate Cardiovascular and Other chronic dialysis for $30 days, kidney
For patients with type 2 diabetes and Long-term Outcomes With Semaglutide transplantation or eGFR ,15 mL/min/
established CKD, special considerations in Subjects With Type 2 Diabetes) 1.73 m2 sustained for $30 days by
for the selection of glucose-lowering med- (59,64,67,71). Specifically, compared central laboratory assessment, doubling
ications include limitations to available with placebo, empagliflozin reduced from the baseline serum creatinine av-
medications when eGFR is diminished the risk of incident or worsening ne- erage sustained for $30 days by central
and a desire to mitigate high risks of phropathy (a composite of progression laboratory assessment, or renal death or
CKD progression, CVD, and hypoglycemia to UACR .300 mg/g Cr, doubling of cardiovascular death, was reduced by
(68,69). Drug dosing may require modifi- serum creatinine, ESRD, or death from 30%. This benefit was on background
cation with eGFR ,60 mL/min/1.73 m2 (1). ESRD) by 39% and the risk of doubling ACE inhibitor or ARB therapy in .99% of
The U.S. Food and Drug Administration of serum creatinine accompanied by the patients (24). Moreover, in this ad-
(FDA) revised its guidance for the use of eGFR #45 mL/min/1.73 m2 by 44%; vanced CKD group, there were clear
metformin in CKD in 2016 (70), recom- canagliflozin reduced the risk of progres- benefits on cardiovascular outcomes
mending use of eGFR instead of serum sion of albuminuria by 27% and the risk demonstrating a 31% reduction in car-
creatinine to guide treatment and ex- of reduction in eGFR, ESRD, or death from diovascular death or heart failure hos-
panding the pool of patients with kidney ESRD by 40%; liraglutide reduced the risk pitalization and a 20% reduction in
disease for whom metformin treatment of new or worsening nephropathy (a cardiovascular death, nonfatal myocar-
should be considered. The revised FDA composite of persistent macroalbumin- dial infarction, or nonfatal stroke (24,74).
guidance states that metformin is uria, doubling of serum creatinine, ESRD, In addition to renal effects, some
contraindicated in patients with an or death from ESRD) by 22%; and sema- SGLT2 inhibitors and GLP-1 RAs have
eGFR ,30 mL/min/1.73 m2; eGFR should glutide reduced the risk of new or wors- demonstrated cardiovascular benefits.
be monitored while taking metformin; ening nephropathy (a composite of Namely, in EMPA-REG OUTCOME, CANVAS,
the benefits and risks of continuing persistent UACR .300 mg/g Cr, doubling and LEADER, empagliflozin, canagliflozin,
treatment should be reassessed when of serum creatinine, or ESRD) by 36% and liraglutide, respectively, each reduced
eGFR falls ,45 mL/min/1.73 m2; met- (each P , 0.01). cardiovascular events, evaluated as primary
formin should not be initiated for These analyses were limited by eval- outcomes, compared with placebo (see
patients with an eGFR ,45 mL/min/ uation of study populations not selected Section 10 “Cardiovascular Disease and
1.73 m2; and metformin should be primarily for CKD and examination of Risk Management,” https://doi.org/10
temporarily discontinued at the time renal effects as secondary outcomes. .2337/dc20-S010 for further discussion).
of or before iodinated contrast imag- However, all of these trials included large While the glucose-lowering effects
ing procedures in patients with eGFR numbers of people with stage 3a (eGFR of SGLT2 inhibitors are blunted with
30–60 mL/min/1.73 m2. Within these 45–59 mL/min/1.73 m2) kidney disease. eGFR ,45 mL/min/1.73 m2, the renal
S140 Microvascular Complications and Foot Care Diabetes Care Volume 43, Supplement 1, January 2020
and cardiovascular benefits were still Cardiovascular Disease and Blood Pressure blockers (92). In a trial of people with
seen down to eGFR levels of 30 mL/ Hypertension is a strong risk factor for type 2 diabetes and normal urine albu-
min/1.73 m2 with no significant change the development and progression of CKD min excretion, an ARB reduced or sup-
in glucose (24,26,43,45,52,56,71). Most (78). Antihypertensive therapy reduces pressed the development of albuminuria
participants with CKD in these trials the risk of albuminuria (79–82), and but increased the rate of cardiovascular
also had diagnosed ASCVD at baseline, among patients with type 1 or 2 diabetes events (93). In a trial of people with type 1
though ;28% of CANVAS participants with established CKD (eGFR ,60 mL/ diabetes exhibiting neither albuminuria
with CKD did not have diagnosed min/1.73 m2 and UACR $300 mg/g Cr), nor hypertension, ACE inhibitors or ARBs
ASCVD (27). ACE inhibitor or ARB therapy reduces the did not prevent the development of
Based on evidence from the CREDENCE risk of progression to ESRD (83–85). diabetic glomerulopathy assessed by kid-
trial and secondary analyses of cardio- Moreover, antihypertensive therapy re- ney biopsy (90) This was further sup-
vascular outcomes trials with SGLT2 duces risks of cardiovascular events (79). ported by a similar trial in patients with
inhibitors, cardiovascular and renal Blood pressure levels ,140/90 mmHg type 2 diabetes (91). Therefore, ACE
events are reduced with SGLT2 inhibitor are generally recommended to reduce inhibitors or ARBs are not recommended
use in patients down to an eGFR of CVD mortality and slow CKD progres- for patients without hypertension to pre-
30 mL/min/1.73 m2 even independent sion among all people with diabetes vent the development of CKD.
of glucose-lowering effects (75). (82). Lower blood pressure targets Two clinical trials studied the combi-
While there is clear cardiovascular risk (e.g., ,130/80 mmHg) should be con- nations of ACE inhibitors and ARBs and
reduction associated with GLP-1 RA use sidered for patients based on individual found no benefits on CVD or CKD, and the
in patients with type 2 diabetes and CKD, anticipated benefits and risks. Patients drug combination had higher adverse
the proof of benefit on renal outcome with CKD are at increased risk of CKD event rates (hyperkalemia and/or AKI)
will come with the results of the ongoing progression (particularly those with al- (94,95). Therefore, the combined use of ACE
FLOW (A Research Study to See How buminuria) and CVD and therefore may inhibitors and ARBs should be avoided.
Semaglutide Works Compared to Pla- be suitable in some cases for lower blood Mineralocorticoid receptor antago-
cebo in People With Type 2 Diabetes pressure targets, especially in those nists (spironolactone, eplerenone, and
and Chronic Kidney Disease) trial with with $300 mg/day albuminuria. finerenone) in combination with ACE
injectable semaglutide (76). As noted ACE inhibitors or ARBs are the pre- inhibitors or ARBs remain an area of
above, published data address a limited ferred first-line agent for blood pressure great interest. Mineralocorticoid recep-
group of CKD patients, mostly with coex- treatment among patients with diabe- tor antagonists are effective for man-
isting ASCVD. Renal events have been tes, hypertension, eGFR ,60 mL/min/ agement of resistant hypertension, have
examined, however, as both primary and 1.73 m2, and UACR $300 mg/g Cr be- been shown to reduce albuminuria in
secondary outcomes in published large cause of their proven benefits for pre- short-term studies of CKD, and may
trials. Also, adverse event profiles of vention of CKD progression (83–86). In have additional cardiovascular benefits
these agents must be considered. Please general, ACE inhibitors and ARBs are (96–98). There has been, however, an
refer to Table 9.1 for drug-specific considered to have similar benefits increase in hyperkalemic episodes in
factors, including adverse event infor- (87,88) and risks. In the setting of lower those on dual therapy, and larger, longer
mation, for these agents. Additional levels of albuminuria (30–299 mg/g Cr), trials with clinical outcomes are needed
clinical trials focusing on CKD and car- ACE inhibitor or ARB therapy has been before recommending such therapy.
diovascular outcomes in CKD patients demonstrated to reduce progression to
Referral to a Nephrologist
are ongoing and will be reported in the more advanced albuminuria ($300 mg/g
next few years. Cr) and cardiovascular events but not Consider referral to a physician experi-
For patients with type 2 diabetes and progression to ESRD (86,89). While ACE enced in the care of kidney disease when
CKD, the selection of specific agents may inhibitors or ARBs are often prescribed there is uncertainty about the etiology
depend on comorbidity and CKD stage. for high albuminuria without hyperten- of kidney disease, for difficult manage-
SGLT2 inhibitors may be more useful for sion, outcome trials have not been per- ment issues (anemia, secondary hyper-
patients at high risk of CKD progression formed in this setting to determine parathyroidism, metabolic bone disease,
(i.e., with albuminuria or a history of whether this improves renal outcomes. resistant hypertension, or electrolyte dis-
documented eGFR loss) (Fig. 9.1) be- Moreover, two long-term, double-blind turbances), or when there is advanced
cause they appear to have large bene- studies demonstrate no renoprotective kidney disease (eGFR ,30 mL/min/
ficial effects on CKD incidence. The SGLT2 effect of either ACE inhibitors or ARBs in 1.73 m2) requiring discussion of renal
inhibitors canagliflozin, empagliflozin, type 1 and type 2 diabetes among those replacement therapy for ESRD (2). The
and dapagliflozin are approved by the who were normotensive with or without threshold for referral may vary depending
FDA for use with eGFR $45 mL/min/ high albuminuria (formerly microalbu- on the frequency with which a provider
1.73 m2 (though pivotal trials for each minuria) (90,91). encounters patients with diabetes and
included participants with eGFR $30 Absent kidney disease, ACE inhibitors kidney disease. Consultation with a ne-
mL/min/1.73 m 2 and demonstrated or ARBs are useful to control blood phrologist when stage 4 CKD develops
benefit in subgroups with low eGFR) pressure but have not proven superior (eGFR ,30 mL/min/1.73 m2) has been
(26,27,77). Some GLP-1 RAs may be used to alternative classes of antihypertensive found to reduce cost, improve quality of
with lower eGFR, but most require dose therapy, including thiazide-like diuretics care, and delay dialysis (99). However,
adjustment. and dihydropyridine calcium channel other specialists and providers should
care.diabetesjournals.org Microvascular Complications and Foot Care S141
also educate their patients about the Diabetic retinopathy is a highly specific
11.18 Women with preexisting type
progressive nature of CKD, the kidney vascular complication of both type 1 and
1 or type 2 diabetes who are
preservation benefits of proactive treat- type 2 diabetes, with prevalence strongly
planning pregnancy or who are
ment of blood pressure and blood glucose, related to both the duration of diabetes
pregnant should be counseled
and the potential need for renal replace- and the level of glycemic control (100).
on the risk of development and/
ment therapy. Diabetic retinopathy is the most frequent
or progression of diabetic reti-
cause of new cases of blindness among
nopathy. B
DIABETIC RETINOPATHY adults aged 20–74 years in developed
11.19 Eye examinations should occur
countries. Glaucoma, cataracts, and other
Recommendations before pregnancy or in the first
disorders of the eye occur earlier and
11.12 Optimize glycemic control to trimester in patients with pre-
more frequently in people with diabetes.
reduce the risk or slow the existing type 1 or type 2 di-
In addition to diabetes duration, fac-
progression of diabetic reti- abetes, and then patients
tors that increase the risk of, or are
nopathy. A should be monitored every tri-
associated with, retinopathy include
11.13 Optimize blood pressure and mester and for 1 year postpar-
chronic hyperglycemia (101), nephropa-
serum lipid control to reduce tum as indicated by the degree
thy (102), hypertension (103), and
the risk or slow the progression of retinopathy. B
dyslipidemia (104). Intensive diabetes
of diabetic retinopathy. A management with the goal of achieving
Treatment near-normoglycemia has been shown in
Screening large prospective randomized studies to
Recommendations
prevent and/or delay the onset and pro-
Recommendations 11.20 Promptly refer patients with
gression of diabetic retinopathy and po-
11.14 Adults with type 1 diabetes any level of macular edema,
tentially improve patient reported visual
should have an initial dilated severe nonproliferative dia-
function (46,105–107).
and comprehensive eye exam- betic retinopathy (a precursor
Several case series and a controlled
ination by an ophthalmologist of proliferative diabetic reti-
prospective study suggest that preg-
or optometrist within 5 years nopathy), or any proliferative
nancy in patients with type 1 diabe-
after the onset of diabetes. B diabetic retinopathy to an oph-
tes may aggravate retinopathy and
11.15 Patients with type 2 diabetes thalmologist who is knowl-
threaten vision, especially when gly-
should have an initial dilated edgeable and experienced in
cemic control is poor at the time of
and comprehensive eye exam- the management of diabetic
conception (108,109). Laser photocoagu-
ination by an ophthalmologist retinopathy. A
lation surgery can minimize the risk of
or optometrist at the time of 11.21 The traditional standard treat-
vision loss (109).
the diabetes diagnosis. B ment, panretinal laser photo-
11.16 If there is no evidence of ret- coagulation therapy, is indicated
Screening
inopathy for one or more an- to reduce the risk of vision loss
The preventive effects of therapy and
nual eye exams and glycemia is in patients with high-risk prolif-
the fact that patients with proliferative
well controlled, then screening erative diabetic retinopathy and,
diabetic retinopathy (PDR) or macular
every 1–2 years may be con- in some cases, severe nonproli-
edema may be asymptomatic provide
sidered. If any level of diabetic ferative diabetic retinopathy. A
strong support for screening to detect
retinopathy is present, subse- 11.22 Intravitreous injections of anti–
diabetic retinopathy.
quent dilated retinal examina- vascular endothelial growth fac-
Diabetic retinopathy screening should
tions should be repeated at least tor ranibizumab are not inferior
be performed using validated ap-
annually by an ophthalmologist to traditional panretinal laser
proaches and methodologies. Youth
or optometrist. If retinopathy is photocoagulation and are also
with type 1 or type 2 diabetes are
progressing or sight-threatening, indicated to reduce the risk of
also at risk for complications and need
then examinations will be re- vision loss in patients with pro-
to be screened for diabetic retinopathy
quired more frequently. B liferative diabetic retinopathy. A
(110). If diabetic retinopathy is evident
11.17 Programs that use retinal pho- 11.23 Intravitreous injections of anti–
on screening, prompt referral to an oph-
tography (with remote reading vascular endothelial growth
thalmologist is recommended. Subse-
or use of a validated assess- factor are indicated for central
quent examinations for patients with
ment tool) to improve access involveddiabeticmacularedema,
type 1 or type 2 diabetes are generally
to diabetic retinopathy screen- which occurs beneath the foveal
repeated annually for patients with min-
ing can be appropriate screen- center and may threaten reading
imal to no retinopathy. Exams every 1–2
ing strategies for diabetic vision. A
years may be cost effective after one or
retinopathy. Such programs 11.24 The presence of retinopathy is
more normal eye exams, and in a pop-
need to provide pathways not a contraindication to aspirin
ulation with well controlled type 2 di-
for timely referral for a com- therapy for cardioprotection, as
abetes, there was essentially no risk of
prehensive eye examination aspirin does not increase the risk
development of significant retinopathy
when indicated. B of retinal hemorrhage. A
with a 3-year interval after a normal
S142 Microvascular Complications and Foot Care Diabetes Care Volume 43, Supplement 1, January 2020
examination (111). Less frequent intervals comprehensive eye examination at the growth factor (anti-VEGF) agent, specif-
have been found in simulated modeling time of diagnosis. ically ranibizumab, resulted in visual acu-
to be potentially effective in screening for Pregnancy
ity outcomes that were not inferior to
diabetic retinopathy in patients without Pregnancy is associated with a rapid those observed in patients treated with
diabetic retinopathy (112). More frequent progression of diabetic retinopathy panretinal laser at 2 years of followup
examinations by the ophthalmologist will (117,118). Women with preexisting (121). In addition, it was observed that
be required if retinopathy is progressing. type 1 or type 2 diabetes who are plan- patients treated with ranibizumab
Retinal photography with remote ning pregnancy or who have become tended to have less peripheral visual
reading by experts has great potential pregnant should be counseled on the field loss, fewer vitrectomy surgeries
to provide screening services in areas risk of development and/or progression for secondary complications from their
where qualified eye care professionals of diabetic retinopathy. In addition, rapid proliferative disease, and a lower risk of
are not readily available (105,106). High implementation of intensive glycemic developing diabetic macular edema.
quality fundus photographs can detect management in the setting of retinopa- However, a potential drawback in using
most clinically significant diabetic reti- thy is associated with early worsening anti-VEGF therapy to manage prolifer-
nopathy. Interpretation of the images of retinopathy (109). Women who de- ative disease is that patients were re-
should be performed by a trained eye velop gestational diabetes mellitus do quired to have a greater number of visits
care provider. Retinal photography may not require eye examinations during and received a greater number of
also enhance efficiency and reduce pregnancy and do not appear to be treatments than is typically required
costs when the expertise of ophthalmol- at increased risk of developing diabetic for management with panretinal laser,
ogists can be used for more complex retinopathy during pregnancy (119). which may not be optimal for some pa-
examinations and for therapy (113,114). tients. Other emerging therapies for
In-person exams are still necessary Treatment retinopathy that may use sustained intra-
when the retinal photos are of unaccept- Two of the main motivations for screen- vitreal delivery of pharmacologic agents
able quality and for follow-up if abnor- ing for diabetic retinopathy are to pre- are currently under investigation. The FDA
malities are detected. Retinal photos are vent loss of vision and to intervene with approved ranibizumab for the treatment
not a substitute for comprehensive eye treatment when vision loss can be pre- of diabetic retinopathy in 2017.
exams, which should be performed at vented or reversed. While the ETDRS (122) established the
least initially and at intervals thereafter benefit of focal laser photocoagulation
Photocoagulation Surgery
as recommended by an eye care pro- surgery in eyes with clinically significant
Two large trials, the Diabetic Retinop-
fessional. Artificial intelligence systems macular edema (defined as retinal edema
athy Study (DRS) in patients with PDR
that detect more than mild diabetic located at or within 500 mm of the center
and the Early Treatment Diabetic Ret-
retinopathy and diabetic macular edema of the macula), current data from well-
inopathy Study (ETDRS) in patients with
authorized for use by the FDA represent designed clinical trials demonstrate that
macular edema, provide the strongest
an alternative to traditional screening intravitreal anti-VEGF agents provide a
support for the therapeutic benefits
approaches (115). However, the bene- more effective treatment regimen for
of photocoagulation surgery. The DRS
fits and optimal utilization of this type central-involved diabetic macular edema
(120) showed in 1978 that panretinal
of screening have yet to be fully de- than monotherapy or even combination
photocoagulation surgery reduced the
termined. Artificial intelligence systems therapy with laser (123,124). There
risk of severe vision loss from PDR from
should not be used for patients with are currently three anti-VEGF agents
15.9% in untreated eyes to 6.4% in
known retinopathy, prior retinopathy commonly used to treat eyes with
treated eyes with the greatest benefit
treatment, or symptoms of vision central-involved diabetic macular
ratio in those with more advanced base-
impairment. Results of eye examina- edemadbevacizumab, ranibizumab,
line disease (disc neovascularization
tions should be documented and trans- and aflibercept (100).
or vitreous hemorrhage). In 1985, the
mitted to the referring health care In both the DRS and the ETDRS, laser
ETDRS also verified the benefits of
professional. photocoagulation surgery was beneficial
panretinal photocoagulation for high-
in reducing the risk of further visual loss
Type 1 Diabetes risk PDR and in older-onset patients
in affected patients but generally not
Because retinopathy is estimated to with severe nonproliferative diabetic
beneficial in reversing already dimin-
take at least 5 years to develop after retinopathy or less-than-high-risk PDR.
ished acuity. Anti-VEGF therapy im-
the onset of hyperglycemia, patients Panretinal laser photocoagulation is still
proves vision and has replaced the
with type 1 diabetes should have an commonly used to manage compli-
need for laser photocoagulation in
initial dilated and comprehensive eye ex- cations of diabetic retinopathy that in-
the vast majority of patients with di-
amination within 5 years after the diagnosis volve retinal neovascularization and its
abetic macular edema (125). Most
of diabetes (116). complications.
patients require near-monthly admin-
Type 2 Diabetes Anti–Vascular Endothelial Growth Factor istration of intravitreal therapy with
Patients with type 2 diabetes who may Treatment anti-VEGF agents during the first 12
have had years of undiagnosed diabetes Recent data from the Diabetic Retinop- months of treatment, with fewer injec-
and have a significant risk of prevalent athy Clinical Research Network and tions needed in subsequent years to
diabetic retinopathy at the time of di- others demonstrate that intravitreal in- maintain remission from central-involved
agnosis should have an initial dilated and jections of anti–vascular endothelial diabetic macular edema.
care.diabetesjournals.org Microvascular Complications and Foot Care S143
.10 mmHg, respectively, upon standing a modest slowing of progression without expensive, although it is not FDA ap-
without an appropriate increase in heart reversal of neuronal loss (48,139). Specific proved for this indication (154).
rate). CAN treatment is generally focused glucose-lowering strategies may have dif- Duloxetine is a selective norepineph-
on alleviating symptoms. ferent effects. In a post hoc analysis, par- rine and serotonin reuptake inhibitor.
Gastrointestinal Neuropathies. Gastroin- ticipants, particularly men, in the Bypass Doses of 60 and 120 mg/day showed
testinal neuropathies may involve any Angioplasty Revascularization Investigation efficacy in the treatment of pain associ-
portion of the gastrointestinal tract with in Type 2 Diabetes (BARI 2D) trial treated ated with DPN in multicenter randomized
manifestations including esophageal with insulin sensitizers had a lower inci- trials, although some of these had
dysmotility, gastroparesis, constipation, dence of distal symmetric polyneuropathy high drop-out rates (143,145,150,152).
diarrhea, and fecal incontinence. Gastro- over4yearsthanthosetreatedwith insulin/ Duloxetine also appeared to improve
paresis should be suspected in individ- sulfonylurea (140). neuropathy-related quality of life (155).
uals with erratic glycemic control or with In longer-term studies, a small increase in
upper gastrointestinal symptoms with- Neuropathic Pain A1C was reported in people with diabetes
out another identified cause. Exclusion of Neuropathic pain can be severe and can treated with duloxetine compared with
organic causes of gastric outlet obstruc- impact quality of life, limit mobility, and placebo (156). Adverse events may be
tion or peptic ulcer disease (with esoph- contribute to depression and social dys- more severe in older people but may be
agogastroduodenoscopy or a barium function (141). No compelling evidence attenuated with lower doses and slower
study of the stomach) is needed before exists in support of glycemic control or titrations of duloxetine.
considering a diagnosis of or specialized lifestyle management as therapies for Tapentadol is a centrally acting opioid
testing for gastroparesis. The diagnostic neuropathic pain in diabetes or predia- analgesic that exerts its analgesic effects
gold standard for gastroparesis is the betes, which leaves only pharmaceutical through both m-opioid receptor agonism
measurement of gastric emptying with interventions (142). and noradrenaline reuptake inhibition.
scintigraphy of digestible solids at Pregabalin and duloxetine have re- Extended-release tapentadol was ap-
15-min intervals for 4 h after food intake. ceived regulatory approval by the FDA, proved by the FDA for the treatment
The use of 13C octanoic acid breath test Health Canada, and the European Med- of neuropathic pain associated with
is emerging as a viable alternative. icines Agency for the treatment of neu- diabetes based on data from two mul-
ropathic pain in diabetes. The opioid ticenter clinical trials in which partici-
Genitourinary Disturbances. Diabetic auto- tapentadol has regulatory approval in pants titrated to an optimal dose of
nomic neuropathy may also cause gen- the U.S. and Canada, but the evidence tapentadol were randomly assigned to
itourinary disturbances, including sexual of its use is weaker (143). Comparative continue that dose or switch to placebo
dysfunction and bladder dysfunction. In effectiveness studies and trials that in- (157,158). However, both used a design
men, diabetic autonomic neuropathy clude quality-of-life outcomes are rare, enriched for patients who responded to
may cause erectile dysfunction and/or so treatment decisions must consider tapentadol and therefore their results are
retrograde ejaculation (130). Female each patient’s presentation and comor- not generalizable. A recent systematic
sexual dysfunction occurs more frequently bidities and often follow a trial-and-error review and meta-analysis by the Special
in those with diabetes and presents as approach. Given the range of partially Interest Group on Neuropathic Pain of the
decreased sexual desire, increased pain effective treatment options, a tailored International Association for the Study of
during intercourse, decreased sexual and stepwise pharmacologic strategy Pain found the evidence supporting the
arousal, and inadequate lubrication with careful attention to relative symp- effectiveness of tapentadol in reducing
(134). Lower urinary tract symptoms tom improvement, medication adher- neuropathic pain to be inconclusive (143).
manifest as urinary incontinence and ence, and medication side effects is Therefore, given the high risk for addiction
bladder dysfunction (nocturia, frequent recommended to achieve pain reduction and safety concerns compared with the
urination, urination urgency, and weak and improve quality of life (144–146). relatively modest pain reduction, the use
urinary stream). Evaluation of bladder Pregabalin, a calcium channel a2-d of extended release tapentadol is not
function should be performed for indi- subunit ligand, is the most extensively
generally recommended as a first- or
viduals with diabetes who have recurrent studied drug for DPN. The majority of
urinary tract infections, pyelonephritis, second-line therapy. The use of any
studies testing pregabalin have reported
incontinence, or a palpable bladder. opioids for management of chronic neu-
favorable effects on the proportion of
ropathic pain carries the risk of addiction
participants with at least 30–50% im-
Treatment
and should be avoided.
provement in pain (143,145,147–150).
Tricyclic antidepressants, venlafaxine,
Glycemic Control However, not all trials with pregabalin
carbamazepine, and topical capsaicin,
Near-normal glycemic control, imple- have been positive (143,145,151,152),
although not approved for the treatment
mented early in the course of diabetes, especially when treating patients with
has been shown to effectively delay or advanced refractory DPN (149). Adverse of painful DPN, may be effective and
prevent the development of DPN and effects may be more severe in older considered for the treatment of painful
CAN in patients with type 1 diabetes patients (153) and may be attenuated DPN (130,143,145).
(135–138). Although the evidence for by lower starting doses and more gradual Orthostatic Hypotension
the benefit of near-normal glycemic titration. The related drug, gabapentin, Treating orthostatic hypotension is chal-
control is not as strong for type 2 di- has also shown efficacy for pain control lenging. The therapeutic goal is to min-
abetes, some studies have demonstrated in diabetic neuropathy and may be less imize postural symptoms rather than
care.diabetesjournals.org Microvascular Complications and Foot Care S145
foot ulcer recurrence or worsening. How- ulcer and peripheral arterial disease consideration and a thorough workup
ever, there is very little evidence for the should be performed: skin perfusion should be performed when patients with
use of interventions to prevent a first foot pressure ($40 mmHg), toe pressure neuropathy present with the acute onset
ulcer or heal ischemic, infected, non- ($30 mmHG), or transcutaneous oxygen of a red, hot, swollen foot or ankle, and
plantar, or proximal foot ulcers (170). pressure (TcPO2 $25 mmHg). Urgent Charcot neuroarthropathy should be ex-
Studies on specific types of footwear vascular imaging and revascularization cluded. Early diagnosis and treatment of
demonstrated that shape and barefoot should be considered in a patient with Charcot neuroarthropathy is the best
plantar pressure–based orthoses were a diabetic foot ulcer and an ankle pres- way to prevent deformities that increase
more effective in reducing submeta- sure (ankle-brachial index) ,50 mmHg, the risk of ulceration and amputation.
tarsal head plantar ulcer recurrence toe pressure ,30 mmHg, or a TcPO2 The routine prescription of therapeutic
than current standard-of-care orthoses ,25 mmHg (130,175). footwear is not generally recommended.
(171). However, patients should be provided
Clinicians are encouraged to review Patient Education adequate information to aid in selection
ADA screening recommendations for fur- All patients with diabetes and partic- of appropriate footwear. General foot-
ther details and practical descriptions of ularly those with high-risk foot condi- wear recommendations include a broad
how to perform components of the com- tions (history of ulcer or amputation, and square toe box, laces with three or
prehensive foot examination (172). deformity, LOPS, or PAD) and their four eyes per side, padded tongue, qual-
families should be provided general ity lightweight materials, and sufficient
Evaluation for Loss of Protective
education about risk factors and ap- size to accommodate a cushioned insole.
Sensation
propriate management (176). Patients Use of custom therapeutic footwear can
All adults with diabetes should undergo a
at risk should understand the implica- help reduce the risk of future foot ulcers
comprehensive foot evaluation at least
tions of foot deformities, LOPS, and in high-risk patients (173,176).
annually. Detailed foot assessments may
PAD; the proper care of the foot, in- Most diabetic foot infections are poly-
occur more frequently in patients with
cluding nail and skin care; and the microbial, with aerobic gram-positive
histories of ulcers or amputations, foot
importance of foot monitoring on a cocci. Staphylococci and streptococci
deformities, insensate feet, and PAD
daily basis. Patients with LOPS should are the most common causative organ-
(173,174). To assess risk, clinicians should
be educated on ways to substitute isms. Wounds without evidence of soft
ask about history of foot ulcers or am-
other sensory modalities (palpation tissue or bone infection do not require
putation, neuropathic and peripheral
or visual inspection using an unbreak- antibiotic therapy. Empiric antibiotic
vascular symptoms, impaired vision, re-
able mirror) for surveillance of early therapy can be narrowly targeted at
nal disease, tobacco use, and foot care
foot problems. gram-positive cocci in many patients
practices. A general inspection of skin
The selection of appropriate footwear with acute infections, but those at risk
integrity and musculoskeletal deform-
and footwear behaviors at home should for infection with antibiotic-resistant
ities should be performed. Vascular as-
also be discussed. Patients’ understand- organisms or with chronic, previously
sessment should include inspection and
ing of these issues and their physical treated, or severe infections require
palpation of pedal pulses.
ability to conduct proper foot surveil- broader-spectrum regimens and should
The neurological exam performed as
lance and care should be assessed. Pa- be referred to specialized care centers
part of the foot examination is designed
tients with visual difficulties, physical (177). Foot ulcers and wound care may
to identify LOPS rather than early neu-
constraints preventing movement, or require care by a podiatrist, orthopedic
ropathy. The 10-g monofilament is the
cognitive problems that impair their abil- or vascular surgeon, or rehabilitation
most useful test to diagnose LOPS.
ity to assess the condition of the foot and specialist experienced in the manage-
Ideally, the 10-g monofilament test
to institute appropriate responses will ment of individuals with diabetes (177).
should be performed with at least
need other people, such as family mem- Hyperbaric oxygen therapy (HBOT) in
one other assessment (pinprick, tem-
bers, to assist with their care. patients with diabetic foot ulcers has
perature or vibration sensation using a
mixed evidence supporting its use as
128-Hz tuning fork, or ankle reflexes).
Treatment an adjunctive treatment to enhance
Absent monofilament sensation sug-
People with neuropathy or evidence of wound healing and prevent amputation
gests LOPS, while at least two normal
increased plantar pressures (e.g., ery- (178–181). A well-conducted random-
tests (and no abnormal test) rules out
thema, warmth, or calluses) may be ized controlled study performed in
LOPS.
adequately managed with well-fitted 103 patients found that HBOT did not
Evaluation for Peripheral Arterial walking shoes or athletic shoes that reduce the indication for amputation or
Disease cushion the feet and redistribute pres- facilitate wound healing compared with
Initial screening for PAD should include a sure. People with bony deformities comprehensive wound care in patients
history of decreased walking speed, leg (e.g., hammertoes, prominent metatar- with chronic diabetic foot ulcers (182).
fatigue, claudication, and an assessment sal heads, bunions) may need extra Moreover, a systematic review by the
of the pedal pulses. Ankle-brachial index wide or deep shoes. People with bony International Working Group on the Di-
testing should be performed in patients deformities, including Charcot foot, who abetic Foot of interventions to improve
with symptoms or signs of PAD. Addi- cannot be accommodated with com- the healing of chronic diabetic foot ulcers
tionally, at least one of the following mercial therapeutic footwear, will re- concluded that analysis of the evidence
tests in a patient with a diabetic foot quire custom-molded shoes. Special continues to present methodological
care.diabetesjournals.org Microvascular Complications and Foot Care S147
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studies remain few, with a majority being 308 flozin and renal outcomes in type 2 diabetes and
9. Groop P-H, Thomas MC, Moran JL, et al.; nephropathy. N Engl J Med 2019;380:2295–2306
of poor quality (179). Thus, HBOT does FinnDiane Study Group. The presence and se- 25. Nadkarni GN, Ferrandino R, Chang A, et al.
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S152 Diabetes Care Volume 43, Supplement 1, January 2020
SPPC), are responsible for updating the Standards of Care annually, or more
frequently as warranted. For a detailed description of ADA standards, statements,
and reports, as well as the evidence-grading system for ADA’s clinical practice
recommendations, please refer to the Standards of Care Introduction (https://doi
.org/10.2337/dc20-SINT). Readers who wish to comment on the Standards of Care
are invited to do so at professional.diabetes.org/SOC.
Recommendations
12.1 Consider the assessment of medical, psychological, functional (self-
management abilities), and social geriatric domains in older adults to
provide a framework to determine targets and therapeutic approaches
for diabetes management. B
12.2 Screen for geriatric syndromes (i.e., polypharmacy, cognitive impair-
ment, depression, urinary incontinence, falls, and persistent pain) in older
adults as they may affect diabetes self-management and diminish quality
of life. B
The comprehensive assessment de- cognitive function or in preventing cog- referral to a behavioral health provider
scribed above may provide a framework nitive decline (17). Pilot studies in pa- for formal cognitive/neuropsychological
to determine targets and therapeutic tients with mild cognitive impairment evaluation (28).
approaches (8–10), including whether evaluating the potential benefits of
referral for diabetes self-management intranasal insulin therapy and metfor-
HYPOGLYCEMIA
education is appropriate (when compli- min therapy provide insights for future
cating factors arise or when transitions in clinical trials and mechanistic studies Recommendation
care occur) or whether the current reg- (18–20). 12.4 Hypoglycemia should be avoided
imen is too complex for the patient’s Despite the paucity of therapies to in older adults with diabetes. It
self-management ability or the care- prevent or remedy cognitive decline, should be assessed and managed
givers providing care. Particular atten- identifying cognitive impairment early by adjusting glycemic targets and
tion should be paid to complications has important implications for diabe- pharmacologic regimens. B
that can develop over short periods of tes care. The presence of cognitive im-
time and/or would significantly impair pairment can make it challenging for
functional status, such as visual and clinicians to help their patients reach Older adults are at higher risk of hypo-
lower-extremity complications. Please individualized glycemic, blood pressure, glycemia for many reasons, including
refer to the American Diabetes Associ- and lipid targets. Cognitive dysfunction insulin deficiency necessitating insulin
ation (ADA) consensus report “Diabetes makes it difficult for patients to perform therapy and progressive renal insuffi-
in Older Adults” for details (2). complex self-care tasks (21), such as ciency (29). As described above, older
monitoring glucose and adjusting insu- adults have higher rates of unidentified
lin doses. It also hinders their ability cognitive impairment and dementia
NEUROCOGNITIVE FUNCTION
to appropriately maintain the timing leading to difficulties in adhering to
Recommendation of meals and content of diet. When complex self-care activities (e.g., glu-
12.3 Screening for early detection of clinicians are managing patients with cose monitoring, insulin dose ad-
mild cognitive impairment or cognitive dysfunction, it is critical to justment, etc.). Cognitive decline has
dementia should be performed simplify drug regimens and to facilitate been associated with increased risk of
for adults 65 years of age or and engage the appropriate support hypoglycemia and, conversely, severe
older at the initial visit and structure to assist the patient in all hypoglycemia has been linked to
annually as appropriate. B aspects of care. increased risk of dementia (30,31).
Older adults with diabetes should be Therefore, as discussed under recom-
Older adults with diabetes are at carefully screened and monitored for mendation 12.3, it is important to rou-
higher risk of cognitive decline and in- cognitive impairment (2) (see Table 4.1 tinely screen older adults for cognitive
stitutionalization (11,12). The presen- for cognitive screening recommenda- impairment and dementia and discuss
tation of cognitive impairment ranges tions). Several simple assessment tools findings with the patients and their
from subtle executive dysfunction to are available to screen for cognitive caregivers.
memory loss and overt dementia. Peo- impairment (22,23), such as the Mini- Patients should be monitored for hy-
ple with diabetes have higher incidences Mental State Examination (24), Mini-Cog poglycemia; glycemic targets and phar-
of all-cause dementia, Alzheimer disease, (25), and the Montreal Cognitive Assess- macologic regimens may need to be
and vascular dementia than people with ment (26), which may help to identify adjusted to minimize the occurrence
normal glucose tolerance (13). The ef- patients requiring neuropsychological of hypoglycemic events (2). Of note, it
fects of hyperglycemia and hyperinsuli- evaluation, particularly those in whom is important to prevent hypoglycemia
nemia on the brain are areas of intense dementia is suspected (i.e., experiencing to reduce the risk of cognitive decline
research. Poor glycemic control is asso- memory loss and decline in their basic (30) and other major adverse outcomes
ciated with a decline in cognitive function and instrumental activities of daily liv- (32). Intensive glucose control in the
(14), and longer duration of diabetes is ing). Annual screening is indicated for Action to Control Cardiovascular Risk
associated with worsening cognitive adults 65 years of age or older for early in Diabetes-Memory in Diabetes study
function. There are ongoing studies eval- detection of mild cognitive impairment (ACCORD-MIND) was not found to ben-
uating whether preventing or delaying or dementia (4,27). Screening for cogni- efit brain structure or cognitive function
diabetes onset may help to maintain tive impairment should additionally be during follow-up (15). In the Diabetes
cognitive function in older adults. How- considered when a patient presents Control and Complications Trial (DCCT),
ever, studies examining the effects of with a significant decline in clinical status no significant long-term declines in cog-
intensive glycemic and blood pressure due to increased problems with self-care nitive function were observed, despite
control to achieve specific targets have activities, such as errors in calculating participants’ relatively high rates of re-
not demonstrated a reduction in brain insulin dose, difficulty counting carbohy- current severe hypoglycemia (33). To
function decline (15,16). drates, skipped meals, skipped insulin achieve the appropriate balance be-
Clinical trials of specific interventionsd doses, and difficulty recognizing, pre- tween glycemic control and risk for hy-
including cholinesterase inhibitors and venting, or treating hypoglycemia. Peo- poglycemia, it is important to carefully
glutamatergic antagonistsdhave not ple who screen positive for cognitive assess and reassess patients’ risk for
shown positive therapeutic benefit in impairment should receive diagnostic worsening of glycemic control and func-
maintaining or significantly improving assessment as appropriate, including tional decline.
S154 Older Adults Diabetes Care Volume 43, Supplement 1, January 2020
TREATMENT GOALS with diabetes have little comorbidity a patient needs a referral for cognitive
and are active. Life expectancies are and physical functional assessment, us-
Recommendations highly variable but are often longer ing age-normalized evaluation tools, as
12.5 Older adults who are otherwise than clinicians realize. Providers caring well as help establishing a support struc-
healthy with few coexisting for older adults with diabetes must take ture for diabetes care (3,28).
chronic illnesses and intact cog- this heterogeneity into consideration
nitive function and functional when setting and prioritizing treatment Patients With Complications and
status should have lower glyce- goals (9,10) (Table 12.1). In addition, Reduced Functionality
mic goals (such as A1C ,7.5% older adults with diabetes should be For patients with advanced diabetes
[58 mmol/mol]), while those assessed for disease treatment and complications, life-limiting comorbid ill-
with multiple coexisting chronic self-management knowledge, health nesses, or substantial cognitive or func-
illnesses, cognitive impairment, literacy, and mathematical literacy (nu- tional impairments, it is reasonable to set
or functional dependence should meracy) at the onset of treatment. See less intensive glycemic goals (Table 12.1).
have less-stringent glycemic Fig. 6.2 for patient- and disease-related Factors to consider in individualizing
goals (such as A1C ,8.0–8.5% factors to consider when determining glycemic goals are outlined in Fig. 6.2.
[64–69 mmol/mol]). C individualized glycemic targets. These patients are less likely to benefit
12.6 Glycemic goals for some older A1C is used as the standard biomarker from reducing the risk of microvascular
adults might reasonably be re- for glycemic control in all patients with complications and more likely to suffer
laxed as part of individualized diabetes but may have limitations in serious adverse effects from hypoglyce-
care, but hyperglycemia lead- patients who have medical conditions mia. However, patients with poorly con-
ing to symptoms or risk of that impact red blood cell turnover (see trolled diabetes may be subject to acute
acute hyperglycemia compli- Section 2 “Classification and Diagnosis of complications of diabetes, including
cations should be avoided in Diabetes” https://doi.org/10.2337/dc20- dehydration, poor wound healing, and
all patients. C S002, for additional details on the limi- hyperglycemic hyperosmolar coma. Gly-
12.7 Screening for diabetes compli- tations of A1C) (37). Many conditions cemic goals should, at a minimum, avoid
cations should be individualized associated with increased red blood cell these consequences.
in older adults. Particular atten- turnover, such as hemodialysis, recent
tion should be paid to compli- blood loss or transfusion, or erythropoi- Vulnerable Patients at the End of Life
cations that would lead to etin therapy, are commonly seen in older For patients receiving palliative care and
functional impairment. C adults with functional limitations and end-of-life care, the focus should be to
12.8 Treatment of hypertension to can falsely increase or decrease A1C. In reduce the burdens and avoid the side
individualized target levels is these instances, plasma blood glucose effects of glycemic management. Thus,
indicated in most older adults. C and fingerstick readings should be used when organ failure develops, several agents
12.9 Treatment of other cardiovas- for goal setting (Table 12.1). will have to be deintensified or discontin-
cular risk factors should be ued. For the dying patient, most agents
individualized in older adults Healthy Patients With Good for type 2 diabetes may be removed (38).
considering the time frame of Functional Status There is, however, no consensus for the
benefit. Lipid-lowering therapy There are few long-term studies in older management of type 1 diabetes in this
and aspirin therapy may benefit adults demonstrating the benefits of in- scenario (39). See END-OF-LIFE CARE, below,
those with life expectancies at tensive glycemic, blood pressure, and for additional information.
least equal to the time frame of lipid control. Patients who can be ex-
primary prevention or second- pected to live long enough to reap the Beyond Glycemic Control
ary intervention trials. E benefits of long-term intensive diabetes Although hyperglycemia control may be
management, who have good cognitive important in older individuals with dia-
The care of older adults with diabetes is and physical function, and who choose to betes, greater reductions in morbidity and
complicated by their clinical, cognitive, do so via shared decision-making may be mortality are likely to result from control
and functional heterogeneity. Some treated using therapeutic interventions of other cardiovascular risk factors rather
older individuals may have developed and goals similar to those for younger than from tight glycemic control alone.
diabetes years earlier and have signifi- adults with diabetes (Table 12.1). There is strong evidence from clinical trials
cant complications, others are newly As with all patients with diabetes, di- of the value of treating hypertension in
diagnosed and may have had years of abetes self-management education and older adults (40,41), with treatment of
undiagnosed diabetes with resultant ongoing diabetes self-management sup- hypertension to individualized target lev-
complications, and still other older adults port are vital components of diabetes care els indicated in most. There is less evi-
may have truly recent-onset disease with for older adults and their caregivers. Self- dence for lipid-lowering therapy and
few or no complications (34). Some older management knowledge and skills should aspirin therapy, although the benefits
adults with diabetes have other under- be reassessed when regimen changes are of these interventions for primary pre-
lying chronic conditions, substantial made or an individual’s functional abili- vention and secondary intervention are
diabetes-related comorbidity, limited ties diminish. In addition, declining or likely to apply to older adults whose life
cognitive or physical functioning, or impaired ability to perform diabetes self- expectancies equal or exceed the time
frailty (35,36). Other older individuals care behaviors may be an indication that frames of the clinical trials.
care.diabetesjournals.org Older Adults S155
Table 12.1—Framework for considering treatment goals for glycemia, blood pressure, and dyslipidemia in older adults with
diabetes
Patient Fasting or
characteristics/ Reasonable preprandial Blood
health status Rationale A1C goal‡ glucose Bedtime glucose pressure Lipids
Healthy (few Longer remaining life ,7.5% 90–130 mg/dL 90–150 mg/dL ,140/90 mmHg Statin unless
coexisting chronic expectancy (58 mmol/mol) (5.0–7.2 mmol/L) (5.0–8.3 contraindicated
illnesses, intact mmol/L) or not tolerated
cognitive and
functional status)
Complex/ Intermediate ,8.0% 90–150 mg/dL 100–180 mg/dL ,140/90 mmHg Statin unless
intermediate remaining life (64 mmol/mol) (5.0–8.3 mmol/L) (5.6–10.0 contraindicated
(multiple expectancy, high mmol/L) or not tolerated
coexisting chronic treatment burden,
illnesses* or 21 hypoglycemia
instrumental ADL vulnerability,
impairments or fall risk
mild-to-moderate
cognitive
impairment)
Very complex/poor Limited remaining life ,8.5%† 100–180 mg/dL 110–200 mg/dL ,150/90 mmHg Consider
health (LTC or end- expectancy makes (69 mmol/mol) (5.6–10.0 (6.1–11.1 likelihood of
stage chronic benefit uncertain mmol/L) mmol/L) benefit with
illnesses** or statin
moderate-to- (secondary
severe cognitive prevention
impairment or 21 more so than
ADL dependencies) primary)
This table represents a consensus framework for considering treatment goals for glycemia, blood pressure, and dyslipidemia in older adults
with diabetes. The patient characteristic categories are general concepts. Not every patient will clearly fall into a particular category.
Consideration of patient and caregiver preferences is an important aspect of treatment individualization. Additionally, a patient’s health
status and preferences may change over time. ADL, activities of daily living; LTC, long-term care. ‡A lower A1C goal may be set for an
individual if achievable without recurrent or severe hypoglycemia or undue treatment burden. *Coexisting chronic illnesses are conditions
serious enough to require medications or lifestyle management and may include arthritis, cancer, congestive heart failure, depression,
emphysema, falls, hypertension, incontinence, stage 3 or worse chronic kidney disease, myocardial infarction, and stroke. “Multiple”
means at least three, but many patients may have five or more (54). **The presence of a single end-stage chronic illness, such as stage
3–4 congestive heart failure or oxygen-dependent lung disease, chronic kidney disease requiring dialysis, or uncontrolled metastatic cancer, may
cause significant symptoms or impairment of functional status and significantly reduce life expectancy. †A1C of 8.5% (69 mmol/mol) equates to
an estimated average glucose of ;200 mg/dL (11.1 mmol/L). Looser A1C targets above 8.5% (69 mmol/mol) are not recommended, as
they may expose patients to more frequent higher glucose values and acute risks from glycosuria, dehydration, hyperglycemic hyperosmolar
syndrome, and poor wound healing. Adapted from Kirkman et al. (2).
agents. Cost may be an important con- may impair their ability to follow their the dose of insulin may not be ade-
sideration, especially as older adults regimen safely. Individualized glycemic quate (55). Simplification of the insulin
tend to be on many medications and goals should be established (Fig. 6.3) and regimen to match an individual’s self-
live on fixed incomes (47). Accordingly, periodically adjusted based on coexist- management abilities and their avail-
the costs of care and insurance coverage ing chronic illnesses, cognitive function, able social and medical support in these
rules should be considered when devel- and functional status (2). Tight glycemic situations has been shown to reduce
oping treatment plans to reduce the risk control in older adults with multiple hypoglycemia and disease-related dis-
of cost-related nonadherence (48,49). medical conditions is considered over- tress without worsening glycemic con-
See Tables 9.2 and 9.3 for median treatment and is associated with an trol (56–58). Fig. 12.1 depicts an
monthly cost in the U.S. of noninsulin increased risk of hypoglycemia; unfor- algorithm that can be used to simplify
glucose-lowering agents and insulin, re- tunately, overtreatment is common in the insulin regimen (56). There are
spectively. It is important to match com- clinical practice (50–54). Deintensifica- now multiple studies evaluating de-
plexity of the treatment regimen to the tion of regimens in patients taking non- intensification protocols; in general,
self-management ability of older pa- insulin glucose-lowering medications the studies demonstrate that de-
tients and their available social and can be achieved by either lowering intensification is safe and possibly
medical support. Many older adults the dose or discontinuing some medi- beneficial for older adults (59). Table
with diabetes struggle to maintain the cations, so long as the individualized 12.2 provides examples of and rationale
frequent blood glucose testing and insu- glycemic target is maintained. When pa- for situations where deintensification
lin injection regimens they previously fol- tients are found to have an insulin and/or insulin regimen simplifica-
lowed, perhaps for many decades, as regimen with complexity beyond their tion may be appropriate in older
they develop medical conditions that self-management abilities, lowering adults.
Figure 12.1—Algorithm to simplify insulin regimen for older patients with type 2 diabetes. eGFR, estimated glomerular filtration rate. *Basal insulins:
glargine U-100 and U-300, detemir, degludec, and human NPH. **See Table 12.1. UMealtime insulins: short-acting (regular human insulin) or rapid-
acting (lispro, aspart, and glulisine). §Premixed insulins: 70/30, 75/25, and 50/50 products. Adapted with permission from Munshi and colleagues
(56,82,83).
care.diabetesjournals.org Older Adults S157
Table 12.2—Considerations for treatment regimen simplification and deintensification/deprescribing in older adults with
diabetes (56,82)
Patient When may treatment
characteristics/health Reasonable A1C/ When may regimen deintensification/
status treatment goal Rationale/considerations simplification be required? deprescribing be required?
Healthy (few A1C ,7.5% c Patients can generally c If severe or recurrent c If severe or recurrent
coexisting chronic (58 mmol/mol) perform complex tasks to hypoglycemia occurs in hypoglycemia occurs in
illnesses, intact maintain good glycemic patients on insulin therapy patients on noninsulin
cognitive and control when health is stable (even if A1C is appropriate) therapies with high risk
functional status) c During acute illness, patients c If wide glucose excursions of hypoglycemia (even if
may be more at risk for are observed A1C is appropriate)
administration or dosing c If cognitive or functional c If wide glucose excursions
errors that can result in decline occurs following are observed
hypoglycemia, falls, fractures, acute illness c In the presence of
etc. polypharmacy
Complex/ A1C ,8.0% c Comorbidities may affect self- c If severe or recurrent c If severe or recurrent
intermediate (64 mmol/mol) management abilities and hypoglycemia occurs in hypoglycemia occurs in
(multiple coexisting capacity to avoid patients on insulin therapy patients on noninsulin
chronic illnesses or hypoglycemia (even if A1C is appropriate) therapies with high risk
21 instrumental c Long-acting medication c If unable to manage of hypoglycemia (even if
ADL impairments or formulations may decrease complexity of an insulin A1C is appropriate)
mild-to-moderate pill burden and complexity of regimen c If wide glucose excursions
cognitive medication regimen c If there is a significant are observed
impairment) change in social c In the presence of
circumstances, such as loss polypharmacy
of caregiver, change in
living situation, or financial
difficulties
Community-dwelling Avoid reliance c Glycemic control is important c If treatment regimen c If the hospitalization for
patients receiving on A1C for recovery, wound healing, increased in complexity acute illness resulted in
care in a skilled hydration, and avoidance of during hospitalization, it is weight loss, anorexia,
nursing facility for infections reasonable, in many cases, short-term cognitive
short-term Glucose target: c Patients recovering from to reinstate the decline, and/or loss of
rehabilitation 100–200 mg/dL illness may not have returned prehospitalization physical functioning
(5.55–11.1 mmol/L) to baseline cognitive function medication regimen during
at the time of discharge the rehabilitation
c Consider the type of support
the patient will receive at
home
Very complex/poor A1C ,8.5% c No benefits of tight glycemic c If on an insulin regimen and c If on noninsulin agents
health (long-term (69 mmol/)† control in this population the patient would like to with a high hypoglycemia
care or end-stage c Hypoglycemia should be decrease the number of risk in the context of
chronic illnesses or avoided injections and fingerstick cognitive dysfunction,
moderate-to- c Most important outcomes are blood glucose monitoring depression, anorexia, or
severe cognitive maintenance of cognitive and events each day inconsistent eating
impairment or 21 functional status c If the patient has an pattern
ADL dependencies) inconsistent eating pattern c If taking any medications
without clear benefits
Patients at end of life Avoid hypoglycemia c Goal is to provide comfort and c If there is pain or c If taking any medications
and symptomatic avoid tasks or interventions discomfort caused by without clear benefits in
hyperglycemia that cause pain or discomfort treatment (e.g., injections improving symptoms
c Caregivers are important in or fingersticks) and/or comfort
providing medical care and c If there is excessive
maintaining quality of life caregiver stress due to
treatment complexity
Treatment regimen simplification refers to changing strategy to decrease the complexity of a medication regimen, e.g., fewer administration times,
fewer fingerstick readings, decreasing the need for calculations (such as sliding scale insulin calculations or insulin-carbohydrate ratio calculations).
Deintensification/deprescribing refers to decreasing the dose or frequency of administration of a treatment or discontinuing a treatment altogether.
ADL, activities of daily living. †Consider adjustment of A1C goal if the patient has a condition that may interfere with erythrocyte life span/turnover.
Metformin glomerular filtration rate $30 mL/min/ hepatic function or congestive heart fail-
Metformin is the first-line agent for older 1.73 m2 (60). However, it is contra- ure because of the increased risk of lactic
adults with type 2 diabetes. Recent indicated in patients with advanced acidosis. Metformin may be temporarily
studies have indicated that it may be renal insufficiency and should be used discontinued before procedures, during
used safely in patients with estimated with caution in patients with impaired hospitalizations, and when acute illness
S158 Older Adults Diabetes Care Volume 43, Supplement 1, January 2020
may compromise renal or liver function. be convenient for older adults with their own medications, whereas those
Additionally, metformin can cause gas- diabetes. In patients with established living in a nursing home (community
trointestinal side effects and a reduc- atherosclerotic cardiovascular disease, living centers) may rely completely on
tion in appetite that can be problematic these agents have shown cardiovascular the care plan and nursing support.
for some older adults. Reduction or benefits (64). This class of agents has also Those receiving palliative care (with or
elimination of metformin may be nec- been found to be beneficial for patients without hospice) may require an ap-
essary for patients experiencing gas- with heart failure and to slow the pro- proach that emphasizes comfort and
trointestinal side effects. gression of chronic kidney disease. See symptom management, while de-
Section 9 “Pharmacologic Approaches emphasizing strict metabolic and blood
Thiazolidinediones to Glycemic Treatment” (https://doi.org/ pressure control.
Thiazolidinediones, if used at all, should 10.2337/dc20-S009) for a more extensive
be used very cautiously in those with, or SPECIAL CONSIDERATIONS
discussion regarding the indications for
at risk for, congestive heart failure, os- FOR OLDER ADULTS WITH
this class of agents. While understand-
teoporosis, falls or fractures, and/or mac- TYPE 1 DIABETES
ing of the clinical benefits of this class is
ular edema (61,62). evolving, side effects such as volume Due in part to the success of modern
Insulin Secretagogues depletion may be more common among diabetes management, patients with
Sulfonylureas and other insulin secreta- older patients. type 1 diabetes are living longer and
gogues are associated with hypoglyce- the population of these patients over
Insulin Therapy 65 years of age is growing (65–67). Many
mia and should be used with caution. If
The use of insulin therapy requires that of the recommendations in this section
used, sulfonylureas with a shorter dura-
patients or their caregivers have good regarding a comprehensive geriatric as-
tion of action, such as glipizide or glime-
visual and motor skills and cognitive sessment and personalization of goals
piride, are preferred. Glyburide is a
ability. Insulin therapy relies on the and treatments are directly applicable
longer-acting sulfonylurea and should
ability of the older patient to admin- to older adults with type 1 diabetes;
be avoided in older adults (63).
ister insulin on their own or with the however, this population has unique
Incretin-Based Therapies assistance of a caregiver. Insulin doses challenges and requires distinct treat-
Oral dipeptidyl peptidase 4 (DPP-4) inhib- should be titrated to meet individu- ment considerations (68). Insulin is an
itors have few side effects and minimal alized glycemic targets and to avoid essential life-preserving therapy for pa-
risk of hypoglycemia, but their cost may hypoglycemia. tients with type 1 diabetes, unlike for
be a barrier to some older patients. DPP-4 Once-daily basal insulin injection ther- those with type 2 diabetes. In order
inhibitors do not increase major adverse apy is associated with minimal side ef- to avoid diabetic ketoacidosis, older
cardiovascular outcomes (64). fects and may be a reasonable option in adults with type 1 diabetes need some
Glucagon-like peptide 1 (GLP-1) re- many older patients. Multiple daily in- form of basal insulin even when they are
ceptor agonists have demonstrated jections of insulin may be too complex unable to ingest meals. Insulin may be
cardiovascular benefits among patients for the older patient with advanced di- delivered through insulin pump or injec-
with established atherosclerotic car- abetes complications, life-limiting co- tions. Continuous glucose monitoring
diovascular disease, and newer trials existing chronic illnesses, or limited (CGM) is approved for use by Medicare
are expanding our understanding of functional status. Fig. 12.1 provides a and can play a critical role in improving
their benefits in other populations potential approach to insulin regimen A1C, reducing glycemic variability, and
(64). See Section 9 “Pharmacologic simplification. reducing risk of hypoglycemia (69) (see
Approaches to Glycemic Treatment” Section 7 “Diabetes Technology,”
(https://doi.org/10.2337/dc20-S009) Other Factors to Consider https://doi.org/10.2337/dc20-S007,
for a more extensive discussion regarding The needs of older adults with diabetes and section 9 “Pharmacologic Approaches
the specific indications for this class. While and their caregivers should be evaluated to Glycemic Treatment,” https://doi.org/
the benefits of this class are emerging, to construct a tailored care plan. Im- 10.2337/dc20-S009). In the older patient
these drugs are injectable agents (with the paired social functioning may reduce with type 1 diabetes, administration of
exception of oral semaglutide), which these patients’ quality of life and increase insulin may become more difficult as
require visual, motor, and cognitive skills the risk of functional dependency (7). The complications, cognitive impairment,
for appropriate administration. They may patient’s living situation must be consid- and functional impairment arise. This
also be associated with nausea, vomiting, ered as it may affect diabetes manage- increases the importance of caregivers
and diarrhea. Given the gastrointestinal ment and support needs. Social and in the lives of these patients. Many older
side effects of this class, GLP-1 receptor instrumental support networks (e.g., patients with type 1 diabetes require
agonists may not be preferred in older adult children, caretakers) that pro- placement in long-term care (LTC) settings
patients who are experiencing unex- vide instrumental or emotional sup- (i.e., nursing homes and skilled nursing
plained weight loss. port for older adults with diabetes facilities) and, unfortunately, these pa-
should be included in diabetes manage- tients encounter providers that are un-
Sodium–Glucose Cotransporter ment discussions and shared decision- familiar with insulin pumps or CGM. Some
2 Inhibitors making. providers may be unaware of the distinc-
Sodium–glucose cotransporter 2 inhibi- Older adults in assisted living facilities tion between type 1 and type 2 diabetes. In
tors are administered orally, which may may not have support to administer these instances, the patient or the patient’s
care.diabetesjournals.org Older Adults S159
family may be more familiar with di- inadvertently lead to decreased food (16.7 mmol/L) over 2 consecutive
abetes management than the providers. intake and contribute to unintentional days,
Education of relevant support staff and weight loss and undernutrition. Diets d) any reading is too high for the
providers in rehabilitation and LTC set- tailored to a patient’s culture, preferen- glucometer, or
tings regarding insulin dosing and use of ces, and personal goals may increase e) the patient is sick, with vomiting,
pumps and CGM is recommended as quality of life, satisfaction with meals, symptomatic hyperglycemia, or
part of general diabetes education (see and nutrition status (72). It may be help- poor oral intake.
recommendations 12.15 and 12.16). ful to give insulin after meals to ensure
that the dose is appropriate for the END-OF-LIFE CARE
TREATMENT IN SKILLED NURSING amount of carbohydrate the patient
Recommendations
FACILITIES AND NURSING HOMES consumed in the meal.
12.17 When palliative care is needed
Recommendations in older adults with diabetes,
12.15 Consider diabetes education Hypoglycemia providers should initiate con-
for the staff of long-term care Older adults with diabetes in LTC are versations regarding the goals
and rehabilitation facilities especially vulnerable to hypoglycemia. and intensity of care. Strict
to improve the management They have a disproportionately high glucose and blood pressure
of older adults with diabetes. number of clinical complications and control may not be necessary
E comorbidities that can increase hypogly- E, and reduction of therapy
12.16 Patients with diabetes residing cemia risk: impaired cognitive and renal may be appropriate. Similarly,
in long-term care facilities function, slowed hormonal regulation the intensity of lipid manage-
need careful assessment to and counterregulation, suboptimal hy- ment can be relaxed, and
establish individualized glyce- dration, variable appetite and nutri- withdrawal of lipid-lowering
mic goals and to make tional intake, polypharmacy, and slowed therapy may be appropriate. A
appropriate choices of glucose- intestinal absorption (73). Oral agents 12.18 Overall comfort, prevention
lowering agents based on their may achieve similar glycemic out- of distressing symptoms, and
clinical and functional status. E comes in LTC populations as basal insu- preservation of quality of life
lin (50,74). and dignity are primary goals
Management of diabetes in the LTC Another consideration for the LTC for diabetes management at
setting is unique. Individualization of setting is that, unlike in the hospital the end of life. C
health care is important in all patients; setting, medical providers are not re-
however, practical guidance is needed quired to evaluate the patients daily.
for medical providers as well as the LTC According to federal guidelines, assess- The management of the older adult
staff and caregivers (70). Training should ments should be done at least every at the end of life receiving palliative
include diabetes detection and institu- 30 days for the first 90 days after ad- medicine or hospice care is a unique
tional quality assessment. LTC facilities mission and then at least once every situation. Overall, palliative medicine
should develop their own policies and 60 days. Although in practice the patients promotes comfort, symptom control
procedures for prevention and manage- may actually be seen more frequently, and prevention (pain, hypoglycemia,
ment of hypoglycemia. the concern is that patients may have hyperglycemia, and dehydration), and
uncontrolled glucose levels or wide ex- preservation of dignity and quality of life
cursions without the practitioner being in patients with limited life expectancy
Resources notified. Providers may make adjust- (71,75). In the setting of palliative care,
Staff of LTC facilities should receive ap- ments to treatment regimens by tele- providers should initiate conversations
propriate diabetes education to improve phone, fax, or in person directly at the regarding the goals and intensity of
the management of older adults with LTC facilities provided they are given diabetes care; strict glucose and blood
diabetes. Treatments for each patient timely notification of blood glucose man- pressure control may not be consistent
should be individualized. Special man- agement issues from a standardized with achieving comfort and quality of
agement considerations include the alert system. life. In a multicenter trial, withdrawal of
need to avoid both hypoglycemia and The following alert strategy could be statins among patients in palliative care
the complications of hyperglycemia considered: has been found to improve quality of
(2,71). For more information, see the life, while similar evidence for glucose
ADA position statement “Management 1. Call provider immediately in cases of and blood pressure control are not yet
of Diabetes in Long-term Care and Skilled low blood glucose levels (,70 mg/dL available (76–78). A patient has the
Nursing Facilities” (70). [3.9 mmol/L]). right to refuse testing and treatment,
2. Call as soon as possible when whereas providers may consider with-
Nutritional Considerations a) glucose values are 70–100 mg/dL drawing treatment and limiting diag-
An older adult residing in an LTC facility (3.9 and 5.6 mmol/L) (regimen nostic testing, including a reduction
may have irregular and unpredictable may need to be adjusted), in the frequency of fingerstick testing
meal consumption, undernutrition, an- b) glucose values are .250 mg/dL (79,80). Glucose targets should aim
orexia, and impaired swallowing. Fur- (13.9 mmol/L) within a 24-h period, to prevent hypoglycemia and hyperglyce-
thermore, therapeutic diets may c) glucose values are .300 mg/dL mia. Treatment interventions need to be
S160 Older Adults Diabetes Care Volume 43, Supplement 1, January 2020
mindful of quality of life. Careful mon- from https://www.niddk.nih.gov/about-niddk/ MIND randomised trial. Diabetologia 2017;60:
itoring of oral intake is warranted. The strategic-plans-reports/diabetes-in-america-3rd- 69–80
edition 17. Ghezzi L, Scarpini E, Galimberti D. Disease-
decision process may need to involve 2. Kirkman MS, Briscoe VJ, Clark N, et al. Di- modifying drugs in Alzheimer’s disease. Drug Des
the patient, family, and caregivers, abetes in older adults. Diabetes Care 2012;35: Devel Ther 2013;7:1471–1478
leading to a care plan that is both 2650–2664 18. Craft S, Baker LD, Montine TJ, et al. Intranasal
convenient and effective for the goals 3. Young-Hyman D, de Groot M, Hill-Briggs F, insulin therapy for Alzheimer disease and am-
of care (81). The pharmacologic therapy Gonzalez JS, Hood K, Peyrot M. Psychosocial care nestic mild cognitive impairment: a pilot clinical
for people with diabetes: a position statement trial. Arch Neurol 2012;69:29–38
may include oral agents as first line, of the American Diabetes Association. Diabetes 19. Freiherr J, Hallschmid M, Frey WH 2nd, et al.
followed by a simplified insulin regi- Care 2016;39:2126–2140 Intranasal insulin as a treatment for Alzheimer’s
men. If needed, basal insulin can be 4. Institute of Medicine of the National Acad- disease: a review of basic research and clinical
implemented, accompanied by oral emies. Cognitive Aging: Progress in Understand- evidence. CNS Drugs 2013;27:505–514
ing and Opportunities for Action, 2015. Accessed 20. Alagiakrishnan K, Sankaralingam S, Ghosh M,
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their methodological characteristics and of the 81. Mallery LH, Ransom T, Steeves B, Cook B, 83. Leung E, Wongrakpanich S, Munshi MN.
quality of their reporting. BMC Palliat Care 2017; Dunbar P, Moorhouse P. Evidence-informed guide- Diabetes management in the elderly. Diabetes
16:10 lines for treating frail older adults with type 2 Spectr 2018;31:245–253
Diabetes Care Volume 43, Supplement 1, January 2020 S163
The management of diabetes in children and adolescents cannot simply be derived from
care routinely provided to adults with diabetes. The epidemiology, pathophysiology,
developmental considerations, and response to therapy in pediatric-onset diabetes
are different from adult diabetes. There are also differences in recommended care
for children and adolescents with type 1 as opposed to type 2 diabetes. This section
first addresses care for children and adolescents with type 1 diabetes and next addresses
care for children and adolescents with type 2 diabetes. Figure 13.1 provides guidance
on managing new-onset diabetes in youth with overweight or obesity before type 1
or type 2 diabetes is diagnosed and so applies to all youth with overweight or obesity.
Lastly, guidance is provided in this section on transition of care from pediatric to
adult providers to ensure that the continuum of care is appropriate as the child
with diabetes develops into adulthood. Due to the nature of clinical research in children,
the recommendations for children and adolescents with diabetes are less likely
to be based on clinical trial evidence. However, expert opinion and a review of
available and relevant experimental data are summarized in the American Diabetes
Association (ADA) position statements “Type 1 Diabetes in Children and Adoles-
cents” (1) and “Evaluation and Management of Youth-Onset Type 2 Diabetes” (2).
The ADA consensus report “Youth-Onset Type 2 Diabetes Consensus Report: Current
Status, Challenges, and Priorities” (3) characterizes type 2 diabetes in children and evalu-
ates treatment options but also discusses knowledge gaps and recruitment
Suggested citation: American Diabetes Associa-
challenges in clinical and translational research in youth-onset type 2 diabetes.
tion. 13. Children and adolescents: Standards of
Monogenic diabetes (neonatal diabetes and maturity-onset diabetes in the young Medical Care in Diabetesd2020. Diabetes Care
[MODY]), which often present in youth, are discussed in section 2 “Classification and 2020;43(Suppl. 1):S163–S182
Diagnosis of Diabetes” (https://doi.org/10.2337/dc20-S002). © 2019 by the American Diabetes Association.
Readers may use this article as long as the work
TYPE 1 DIABETES is properly cited, the use is educational and not
for profit, and the work is not altered. More infor-
Type 1 diabetes is the most common form of diabetes in youth (4), although mation is available at http://www.diabetesjournals
recent data suggest that it may account for a large proportion of cases diagnosed in .org/content/license.
S164 Children and Adolescents Diabetes Care Volume 43, Supplement 1, January 2020
adult life (5). The provider must consider diabetes management throughout child- Physical Activity and Exercise
the unique aspects of care and manage- hood and adolescence. Health care
Recommendations
ment of children and adolescents with providers in the diabetes care team
13.5 Exercise is recommended for all
type 1 diabetes, such as changes in insu- who care for children and adolescents
youth with type 1 diabetes with
lin sensitivity related to physical growth must be capable of evaluating the edu-
the goal of 60 min of moderate-
and sexual maturation, ability to pro- cational, behavioral, emotional, and
to-vigorous intensity aerobic
vide self-care, supervision in the childcare psychosocial factors that impact imple-
activity daily, with vigorous
and school environment, neurological mentation of a treatment plan and must
muscle-strengthening and bone-
vulnerability to hypoglycemia and hy- work with the individual and family to
strengthening activities at least
perglycemia in young children, and pos- overcome barriers or redefine goals as
3 days per week. C
sible adverse neurocognitive effects of appropriate. Diabetes self-management
13.6 Education about frequent pat-
diabetic ketoacidosis (DKA) (6,7). Atten- education and support requires peri-
terns of glycemia during and
tion to family dynamics, developmental odic reassessment, especially as the
after exercise, which may in-
stages, and physiologic differences re- youth grows, develops, and acquires the
clude initial transient hyperglyce-
lated to sexual maturity is essential in need for greater independent self-care
mia followed by hypoglycemia,
skills. In addition, it is necessary to as-
developing and implementing an optimal is essential. Families should
sess the educational needs and skills of
diabetes treatment plan (8). also receive education on pre-
day care providers, school nurses, or other
A multidisciplinary team of special- vention and management of
school personnel who participate in the
ists trained in pediatric diabetes man- hypoglycemia during and after
care of the child with diabetes (9).
agement and sensitive to the challenges exercise, including ensuring
of children and adolescents with type patients have a preexercise glu-
1 diabetes and their families should Nutrition Therapy cose level of 90–250 mg/dL (5.0–
provide care for this population. It is 13.9 mmol/L) and accessible
Recommendations
essential that diabetes self-management carbohydrates before engaging
13.2 Individualized medical nutrition
education and support, medical nutri- in activity, individualized accord-
therapy is recommended for
tion therapy, and psychosocial support ing to the type/intensity of the
children and adolescents with
be provided at diagnosis and regularly planned physical activity. E
type 1 diabetes as an essential
thereafter in a developmentally appro- 13.7 Patients should be educated on
component of the overall treat-
priate format that builds on prior knowl- strategies to prevent hypoglyce-
ment plan. A
edge by individuals experienced with the mia during exercise, after exercise,
13.3 Monitoring carbohydrate in-
biological, educational, nutritional, be- and overnight following exercise,
take, whether by carbohydrate
havioral, and emotional needs of the which may include reducing pran-
counting or experience-based
growing child and family. The appropri- dial insulin dosing for the meal/
estimation, is key to achieving
ate balance between adult supervision snack preceding (and, if needed,
optimal glycemic control. B
and independent self-care should be de- following) exercise, reducing basal
13.4 Comprehensive nutrition edu-
fined at the first interaction and reeval- insulin doses, increasing carbohy-
cation at diagnosis, with annual
uated at subsequent visits, with the drate intake, eating bedtime
updates, by an experienced reg-
expectation that it will evolve as the snacks, and/or using continuous
istered dietitian nutritionist is
adolescent gradually becomes an emerg- glucose monitoring. C
recommended to assess caloric
ing young adult. 13.8 Frequent glucose monitoring
and nutrition intake in relation
before, during, and after exer-
Diabetes Self-Management Education to weight status and cardiovas-
cise, with or without use of
and Support cular disease risk factors and to
continuous glucose monitoring,
inform macronutrient choices. E
Recommendation is important to prevent, detect,
13.1 Youth with type 1 diabetes and and treat hypoglycemia and hy-
Dietary management should be individ-
parents/caregivers (for patients perglycemia with exercise. C
ualized: family habits, food preferences,
aged ,18 years) should receive religious or cultural needs, finances,
culturally sensitive and develop- schedules, physical activity, and the pa- Exercise positively affects insulin sensitivity,
mentally appropriate individual- tient’s and family’s abilities in numeracy, physical fitness, strength building, weight
ized diabetes self-management literacy, and self-management should be management, social interaction, mood,
education and support according considered. Visits with a registered di- self-esteem building, and creation of
to national standards at diagno- etitian nutritionist should include assess- healthful habits for adulthood, but it
sis and routinely thereafter. B ment for changes in food preferences also has the potential to cause both
over time, access to food, growth and hypoglycemia and hyperglycemia.
No matter how sound the medical reg- development, weight status, cardiovas- See below for strategies to mitigate
imen, it can only be effective if the cular risk, and potential for eating dis- hypoglycemia risk and minimize hyper-
family and/or affected individuals are orders. Dietary adherence is associated glycemia with exercise. For an in-depth
able to implement it. Family involve- with better glycemic control in youth discussion, see recently published re-
ment is a vital component of optimal with type 1 diabetes (10). views and guidelines (11–13).
care.diabetesjournals.org Children and Adolescents S165
information on the use of blood glucose continuous glucose monitors are not other autoimmune conditions, such as
meters, continuous glucose monitors, and currently approved for use in children Addison disease (primary adrenal insuf-
insulin pumps. More information on in- and adolescents. A strong relationship ficiency), autoimmune hepatitis, autoim-
sulin injection technique can be found exists between frequency of blood glu- mune gastritis, dermatomyositis, and
in Section 9 “Pharmacologic Approaches cose monitoring and glycemic stability myasthenia gravis, occur more com-
to Glycemic Treatment (https://doi.org/ (77–86). Recent data with newer devi- monly in the population with type 1
10.2337/dc20-S009).” ces and insulins indicate that the risk of diabetes than in the general pediatric
The Diabetes Control and Complica- hypoglycemia with lower A1C is less than population and should be assessed and
tions Trial (DCCT), which did not enroll it was before (52,76,87–94). Some data monitored as clinically indicated. In ad-
children ,13 years of age, demonstrated suggest that there could be a threshold dition, relatives of patients should be
that near normalization of blood glucose where lower A1C is associated with more offered testing for islet autoantibodies
levels was more difficult to achieve in hypoglycemia (95,96); however, the con- through research studies (e.g., TrialNet)
adolescents than in adults. Nevertheless, fidence intervals were large, suggesting for early diagnosis of preclinical type 1
the increased use of basal-bolus regi- great variability. diabetes (stages 1 and 2).
mens, insulin pumps, frequent blood In selecting glycemic targets, the
glucose monitoring, goal setting, and long-term health benefits of achieving a Thyroid Disease
improved patient education in youth lower A1C should be balanced against
from infancy through adolescence has the risks of hypoglycemia and the de- Recommendations
been associated with more children velopmental burdens of intensive regi- 13.26 Consider testing children with
reaching the blood glucose targets rec- mens in children and youth. In addition, type 1 diabetes for antithyroid
ommended by ADA (55–58), particularly achieving lower A1C levels is likely fa- peroxidase and antithyroglob-
in patients of families in which both the cilitated by setting lower A1C targets ulin antibodies soon after
parents and the child with diabetes par- (51,97). Lower goals may be possible diagnosis. B
ticipate jointly to perform the required during the “honeymoon” phase of type 1 13.27 Measure thyroid-stimulating
diabetes-related tasks. Furthermore, diabetes. hormone concentrations at di-
studies documenting neurocognitive agnosis when clinically stable
Key Concepts in Setting Glycemic or soon after glycemic control
imaging differences related to hy-
Targets has been established. If nor-
perglycemia in children provide an-
c Targets should be individualized, and mal, suggest rechecking every
other motivation for lowering glycemic
lower targets may be reasonable based 1–2 years or sooner if the
targets (6).
on a benefit-risk assessment. patient has positive thyroid
Lower A1C in adolescence and young
c Blood glucose targets should be antibodies or develops symp-
adulthood is associated with lower risk
modified in children with frequent toms or signs suggestive of
and rate of microvascular and macro-
hypoglycemia or hypoglycemia un- thyroid dysfunction, thyrome-
vascular complications, as shown in stud-
awareness. galy, an abnormal growth rate,
ies in youth (59–62) and in studies that
c Postprandial blood glucose values or unexplained glycemic vari-
include youth and adults and demon-
should be measured when there is ability. B
strate the effects of metabolic memory
a discrepancy between preprandial
(63–66).
blood glucose values and A1C levels
In addition, type 1 diabetes can be Autoimmune thyroid disease is the
and to assess preprandial insulin
associated with adverse effects on cog- most common autoimmune disorder
doses in those on basal-bolus or pump
nition during childhood and adoles- associated with diabetes, occurring in
regimens.
cence (6,67,68). DKA has been shown 17–30% of patients with type 1 diabetes
to cause adverse effects on brain de-
Autoimmune Conditions (99,103,104). At the time of diagnosis,
velopment and function. Additional fac-
;25% of children with type 1 diabe-
tors (69–72) that contribute to adverse Recommendation
tes have thyroid autoantibodies (105);
effects on brain development and func- 13.25 Assess for additional autoim-
their presence is predictive of thyroid
tion include young age, severe hypo- mune conditions soon after
dysfunctiondmost commonly hypo-
glycemia at ,6 years of age, and chronic the diagnosis of type 1 diabe-
hyperglycemia (73,74). However, me- thyroidism, although hyperthyroid-
tes and if symptoms develop. B
ticulous use of new therapeutic modal- ism occurs in ;0.5% of patients with
ities such as rapid- and long-acting Because of the increased frequency of type 1 diabetes (106,107). For thyroid
insulin analogs, technological advances other autoimmune diseases in type 1 autoantibodies, a study from Sweden
(e.g., continuous glucose monitors, low- diabetes, screening for thyroid dysfunc- indicated that antithyroid peroxidase
glucose suspend insulin pumps, and tion and celiac disease should be con- antibodies were more predictive than
automated insulin delivery systems), and sidered (98–102). Periodic screening in antithyroglobulin antibodies in multi-
intensive self-management education asymptomatic individuals has been rec- variate analysis (108). Thyroid function
now make it more feasible to achieve ommended, but the optimal frequency tests may be misleading (euthyroid sick
excellent glycemic control while reduc- of screening is unclear. syndrome) if performed at the time of
ing the incidence of severe hypoglyce- Although much less common than diagnosis owing to the effect of previous
mia (75–84). Intermittently scanned thyroid dysfunction and celiac disease, hyperglycemia, ketosis or ketoacidosis,
S168 Children and Adolescents Diabetes Care Volume 43, Supplement 1, January 2020
weight loss, etc. Therefore, if performed IgA deficiency, screening can include Management of Cardiovascular Risk
at diagnosis and slightly abnormal, thy- measuring IgG tissue transglutaminase Factors
roid function tests should be repeated antibodies or IgG deamidated gliadin Hypertension Screening
soon after a period of metabolic stability peptide antibodies. Because most cases
Recommendations
and achievement of glycemic targets. of celiac disease are diagnosed within
13.31 Blood pressure should be mea-
Subclinical hypothyroidism may be the first 5 years after the diagnosis of
sured at each routine visit. Chil-
associated with increased risk of symp- type 1 diabetes, screening should be
dren found to have elevated
tomatic hypoglycemia (109) and reduced considered at the time of diagnosis and
blood pressure (systolic blood
linear growth rate. Hyperthyroidism repeated at 2 and then 5 years (112) or
pressure or diastolic blood
if clinical symptoms indicate, such as
alters glucose metabolism and usu- pressure $90th percentile for
poor growth or increased hypoglycemia
ally causes deterioration of glycemic age, sex, and height or, in
(113,115).
control. adolescents $13 years, systolic
Although celiac disease can be di-
blood pressure 120–129 mmHg
agnosed more than 10 years after di-
Celiac Disease with diastolic blood pressure
abetes diagnosis, there are insufficient
,80 mmHg) or hypertension
Recommendations data after 5 years to determine the
(systolic blood pressure or di-
13.28 Screen children with type 1 optimal screening frequency. Measure-
astolic blood pressure $95th
diabetes for celiac disease by ment of tissue transglutaminase anti-
percentile for age, sex, and
measuring IgA tissue transglu- body should be considered at other
height or, in adolescents $13
taminase (tTG) antibodies, times in patients with symptoms sug-
years, systolic blood pressure
with documentation of normal gestive of celiac disease (112). Moni-
$130 mmHg or diastolic blood
total serum IgA levels, soon toring for symptoms should include
pressure $80 mmHg) should
after the diagnosis of diabetes, assessment of linear growth and weight
have elevated blood pressure
or IgG to tTG and deamida- gain (113,115). A small bowel biopsy
confirmed on three separate
ted gliadin antibodies if IgA in antibody-positive children is recom-
days. B
deficient. B mended to confirm the diagnosis (119).
13.29 Repeat screening within European guidelines on screening for
2 years of diabetes diagno- celiac disease in children (not specific to Hypertension Treatment
sis and then again after children with type 1 diabetes) suggest
Recommendations
5 years and consider more that biopsy may not be necessary in
symptomatic children with high anti- 13.32 Initial treatment of elevated
frequent screening in chil- blood pressure (systolic blood
dren who have symptoms body titers (i.e., greater than 10 times
the upper limit of normal) provided that pressure or diastolic blood
or a first-degree relative with pressure consistently $90th
celiac disease. B further testing is performed (verifica-
tion of endomysial antibody positivity percentile for age, sex, and
13.30 Individuals with biopsy- height or $120/80 mmHg in
confirmed celiac disease should on a separate blood sample). Whether
this approach may be appropriate adolescents $13 years) in-
be placed on a gluten-free cludes dietary modification
diet for treatment and to avoid for asymptomatic children in high-
risk groups remains an open question, and increased exercise, if ap-
complications; they should also propriate, aimed at weight
have a consultation with a die- though evidence is emerging (120).
It is also advisable to check for celiac control. If target blood pres-
titian experienced in manag- sure is not reached within 3–
ing both diabetes and celiac disease–associated HLA types in pa-
tients who are diagnosed without a 6 months of initiating lifestyle
disease. B intervention, pharmacologic
small intestinal biopsy. In symptomatic
children with type 1 diabetes and con- treatment should be consid-
Celiac disease is an immune-mediated ered. E
firmed celiac disease, gluten-free diets
disorder that occurs with increased fre- 13.33 In addition to lifestyle modifi-
reduce symptoms and rates of hypogly-
quency in patients with type 1 diabe- cation, pharmacologic treat-
cemia (121).The challenging dietary re-
tes (1.6–16.4% of individuals compared strictions associated with having both ment of hypertension (systolic
with 0.3–1% in the general population) type 1 diabetes and celiac disease blood pressure or diastolic blood
(98,101,102,110–114). Screening pa- place a significant burden on individuals. pressure consistently $95th per-
tients with type 1 diabetes for celiac Therefore, a biopsy to confirm the di- centile for age, sex, and height or
disease is further justified by its associ- agnosis of celiac disease is recommen- $140/90 mmHg in adolescents
ation with osteoporosis, iron deficiency, ded, especially in asymptomatic children, $13 years) should be considered
growth failure, and potential increased before establishing a diagnosis of celiac as soon as hypertension is con-
risk of retinopathy and albuminuria disease (122) and endorsing significant firmed. E
(115–118). dietary changes. A gluten-free diet was 13.34 ACE inhibitors or angioten-
Screening for celiac disease includes beneficial in asymptomatic adults with sin receptor blockers should
measuring serum levels of IgA and tissue positive antibodies confirmed by biopsy be considered for the initial
transglutaminase antibodies, or, with (123). pharmacologic treatment of
care.diabetesjournals.org Children and Adolescents S169
type 2 diabetes, lifestyle inter- 13.61 A1C targets for patients on carcinoma or multiple endo-
vention should be based on insulin should be individual- crine neoplasia type 2. A
a chronic care model and of- ized, taking into account the 13.68 Patients treated with basal in-
fered in the context of diabe- relatively low rates of hypogly- sulin up to 1.5 units/kg/day
tes care. E cemia in youth-onset type 2 who do not meet A1C target
13.55 Youth with diabetes, like all diabetes. E should be moved to multiple
children, should be encouraged daily injections with basal and
to participate in at least 30–60 Pharmacologic Management premeal bolus insulins. E
min of moderate-to-vigorous 13.69 In patients initially treated with
Recommendations
physical activity at least 5 days insulin and metformin who are
13.62 Initiate pharmacologic therapy,
per week (and strength train- meeting glucose targets based
in addition to lifestyle therapy,
ing on at least 3 days/week) B on home blood glucose moni-
at diagnosis of type 2 diabetes.
and to decrease sedentary be- toring, insulin can be tapered
A
havior. C over 2–6 weeks by decreasing
13.63 In incidentally diagnosed or
13.56 Nutrition for youth with type the insulin dose 10–30% every
metabolically stable patients
2 diabetes, like for all chil- few days. B
(A1C ,8.5% [69 mmol/mol] and
dren, should focus on healthy 13.70 Use of medications not ap-
asymptomatic), metforminis the
eating patterns that empha- proved by the U.S. Food and
initial pharmacologic treatment
size consumption of nutrient- Drug Administration for youth
of choice if renal function is
dense, high-quality foods and with type 2 diabetes is not
normal. A
decreased consumption of cal- recommended outside of re-
13.64 Youth with marked hypergly-
orie-dense, nutrient-poor foods, search trials. B
cemia (blood glucose $250
particularly sugar-added bever-
mg/dL [13.9 mmol/L], A1C
ages. B Treatment of youth-onset type 2 diabe-
$8.5% [69 mmol/mol]) with-
out acidosis at diagnosis who tes should include lifestyle management,
Glycemic Targets are symptomatic with polyuria, diabetes self-management education,
polydipsia, nocturia, and/or and pharmacologic treatment. Initial
Recommendations
weight loss should be treated treatment of youth with obesity and
13.57 Home self-monitoring of blood
initially with basal insulin while diabetes must take into account that
glucose regimens should be in-
metformin is initiated and ti- diabetes type is often uncertain in the
dividualized, taking into consid-
trated. B first few weeks of treatment, due to
eration the pharmacologic
13.65 In patients with ketosis/ overlap in presentation, and that a sub-
treatment of the patient. E
ketoacidosis, treatment with stantial percentage of youth with type 2
13.58 A1C should be measured every
subcutaneous or intravenous diabetes will present with clinically sig-
3 months. E
insulin should be initiated to nificant ketoacidosis (180). Therefore,
13.59 A reasonable A1C target for
rapidly correct the hypergly- initial therapy should address the hyper-
most children and adolescents
cemia and the metabolic de- glycemia and associated metabolic de-
with type 2 diabetes treated
rangement. Once acidosis is rangements irrespective of ultimate
with oral agents alone is
resolved, metformin should be diabetes type, with adjustment of ther-
,7% (53 mmol/mol). More
initiated while subcutane- apy once metabolic compensation has
stringent A1C targets (such
ous insulin therapy is contin- been established and subsequent infor-
as ,6.5% [48 mmol/mol])
ued. A mation, such as islet autoantibody results,
may be appropriate for se-
13.66 In individuals presenting with becomes available. Figure 13.1 provides
lected individual patients if
severe hyperglycemia (blood an approach to initial treatment of new-
they can be achieved without
significant hypoglycemia or glucose $600 mg/dL [33.3 onset diabetes in youth with overweight
mmol/L]), consider assessment or obesity.
other adverse effects of treat-
for hyperglycemic hyperosmo- Glycemic targets should be individu-
ment.Appropriatepatientsmight
lar nonketotic syndrome. A alized, taking into consideration long-
include those with short dura-
13.67 If glycemic targets are no term health benefits of more stringent
tion of diabetes and lesser
longer met with metformin targets and risk for adverse effects,
degrees of b-cell dysfunction
(with or without basal insu- such as hypoglycemia. A lower target
and patients treated with life-
lin), liraglutide (a glucagon-like A1C in youth with type 2 diabetes when
style or metformin only who
peptide 1 receptor agonist) compared with those recommended
achieve significant weight im-
therapy should be considered in type 1 diabetes is justified by lower
provement. E
in children 10 years of age or risk of hypoglycemia and higher risk of
13.60 Less-stringent A1C goals (such
older if they have no past complications (181–184).
as 7.5% [58 mmol/mol]) may
Patients and their families must pri-
be appropriate if there is in- medical history or family his-
oritize lifestyle modifications such
creased risk of hypoglycemia. E tory of medullary thyroid
as eating a balanced diet, achieving
care.diabetesjournals.org Children and Adolescents S173
Figure 13.1—Management of new-onset diabetes in youth with overweight or obesity. A1C 8.5% 5 69 mmol/mol. Adapted from the ADA position
statement “Evaluation and Management of Youth-Onset Type 2 Diabetes” (2). DKA, diabetic ketoacidosis; HHNK, hyperosmolar hyperglycemic
nonketotic syndrome; MDI, multiple daily injections.
and maintaining a healthy weight, and (185–187), initial treatment must include recommended. The Treatment Options
exercising regularly. A family-centered management of comorbidities such as for Type 2 Diabetes in Adolescents and
approach to nutrition and lifestyle obesity, dyslipidemia, hypertension, and Youth (TODAY) study found that metfor-
modification is essential in children microvascular complications. min alone provided durable glycemic
with type 2 diabetes, and nutrition rec- Current pharmacologic treatment op- control (A1C #8% [64 mmol/mol] for
ommendations should be culturally ap- tions for youth-onset type 2 diabetes 6 months) in approximately half of the
propriate and sensitive to family are limited to three approved drugsd subjects (189). The RISE Consortium
resources (see Section 5 “Facilitating insulin, metformin, and liraglutide (2). study did not demonstrate differences
Behavior Change and Well-being to Im- Presentation with ketoacidosis or marked in measures of glucose or b-cell function
prove Health Outcomes,” https://doi ketosis requires a period of insulin ther- preservation between metformin and
.org/10.2337/dc20-S005). Given the com- apy until fasting and postprandial glyce- insulin, but there was more weight gain
plex social and environmental context mia have been restored to normal or with insulin (190).
surrounding youth with type 2 diabetes, near-normal levels. Metformin therapy To date, the TODAY study is the only
individual-level lifestyle interventions may may be used as an adjunct after resolu- trial combining lifestyle and metformin
not be sufficient to target the complex tion of ketosis/ketoacidosis. Initial treat- therapy in youth with type 2 diabetes;
interplay of family dynamics, mental health, ment should also be with insulin when the combination did not perform better
community readiness, and the broader the distinction between type 1 diabetes than metformin alone in achieving du-
environmental system (2). and type 2 diabetes is unclear and in rable glycemic control (189).
A multidisciplinary diabetes team, patients who have random blood glu- A recent randomized clinical trial in
including a physician, diabetes nurse cose concentrations $250 mg/dL (13.9 children aged 10–17 years with type 2
educator, registered dietitian, and psy- mmol/L) and/or A1C $8.5% (69 mmol/mol) diabetes demonstrated the addition of
chologist or social worker, is essential. (188). subcutaneous liraglutide (up to 1.8 mg
In addition to achieving glycemic tar- When insulin treatment is not daily) to metformin (with or without
gets and self-management education required, initiation of metformin is basal insulin) as safe and effective to
S174 Children and Adolescents Diabetes Care Volume 43, Supplement 1, January 2020
Most youth with type 2 diabetes come Care and close supervision of diabetes
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Diabetes Care Volume 43, Supplement 1, January 2020 S183
DIABETES IN PREGNANCY
The prevalence of diabetes in pregnancy has been increasing in the U.S. in parallel with
the worldwide epidemic of obesity. Not only is the prevalence of type 1 diabetes and
type 2 diabetes increasing in women of reproductive age, but there is also a dramatic
increase in the reported rates of gestational diabetes mellitus. Diabetes confers
significantly greater maternal and fetal risk largely related to the degree of
hyperglycemia but also related to chronic complications and comorbidities of
diabetes. In general, specific risks of diabetes in pregnancy include spontaneous
abortion, fetal anomalies, preeclampsia, fetal demise, macrosomia, neonatal hypo-
glycemia, hyperbilirubinemia, and neonatal respiratory distress syndrome, among
others. In addition, diabetes in pregnancy may increase the risk of obesity,
hypertension, and type 2 diabetes in offspring later in life (1,2).
PRECONCEPTION COUNSELING
Recommendations
14.1 Starting at puberty and continuing in all women with diabetes and re-
productive potential, preconception counseling should be incorporated into
routine diabetes care. A
14.2 Family planning should be discussed, and effective contraception (with consid-
eration of long-acting, reversible contraception) should be prescribed and used Suggested citation: American Diabetes Associa-
until a woman’s treatment regimen and A1C are optimized for pregnancy. A tion. 14. Management of diabetes in pregnancy:
14.3 Preconception counseling should address the importance of achieving Standards of Medical Care in Diabetesd2020.
glucose levels as close to normal as is safely possible, ideally Diabetes Care 2020;43(Suppl. 1):S183-S192
A1C ,6.5% (48 mmol/mol), to reduce the risk of congenital anomalies, © 2019 by the American Diabetes Association.
preeclampsia, macrosomia, and other complications. B Readers may use this article as long as the work
is properly cited, the use is educational and not
for profit, and the work is not altered. More infor-
All women of childbearing age with diabetes should be informed about the mation is available at http://www.diabetesjournals
importance of achieving and maintaining as near euglycemia as safely possible prior .org/content/license.
S184 Management of Diabetes in Pregnancy Diabetes Care Volume 43, Supplement 1, January 2020
Table 14.1—Checklist for preconception care for women with diabetes (15,17)
Preconception education should include:
☐ Comprehensive nutrition assessment and recommendations for:
c Overweight/obesity or underweight
c Meal planning
c Correction of dietary nutritional deficiencies
c Caffeine intake
c Safe food preparation technique
☐ Lifestyle recommendations for:
c Regular moderate exercise
c Avoidance of hyperthermia (hot tubs)
c Adequate sleep
☐ Comprehensive diabetes self-management education
☐ Counseling on diabetes in pregnancy per current standards, including: natural history of insulin resistance in pregnancy and postpartum;
preconception glycemic targets; avoidance of DKA/severe hyperglycemia; avoidance of severe hypoglycemia; progression of retinopathy; PCOS
(if applicable); fertility in patients with diabetes; genetics of diabetes; risks to pregnancy including miscarriage, still birth, congenital
malformations, macrosomia, preterm labor and delivery, hypertensive disorders in pregnancy, etc.
☐ Supplementation
c Folic acid supplement (400 mg routine)
c Appropriate use of over-the-counter medications and supplements
in a given patient should be achieved between the woman and an RD/RDN fa-
medications lack long-term
without hypoglycemia, which, in addition miliar with the management of GDM
safety data.
to the usual adverse sequelae, may in- (50,51). The food plan should provide
14.15 Metformin, when used to treat
crease the risk of low birth weight (42). adequate calorie intake to promote
polycystic ovary syndrome and
Given the alteration in red blood cell fetal/neonatal and maternal health,
induce ovulation, should be
kinetics during pregnancy and physiolog- achieve glycemic goals, and promote
discontinued by the end of
ical changes in glycemic parameters, A1C weight gain according to 2009 Institute
the first trimester. A
levels may need to be monitored more of Medicine recommendations (52).
frequently than usual (e.g., monthly). There is no definitive research that
GDM is characterized by increased risk identifies a specific optimal calorie intake
Continuous Glucose Monitoring in of macrosomia and birth complications for women with GDM or suggests that
Pregnancy and an increased risk of maternal type 2 their calorie needs are different from
CONCEPTT (Continuous Glucose Moni- diabetes after pregnancy. The associa- those of pregnant women without
toring in Pregnant Women With Type 1 tion of macrosomia and birth complica- GDM. The food plan should be based
Diabetes Trial) was a randomized con- tions with oral glucose tolerance test on a nutrition assessment with guidance
trolled trial of continuous glucose mon- (OGTT) results is continuous with no from the Dietary Reference Intakes
itoring (CGM) in addition to standard clear inflection points (34). In other (DRI). The DRI for all pregnant women
care, including optimization of pre- words, risks increase with progressive recommends a minimum of 175 g of
and postprandial glucose targets versus hyperglycemia. Therefore, all women carbohydrate, a minimum of 71 g of
standard care for pregnant women with should be tested as outlined in Sec- protein, and 28 g of fiber. The diet should
type 1 diabetes. It demonstrated the tion 2 “Classification and Diagnosis of not be high in saturated fat. As is true
value of CGM in pregnancy complicated Diabetes” (https://doi.org/10.2337/dc20- for all nutrition therapy in patients with
by type 1 diabetes by showing a mild S002). Although there is some heteroge- diabetes, the amount and type of car-
improvement in A1C without an increase neity, many randomized controlled trials bohydrate will impact glucose levels.
in hypoglycemia and reductions in large- (RCTs) suggest that the risk of GDM may be Simple carbohydrates will result in higher
for-gestational-age births, length of stay, reduced by diet, exercise, and lifestyle postmeal excursions.
and neonatal hypoglycemia (43). An ob- counseling, particularly when interven-
servational cohort study that evaluated tions are started during the first or early Pharmacologic Therapy
in the second trimester (46–48). Treatment of GDM with lifestyle and
the glycemic variables reported using
insulin has been demonstrated to im-
CGM and their association with large-
Lifestyle Management prove perinatal outcomes in two large
for-gestational-age births found that
After diagnosis, treatment starts with randomized studies as summarized in a
mean glucose had a greater association
medical nutrition therapy, physical ac- U.S. Preventive Services Task Force re-
than time in range, time below range, or
tivity, and weight management depend- view (53). Insulin is the first-line agent
time above range (44). Using the CGM-
ing on pregestational weight, as outlined recommended for treatment of GDM in
reported mean glucose is superior to the
in the section below on preexisting type 2 the U.S. While individual RCTs support
use of estimated A1C, glucose manage-
diabetes, and glucose monitoring aiming limited efficacy of metformin (54,55) and
ment indicator, and other calculations
for the targets recommended by the Fifth glyburide (56) in reducing glucose levels
to estimate A1C given the changes to
International Workshop-Conference on for the treatment of GDM, these agents
A1C that occur in pregnancy (45).
Gestational Diabetes Mellitus (48): are not recommended as first-line treat-
ment for GDM because they are known to
MANAGEMENT OF GESTATIONAL c Fasting glucose ,95 mg/dL (5.3 cross the placenta and data on long-term
DIABETES MELLITUS mmol/L) and either safety for offspring is of some concern
Recommendations c One-hour postprandial glucose ,140 (32). Furthermore, glyburide and met-
14.13 Lifestyle behavior change is an mg/dL (7.8 mmol/L) or formin failed to provide adequate glyce-
essential component of man- c Two-hour postprandial glucose ,120 mic control in separate randomized
agement of gestational diabe- mg/dL (6.7 mmol/L) controlled trials, failing in 23% and
tes mellitus and may suffice for 25–28% of women with GDM, respec-
the treatment of many women. Depending on the population, studies tively (57,58).
Insulinshouldbeaddedifneeded suggest that 70–85% of women diag-
nosed with GDM under Carpenter- Sulfonylureas
to achieve glycemic targets. A
Coustan can control GDM with lifestyle Sulfonylureas are known to cross the
14.14 Insulin is the preferred medi-
modification alone; it is anticipated placenta and have been associated
cation for treating hyperglyce-
that this proportion will be even higher with increased neonatal hypoglycemia.
mia in gestational diabetes
if the lower International Association of Concentrations of glyburide in umbilical
mellitus. Metformin and gly-
Diabetes and Pregnancy Study Groups cord plasma are approximately 50–70%
buride should not be used as
of maternal levels (57,58). Glyburide
first-line agents, as both cross (49) diagnostic thresholds are used.
was associated with a higher rate of
the placenta to the fetus. A
Medical Nutrition Therapy neonatal hypoglycemia and macrosomia
Other oral and noninsulin
Medical nutrition therapy for GDM is an than insulin or metformin in a 2015 meta-
injectable glucose-lowering
individualized nutrition plan developed analysis and systematic review (59).
S188 Management of Diabetes in Pregnancy Diabetes Care Volume 43, Supplement 1, January 2020
More recently, glyburide failed to be cost, language barriers, comprehension, While many providers prefer insulin
found noninferior to insulin based on a or cultural influences, may not be able to pumps in pregnancy, it is not clear that
composite outcome of neonatal hypogly- use insulin safely or effectively in preg- they are superior to multiple daily
cemia, macrosomia, and hyperbilirubine- nancy. Oral agents may be an alternative injections (88–90). Closed-loop technol-
mia (60). Long-term safety data for in these women after a discussion of ogy that is U.S. Food and Drug Admin-
offspring exposed to glyburide are not the known risks and the need for more istration approved outside of pregnancy
available (60). long-term safety data in offspring. How- can only target a glucose of 120 mg/dL at
Metformin ever, due to the potential for growth this time, which is likely to be too high for
Metformin was associated with a lower restriction or acidosis in the setting optimal nocturnal control in pregnancy.
risk of neonatal hypoglycemia and less of placental insufficiency, metformin However, given potential benefits, on-
maternal weight gain than insulin in should not be used in women with hy- going work is being done in this area.
systematic reviews (59,61,62,65). How- pertension, preeclampsia, or at risk for
Type 1 Diabetes
ever, metformin readily crosses the pla- intrauterine growth restriction (78,79).
Women with type 1 diabetes have an
centa, resulting in umbilical cord blood Insulin increased risk of hypoglycemia in the first
levels of metformin as high or higher than Insulin use should follow the guidelines trimester and, like all women, have al-
simultaneous maternal levels (66,67). In below. Both multiple daily insulin injec- tered counterregulatory response in
the Metformin in Gestational Diabetes: tions and continuous subcutaneous in- pregnancy that may decrease hypogly-
The Offspring Follow-Up (MiG TOFU) sulin infusion are reasonable delivery cemia awareness. Education for patients
study’s analyses of 7- to 9-year-old off- strategies, and neither has been shown and family members about the preven-
spring, the 9-year-old offspring exposed to be superior to the other during preg- tion, recognition, and treatment of hy-
to metformin in the Auckland cohort for nancy (80). poglycemia is important before, during,
the treatment of GDM were heavier and and after pregnancy to help to prevent
had a higher waist-to-height ratio and MANAGEMENT OF PREEXISTING and manage the risks of hypoglycemia.
waist circumference than those exposed TYPE 1 DIABETES AND TYPE Insulin resistance drops rapidly with de-
to insulin (68). This was not found in the 2 DIABETES IN PREGNANCY livery of the placenta.
Adelaide cohort. In two RCTs of metfor- Insulin Use Pregnancy is a ketogenic state, and
min use in pregnancy for polycystic ovary women with type 1 diabetes, and to a
Recommendations
syndrome, follow-up of 4-year-old off- lesser extent those with type 2 diabetes,
14.16 Insulin is the preferred agent
spring demonstrated higher BMI and are at risk for diabetic ketoacidosis (DKA)
for management of both type 1
increased obesity in the offspring ex- at lower blood glucose levels than in the
diabetes and type 2 diabetes in
posed to metformin (69,70). A follow-up nonpregnant state. Women with type 1
pregnancy. E
study at 5–10 years showed that the diabetes should be prescribed ketone
14.17 Either multiple daily injections
offspring had higher BMI, weight-to- strips and receive education on diabetic
or insulin pump technology
height ratios, waist circumferences, ketoacidosis prevention and detection.
can be used in pregnancy com-
and a borderline increase in fat mass DKA carries a high risk of stillbirth.
plicated by type 1 diabetes. C
(70,71). Metformin is being studied in Women in DKA who are unable to eat
two ongoing trials in type 2 diabetes often require 10% dextrose with an in-
The physiology of pregnancy necessi-
(Metformin in Women with Type 2 Di- sulin drip to adequately meet the higher
tates frequent titration of insulin to
abetes in Pregnancy Trial [MiTY] [72] and carbohydrate demands of the placenta
match changing requirements and
Medical Optimization of Management of and fetus in the third trimester in order to
underscores the importance of daily
Type 2 Diabetes Complicating Pregnancy resolve their ketosis.
and frequent self-monitoring of blood
[MOMPOD] [73]), but long-term off- Retinopathy is a special concern in
glucose. Due to the complexity of insulin
spring data will not be available for pregnancy. Rapid implementation of eu-
management in pregnancy, referral to a
some time. A recent meta-analysis con- glycemia in the setting of retinopathy is
specialized center offering team-based
cluded that metformin exposure resulted associated with worsening of retinopa-
care (with team members including
in smaller neonates with acceleration of thy (21).
maternal-fetal medicine specialist, en-
postnatal growth resulting in higher BMI docrinologist, or other provider experi- Type 2 Diabetes
in childhood (68,69). enced in managing pregnancy in women Type 2 diabetes is often associated with
Randomized, double-blind, controlled with preexisting diabetes, dietitian, obesity. Recommended weight gain dur-
trials comparing metformin with other nurse, and social worker, as needed) ing pregnancy for overweight women is
therapies for ovulation induction in is recommended if this resource is 15–25 lb and for obese women is 10–20 lb
women with polycystic ovary syndrome available. (52). There is no adequate data on op-
have not demonstrated benefit in pre- None of the currently available human timal weight gain versus weight mainte-
venting spontaneous abortion or GDM insulin preparations have been demon- nance in women with a BMI .35 kg/m2.
(74), and there is no evidence-based strated to cross the placenta (80–86). A Glycemic control is often easier to
need to continue metformin in such recent Cochrane systematic review was achieve in women with type 2 diabetes
patients (75–77). not able to recommend any specific in- than in those with type 1 diabetes but
There are some women with GDM sulin regimen over another for the treat- can require much higher doses of insulin,
requiring medical therapy who, due to ment of diabetes in pregnancy (87). sometimes necessitating concentrated
care.diabetesjournals.org Management of Diabetes in Pregnancy S189
including both prediabetes and diabetes. following 1–2 weeks. In women taking pregnancy outcome in 933 women with type 1
Women of reproductive age with pre- insulin, particular attention should be diabetes. Diabetes Care 2009;32:1046–1048
5. Nielsen GL, Møller M, Sørensen HT. HbA1c in
diabetes may develop type 2 diabetes by directed to hypoglycemia prevention in
early diabetic pregnancy and pregnancy out-
the time of their next pregnancy and will the setting of breastfeeding and erratic comes: a Danish population-based cohort study
need preconception evaluation. Because sleep and eating schedules (111). of 573 pregnancies in women with type 1 di-
GDM is associated with an increased abetes. Diabetes Care 2006;29:2612–2616
lifetime maternal risk for diabetes esti- Lactation 6. Suhonen L, Hiilesmaa V, Teramo K. Glycaemic
control during early pregnancy and fetal
mated at 50–70% after 15–25 years In light of the immediate nutritional and malformations in women with type I diabetes
(103,104), women should also be tested immunological benefits of breastfeeding mellitus. Diabetologia 2000;43:79–82
every 1–3 years thereafter if the 4– for the baby, all women including those 7. Charron-Prochownik D, Sereika SM, Becker D,
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normal. Ongoing evaluation may be attempts to breastfeed. Breastfeeding READY-Girls preconception counseling program
on intentions and behaviors for family planning
performed with any recommended gly- may also confer longer-term metabolic in teens with diabetes. Diabetes Care 2013;36:
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ct2/show/NCT02932475 Eur J Obstet Gynecol Reprod Biol 2008;137:47–49 Diabetes Prevention Program Research Group.
74. Vanky E, Stridsklev S, Heimstad R, et al. 90. Feig DS, Corcoy R, Donovan LE, et al.; CON- Prevention of diabetes in women with a history
Metformin versus placebo from first trimester CEPTT Collaborative Group. Pumps or multiple daily of gestational diabetes: effects of metformin
to delivery in polycystic ovary syndrome: a ran- injections in pregnancy involving type 1 diabetes: and lifestyle interventions. J Clin Endocrinol
domized, controlled multicenter study. J Clin a prespecified analysis of the CONCEPTT random- Metab 2008;93:4774–4779
Endocrinol Metab 2010;95:E448–E455 ized trial. Diabetes Care 2018;41:2471–2479 108. Aroda VR, Christophi CA, Edelstein SL, et al.;
75. Legro RS, Barnhart HX, Schlaff WD, et al.; 91. Clausen TD, Mathiesen E, Ekbom P, Hellmuth Diabetes Prevention Program Research Group.
Cooperative Multicenter Reproductive Medi- E, Mandrup-Poulsen T, Damm P. Poor pregnancy The effect of lifestyle intervention and metfor-
cine Network. Clomiphene, metformin, or both outcome in women with type 2 diabetes. Di- min on preventing or delaying diabetes among
for infertility in the polycystic ovary syndrome. abetes Care 2005;28:323–328 women with and without gestational diabetes:
N Engl J Med 2007;356:551–566 92. Cundy T, Gamble G, Neale L, et al. Differing the Diabetes Prevention Program outcomes
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tive parallel randomized, double-blind, double- diabetes. Diabetes Care 2007;30:2603–2607 2015;100:1646–1653
dummy controlled clinical trial comparing 93. Duckitt K, Harrington D. Risk factors for pre- 109. Achong N, Duncan EL, McIntyre HD,
clomiphene citrate and metformin as the eclampsia at antenatal booking: systematic re- Callaway L. Peripartum management of glycemia
first-line treatment for ovulation induction view of controlled studies. BMJ 2005;330:565 in women with type 1 diabetes. Diabetes Care
in nonobese anovulatory women with poly- 94. Roberge S, Bujold E, Nicolaides KH. Aspirin 2014;37:364–371
cystic ovary syndrome. J Clin Endocrinol for the prevention of preterm and term pre- 110. Roeder HA, Moore TR, Ramos GA. Changes
Metab 2005;90:4068–4074 eclampsia: systematic review and metaanalysis. in postpartum insulin requirements for patients
77. Palomba S, Orio F Jr, Nardo LG, et al. Met- Am J Obstet Gynecol 2018;218:287–293.e1 with well-controlled type 1 diabetes. Am J Peri-
formin administration versus laparoscopic ovar- 95. Henderson JT, Whitlock EP, O’Conner E, natol 2016;33:683–687
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Metab 2004;89:4801–4809 Task Force, 2014. Rockville, MD, Agency for Manson JE, Michels KB. Duration of lactation and
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Diabetes Care Volume 43, Supplement 1, January 2020 S193
Initial orders should state the type of following hospitalization that has been and Diagnosis of Diabetes,” https://doi
diabetes (i.e., type 1, type 2, gestational attributed to diabetes can be reduced, .org/10.2337/dc20-S002) (2,25). Hypo-
diabetes mellitus, pancreatic diabetes) and costs saved, when inpatient care glycemia in hospitalized patients is cate-
when it is known. Because inpatient is provided by a specialized diabetes gorized by blood glucose concentration
treatment and discharge planning are management team (20,21). In a cross- and clinical correlates (Table 6.4) (26):
more effective if based on preadmission sectional comparison of usual care to Level 1 hypoglycemia is a glucose concen-
glycemia, an A1C should be measured on management by specialists who re- tration 54–70 mg/dL (3.0–3.9 mmol/L).
all patients with diabetes or hyperglyce- viewed cases and made recommenda- Level 2 hypoglycemia is a blood glucose
mia admitted to the hospital if the test tions solely through the electronic concentration ,54 mg/dL (3.0 mmol/L),
has not been performed in the previous medical record, rates of both hyper- which is typically the threshold for neuro-
3 months (7–10). In addition, diabetes and hypoglycemia were reduced 30– glycopenic symptoms. Level 3 hypoglyce-
self-management knowledge and behav- 40% by electronic “virtual care” (22). mia is a clinical event characterized by
iors should be assessed on admission Details of team formation are available altered mental and/or physical function-
and diabetes self-management educa- in The Joint Commission Standards for ing that requires assistance from another
tion provided, if appropriate. Diabetes programs and from the Society of Hos- person for recovery. Levels 2 and 3
self-management education should in- pital Medicine (23,24). require immediate correction of low
clude appropriate skills needed after Even the best orders may not be blood glucose.
discharge, such as medication dosing and carried out in a way that improves qual-
administration, glucose monitoring, and ity, nor are they automatically updated Glycemic Targets
recognition and treatment of hypogly- when new evidence arises. To this end, In a landmark clinical trial, Van den
cemia (2). There is evidence to support the Joint Commission has an accredita- Berghe et al. (27) demonstrated that
preadmission treatment of hyperglyce- tion program for the hospital care of an intensive intravenous insulin regimen
mia in patients scheduled for elective diabetes (23), and the Society of Hospital to reach a target glycemic range of 80–
surgery as an effective means of reducing Medicine has a workbook for program 110 mg/dL (4.4–6.1 mmol/L) reduced
adverse outcomes (11–13). development (24). mortality by 40% compared with a stan-
The National Academy of Medicine dard approach targeting blood glucose of
recommends CPOE to prevent medication- GLYCEMIC TARGETS IN 180–215 mg/dL (10–12 mmol/L) in crit-
related errors and to increase efficiency HOSPITALIZED PATIENTS ically ill patients with recent surgery (4).
in medication administration (14). A This study provided robust evidence that
Recommendations
Cochrane review of randomized con- active treatment to lower blood glucose
trolled trials using computerized advice 15.4 Insulin therapy should be initi- in hospitalized patients had immediate
to improve glucose control in the hospital ated for treatment of persistent benefits. However, a large, multicenter
found significant improvement in the hyperglycemia starting at a thresh- follow-up study, the Normoglycemia in
percentage of time patients spent in old $180 mg/dL (10.0 mmol/L). Intensive Care Evaluation and Survival
the target glucose range, lower mean Once insulin therapy is started, a Using Glucose Algorithm Regulation
blood glucose levels, and no increase in target glucose range of 140–180 (NICE-SUGAR) trial (28), led to a recon-
hypoglycemia (15). Thus, where feasible, mg/dL (7.8–10.0 mmol/L) is rec- sideration of the optimal target range for
there should be structured order sets ommended for the majority of glucose lowering in critical illness. In this
that provide computerized advice for critically ill patients and non- trial critically ill patients randomized
glucose control. Electronic insulin critically ill patients. A to intensive glycemic control (80–110
order templates also improve mean 15.5 More stringent goals, such as 110– mg/dL) derived no significant treatment
glucose levels without increasing hy- 140 mg/dL (6.1–7.8 mmol/L), advantage compared with a group with
poglycemia in patients with type 2 may be appropriate for selected more moderate glycemic targets (140–
diabetes, so structured insulin order patients if they can be achieved 180 mg/dL [7.8–10.0 mmol/L]) and in fact
sets should be incorporated into the without significant hypoglyce- had slightly but significantly higher mor-
CPOE (16,17). mia. C tality (27.5% vs. 25%). The intensively
treated group had 10- to 15-fold greater
Diabetes Care Providers in the Hospital
Standard Definitions of Glucose rates of hypoglycemia, which may have
Recommendation Abnormalities contributed to the adverse outcomes
15.3 When caring for hospitalized Hyperglycemia in hospitalized patients is noted. The findings from NICE-SUGAR
patients with diabetes, consult defined as blood glucose levels .140 are supported by several meta-analyses,
with a specialized diabetes or mg/dL (7.8 mmol/L) (2,25). Blood glu- some of which suggest that tight glyce-
glucose management team when cose levels persistently above this level mic control increases mortality com-
possible. C should prompt conservative interven- pared with more moderate glycemic
tions, such as alterations in diet or targets and generally causes higher rates
Appropriately trained specialists or spe- changes to medications that cause hy- of hypoglycemia (29–31). Based on these
cialty teams may reduce length of stay, perglycemia. An admission A1C value results, insulin therapy should be initi-
improve glycemic control, and improve $6.5% (48 mmol/mol) suggests that ated for treatment of persistent hyper-
outcomes (11,18,19). In addition, the the onset of diabetes preceded hospi- glycemia $180 mg/dL (10.0 mmol/L)
greater risk of 30-day readmission talization (see Section 2 “Classification and targeted to a glucose range of
care.diabetesjournals.org Diabetes Care in the Hospital S195
140–180 mg/dL (7.8–10.0 mmol/L) for Administration (FDA) has established GLUCOSE-LOWERING TREATMENT
the majority of critically ill patients (2). standards for capillary (fingerstick) blood IN HOSPITALIZED PATIENTS
Although not as well supported by data glucose meters used in the ambulatory Recommendations
from randomized controlled trials, these setting, as well as standards to be 15.6 Basal insulin or a basal plus bolus
recommendations have been extended applied for POC measures in the correction insulin regimen is the
to hospitalized patients without critical hospital (34). The balance between preferred treatment for noncriti-
illness. More stringent goals, such as analytic requirements (e.g., accuracy, cally ill hospitalized patients with
110–140 mg/dL (6.1–7.8 mmol/L), may precision, interference) and clinical re- poor oral intake or those who are
be appropriate for selected patients (e.g., quirements (rapidity, simplicity, point of taking nothing by mouth. A An
critically ill postsurgical patients or pa- care) has not been uniformly resolved insulin regimen with basal, pran-
tients with cardiac surgery), as long as (33,35), and most hospitals/medical dial, and correction components is
they can be achieved without significant centers have arrived at their own policies the preferred treatment for non-
hypoglycemia. On the other hand, glu- to balance these parameters. It is criti- critically ill hospitalized patients
cose concentrations .180 mg/dL (10 cally important that devices selected for with good nutritional intake. A
mmol/L) may be acceptable in terminally in-hospital use, and the work flow 15.7 Use of only a sliding scale insulin
ill patients, in patients with severe co- through which they are applied, have regimen in the inpatient hospi-
morbidities, and in inpatient care set- careful analysis of performance and re- tal setting is strongly discour-
tings where frequent glucose monitoring liability and ongoing quality assess- aged. A
or close nursing supervision is not fea- ments. Recent studies indicate that
sible. In these patients less aggressive POC measures provide adequate infor- In most instances, insulin is the preferred
insulin regimens to minimize glucosuria, mation for usual practice, with only rare treatment for hyperglycemia in hospital-
dehydration, and electrolyte disturban- instances where care has been com- ized patients (2). However, in certain
ces are often more appropriate. Clinical promised (36,37). Good practice dic- circumstances, it may be appropriate
judgment combined with ongoing as- tates that any glucose result that does to continue home regimens including
sessment of clinical status, including not correlate with the patient’s clinical oral glucose-lowering medications (42).
changes in the trajectory of glucose status should be confirmed through If oral medications are held in the hos-
measures, illness severity, nutritional measurement of a serum sample in the pital, there should be a protocol for
status, or concomitant medications clinical laboratory. resuming them 1–2 days before dis-
that might affect glucose levels (e.g., charge. For patients using insulin, recent
glucocorticoids), should be incorporated Continuous Glucose Monitoring reports indicate that inpatient use of
into the day-to-day decisions regarding Real-time continuous glucose monitor- insulin pens is safe and may be associated
insulin dosing (2). ing (CGM) provides frequent measure- with improved nurse satisfaction com-
ments of interstitial glucose levels, as pared with the use of insulin vials and
BEDSIDE BLOOD GLUCOSE well as direction and magnitude of glu- syringes (43–45). Insulin pens have been
MONITORING cose trends. It has theoretical advantages the subject of an FDA warning because
In hospitalized patients with diabetes over POC glucose testing in detecting and of potential blood-borne diseases; the
who are eating, glucose monitoring reducing the incidence of hypoglycemia warning “For single patient use only”
should be performed before meals; in in the hospital setting that have been should be rigorously followed (46).
those not eating, glucose monitoring borne out in some but not all studies
is advised every 4–6 h (2). More frequent (38,39). Several inpatient studies have
Insulin Therapy
blood glucose testing ranging from every shown that CGM use did not improve
Critical Care Setting
30 min to every 2 h is the required glucose control but detected a greater
In the critical care setting, continuous
standard for safe use of intravenous number of hypoglycemic events than
intravenous insulin infusion is the most
insulin. Safety standards for blood glu- POC glucose testing (40,41). However,
effective method for achieving glycemic
cose monitoring that prohibit the sharing at present, there are insufficient data on
targets. Intravenous insulin infusions
of lancets, other testing materials, and clinical outcomes, safety, or cost effec-
should be administered based on vali-
needles are mandatory (32). tiveness to recommend widespread use
dated written or computerized protocols
The vast majority of hospital glucose of CGM in hospitalized patients (38,40).
that allow for predefined adjustments in
monitoring is performed using standard In particular, more research is needed
the infusion rate, accounting for glycemic
glucose monitors and capillary blood to support application of CGM for crit-
fluctuations and insulin dose (2).
taken from fingersticks, similar to the ical care (41). In patients who use CGM
process used by outpatients for home in the ambulatory setting for self- Noncritical Care Setting
glucose monitoring (33). Point-of-care management of diabetes, use of CGM Outside of critical care units, scheduled
(POC) meters are not as accurate or as for this purpose during hospitalization insulin regimens are recommended to
precise as laboratory glucose analyzers, can be appropriate but requires hospitals manage hyperglycemia in patients with
and capillary blood glucose readings are to have protocols for guidance, as well as diabetes. Regimens using insulin analogs
subject to artifact due to perfusion, access to specialist care (39). For more and human insulin result in similar glyce-
edema, anemia/erythrocytosis, and sev- information on CGM, see Section 7 “Di- mic control in the hospital setting (47). The
eral medications commonly used in the abetes Technology” (https://doi.org/10 use of subcutaneous rapid- or short-acting
hospital (4,34). The U.S. Food and Drug .2337/dc20-S007). insulin before meals, or every 4–6 h if no
S196 Diabetes Care in the Hospital Diabetes Care Volume 43, Supplement 1, January 2020
to an unexpected interruption of nutri- reduce rates of hypoglycemia in hospi- management is appropriate. If CSII or
tion. A recent study describes acute kid- talized patients. CGM is to be used, hospital policy and
ney injury as an important risk factor for procedures delineating guidelines for
hypoglycemia in the hospital (68), possibly MEDICAL NUTRITION THERAPY IN CSII therapy, including the changing of
as a result of decreased insulin clearance. THE HOSPITAL infusion sites, are advised (39,81).
Studies of “bundled” preventive thera- The goals of medical nutrition therapy in
pies, including proactive surveillance of the hospital are to provide adequate STANDARDS FOR SPECIAL
glycemic outliers and an interdisciplinary calories to meet metabolic demands, SITUATIONS
data-driven approach to glycemic man- optimize glycemic control, address per- Enteral/Parenteral Feedings
agement, showed that hypoglycemic sonal food preferences, and facilitate For patients receiving enteral or paren-
episodes in the hospital could be pre- creation of a discharge plan. The ADA teral feedings who require insulin, the
vented. Compared with baseline, two does not endorse any single meal plan or regimen should include coverage of
such studies found that hypoglycemic specified percentages of macronutrients. basal, prandial, and correctional needs.
events fell by 56–80% (69,70). The Joint Current nutrition recommendations ad- It is particularly important that patients
Commission recommends that all hypo- vise individualization based on treatment with type 1 diabetes continue to receive
glycemic episodes be evaluated for a goals, physiological parameters, and basal insulin even if feedings are discon-
root cause and the episodes be aggre- medication use. Consistent carbohydrate tinued. A reasonable estimate of basal
gated and reviewed to address systemic meal plans are preferred by many hos- needs can be made from the preadmis-
issues (23). pitals as they facilitate matching the sion dose of long-acting or intermediate
In addition to errors with insulin treat- prandial insulin dose to the amount of insulin or a percentage of the total daily
ment, iatrogenic hypoglycemia may be carbohydrate consumed (77). For enteral requirements established in the hospital
induced by a sudden reduction of corti- nutritional therapy, diabetes-specific for- (usually 30–50% of the total daily dose of
costeroid dose, reduced oral intake, eme- mulas appear to be superior to standard insulin). In the absence of previous in-
sis, inappropriate timing of short- or rapid- formulas in controlling postprandial glu- sulin dosing, a reasonable starting point
acting insulin in relation to meals, re- cose, A1C, and the insulin response (78). is to use 5 units of NPH/detemir insulin
duced infusion rate of intravenous When the nutritional issues in the subcutaneously every 12 h or 10 units of
dextrose, unexpected interruption of hospital are complex, involvement of a insulin glargine every 24 h (82).
enteral or parenteral feedings, and al- registered dietitian nutritionist can con- For patients receiving continuous tube
tered ability of the patient to report tribute to patient care by integrating feedings, the total daily nutritional com-
symptoms (5). information about the patient’s clinical ponent may be calculated as 1 unit of
condition, meal planning, and lifestyle insulin for every 10–15 g carbohydrate
Predictors of Hypoglycemia habits and by establishing realistic treat- per day or as a percentage of the total
In ambulatory patients with diabetes, it ment goals after discharge. Orders should daily dose of insulin when the patient is
is well established that an episode of also indicate that the meal delivery and being fed (usually 50–70% of the total
severe hypoglycemia increases the risk nutritional insulin coverage should be daily dose of insulin). Correctional insulin
for a subsequent event, in part be- coordinated, as their variability often should also be administered subcutane-
cause of impaired counterregulation creates the possibility of hyperglycemic ously every 6 h using human regular
(71,72). This relationship also holds for and hypoglycemic events. insulin or every 4 h using a rapid-acting
inpatients. For example, in a study of insulin such as lispro, aspart, or glulisine.
hospitalized patients treated for hyper- SELF-MANAGEMENT IN THE For patients receiving enteral bolus
glycemia, 84% who had an episode of HOSPITAL feedings, approximately 1 unit of regular
“severe hypoglycemia” (defined as ,40 Diabetes self-management in the hospi- human insulin or rapid-acting insulin per
mg/dL [2.2 mmol/L]) had a preceding tal may be appropriate for specific pa- 10–15 g carbohydrate should be given
episode of hypoglycemia (,70 mg/dL tients (79,80). Candidates include both subcutaneously before each feeding.
[3.9 mmol/L]) during the same admission adolescent and adult patients who suc- Correctional insulin coverage should
(73). In another study of hypoglyce- cessfully conduct self-management of be added as needed before each feeding.
mic episodes (defined as ,50 mg/dL diabetes at home, and whose cognitive For patients receiving continuous pe-
[2.8 mmol/L]), 78% of patients were and physical skills needed to successfully ripheral or central parenteral nutrition,
using basal insulin, with the incidence self-administer insulin and perform self- human regular insulin may be added to
of hypoglycemia peaking between mid- monitoring of blood glucose are not the solution, particularly if .20 units of
night and 6:00 A.M. Despite recognition of compromised. In addition, they should correctional insulin have been required
hypoglycemia, 75% of patients did not have adequate oral intake, be proficient in the past 24 h. A starting dose of 1 unit
have their dose of basal insulin changed in carbohydrate estimation, use multiple of human regular insulin for every 10 g
before the next insulin administration (74). daily insulin injections or continuous sub- dextrose has been recommended (83),
Recently, several groups have devel- cutaneous insulin infusion (CSII), have stable and should be adjusted daily in the
oped algorithms to predict episodes of insulin requirements, and understand sick- solution. Correctional insulin should be
hypoglycemia among inpatients (75,76). day management. If self-management is to administered subcutaneously. For full
Models such as these are potentially be used, a protocol should include a re- enteral/parenteral feeding guidance,
important and, once validated for gen- quirement that the patient, nursing staff, the reader is encouraged to consult re-
eral use, could provide a valuable tool to and physician agree that patient self- view articles detailing this topic (2,84).
S198 Diabetes Care in the Hospital Diabetes Care Volume 43, Supplement 1, January 2020
Glucocorticoid Therapy A recent review concluded that peri- down units (97), an approach that
The prevalence of glucocorticoid therapy operative glycemic control tighter than may be safer and more cost-effective
in hospitalized patients can approach 80–180 mg/dL (4.4–10.0 mmol/L) did not than treatment with intravenous insulin
10%, and these medications can induce improve outcomes and was associated (98). If subcutaneous insulin adminis-
hyperglycemia in patients with and with- with more hypoglycemia (89); therefore, tration is used, it is important to pro-
out antecedent diabetes (85). Glucocor- in general, tighter glycemic targets are vide adequate fluid replacement,
ticoid type and duration of action must not advised. Evidence from a recent frequent bedside testing, appropriate
be considered in determining insulin study indicates that compared with usual treatment of any concurrent infections,
treatment regimens. Daily ingestion of dosing, a reduction of insulin given the and appropriate follow-up to avoid re-
short-acting glucocorticoids such as evening before surgery by ;25% was current DKA. Several studies have shown
prednisone reach peak plasma levels more likely to achieve perioperative that the use of bicarbonate in patients
in 4–6 h (86) but have pharmacologic blood glucose levels in the target range with DKA made no difference in resolu-
actions that last through the day. Pa- with lower risk for hypoglycemia (90). tion of acidosis or time to discharge, and
tients on morning steroid regimens have In noncardiac general surgery pa- its use is generally not recommended
disproportionate hyperglycemia during tients, basal insulin plus premeal short- (99). For further information regarding
the day, but they frequently reach nor- or rapid-acting insulin (basal-bolus) treatment, refer to recent in-depth re-
mal blood glucose levels overnight re- coverage has been associated with im- views (5).
gardless of treatment (85). In subjects proved glycemic control and lower rates
on once-daily steroids, prandial insulin TRANSITION FROM THE HOSPITAL
of perioperative complications compared
dosing, often with intermediate-acting TO THE AMBULATORY SETTING
with the reactive, sliding scale regimens
(NPH) insulin, is a standard approach. For (short- or rapid-acting insulin coverage Recommendation
long-acting glucocorticoids such as dexa- only with no basal insulin dosing) (48,91). 15.10 There should be a structured dis-
methasone and multidose or continuous charge plan tailored to the in-
glucocorticoid use, long-acting insulin Diabetic Ketoacidosis and dividual patient with diabetes. B
may be required to control fasting blood Hyperosmolar Hyperglycemic State
glucose (42,84). For higher doses of There is considerable variability in the A structured discharge plan tailored to
glucocorticoids, increasing doses of pran- presentation of diabetic ketoacidosis the individual patient may reduce length
dial and correctional insulin, sometimes (DKA) and hyperosmolar hyperglycemic of hospital stay and readmission rates
in extraordinary amounts, are often states, ranging from euglycemia or mild and increase patient satisfaction (100).
needed in addition to basal insulin hyperglycemia and acidosis to severe Discharge planning should begin at ad-
(87). Whatever orders are started, ad- hyperglycemia, dehydration, and coma; mission and be updated as patient needs
justments based on anticipated changes therefore, individualization of treatment change.
in glucocorticoid dosing and POC glucose based on a careful clinical and laboratory Transition from the acute care setting
test results are critical. assessment is needed (92–95). presents risks for all patients. Inpatients
Management goals include restora- may be discharged to varied settings,
Perioperative Care tion of circulatory volume and tissue including home (with or without visiting
Many standards for perioperative care perfusion, resolution of hyperglycemia, nurse services), assisted living, rehabili-
lack a robust evidence base. However, and correction of electrolyte imbalance tation, or skilled nursing facilities. For the
the following approach (88) may be and acidosis. It is also important to treat patient who is discharged to home or to
considered: any correctable underlying cause of assisted living, the optimal program will
DKA such as sepsis, myocardial infarction, need to consider diabetes type and se-
1. The target range for blood glucose in or stroke. In critically ill and mentally verity, effects of the patient’s illness on
the perioperative period should be obtunded patients with DKA or hyper- blood glucose levels, and the patient’s
80–180 mg/dL (4.4–10.0 mmol/L). osmolar hyperglycemia, continuous in- capacities and preferences. See Section
2. A preoperative risk assessment should travenous insulin is the standard of care. 12 “Older Adults” (https://doi.org/10
be performed for patients with diabe- Successful transition of patients from .2337/dc20-S012) for more information.
tes who are at high risk for ischemic intravenous to subcutaneous insulin re- An outpatient follow-up visit with the
heart disease and those with auto- quires administration of basal insulin primary care provider, endocrinologist,
nomic neuropathy or renal failure. 2–4 h prior to the intravenous insulin or diabetes educator within 1 month of
3. Metformin should be withheld on the being stopped to prevent recurrence of discharge is advised for all patients ex-
day of surgery. ketoacidosis and rebound hyperglycemia periencing hyperglycemia in the hospital.
4. Withhold any other oral glucose-lowering (95). There is no significant difference in If glycemic medications are changed or
agents the morning of surgery or pro- outcomes for intravenous human regular glucose control is not optimal at dis-
cedure and give half of NPH dose or insulin versus subcutaneous rapid-acting charge, an earlier appointment (in 1–
60–80% doses of long-acting analog or analogs when combined with aggressive 2 weeks) is preferred, and frequent
pump basal insulin. fluid management for treating mild or contact may be needed to avoid hyper-
5. Monitor blood glucose at least every moderate DKA (96). Patients with un- glycemia and hypoglycemia. A recently
4–6 h while patient is taking nothing by complicated DKA may sometimes be described discharge algorithm for glyce-
mouth and dose with short- or rapid- treated with subcutaneous insulin in mic medication adjustment based on
acting insulin as needed. the emergency department or step- admission A1C was found useful to
care.diabetesjournals.org Diabetes Care in the Hospital S199
guide treatment decisions and signif- c Information on making healthy food patients 80 years of age or older are
icantly improved A1C after discharge choices at home and referral to an more than twice as likely as those 45–64
(8). Therefore, if an A1C from the prior outpatient registered dietitian nutri- years of age to visit the emergency
3 months is unavailable, measuring the tionist to guide individualization of department and nearly five times as
A1C in all patients with diabetes or hy- meal plan, if needed. If relevant, likely to be admitted for insulin-related
perglycemia admitted to the hospital is when and how to take blood glucose– hypoglycemia (110). One approach to
recommended. lowering medications, including insulin reducing insulin-related morbidity in
Clear communication with outpatient administration. older adults with type 2 diabetes is to
providers either directly or via hospital c Sick-day management. substitute oral agents for insulin in
discharge summaries facilitates safe c Proper use and disposal of needles and patients in whom these drugs are
transitions to outpatient care. Providing syringes. effective. Among elderly patients in
information regarding the cause of hy- long-term care facilities, there was no
perglycemia (or the plan for determining It is important that patients be pro- significant difference in glycemic control
the cause), related complications and vided with appropriate durable med- between those taking basal insulin and
comorbidities, and recommended treat- ical equipment, medications, supplies those on oral glucose-lowering medica-
ments can assist outpatient providers as (e.g., blood glucose test strips), and tions (111). In addition, many older
they assume ongoing care. prescriptions along with appropriate adults with diabetes are overtreated
The Agency for Healthcare Research education at the time of discharge in (112), with half of those maintaining an
and Quality (AHRQ) recommends that, order to avoid a potentially dangerous A1C ,7% (53 mmol/mol) being treated
at a minimum, discharge plans include hiatus in care. with insulin or a sulfonylurea, which
the following (101): are associated with hypoglycemia. To
PREVENTING ADMISSIONS AND further lower the risk of hypoglycemia-
READMISSIONS related admissions in older adults,
Medication Reconciliation
c The patient’s medications must be In patients with diabetes, the hospital providers should consider relaxing
cross-checked to ensure that no readmission rate is between 14% and A1C targets to 8% (64 mmol/mol) or
chronic medications were stopped and 20%, nearly twice that in patients without 8.5% (69 mmol/mol) in patients with
to ensure the safety of new prescriptions. diabetes (102,103). This reflects increased shortened life expectancies and signif-
c Prescriptions for new or changed med- disease burden for patients and has im- icant comorbidities (refer to Section
ication should be filled and reviewed portant financial implications. Of patients 12 “Older Adults,” https://doi.org/10
with the patient and family at or with diabetes who are hospitalized, 30% .2337/dc20-S012, for detailed criteria).
before discharge. have two or more hospital stays, and these
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mission in high-risk patients with diabetes: the abetic kidney disease: a report from an ADA 362
Diabetes Care Volume 43, Supplement 1, January 2020 S203
The American Diabetes Association position statements. The ADA publishes Diabetes Care in the School Setting
(ADA) “Standards of Medical Care in evidence-based, peer-reviewed state- A sizable portion of a child’s day is spent in
Diabetes” includes the ADA’s current ments on topics such as diabetes and school, so close communication with and
clinical practice recommendations and employment, diabetes and driving, in- cooperation of school personnel are es-
is intended to provide the components sulin access and affordability, and dia- sential to optimize diabetes management,
of diabetes care, general treatment betes management in certain settings safety, and academic opportunities. See
goals and guidelines, and tools to eval- such as schools, childcare programs, and the following ADA position statement for
uate quality of care. Members of the correctional institutions. In addition to the diabetes management information for
ADA Professional Practice Committee, ADA’s clinical documents, these advocacy students with diabetes in the elementary
statements are important tools in educating and secondary school settings.
a multidisciplinary expert committee
schools, employers, licensing agencies,
(https://doi.org/10.2337/dc20-SPPC),
Suggested citation: American Diabetes Association. 16. Diabetes advocacy: Standards of Medical Care in Diabetesd2020. Diabetes Care 2020;
43(Suppl. 1):S203–S204
© 2019 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit,
and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.
S204 Diabetes Advocacy Diabetes Care Volume 43, Supplement 1, January 2020
Diabetes and Driving Diabetes and Employment (first publication 1984; latest revision
People with diabetes who wish to oper- Any person with diabetes, whether 2009)
ate motor vehicles are subject to a great insulin treated or noninsulin treated,
variety of licensing requirements applied should be eligible for any employment
Diabetes Care in Correctional
by both state and federal jurisdictions. for which he or she is otherwise qualified.
Institutions
For an overview of existing licensing rules Employment decisions should never be
for people with diabetes, factors that People with diabetes in correctional
based on generalizations or stereotypes
impact driving for this population, and facilities should receive care that meets
regarding the effects of diabetes. For a national standards. Correctional insti-
general guidelines for assessing driver
general set of guidelines for evaluating tutions should have written policies and
fitness and determining appropriate li-
censing restrictions, see the following individuals with diabetes for employ- procedures for the management of di-
ADA position statement. ment, including how an assessment abetes and for the training of medical
Editor’s note: Federal commercial driving should be performed and what changes and correctional staff in diabetes care
rules for individuals with insulin-related di- (accommodations) in the workplace practices. For a general set of guidelines
abetes changed on 19 November 2018. may be needed for an individual with for diabetes care in correction institu-
These changes will be reflected in tions, see the following ADA position
diabetes, see the following ADA position
a future updated ADA statement. statement.
statement.
Lorber D, Anderson J, Arent S, et al.; American Diabetes Association. Diabetes
American Diabetes Association. Diabetes Anderson JE, Greene MA, Griffin JW management in correctional institutions.
and driving. Diabetes Care 2014;37- Jr, et al.; American Diabetes Associa- Diabetes Care 2014;37(Suppl. 1):S104–
(Suppl. 1):S97–S103; https://doi.org/ tion. Diabetes and employment. Dia- S111; https://doi.org/10.2337/dc14-S104
10.2337/dc14-S097 (first publication betes Care 2014;37(Suppl. 1):S112–S117; (first publication 1989; latest revision
2012) https://doi.org/10.2337/dc14-S112 2008)