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ISSN 0149-5992
January 2018 Volume 41, Supplement 1

[T]he simple word Care may suffice to express [the journal’s] philosophical
mission. The new journal is designed to promote better patient care by
serving the expanded needs of all health professionals committed to the care
of patients with diabetes. As such, the American Diabetes Association views
Diabetes Care as a reaffirmation of Francis Weld Peabody’s contention that
“the secret of the care of the patient is in caring for the patient.”
—Norbert Freinkel, Diabetes Care, January-February 1978


Matthew C. Riddle, MD


George Bakris, MD Nicola Abate, MD Maureen Monaghan, PhD, CDE
Lawrence Blonde, MD, FACP Vanita R. Aroda, MD Kristen J. Nadeau, MD, MS
Andrew J.M. Boulton, MD Geremia Bolli, MD Kwame Osei, MD
David D’Alessio, MD John B. Buse, MD, PhD Kevin A. Peterson, MD, MPH, FRCS(Ed),
Mary de Groot, PhD Robert J. Chilton, DO, FACC, FAHA FAAFP
Eddie L. Greene, MD Kenneth Cusi, MD, FACP, FACE Jonathan Q. Purnell, MD
Frank B. Hu, MD, MPH, PhD Paresh Dandona, MD, PhD Peter Reaven, MD
Steven E. Kahn, MB, ChB J. Hans DeVries, MD, PhD Ravi Retnakaran, MD, MSc, FRCPC
Sanjay Kaul, MD, FACC, FAHA Ele Ferrannini, MD Helena Wachslicht Rodbard, MD
Derek LeRoith, MD, PhD Franco Folli, MD, PhD Elizabeth Seaquist, MD
Robert G. Moses, MD Meredith A. Hawkins, MD, MS Guntram Schernthaner, MD
Stephen Rich, PhD Richard Hellman, MD David J. Schneider, MD
Julio Rosenstock, MD Norbert Hermanns, PhD, MSc Norbert Stefan, MD
William V. Tamborlane, MD Irl B. Hirsch, MD, MACP Jan S. Ulbrecht, MB, BS
Judith Wylie-Rosett, EdD, RD George S. Jeha, MD Joseph Wolfsdorf, MD, BCh
Lee M. Kaplan, MD, PhD Tien Yin Wong, MBBS, FRCSE, FRANZCO,
M. Sue Kirkman, MD MPH, PhD
Ildiko Lingvay, MD, MPH, MSCS Bernard Zinman, CM, MD, FRCPC, FACP
Harold David McIntyre, MD, FRACP

Karen Talmadge, PhD Louis Philipson, MD
Gretchen Youssef, MS, RD, CDE
Felicia Hill-Briggs, PhD, ABPP Brian Bertha, JD, MBA
Michael Ching, CPA Martha Parry Clark
David J. Herrick, MBA William T. Cefalu, MD

The mission of the American Diabetes Association
is to prevent and cure diabetes and to improve
the lives of all people affected by diabetes.
Diabetes Care is a journal for the health care practitioner that is intended to
increase knowledge, stimulate research, and promote better management of people
with diabetes. To achieve these goals, the journal publishes original research on
human studies in the following categories: Clinical Care/Education/Nutrition/
Psychosocial Research, Epidemiology/Health Services Research, Emerging
Technologies and Therapeutics, Pathophysiology/Complications, and Cardiovascular
and Metabolic Risk. The journal also publishes ADA statements, consensus reports,
clinically relevant review articles, letters to the editor, and health/medical news or points
of view. Topics covered are of interest to clinically oriented physicians, researchers,
epidemiologists, psychologists, diabetes educators, and other health professionals.
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January 2018 Volume 41, Supplement 1

Standards of Medical Care in Diabetes—2018
S1 Introduction S86 9. Cardiovascular Disease and Risk
S3 Professional Practice Committee Management
S4 Summary of Revisions: Standards of Medical Care in Hypertension/Blood Pressure Control
Diabetes—2018 Lipid Management
S7 1. Improving Care and Promoting Health in Antiplatelet Agents
Populations Coronary Heart Disease
Diabetes and Population Health S105 10. Microvascular Complications and Foot Care
Tailoring Treatment for Social Context Diabetic Kidney Disease
S13 2. Classification and Diagnosis of Diabetes Diabetic Retinopathy
Foot Care
Diagnostic Tests for Diabetes
Categories of Increased Risk for Diabetes (Prediabetes) S119 11. Older Adults
Type 1 Diabetes
Type 2 Diabetes Neurocognitive Function
Gestational Diabetes Mellitus Hypoglycemia
Monogenic Diabetes Syndromes Treatment Goals
Cystic Fibrosis–Related Diabetes Pharmacologic Therapy
Posttransplantation Diabetes Mellitus Treatment in Skilled Nursing Facilities
and Nursing Homes
S28 3. Comprehensive Medical Evaluation and End-of-Life Care
Assessment of Comorbidities
S126 12. Children and Adolescents
Patient-Centered Collaborative Care
Comprehensive Medical Evaluation Type 1 Diabetes
Assessment of Comorbidities Type 2 Diabetes
Transition From Pediatric to Adult Care
S38 4. Lifestyle Management
Diabetes Self-Management Education and Support S137 13. Management of Diabetes in Pregnancy
Nutrition Therapy Diabetes in Pregnancy
Physical Activity Preconception Counseling
Smoking Cessation: Tobacco and e-Cigarettes Glycemic Targets in Pregnancy
Psychosocial Issues Management of Gestational Diabetes Mellitus
Management of Preexisting Type 1 Diabetes
S51 5. Prevention or Delay of Type 2 Diabetes and Type 2 Diabetes in Pregnancy
Lifestyle Interventions Pregnancy and Drug Considerations
Pharmacologic Interventions Postpartum Care
Prevention of Cardiovascular Disease
Diabetes Self-management Education and Support S144 14. Diabetes Care in the Hospital
S55 6. Glycemic Targets Hospital Care Delivery Standards
Glycemic Targets in Hospitalized Patients
Assessment of Glycemic Control Bedside Blood Glucose Monitoring
A1C Testing Antihyperglycemic Agents in Hospitalized Patients
A1C Goals Hypoglycemia
Hypoglycemia Medical Nutrition Therapy in the Hospital
Intercurrent Illness Self-management in the Hospital
S65 7. Obesity Management for the Treatment of Type 2 Standards for Special Situations
Diabetes Transition From the Acute Care Setting
Preventing Admissions and Readmissions
Diet, Physical Activity, and Behavioral Therapy S152 15. Diabetes Advocacy
Metabolic Surgery Advocacy Position Statements

S73 8. Pharmacologic Approaches to Glycemic Treatment S154 Professional Practice Committee, American College of
Cardiology—Designated Representatives, and
Pharmacologic Therapy for Type 1 Diabetes American Diabetes Association Staff Disclosures
Surgical Treatment for Type 1 Diabetes
Pharmacologic Therapy for Type 2 Diabetes S156 Index

This issue is freely accessible online at

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Diabetes Care Volume 41, Supplement 1, January 2018


Professional Practice Committee:
Standards of Medical Care in Diabetesd2018
Diabetes Care 2018;41(Suppl. 1):S3 |

The Professional Practice Committee (see pp. S154–S155). The ADA funds de- CPsychol; Jane Reusch, MD; and Sharon
(PPC) of the American Diabetes Asso- velopment of the Standards of Care out of Solomon, MD.
ciation (ADA) is responsible for the its general revenues and does not use in-
“Standards of Medical Care in Diabetes” dustry support for this purpose. MEMBERS OF THE PPC
position statement, referred to as the For the current revision, PPC members
Rita R. Kalyani, MD, MHS, FACP (Chair)
Standards of Care. The PPC is a multidis- systematically searched MEDLINE for hu-
Christopher P. Cannon, MD
ciplinary expert committee comprised man studies related to each section and
Andrea L. Cherrington, MD, MPH*
of physicians, diabetes educators, regis- published since 1 January 2017. Recom-
Donald R. Coustan, MD
tered dietitians, and others who have mendations were revised based on new
Ian H. de Boer, MD, MS*
expertise in a range of areas, including evidence or, in some cases, to clarify the
Hope Feldman, CRNP, FNP-BC
adult and pediatric endocrinology, epi- prior recommendation or match the
Judith Fradkin, MD
demiology, public health, lipid research, strength of the wording to the strength
David Maahs, MD, PhD
hypertension, preconception planning, of the evidence. A table linking the
Melinda Maryniuk, MEd, RD, CDE
and pregnancy care. Appointment to changes in recommendations to new ev-
Medha N. Munshi, MD*
the PPC is based on excellence in clinical idence can be reviewed at professional
Joshua J. Neumiller, PharmD, CDE, FASCP
practice and research. Although the pri- The Standards of Care
Guillermo E. Umpierrez, MD, CDE, FACE, FACP*
mary role of the PPC is to review and was approved by ADA’s Board of Directors,
*Subgroup leaders
update the Standards of Care, it may which includes health care professionals,
also be involved in ADA statements, re- scientists, and lay people.
ports, and reviews. Feedback from the larger clinical com- AMERICAN COLLEGE OF
The ADA adheres to the National munity was valuable for the 2017 revision CARDIOLOGY—DESIGNATED
Academy of Medicine Standards for De- of the Standards of Care. Readers who REPRESENTATIVES (SECTION 9)
veloping Trustworthy Clinical Practice wish to comment on the 2018 Standards Sandeep Das, MD, MPH, FACC
Guidelines. All members of the PPC of Care are invited to do so at professional Mikhail Kosiborod, MD, FACC
are required to disclose potential con-
flicts of interest with industry and/or The PPC would like to thank the follow-
other relevant organizations. These dis- ing individuals who provided their exper- ADA STAFF
closures are discussed at the onset of tise in reviewing and/or consulting with Erika Gebel Berg, PhD
each Standards of Care revision meet- the committee: Pamela Allweiss, MD, MPH; (Corresponding author:
ing. Members of the committee, their David D’Alessio, MD; Thomas Gardner, Tamara Darsow, PhD
employers, and their disclosed conflicts MD, MS; William H. Herman, MD, MPH; Matthew P. Petersen
of interest are listed in the “Professional Felicia Hill-Briggs, PhD; Nisa Maruthur, Sacha Uelmen, RDN, CDE
Practice Committee Disclosures” table MD, MHS; Alicia McAuliffe-Fogarty, PhD, William T. Cefalu, MD

© 2017 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
Diabetes Care Volume 41, Supplement 1, January 2018 S1

Introduction: Standards of Medical
Care in Diabetesd2018
Diabetes Care 2018;41(Suppl. 1):S1–S2 |

Diabetes is a complex, chronic illness re- continue to rely on them as the most au- current position. The Standards of Care
quiring continuous medical care with mul- thoritative and current guidelines for dia- receives annual review and approval by
tifactorial risk-reduction strategies beyond betes care. Readers who wish to comment the ADA Board of Directors.
glycemic control. Ongoing patient self- on the 2018 Standards of Care are invited
management education and support are to do so at ADA Statement
critical to preventing acute complications An ADA statement is an official ADA point
and reducing the risk of long-term compli- ADA STANDARDS, STATEMENTS, of view or belief that does not contain clin-
REPORTS, and REVIEWS ical practice recommendations and may be
cations. Significant evidence exists that
supports a range of interventions to im- The ADA has been actively involved in the issued on advocacy, policy, economic, or
prove diabetes outcomes. development and dissemination of diabe- medical issues related to diabetes. ADA
The American Diabetes Association’s tes care standards, guidelines, and related statements undergo a formal review pro-
(ADA’s) “Standards of Medical Care in documents for over 25 years. The ADA’s cess, including a review by the appropriate
Diabetes,” referred to as the Standards clinical practice recommendations are national committee, ADA mission staff, and
of Care, is intended to provide clinicians, viewed as important resources for health the Board of Directors.
patients, researchers, payers, and other care professionals who care for people
interested individuals with the compo- with diabetes. Consensus Report
nents of diabetes care, general treatment An expert consensus report of a particu-
Standards of Care
goals, and tools to evaluate the quality of lar topic contains a comprehensive ex-
This document is an official ADA position,
care. The Standards of Care recommen- amination and is authored by an expert
is authored by the ADA, and provides all
dations are not intended to preclude clin- panel (i.e., consensus panel) and repre-
of the ADA’s current clinical practice rec-
ical judgment and must be applied in the sents the panel’s collective analysis, eval-
ommendations. To update the Standards
context of excellent clinical care, with uation, and opinion. The need for an
of Care, the ADA’s Professional Practice
adjustments for individual preferences, expert consensus report arises when clini-
Committee (PPC) performs an extensive
comorbidities, and other patient factors. cians, scientists, regulators, and/or policy
clinical diabetes literature search, supple-
For more detailed information about makers desire guidance and/or clarity
mented with input from ADA staff and the
management of diabetes, please refer to on a medical or scientific issue related
medical community at large. The PPC up-
Medical Management of Type 1 Diabetes to diabetes for which the evidence
dates the Standards of Care annually, or
(1) and Medical Management of Type 2 more frequently online should the PPC is contradictory, emerging, or incomplete.
Diabetes (2). determine that new evidence or regula- Expert consensus reports may also high-
The recommendations include screen- tory changes (e.g., drug approvals, label light gaps in evidence and propose areas
ing, diagnostic, and therapeutic actions changes) merit immediate incorporation. of future research to address these gaps.
that are known or believed to favorably The Standards of Care supersedes all pre- An expert consensus report is not an ADA
affect health outcomes of patients with di- vious ADA position statementsdand the position and represents expert opinion
abetes. Many of these interventions have recommendations thereindon clinical only but is produced under the auspices
also been shown to be cost-effective (3). topics within the purview of the Stand- of the Association by invited experts. An
The ADA strives to improve and update ards of Care; ADA position statements, expert consensus report may be devel-
the Standards of Care to ensure that clini- while still containing valuable analyses, oped after an ADA Clinical Conference
cians, health plans, and policy makers can should not be considered the ADA’s or Research Symposium.

“Standards of Medical Care in Diabetes” was originally approved in 1988.
© 2017 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
S2 Introduction Diabetes Care Volume 41, Supplement 1, January 2018

Table 1—ADA evidence-grading system for “Standards of Medical Care in Diabetes” B, or C, depending on the quality of evi-
Level of evidence Description
dence. Expert opinion E is a separate cat-
egory for recommendations in which
A Clear evidence from well-conducted, generalizable
there is no evidence from clinical trials,
randomized controlled trials that are adequately
powered, including
in which clinical trials may be impractical,
c Evidence from a well-conducted multicenter trial or in which there is conflicting evidence.
c Evidence from a meta-analysis that incorporated Recommendations with an A rating are
quality ratings in the analysis based on large well-designed clinical trials
Compelling nonexperimental evidence, i.e., “all or none” or well-done meta-analyses. Generally,
rule developed by the Centre for Evidence-Based these recommendations have the best
Medicine at the University of Oxford
chance of improving outcomes when ap-
Supportive evidence from well-conducted randomized
controlled trials that are adequately powered, including plied to the population to which they
c Evidence from a well-conducted trial at one or more are appropriate. Recommendations
institutions with lower levels of evidence may be
c Evidence from a meta-analysis that incorporated equally important but are not as well
quality ratings in the analysis supported.
B Supportive evidence from well-conducted cohort studies Of course, evidence is only one compo-
c Evidence from a well-conducted prospective cohort
nent of clinical decision- making. Clini-
study or registry
cians care for patients, not populations;
c Evidence from a well-conducted meta-analysis of
cohort studies guidelines must always be interpreted
Supportive evidence from a well-conducted case-control with the individual patient in mind. Indi-
study vidual circumstances, such as comorbid
C Supportive evidence from poorly controlled or and coexisting diseases, age, education,
uncontrolled studies disability, and, above all, patients’ val-
c Evidence from randomized clinical trials with one or ues and preferences, must be considered
more major or three or more minor methodological and may lead to different treatment tar-
flaws that could invalidate the results
gets and strategies. Furthermore, con-
c Evidence from observational studies with high
potential for bias (such as case series with comparison ventional evidence hierarchies, such as
with historical controls) the one adapted by the ADA, may miss
c Evidence from case series or case reports nuances important in diabetes care. For
Conflicting evidence with the weight of evidence example, although there is excellent evi-
supporting the recommendation dence from clinical trials supporting the
E Expert consensus or clinical experience importance of achieving multiple risk
factor control, the optimal way to achieve
this result is less clear. It is difficult to as-
Scientific Review evolution in the evaluation of scientific evi- sess each component of such a complex
A scientific review is a balanced review dence and in the development of evidence- intervention.
and analysis of the literature on a scien- based guidelines. In 2002, the ADA devel-
tific or medical topic related to diabetes. oped a classification system to grade the References
A scientific review is not an ADA position quality of scientific evidence supporting 1. American Diabetes Association. Medical Man-
and does not contain clinical practice agement of Type 1 Diabetes. 7th ed. Wang CC,
ADA recommendations. A 2015 analysis of
Shah AC, Eds. Alexandria, VA, American Diabetes
recommendations but is produced un- the evidence cited in the Standards of Care Association, 2017
der the auspices of the Association by found steady improvement in quality 2. American Diabetes Association. Medical Man-
invited experts. The scientific review may over the previous 10 years, with the agement of Type 2 Diabetes. 7th ed. Burant CF,
provide a scientific rationale for clini- 2014 Standards of Care for the first time Young LA, Eds. Alexandria, VA, American Diabetes
cal practice recommendations in the Association, 2012
having the majority of bulleted recom- 3. Li R, Zhang P, Barker LE, Chowdhury FM, Zhang
Standards of Care. The category may also mendations supported by A- or B-level X. Cost-effectiveness of interventions to prevent
include task force and expert committee evidence (4). A grading system (Table 1) and control diabetes mellitus: a systematic re-
reports. developed by the ADA and modeled view. Diabetes Care 2010;33:1872–1894
after existing methods was used to clarify 4. Grant RW, Kirkman MS. Trends in the evi-
GRADING OF SCIENTIFIC EVIDENCE dence level for the American Diabetes Associ-
and codify the evidence that forms the ation’s “Standards of Medical Care in Diabetes”
Since the ADA first began publishing practice basis for the recommendations. ADA rec- from 2005 to 2014. Diabetes Care 2015;38:
guidelines, there has been considerable ommendations are assigned ratings of A, 6–8
S4 Diabetes Care Volume 41, Supplement 1, January 2018

Summary of Revisions: Standards of Medical Care
in Diabetesd2018
Diabetes Care 2018;41(Suppl. 1):S4–S6 |

GENERAL CHANGES A new recommendation was added The immunization section was updated
The field of diabetes care is rapidly changing about using reliable data metrics to assess for clarity to more closely align with rec-
as new research, technology, and treat- and improve the quality of diabetes care ommendations from the Centers for Dis-
ments that can improve the health and and reduce costs. ease Control and Prevention.
well-being of people with diabetes continue Additional discussion was included on Text was added about the importance
to emerge. With annual updates since 1989, the social determinants of health. of language choice in patient-centered
the American Diabetes Association’s (ADA’s) Text was added describing the emerg- communication.
“Standards of Medical Care in Diabetes” ing use of telemedicine in diabetes care. Pancreatitis was added to the section
(Standards of Care) has long been a leader on comorbidities, including a new recom-
Section 2. Classification and Diagnosis
in producing guidelines that capture the mendation about the consideration of
of Diabetes
most current state of the field. Starting in As a result of recent evidence describing
islet autotransplantation to prevent post-
2018, the ADA will update the Standards of surgical diabetes in patients with medi-
potential limitations in A1C measure-
Care even more frequently online should cally refractory chronic pancreatitis who
ments due to hemoglobin variants, assay
the Professional Practice Committee de- require total pancreatectomy.
interference, and conditions associated
termine that new evidence or regulatory A recommendation was added to
with red blood cell turnover, additional
changes merit immediate incorporation consider checking serum testosterone in
recommendations were added to clarify
into the Standards of Care. In addition, men with diabetes and signs and symp-
the appropriate use of the A1C test gener-
the Standards of Care will now become toms of hypogonadism.
ally and in the diagnosis of diabetes in
the ADA’s sole source of clinical practice these special cases. Section 4. Lifestyle Management
recommendations, superseding all prior The recommendation for testing for A recommendation was modified to in-
position and scientific statements. The prediabetes and type 2 diabetes in children clude individual and group settings as
change is intended to clarify the Associa- and adolescents was changed, suggesting well as technology-based platforms for
tion’s current positions by consolidating testing for youth who are overweight or the delivery of effective diabetes self-
all clinical practice recommendations into obese and have one or more additional management education and support.
the Standards of Care. For further informa- risk factors (Table 2.5). Additional explanation was added to
tion on changes to the classification and A clarification was added that, while the nutrition section to clarify the ADA’s
definitions of ADA Standards of Care, generally not recommended, commu- recommendations that there is no univer-
statements, reports, and reviews, see nity screening may be considered in sal ideal macronutrient distribution and
the Introduction. specific situations where an adequate that eating plans should be individualized.
Although levels of evidence for several referral system for positive tests is Text was added to address the role of
recommendations have been updated, established. low-carbohydrate diets in people with
these changes are not addressed below Additional detail was added regarding diabetes.
as the clinical recommendations have re- current research on antihyperglycemic
mained the same. Changes in evidence level treatment in people with posttransplan- Section 5. Prevention or Delay of
from, for example, E to C are not noted tation diabetes mellitus. Type 2 Diabetes
below. The 2018 Standards of Care con- The recommendation regarding the use of
tains, in addition to many minor changes Section 3. Comprehensive Medical metformin in the prevention of prediabe-
that clarify recommendations or reflect Evaluation and Assessment of tes was reworded to better reflect the data
new evidence, the following more substan- Comorbidities from the Diabetes Prevention Program.
tive revisions. The table describing the components of a
comprehensive medical evaluation (Table Section 6. Glycemic Targets
SECTION CHANGES 3.1) was substantially redesigned and re- Based on new data, the recommendation
Section 1. Improving Care and organized, incorporating information about for the use of continuous glucose monitor-
Promoting Health in Populations the recommended frequency of the compo- ing (CGM) in adults with type 1 diabetes is
This section was renamed to better capture its nents of care at both initial and follow-up no longer limited to those ages 25 and
subject matter and was reorganized for clarity. visits. above but has been expanded to all adults

© 2017 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 Summary of Revisions S5

(18 and above) who are not meeting glyce- Section 9. Cardiovascular Disease that combines information on staging
mic targets. and Risk Management chronic kidney disease and the appro-
Additional text was added about a new A new recommendation was added that all priate kidney-related care for each stage.
intermittent or “flash” CGM device that hypertensive patients with diabetes should A new Table 10.2 was included describ-
was recently approved for adult use. monitor their blood pressure at home to help ing the complications of chronic kidney
Details were added about new CGM de- identify masked or white coat hypertension, as disease and related medical and labora-
vices that no longer require confirmatory well as to improve medication-taking behavior. tory evaluations.
self-monitoring of blood glucose for treat- A new figure (Fig. 9.1) was added to A new section on acute kidney injury
ment decisions. illustrate the recommended antihyper- was included.
As in Section 2, this section now includes tensive treatment approach for adults The effect of specific glucose-lowering
an expanded discussion of the limitations with diabetes and hypertension. medications on the delay and progression
of A1C in certain populations based on the A new table (Table 9.1) was added sum- of kidney disease was discussed, with ref-
presence of hemoglobin variants, differ- marizing studies of intensive versus stan- erence to recent CVOT trials that examined
ences in red blood cell turnover rates, eth- dard hypertension treatment strategies. kidney effects as secondary outcomes.
nicity, and age. A recommendation was added to consider A new recommendation was added on
To clarify the classification of hypogly- mineralocorticoid receptor antagonist ther- the noninferiority of the anti–vascular endo-
cemia, level 1 hypoglycemia was renamed apy in patients with resistant hypertension. thelial growth factor treatment ranibizumab
“hypoglycemia alert value” from “glucose The lipid management recommendations in reducing the risk of vision loss in patients
alert value.” were modified to stratify risk based on two with proliferative diabetic retinopathy
broad categories: those with documented when compared with the traditional stan-
Section 7. Obesity Management
ASCVD and those without. dard treatment, panretinal laser photoco-
for the Treatment of Type 2 Diabetes
Owing to studies suggesting similar ben- agulation therapy.
To provide a second set of cost informa-
efits in older versus middle-aged adults, recom- A new section was added describing
tion, the table of medications for the
mendations were consolidated for patients the mixed evidence on the use of hyper-
treatment of obesity (Table 7.2) was up-
with diabetes 40–75 years and .75 years of baric oxygen therapy in people with dia-
dated to include National Average Drug
age without ASCVD to use moderate-intensity betic foot ulcers.
Acquisition Cost (NADAC) prices.
Section 8. Pharmacologic Approaches Table 9.2 (“Recommendations for sta- Section 11. Older Adults
to Glycemic Treatment tin and combination treatment in adults Three new recommendations were added
New recommendations for antihyperglyce- with diabetes”) was updated based on to highlight the importance of individualiz-
mic therapy for adults with type 2 diabetes the new risk stratification approach and ing pharmacologic therapy in older adults to
have been added to reflect recent cardio- consolidated age-groups. reduce the risk of hypoglycemia, avoid over-
vascular outcomes trial (CVOT) data, indi- To accommodate recent data on new treatment, and simplify complex regimens if
cating that people with atherosclerotic classes of lipid-lowering medications, a re- possible while maintaining the A1C target.
cardiovascular disease (ASCVD) should be- commendation was modified to provide
gin with lifestyle management and metfor- additional guidance on adding nonstatin Section 12. Children and Adolescents
min and subsequently incorporate an LDL-lowering therapies for patients with To make the section more comprehensive
agent proven to reduce major adverse diabetes and ASCVD who have LDL choles- and to reflect emerging data on diabetes
cardiovascular events and/or cardiovascu- terol $70 mg/dL despite maximally toler- technologies, additional recommendations
lar mortality after considering drug-specific ated statin dose. were added on the treatment of type 1
and patient factors. The same recommendations were added diabetes in children and adolescents regard-
The algorithm for antihyperglycemic here as in Section 8 that people with type 2 ing intensive insulin regimens, self-monitoring
treatment (Fig. 8.1) was updated to incor- diabetes and ASCVD should begin with life- ofbloodglucose,CGM,and automated insulin
porate the new ASCVD recommendation. style management and metformin and sub- delivery systems.
A new table was added (Table 8.1) to sequently incorporate an agent proven to The recommended risk-based timing of
summarize drug-specific and patient fac- reduce major adverse cardiovascular events celiac disease screenings for youth and ad-
tors of antihyperglycemic agents. Figure and/or cardiovascular mortality after con- olescents with type 1 diabetes was defined.
8.1 and Table 8.1 are meant to be used sidering drug-specific and patient factors. A recommendation regarding esti-
together to guide the choice of antihy- The text was substantially modified to mating glomerular filtration rate was re-
perglycemic agents as part of patient– describe CVOT data on new diabetes agents moved because of the poor performance
provider shared decision-making. and outcomes in people with type 2 diabe- of the estimating equation in youth.
Table 8.2 was modified to focus on the tes, providing support for the new ASCVD The type 2 diabetes in children section
pharmacology and mechanisms of avail- recommendations. was substantially expanded, with several
able glucose-lowering medicines in the A new Table 9.4 was added to summa- new recommendations, based on a re-
U.S. rize the CVOT studies. cent ADA review.
To provide a second set of cost infor-
mation for antihyperglycemic agents, Section 10. Microvascular Section 13. Management of Diabetes
NADAC data was added to the average Complications and Foot Care in Pregnancy
wholesale prices information in Table A new table was added (Table 10.1), re- A recommendation was added to empha-
8.3 and Table 8.4. placing previous tables 10.1 and 10.2, size that insulin is the preferred agent for
S6 Summary of Revisions Diabetes Care Volume 41, Supplement 1, January 2018

the management of type 1 and type 2 di- type 1 and type 2 diabetes to take Section 14. Diabetes Care in the Hospital
abetes in pregnancy. low-dose aspirin starting at the end of Insulin degludec was added to the insulin
Based on new evidence, a recom- the first trimester to lower the risk of dosing for enteral/parenteral feedings
mendation was added for women with preeclampsia. (Table 14.1).
Diabetes Care Volume 41, Supplement 1, January 2018 S7

American Diabetes Association
1. Improving Care and Promoting
Health in Populations: Standards of
Medical Care in Diabetesd2018
Diabetes Care 2018;41(Suppl. 1):S7–S12 |

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes”
includes 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
multi-disciplinary expert committee, 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.
Readers who wish to comment on the Standards of Care are invited to do so at


c Ensure treatment decisions are timely, rely on evidence-based guidelines, and are
made collaboratively with patients based on individual preferences, prognoses, and
comorbidities. B
c Align approaches to diabetes management with the Chronic Care Model, em-
phasizing productive interactions between a prepared proactive care team and
an informed activated patient. A
c Care systems should facilitate team-based care, patient registries, decision sup-
port tools, and community involvement to meet patient needs. B
c Efforts to assess the quality of diabetes care and create quality improvement
strategies should incorporate reliable data metrics, to promote improved processes
of care and health outcomes, with simultaneous emphasis on costs. E

Population health is defined as “the health outcomes of a group of individuals,
including the distribution of health outcomes within the group”; these outcomes
can be measured in terms of health outcomes (mortality, morbidity, health, and func-
Suggested citation: American Diabetes Associa-
tional status), disease burden (incidence and prevalence), and behavioral and meta- tion. 1. Improving care and promoting health in
bolic factors (exercise, diet, A1C, etc.) (1). Clinical practice recommendations for health populations: Standards of Medical Care in
care providers are tools that can ultimately improve health across populations; how- Diabetesd2018. Diabetes Care 2018;41(Suppl.
ever, for optimal outcomes, diabetes care must also be individualized for each patient. 1):S7–S12
Thus, efforts to improve population health will require a combination of system-level © 2017 by the American Diabetes Association.
and patient-level approaches. With such an integrated approach in mind, the American Readers may use this article as long as the work
is properly cited, the use is educational and not
Diabetes Association (ADA) highlights the importance of patient-centered care, defined for profit, and the work is not altered. More infor-
as care that is respectful of and responsive to individual patient preferences, needs, and mation is available at http://www.diabetesjournals
values and that ensures that patient values guide all clinical decisions (2). Clinical .org/content/license.
S8 Improving Care and Promoting Health Diabetes Care Volume 41, Supplement 1, January 2018

practice recommendations, whether these factors into consideration and is psychosocial issues (25,26); and identify-
based on evidence or expert opinion, an effective framework for improving ing, developing, and engaging community
are intended to guide an overall ap- the quality of diabetes care (8). resources and public policies that support
proach to care. The science and art of Six Core Elements. The CCM includes six healthy lifestyles (27). The National Diabe-
medicine come together when the clini- core elements to optimize the care of pa- tes Education Program maintains an on-
cian is faced with making treatment rec- tients with chronic disease: line resource (www.betterdiabetescare
ommendations for a patient who may to help health care professionals
not meet the eligibility criteria used in 1. Delivery system design (moving from a design and implement more effective
the studies on which guidelines are based. reactive to a proactive care delivery health care delivery systems for those
Recognizing that one size does not fit all, system where planned visits are coordi- with diabetes.
the standards presented here provide nated through a team-based approach) The care team, which includes the pa-
guidance for when and how to adapt recom- 2. Self-management support tient, should prioritize timely and appro-
mendations for an individual. 3. Decision support (basing care on evidence- priate intensification of lifestyle and/or
based, effective care guidelines) pharmacologic therapy for patients who
Care Delivery Systems
4. Clinical information systems (using regis- have not achieved the recommended
Over the past 10 years, the proportion of tries that can provide patient-specific and metabolic targets (28–30). Strategies
patients with diabetes who achieve recom- population-based support to the care shown to improve care team behavior
mended A1C, blood pressure, and LDL cho- team) and thereby catalyze reductions in A1C,
lesterol levels has increased (3). The mean 5. Community resources and policies blood pressure, and/or LDL cholesterol
A1C nationally among people with diabe- (identifying or developing resources include engaging in explicit and collabo-
tes has declined from 7.6% (60 mmol/mol) to support healthy lifestyles) rative goal setting with patients (31,32);
6. Health systems (to create a quality- identifying and addressing language,
in 1999–2002 to 7.2% (55 mmol/mol) in
oriented culture) numeracy, or cultural barriers to care
2007–2010 based on the National Health
and Nutrition Examination Survey (NHANES), Redefining the roles of the health care (33–35); integrating evidence-based
with younger adults less likely to meet delivery team and empowering patient guidelines and clinical information tools
treatment targets than older adults (3). self-management are fundamental to into the process of care (16,36,37); solic-
This has been accompanied by improve- the successful implementation of the iting performance feedback, setting re-
ments in cardiovascular outcomes and CCM (9). Collaborative, multidisciplinary minders, and providing structured care
has led to substantial reductions in end- teams are best suited to provide care (e.g., guidelines, formal case manage-
stage microvascular complications. for people with chronic conditions such ment, and patient education resources)
Nevertheless, 33–49% of patients still as diabetes and to facilitate patients’ (7); and incorporating care management
do not meet targets for glycemic, blood self-management (10–12). teams including nurses, dietitians, pharma-
pressure, or cholesterol control, and only cists, and other providers (17,38). Initiatives
14% meet targets for all three measures Strategies for System-Level Improvement such as the Patient-Centered Medical
while also avoiding smoking (3). Evidence Optimal diabetes management requires Home show promise for improving health
suggests that progress in cardiovascular an organized, systematic approach and outcomes by fostering comprehensive
risk factor control (particularly tobacco the involvement of a coordinated team primary care and offering new opportuni-
use) may be slowing (3,4). Certain seg- of dedicated health care professionals ties for team-based chronic disease man-
ments of the population, such as young working in an environment where patient- agement (39).
adults and patients with complex comor- centered high-quality care is a priority For rural populations or those with lim-
bidities, financial or other social hard- (7,13,14). While many diabetes processes ited physical access to health care, teleme-
ships, and/or limited English proficiency, of care have improved nationally in the dicine is an approach with a growing body
face particular challenges to goal-based past decade, the overall quality of care for of evidence for its effectiveness, particu-
care (5–7). Even after adjusting for these patients with diabetes remains subopti- larly with regards to glycemic control as
patient factors, the persistent variability mal (15). Efforts to increase the quality measured by A1C (40,41). Telemedicine
in the quality of diabetes care across pro- of diabetes care include providing care is defined as the use of telecommunica-
viders and practice settings indicates that that is concordant with evidence-based tions to facilitate remote delivery of health-
substantial system-level improvements guidelines (16); expanding the role of related services and clinical information
are still needed. teams to implement more intensive dis- (42). Interactive strategies that facilitate
ease management strategies (7,17,18); communication between providers and
Chronic Care Model tracking medication-taking behavior at a patients, including the use of web-based
Numerous interventions to improve ad- systems level (19); redesigning the orga- portal or text messaging and those that
herence to the recommended standards nization of care process (20); implement- incorporate medication adjustment ap-
have been implemented. However, a ma- ing electronic health record tools (21,22); pear more effective. There is limited data
jor barrier to optimal care is a delivery empowering and educating patients available on the cost-effectiveness of these
system that is often fragmented, lacks (23,24); removing financial barriers and strategies.
clinical information capabilities, dupli- reducing patient out-of-pocket costs Successful diabetes care also requires a
cates services, and is poorly designed for for diabetes education, eye exams, self- systematic approach to supporting patients’
the coordinated delivery of chronic care. monitoring of blood glucose, and necessary behavior change efforts. High-quality di-
The Chronic Care Model (CCM) takes medications (7); assessing and addressing abetes self-management education and Improving Care and Promoting Health S9

support (DSMES) has been shown to im- quality (48,49). Using patient registries can be drawn upon to inform systems-
prove patient self-management, satisfac- and electronic health records, health sys- level strategies in diabetes. For example,
tion, and glucose outcomes. National tems can evaluate the quality of diabetes the National Academy of Medicine has
DSMES standards call for an integrated care being delivered and perform inter- published a framework for educating
approach that includes clinical content vention cycles as part of quality improve- health care professionals on the impor-
and skills, behavioral strategies (goal set- ment strategies (50). Critical to these tance of social determinants of health. Fur-
ting, problem solving), and engagement efforts is provider adherence to clinical thermore, there are resources available for
with psychosocial concerns (26). For practice recommendations and accurate, the inclusion of standardized sociodemo-
more information on DSMES, see Section reliable data metrics that include socio- graphic variables in electronic medical re-
4 “Lifestyle Management.” demographic variables to examine health cords to facilitate the measurement of
In devising approaches to support dis- equity within and across populations (51). health inequities as well as the impact of
ease self-management, it is notable that In addition to quality improvement interventions designed to reduce those in-
in 23% of cases, uncontrolled A1C, blood efforts, other strategies that simulta- equities (61–63).
pressure, or lipids was associated with neously improve the quality of care and Social determinants of health are not
poor medication-taking behaviors (19). could potentially reduce costs are gaining always recognized and often go undis-
At a system level, “adequate” medication momentum and include reimbursement cussed in the clinical encounter (57). A
taking is defined as 80% (calculated as the structures that, in contrast to visit-based study by Piette et al. (64) found that among
number of pills taken by the patient in a billing, reward the provision of appropriate patients with chronic illnesses, two-thirds
given time period divided by the number and high-quality care to achieve metabolic of those who reported not taking medi-
of pills prescribed by the physician in that goals (52) and incentives that accommo- cations as prescribed due to cost never
same time period) (19). If medication tak- date personalized care goals (7,53). shared this with their physician. In a
ing is 80% or above and treatment goals more recent study using data from the
are not met, then treatment intensifica- National Health Interview Survey (NHIS),
tion should be considered (e.g., uptitra- Patel et al. (57) found that half of adults
tion). Barriers to medication taking may with diabetes reported financial stress
include patient factors (remembering to Recommendations and one-fifth reported food insecurity
obtain or take medications, fear, depres- c Providers should assess social con- (FI). Creating systems-level mechanisms
sion, or health beliefs), medication factors text, including potential food insecu- to screen for social determinants of
(complexity, multiple daily dosing, cost, rity, housing stability, and financial health may help overcome structural bar-
or side effects), and system factors (inad- barriers, and apply that information riers and communication gaps between
equate follow-up or support). Success in to treatment decisions. A patients and providers (57). In addition,
overcoming barriers to medication taking c Refer patients to local community brief, validated screening tools for some
may be achieved if the patient and pro- resources when available. B social determinants of health exist and
vider agree on a targeted approach for a c Provide patients with self-management could facilitate discussion around factors
specific barrier (11). support from lay health coaches, that significantly impact treatment during
The Affordable Care Act has resulted in navigators, or community health the clinical encounter. Below is a discussion
increased access to care for many individ- workers when available. A of assessment and treatment consider-
uals with diabetes with an emphasis on ations in the context of FI, homelessness,
health promotion and disease prevention Health inequities related to diabetes and and limited English proficiency/low literacy.
(43). As mandated by the Affordable Care its complications are well documented
Act, the Agency for Healthcare Research and are heavily influenced by social deter- Food Insecurity
and Quality developed a National Quality minants of health (54–58). Social determi- FI is the unreliable availability of nutri-
Strategy based on the triple aims that nants of health are defined as the economic, tious food and the inability to consistently
include improving the health of a popula- environmental, political, and social condi- obtain food without resorting to socially
tion, overall quality and patient experi- tions in which people live and are responsi- unacceptable practices. Over 14% (or one
ence of care, and per capita cost (44,45). ble for a major part of health inequality of every seven people) of the U.S. popu-
As health care systems and practices worldwide (59). The ADA recognizes the lation is food insecure. The rate is higher
adapt to the changing landscape of health association between social and environ- in some racial/ethnic minority groups, in-
care, it will be important to integrate tra- mental factors and the prevention and cluding African American and Latino pop-
ditional disease-specific metrics with treatment of diabetes and has issued a ulations, in low-income households, and
measures of patient experience, as well call for research that seeks to better un- in homes headed by a single mother. The
as cost, in assessing the quality of diabe- derstand how these social determinants risk for type 2 diabetes is increased twofold
tes care (46,47). Information and guid- influence behaviors and how the relation- in those with FI (60). Risk for FI can be as-
ance specific to quality improvement ships between these variables might be sessed with a validated two-item screen-
and practice transformation for diabetes modified for the prevention and manage- ing tool (65) that includes the statements:
care is available from the National Diabe- ment of diabetes (60). While a comprehen- 1) “Within the past 12 months we worried
tes Education Program practice transfor- sive strategy to reduce diabetes-related whether our food would run out before
mation website and the National Institute health inequities in populations has not we got money to buy more” and 2)
for Diabetes and Digestive and Kidney been formally studied, general recommen- “Within the past 12 months the food we
Diseases report on diabetes care and dations from other chronic disease models bought just didn’t last and we didn’t have
S10 Improving Care and Promoting Health Diabetes Care Volume 41, Supplement 1, January 2018

money to get more.” An affirmative re- be familiar with resources or have access in U.S. diabetes care, 1999-2010. N Engl J Med
sponse to either statement had a sensi- to social workers that can facilitate tem- 2013;368:1613–1624
4. Wang J, Geiss LS, Cheng YJ, et al. Long-term
tivity of 97% and specificity of 83%. porary housing for their patients as a way
and recent progress in blood pressure levels
to improve diabetes care. among U.S. adults with diagnosed diabetes,
Treatment Considerations
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In those with diabetes and FI, the priority Language Barriers 5. Kerr EA, Heisler M, Krein SL, et al. Beyond co-
is mitigating the increased risk for uncon- Providers who care for non-English speak- morbidity counts: how do comorbidity type and
trolled hyperglycemia and severe hypo- ers should develop or offer educational severity influence diabetes patients’ treatment
glycemia. Reasons for the increased risk programs and materials in multiple lan- priorities and self-management? J Gen Intern
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ing diabetes and building diabetes
Language barriers, physician-patient language
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low-income Latinos: Latinos en control. Diabetes quality-care/diabetes-care-quality/Pages/default 80%94Measuring_Healthcare_Disparities.aspx.
Care 2011;34:838–844 .aspx. Accessed 26 September 2017 Accessed 21 October 2017
35. Osborn CY, Cavanaugh K, Wallston KA, et al. 50. O’Connor PJ, Sperl-Hillen JM, Fazio CJ, 64. Piette JD, Heisler M, Wagner TH. Cost-related
Health literacy explains racial disparities in diabe- Averbeck BM, Rank BH, Margolis KL. Outpatient medication underuse among chronically ill adults:
tes medication adherence. J Health Commun diabetes clinical decision support: current status and the treatments people forgo, how often, and who
2011;16(Suppl. 3):268–278 future directions. Diabet Med 2016;33:734–741 is at risk. Am J Public Health 2004;94:1782–1787
S12 Improving Care and Promoting Health Diabetes Care Volume 41, Supplement 1, January 2018

65. Hager ER, Quigg AM, Black MM, et al. Devel- prevention-chronic-care/improve/community/ conditions. Cochrane Database Syst Rev 2007;4:
opment and validity of a 2-item screen to identify index.html. Accessed 10 October 2016 CD005108
families at risk for food insecurity. Pediatrics 2010; 70. Shah M, Kaselitz E, Heisler M. The role of 74. Rosenthal EL, Rush CH, Allen CG; Project on
126:e26–e32 community health workers in diabetes: update CHW Policy & Practice. Understanding scope and
66. Seligman HK, Schillinger D. Hunger and socio- on current literature. Curr Diab Rep 2013;13: competencies: a contemporary look at the United
economic disparities in chronic disease. N Engl J 163–171 States community health worker field: progress report
Med 2010;363:6–9 71. Heisler M, Vijan S, Makki F, Piette JD. Diabe- of the community health worker (CHW) core consen-
67. Montgomery AE, Fargo JD, Kane V, Culhane tes control with reciprocal peer support versus sus (C3) project: building national consensus on CHW
DP. Development and validation of an instrument nurse care management: a randomized trial. core roles, skills, and qualities [Internet], 2016. Avail-
to assess imminent risk of homelessness among Ann Intern Med 2010;153:507–515 able from
veterans. Public Health Rep 2014;129:428–436 72. Long JA, Jahnle EC, Richardson DM, 1c1289f0-88cc-49c3-a238-66def942c147pdf. Ac-
68. U.S. Department of Health and Human Ser- Loewenstein G, Volpp KG. Peer mentoring and cessed 26 September 2017
vices. Think cultural health [Internet]. Available financial incentives to improve glucose control 75. U.S. Department of Health and Human Ser-
from in African American veterans: a randomized trial. vices. Community health workers help patients
Accessed 26 September 2017 Ann Intern Med 2012;156:416–424 manage diabetes [Internet]. Available from
69. Agency for Healthcare Research and Quality. 73. Foster G, Taylor SJC, Eldridge SE, Ramsay J,
Clinical-community linkages [Internet]. Avail- Griffiths CJ. Self-management education pro- community-health-workers-help-patients-
able from grammes by lay leaders for people with chronic manage-diabetes. Accessed 26 September 2017
Diabetes Care Volume 41, Supplement 1, January 2018 S13

American Diabetes Association
2. Classification and Diagnosis of
Diabetes: Standards of Medical
Care in Diabetesd2018
Diabetes Care 2018;41(Suppl. 1):S13–S27 |

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes”
includes 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, 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 Introduc-
tion. Readers who wish to comment on the Standards of Care are invited to do so

Diabetes can be classified into the following general categories:
1. Type 1 diabetes (due to autoimmune b-cell destruction, usually leading to absolute
insulin deficiency)
2. Type 2 diabetes (due to a progressive loss of b-cell insulin secretion frequently on
the background of insulin resistance)
3. Gestational diabetes mellitus (GDM) (diabetes diagnosed in the second or third
trimester of pregnancy that was not clearly overt diabetes prior to gestation)
4. Specific types of diabetes due to other causes, e.g., monogenic diabetes syndromes
(such as neonatal diabetes and maturity-onset diabetes of the young [MODY]),
diseases of the exocrine pancreas (such as cystic fibrosis and pancreatitis), and
drug- or chemical-induced diabetes (such as with glucocorticoid use, in the treat-
ment of HIV/AIDS, or after organ transplantation)

This section reviews most common forms of diabetes but is not comprehensive. For
additional information, see the American Diabetes Association (ADA) position state-
ment “Diagnosis and Classification of Diabetes Mellitus” (1).
Type 1 diabetes and type 2 diabetes are heterogeneous diseases in which clinical
presentation and disease progression may vary considerably. Classification is important
for determining therapy, but some individuals cannot be clearly classified as having Suggested citation: American Diabetes Associa-
type 1 or type 2 diabetes at the time of diagnosis. The traditional paradigms of type 2 tion. 2. Classification and diagnosis of diabetes:
diabetes occurring only in adults and type 1 diabetes only in children are no longer Standards of Medical Care in Diabetesd2018.
accurate, as both diseases occur in both age-groups. Children with type 1 diabe- Diabetes Care 2018;41(Suppl. 1):S13–S27
tes typically present with the hallmark symptoms of polyuria/polydipsia, and approx- © 2017 by the American Diabetes Association.
imately one-third present with diabetic ketoacidosis (DKA) (2). The onset of type 1 Readers may use this article as long as the work
is properly cited, the use is educational and not
diabetes may be more variable in adults, and they may not present with the classic for profit, and the work is not altered. More infor-
symptoms seen in children. Occasionally, patients with type 2 diabetes may present mation is available at http://www.diabetesjournals
with DKA, particularly ethnic minorities (3). Although difficulties in distinguishing .org/content/license.
S14 Classification and Diagnosis of Diabetes Diabetes Care Volume 41, Supplement 1, January 2018

diabetes type may occur in all age-groups defects related to inflammation and met- that compared with FPG and A1C cut
at onset, the true diagnosis becomes abolic stress among other contributors, points, the 2-h PG value diagnoses more
more obvious over time. including genetic factors. Future classi- people with diabetes.
In both type 1 and type 2 diabetes, fication schemes for diabetes will likely
various genetic and environmental fac- focus on the pathophysiology of the un-
tors can result in the progressive loss of derlying b-cell dysfunction and the stage
b-cell mass and/or function that mani- of disease as indicated by glucose status Recommendations
fests clinically as hyperglycemia. Once (normal, impaired, or diabetes) (4). c To avoid misdiagnosis or missed
hyperglycemia occurs, patients with all diagnosis, the A1C test should be
forms of diabetes are at risk for devel- DIAGNOSTIC TESTS FOR DIABETES performed using a method that is
oping the same chronic complications, Diabetes may be diagnosed based on certified by the NGSP and standard-
although rates of progression may differ. plasma glucose criteria, either the fasting ized to the Diabetes Control and
The identification of individualized thera- plasma glucose (FPG) or the 2-h plasma Complications Trial (DCCT) assay. B
pies for diabetes in the future will require glucose (2-h PG) value during a 75-g oral c Marked discordance between mea-
better characterization of the many paths glucose tolerance test (OGTT), or A1C cri- sured A1C and plasma glucose
to b-cell demise or dysfunction (4). teria (6) (Table 2.2). levels should raise the possibility
Characterization of the underlying Generally, FPG, 2-h PG during 75-g of A1C assay interference due to
pathophysiology is more developed in OGTT, and A1C are equally appropriate hemoglobin variants (i.e., hemoglo-
type 1 diabetes than in type 2 diabetes. for diagnostic testing. It should be noted binopathies) and consideration of
It is now clear from studies of first-degree that the tests do not necessarily detect using an assay without interference
relatives of patients with type 1 diabetes diabetes in the same individuals. The ef- or plasma blood glucose criteria to
that the persistent presence of two or ficacy of interventions for primary pre- diagnose diabetes. B
more autoantibodies is an almost certain vention of type 2 diabetes (7,8) has c In conditions associated with in-
predictor of clinical hyperglycemia and primarily been demonstrated among in- creased red blood cell turnover,
diabetes. The rate of progression is de- dividuals who have impaired glucose tol- such as sickle cell disease, pregnancy
pendent on the age at first detection of erance (IGT) with or without elevated (second and third trimesters), hemo-
antibody, number of antibodies, antibody fasting glucose, not for individuals with dialysis, recent blood loss or transfu-
specificity, and antibody titer. Glucose isolated impaired fasting glucose (IFG) sion, or erythropoietin therapy, only
and A1C levels rise well before the clinical or for those with prediabetes defined by plasma blood glucose criteria should
onset of diabetes, making diagnosis A1C criteria. be used to diagnose diabetes. B
feasible well before the onset of DKA. Three The same tests may be used to screen
distinct stages of type 1 diabetes can be for and diagnose diabetes and to detect The A1C test should be performed using a
identified (Table 2.1) and serve as a individuals with prediabetes. Diabetes method that is certified by the NGSP
framework for future research and regu- may be identified anywhere along the ( and standardized or
latory decision-making (4,5). spectrum of clinical scenarios: in seem- traceable to the Diabetes Control and
The paths to b-cell demise and dys- ingly low-risk individuals who happen to Complications Trial (DCCT) reference as-
function are less well defined in type 2 have glucose testing, in individuals tested say. Although point-of-care A1C assays
diabetes, but deficient b-cell insulin se- based on diabetes risk assessment, and in may be NGSP certified, proficiency testing
cretion, frequently in the setting of insulin symptomatic patients. is not mandated for performing the test,
resistance, appears to be the common de- so use of point-of-care assays for diagnos-
nominator. Characterization of subtypes Fasting and 2-Hour Plasma Glucose tic purposes is not recommended but
of this heterogeneous disorder have been The FPG and 2-h PG may be used to di- may be considered in the future if pro-
developed and validated in Scandinavian agnose diabetes (Table 2.2). The concor- ficiency testing is performed, documented,
and Northern European populations but dance between the FPG and 2-h PG tests and deemed acceptable.
have not been confirmed in other ethnic is imperfect, as is the concordance be- The A1C has several advantages com-
and racial groups. Type 2 diabetes is pri- tween A1C and either glucose-based pared with the FPG and OGTT, including
marily associated with insulin secretory test. Numerous studies have confirmed greater convenience (fasting not required),

Table 2.1—Staging of type 1 diabetes (4,5)
Stage 1 Stage 2 Stage 3
Characteristics c Autoimmunity c Autoimmunity c New-onset hyperglycemia
c Normoglycemia c Dysglycemia c Symptomatic
c Presymptomatic c Presymptomatic

Diagnostic criteria c Multiple autoantibodies c Multiple autoantibodies c Clinical symptoms
c No IGT or IFG c Dysglycemia: IFG and/or IGT c Diabetes by standard criteria
c FPG 100–125 mg/dL (5.6–6.9 mmol/L)
c 2-h PG 140–199 mg/dL (7.8–11.0 mmol/L)
c A1C 5.7–6.4% (39–47 mmol/mol) or $10% increase in A1C Classification and Diagnosis of Diabetes S15

Table 2.2—Criteria for the diagnosis of diabetes
Confirming the Diagnosis
FPG $126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 h.* Unless there is a clear clinical diagnosis
OR (e.g., patient in a hyperglycemic crisis
2-h PG $200 mg/dL (11.1 mmol/L) during OGTT. The test should be performed as described by the
or with classic symptoms of hyperglyce-
WHO, using a glucose load containing the equivalent of 75-g anhydrous glucose dissolved in water.* mia and a random plasma glucose $200
OR mg/dL [11.1 mmol/L]), a second test is
A1C $6.5% (48 mmol/mol). The test should be performed in a laboratory using a method that is required for confirmation. It is recom-
NGSP certified and standardized to the DCCT assay.* mended that the same test be repeated
OR or a different test be performed without
In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma delay using a new blood sample for con-
glucose $200 mg/dL (11.1 mmol/L). firmation. For example, if the A1C is 7.0%
(53 mmol/mol) and a repeat result is 6.8%
*In the absence of unequivocal hyperglycemia, results should be confirmed by repeat testing.
(51 mmol/mol), the diagnosis of diabetes
is confirmed. If two different tests (such
greater preanalytical stability, and less red blood cell turnover, such as those as A1C and FPG) are both above the di-
day-to-day perturbations during stress with the sickle cell trait, an A1C assay with- agnostic threshold, this also confirms
and illness. However, these advantages out interference from hemoglobin variants the diagnosis. On the other hand, if a pa-
may be offset by the lower sensitivity of should be used. An updated list of A1C tient has discordant results from two
A1C at the designated cut point, greater assays with interferences is available at different tests, then the test result that
cost, limited availability of A1C testing in is above the diagnostic cut point should
certain regions of the developing world, African Americans heterozygous for the be repeated, with consideration of the
and the imperfect correlation between common hemoglobin variant HbS may possibility of A1C assay interference. The
A1C and average glucose in certain indi- have, for any given level of mean glycemia, diagnosis is made on the basis of the con-
viduals. National Health and Nutrition lower A1C by about 0.3% than those with- firmed test. For example, if a patient meets
Examination Survey (NHANES) data indi- out the trait (11). Another genetic variant, the diabetes criterion of the A1C (two
cate that an A1C cut point of $6.5% X-linked glucose-6-phosphate dehydro- results $6.5% [48 mmol/mol]) but not
(48 mmol/mol) identifies a prevalence genase G202A, carried by 11% of African FPG (,126 mg/dL [7.0 mmol/L]), that per-
of undiagnosed diabetes that is one-third Americans, was associated with a decrease son should nevertheless be considered to
of that using glucose criteria (9). in A1C of about 0.8% in hemizygous men have diabetes.
When using A1C to diagnose diabetes, and 0.7% in homozygous women com- Since all the tests have preanalytic and
it is important to recognize that A1C is pared with those without the variant (12). analytic variability, it is possible that an
an indirect measure of average blood Even in the absence of hemoglobin abnormal result (i.e., above the diagnostic
glucose levels and to take other factors variants, A1C levels may vary with race/ threshold), when repeated, will produce a
into consideration that may impact he- ethnicity independently of glycemia value below the diagnostic cut point. This
moglobin glycation independently of (13–15). For example, African Americans scenario is likely for FPG and 2-h PG if the
glycemia including age, race/ethnicity, may have higher A1C levels than non- glucose samples remain at room temper-
and anemia/hemoglobinopathies. Hispanic whites with similar fasting and ature and are not centrifuged promptly.
postglucose load glucose levels (16), and Because of the potential for preanalytic
Age A1C levels may be higher for a given mean variability, it is critical that samples for
The epidemiological studies that formed glucose concentration when measured plasma glucose be spun and separated
the basis for recommending A1C to diag- with continuous glucose monitoring immediately after they are drawn. If pa-
nose diabetes included only adult popula- (17). Though conflicting data exists, African tients have test results near the margins
tions. Therefore, it remains unclear whether Americans may also have higher levels of the diagnostic threshold, the health care
A1C and the same A1C cut point should be of fructosamine and glycated albumin professional should follow the patient
used to diagnose diabetes in children and and lower levels of 1,5-anhydroglucitol, closely and repeat the test in 3–6 months.
adolescents (see p. S20 SCREENING AND TESTING suggesting that their glycemic burden
AND ADOLESCENTS for additional information) (18,19). The association of A1C with risk FOR DIABETES (PREDIABETES)
(9,10). for complications appears to be similar in Recommendations
African Americans and non-Hispanic c Screening for prediabetes and risk
Hemoglobin variants can interfere with whites (20,21). for future diabetes with an informal
the measurement of A1C, although most assessment of risk factors or vali-
Red Blood Cell Turnover
assays in use in the U.S. are unaffected by dated tools should be considered
In conditions associated with increased in asymptomatic adults. B
the most common variants. Marked dis- red blood cell turnover, such as sickle c Testing for prediabetes and risk for
crepancies between measured A1C and cell disease, pregnancy (second and third future diabetes in asymptomatic
plasma glucose levels should prompt con- trimesters), hemodialysis, recent blood people should be considered in
sideration that the A1C assay may not be loss or transfusion, or erythropoietin ther- adults of any age who are over-
reliable for that individual. For patients apy, only plasma blood glucose criteria weight or obese (BMI $25 kg/m2
with a hemoglobin variant but normal should be used to diagnose diabetes (22).
S16 Classification and Diagnosis of Diabetes Diabetes Care Volume 41, Supplement 1, January 2018

or $23 kg/m2 in Asian Americans) Table 2.3—Criteria for testing for diabetes or prediabetes in asymptomatic adults
and who have one or more addi- 1. Testing should be considered in overweight or obese (BMI $25 kg/m2 or $23 kg/m2 in Asian
tional risk factors for diabetes (Table Americans) adults who have one or more of the following risk factors:
c First-degree relative with diabetes
2.3). B
c High-risk race/ethnicity (e.g., African American, Latino, Native American, Asian American, Pacific
c For all people, testing should begin Islander)
at age 45 years. B c History of CVD
c If tests are normal, repeat testing car- c Hypertension ($140/90 mmHg or on therapy for hypertension)
ried out at a minimum of 3-year in- c HDL cholesterol level ,35 mg/dL (0.90 mmol/L) and/or a triglyceride level .250 mg/dL

tervals is reasonable. C (2.82 mmol/L)
c Women with polycystic ovary syndrome
c To test for prediabetes, fasting plasma
c Physical inactivity
glucose, 2-h plasma glucose during
c Other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis
75-g oral glucose tolerance test, and nigricans)
A1C are equally appropriate. B 2. Patients with prediabetes (A1C $5.7% [39 mmol/mol], IGT, or IFG) should be tested yearly.
c In patients with prediabetes, identify 3. Women who were diagnosed with GDM should have lifelong testing at least every 3 years.
and, if appropriate, treat other car-
4. For all other patients, testing should begin at age 45 years.
diovascular disease risk factors. B
5. If results are normal, testing should be repeated at a minimum of 3-year intervals, with
c Testing for prediabetes should be consideration of more frequent testing depending on initial results and risk status.
considered in children and adoles-
cents who are overweight or obese
(BMI .85th percentile for age and
review of 44,203 individuals from 16 co- interventions and vigilant follow-up should
sex, weight for height .85th per-
hort studies with a follow-up interval be pursued for those considered at very
centile, or weight .120% of ideal
averaging 5.6 years (range 2.8–12 years), high risk (e.g., those with A1C .6.0%
for height) and who have additional
those with A1C between 5.5 and 6.0% [42 mmol/mol]).
risk factors for diabetes (Table 2.5). E
(between 37 and 42 mmol/mol) had a Table 2.4 summarizes the categories of
substantially increased risk of diabetes prediabetes and Table 2.3 the criteria for
(5-year incidence from 9 to 25%). Those prediabetes testing. The ADA diabetes
“Prediabetes” is the term used for individ-
with an A1C range of 6.0–6.5% (42– risk test is an additional option for screen-
uals whose glucose levels do not meet the
48 mmol/mol) had a 5-year risk of devel- ing (Fig. 2.1) (
criteria for diabetes but are too high to be
oping diabetes between 25 and 50% For additional background regarding risk
considered normal (23,24). Patients with
and a relative risk 20 times higher com- factors and screening for prediabetes, see
prediabetes are defined by the presence
pared with A1C of 5.0% (31 mmol/mol) pp. S19–S20 (SCREENING AND TESTING FOR TYPE 2
of IFG and/or IGT and/or A1C 5.7–6.4%
(26). In a community-based study of Afri- DIABETES AND PREDIABETES IN ASYMPTOMATIC ADULTS
(39–47 mmol/mol) (Table 2.4). Prediabe-
can American and non-Hispanic white and SCREENING AND TESTING FOR TYPE 2 DIABETES
tes should not be viewed as a clinical
adults without diabetes, baseline A1C AND PREDIABETES IN CHILDREN AND ADOLESCENTS).
entity in its own right but rather as an
was a stronger predictor of subsequent
increased risk for diabetes and cardio- TYPE 1 DIABETES
diabetes and cardiovascular events
vascular disease (CVD). Criteria for testing
than fasting glucose (27). Other analyses
for diabetes or prediabetes in asymp- Recommendations
suggest that A1C of 5.7% (39 mmol/mol)
tomatic adults is outlined in Table 2.3. c Plasma blood glucose rather than
or higher is associated with a diabetes risk
Prediabetes is associated with obesity (es- A1C should be used to diagnose the
similar to that of the high-risk participants
pecially abdominal or visceral obesity), acute onset of type 1 diabetes in in-
in the Diabetes Prevention Program (DPP)
dyslipidemia with high triglycerides and/or dividuals with symptoms of hypergly-
(28), and A1C at baseline was a strong
low HDL cholesterol, and hypertension. cemia. E
predictor of the development of glucose-
c Screening for type 1 diabetes with a
Diagnosis defined diabetes during the DPP and its
panel of autoantibodies is currently
IFG is defined as FPG levels between follow-up (29).
recommended only in the setting
100 and 125 mg/dL (between 5.6 and Hence, it is reasonable to consider an A1C
of a research trial or in first-degree
6.9 mmol/L) (24,25) and IGT as 2-h PG range of 5.7–6.4% (39–47 mmol/mol) as
family members of a proband with
during 75-g OGTT levels between 140 and identifying individuals with prediabe-
type 1 diabetes. B
199 mg/dL (between 7.8 and 11.0 mmol/L) tes. Similar to those with IFG and/or
c Persistence of two or more autoan-
(23). It should be noted that the World IGT, individuals with A1C of 5.7–6.4%
tibodies predicts clinical diabetes
Health Organization (WHO) and numerous (39–47 mmol/mol) should be informed
and may serve as an indication for
other diabetes organizations define the IFG of their increased risk for diabetes and
intervention in the setting of a clin-
cutoff at 110 mg/dL (6.1 mmol/L). CVD and counseled about effective
ical trial. B
As with the glucose measures, several strategies to lower their risks (see Sec-
prospective studies that used A1C to tion 5 “Prevention or Delay of Type 2
predict the progression to diabetes as Diabetes”). Similar to glucose measure- Diagnosis
defined by A1C criteria demonstrated a ments, the continuum of risk is curvi- In a patient with classic symptoms,
strong, continuous association between A1C linear, so as A1C rises, the diabetes risk measurement of plasma glucose is suf-
and subsequent diabetes. In a systematic rises disproportionately (26). Aggressive ficient to diagnose diabetes (symptoms Classification and Diagnosis of Diabetes S17

Table 2.4—Categories of increased risk for diabetes (prediabetes)* cohorts from Finland, Germany, and the
FPG 100 mg/dL (5.6 mmol/L) to 125 mg/dL (6.9 mmol/L) (IFG) U.S. Of the 585 children who developed
OR more than two autoantibodies, nearly
2-h PG during 75-g OGTT 140 mg/dL (7.8 mmol/L) to 199 mg/dL (11.0 mmol/L) (IGT) 70% developed type 1 diabetes within
OR 10 years and 84% within 15 years (31).
A1C 5.7–6.4% (39–47 mmol/mol)
These findings are highly significant be-
cause while the German group was re-
*For all three tests, risk is continuous, extending below the lower limit of the range and becoming
disproportionately greater at the higher end of the range.
cruited from offspring of parents with
type 1 diabetes, the Finnish and American
groups were recruited from the general
of hyperglycemia or hyperglycemic crisis also related to environmental factors population. Remarkably, the findings
plus a random plasma glucose $200 mg/ that are still poorly defined. Although pa- in all three groups were the same, sug-
dL [11.1 mmol/L]). In these cases, know- tients are not typically obese when they gesting that the same sequence of events
ing the plasma glucose level is critical be- present with type 1 diabetes, obesity led to clinical disease in both “sporadic”
cause, in addition to confirming that should not preclude the diagnosis. Pa- and familial cases of type 1 diabetes. In-
symptoms are due to diabetes, it will in- tients with type 1 diabetes are also prone deed, the risk of type 1 diabetes increases
form management decisions. Some pro- to other autoimmune disorders such as as the number of relevant autoantibodies
viders may also want to know the A1C to Hashimoto thyroiditis, Graves disease, detected increases (32–34).
determine how long a patient has had Addison disease, celiac disease, vitiligo, Although there is currently a lack of
hyperglycemia. The criteria to diagnose autoimmune hepatitis, myasthenia gravis, accepted screening programs, one should
diabetes are listed in Table 2.2. and pernicious anemia (see Section 3 consider referring relatives of those with
“Comprehensive Medical Evaluation and type 1 diabetes for antibody testing for
Immune-Mediated Diabetes Assessment of Comorbidities”). risk assessment in the setting of a clinical
This form, previously called “insulin- research study (www.diabetestrialnet
dependent diabetes” or “juvenile-onset Idiopathic Type 1 Diabetes .org). Widespread clinical testing of asymp-
diabetes,” accounts for 5–10% of diabetes Some forms of type 1 diabetes have no tomatic low-risk individuals is not currently
and is due to cellular-mediated autoimmune known etiologies. These patients have recommended due to lack of approved
destruction of the pancreatic b-cells. Auto- permanent insulinopenia and are prone therapeutic interventions. Individuals who
immune markers include islet cell auto- to DKA, but have no evidence of b-cell test positive should be counseled about
antibodies and autoantibodies to GAD autoimmunity. Although only a minority the risk of developing diabetes, diabetes
(GAD65), insulin, the tyrosine phospha- of patients with type 1 diabetes fall into symptoms, and DKA prevention. Numer-
tases IA-2 and IA-2b, and ZnT8. Type 1 this category, of those who do, most are ous clinical studies are being conducted
diabetes is defined by the presence of of African or Asian ancestry. Individuals to test various methods of preventing
one or more of these autoimmune markers. with this form of diabetes suffer from ep- type 1 diabetes in those with evidence of
The disease has strong HLA associations, isodic DKA and exhibit varying degrees of autoimmunity (
with linkage to the DQA and DQB genes. insulin deficiency between episodes. This
These HLA-DR/DQ alleles can be either form of diabetes is strongly inherited and TYPE 2 DIABETES
predisposing or protective. is not HLA associated. An absolute re-
The rate of b-cell destruction is quite quirement for insulin replacement therapy
c Screening for type 2 diabetes with
variable, being rapid in some individuals in affected patients may be intermittent.
an informal assessment of risk fac-
(mainly infants and children) and slow in
tors or validated tools should be
others (mainly adults). Children and ado- Testing for Type 1 Diabetes Risk
considered in asymptomatic adults. B
lescents may present with DKA as the first The incidence and prevalence of type 1
c Testing for type 2 diabetes in asymp-
manifestation of the disease. Others have diabetes is increasing (30). Patients with
tomatic people should be consid-
modest fasting hyperglycemia that can type 1 diabetes often present with acute
ered in adults of any age who are
rapidly change to severe hyperglycemia symptoms of diabetes and markedly
overweight or obese (BMI $25
and/or DKA with infection or other stress. elevated blood glucose levels, and ap-
kg/m2 or $23 kg/m2 in Asian Amer-
Adults may retain sufficient b-cell function proximately one-third are diagnosed
icans) and who have one or more
to prevent DKA for many years; such in- with life-threatening DKA (2). Several
additional risk factors for diabetes
dividuals eventually become dependent studies indicate that measuring islet au-
(Table 2.3). B
on insulin for survival and are at risk for toantibodies in relatives of those with
c For all people, testing should begin
DKA. At this latter stage of the disease, type 1 diabetes may identify individuals
at age 45 years. B
there is little or no insulin secretion, as who are at risk for developing type 1 di-
c If tests are normal, repeat testing
manifested by low or undetectable levels abetes (5). Such testing, coupled with ed-
carried out at a minimum of 3-year
of plasma C-peptide. Immune-mediated di- ucation about diabetes symptoms and
intervals is reasonable. C
abetes commonly occurs in childhood and close follow-up, may enable earlier iden-
c To test for type 2 diabetes, fasting
adolescence, but it can occur at any age, tification of type 1 diabetes onset. A study
plasma glucose, 2-h plasma glucose
even in the 8th and 9th decades of life. reported the risk of progression to type 1
during 75-g oral glucose tolerance test,
Autoimmune destruction of b-cells has diabetes from the time of seroconversion
and A1C are equally appropriate. B
multiple genetic predispositions and is to autoantibody positivity in three pediatric
S18 Classification and Diagnosis of Diabetes Diabetes Care Volume 41, Supplement 1, January 2018

Figure 2.1—ADA risk test ( Classification and Diagnosis of Diabetes S19

36). Type 2 diabetes frequently goes un- assessment tool, such as the ADA risk
c In patients with diabetes, identify
diagnosed for many years because hy- test (Fig. 2.1) (,
and treat other cardiovascular dis-
perglycemia develops gradually and, is recommended to guide providers on
ease risk factors. B
at earlier stages, is often not severe whether performing a diagnostic test
c Testing for type 2 diabetes should
enough for the patient to notice the clas- (Table 2.2) is appropriate. Prediabetes
be considered in children and ado-
sic diabetes symptoms. Nevertheless, and type 2 diabetes meet criteria for con-
lescents who are overweight or
even undiagnosed patients are at in- ditions in which early detection is appro-
obese (BMI .85th percentile for
creased risk of developing macrovascular priate. Both conditions are common and
age and sex, weight for height
and microvascular complications. impose significant clinical and public
.85th percentile, or weight .120%
Whereas patients with type 2 diabetes health burdens. There is often a long pre-
of ideal for height) and who have
may have insulin levels that appear nor- symptomatic phase before the diagnosis
additional risk factors for diabetes
mal or elevated, the higher blood glucose of type 2 diabetes. Simple tests to detect
(Table 2.5). E
levels in these patients would be expected preclinical disease are readily available.
to result in even higher insulin values had The duration of glycemic burden is a strong
Description their b-cell function been normal. Thus, predictor of adverse outcomes. There are
Type 2 diabetes, previously referred to insulin secretion is defective in these pa- effective interventions that prevent pro-
as “noninsulin-dependent diabetes” or tients and insufficient to compensate for gression from prediabetes to diabetes (see
“adult-onset diabetes,” accounts for 90– insulin resistance. Insulin resistance may Section 5 “Prevention or Delay of Type 2
95% of all diabetes. This form encom- improve with weight reduction and/or Diabetes”) and reduce the risk of diabetes
passes individuals who have relative pharmacologic treatment of hyperglyce- complications (see Section 9 “Cardiovas-
(rather than absolute) insulin deficiency mia but is seldom restored to normal. cular Disease and Risk Management” and
and have peripheral insulin resistance. The risk of developing type 2 diabe- Section 10 “Microvascular Complications
At least initially, and often throughout tes increases with age, obesity, and lack and Foot Care”).
their lifetime, these individuals may not of physical activity. It occurs more fre- Approximately one-quarter of people
need insulin treatment to survive. quently in women with prior GDM, in with diabetes in the U.S. and nearly half
There are various causes of type 2 di- those with hypertension or dyslipidemia, of Asian and Hispanic Americans with di-
abetes. Although the specific etiologies and in certain racial/ethnic subgroups abetes are undiagnosed (37,38). Although
are not known, autoimmune destruction (African American, American Indian, screening of asymptomatic individuals to
of b-cells does not occur and patients do Hispanic/Latino, and Asian American). It identify those with prediabetes or diabe-
not have any of the other known causes is often associated with a strong genetic tes might seem reasonable, rigorous clin-
of diabetes. Most but not all patients with predisposition or family history in first- ical trials to prove the effectiveness of
type 2 diabetes are overweight or obese. degree relatives, more so than type 1 di- such screening have not been conducted
Excess weight itself causes some degree abetes. However, the genetics of type 2 and are unlikely to occur.
of insulin resistance. Patients who are not diabetes is poorly understood. In adults A large European randomized con-
obese or overweight by traditional weight without traditional risk factors for type 2 trolled trial compared the impact of
criteria may have an increased percent- diabetes and/or younger age, consider screening for diabetes and intensive
age of body fat distributed predominantly antibody testing to exclude the diagnosis multifactorial intervention with that of
in the abdominal region. of type 1 diabetes (i.e., GAD). screening and routine care (39). General
DKA seldom occurs spontaneously in practice patients between the ages of
type 2 diabetes; when seen, it usually Screening and Testing for Type 2 40 and 69 years were screened for diabe-
arises in association with the stress of an- Diabetes and Prediabetes in tes and randomly assigned by practice to
other illness such as infection or with the Asymptomatic Adults intensive treatment of multiple risk fac-
use of certain drugs (e.g., corticosteroids, Screening for prediabetes and type 2 di- tors or routine diabetes care. After 5.3
atypical antipsychotics, and sodium– abetes through an informal assessment years of follow-up, CVD risk factors were
glucose cotransporter 2 inhibitors) (35, of risk factors (Table 2.3) or with an modestly but significantly improved with
intensive treatment compared with rou-
tine care, but the incidence of first CVD
Table 2.5—Risk-based screening for type 2 diabetes or prediabetes in asymptomatic events or mortality was not significantly
children and adolescents in a clinical setting* different between the groups (39). The
Criteria excellent care provided to patients in
c Overweight (BMI .85th percentile for age and sex, weight for height .85th percentile, or the routine care group and the lack of
weight .120% of ideal for height) A an unscreened control arm limited the
Plus one or more additional risk factors based on the strength of their association with diabetes as authors’ ability to determine whether
indicated by evidence grades: screening and early treatment improved
c Maternal history of diabetes or GDM during the child’s gestation A
outcomes compared with no screening
c Family history of type 2 diabetes in first- or second-degree relative A
and later treatment after clinical diag-
c Race/ethnicity (Native American, African American, Latino, Asian American, Pacific Islander) A
c Signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans,
noses. Computer simulation modeling
hypertension, dyslipidemia, polycystic ovary syndrome, or small-for-gestational-age birth weight) B studies suggest that major benefits are
likely to accrue from the early diagnosis
*Persons aged ,18 years.
and treatment of hyperglycemia and
S20 Classification and Diagnosis of Diabetes Diabetes Care Volume 41, Supplement 1, January 2018

cardiovascular risk factors in type 2 reduced and individuals with false-negative limited data supporting A1C for diag-
diabetes (40); moreover, screening, be- tests will be retested before substantial time nosing type 2 diabetes in children and
ginning at age 30 or 45 years and indepen- elapses and complications develop (47). adolescents. Although A1C is not recom-
dent of risk factors, may be cost-effective mended for diagnosis of diabetes in chil-
Community Screening
(,$11,000 per quality-adjusted life-year dren with cystic fibrosis or symptoms
Ideally, testing should be carried out
gained) (41). suggestive of acute onset of type 1 diabe-
within a health care setting because of
Additional considerations regarding tes and only A1C assays without interfer-
the need for follow-up and treatment.
testing for type 2 diabetes and prediabe- ence are appropriate for children with
Community screening outside a health
tes in asymptomatic patients include the hemoglobinopathies, the ADA continues
care setting is generally not recom-
following. to recommend A1C for diagnosis of type 2
mended because people with positive
diabetes in this cohort (54,55).
Age tests may not seek, or have access to,
Age is a major risk factor for diabetes. appropriate follow-up testing and care.
Testing should begin at age 45 years for However, in specific situations where an GESTATIONAL DIABETES MELLITUS
all patients. Screening should be consid- adequate referral system is established Recommendations
ered in overweight or obese adults of beforehand for positive tests, community c Test for undiagnosed diabetes at
any age with one or more risk factors for screening may be considered. Commu- the first prenatal visit in those
diabetes. nity testing may also be poorly targeted; with risk factors, using standard di-
BMI and Ethnicity
i.e., it may fail to reach the groups most at agnostic criteria. B
In general, BMI $25 kg/m2 is a risk factor risk and inappropriately test those at very c Test for gestational diabetes melli-
for diabetes. However, data suggest that low risk or even those who have already tus at 24–28 weeks of gestation in
the BMI cut point should be lower for been diagnosed (48). pregnant women not previously
the Asian American population (42,43). Screening in Dental Practices known to have diabetes. A
The BMI cut points fall consistently be- Because periodontal disease is associated c Test women with gestational diabe-
tween 23 and 24 kg/m2 (sensitivity of with diabetes, the utility of screening in a tes mellitus for persistent diabetes
80%) for nearly all Asian American sub- dental setting and referral to primary care at 4–12 weeks postpartum, using
groups (with levels slightly lower for Jap- as a means to improve the diagnosis of the oral glucose tolerance test and
anese Americans). This makes a rounded prediabetes and diabetes has been ex- clinically appropriate nonpregnancy
cut point of 23 kg/m2 practical. An argu- plored (49–51), with one study estimating diagnostic criteria. E
ment can be made to push the BMI cut that 30% of patients $30 years of age c Women with a history of gesta-
point to lower than 23 kg/m2 in favor of seen in general dental practices had dys- tional diabetes mellitus should
increased sensitivity; however, this would glycemia (51). Further research is needed have lifelong screening for the de-
lead to an unacceptably low specificity to demonstrate the feasibility, effective- velopment of diabetes or prediabe-
(13.1%). Data from the WHO also suggest ness, and cost-effectiveness of screening tes at least every 3 years. B
that a BMI of $23 kg/m2 should be used in this setting. c Women with a history of gesta-
to define increased risk in Asian Ameri- tional diabetes mellitus found to
cans (44). The finding that half of diabetes Screening and Testing for Type 2 have prediabetes should receive in-
in Asian Americans is undiagnosed sug- Diabetes and Prediabetes in Children tensive lifestyle interventions or
gests that testing is not occurring at lower and Adolescents metformin to prevent diabetes. A
BMI thresholds (37,38). In the last decade, the incidence and prev-
Evidence also suggests that other pop- alence of type 2 diabetes in adolescents Definition
ulations may benefit from lower BMI cut has increased dramatically, especially in For many years, GDM was defined as any
points. For example, in a large multiethnic racial and ethnic minority populations degree of glucose intolerance that was
cohort study, for an equivalent incidence (30). See Table 2.5 for recommendations first recognized during pregnancy (23), re-
rate of diabetes, a BMI of 30 kg/m2 in non- on risk-based screening for type 2 diabe- gardless of whether the condition may
Hispanic whites was equivalent to a BMI tes or prediabetes in asymptomatic chil- have predated the pregnancy or persisted
of 26 kg/m2 in African Americans (45). dren and adolescents in a clinical setting. See after the pregnancy. This definition facili-
Section 12 “Children and Adolescents” for tated a uniform strategy for detection and
additional information on type 2 diabetes classification of GDM, but it was limited by
Certain medications, such as glucocorti-
in children and adolescents. imprecision.
coids, thiazide diuretics, and atypical an-
Some studies question the validity of The ongoing epidemic of obesity and
tipsychotics (46), are known to increase
A1C in the pediatric population, especially diabetes has led to more type 2 diabetes
the risk of diabetes and should be consid-
among certain ethnicities, and suggest in women of childbearing age, with an in-
ered when deciding whether to screen.
OGTT or FPG as more suitable diagnos- crease in the number of pregnant women
Testing Interval tic tests (52). However, many of these with undiagnosed type 2 diabetes (56).
The appropriate interval between screen- studies do not recognize that diabetes di- Because of the number of pregnant
ing tests is not known (47). The rationale agnostic criteria are based on long-term women with undiagnosed type 2 diabetes,
for the 3-year interval is that with this in- health outcomes, and validations are not it is reasonable to test women with risk
terval, the number of false-positive tests currently available in the pediatric popu- factors for type 2 diabetes (Table 2.3) at
that require confirmatory testing will be lation (53). The ADA acknowledges the their initial prenatal visit, using standard Classification and Diagnosis of Diabetes S21

diagnostic criteria (Table 2.2). Women di- One-Step Strategy Two-Step Strategy
agnosed with diabetes by standard diag- The IADPSG defined diagnostic cut points In 2013, the National Institutes of Health
nostic criteria in the first trimester should for GDM as the average fasting, 1-h, and (NIH) convened a consensus develop-
be classified as having preexisting preges- 2-h PG values during a 75-g OGTT in ment conference to consider diagnostic
tational diabetes (type 2 diabetes or, very women at 24–28 weeks of gestation criteria for diagnosing GDM (68). The
rarely, type 1 diabetes or monogenic dia- who participated in the HAPO study at 15-member panel had representatives
betes). GDM is diabetes that is first diag- which odds for adverse outcomes reached from obstetrics/gynecology, maternal-
nosed in the second or third trimester of 1.75 times the estimated odds of these fetal medicine, pediatrics, diabetes re-
pregnancy that is not clearly either preex- outcomes at the mean fasting, 1-h, and search, biostatistics, and other related
isting type 1 or type 2 diabetes (see Section 2-h PG levels of the study population. fields. The panel recommended a two-
13 “Management of Diabetes in Preg- This one-step strategy was anticipated to step approach to screening that used a
nancy”). The International Association of significantly increase the incidence of 1-h 50-g glucose load test (GLT) followed
the Diabetes and Pregnancy Study Groups GDM (from 5–6% to 15–20%), primarily by a 3-h 100-g OGTT for those who screened
(IADPSG) GDM diagnostic criteria for the because only one abnormal value, not positive. The American College of Ob-
75-g OGTT as well as the GDM screening two, became sufficient to make the di- stetricians and Gynecologists (ACOG) rec-
and diagnostic criteria used in the two- agnosis (63). The anticipated increase in ommends any of the commonly used
step approach were not derived from the incidence of GDM could have a sub- thresholds of 130, 135, or 140 mg/dL for
data in the first half of pregnancy, so stantial impact on costs and medical in- the 1-h 50-g GLT (69). A systematic review
the diagnosis of GDM in early pregnancy frastructure needs and has the potential for the U.S. Preventive Services Task Force
by either FPG or OGTT values is not evi- to “medicalize” pregnancies previously compared GLT cutoffs of 130 mg/dL
dence based (57). categorized as normal. Nevertheless, (7.2 mmol/L) and 140 mg/dL (7.8 mmol/L)
Because GDM confers increased risk the ADA recommends these diagnostic (70). The higher cutoff yielded sensitivity
for the development of type 2 diabetes criteria with the intent of optimizing of 70–88% and specificity of 69–89%,
after delivery (58,59) and because effec- gestational outcomes because these cri- while the lower cutoff was 88–99% sensi-
tive prevention interventions are avail- teria were the only ones based on preg- tive and 66–77% specific. Data regarding
able (60,61), women diagnosed with nancy outcomes rather than end points a cutoff of 135 mg/dL are limited. As for
GDM should receive lifelong screening such as prediction of subsequent mater- other screening tests, choice of a cutoff
for prediabetes and type 2 diabetes. nal diabetes. is based upon the trade-off between sen-
The expected benefits to the offspring sitivity and specificity. The use of A1C at
are inferred from intervention trials that 24–28 weeks of gestation as a screening
GDM carries risks for the mother and ne- focused on women with lower levels of test for GDM does not function as well as
onate. Not all adverse outcomes are of hyperglycemia than identified using older the GLT (71).
equal clinical importance. The Hypergly- GDM diagnostic criteria. Those trials Key factors cited by the NIH panel in
cemia and Adverse Pregnancy Outcome found modest benefits including reduced their decision-making process were the
(HAPO) study (62), a large-scale multina- rates of large-for-gestational-age births lack of clinical trial data demonstrating
tional cohort study completed by more and preeclampsia (64,65). It is important the benefits of the one-step strategy
than 23,000 pregnant women, demon- to note that 80–90% of women being and the potential negative consequences
strated that risk of adverse maternal, fe- treated for mild GDM in two randomized of identifying a large group of women
tal, and neonatal outcomes continuously controlled trials could be managed with with GDM, including medicalization of
increased as a function of maternal glyce- lifestyle therapy alone. The OGTT glucose pregnancy with increased health care uti-
mia at 24–28 weeks of gestation, even cutoffs in these two trials overlapped lization and costs. Moreover, screening
within ranges previously considered nor- with the thresholds recommended by with a 50-g GLT does not require fasting
mal for pregnancy. For most complications, the IADPSG, and in one trial (65), the 2-h and is therefore easier to accomplish for
there was no threshold for risk. These re- PG threshold (140 mg/dL [7.8 mmol/L]) many women. Treatment ofhigher-threshold
sults have led to careful reconsideration of was lower than the cutoff recommended maternal hyperglycemia, as identified by the
the diagnostic criteria for GDM. GDM di- by the IADPSG (153 mg/dL [8.5 mmol/L]). two-step approach, reduces rates of neona-
agnosis (Table 2.6) can be accomplished No randomized controlled trials of identi- tal macrosomia, large-for-gestational-age
with either of two strategies: fying and treating GDM using the IADPSG births (72), and shoulder dystocia, without
criteria versus older criteria have been increasing small-for-gestational-age births.
1. “One-step” 75-g OGTT or published to date. Data are also lacking ACOG currently supports the two-step ap-
2. “Two-step” approach with a 50-g (non- on how the treatment of lower levels of proach (69) but most recently noted that
fasting) screen followed by a 100-g hyperglycemia affects a mother’s future one elevated value, as opposed to two, may
OGTT for those who screen positive risk for the development of type 2 diabe- be used for the diagnosis of GDM. If this
tes and her offspring’s risk for obesity, approach is implemented, the incidence of
Different diagnostic criteria will identify diabetes, and other metabolic disorders. GDM by the two-step strategy will likely in-
different degrees of maternal hypergly- Additional well-designed clinical studies crease markedly. ACOG recommends either
cemia and maternal/fetal risk, leading are needed to determine the optimal in- of two sets of diagnostic thresholds for the
some experts to debate, and disagree on, tensity of monitoring and treatment of 3-h 100-g OGTT (73,74). Each is based on
optimal strategies for the diagnosis of women with GDM diagnosed by the different mathematical conversions of
GDM. one-step strategy (66,67). the original recommended thresholds,
S22 Classification and Diagnosis of Diabetes Diabetes Care Volume 41, Supplement 1, January 2018

Table 2.6—Screening for and diagnosis of GDM
One-step strategy
Perform a 75-g OGTT, with plasma glucose measurement when patient is fasting and at 1 and 2 h, at 24–28 weeks of gestation in women not previously
diagnosed with overt diabetes.
The OGTT should be performed in the morning after an overnight fast of at least 8 h.
The diagnosis of GDM is made when any of the following plasma glucose values are met or exceeded:
c Fasting: 92 mg/dL (5.1 mmol/L)
c 1 h: 180 mg/dL (10.0 mmol/L)
c 2 h: 153 mg/dL (8.5 mmol/L)
Two-step strategy
Step 1: Perform a 50-g GLT (nonfasting), with plasma glucose measurement at 1 h, at 24–28 weeks of gestation in women not previously diagnosed with
overt diabetes.
If the plasma glucose level measured 1 h after the load is $130 mg/dL, 135 mg/dL, or 140 mg/dL (7.2 mmol/L, 7.5 mmol/L, or 7.8 mmol/L), proceed to a
100-g OGTT.
Step 2: The 100-g OGTT should be performed when the patient is fasting.
The diagnosis of GDM is made if at least two* of the following four plasma glucose levels (measured fasting and 1 h, 2 h, 3 h during OGTT) are met or
Carpenter-Coustan (73) or NDDG (74)
cFasting 95 mg/dL (5.3 mmol/L) 105 mg/dL (5.8 mmol/L)
c1h 180 mg/dL (10.0 mmol/L) 190 mg/dL (10.6 mmol/L)
c2h 155 mg/dL (8.6 mmol/L) 165 mg/dL (9.2 mmol/L)
c3h 140 mg/dL (7.8 mmol/L) 145 mg/dL (8.0 mmol/L)
NDDG, National Diabetes Data Group. *ACOG recently noted that alternatively one elevated value can be used for diagnosis.

which used whole blood and nonenzymatic outcomes with one-step versus two-step
approach further evaluation, treat-
methods for glucose determination. A re- approaches have been inconsistent to date
ment, and genetic counseling. E
cent secondary analysis of data from a ran- (78,79). In addition, pregnancies compli-
domized clinical trial of identification and cated by GDM per the IADPSG criteria, but
Monogenic defects that cause b-cell dys-
treatment of mild GDM (75) demon- not recognized as such, have comparable
function, such as neonatal diabetes and
strated that treatment was similarly ben- outcomes to pregnancies diagnosed as
MODY, represent a small fraction of pa-
eficial in patients meeting only the lower GDM by the more stringent two-step crite-
tients with diabetes (,5%). Table 2.7
thresholds (73) and in those meeting only ria (80,81). There remains strong consen-
describes the most common causes of
the higher thresholds (74). If the two-step sus that establishing a uniform approach
monogenic diabetes. For a comprehen-
approach is used, it would appear advan- to diagnosing GDM will benefit patients,
sive list of causes, see Genetic Diagnosis
tageous to use the lower diagnostic thresh- caregivers, and policy makers. Longer-
of Endocrine Disorders (82).
olds as shown in step 2 in Table 2.6. term outcome studies are currently under
Future Considerations Neonatal Diabetes
The conflicting recommendations from MONOGENIC DIABETES Diabetes occurring under 6 months of age
expert groups underscore the fact that SYNDROMES is termed “neonatal” or “congenital” di-
there are data to support each strategy. abetes, and about 80–85% of cases can be
A cost-benefit estimation comparing the found to have an underlying monogenic
c All children diagnosed with diabe-
two strategies concluded that the one- cause (83). Neonatal diabetes occurs much
tes in the first 6 months of life
step approach is cost-effective only if less often after 6 months of age, whereas
should have immediate genetic
patients with GDM receive postdelivery autoimmune type 1 diabetes rarely occurs
testing for neonatal diabetes. A
counseling and care to prevent type 2 di- before 6 months of age. Neonatal diabetes
c Children and adults, diagnosed in
abetes (76). The decision of which strategy can either be transient or permanent. Tran-
early adulthood, who have diabetes
to implement must therefore be made sient diabetes is most often due to over-
not characteristic of type 1 or type 2
based on the relative values placed on fac- expression of genes on chromosome 6q24,
diabetes that occurs in successive
tors that have yet to be measured (e.g., is recurrent in about half of cases, and may
generations (suggestive of an auto-
willingness to change practice based on be treatable with medications other than
somal dominant pattern of inheri-
correlation studies rather than intervention insulin. Permanent neonatal diabetes is
tance) should have genetic testing
trial results, available infrastructure, and most commonly due to autosomal domi-
for maturity-onset diabetes of the
importance of cost considerations). nant mutations in the genes encoding the
young. A
As the IADPSG criteria (“one-step strat- Kir6.2 subunit (KCNJ11) and SUR1 subunit
c In both instances, consultation
egy”) have been adopted internationally, (ABCC8) of the b-cell KATP channel. Correct
with a center specializing in diabe-
further evidence has emerged to support diagnosis has critical implications because
tes genetics is recommended to
improved pregnancy outcomes with cost most patients with KATP-related neonatal
understand the significance of
savings (77) and may be the preferred ap- diabetes will exhibit improved glycemic
these mutations and how best to
proach. Data comparing population-wide control when treated with high-dose oral Classification and Diagnosis of Diabetes S23

Table 2.7—Most common causes of monogenic diabetes (82)
Gene Inheritance Clinical features
GCK AD GCK-MODY: stable, nonprogressive elevated fasting blood
glucose; typically does not require treatment;
microvascular complications are rare; small rise in 2-h PG
level on OGTT (,54 mg/dL [3 mmol/L])
HNF1A AD HNF1A-MODY: progressive insulin secretory defect with
presentation in adolescence or early adulthood; lowered
renal threshold for glucosuria; large rise in 2-h PG level on
OGTT (.90 mg/dL [5 mmol/L]); sensitive to sulfonylureas
HNF4A AD HNF4A-MODY: progressive insulin secretory defect with
presentation in adolescence or early adulthood; may have
large birth weight and transient neonatal hypoglycemia;
sensitive to sulfonylureas
HNF1B AD HNF1B-MODY: developmental renal disease (typically
cystic); genitourinary abnormalities; atrophy of the
pancreas; hyperuricemia; gout
Neonatal diabetes
KCNJ11 AD Permanent or transient: IUGR; possible developmental delay
and seizures; responsive to sulfonylureas
INS AD Permanent: IUGR; insulin requiring
ABCC8 AD Transient or permanent: IUGR; rarely developmental delay;
responsive to sulfonylureas
6q24 (PLAGL1, HYMA1) AD for paternal duplications Transient: IUGR; macroglossia; umbilical hernia;
mechanisms include UPD6, paternal duplication or
maternal methylation defect; may be treatable with
medications other than insulin
GATA6 AD Permanent: pancreatic hypoplasia; cardiac malformations;
pancreatic exocrine insufficiency; insulin requiring
EIF2AK3 AR Permanent: Wolcott-Rallison syndrome: epiphyseal
dysplasia; pancreatic exocrine insufficiency; insulin
FOXP3 X-linked Permanent: immunodysregulation, polyendocrinopathy,
enteropathy X-linked (IPEX) syndrome: autoimmune
diabetes; autoimmune thyroid disease; exfoliative
dermatitis; insulin requiring
AD, autosomal dominant; AR, autosomal recessive; IUGR, intrauterine growth restriction.

sulfonylureas instead of insulin. Insulin gene (MODY2), HNF1A-MODY (MODY3), and therapy for GCK-MODY; sulfonylureas as
(INS) mutations are the second most com- HNF4A-MODY (MODY1). first-line therapy for HNF1A-MODY and
mon cause of permanent neonatal dia- Clinically, patients with GCK-MODY ex- HNF4A-MODY). Additionally, diagnosis
betes, and, while treatment presently is hibit mild, stable, fasting hyperglycemia can lead to identification of other affected
intensive insulin management, there are and do not require antihyperglycemic family members.
important genetic considerations, as most therapy except sometimes during preg- A diagnosis of MODY should be consid-
of the mutations that cause diabetes are nancy. Patients with HNF1A- or HNF4A- ered in individuals who have atypical di-
dominantly inherited. MODY usually respond well to low doses abetes and multiple family members with
of sulfonylureas, which are considered diabetes not characteristic of type 1 or
Maturity-Onset Diabetes of the Young first-line therapy. Mutations or deletions in type 2 diabetes, although admittedly “atyp-
MODY is frequently characterized by on- HNF1B are associated with renal cysts and ical diabetes” is becoming increasingly
set of hyperglycemia at an early age (clas- uterine malformations (renal cysts and di- difficult to precisely define in the absence
sically before age 25 years, although abetes [RCAD] syndrome). Other extremely of a definitive set of tests for either type
diagnosis may occur at older ages). rare forms of MODY have been reported to of diabetes. In most cases, the presence of
MODY is characterized by impaired insu- involve other transcription factor genes in- autoantibodies for type 1 diabetes pre-
lin secretion with minimal or no defects in cluding PDX1 (IPF1) and NEUROD1. cludes further testing for monogenic dia-
insulin action (in the absence of coexis- betes, but the presence of autoantibodies
tent obesity). It is inherited in an autoso- Diagnosis in patients with monogenic diabetes has
mal dominant pattern with abnormalities A diagnosis of one of the three most com- been reported (84). Individuals in whom
in at least 13 genes on different chromo- mon forms of MODY including GCK- monogenic diabetes is suspected should
somes identified to date. The most com- MODY, HNF1A-MODY, and HNF4A-MODY be referred to a specialist for further eval-
monly reported forms are GCK-MODY allows for more cost-effective therapy (no uation if available, and consultation is
S24 Classification and Diagnosis of Diabetes Diabetes Care Volume 41, Supplement 1, January 2018

available from several centers. Readily Insulin remains the most widely used
c Patients with cystic fibrosis–related
available commercial genetic testing fol- therapy for CFRD (94).
diabetes should be treated with in-
lowing the criteria listed below now Additional resources for the clinical
sulin to attain individualized glyce-
enables a cost-effective (85), often cost- management of CFRD can be found in
mic goals. A
saving, genetic diagnosis that is increas- the position statement “Clinical Care
c Beginning 5 years after the diagnosis
ingly supported by health insurance. A Guidelines for Cystic Fibrosis–Related Di-
of cystic fibrosis–related diabetes,
biomarker screening pathway such as the abetes: A Position Statement of the
annual monitoring for complications
combination of urinary C-peptide/creatinine American Diabetes Association and a Clin-
of diabetes is recommended. E
ratio and antibody screening may aid in ical Practice Guideline of the Cystic Fibro-
determining who should get genetic sis Foundation, Endorsed by the Pediatric
Cystic fibrosis–related diabetes (CFRD) is
testing for MODY (86). It is critical to cor- Endocrine Society” (95) and in the Interna-
the most common comorbidity in people
rectly diagnose one of the monogenic tional Society for Pediatric and Adoles-
with cystic fibrosis, occurring in about
forms of diabetes because these pa- cent Diabetes’s 2014 clinical practice
20% of adolescents and 40–50% of adults.
tients may be incorrectly diagnosed consensus guidelines (96).
Diabetes in this population, compared
with type 1 or type 2 diabetes, leading to
with individuals with type 1 or type 2 di-
suboptimal, even potentially harmful, treat-
abetes, is associated with worse nutri- POSTTRANSPLANTATION
ment regimens and delays in diagnosing
tional status, more severe inflammatory DIABETES MELLITUS
other family members (87). The correct di-
lung disease, and greater mortality. Insu-
agnosis is especially critical for those with Recommendations
lin insufficiency is the primary defect in
GCK-MODY mutations where multiple c Patients should be screened after
studies have shown that no complications CFRD. Genetically determined b-cell func-
organ transplantation for hypergly-
ensue in the absence of glucose-lowering tion and insulin resistance associated with
cemia, with a formal diagnosis of
therapy (88). Genetic counseling is rec- infection and inflammation may also con-
posttransplantation diabetes melli-
ommended to ensure that affected individ- tribute to the development of CFRD. tus being best made once a patient
uals understand the patterns of inheritance Milder abnormalities of glucose tolerance is stable on an immunosuppressive
and the importance of a correct diagnosis. are even more common and occur at ear- regimen and in the absence of an
The diagnosis of monogenic diabetes lier ages than CFRD. Whether individuals acute infection. E
should be considered in children and with IGT should be treated with insulin c The oral glucose tolerance test is
adults diagnosed with diabetes in early replacement has not currently been de- the preferred test to make a diag-
adulthood with the following findings: termined. Although screening for diabe- nosis of posttransplantation diabe-
tes before the age of 10 years can identify tes mellitus. B
○ Diabetes diagnosed within the first risk for progression to CFRD in those with c Immunosuppressive regimens shown
6 months of life (with occasional cases abnormal glucose tolerance, no benefit to provide the best outcomes for pa-
presenting later, mostly INS and ABCC8 has been established with respect to tient and graft survival should be
mutations) (83,89) weight, height, BMI, or lung function. used, irrespective of posttransplanta-
○ Diabetes without typical features of Continuous glucose monitoring or HOMA tion diabetes mellitus risk. E
type 1 or type 2 diabetes (negative di- of b-cell function (90) may be more sen-
abetes-associated autoantibodies, sitive than OGTT to detect risk for pro- Several terms are used in the literature to
nonobese, lacking other metabolic fea- gression to CFRD; however, evidence describe the presence of diabetes follow-
tures, especially with strong family linking these results to long-term out- ing organ transplantation. “New-onset di-
history of diabetes) comes is lacking, and these tests are not abetes after transplantation” (NODAT) is
○ Stable, mild fasting hyperglycemia recommended for screening (91). one such designation that describes indi-
(100–150 mg/dL [5.5–8.5 mmol/L]), CFRD mortality has significantly de- viduals who develop new-onset diabetes
stable A1C between 5.6 and 7.6% (be- creased over time, and the gap in mortal- following transplant. NODAT excludes pa-
tween 38 and 60 mmol/mol), espe- ity between cystic fibrosis patients with tients with pretransplant diabetes that
cially if nonobese and without diabetes has considerably was undiagnosed as well as posttrans-
narrowed (92). There are limited clinical plant hyperglycemia that resolves by the
CYSTIC FIBROSIS–RELATED trial data on therapy for CFRD. The largest time of discharge (97). Another term,
DIABETES study compared three regimens: premeal “posttransplantation diabetes mellitus”
insulin aspart, repaglinide, or oral placebo (PTDM) (97,98), describes the presence
in cystic fibrosis patients with diabetes or of diabetes in the posttransplant setting
c Annual screening for cystic fibrosis–
abnormal glucose tolerance. Participants irrespective of the timing of diabetes onset.
related diabetes with oral glucose
all had weight loss in the year preced- Hyperglycemia is very common during
tolerance test should begin by age
ing treatment; however, in the insulin- the early posttransplant period, with
10 years in all patients with cystic fi-
treated group, this pattern was reversed, ;90% of kidney allograft recipients ex-
brosis not previously diagnosed with
and patients gained 0.39 (6 0.21) BMI hibiting hyperglycemia in the first few
cystic fibrosis–related diabetes. B
units (P 5 0.02). The repaglinide-treated weeks following transplant (97–100).
c A1C is not recommended as a
group had initial weight gain, but this was In most cases, such stress- or steroid-
screening test for cystic fibrosis–
not sustained by 6 months. The placebo induced hyperglycemia resolves by the
related diabetes. B
group continued to lose weight (93). time of discharge (100,101). Although Classification and Diagnosis of Diabetes S25

the use of immunosuppressive therapies metformin was safe to use in renal trans- transethnic genome-wide meta-analysis. PLoS
is a major contributor to the development plant recipients (108), but its safety has Med 2017;14:e1002383
13. Ziemer DC, Kolm P, Weintraub WS, et al.
of PTDM, the risks of transplant rejection not been determined in other types of Glucose-independent, black-white differences in
outweigh the risks of PTDM and the role organ transplant. Thiazolidinediones hemoglobin A1c levels: a cross-sectional analysis
of the diabetes care provider is to treat have been used successfully in patients of 2 studies. Ann Intern Med 2010;152:770–777
hyperglycemia appropriately regard- with liver and kidney transplants, but 14. Kumar PR, Bhansali A, Ravikiran M, et al. Util-
less of the type of immunosuppression side effects include fluid retention, heart ity of glycated hemoglobin in diagnosing type 2
diabetes mellitus: a community-based study.
(97). Risk factors for PTDM include both failure, and osteopenia (109,110). Dipep- J Clin Endocrinol Metab 2010;95:2832–2835
general diabetes risks (such as age, fam- tidyl peptidase 4 inhibitors do not interact 15. Herman WH. Are there clinical implications of
ily history of diabetes, etc.) as well as with immunosuppressant drugs and have racial differences in HbA1c? Yes, to not consider
transplant-specific factors, such as use demonstrated safety in small clinical trials can do great harm! Diabetes Care 2016;39:1458–
of immunosuppressant agents (102). (111,112). Well-designed intervention tri- 1461
16. Herman WH, Ma Y, Uwaifo G, et al.; Diabetes
Whereas posttransplantation hyperglyce- als examining the efficacy and safety of Prevention Program Research Group. Differences
mia is an important risk factor for subse- these and other antihyperglycemic agents in A1C by race and ethnicity among patients with
quent PTDM, a formal diagnosis of PTDM in patients with PTDM are needed. impaired glucose tolerance in the Diabetes Pre-
is optimally made once the patient is sta- vention Program. Diabetes Care 2007;30:2453–
ble on maintenance immunosuppression 2457
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S28 Diabetes Care Volume 41, Supplement 1, January 2018

American Diabetes Association
3. Comprehensive Medical
Evaluation and Assessment
of Comorbidities: Standards of
Medical Care in Diabetesd2018
Diabetes Care 2018;41(Suppl. 1):S28–S37 |

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes”
includes 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, 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 In-
troduction. Readers who wish to comment on the Standards of Care are invited to
do so at

c A patient-centered communication style that uses person-centered and
strength-based language, active listening, elicits patient preferences and beliefs,
and assesses literacy, numeracy, and potential barriers to care should be used to
optimize patient health outcomes and health-related quality of life. B

A successful medical evaluation depends on beneficial interactions between the pa-
tient and the care team. The Chronic Care Model (1–3) (see Section 1 “Improving Care
and Promoting Health in Populations”) is a patient-centered approach to care that
requires a close working relationship between the patient and clinicians involved in treat-
ment planning. People with diabetes should receive health care from an interdisciplinary
team that may include physicians, nurse practitioners, physician assistants, nurses, dietitians,
exercise specialists, pharmacists, dentists, podiatrists, and mental health professionals.
Individuals with diabetes must assume an active role in their care. The patient, family
or support persons, physician, and health care team should together formulate the
Suggested citation: American Diabetes Association.
management plan, which includes lifestyle management (see Section 4 “Lifestyle 3. Comprehensive medical evaluation and assess-
Management”). ment of comorbidities: Standards of Medical Care in
Treatment goals and plans should be created with the patients based on their indi- Diabetesd2018. Diabetes Care 2018;41(Suppl. 1):
vidual preferences, values, and goals. The management plan should take into account S28–S37
the patient’s age, cognitive abilities, school/work schedule and conditions, health © 2017 by the American Diabetes Association.
beliefs, support systems, eating patterns, physical activity, social situation, finan- Readers may use this article as long as the work
is properly cited, the use is educational and not
cial concerns, cultural factors, literacy and numeracy (mathematical literacy), for profit, and the work is not altered. More infor-
diabetes complications and duration of disease, comorbidities, health priorities, mation is available at http://www.diabetesjournals
other medical conditions, preferences for care, and life expectancy. Various .org/content/license. Comprehensive Medical Evaluation and Assessment of Comorbidities S29

strategies and techniques should be used Additional referrals should be arranged as nec-
○ Begin patient engagement in the
to support patients’ self-management essary (Table 3.2). Clinicians should ensure
formulation of a care management
efforts, including providing education on that individuals with diabetes are appropri-
plan. B
problem-solving skills for all aspects of ately screened for complications and comor-
○ Develop a plan for continuing care. B
diabetes management. bidities. Discussing and implementing an
c A follow-up visit should include
Provider communications with patients/ approach to glycemic control with the patient
most components of the initial com-
families should acknowledge that multiple is a part, not the sole goal, of care.
prehensive medical evaluation in-
factors impact glycemic management, but
cluding: interval medical history;
also emphasize that collaboratively de- Immunization
assessment of medication-taking be-
veloped treatment plans and a healthy
havior and intolerance/side effects; Recommendations
lifestyle can significantly improve dis-
physical examination; laboratory c Provide routinely recommended
ease outcomes and well-being (4–7).
evaluation as appropriate to assess vaccinations for children and adults
Thus, the goal of provider-patient com-
attainment of A1C and metabolic tar- with diabetes by age. C
munication is to establish a collaborative
gets; and assessment of risk for com- c Annual vaccination against influenza
relationship and to assess and address
plications, diabetes self-management is recommended for all people $6
self-management barriers without blaming
behaviors, nutrition, psychosocial
patients for “noncompliance” or “nonad- months of age, including those with
health, and the need for referrals, diabetes. C
herence” when the outcomes of self-
immunizations, or other routine c Vaccination against pneumococcal
management are not optimal (8). The
health maintenance screening. B
familiar terms “noncompliance” and “non- disease, including pneumococcal
adherence” denote a passive, obedient pneumonia, with 13-valent pneumo-
role for a person with diabetes in “follow- coccal conjugate vaccine (PCV13) is
ing doctor’s orders” that is at odds with The comprehensive medical evaluation recommended for children before
the active role people with diabetes take includes the initial and follow-up evalua- age 2 years. People with diabetes
in directing the day-to-day decision- tions, assessment of complications, psy- ages 2 through 64 years should also
making, planning, monitoring, evaluation, chosocial assessment, management of receive 23-valent pneumococcal
and problem-solving involved in diabetes comorbid conditions, and engagement polysaccharide vaccine (PPSV23). At
self-management. Using a nonjudgmen- of the patient throughout the process. age $65 years, regardless of vacci-
tal approach that normalizes periodic lapses While a comprehensive list is provided nation history, additional PPSV23
in self-management may help minimize pa- in Table 3.1, in clinical practice, the pro- vaccination is necessary. C
tients’ resistance to reporting problems vider may need to prioritize the compo- c Administer 3-dose series of hepatitis
with self-management. Empathizing and nents of the medical evaluation given the B vaccine to unvaccinated adults with
using active listening techniques, such as available resources and time. The goal is to diabetes ages 19 through 59 years. C
open-ended questions, reflective state- provide the health care team information c Consider administering 3-dose se-
ments, and summarizing what the patient to optimally support a patient. In addition ries of hepatitis B vaccine to unvac-
said, can help facilitate communication. to the medical history, physical examina- cinated adults with diabetes ages
Patients’ perceptions about their own abil- tion, and laboratory tests, providers should $60 years. C
ity, or self-efficacy, to self-manage dia- assess diabetes self-management behav-
betes are one important psychosocial iors, nutrition, and psychosocial health Children and adults with diabetes should
factor related to improved diabetes self- (see Section 4 “Lifestyle Management”) receive vaccinations according to age-
management and treatment outcomes in and give guidance on routine immuniza- specific recommendations (15,16). The
diabetes (9–13) and should be a target of tions. The assessment of sleep pattern and child and adolescent vaccination schedule
ongoing assessment, patient education, duration should be considered; a recent is available at
and treatment planning. meta-analysis found that poor sleep quality, schedules/hcp/imz/child-adolescent.
short sleep, and long sleep were associated html, and the adult vaccination schedule
with higher A1C in people with type 2 di- is available at
COMPREHENSIVE MEDICAL abetes (14). Interval follow-up visits should schedules/hcp/imz/adult.html. These im-
EVALUATION occur at least every 3–6 months, individual- munization schedules include vaccination
Recommendations ized to the patient, and then annually. schedules specifically for children, adoles-
c A complete medical evaluation Lifestyle management and psychosocial cents, and adults with diabetes.
should be performed at the initial care are the cornerstones of diabetes man- People with diabetes are at higher risk
visit to: agement. Patients should be referred for for hepatitis B infection and are more likely
diabetes self-management education and to develop complications from influenza
○ Confirm the diagnosis and classify
support (DSMES), medical nutrition therapy and pneumococcal disease. The Centers
diabetes. B
(MNT), and psychosocial/emotional health for Disease Control and Prevention (CDC)
○ Evaluate for diabetes complications
concerns if indicated. Patients should receive Advisory Committee on Immunization Prac-
and potential comorbid conditions. E
recommended preventive care services (e.g., tices (ACIP) recommends influenza, pneumo-
○ Review previous treatment and risk
immunizations, cancer screening, etc.); coccal, and hepatitis B vaccinations specifically
factor control in patients with es-
smoking cessation counseling; and ophthal- for people with diabetes. Vaccination against
tablished diabetes. E
mological, dental, and podiatric referrals. tetanus-diphtheria-pertussis, measles-mumps-
S30 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 41, Supplement 1, January 2018

Continued on p. S31 Comprehensive Medical Evaluation and Assessment of Comorbidities S31
S32 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 41, Supplement 1, January 2018

Table 3.2—Referrals for initial care need to be aware of common comorbidities
to remediate deficits. Treatment
management that affect people with diabetes and may
should be tailored to avoid signifi-
c Eye care professional for annual dilated complicate management (19–23). Diabetes
cant hypoglycemia. B
eye exam comorbidities are conditions that affect
c Family planning for women of people with diabetes more often than age-
reproductive age Diabetes is associated with a significantly
matched people without diabetes. The list
c Registered dietitian for MNT increased risk and rate of cognitive decline
below includes many of the common comor-
c DSMES and an increased risk of dementia (30,31).
bidities observed in patients with diabetes
c Dentist for comprehensive dental and A recent meta-analysis of prospective ob-
but is not necessarily inclusive of all the con-
periodontal examination servational studies in people with diabe-
ditions that have been reported.
c Mental health professional, if indicated tes showed 73% increased risk of all types
Autoimmune Diseases
of dementia, 56% increased risk of Alz-
heimer dementia, and 127% increased
rubella, human papillomavirus, and shin- Recommendation risk of vascular dementia compared with
gles are also important for adults with diabe- c Consider screening patients with individuals without diabetes (32). The re-
tes, as they are for the general population. type 1 diabetes for autoimmune verse is also true: people with Alzheimer
Influenza thyroid disease and celiac disease dementia are more likely to develop di-
Influenza is a common, preventable infec- soon after diagnosis. B abetes than people without Alzheimer
tious disease associated with high mortality dementia. In a 15-year prospective study
and morbidity in vulnerable populations in- People with type 1 diabetes are at in-
of community-dwelling people .60 years
cluding the young and the elderly and people creased risk for other autoimmune dis-
of age, the presence of diabetes at base-
with chronic diseases. Influenza vaccination eases including thyroid disease, primary
line significantly increased the age- and
in people with diabetes has been found to adrenal insufficiency, celiac disease, auto-
sex-adjusted incidence of all-cause de-
significantly reduce influenza and diabetes- immune gastritis, autoimmune hepatitis,
mentia, Alzheimer disease, and vascular
related hospital admissions (17). dermatomyositis, and myasthenia gravis
dementia compared with rates in those
Pneumococcal Pneumonia
(24–26). Type 1 diabetes may also occur
with other autoimmune diseases in the with normal glucose tolerance (33).
Like influenza, pneumococcal pneumonia
is a common, preventable disease. People context of specific genetic disorders or pol-
with diabetes may be at increased risk for yglandular autoimmune syndromes (27).
In those with type 2 diabetes, the degree
the bacteremic form of pneumococcal infec- In autoimmune diseases, the immune sys-
and duration of hyperglycemia are re-
tion and have been reported to have a high tem fails to maintain self-tolerance to spe-
lated to dementia. More rapid cognitive
risk of nosocomial bacteremia, with a mortal- cific peptides within target organs. It is likely
that many factors trigger autoimmune dis- decline is associated with both increased
ity rate as high as 50% (18). The American A1C and longer duration of diabetes (34).
Diabetes Association (ADA) endorses recom- ease; however, common triggering factors
are known for only some autoimmune con- The Action to Control Cardiovascular Risk
mendations from the CDC ACIP that adults in Diabetes (ACCORD) study found that
age $65 years, who are at higher risk for ditions (i.e., gliadin peptides in celiac disease)
(see Section 12 “Children and Adolescents”). each 1% higher A1C level was associated
pneumococcal disease, receive an additional with lower cognitive function in individu-
23-valent pneumococcal polysaccharide als with type 2 diabetes (35). However,
vaccine (PPSV23), regardless of prior pneumo- Cancer
Diabetes is associated with increased risk of the ACCORD study found no difference
coccal vaccination history. See detailed rec-
cancers of the liver, pancreas, endometrium, in cognitive outcomes in participants ran-
ommendations at
colon/rectum, breast, and bladder (28). The domly assigned to intensive and standard
association may result from shared risk fac- glycemic control, supporting the recom-
Hepatitis B mendation that intensive glucose control
tors between type 2 diabetes and cancer
Compared with the general population, (older age, obesity, and physical inactivity) should not be advised for the improve-
people with type 1 or type 2 diabetes but may also be due to diabetes-related ment of cognitive function in individuals
have higher rates of hepatitis B. This may factors (29), such as underlying disease with type 2 diabetes (36).
be due to contact with infected blood or physiology or diabetes treatments, al-
through improper equipment use (glucose Hypoglycemia
though evidence for these links is scarce. In type 2 diabetes, severe hypoglycemia is
monitoring devices or infected needles). Be-
Patients with diabetes should be encour- associated with reduced cognitive func-
cause of the higher likelihood of transmis-
aged to undergo recommended age- and tion, and those with poor cognitive func-
sion, hepatitis B vaccine is recommended for
sex-appropriate cancer screenings and to
adults with diabetes age ,60 years. For tion have more severe hypoglycemia. In a
reduce their modifiable cancer risk factors
adults age $60 years, hepatitis B vaccine (obesity, physical inactivity, and smoking).
long-term study of older patients with
may be administered at the discretion of the type 2 diabetes, individuals with one or
treating clinician based on the patient’s like- Cognitive Impairment/Dementia more recorded episode of severe hypo-
lihood of acquiring hepatitis B infection. glycemia had a stepwise increase in risk
of dementia (37). Likewise, the ACCORD
c In people with a history of cognitive
ASSESSMENT OF COMORBIDITIES trial found that as cognitive function de-
impairment/dementia, intensive
Besides assessing diabetes-related com- creased, the risk of severe hypoglycemia
glucose control cannot be expected
plications, clinicians and their patients increased (38). Tailoring glycemic therapy Comprehensive Medical Evaluation and Assessment of Comorbidities S33

may help to prevent hypoglycemia in in- Conversely, prediabetes and/or diabetes Hearing Impairment
dividuals with cognitive dysfunction. has been found to develop in approxi- Hearing impairment, both in high-
Nutrition mately one-third of patients after an epi- frequency and low/mid-frequency ranges,
In one study, adherence to the Mediter- sode of acute pancreatitis (47), thus the is more common in people with diabetes
ranean diet correlated with improved relationship is likely bidirectional. Postpan- than in those without, perhaps due to
creatitis diabetes may include either new- neuropathy and/or vascular disease. In a
cognitive function (39). However, a recent
onset disease or previously unrecognized National Health and Nutrition Examination
Cochrane review found insufficient ev-
diabetes (48). Studies of patients treated Survey (NHANES) analysis, hearing impair-
idence to recommend any dietary change
with incretin-based therapies for diabetes ment was about twice as prevalent in peo-
for the prevention or treatment of cogni-
have also reported that pancreatitis may ple with diabetes compared with those
tive dysfunction (40).
occur more frequently with these medica- without, after adjusting for age and other
Statins risk factors for hearing impairment (61).
tions, but results have been mixed (49,50).
A systematic review has reported that Islet autotransplantation should be con-
data do not support an adverse effect HIV
sidered for patients requiring total pancre-
of statins on cognition (41). The U.S. atectomy for medically refractory chronic Recommendation
Food and Drug Administration (FDA) post- pancreatitis to prevent postsurgical diabe- c Patients with HIV should be screened
marketing surveillance databases have tes. Approximately one-third of patients for diabetes and prediabetes with
also revealed a low reporting rate for cog- undergoing total pancreatectomy with is- a fasting glucose level every 6–12
nitive-related adverse events, including let autotransplantation are insulin free one months before starting antiretrovi-
cognitive dysfunction or dementia, with year postoperatively, and observational ral therapy and 3 months after
statin therapy, similar to rates seen with studies from different centers have dem- starting or changing antiretroviral
other commonly prescribed cardiovascular onstrated islet graft function up to a de- therapy. If initial screening results
medications (41). Therefore, fear of cog- cade after the surgery in some patients are normal, checking fasting glu-
nitive decline should not be a barrier to (51–55). Both patient and disease factors cose every year is advised. E
statin use in individuals with diabetes should be carefully considered when de-
and a high risk for cardiovascular disease. ciding the indications and timing of this Diabetes risk is increased with certain
surgery. Surgeries should be performed in protease inhibitors (PIs) and nucleoside
Fatty Liver Disease
skilled facilities that have demonstrated reverse transcriptase inhibitors (NRTIs).
Diabetes is associated with the develop-
expertise in islet autotransplantation. New-onset diabetes is estimated to oc-
ment of nonalcoholic chronic liver disease
cur in more than 5% of patients infected
and with hepatocellular carcinoma (42).
Fractures with HIV on PIs, whereas more than 15%
Elevations of hepatic transaminase con-
Age-specific hip fracture risk is signifi- may have prediabetes (62). PIs are asso-
centrations are associated with higher
cantly increased in people with both ciated with insulin resistance and may
BMI, waist circumference, and triglycer-
type 1 (relative risk 6.3) and type 2 (relative also lead to apoptosis of pancreatic b-cells.
ide levels and lower HDL cholesterol lev-
risk 1.7) diabetes in both sexes (56). Type 1 NRTIs also affect fat distribution (both lip-
els. Interventions that improve metabolic
diabetes is associated with osteoporosis, ohypertrophy and lipoatrophy), which is
abnormalities in patients with diabetes but in type 2 diabetes, an increased risk of associated with insulin resistance.
(weight loss, glycemic control, and treat- hip fracture is seen despite higher bone Individuals with HIV are at higher risk
ment with specific drugs for hyperglyce- mineral density (BMD) (57). In three large for developing prediabetes and diabe-
mia or dyslipidemia) are also beneficial observational studies of older adults, tes on antiretroviral (ARV) therapies,
for fatty liver disease (43,44). femoral neck BMD T score and the World so a screening protocol is recommended
Health Organization Fracture Risk Assess- (63). The A1C test underestimates glyce-
ment Tool (FRAX) score were associated mia in people with HIV and is not recom-
Recommendation with hip and nonspine fractures. Fracture mended for diagnosis and may present
c Islet autotransplantation should be risk was higher in participants with dia- challenges for monitoring (64). In those
considered for patients requiring betes compared with those without dia- with prediabetes, weight loss through
total pancreatectomy for medically betes for a given T score and age or for a healthy nutrition and physical activity
refractory chronic pancreatitis to given FRAX score (58). Providers should may reduce the progression toward dia-
prevent postsurgical diabetes. C assess fracture history and risk factors in betes. Among patients with HIV and
older patients with diabetes and recom- diabetes, preventive health care using
Diabetes is linked to diseases of the exo- mend measurement of BMD if appro- an approach similar to that used in pa-
crine pancreas such as pancreatitis, which priate for the patient’s age and sex. tients without HIV is critical to reduce
may disrupt the global architecture or Fracture prevention strategies for people the risks of microvascular and macrovas-
physiology of the pancreas, often result- with diabetes are the same as for the cular complications.
ing in both exocrine and endocrine general population and include vitamin D For patients with HIV and ARV-associated
dysfunction. Up to half of patients with di- supplementation. For patients with type hyperglycemia, it may be appropriate to
abetes may have impaired exocrine pan- 2 diabetes with fracture risk factors, consider discontinuing the problematic
creas function (45). People with diabetes thiazolidinediones (59) and sodium– ARV agents if safe and effective alternatives
are at an approximately twofold higher glucose cotransporter 2 inhibitors (60) are available (65). Before making ARV sub-
risk of developing acute pancreatitis (46). should be used with caution. stitutions, carefully consider the possible
S34 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 41, Supplement 1, January 2018

effect on HIV virological control and the diabetes than in those without (74,75). The Behavioral Risk Factor Surveillance
potential adverse effects of new ARV Current evidence suggests that periodon- System (BRFSS) estimated the lifetime
agents. In some cases, antihyperglycemic tal disease adversely affects diabetes out- prevalence of generalized anxiety disorder
agents may still be necessary. comes, although evidence for treatment to be 19.5% in people with either type 1 or
benefits remains controversial (23). type 2 diabetes (79). Common diabetes-
Low Testosterone in Men
specific concerns include fears related to
Recommendation Psychosocial/Emotional Disorders hypoglycemia (80,81), not meeting blood
c In men with diabetes who have Prevalence of clinically significant psycho- glucose targets (78), and insulin injections
symptoms or signs of hypogonadism pathology diagnoses are considerably or infusion (82). Onset of complications
such as decreased sexual desire more common in people with diabetes presents another critical point when
(libido) or activity, or erectile dys- than in those without the disease (76). anxiety can occur (83). People with dia-
function, consider screening with a Symptoms, both clinical and subclinical, betes who exhibit excessive diabetes self-
morning serum testosterone level. B that interfere with the person’s ability management behaviors well beyond what
to carry out daily diabetes self-manage- is prescribed or needed to achieve glycemic
Mean levels of testosterone are lower in ment tasks must be addressed. Providers targets may be experiencing symptoms of
men with diabetes compared with age- should consider an assessment of symp- obsessive-compulsive disorder (84).
matched men without diabetes, but obesity toms of depression, anxiety, and disor- General anxiety is a predictor of injection-
is a major confounder (66,67). Treatment dered eating, and of cognitive capacities related anxiety and associated with
in asymptomatic men is controversial. using patient-appropriate standardized/ fear of hypoglycemia (81,85). Fear of hy-
Testosterone replacement in men with validated tools at the initial visit, at peri- poglycemia and hypoglycemia unaware-
symptomatic hypogonadism may have ben- odic intervals, and when there is a change ness often co-occur, and interventions
efits including improved sexual function, in disease, treatment, or life circum- aimed at treating one often benefit both
well being, muscle mass and strength, and stance. Including caregivers and family (86). Fear of hypoglycemia may explain
bone density. (68). In men with diabetes members in this assessment is recom- avoidance of behaviors associated with
who have symptoms or signs of low testos- mended. Diabetes distress is addressed lowering glucose such as increasing in-
terone (hypogonadism), a morning total in Section 4 “Lifestyle Management,” as sulin doses or frequency of monitoring.
testosterone should be measured using an this state is very common and distinct If fear of hypoglycemia is identified and
accurate and reliable assay. Free or bioavail- from the psychological disorders dis- a person does not have symptoms of
able testosterone levels should also be mea- cussed below (77). hypoglycemia, a structured program,
sured in men with diabetes who have total blood glucose awareness training, deliv-
Anxiety Disorders
testosterone levels close to the lower limit, ered in routine clinical practice, can im-
given expected decreases in sex hormone– Recommendations prove A1C, reduce the rate of severe
binding globulin with diabetes. Further c Consider screening for anxiety in hypoglycemia, and restore hypoglycemia
testing (such as luteinizing hormone and people exhibiting anxiety or worries awareness (87,88).
follicle-stimulating hormone levels) may regarding diabetes complications,
be needed to distinguish between pri- insulin injections or infusion, taking Depression
mary and secondary hypogonadism. medications, and/or hypoglycemia Recommendations
that interfere with self-management c Providers should consider annual
Obstructive Sleep Apnea
behaviors and those who express screening of all patients with diabetes,
Age-adjusted rates of obstructive sleep
fear, dread, or irrational thoughts especially those with a self-reported
apnea, a risk factor for cardiovascular
and/or show anxiety symptoms history of depression, for depressive
disease, are significantly higher (4- to
such as avoidance behaviors, exces- symptoms with age-appropriate de-
10-fold) with obesity, especially with cen-
sive repetitive behaviors, or social pression screening measures, recog-
tral obesity (69). The prevalence of ob-
withdrawal. Refer for treatment if nizing that further evaluation will be
structive sleep apnea in the population
anxiety is present. B necessary for individuals who have a
with type 2 diabetes may be as high as
c People with hypoglycemia unaware-
23%, and the prevalence of any sleep dis- positive screen. B
ness, which can co-occur with fear of c Beginning at diagnosis of complica-
ordered breathing may be as high as 58%
hypoglycemia, should be treated us- tions or when there are significant
(70,71). In obese participants enrolled in
ing blood glucose awareness training changes in medical status, consider
the Action for Health in Diabetes (Look
(or other evidence-based interven- assessment for depression. B
AHEAD) trial, it exceeded 80% (72). Sleep
tion) to help reestablish awareness c Referrals for treatment of depres-
apnea treatment (lifestyle modification,
of hypoglycemia and reduce fear of sion should be made to mental
continuous positive airway pressure,
hypoglycemia. A health providers with experience us-
oral appliances, and surgery) significantly
improves quality of life and blood pressure ing cognitive behavioral therapy,
Anxiety symptoms and diagnosable disor-
control. The evidence for a treatment ef- interpersonal therapy, or other evi-
ders (e.g., generalized anxiety disorder,
fect on glycemic control is mixed (73). dence-based treatment approaches
body dysmorphic disorder, obsessive-
in conjunction with collaborative
Periodontal Disease compulsive disorder, specific phobias,
care with the patient’s diabetes
Periodontal disease is more severe, and and posttraumatic stress disorder) are
treatment team. A
may be more prevalent, in patients with common in people with diabetes (78). Comprehensive Medical Evaluation and Assessment of Comorbidities S35

History of depression, current depression, (98,99); in people with type 2 diabetes, those taking second-generation (atypical)
and antidepressant medication use are bingeing (excessive food intake with an antipsychotics such as olanzapine require
risk factors for the development of type accompanying sense of loss of control) greater monitoring because of an increase
2 diabetes, especially if the individual is most commonly reported. For people in risk of type 2 diabetes associated with
has other risk factors such as obesity with type 2 diabetes treated with insulin, this medication (106).
and family history of type 2 diabetes intentional omission is also frequently re-
(89–91). Elevated depressive symptoms ported (100). People with diabetes and
and depressive disorders affect one in diagnosable eating disorders have high References
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thinking and judgment can be expected
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Estimated prevalence of disordered to make it difficult to engage in behaviors efficacy and self-care with glycemic control in di-
eating behaviors and diagnosable eating that reduce risk factors for type 2 diabe- abetes. Diabetes Spectr 2013;26:172–178
disorders in people with diabetes varies tes, such as restrained eating for weight 13. Iannotti RJ, Schneider S, Nansel TR, et al. Self-
(95–97). For people with type 1 diabetes, management. Coordinated management efficacy, outcome expectations, and diabetes self-
management in adolescents with type 1 diabetes.
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type 2 diabetes: a systematic review and meta- 33. Ohara T, Doi Y, Ninomiya T, et al. Glucose 48. Petrov MS. Diabetes of the exocrine pan-
analysis. Sleep Med Rev 2017;31:91–101 tolerance status and risk of dementia in the com- creas: American Diabetes Association-compliant
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Diabetes Care Volume 41, Supplement 1, January 2018 S51

American Diabetes Association
5. Prevention or Delay of Type 2
Diabetes: Standards of Medical
Care in Diabetesd2018
Diabetes Care 2018;41(Suppl. 1):S51–S54 |

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes”
includes 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, 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.
Readers who wish to comment on the Standards of Care are invited to do so at

For guidelines related to screening for increased risk for type 2 diabetes (prediabetes),
please refer to Section 2 “Classification and Diagnosis of Diabetes.”
c At least annual monitoring for the development of diabetes in those with pre-
diabetes is suggested. E
c Patients with prediabetes should be referred to an intensive behavioral lifestyle
intervention program modeled on the Diabetes Prevention Program to achieve
and maintain 7% loss of initial body weight and increase moderate-intensity
physical activity (such as brisk walking) to at least 150 min/week. A
c Technology-assisted tools including Internet-based social networks, distance
learning, and mobile applications that incorporate bidirectional communi-
cation may be useful elements of effective lifestyle modification to prevent
diabetes. B
c Given the cost-effectiveness of diabetes prevention, such intervention programs
should be covered by third-party payers. B

Screening for prediabetes and type 2 diabetes risk through an informal assess-
ment 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 Suggested citation: American Diabetes Association.
whether performing a diagnostic test for prediabetes (Table 2.4) and previ- 5. Prevention or delay of type 2 diabetes: Standards
ously undiagnosed type 2 diabetes (Table 2.2) is appropriate (see Section of Medical Care in Diabetesd2018. Diabetes Care
2 “Classification and Diagnosis of Diabetes”). Those determined to be at high risk 2018;41(Suppl. 1):S51–S54
for type 2 diabetes, including people with A1C 5.7–6.4% (39–47 mmol/mol), im- © 2017 by the American Diabetes Association.
paired glucose tolerance, or impaired fasting glucose, are ideal candidates for Readers may use this article as long as the work
is properly cited, the use is educational and not
diabetes prevention efforts. Using A1C to screen for prediabetes may be problem- for profit, and the work is not altered. More infor-
atic in the presence of certain hemoglobinopathies or conditions that affect red mation is available at http://www.diabetesjournals
blood cell turnover. See Section 2 “Classification and Diagnosis of Diabetes” and .org/content/license.
S52 Prevention or Delay of Type 2 Diabetes Diabetes Care Volume 41, Supplement 1, January 2018

Section 6 “Glycemic Targets” for addi- encouraged to distribute their activity showed beneficial effects in those with pre-
tional details on the appropriate use of throughout the week with a minimum fre- diabetes (1), moderate-intensity physical
the A1C test. quency of three times per week with at least activity has been shown to improve insu-
At least annual monitoring for the de- 10 min per session. A maximum of 75 min of lin sensitivity and reduce abdominal fat in
velopment of diabetes in those with pre- strength training could be applied toward the children and young adults (18,19). On the
diabetes is suggested. total 150 min/week physical activity goal (6). basis of these findings, providers are en-
To implement the weight loss and couraged to promote a DPP-style pro-
physical activity goals, the DPP used an in- gram, including its focus on physical
LIFESTYLE INTERVENTIONS dividual model of treatment rather than a activity, to all individuals who have been
The Diabetes Prevention Program group-based approach. This choice was identified to be at an increased risk of
The strongest evidence for diabetes preven- based on a desire to intervene before par- type 2 diabetes. In addition to aerobic
tion comes from the Diabetes Prevention ticipants had the possibility of developing activity, an exercise regimen designed to
Program (DPP) (1). The DPP demonstrated diabetes or losing interest in the program. prevent diabetes may include resistance
that an intensive lifestyle intervention The individual approach also allowed for training (6,20). Breaking up prolonged
could reduce the incidence of type 2 di- tailoring of interventions to reflect the di- sedentary time may also be encouraged,
abetes by 58% over 3 years. Follow-up of versity of the population (6). as it is associated with moderately lower
three large studies of lifestyle interven- The DPP intervention was administered postprandial glucose levels (21,22). The
tion for diabetes prevention has shown as a structured core curriculum followed preventative effects of exercise appear
sustained reduction in the rate of conver- by a more flexible maintenance program to extend to the prevention of gestational
sion to type 2 diabetes: 43% reduction at of individual sessions, group classes, moti- diabetes mellitus (GDM) (23).
20 years in the Da Qing study (2), 43% vational campaigns, and restart opportuni-
Technology Assistance to Deliver
reduction at 7 years in the Finnish Diabetes ties. The 16-session core curriculum was
Lifestyle Interventions
Prevention Study (DPS) (3), and 34% reduc- completed within the first 24 weeks of
Information technology platforms may
tion at 10 years (4) and 27% reduction at the program and included sections on low-
effectively deliver the core components of
15 years (5) in the U.S. Diabetes Preven- ering calories, increasing physical activity,
the DPP (24–26), lowering weight, reduc-
tion Program Outcomes Study (DPPOS). self-monitoring, maintaining healthy life-
ing risk for diabetes and cardiovascular
The two major goals of the DPP inten- style behaviors, and psychological, social,
disease, and achieving cost savings
sive, behavioral, lifestyle intervention and motivational challenges. For further de-
(27,28). Recent studies support content
were to achieve and maintain a minimum tails on the core curriculum sessions, refer
delivery through virtual small groups
of 7% weight loss and 150 min of physical to ref. 6.
(29), Internet-driven social networks
activity per week similar in intensity to
Nutrition (30,31), cell phones, and other mobile de-
brisk walking. The DPP lifestyle interven-
Reducing caloric intake is of paramount im- vices. Mobile applications for weight loss
tion was a goal-based intervention: all
portance for those at high risk for develop- and diabetes prevention have been vali-
participants were given the same weight
ing type 2 diabetes, though recent evidence dated for their ability to reduce A1C in
loss and physical activity goals, but indi-
suggests that the quality of fats consumed the setting of prediabetes (31). The Cen-
vidualization was permitted in the specific
in the diet is more important than the total ters for Disease Control and Prevention
methods used to achieve the goals (6).
quantity of dietary fat (7–9). For example, (CDC) Diabetes Prevention Recognition
The 7% weight loss goal was selected be-
the Mediterranean diet, which is relative- Program (DPRP) (
cause it was feasible to achieve and maintain
ly high in monounsaturated fats, may diabetes/prevention/recognition/index
and likely to lessen the risk of developing
help to prevent type 2 diabetes (10–12). .htm) has begun to certify electronic and
diabetes. Participants were encouraged to
Whereas overall healthy low-calorie mobile health-based modalities as effec-
achieve the 7% weight loss during the first
eating patterns should be encouraged, tive vehicles for DPP-based interventions
6 months of the intervention. The recom-
there is also some evidence that particu- that may be considered alongside more
mended pace of weight loss was 1–2
lar dietary components impact diabetes traditional face-to-face and coach-driven
lb/week. Calorie goals were calculated by
risk. Higher intakes of nuts (13), berries programs. A recent study showed that an
estimating the daily calories needed to
(14), yogurt (15), coffee, and tea (16) are as- all-mobile approach to administering DPP
maintain the participant’s initial weight
sociated with reduced diabetes risk. Con- content can be effective as a prevention
and subtracting 500–1,000 calories/day
versely, red meats and sugar-sweetened tool, at least over the short term, in over-
(depending on initial body weight). The
beverages are associated with an in- weight and obese individuals at high risk
initial focus was on reducing total dietary
creased risk of type 2 diabetes (8). for diabetes (32).
fat. After several weeks, the concept of
As is the case for those with diabetes,
calorie balance and the need to restrict Cost-effectiveness
individualized medical nutrition therapy
calories as well as fat was introduced (6). A cost-effectiveness model suggested
(see Section 4 “Lifestyle Management”
The goal for physical activity was selected that the lifestyle intervention used in
for more detailed information) is effective
to approximate at least 700 kcal/week the DPP was cost-effective (33). Actual
in lowering A1C in individuals diagnosed
expenditure from physical activity. For cost data from the DPP and DPPOS con-
with prediabetes (17).
ease of translation, this goal was described firmed this (34). Group delivery of DPP
as at least 150 min of moderate-intensity Physical Activity content in community or primary care
physical activity per week similar in inten- Just as 150 min/week of moderate-intensity settings has the potential to reduce over-
sity to brisk walking. Participants were physical activity, such as brisk walking, all program costs while still producing Prevention or Delay of Type 2 Diabetes S53

weight loss and diabetes risk reduction Metformin was overall less effective to people with prediabetes. Currently,
(35–37). The use of community health than lifestyle modification in the DPP there are significant barriers to the pro-
workers to support DPP efforts has been and DPPOS, though group differences de- vision of education and support to those
shown to be effective with cost savings clined over time (5) and metformin may with prediabetes. However, the strate-
(38) (see Section 1 “Improving Care and be cost-saving over a 10-year period (34). gies for supporting successful behavior
Promoting Health in Populations” for more It was as effective as lifestyle modification change and the healthy behaviors recom-
information). The CDC helps to coordi- in participants with BMI $35 kg/m2 but mended for people with prediabetes are
nate the National Diabetes Prevention not significantly better than placebo in comparable to those for diabetes. Al-
Program (National DPP), a resource de- those over 60 years of age (1). In the though reimbursement remains a barrier,
signed to bring evidence-based lifestyle DPP, for women with history of GDM, studies show that providers of diabetes
change programs for preventing type 2 metformin and intensive lifestyle mod- self-management education and support
diabetes to communities (http://www ification led to an equivalent 50% reduc- are particularly well equipped to assist tion in diabetes risk (46), and both people with prediabetes in developing
Early results from the CDC’s National DPP interventions remained highly effective and maintaining behaviors that can pre-
during the first 4 years of implementation during a 10-year follow-up period (47). vent or delay the development of diabe-
are promising (39). On 7 July 2016, the Metformin should be recommended as tes (17,50).
Centers for Medicare and Medicaid Ser- an option for high-risk individuals (e.g.,
vices (CMS) proposed expanded Medi- those with a history of GDM or those
care reimbursement coverage for DPP with BMI $35). Consider monitoring
1. Knowler WC, Barrett-Connor E, Fowler SE,
programs in an effort to expand preventive B12 levels in those taking metformin et al.; Diabetes Prevention Program Research
services using a cost-effective model with chronically to check for possible defi- Group. Reduction in the incidence of type 2 di-
proposed implementation in 2018 (https:// ciency (see Section 8 “Pharmacologic abetes with lifestyle intervention or metformin. Approaches to Glycemic Treatment” for N Engl J Med 2002;346:393–403
2. Li G, Zhang P, Wang J, et al. The long-term
diabetes-prevention-program/). more details).
effect of lifestyle interventions to prevent diabe-
tes in the China Da Qing Diabetes Prevention
PREVENTION OF Study: a 20-year follow-up study. Lancet 2008;
Recommendations 3. Lindström J, Ilanne-Parikka P, Peltonen M,
Recommendation et al.; Finnish Diabetes Prevention Study Group.
c Metformin therapy for prevention
c Screening for and treatment of Sustained reduction in the incidence of type 2 di-
of type 2 diabetes should be consid- abetes by lifestyle intervention: follow-up of the
modifiable risk factors for cardio-
ered in those with prediabetes, espe- Finnish Diabetes Prevention Study. Lancet 2006;
vascular disease is suggested for
cially for those with BMI $35 kg/m2, 368:1673–1679
those with prediabetes. B
those aged ,60 years, and women 4. Knowler WC, Fowler SE, Hamman RF, et al.;
Diabetes Prevention Program Research Group.
with prior gestational diabetes People with prediabetes often have other 10-year follow-up of diabetes incidence and
mellitus. A cardiovascular risk factors, including hyper- weight loss in the Diabetes Prevention Program
c Long-term use of metformin may be Outcomes Study. Lancet 2009;374:1677–1686
tension and dyslipidemia, and are at in-
associated with biochemical vitamin 5. Nathan DM, Barrett-Connor E, Crandall JP,
creased risk for cardiovascular disease et al. Long-term effects of lifestyle intervention
B12 deficiency, and periodic mea- (48). Although treatment goals for people or metformin on diabetes development and mi-
surement of vitamin B12 levels should with prediabetes are the same as for the crovascular complications: the DPP Outcomes
be considered in metformin-treated general population (49), increased vigi- Study. Lancet Diabetes Endocrinol 2015;3:866–
patients, especially in those with ane- lance is warranted to identify and treat
mia or peripheral neuropathy. B these and other cardiovascular risk fac-
6. Diabetes Prevention Program (DPP) Research
Group. The Diabetes Prevention Program (DPP):
tors (e.g., smoking). description of lifestyle intervention. Diabetes Care
Pharmacologic agents including metfor- 2002;25:2165–2171
min, a-glucosidase inhibitors, orlistat, 7. Jacobs S, Harmon BE, Boushey CJ, et al. A priori-
glucagon-like peptide 1 (GLP-1) receptor DIABETES SELF-MANAGEMENT defined diet quality indexes and risk of type 2 di-
EDUCATION AND SUPPORT abetes: the Multiethnic Cohort. Diabetologia
agonists, and thiazolidinediones have
each been shown to decrease incident di- Recommendation
8. Ley SH, Hamdy O, Mohan V, Hu FB. Prevention
abetes to various degrees in those with c Diabetes self-management educa- and management of type 2 diabetes: dietary com-
prediabetes in research studies (1,40–45), tion and support programs may be ponents and nutritional strategies. Lancet 2014;
though none are approved by the U.S. appropriate venues for people with 383:1999–2007
Food and Drug Administration specifically prediabetes to receive education 9. Chiuve SE, Fung TT, Rimm EB, et al. Alternative
dietary indices both strongly predict risk of
for diabetes prevention. One has to bal- and support to develop and maintain chronic disease. J Nutr 2012;142:1009–1018
ance the risk/benefit of each medication. behaviors that can prevent or delay 10. Salas-Salvadó J, Bulló M, Babio N, et al.;
Metformin has the strongest evidence the development of type 2 diabetes. B PREDIMED Study Investigators. Reduction in the
base and demonstrated long-term safety incidence of type 2 diabetes with the Mediterra-
as pharmacologic therapy for diabetes As for those with established diabetes, the nean diet: results of the PREDIMED-Reus nutrition
intervention randomized trial. Diabetes Care
prevention (45). For other drugs, cost, standards for diabetes self-management 2011;34:14–19
side effects, and durable efficacy require education and support (see Section 4 11. Salas-Salvadó J, Guasch-Ferré M, Lee CH,
consideration. “Lifestyle Management”) can also apply Estruch R, Clish CB, Ros E. Protective effects of
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the Mediterranean diet on type 2 diabetes and 26. Oldenburg B, Taylor CB, O’Neil A, Cocker F, 39. Ely EK, Gruss SM, Luman ET, et al. A national
metabolic syndrome. J Nutr 2016;146:920S–927S Cameron LD. Using new technologies to improve effort to prevent type 2 diabetes: participant-level
12. Bloomfield HE, Koeller E, Greer N, MacDonald the prevention and management of chronic con- evaluation of CDC’s National Diabetes Prevention
R, Kane R, Wilt TJ. Effects on health outcomes of a ditions in populations. Annu Rev Public Health Program. Diabetes Care 2017;40:1331–1341
Mediterranean diet with no restriction on fat in- 2015;36:483–505 40. Chiasson J-L, Josse RG, Gomis R, Hanefeld M,
take: a systematic review and meta-analysis. Ann 27. Bian RR, Piatt GA, Sen A, et al. The effect of Karasik A, Laakso M; STOP-NIDDM Trial Research
Intern Med 2016;165:491–500 technology-mediated diabetes prevention inter- Group. Acarbose for prevention of type 2 diabetes
13. Afshin A, Micha R, Khatibzadeh S, Mozaffarian ventions on weight: a meta-analysis. J Med Inter- mellitus: the STOP-NIDDM randomised trial. Lan-
D. Consumption of nuts and legumes and risk of net Res 2017;19:e76 cet 2002;359:2072–2077
incident ischemic heart disease, stroke, and diabe- 28. Chen F, Su W, Becker SH, et al. Clinical and 41. Torgerson JS, Hauptman J, Boldrin MN,
tes: a systematic review and meta-analysis. Am J Clin economic impact of a digital, remotely-delivered Sjöström L. XENical in the prevention of diabetes
Nutr 2014;100:278–288 intensive behavioral counseling program on in obese subjects (XENDOS) study: a randomized
14. Mursu J, Virtanen JK, Tuomainen T-P, Nurmi Medicare beneficiaries at risk for diabetes and study of orlistat as an adjunct to lifestyle changes
T, Voutilainen S. Intake of fruit, berries, and veg- cardiovascular disease. PLoS One 2016;11: for the prevention of type 2 diabetes in obese
etables and risk of type 2 diabetes in Finnish men: e0163627 patients. Diabetes Care 2004;27:155–161
the Kuopio Ischaemic Heart Disease Risk Factor 29. Azar KMJ, Aurora M, Wang EJ, Muzaffar A, 42. le Roux CW, Astrup A, Fujioka K, et al.; SCALE
Study. Am J Clin Nutr 2014;99:328–333 Pressman A, Palaniappan LP. Virtual small groups Obesity Prediabetes NN8022-1839 Study Group. 3
15. Chen M, Sun Q, Giovannucci E, et al. Dairy for weight management: an innovative delivery years of liraglutide versus placebo for type 2 di-
consumption and risk of type 2 diabetes: 3 cohorts mechanism for evidence-based lifestyle interven- abetes risk reduction and weight management in
of US adults and an updated meta-analysis. BMC tions among obese men. Transl Behav Med 2015; individuals with prediabetes: a randomised, double-
Med 2014;12:215 5:37–44 blind trial. Lancet 2017;389:1399–1409
16. Mozaffarian D. Dietary and policy priorities 30. Sepah SC, Jiang L, Peters AL. Translating the 43. Gerstein HC, Yusuf S, Bosch J, et al.; DREAM
for cardiovascular disease, diabetes, and obesity: Diabetes Prevention Program into an online social (Diabetes REduction Assessment with ramipril
a comprehensive review. Circulation 2016;133: network: validation against CDC standards. Diabe- and rosiglitazone Medication) Trial Investigators.
187–225 tes Educ 2014;40:435–443 Effect of rosiglitazone on the frequency of diabe-
17. Parker AR, Byham-Gray L, Denmark R, Winkle 31. Sepah SC, Jiang L, Peters AL. Long-term out- tes in patients with impaired glucose tolerance or
PJ. The effect of medical nutrition therapy by a comes of a Web-based diabetes prevention pro- impaired fasting glucose: a randomised controlled
registered dietitian nutritionist in patients with gram: 2-year results of a single-arm longitudinal trial. Lancet 2006;368:1096–1105
prediabetes participating in a randomized con- study. J Med Internet Res 2015;17:e92 44. DeFronzo RA, Tripathy D, Schwenke DC, et al.;
trolled clinical research trial. J Acad Nutr Diet 32. Michaelides A, Raby C, Wood M, Farr K, Toro- ACT NOW Study. Pioglitazone for diabetes pre-
2014;114:1739–1748 Ramos T. Weight loss efficacy of a novel mobile vention in impaired glucose tolerance. N Engl J
18. Fedewa MV, Gist NH, Evans EM, Dishman RK. Diabetes Prevention Program delivery platform Med 2011;364:1104–1115
Exercise and insulin resistance in youth: a meta- with human coaching. BMJ Open Diabetes Res 45. Diabetes Prevention Program Research
analysis. Pediatrics 2014;133:e163–e174 Care 2016;4:e000264 Group. Long-term safety, tolerability, and weight
19. Davis CL, Pollock NK, Waller JL, et al. Exercise 33. Herman WH, Hoerger TJ, Brandle M, et al.; loss associated with metformin in the Diabetes
dose and diabetes risk in overweight and obese Diabetes Prevention Program Research Group. Prevention Program Outcomes Study. Diabetes
children: a randomized controlled trial. JAMA The cost-effectiveness of lifestyle modification Care 2012;35:731–737
2012;308:1103–1112 or metformin in preventing type 2 diabetes in 46. Ratner RE, Christophi CA, Metzger BE, et al.;
20. Sigal RJ, Alberga AS, Goldfield GS, et al. Effects adults with impaired glucose tolerance. Ann In- Diabetes Prevention Program Research Group.
of aerobic training, resistance training, or both on tern Med 2005;142:323–332 Prevention of diabetes in women with a history
percentage body fat and cardiometabolic risk 34. Diabetes Prevention Program Research of gestational diabetes: effects of metformin and
markers in obese adolescents: the healthy eating Group. The 10-year cost-effectiveness of lifestyle lifestyle interventions. J Clin Endocrinol Metab
aerobic and resistance training in youth random- intervention or metformin for diabetes preven- 2008;93:4774–4779
ized clinical trial. JAMA Pediatr 2014;168:1006– tion: an intent-to-treat analysis of the DPP/ 47. Aroda VR, Christophi CA, Edelstein SL, et al.;
1014 DPPOS. Diabetes Care 2012;35:723–730 Diabetes Prevention Program Research Group.
21. Thorp AA, Kingwell BA, Sethi P, Hammond L, 35. Ackermann RT, Finch EA, Brizendine E, Zhou The effect of lifestyle intervention and metformin
Owen N, Dunstan DW. Alternating bouts of sitting H, Marrero DG. Translating the Diabetes Preven- on preventing or delaying diabetes among
and standing attenuate postprandial glucose re- tion Program into the community. The DEPLOY women with and without gestational diabetes:
sponses. Med Sci Sports Exerc 2014;46:2053– Pilot Study. Am J Prev Med 2008;35:357–363 the Diabetes Prevention Program Outcomes
2061 36. Balk EM, Earley A, Raman G, Avendano EA, Study 10-year follow-up. J Clin Endocrinol Metab
22. Healy GN, Dunstan DW, Salmon J, et al. Pittas AG, Remington PL. Combined diet and phys- 2015;100:1646–1653
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with metabolic risk. Diabetes Care 2008;31:661– diabetes among persons at increased risk: a system- risk for cardiovascular disease: a systematic re-
666 atic review for the Community Preventive Services view of the evidence. J Am Coll Cardiol 2010;55:
23. Russo LM, Nobles C, Ertel KA, Chasan-Taber L, Task Force. Ann Intern Med 2015;163:437–451 1310–1317
Whitcomb BW. Physical activity interventions in 37. Li R, Qu S, Zhang P, et al. Economic evaluation 49. Bress AP, King JB, Kreider KE, et al.; SPRINT
pregnancy and risk of gestational diabetes melli- of combined diet and physical activity promotion Research Group. Effect of intensive versus stan-
tus: a systematic review and meta-analysis. Ob- programs to prevent type 2 diabetes among per- dard blood pressure treatment according to base-
stet Gynecol 2015;125:576–582 sons at increased risk: a systematic review for the line prediabetes status: a post hoc analysis of a
24. Levine DM, Savarimuthu S, Squires A, Community Preventive Services Task Force. Ann randomized trial. Diabetes Care 2017;40:1401–
Nicholson J, Jay M. Technology-assisted weight Intern Med 2015;163:452–460 1408
loss interventions in primary care: a systematic 38. The Community Guide. Diabetes prevention: 50. Butcher MK, Vanderwood KK, Hall TO,
review. J Gen Intern Med 2015;30:107–117 interventions engaging community health work- Gohdes D, Helgerson SD, Harwell TS. Capacity of
25. Allen JK, Stephens J, Patel A. Technology- ers [Internet], 2016. Available from https://www diabetes education programs to provide both di-
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Diabetes Care Volume 41, Supplement 1, January 2018 S55

American Diabetes Association
6. Glycemic Targets: Standards of
Medical Care in Diabetesd2018
Diabetes Care 2018;41(Suppl. 1):S55–S64 |

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes”

includes 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, 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.
Readers who wish to comment on the Standards of Care are invited to do so at

Patient self-monitoring of blood glucose (SMBG) and A1C are available to health
care providers and patients to assess the effectiveness and safety of a manage-
ment plan on glycemic control. Continuous glucose monitoring (CGM) also has
an important role in assessing the effectiveness and safety of treatment in sub-
groups of patients with type 1 diabetes and in selected patients with type 2 di-
abetes. Data indicate similar A1C and safety with the use of CGM compared with
SMBG (1).

c Most patients using intensive insulin regimens (multiple-dose insulin or in-
sulin pump therapy) should perform self-monitoring of blood glucose (SMBG)
prior to meals and snacks, at bedtime, occasionally postprandially, prior to
exercise, when they suspect low blood glucose, after treating low blood
glucose until they are normoglycemic, and prior to critical tasks such as
driving. B
c When prescribed as part of a broad educational program, SMBG may help to
guide treatment decisions and/or self-management for patients taking less fre-
quent insulin injections B or noninsulin therapies. E
c When prescribing SMBG, ensure that patients receive ongoing instruction and
regular evaluation of SMBG technique, SMBG results, and their ability to use
SMBG data to adjust therapy. E Suggested citation: American Diabetes Associa-
tion. 6. Glycemic targets: Standards of Medical
c When used properly, continuous glucose monitoring (CGM) in conjunction with
Care in Diabetesd2018. Diabetes Care 2018;
intensive insulin regimens is a useful tool to lower A1C in adults with type 1 41(Suppl. 1):S55–S64
diabetes who are not meeting glycemic targets. A © 2017 by the American Diabetes Association.
c CGM may be a useful tool in those with hypoglycemia unawareness and/or Readers may use this article as long as the work
frequent hypoglycemic episodes. C is properly cited, the use is educational and not
c Given the variable adherence to CGM, assess individual readiness for continuing for profit, and the work is not altered. More infor-
CGM use prior to prescribing. E mation is available at http://www.diabetesjournals
S56 Glycemic Targets Diabetes Care Volume 41, Supplement 1, January 2018

should be advised against purchasing or most CGM devices include alarms for hypo-
c When prescribing CGM, robust di-
reselling preowned or secondhand test and hyperglycemic excursions. The inter-
abetes education, training, and sup-
strips, as these may give incorrect results. mittent or “flash” CGM device, very re-
port are required for optimal CGM
Only unopened vials of glucose test strips cently approved for adult use only (18),
implementation and ongoing use. E
should be used to ensure SMBG accuracy. differs from previous CGM devices. Spe-
c People who have been successfully
For Patients on Intensive Insulin Regimens cifically, it does not have alarms, does not
using CGM should have continued
Most patients using intensive insulin require calibration with SMBG, and does
access after they turn 65 years of
not communicate continuously (only on
age. E regimens (multiple-dose insulin or insulin
pump therapy) should perform SMBG demand). It is reported to have a lower
prior to meals and snacks, at bedtime, oc- cost than traditional systems. A study in
Self-monitoring of Blood Glucose
casionally postprandially, prior to exercise, adults with well-controlled type 1 diabe-
Major clinical trials of insulin-treated pa-
when they suspect low blood glucose, af- tes found that flash CGM users spent less
tients have included SMBG as part of
ter treating low blood glucose until they time in hypoglycemia than those using
multifactorial interventions to demon-
are normoglycemic, and prior to critical SMBG (19). However, due to significant
strate the benefit of intensive glycemic
tasks such as driving. For many patients, differences between flash CGM and other
control on diabetes complications. SMBG
this will require testing 6–10 (or more) CGM devices, more discussion is needed
is thus an integral component of effective
times daily, although individual needs on outcomes and regarding specific rec-
therapy (2). SMBG allows patients to eval-
may vary. A database study of almost ommendations.
uate their individual response to therapy
27,000 children and adolescents with For most CGM systems, confirmatory
and assess whether glycemic targets are
type 1 diabetes showed that, after adjust- SMBG is required to make treatment de-
being achieved. Integrating SMBG results
ment for multiple confounders, increased cisions, though a randomized controlled
into diabetes management can be a
daily frequency of SMBG was significantly trial of 226 adults suggested that an en-
useful tool for guiding medical nutrition
associated with lower A1C (–0.2% per ad- hanced CGM device could be used safely
therapy and physical activity, preventing
ditional test per day) and with fewer and effectively without regular confirma-
hypoglycemia, and adjusting medications
acute complications (8). tory SMBG in patients with well-controlled
(particularly prandial insulin doses). Among
type 1 diabetes at low risk of severe hy-
patients with type 1 diabetes, there is a
For Patients Using Basal Insulin and/or Oral poglycemia (1). Two CGM devices are now
correlation between greater SMBG fre-
Agents approved by the U.S. Food and Drug Ad-
quency and lower A1C (3). The patient’s
The evidence is insufficient regarding ministration (FDA) for making treatment
specific needs and goals should dictate
when to prescribe SMBG and how often decisions without SMBG confirmation
SMBG frequency and timing.
testing is needed for patients who do not use (18,20), including the flash CGM device.
Optimization intensive insulin regimens, such as those Although performed with older gener-
SMBG accuracy is dependent on the instru- with type 2 diabetes using oral agents ation CGM devices, a 26-week random-
ment and user, so it is important to evalu- and/or basal insulin. For patients using ized trial of 322 patients with type 1
ate each patient’s monitoring technique, basal insulin, assessing fasting glucose diabetes showed that adults aged $25 years
both initially and at regular intervals with SMBG to inform dose adjustments using intensive insulin therapy and CGM
thereafter. Optimal use of SMBG requires to achieve blood glucose targets results experienced a 0.5% reduction in A1C
proper review and interpretation of the in lower A1Cs (9,10). (from ;7.6% to 7.1% [;60 mmol/mol
data, by both the patient and the pro- For individuals with type 2 diabetes on to 54 mmol/mol]) compared with those
vider. Among patients who check their less intensive insulin therapy, more fre- using intensive insulin therapy with SMBG
blood glucose at least once daily, many quent SMBG (e.g., fasting, before/after (21). The greatest predictor of A1C lower-
report taking no action when results are meals) may be helpful, as increased fre- ing for all age-groups was frequency of
high or low. In a yearlong study of insulin- quency is associated with meeting A1C sensor use, which was highest in those
naive patients with suboptimal initial targets (11). aged $25 years and lower in younger
glycemic control, a group trained in struc- Several randomized trials have called age-groups. Two clinical trials in adults
tured SMBG (a paper tool was used at into question the clinical utility and cost- with type 1 diabetes not meeting A1C
least quarterly to collect and interpret effectiveness of routine SMBG in noninsu- targets and using multiple daily injections
7-point SMBG profiles taken on 3 consec- lin-treated patients (12–15). Meta-analyses also found that the use of CGM compared
utive days) reduced their A1C by 0.3 per- have suggested that SMBG can reduce A1C with usual care resulted in lower A1C levels
centage points more than the control by 0.25–0.3% at 6 months (16,17), but the than SMBG over 24–26 weeks (22,23).
group (4). Patients should be taught effect was attenuated at 12 months in Other small, short-term studies have
how to use SMBG data to adjust food in- one analysis (16). A key consideration is demonstrated similar A1C reductions us-
take, exercise, or pharmacologic therapy that performing SMBG alone does not ing CGM compared with SMBG in adults
to achieve specific goals. The ongoing lower blood glucose levels. To be useful, with A1C levels $7% (53 mmol/mol)
need for and frequency of SMBG should the information must be integrated into (24,25).
be reevaluated at each routine visit to clinical and self-management plans. A registry study of 17,317 participants
avoid overuse (5–7). SMBG is especially confirmed that more frequent CGM use is
important for insulin-treated patients to Continuous Glucose Monitoring associated with lower A1C (26), whereas
monitor for and prevent asymptomatic CGM measures interstitial glucose (which another study showed that children
hypoglycemia and hyperglycemia. Patients correlates well with plasma glucose), and with .70% sensor use (i.e., $5 days per Glycemic Targets S57

week) missed fewer school days (27). A1C TESTING when the A1C result does not correlate
Small randomized controlled trials in with the patient’s SMBG levels. Options
adults and children with baseline A1C for monitoring include more frequent and/
c Perform the A1C test at least two
,7.0–7.5% (53–58 mmol/mol) have con- or different timing of SMBG or CGM use.
times a year in patients who are
firmed favorable outcomes including a Other measures of average glycemia such
meeting treatment goals (and who
reduced frequency of hypoglycemia (de- as fructosamine and 1,5-anhydroglucitol
have stable glycemic control). E
fined as a blood glucose level ,70 mg/dL are available, but their translation into
c Perform the A1C test quarterly in
[3.9 mmol/L]) and maintaining A1C ,7% average glucose levels and their prog-
patients whose therapy has changed
(53 mmol/mol) during the study period in nostic significance are not as clear as
or who are not meeting glycemic
groups using CGM, suggesting that CGM for A1C. Though some variability exists
goals. E
may provide further benefit for individu- among different individuals, generally
c Point-of-care testing for A1C provides
als with type 1 diabetes who already have the association between mean glucose
the opportunity for more timely
good glycemic control (28–30). and A1C within an individual correlates
treatment changes. E
A meta-analysis suggests that com- over time (42).
pared with SMBG, CGM is associated A1C reflects average glycemia over A1C does not provide a measure of
with short-term A1C lowering of ;0.26% approximately 3 months and has strong glycemic variability or hypoglycemia. For
in insulin-treated patients (31). The long- predictive value for diabetes complica- patients prone to glycemic variability,
term effectiveness of CGM needs to be tions (39,40). Thus, A1C testing should especially patients with type 1 diabetes
determined. This technology may be par- be performed routinely in all patients or type 2 diabetes with severe insulin de-
ticularly useful in insulin-treated patients with diabetesdat initial assessment and ficiency, glycemic control is best evalu-
with hypoglycemia unawareness and/or as part of continuing care. Measurement ated by the combination of results from
frequent hypoglycemic episodes, although approximately every 3 months deter- A1C and SMBG or CGM. A1C may also
studies have not shown consistent reduc- mines whether patients’ glycemic targets confirm the accuracy of the patient’s me-
tions in severe hypoglycemia (31–33). A have been reached and maintained. The ter (or the patient’s reported SMBG re-
CGM device equipped with an automatic frequency of A1C testing should depend sults) and the adequacy of the SMBG
low glucose suspend feature has been on the clinical situation, the treatment testing schedule.
approved by the FDA. The Automation regimen, and the clinician’s judgment.
to Simulate Pancreatic Insulin Response The use of point-of-care A1C testing may A1C and Mean Glucose
(ASPIRE) trial of 247 patients with type 1 provide an opportunity for more timely Table 6.1 shows the correlation between
diabetes and documented nocturnal hypo- treatment changes during encounters be- A1C levels and mean glucose levels based
glycemia showed that sensor-augmented tween patients and providers. Patients on two studies: the international A1C-
insulin pump therapy with a low glucose with type 2 diabetes with stable glycemia Derived Average Glucose (ADAG) study,
suspend function significantly reduced well within target may do well with A1C which assessed the correlation between
nocturnal hypoglycemia over 3 months testing only twice per year. Unstable or A1C and frequent SMBG and CGM in
without increasing A1C levels (34). intensively managed patients (e.g., preg- 507 adults (83% non-Hispanic whites)
These devices may offer the opportunity nant women with type 1 diabetes) may with type 1, type 2, and no diabetes (43),
to reduce hypoglycemia for those with require testing more frequently than every and an empirical study of the average
a history of nocturnal hypoglycemia. 3 months (41). blood glucose levels at premeal, post-
The FDA has also approved the first meal, and bedtime associated with spec-
hybrid closed-loop system. The safety of A1C Limitations ified A1C levels using data from the
hybrid closed-loop systems has been sup- The A1C test is an indirect measure of ADAG trial (37). The American Diabetes
ported in the literature (35) and may have average glycemia and, as such, is subject Association (ADA) and the American As-
advantages over sensor-augmented to limitations. As with any laboratory test, sociation for Clinical Chemistry have de-
pump therapy in specific populations, there is variability in the measurement of termined that the correlation (r 5 0.92) in
such as pregnant women with type 1 A1C. Although such variability is less on an the ADAG trial is strong enough to justify
diabetes (36). intraindividual basis than that of blood reporting both the A1C result and the es-
Due to variable adherence, optimal glucose measurements, clinicians should timated average glucose (eAG) result
CGM use requires an assessment of indi- exercise judgment when using A1C as the when a clinician orders the A1C test. Clini-
vidual readiness for the technology as sole basis for assessing glycemic control, cians should note that the mean plasma
well as initial and ongoing education particularly if the result is close to the glucose numbers in the table are based on
and support (26,37). Additionally, pro- threshold that might prompt a change in ;2,700 readings per A1C in the ADAG
viders need to provide robust diabetes medication therapy. Conditions that affect trial. In a recent report, mean glucose
education, training, and support for opti- red blood cell turnover (hemolytic and measured with CGM versus central labo-
mal CGM implementation and ongoing other anemias, recent blood transfusion, ratory–measured A1C in 387 participants
use. As people with type 1 or type 2 use of drugs that stimulate erythropo- in three randomized trials demonstrated
diabetes are living longer, healthier lives, esis, end-stage kidney disease, and that A1C may underestimate or overesti-
individuals who have been successfully pregnancy) may result in discrepancies mate mean glucose. Thus, as suggested, a
using CGM should have continued access between the A1C result and the pa- patient’s CGM profile has considerable
to these devices after they turn 65 years tient’s true mean glycemia. Hemoglobin potential for optimizing his or her glyce-
of age (38). variants must be considered, particularly mic management (42).
S58 Glycemic Targets Diabetes Care Volume 41, Supplement 1, January 2018

A1C Differences in Ethnic Populations

Data in parentheses represent 95% CI, unless otherwise noted. A calculator for converting A1C results into eAG, in either mg/dL or mmol/L, is available at *These estimates are
and Children

12.3 (10.9–13.8)

based on ADAG data of ;2,700 glucose measurements over 3 months per A1C measurement in 507 adults with type 1, type 2, and no diabetes. The correlation between A1C and average glucose was 0.92 (43).
9.8 (9.2–10.4)
9.7 (9.0–10.4)
7.5 (7.3–7.8)
8.5 (8.0–8.9)
In the ADAG study, there were no signif-

icant differences among racial and ethnic

Mean bedtime glucose
groups in the regression lines between
A1C and mean glucose, although the
study was underpowered to detect a
difference and there was a trend toward

136 (131–141)
153 (145–161)

177 (166–188)
175 (163–188)

222 (197–248)
a difference between the African/African

American and non-Hispanic white co-
horts, with higher A1C values observed
in Africans/African Americans compared
with non-Hispanic whites for a given
10.5 (10.0–10.9)

11.4 (10.8–12.0)
9.8 (9.4–10.2)
8.0 (7.7–8.2)
9.1 (8.8–9.4)

mean glucose. Other studies have also
Mean postmeal glucose

demonstrated higher A1C levels in African
Americans than in whites at a given mean
glucose concentration (44,45). Moreover,
African Americans heterozygous for the
144 (139–148)
164 (159–169)

176 (170–183)
189 (180–197)

206 (195–217)

common hemoglobin variant HbS may
have, for any level of mean glycemia,

lower A1C by about 0.3 percentage points
than those without the trait (46). Another
genetic variant, X-linked glucose-6-phosphate
dehydrogenase G202A, carried by 11% of
9.9 (9.3–10.6)
6.5 (6.4–6.7)
7.7 (7.4–8.0)

8.4 (8.2–8.7)
8.6 (8.2–8.9)

African Americans, was associated with a
Mean premeal glucose

decrease in A1C of about 0.8% in hemi-
zygous men and 0.7% in homozygous
women compared to those without the
trait (47).
118 (115–121)
139 (134–144)

152 (147–157)
155 (148–161)

179 (167–191)

A small study comparing A1C to CGM

data in children with type 1 diabetes
found a highly statistically significant cor-
relation between A1C and mean blood glu-
cose, although the correlation (r 5 0.7) was
9.9 (9.1–10.7)
6.8 (6.5–7.0)
7.9 (7.5–8.3)

8.4 (7.9–9.0)
9.3 (8.7–9.8)

significantly lower than in the ADAG trial
Mean fasting glucose

(48). Whether there are clinically mean-
ingful differences in how A1C relates to
average glucose in children or in different
ethnicities is an area for further study
122 (117–127)
142 (135–150)

152 (143–162)
167 (157–177)

178 (164–192)

(44,49,50). Until further evidence is avail-
Table 6.1—Mean glucose levels for specified A1C levels (37,43)


able, it seems prudent to establish A1C
goals in these populations with consider-
ation of both individualized SMBG and
A1C results.
13.4 (10.7–15.7)
14.9 (12.0–17.5)
16.5 (13.3–19.3)
10.2 (8.1–12.1)

11.8 (9.4–13.9)
8.6 (6.8–10.3)
7.0 (5.5–8.5)

Mean plasma glucose*

For glycemic goals in children, please refer to
Section 12 “Children and Adolescents.”
For glycemic goals in pregnant women,
please refer to Section 13 “Management
126 (100–152)

154 (123–185)

183 (147–217)

212 (170–249)
240 (193–282)
269 (217–314)
298 (240–347)

of Diabetes in Pregnancy.”

c A reasonable A1C goal for many
nonpregnant adults is ,7% (53
mmol/mol). A
5.5–6.49 (37–47)
6.5–6.99 (47–53)

7.0–7.49 (53–58)
7.5–7.99 (58–64)

8.0–8.5 (64–69)
% (mmol/mol)

c Providers might reasonably suggest
more stringent A1C goals (such
12 (108)
10 (86)
11 (97)

as ,6.5% [48 mmol/mol]) for se-
6 (42)

7 (53)

8 (64)

9 (75)

lected individual patients if this Glycemic Targets S59

curvilinear relationship between A1C and death compared with those previously ran-
can be achieved without significant
microvascular complications. Such anal- domized to the standard arm (62). The
hypoglycemia or other adverse ef-
yses suggest that, on a population level, benefit of intensive glycemic control in
fects of treatment (i.e., polyphar-
the greatest number of complications will this cohort with type 1 diabetes has
macy). Appropriate patients might
be averted by taking patients from very been shown to persist for several decades
include those with short duration of
poor control to fair/good control. These (63) and to be associated with a modest
diabetes, type 2 diabetes treated
analyses also suggest that further lower- reduction in all-cause mortality (64).
with lifestyle or metformin only,
ing of A1C from 7% to 6% [53 mmol/mol
long life expectancy, or no signifi- Cardiovascular Disease and Type 2 Diabetes
to 42 mmol/mol] is associated with fur-
cant cardiovascular disease. C In type 2 diabetes, there is evidence that
ther reduction in the risk of microvascular
c Less stringent A1C goals (such more intensive treatment of glycemia in
complications, although the absolute risk
as ,8% [64 mmol/mol]) may be ap- newly diagnosed patients may reduce
reductions become much smaller. Given
propriate for patients with a history long-term CVD rates. During the UKPDS,
the substantially increased risk of hypo-
of severe hypoglycemia, limited life there was a 16% reduction in CVD events
glycemia in type 1 diabetes trials and
expectancy, advanced microvascu- (combined fatal or nonfatal MI and sud-
with polypharmacy in type 2 diabetes,
lar or macrovascular complications, den death) in the intensive glycemic con-
the risks of lower glycemic targets out-
extensive comorbid conditions, or trol arm that did not reach statistical
weigh the potential benefits on microvas-
long-standing diabetes in whom significance (P 5 0.052), and there was
cular complications.
the goal is difficult to achieve de- no suggestion of benefit on other CVD
spite diabetes self-management ACCORD, ADVANCE, and VADT outcomes (e.g., stroke). However, after
education, appropriate glucose Three landmark trials (Action to Control 10 years of observational follow-up, those
monitoring, and effective doses of Cardiovascular Risk in Diabetes [ACCORD], originally randomized to intensive glyce-
multiple glucose-lowering agents Action in Diabetes and Vascular Disease: mic control had significant long-term re-
including insulin. B Preterax and Diamicron MR Controlled ductions in MI (15% with sulfonylurea or
Evaluation [ADVANCE], and Veterans Af- insulin as initial pharmacotherapy, 33%
A1C and Microvascular Complications fairs Diabetes Trial [VADT]) showed that with metformin as initial pharmacother-
Hyperglycemia defines diabetes, and gly- lower A1C levels were associated with re- apy) and in all-cause mortality (13% and
cemic control is fundamental to diabetes duced onset or progression of some micro- 27%, respectively) (56).
management. The Diabetes Control and vascular complications (58–60). ACCORD, ADVANCE, and VADT sug-
Complications Trial (DCCT) (2), a prospec- The concerning mortality findings in gested no significant reduction in CVD
tive randomized controlled trial of inten- the ACCORD trial (61), discussed below, outcomes with intensive glycemic control
sive versus standard glycemic control in and the relatively intense efforts required in participants followed for 3.5–5.6 years
patients with type 1 diabetes, showed de- to achieve near-euglycemia should also who had more advanced type 2 diabetes
finitively that better glycemic control is be considered when setting glycemic tar- than UKPDS participants. All three trials
associated with significantly decreased gets. However, on the basis of physician were conducted in relatively older partic-
rates of development and progression of judgment and patient preferences, select ipants with longer known duration of di-
microvascular (retinopathy [51], neurop- patients, especially those with little co- abetes (mean duration 8–11 years) and
athy, and diabetic kidney disease) compli- morbidity and long life expectancy, may either CVD or multiple cardiovascular risk
cations. Follow-up of the DCCT cohorts in benefit from adopting more intensive gly- factors. The target A1C among intensive
the Epidemiology of Diabetes Interven- cemic targets (e.g., A1C target ,6.5% control subjects was ,6% (42 mmol/mol)
tions and Complications (EDIC) study [48 mmol/mol]) as long as significant hy- in ACCORD, ,6.5% (48 mmol/mol) in
(52) demonstrated persistence of these poglycemia does not become a barrier. ADVANCE, and a 1.5% reduction in A1C
microvascular benefits despite the fact compared with control subjects in VADT,
that the glycemic separation between A1C and Cardiovascular Disease with achieved A1C of 6.4% vs. 7.5%
the treatment groups diminished and dis- Outcomes (46 mmol/mol vs. 58 mmol/mol) in ACCORD,
appeared during follow-up. Cardiovascular Disease and Type 1 Diabetes 6.5% vs. 7.3% (48 mmol/mol vs. 56
The Kumamoto Study (53) and UK Pro- Cardiovascular disease (CVD) is a more mmol/mol) in ADVANCE, and 6.9% vs.
spective Diabetes Study (UKPDS) (54,55) common cause of death than microvascular 8.4% (52 mmol/mol vs. 68 mmol/mol) in
confirmed that intensive glycemic control complications in populations with diabetes. VADT. Details of these studies are re-
significantly decreased rates of microvas- There is evidence for a cardiovascular ben- viewed extensively in “Intensive Glycemic
cular complications in patients with type 2 efit of intensive glycemic control after long- Control and the Prevention of Cardiovas-
diabetes. Long-term follow-up of the term follow-up of cohorts treated early in cular Events: Implications of the ACCORD,
UKPDS cohorts showed enduring effects the course of type 1 diabetes. In the DCCT, ADVANCE, and VA Diabetes Trials” (65).
of early glycemic control on most micro- there was a trend toward lower risk of CVD The glycemic control comparison in
vascular complications (56). events with intensive control. In the 9-year ACCORD was halted early due to an in-
Therefore, achieving A1C targets post-DCCT follow-up of the EDIC cohort, creased mortality rate in the intensive
of ,7% (53 mmol/mol) has been shown participants previously randomized to the compared with the standard treatment
to reduce microvascular complications of intensive arm had a significant 57% reduc- arm (1.41% vs. 1.14% per year; hazard ra-
diabetes. Epidemiological analyses of the tion in the risk of nonfatal myocardial in- tio 1.22 [95% CI 1.01–1.46]), with a similar
DCCT (2) and UKPDS (57) demonstrate a farction (MI), stroke, or cardiovascular increase in cardiovascular deaths. Analysis
S60 Glycemic Targets Diabetes Care Volume 41, Supplement 1, January 2018

Table 6.2—Summary of glycemic recommendations for many nonpregnant adults have been associated with increased car-
with diabetes diovascular risk independent of fasting
A1C <7.0% (53 mmol/mol)* plasma glucose in some epidemiological
Preprandial capillary plasma glucose 80–130 mg/dL* (4.4–7.2 mmol/L) studies, but intervention trials have not
Peak postprandial capillary plasma glucose† <180 mg/dL* (10.0 mmol/L) shown postprandial glucose to be a cardio-
*More or less stringent glycemic goals may be appropriate for individual patients. Goals should be
vascular risk factor independent of A1C. In
individualized based on duration of diabetes, age/life expectancy, comorbid conditions, known CVD subjects with diabetes, surrogate measures
or advanced microvascular complications, hypoglycemia unawareness, and individual patient of vascular pathology, such as endothelial
considerations. †Postprandial glucose may be targeted if A1C goals are not met despite reaching dysfunction, are negatively affected by post-
preprandial glucose goals. Postprandial glucose measurements should be made 1–2 h after the
beginning of the meal, generally peak levels in patients with diabetes. prandial hyperglycemia. It is clear that post-
prandial hyperglycemia, like preprandial
hyperglycemia, contributes to elevated
of the ACCORD data did not identify a proposes optimal targets, but each target A1C levels, with its relative contribution be-
clear explanation for the excess mortality must be individualized to the needs of each ing greater at A1C levels that are closer to
in the intensive treatment arm (61). patient and his or her disease factors. 7% (53 mmol/mol). However, outcome
Longer-term follow-up has shown no ev- When possible, such decisions should be studies have clearly shown A1C to be the
idence of cardiovascular benefit or harm in made with the patient, reflecting his or her primary predictor of complications, and
the ADVANCE trial (66). The end-stage re- preferences, needs, and values. Fig. 6.1 landmark trials of glycemic control such as
nal disease rate was lower in the intensive is not designed to be applied rigidly but the DCCT and UKPDS relied overwhelmingly
treatment group over follow-up. However, to be used as a broad construct to guide on preprandial SMBG. Additionally, a ran-
10-year follow-up of the VADT cohort clinical decision-making (72), in both type 1 domized controlled trial in patients with
(67) showed a reduction in the risk of car- and type 2 diabetes. known CVD found no CVD benefit of insulin
diovascular events (52.7 [control group] Recommended glycemic targets for regimens targeting postprandial glucose
vs. 44.1 [intervention group] events per many nonpregnant adults are shown in compared with those targeting preprandial
1,000 person-years) with no benefit in Table 6.2. The recommendations include glucose (74). Therefore, it is reasonable for
cardiovascular or overall mortality. Hetero- blood glucose levels that appear to corre- postprandial testing to be recommended
geneity of mortality effects across studies late with achievement of an A1C of ,7% for individuals who have premeal glucose
was noted, which may reflect differences (53 mmol/mol). The issue of preprandial values within target but have A1C values
in glycemic targets, therapeutic approaches, versus postprandial SMBG targets is com- above target. Measuring postprandial
and population characteristics (68). plex (73). Elevated postchallenge (2-h oral plasma glucose 1–2 h after the start of a
Mortality findings in ACCORD (61) and glucose tolerance test) glucose values meal and using treatments aimed at
subgroup analyses of VADT (69) suggest
that the potential risks of intensive glyce-
mic control may outweigh its benefits in
higher-risk patients. In all three trials, se-
vere hypoglycemia was significantly more
likely in participants who were randomly
assigned to the intensive glycemic control
arm. Those patients with long duration of
diabetes, a known history of hypoglyce-
mia, advanced atherosclerosis, or ad-
vanced age/frailty may benefit from less
aggressive targets (70,71).
Providers should be vigilant in preventing
hypoglycemia and should not aggressively
attempt to achieve near-normal A1C levels
in patients in whom such targets cannot be
safely and reasonably achieved. Severe or
frequent hypoglycemia is an absolute indi-
cation for the modification of treatment
regimens, including setting higher glycemic
Many factors, including patient prefer-
ences, should be taken into account when
developing a patient’s individualized
goals (Table 6.2).

A1C and Glycemic Targets Figure 6.1—Depicted are patient and disease factors used to determine optimal A1C targets.
Numerous aspects must be considered Characteristics and predicaments toward the left justify more stringent efforts to lower A1C; those
when setting glycemic targets. The ADA toward the right suggest less stringent efforts. Adapted with permission from Inzucchi et al. (72). Glycemic Targets S61

Table 6.3—Classification of hypoglycemia*
Level Glycemic criteria Description
Hypoglycemia alert value (level 1) #70 mg/dL (3.9 mmol/L) Sufficiently low for treatment with fast-acting carbohydrate and dose
adjustment of glucose-lowering therapy
Clinically significant hypoglycemia (level 2) ,54 mg/dL (3.0 mmol/L) Sufficiently low to indicate serious, clinically important hypoglycemia
Severe hypoglycemia (level 3) No specific glucose threshold Hypoglycemia associated with severe cognitive impairment requiring
external assistance for recovery
*Adapted from ref. 75.

reducing postprandial plasma glucose val- Hypoglycemia may be inconvenient or
c Hypoglycemia unawareness or one
ues to ,180 mg/dL (10.0 mmol/L) may frightening to patients with diabetes. Se-
or more episodes of severe hypo-
help to lower A1C. vere hypoglycemia may be recognized or
glycemia should trigger reevalua-
An analysis of data from 470 participants unrecognized and can progress to loss of
tion of the treatment regimen. E
in the ADAG study (237 with type 1 diabe- consciousness, seizure, coma, or death. It is
c Insulin-treated patients with hy-
tes and 147 with type 2 diabetes) found reversed by administration of rapid-acting
poglycemia unawareness or an
that actual average glucose levels associ- glucose or glucagon. Clinically significant
episode of clinically significant hy-
ated with conventional A1C targets were hypoglycemia can cause acute harm to
poglycemia should be advised to
higher than older DCCT and ADA targets the person with diabetes or others, espe-
raise their glycemic targets to
(Table 6.1) (37,39). These findings support cially if it causes falls, motor vehicle acci-
strictly avoid hypoglycemia for at
that premeal glucose targets may be relaxed dents, or other injury. A large cohort study
least several weeks in order to par-
without undermining overall glycemic con- suggested that among older adults with
tially reverse hypoglycemia un-
trol as measured by A1C. These data promp- type 2 diabetes, a history of severe hypo-
awareness and reduce risk of future
ted the revision in the ADA-recommended glycemia was associated with greater risk
episodes. A
premeal glucose target to 80–130 mg/dL of dementia (77). Conversely, in a sub-
c Ongoing assessment of cognitive
(4.4–7.2 mmol/L) but did not affect the study of the ACCORD trial, cognitive
function is suggested with increased
definition of hypoglycemia. impairment at baseline or decline in cog-
vigilance for hypoglycemia by the
nitive function during the trial was sig-
clinician, patient, and caregivers if
HYPOGLYCEMIA nificantly associated with subsequent
low cognition or declining cognition
episodes of severe hypoglycemia (78). Ev-
Recommendations is found. B
idence from DCCT/EDIC, which involved
c Individuals at risk for hypoglycemia
adolescents and younger adults with
should be asked about symptom-
Hypoglycemia is the major limiting factor type 1 diabetes, found no association be-
atic and asymptomatic hypoglyce-
in the glycemic management of type 1 tween frequency of severe hypoglycemia
mia at each encounter. C
and type 2 diabetes. Recommendations and cognitive decline (79), as discussed in
c Glucose (15–20 g) is the preferred
from the International Hypoglycemia Study Section 12 “Children and Adolescents.”
treatment for the conscious individ-
Group regarding the classification of hypo- Severe hypoglycemia was associated
ual with blood glucose #70 mg/dL
glycemia in clinical trials are outlined in Ta- with mortality in participants in both the
[3.9 mmol/L]), although any form of
ble 6.3 (75). Of note, this classification standard and the intensive glycemia arms
carbohydrate that contains glucose
scheme considers a blood glucose ,54 of the ACCORD trial, but the relationships
may be used. Fifteen minutes after
mg/dL (3.0 mmol/L) detected by SMBG, between hypoglycemia, achieved A1C,
treatment, if SMBG shows contin-
CGM (for at least 20 min), or laboratory and treatment intensity were not straight-
ued hypoglycemia, the treatment
measurement of plasma glucose as suffi- forward. An association of severe hypo-
should be repeated. Once SMBG
ciently low to indicate clinically significant glycemia with mortality was also found
returns to normal, the individual
hypoglycemia that should be included in in the ADVANCE trial (80). An association
should consume a meal or snack to
reports of clinical trials of glucose-lowering between self-reported severe hypoglyce-
prevent recurrence of hypoglycemia. E
drugs for the treatment of diabetes (75). mia and 5-year mortality has also been
c Glucagon should be prescribed for
However, a hypoglycemia alert value reported in clinical practice (81).
all individuals at increased risk of
of #70 mg/dL (3.9 mmol/L) can be impor- Young children with type 1 diabetes and
clinically significant hypoglycemia,
tant for therapeutic dose adjustment of the elderly, including those with type 1 and
defined as blood glucose ,54 mg/dL
glucose-lowering drugs in clinical care and type 2 diabetes (77,82), are noted as par-
(3.0 mmol/L), so it is available should
is often related to symptomatic hypogly- ticularly vulnerable to clinically significant
it be needed. Caregivers, school
cemia. Severe hypoglycemia is defined as hypoglycemia because of their reduced
personnel, or family members of
severe cognitive impairment requiring as- ability to recognize hypoglycemic symp-
these individuals should know
sistance from another person for recov- toms and effectively communicate their
where it is and when and how to
ery (76). needs. Individualized glucose targets, pa-
administer it. Glucagon administra-
Symptoms of hypoglycemia include, tient education, dietary intervention (e.g.,
tion is not limited to health care
but are not limited to, shakiness, irritabil- bedtime snack to prevent overnight hypo-
professionals. E
ity, confusion, tachycardia, and hunger. glycemia when specifically needed to treat
S62 Glycemic Targets Diabetes Care Volume 41, Supplement 1, January 2018

low blood glucose), exercise management, with hypoglycemia-prone diabetes (fam- prone patients also require urine or
medication adjustment, glucose monitor- ily members, roommates, school person- blood ketone monitoring. If accompa-
ing, and routine clinical surveillance may nel, child care providers, correctional nied by ketosis, vomiting, or alteration in
improve patient outcomes (76). CGM with institution staff, or coworkers) should be the level of consciousness, marked hyper-
automated low glucose suspend has been instructed on the use of glucagon kits in- glycemia requires temporary adjustment of
shown to be effective in reducing hypogly- cluding where the kit is and when and the treatment regimen and immediate in-
cemia in type 1 diabetes (34). For patients how to administer glucagon. An individual teraction with the diabetes care team. The
with type 1 diabetes with severe hypogly- does not need to be a health care pro- patient treated with noninsulin therapies or
cemia and hypoglycemia unawareness fessional to safely administer glucagon. medical nutrition therapy alone may tem-
that persists despite medical treatment, Care should be taken to ensure that glu- porarily require insulin. Adequate fluid and
human islet transplantation may be an op- cagon kits are not expired. caloric intake must be ensured. Infection or
tion, but the approach remains experimen- Hypoglycemia Prevention
dehydration is more likely to necessitate
tal (83,84). Hypoglycemia prevention is a critical com- hospitalization of the person with diabetes
In 2015, the ADA changed its prepran- ponent of diabetes management. SMBG than the person without diabetes.
dial glycemic target from 70–130 mg/dL and, for some patients, CGM are essential A physician with expertise in diabetes
(3.9–7.2 mmol/L) to 80–130 mg/dL (4.4– tools to assess therapy and detect incipient management should treat the hospital-
7.2 mmol/L). This change reflects the results hypoglycemia. Patients should understand ized patient. For further information on
of the ADAG study, which demonstrated situations that increase their risk of hypo- the management of diabetic ketoacidosis
that higher glycemic targets corresponded glycemia, such as fasting for tests or pro- and the hyperglycemic nonketotic hyper-
to A1C goals (37). An additional goal of cedures, delayed meals, during or after osmolar state, please refer to the ADA con-
raising the lower range of the glycemic intense exercise, and during sleep. Hypo- sensus report “Hyperglycemic Crises in
target was to limit overtreatment and glycemia may increase the risk of harm to Adult Patients With Diabetes” (87).
provide a safety margin in patients titrat- self or others, such as with driving. Teach-
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15. Young LA, Buse JB, Weaver MA, et al.; Mon- cose monitoring on hypoglycemia in type 1 diabe- Schoenfeld D, Heine RJ; A1c-Derived Average Glu-
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insulin-treated patients with type 2 diabetes in 29. Beck RW, Hirsch IB, Laffel L, et al.; Juvenile estimated average glucose values. Diabetes Care
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16. Malanda UL, Welschen LMC, Riphagen II, tinuous glucose monitoring in well-controlled cial differences in HbA1c? A difference, to be a
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of blood glucose in patients with type 2 diabetes 1383 Care 2016;39:1462–1467
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17. Willett LR. ACP Journal Club. Meta-analysis: Monitoring Study Group. Sustained benefit of differences in the relationship of glucose concen-
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18. U.S. Food and Drug Administration. FDA ap- 31. Yeh H-C, Brown TT, Maruthur N, et al. Com- sociation of sickle cell trait with hemoglobin A1c in
proves first continuous glucose monitoring system parative effectiveness and safety of methods African Americans. JAMA 2017;317:507–515
for adults not requiring blood sample calibration of insulin delivery and glucose monitoring 47. Wheeler E, Leong A, Liu C-T, et al.; EPIC-CVD
[Internet]. Available from for diabetes mellitus: a systematic review and Consortium; EPIC-InterAct Consortium; Lifelines
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19. Bolinder J, Antuna R, Geelhoed-Duijvestijn P, 32. Choudhary P, Ramasamy S, Green L, et al. risk and diagnosis in ancestrally diverse popula-
Kröger J, Weitgasser R. Novel glucose-sensing Real-time continuous glucose monitoring signifi- tions: a transethnic genome-wide meta-analysis.
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20. U.S. Food and Drug Administration. FDA ex- 33. Choudhary P, Rickels MR, Senior PA, et al. lationship of A1C to glucose concentrations in
pands indication for continuous glucose monitor- Evidence-informed clinical practice recommenda- children with type 1 diabetes: assessments by
ing system, first to replace fingerstick testing for tions for treatment of type 1 diabetes compli- high-frequency glucose determinations by sen-
diabetes treatment decisions [Internet]. Avail- cated by problematic hypoglycemia. Diabetes sors. Diabetes Care 2008;31:381–385
able from Care 2015;38:1016–1029 49. Buse JB, Kaufman FR, Linder B, Hirst K, El
newsroom/pressannouncements/ucm534056 34. Bergenstal RM, Klonoff DC, Garg SK, et al.; Ghormli L, Willi S; HEALTHY Study Group. Diabetes
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Juvenile Diabetes Research Foundation Continu- glycemia. N Engl J Med 2013;369:224–232 hort. Diabetes Care 2013;36:429–435
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glucose monitoring and intensive treatment of Safety of a hybrid closed-loop insulin delivery sys- parity in A1C independent of mean blood glucose
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Complications Research Group. Retinopathy and plications Trial/Epidemiology of Diabetes Interven- (54 mg/dL) should be reported in clinical trials:
nephropathy in patients with type 1 diabetes four tions and Complications and Pittsburgh Epidemiology a joint position statement of the American Diabe-
years after a trial of intensive therapy. N Engl J of Diabetes Complications experience (1983-2005). tes Association and the European Association for
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diabetic microvascular complications in Japanese Association between 7 years of intensive treat- glycemia and diabetes: a report of a workgroup of
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Group. Intensive blood-glucose control with sul- Association and a scientific statement of the severe hypoglycemia in type 2 diabetes: post hoc
phonylureas or insulin compared with conven- American College of Cardiology Foundation and epidemiologic analysis of the ACCORD trial. Dia-
tional treatment and risk of complications in the American Heart Association. Diabetes Care betes Care 2012;35:787–793
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1998;352:837–853 66. Zoungas S, Chalmers J, Neal B, et al.; Diabetes Control and Complications Trial/
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DR, Neil HAW. 10-year follow-up of intensive glu- blood-pressure lowering and glucose control in plications Study Research Group. Long-term ef-
cose control in type 2 diabetes. N Engl J Med 2008; type 2 diabetes. N Engl J Med 2014;371:1392–1406 fect of diabetes and its treatment on cognitive
359:1577–1589 67. Hayward RA, Reaven PD, Wiitala WL, et al.; function. N Engl J Med 2007;356:1842–1852
57. Adler AI, Stratton IM, Neil HAW, et al. Asso- VADT Investigators. Follow-up of glycemic control 80. Zoungas S, Patel A, Chalmers J, et al.; ADVANCE
ciation of systolic blood pressure with macrovas- and cardiovascular outcomes in type 2 diabetes. N Collaborative Group. Severe hypoglycemia and
cular and microvascular complications of type 2 Engl J Med 2015;372:2197–2206 risks of vascular events and death. N Engl J Med
diabetes (UKPDS 36): prospective observational 68. Turnbull FM, Abraira C, Anderson RJ, et al.; 2010;363:1410–1418
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58. Duckworth W, Abraira C, Moritz T, et al.; rovascular outcomes in type 2 diabetes [published Shah ND, Wermers RA, Smith SA. Increased mor-
VADT Investigators. Glucose control and vascular correction appears in Diabetologia 2009;52: tality of patients with diabetes reporting severe
complications in veterans with type 2 diabetes. N 2470]. Diabetologia 2009;52:2288–2298 hypoglycemia. Diabetes Care 2012;35:1897–
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60. Ismail-Beigi F, Craven T, Banerji MA, et al.; 70. Lipska KJ, Ross JS, Miao Y, Shah ND, Lee SJ, ical Islet Transplantation Consortium. Phase 3 trial
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of hyperglycaemia on microvascular outcomes in tes mellitus in older adults with tight glycemic betes complicated by severe hypoglycemia. Dia-
type 2 diabetes: an analysis of the ACCORD rand- control. JAMA Intern Med 2015;175:356–362 betes Care 2016;39:1230–1240
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Diabetes Care Volume 41, Supplement 1, January 2018 S65

American Diabetes Association
7. Obesity Management for the
Treatment of Type 2 Diabetes:
Standards of Medical Care in
Diabetes Care 2018;41(Suppl. 1):S65–S72 |

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes”
includes 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, 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.
Readers who wish to comment on the Standards of Care are invited to do so at

There is strong and consistent evidence that obesity management can delay the progression
from prediabetes to type 2 diabetes (1,2) and may be beneficial in the treatment of type 2
diabetes (3–8). In overweight and obese patients with type 2 diabetes, modest and
sustained weight loss has been shown to improve glycemic control and to reduce the
need for glucose-lowering medications (3–5). Small studies have demonstrated that in
obese patients with type 2 diabetes 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 (7,9,10). Weight loss–induced improvements in glycemia are most likely to
occur early in the natural history of type 2 diabetes when obesity-associated insulin
resistance has caused reversible b-cell dysfunction but insulin secretory capacity re-
mains relatively preserved (5,8,10,11).The goal of this section is to provide evidence-
based recommendations for dietary, pharmacologic, and surgical interventions for
obesity management as treatments for hyperglycemia in type 2 diabetes.

Suggested citation: American Diabetes Associa-
c At each patient encounter, BMI should be calculated and documented in the tion. 7. Obesity management for the treatment
medical record. B of type 2 diabetes: Standards of Medical Care in
Diabetesd2018. Diabetes Care 2018;41(Suppl. 1):
At each routine patient encounter, BMI should be calculated as weight divided by S65–S72
height squared (kg/m2) (12). BMI should be classified to determine the presence of © 2017 by the American Diabetes Association.
overweight or obesity, discussed with the patient, and documented in the patient Readers may use this article as long as the work
is properly cited, the use is educational and not
record. In Asian Americans, the BMI cutoff points to define overweight and obesity for profit, and the work is not altered. More infor-
are lower than in other populations (Table 7.1) (13,14). Providers should advise over- mation is available at http://www.diabetesjournals
weight and obese patients that, in general, higher BMIs increase the risk of .org/content/license.
S66 Obesity Management for the Treatment of Type 2 Diabetes Diabetes Care Volume 41, Supplement 1, January 2018

Table 7.1—Treatment options for overweight and obesity in type 2 diabetes
BMI category (kg/m2)
25.0–26.9 27.0–29.9 30.0–34.9 35.0–39.9 $40
Treatment (or 23.0–26.9*) (or 27.5–32.4*) (or 32.5–37.4*) (or $37.5*)
Diet, physical activity, and behavioral therapy † † † † †
Pharmacotherapy † † † †
Metabolic surgery † † †
*Cutoff points for Asian American individuals. †Treatment may be indicated for selected motivated patients.

cardiovascular disease and all-cause mor- functioning, and health-related quality
carefully selected patients by
tality. Providers should assess each pa- of life (17). A post hoc analysis of the
trained practitioners in medical
tient’s readiness to achieve weight loss Look AHEAD study suggests that hetero-
care settings with close medical
and jointly determine weight loss goals geneous treatment effects may have
monitoring. To maintain weight
and intervention strategies. Strategies in- been present. Participants who had mod-
loss, such programs must incorpo-
clude diet, physical activity, behavioral erately or poorly controlled diabetes (A1C
rate long-term comprehensive
therapy, pharmacologic therapy, and met- 6.8% or higher) as well as both those with
weight maintenance counseling. B
abolic surgery (Table 7.1). The latter two well-controlled diabetes (A1C less than
strategies may be prescribed for carefully 6.8%) and good self-reported health
Among overweight or obese patients with
selected patients as adjuncts to diet, were found to have significantly reduced
type 2 diabetes and inadequate glycemic,
physical activity, and behavioral therapy. cardiovascular events with intensive life-
blood pressure, and lipid control and/or
style intervention during follow-up (18).
other obesity-related medical conditions,
lifestyle changes that result in modest
DIET, PHYSICAL ACTIVITY, AND Lifestyle Interventions
BEHAVIORAL THERAPY and sustained weight loss produce clini-
Weight loss can be attained with lifestyle
cally meaningful reductions in blood glu-
programs that achieve a 500–750 kcal/day
cose, A1C, and triglycerides (3–5). Greater
c Diet, physical activity, and behavior- energy deficit or provide approximately
weight loss produces even greater bene-
al therapy designed to achieve .5% 1,200–1,500 kcal/day for women and
fits, including reductions in blood pres-
weight loss should be prescribed for 1,500–1,800 kcal/day for men, adjusted
sure, improvements in LDL and HDL
overweight and obese patients with for the individual’s baseline body weight.
cholesterol, and reductions in the need
type 2 diabetes ready to achieve Although benefits may be seen with as
for medications to control blood glucose,
weight loss. A little as 5% weight loss (19), sustained
blood pressure, and lipids (3–5).
c Such interventions should be high weight loss of $7% is optimal.
intensity ($16 sessions in 6 months) These diets may differ in the types of
and focus on diet, physical activity, Look AHEAD Trial foods they restrict (such as high-fat or
and behavioral strategies to achieve Although the Action for Health in Diabe- high-carbohydrate foods) but are effec-
a 500–750 kcal/day energy deficit. A tes (Look AHEAD) trial did not show that tive if they create the necessary energy
c Diets should be individualized, as an intensive lifestyle intervention reduced deficit (12,20–22). Use of meal replace-
those that provide the same caloric cardiovascular events in overweight or ment plans prescribed by trained practi-
restriction but differ in protein, carbo- obese adults with type 2 diabetes (15), it tioners, with close patient monitoring,
hydrate, and fat content are equally did show the feasibility of achieving and can be beneficial. Within the intensive
effective in achieving weight loss. A maintaining long-term weight loss in pa- lifestyle intervention group of the Look
c For patients who achieve short- tients with type 2 diabetes. In the Look AHEAD trial, for example, use of a partial
term weight-loss goals, long-term AHEAD intensive lifestyle intervention meal replacement plan was associated
($1 year) comprehensive weight group, mean weight loss was 4.7% at with improvements in diet quality (23).
maintenance programs should be 8 years (16). Approximately 50% of inten- The diet choice should be based on the
prescribed. Such programs should sive lifestyle intervention participants patient’s health status and preferences.
provide at least monthly contact lost $5%, and 27% lost $10% of their Intensive behavioral lifestyle interven-
and encourage ongoing monitoring initial body weight at 8 years (16). Partic- tions should include $16 sessions in
of body weight (weekly or more fre- ipants randomly assigned to the intensive 6 months and focus on diet, physical ac-
quently), continued consumption lifestyle group achieved equivalent risk tivity, and behavioral strategies to achieve
of a reduced-calorie diet, and par- factor control but required fewer glucose-, an ;500–750 kcal/day energy deficit. In-
ticipation in high levels of physical blood pressure–, and lipid-lowering med- terventions should be provided by trained
activity (200–300 min/week). A ications than those randomly assigned to interventionists in either individual or
c To achieve weight loss of .5%, standard care. Secondary analyses of the group sessions (19).
short-term (3-month) interventions Look AHEAD trial and other large cardio- Overweight and obese patients with
that use very-low-calorie diets vascular outcome studies document type 2 diabetes who have lost weight
(#800 kcal/day) and total meal re- other benefits of weight loss in patients during the 6-month intensive behavioral
placements may be prescribed for with type 2 diabetes, including improve- lifestyle intervention should be enrolled
ments in mobility, physical and sexual in long-term ($1 year) comprehensive Obesity Management for the Treatment of Type 2 Diabetes S67

weight loss maintenance programs that promote weight loss or to be weight neu- adhere to low-calorie diets and to rein-
provide at least monthly contact with a tral. Agents associated with weight loss force lifestyle changes including physical
trained interventionist and focus on on- include metformin, a-glucosidase inhibi- activity. Providers should be knowledge-
going monitoring of body weight (weekly tors, sodium–glucose cotransporter 2 in- able about the product label and should
or more frequently), continued consump- hibitors, glucagon-like peptide 1 agonists, balance the potential benefits of success-
tion of a reduced-calorie diet, and partic- and amylin mimetics. Dipeptidyl peptidase ful weight loss against the potential risks
ipation in high levels of physical activity 4 inhibitors appear to be weight neutral. of the medication for each patient. These
(200–300 min/week [24]). Some com- Unlike these agents, insulin secretagogues, medications are contraindicated in women
mercial and proprietary weight loss pro- thiazolidinediones, and insulin have often who are or may become pregnant. Women
grams have shown promising weight loss been associated with weight gain (see in their reproductive years must be cautioned
results (25). Section 8. Pharmacologic Approaches to use a reliable method of contraception.
When provided by trained practitioners to Glycemic Treatment”).
Assessing Efficacy and Safety
in medical care settings with close medical A recent meta-analysis of 227 random-
Efficacy and safety should be assessed at least
monitoring, short-term (3-month) inter- ized controlled trials of antihyperglycemic
monthly for the first 3 months of treatment.
ventions that use very-low-calorie diets treatments in type 2 diabetes found that
If a patient’s response is deemed insuffi-
(defined as #800 kcal/day) and total A1C changes were not associated with
cient (weight loss ,5%) after 3 months or
meal replacements may achieve greater baseline BMI, indicating that obese pa-
if there are any safety or tolerability is-
short-term weight loss (10–15%) than in- tients can benefit from the same types
sues at any time, the medication should
tensive behavioral lifestyle interventions of treatments for diabetes as normal-
be discontinued and alternative medica-
that typically achieve 5% weight loss. weight patients (28).
tions or treatment approaches should be
However, weight regain following the ces-
sation of very-low-calorie diets is greater Concomitant Medications
In general, pharmacologic treatment of
than following intensive behavioral life- Providers should carefully review the pa-
obesity has been limited by low adherence,
style interventions unless a long-term tient’s concomitant medications and,
modest efficacy, adverse effects, and weight
comprehensive weight loss maintenance whenever possible, minimize or provide
regain after medication cessation (30).
program is provided (26,27). alternatives for medications that pro-
mote weight gain. Medications associ-
PHARMACOTHERAPY ated with weight gain include atypical METABOLIC SURGERY
antipsychotics (e.g., clozapine, olanza- Recommendations
pine, risperidone, etc.) and antidepres- c Metabolic surgery should be recom-
c When choosing glucose-lowering sants (e.g., tricyclic antidepressants, mended as an option to treat type 2
medications for overweight or obese selective serotonin reuptake inhibitors,
patients with type 2 diabetes, con- diabetes in appropriate surgical
and monoamine oxidase inhibitors), glu- candidates with BMI $40 kg/m2
sider their effect on weight. E cocorticoids, oral contraceptives that
c Whenever possible, minimize the (BMI $37.5 kg/m2 in Asian Ameri-
contain progestins, anticonvulsants in- cans), regardless of the level of gly-
medications for comorbid conditions cluding gabapentin, and a number of an-
that are associated with weight gain. E cemic control or complexity of
tihistamines and anticholinergics. glucose-lowering regimens, and in
c Weight loss medications may be ef-
fective as adjuncts to diet, physical ac- adults with BMI 35.0–39.9 kg/m2
Approved Weight Loss Medications (32.5–37.4 kg/m2 in Asian Ameri-
tivity, and behavioral counseling for The U.S. Food and Drug Administration
selected patients with type 2 diabetes cans) when hyperglycemia is inade-
(FDA) has approved medications for quately controlled despite lifestyle
and BMI $27 kg/m2. Potential ben- both short-term and long-term weight
efits must be weighed against the and optimal medical therapy. A
management. Phentermine is indicated c Metabolic surgery should be con-
potential risks of the medications. A as short-term (a few weeks) adjunct in
c If a patient’s response to weight loss sidered as an option for adults with
conjunction with lifestyle and behavioral type 2 diabetes and BMI 30.0–
medications is ,5% weight loss af- weight loss interventions (29). Five
ter 3 months or if there are any 34.9 kg/m2 (27.5–32.4 kg/m2 in
weight loss medications (or combination Asian Americans) if hyperglycemia
safety or tolerability issues at any medications) are FDA-approved for long-
time, the medication should be dis- is inadequately controlled despite
term use (more than a few weeks) by optimal medical control by either
continued and alternative medica- patients with BMI $27 kg/m2 with one
tions or treatment approaches oral or injectable medications (in-
or more obesity-associated comorbid cluding insulin). B
should be considered. A conditions (e.g., type 2 diabetes, hyperten- c Metabolic surgery should be per-
sion, and dyslipidemia) and by patients formed in high-volume centers
Antihyperglycemic Therapy with BMI $30 kg/m2 who are motivated with multidisciplinary teams that
When evaluating pharmacologic treat- to lose weight (30–34). Medications ap- understand and are experienced in
ments for overweight or obese patients proved by the FDA for the treatment of the management of diabetes and
with type 2 diabetes, providers should obesity and their advantages and disad- gastrointestinal surgery. C
first consider their choice of glucose- vantages are summarized in Table 7.2. c Long-term lifestyle support and rou-
lowering medications. Whenever possi- The rationale for weight loss medications tine monitoring of micronutrient
ble, medications should be chosen to is to help patients to more consistently

Table 7.2—Medications approved by the FDA for the treatment of obesity
1-Year weight change status1–4
Generic drug name National Average Drug
Adverse effects1,5–12
(proprietary name[s]), dosage, Usual adult dosing Average wholesale Acquisition Cost (per Average weight loss % Patients with $5%
strength, and form frequency price (per month)13 month)14 relative to placebo loss of baseline weight Common6 Serious6
Short-term treatment (a few weeks)
Phentermine (Lomaira) 37.5mgq.d.or8mgt.i.d. $5-$76 (37.5 mg); $3-$60 (37.5 mg); N/A* N/A* Headache, elevated blood Dyspnea, angina pectoris,
$52 (8 mg) Unavailable (8 mg) pressure, elevated syncope, severe
heart rate, insomnia, hypertension
dry mouth,
constipation, anxiety,
Long-term treatment (more than a few weeks)
Lipase inhibitor
Orlistat (Alli) 60 mg caps 60 mg or 120 mg t.i.d. $41–82 (60 mg); $42 (60 mg); 2.5 kg (60 mg); 35–73% Abdominal pain/ Liver failure and oxalate
or orlistat (Xenical) (during or up to 1 h $703 (120 mg) $556 (120 mg) 3.4 kg (120 mg) discomfort, oily spotting/ nephropathy
120 mg caps after a low-fat meal) stool, fecal urgency,
Obesity Management for the Treatment of Type 2 Diabetes

malabsorption of fat
soluble vitamins (A, D, E,
K) and medications (e.g.,
cyclosporine, thyroid
hormone replacement,
or anticonvulsants),
potentiation of the
effects of warfarin
Selective serotonin (5-HT) 5-HT2C receptor agonist
Lorcaserin (Belviq) 10 mg 10 mg b.i.d. $289 $230 3.2 kg 38–48% Hypoglycemia, headache, Serotonin syndrome or
tabs fatigue NMS-like reactions,
suicidal ideation, heart
valve disorder (,2.4%),
Lorcaserin (Belviq XR) 20 mg q.d. $289 $232 3.2 kg 38–48% Hypoglycemia, headache, Serotonin syndrome or
20 mg extended-release fatigue NMS-like reactions,
tabs suicidal ideation, heart
valve disorder (,2.4%),
Sympathomimetic amine anorectic/antiepileptic combination
Phentermine/topiramate Recommended dose: $239 (maximum dose $192 (maximum dose 6.7 kg (7.5 mg/46 mg); 45–70% Paresthesia, xerostomia, Topiramate is teratogenic
ER (Qsymia) 3.75 mg/ 3.75 mg/23 mg q.d. using the highest using the highest 8.9 kg (15 mg/92 mg) constipation, headache and has been associated
23 mg caps, 7.5 mg/ for 14 days, then strength) strength) with cleft lip/palate
46 mg caps, 11.25 mg/ increase to 7.5 mg/
69 mg caps, 15 mg/ 46 mg q.d.
92 mg caps Maximum dose:
15 mg/92 mg q.d.

Continued on p. S69
Diabetes Care Volume 41, Supplement 1, January 2018
Table 7.2—Continued
1-Year weight change status1–4
Generic drug name National Average Drug
Adverse effects1,5–12
(proprietary name[s]), dosage, Usual adult dosing Average wholesale Acquisition Cost (per Average weight loss % Patients with $5%
strength, and form frequency price (per month)13 month)14 relative to placebo loss of baseline weight Common Serious6

Opioid antagonist/aminoketone antidepressant combination
Naltrexone/bupropion Maximum dose: two $290 (maximum dose) $231 (maximum dose) 2.0–4.1 kg 36–57% Nausea, constipation, Depression, precipitation of
(Contrave) 8 mg/90 mg tablets of Contrave (32 mg/360 mg) headache, vomiting mania, contraindicated in
tabs b.i.d. for a total daily patients with a seizure
dosage of naltrexone disorder
32 mg/bupropion
360 mg
Glucagon-like peptide 1 receptor agonist
Liraglutide (Saxenda) Maintenance dose: $1,385 $1,105 5.8–5.9 kg 51–73% Hypoglycemia, nausea, Pancreatitis, thyroid C-cell
6 mg/mL prefilled pen 3 mg s.c. q.d. vomiting, diarrhea, tumors in rodents,
constipation, headache contraindicated in
patients with personal/
family history of MTC or
MEN2, acute renal
All medications are contraindicated in women who are or may become pregnant. Women in their reproductive years must be cautioned to use a reliable method of contraception. Caps, capsules; ER, extended release;
MEN2, multiple endocrine neoplasia type 2; MTC, medullary thyroid carcinoma; N/A, not applicable; NMS, neuroleptic malignant syndrome; s.c., subcutaneous; tabs, tablets. *Phentermine is FDA-approved as a short-
term adjunct (a few weeks) in a regimen of weight reduction based on exercise, behavioral modification, and caloric restriction.
Physicians’ Desk Reference. PDR Network, LLC (electronic version). Truven Health Analytics, Greenwood Village, CO.
Yanovski SZ, Yanovski JA. Long-term drug treatment for obesity: a systematic and clinical review. JAMA 2014;311:74–86 (30).
Astrup A, Carraro R, Finer N, et al.; NN8022–1807 Investigators. Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. Int J Obes (Lond) 2012;36:843–854.
Wadden TA, Hollander P, Klein S, et al.; NN8022–1923 Investigators. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study.
Int J Obes (Lond) 2013;37:1443–1451.
DrugPoints System (electronic version). Truven Health Analytics, Greenwood Village, CO.
Selective common (defined as an incidence of .5%) and serious adverse effects are noted. Refer to the medication package inserts for full information about adverse effects, cautions, and contraindications.
Data of common adverse effects for Xenical were derived from seven double-blind, placebo-controlled clinical trials in mixed-type study populations (i.e., patients with or without type 2 diabetes), but the percentage of
patients with type 2 diabetes was not reported. In clinical trials in obese patients with diabetes, hypoglycemia and abdominal distension were also observed.
Data of common adverse effects for Belviq were derived from placebo-controlled clinical trials in patients with type 2 diabetes.
Data of common adverse effects for Qsymia were derived from four clinical trials in mixed-type study populations (i.e., patients with or without type 2 diabetes); 13% had type 2 diabetes.
Data of common adverse effects for Contrave were derived from five double-blind, placebo-controlled clinical trials in mixed-type study populations (i.e., patients with or without type 2 diabetes); 13% had type 2
Data of common adverse effects for Saxenda were derived from clinical trials in mixed-type study populations (i.e., patients with or without type 2 diabetes). Percentage of patients with type 2 diabetes was not
Phentermine. FDA prescribing information, side effects and uses [Internet], 2017. Available from Accessed 22 September 2017 (29).
RED BOOK Online. Micromedex 2.0 (electronic version). Truven Health Analytics, Greenwood Village, CO. Accessed 18 July 2017.
National Average Drug Acquisition Cost data available at: Accessed 19 July 2017.
Obesity Management for the Treatment of Type 2 Diabetes
S70 Obesity Management for the Treatment of Type 2 Diabetes Diabetes Care Volume 41, Supplement 1, January 2018

Please refer to “Metabolic Surgery in the mortality, complications, reoperations,
and nutritional status must be pro-
Treatment Algorithm for Type 2 Diabe- and readmissions (71).
vided to patients after surgery, accord-
tes: A Joint Statement by International Although metabolic surgery has been
ing to guidelines for postoperative
Diabetes Organizations” for a thorough shown to improve the metabolic profiles
management of metabolic surgery
review (35). of morbidly obese patients with type 1
by national and international profes-
Randomized controlled trials with diabetes, establishing the role of meta-
sional societies. C
postoperative follow up ranging from bolic surgery in such patients will require
c People presenting for metabolic
1 to 5 years have documented sustained larger and longer studies (72).
surgery should receive a compre-
diabetes remission in 30–63% of patients Retrospective analyses and modeling
hensive mental health assessment.
(35). Available data suggest an erosion of studies suggest that metabolic surgery
B Surgery should be postponed in
diabetes remission over time (51): 35– may be cost-effective or even cost-saving
patients with histories of alcohol or
50% or more of patients who initially for patients with type 2 diabetes, but the
substance abuse, significant depres-
achieve remission of diabetes eventually results are largely dependent on assump-
sion, suicidal ideation, or other mental
experience recurrence. However, the me- tions about the long-term effectiveness
health conditions until these condi-
dian disease-free period among such in- and safety of the procedures (73,74).
tions have been fully addressed. E
dividuals following Roux-en-Y gastric
c People who undergo metabolic sur-
bypass (RYGB) is 8.3 years (52,53). With Adverse Effects
gery should be evaluated to assess
or without diabetes relapse, the majority Metabolic surgery is costly and has associ-
the need for ongoing mental health
of patients who undergo surgery main- ated risks. Longer-term concerns include
services to help them adjust to
tain substantial improvement of glycemic dumping syndrome (nausea, colic, diarrhea),
medical and psychosocial changes
control from baseline for at least 5 (54,55)
after surgery. C vitamin and mineral deficiencies, anemia,
to 15 (38,39,53,56–58) years. osteoporosis, and, rarely (75), severe hypo-
Younger age, shorter duration of diabe- glycemia from insulin hypersecretion.
Several gastrointestinal (GI) operations
tes (e.g., ,8 years) (59), nonuse of insulin, Long-term nutritional and micronutrient
including partial gastrectomies and bari-
and better glycemic control are consis- deficiencies and related complications oc-
atric procedures (35) promote dramatic
tently associated with higher rates of di- cur with variable frequency depending on
and durable improvement of type 2 diabe-
abetes remission and/or lower risk of the type of procedure and require lifelong
tes. Given the magnitude and rapidity of
recidivism (38,57,59). Greater baseline vitamin/nutritional supplementation
the effect of GI surgery on hyperglycemia,
visceral fat area may also help to predict (76,77). Postprandial hypoglycemia is
and experimental evidence that rearrange-
better postoperative outcomes, espe- most likely to occur with RYGB (77,78).
ments of GI anatomy similar to those in
cially among Asian American patients The exact prevalence of symptomatic hy-
some metabolic procedures directly affect with type 2 diabetes, who typically
glucose homeostasis (36), GI interventions poglycemia is unknown. In one study, it
have more visceral fat compared with affected 11% of 450 patients who had un-
have been suggested as treatments for Caucasians with diabetes of the same
type 2 diabetes, and in that context are dergone RYGB or vertical sleeve gastrectomy
BMI (60). (75). Patients who undergo metabolic sur-
termed “metabolic surgery.” Beyond improving glycemia, metabolic
A substantial body of evidence has now gery may be at increased risk for sub-
surgery has been shown to confer addi- stance use, including drug and alcohol
accumulated, including data from numer- tional health benefits in randomized con-
ous randomized controlled clinical trials, use and cigarette smoking (79).
trolled trials, including greater reductions People with diabetes presenting for
demonstrating that metabolic surgery in cardiovascular disease risk factors (35)
achieves superior glycemic control and re- metabolic surgery also have increased rates
and enhancements in quality of life of depression and other major psychiatric
duction of cardiovascular risk factors in (54,59,61). disorders (80). Candidates for metabolic
obese patients with type 2 diabetes com- The safety of metabolic surgery has im- surgery with histories of alcohol or sub-
pared with various lifestyle/medical inter- proved significantly over the past two de- stance abuse, significant depression, sui-
ventions (35). Improvements in micro- and cades, with continued refinement of cidal ideation, or other mental health
macrovascular complications of diabetes, minimally invasive approaches (laparo- conditions should therefore first be as-
cardiovascular disease, and cancer have scopic surgery), enhanced training and sessed by a mental health professional
been observed only in nonrandomized credentialing, and involvement of multi- with expertise in obesity management prior
observational studies (37–46). Cohort disciplinary teams. Mortality rates with to consideration for surgery (81). Individu-
studies attempting to match surgical metabolic operations are typically 0.1– als with preoperative psychopathology
and nonsurgical subjects suggest that 0.5%, similar to cholecystectomy or hys- should be assessed regularly following
the procedure may reduce longer-term terectomy (62–66). Morbidity has also metabolic surgery to optimize mental
mortality (38). dramatically declined with laparoscopic health management and to ensure psy-
On the basis of this mounting evidence, approaches. Major complications rates chiatric symptoms do not interfere with
several organizations and government are 2–6%, with minor complications in weight loss and lifestyle changes.
agencies have recommended expanding up to 15% (62–70), comparing favorably
the indications for metabolic surgery to with other commonly performed elective References
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diabetes in patients with body mass index lower JS, Hoyt DB. A prospective randomized trial of 80. Young-Hyman D, Peyrot M. Psychosocial Care
than 35: five-year outcomes. JAMA Surg 2015; laparoscopic gastric bypass versus laparoscopic for People with Diabetes. 1st ed. Virginia, Ameri-
150:1117–1124 adjustable gastric banding for the treatment of can Diabetes Association, 2012, p. 240
59. Schauer PR, Bhatt DL, Kirwan JP, et al.; morbid obesity: outcomes, quality of life, and 81. Greenberg I, Sogg S, M Perna F. Behavioral
STAMPEDE Investigators. Bariatric surgery versus costs. Ann Surg 2009;250:631–641 and psychological care in weight loss surgery: best
intensive medical therapy for diabetes: 3-year 71. Birkmeyer JD, Finks JF, O’Reilly A, et al.; Mich- practice update. Obesity (Silver Spring) 2009;17:
outcomes. N Engl J Med 2014;370:2002–2013 igan Bariatric Surgery Collaborative. Surgical skill 880–884
Diabetes Care Volume 41, Supplement 1, January 2018 S73

American Diabetes Association
8. Pharmacologic Approaches to
Glycemic Treatment: Standards of
Medical Care in Diabetesd2018
Diabetes Care 2018;41(Suppl. 1):S73–S85 |

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes”
includes 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, 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. Readers who wish to comment on the Standards of Care are invited to
do so at

c Most people with type 1 diabetes should be treated with multiple daily in-
jections of prandial insulin and basal insulin or continuous subcutaneous
insulin infusion. A
c Most individuals with type 1 diabetes should use rapid-acting insulin analogs to
reduce hypoglycemia risk. A
c Consider educating individuals with type 1 diabetes on matching prandial insulin
doses to carbohydrate intake, premeal blood glucose levels, and anticipated
physical activity. E
c Individuals with type 1 diabetes who have been successfully using continuous
subcutaneous insulin infusion should have continued access to this therapy after
they turn 65 years of age. E

Insulin Therapy
Insulin is the mainstay of therapy for individuals with type 1 diabetes. Generally,
the starting insulin dose is based on weight, with doses ranging from 0.4 to
Suggested citation: American Diabetes Associ-
1.0 units/kg/day of total insulin with higher amounts required during puberty. ation. 8. Pharmacologic approaches to glyce-
The American Diabetes Association/JDRF Type 1 Diabetes Sourcebook notes mic treatment: Standards of Medical Care in
0.5 units/kg/day as a typical starting dose in patients with type 1 diabetes who Diabetesd2018. Diabetes Care 2018;41(Suppl. 1):
are metabolically stable, with higher weight-based dosing required immediately S73–S85
following presentation with ketoacidosis (1), and provides detailed information © 2017 by the American Diabetes Association.
on intensification of therapy to meet individualized needs. The American Diabetes Readers may use this article as long as the work
is properly cited, the use is educational and not
Association (ADA) position statement “Type 1 Diabetes Management Through for profit, and the work is not altered. More infor-
the Life Span” additionally provides a thorough overview of type 1 diabetes mation is available at http://www.diabetesjournals
treatment (2). .org/content/license.
S74 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 41, Supplement 1, January 2018

Education regarding matching prandial compared with U-100 glargine in patients placebo (23). The Reducing With Metformin
insulin dosing to carbohydrate intake, with type 1 diabetes (19,20). Vascular Adverse Lesions in Type 1 Diabetes
premeal glucose levels, and anticipated Rapid-acting inhaled insulin used be- (REMOVAL) trial investigated the addition
activity should be considered, and se- fore meals in patients with type 1 diabe- of metformin therapy to titrated insulin
lected individuals who have mastered tes was shown to be noninferior when therapy in adults with type 1 diabetes at
carbohydrate counting should be edu- compared with aspart insulin for A1C low- increased risk for cardiovascular disease
cated on fat and protein gram estimation ering, with less hypoglycemia observed and found that metformin did not signifi-
(3–5). Although most studies of multiple with inhaled insulin therapy (21). How- cantly improve glycemic control beyond
daily injections versus continuous subcu- ever, the mean reduction in A1C was the first 3 months of treatment and that
taneous insulin infusion (CSII) have been greater with aspart (–0.21% vs. –0.40%, progression of atherosclerosis (measured
small and of short duration, a systematic satisfying the noninferiority margin of by carotid artery intima-media thickness)
review and meta-analysis concluded that 0.4%), and more patients in the insulin was not significantly reduced, although
there are minimal differences between aspart group achieved A1C goals of other cardiovascular risk factors such as
the two forms of intensive insulin therapy #7.0% (53 mmol/mol) and #6.5% (48 body weight and LDL cholesterol im-
in A1C (combined mean between-group mmol/mol). Because inhaled insulin car- proved (24). Metformin is not FDA-
difference favoring insulin pump therapy tridges are only available in 4-, 8-, and approved for use in patients with type 1
–0.30% [95% CI –0.58 to –0.02]) and se- 12-unit doses, limited dosing increments diabetes.
vere hypoglycemia rates in children and to fine-tune prandial insulin doses in type 1
Incretin-Based Therapies
adults (6). A 3-month randomized trial in diabetes are a potential limitation.
Due to their potential protection of b-cell
patients with type 1 diabetes with noctur- Postprandial glucose excursions may
mass and suppression of glucagon release,
nal hypoglycemia reported that sensor- be better controlled by adjusting the tim-
glucagon-like peptide 1 (GLP-1) receptor
augmented insulin pump therapy with ing of prandial (bolus) insulin dose admin-
agonists (25) and dipeptidyl peptidase
the threshold suspend feature reduced istration. The optimal time to administer
4 (DPP-4) inhibitors (26) are being studied
nocturnal hypoglycemia without increas- prandial insulin varies, based on the type
in patients with type 1 diabetes but are
ing glycated hemoglobin levels (7). The of insulin used (regular, rapid-acting ana-
not currently FDA-approved for use in pa-
U.S. Food and Drug Administration (FDA) log, inhaled, etc.), measured blood glucose
tients with type 1 diabetes.
has also approved the first hybrid closed- level, timing of meals, and carbohydrate
loop system pump. The safety and effi- consumption. Recommendations for pran- Sodium–Glucose Cotransporter 2 Inhibitors
cacy of hybrid closed-loop systems has dial insulin dose administration should Sodium–glucose cotransporter 2 (SGLT2)
been supported in the literature in ado- therefore be individualized. inhibitors provide insulin-independent
lescents and adults with type 1 diabetes glucose lowering by blocking glucose re-
(8,9). Pramlintide absorption in the proximal renal tubule by
Intensive management using CSII and Pramlintide, an amylin analog, is an agent inhibiting SGLT2. These agents provide
continuous glucose monitoring should be that delays gastric emptying, blunts pan- modest weight loss and blood pressure
encouraged in selected patients when creatic secretion of glucagon, and en- reduction in type 2 diabetes. There are
there is active patient/family participa- hances satiety. It is FDA-approved for use three FDA-approved agents for patients
tion (10–12). in adults with type 1 diabetes. It has been with type 2 diabetes, but none are FDA-
The Diabetes Control and Complica- shown to induce weight loss and lower in- approved for the treatment of patients
tions Trial (DCCT) clearly showed that in- sulin doses. Concurrent reduction of pran- with type 1 diabetes (2). SGLT2 inhibitors
tensive therapy with multiple daily dial insulin dosing is required to reduce the may have glycemic benefits in patients
injections or CSII delivered by multidisci- risk of severe hypoglycemia. with type 1 or type 2 diabetes on insulin
plinary teams of physicians, nurses, dieti- therapy (27). The FDA issued a warning
tians, and behavioral scientists improved Investigational Agents about the risk of ketoacidosis occurring
glycemia and resulted in better long-term Metformin in the absence of significant hyperglyce-
outcomes (13–15). The study was carried Adding metformin to insulin therapy may mia (euglycemic diabetic ketoacidosis)
out with short-acting and intermediate- reduce insulin requirements and improve in patients with type 1 or type 2 diabe-
acting human insulins. Despite better mi- metabolic control in patients with type 1 tes treated with SGLT2 inhibitors.
crovascular, macrovascular, and all-cause diabetes. In one study, metformin was Symptoms of ketoacidosis include dysp-
mortality outcomes, intensive therapy found to reduce insulin requirements nea, nausea, vomiting, and abdominal
was associated with a high rate of severe (6.6 units/day, P , 0.001), and led to pain. Patients should be instructed to
hypoglycemia (61 episodes per 100 patient- small reductions in weight and total and stop taking SGLT2 inhibitors and seek
years of therapy). Since the DCCT, a number LDL cholesterol but not to improved gly- medical attention immediately if they
of rapid-acting and long-acting insulin an- cemic control (absolute A1C reduction have symptoms or signs of ketoacidosis
alogs have been developed. These analogs 0.11%, P 5 0.42) (22). A randomized clin- (28).
are associated with less hypoglycemia, ical trial similarly found that, among over-
less weight gain, and lower A1C than human weight adolescents with type 1 diabetes, SURGICAL TREATMENT FOR
insulins in people with type 1 diabetes the addition of metformin to insulin did TYPE 1 DIABETES
(16–18). Longer-acting basal analogs not improve glycemic control and in- Pancreas and Islet Transplantation
(U-300 glargine or degludec) may addi- creased risk for gastrointestinal adverse Pancreas and islet transplantation have
tionally convey a lower hypoglycemia risk events after 6 months compared with been shown to normalize glucose levels Pharmacologic Approaches to Glycemic Treatment S75

but require life-long immunosuppression and may reduce risk of cardiovascular
therapy should begin with lifestyle
to prevent graft rejection and recurrence events and death (32). Compared with
management and metformin and
of autoimmune islet destruction. Given sulfonylureas, metformin as first-line
subsequently incorporate an agent
the potential adverse effects of immuno- therapy has beneficial effects on A1C,
proven to reduce major adverse car-
suppressive therapy, pancreas transplan- weight, and cardiovascular mortality
diovascular events and cardiovascu-
tation should be reserved for patients (33). Metformin may be safely used in
lar mortality (currently empagliflozin
with type 1 diabetes undergoing simulta- patients with estimated glomerular filtra-
and liraglutide), after considering
neous renal transplantation, following re- tion rate (eGFR) as low as 30 mL/min/
drug-specific and patient factors
nal transplantation, or for those with 1.73 m2, and the FDA recently revised
(Table 8.1). A*
recurrent ketoacidosis or severe hypogly- the label for metformin to reflect its
c In patients with type 2 diabetes and
cemia despite intensive glycemic man- safety in patients with eGFR $30 mL/
established atherosclerotic cardiovascu-
agement (29). min/1.73 m2 (34). Patients should be ad-
lar disease, after lifestyle management
vised to stop the medication in cases of
PHARMACOLOGIC THERAPY FOR and metformin, the antihyperglycemic
nausea, vomiting, or dehydration. Met-
TYPE 2 DIABETES agent canagliflozin may be considered
formin is associated with vitamin B12
to reduce major adverse cardiovascular
Recommendations deficiency, with a recent report from the
events, based on drug-specific and pa-
c Metformin, if not contraindicated Diabetes Prevention Program Outcomes
tient factors (Table 8.1). C*
and if tolerated, is the preferred ini- Study (DPPOS) suggesting that periodic
c Continuous reevaluation of the med-
tial pharmacologic agent for the testing of vitamin B12 levels should be
ication regimen and adjustment as
treatment of type 2 diabetes. A needed to incorporate patient fac-
considered in metformin-treated pa-
c Long-term use of metformin may be tients, especially in those with anemia
tors (Table 8.1) and regimen com-
associated with biochemical vitamin or peripheral neuropathy (35).
plexity is recommended. E
B12 deficiency, and periodic mea- In patients with metformin contrain-
c For patients with type 2 diabetes
surement of vitamin B12 levels should dications or intolerance, consider an ini-
who are not achieving glycemic goals,
be considered in metformin-treated tial drug from another class depicted in
drug intensification, including consid-
patients, especially in those with ane- Fig. 8.1 under “Dual Therapy” and pro-
eration of insulin therapy, should not
mia or peripheral neuropathy. B ceed accordingly. When A1C is $9% (75
be delayed. B
c Consider initiating insulin therapy mmol/mol), consider initiating dual com-
c Metformin should be continued
(with or without additional agents) bination therapy (Fig. 8.1) to more expe-
when used in combination with other
in patients with newly diagnosed ditiously achieve the target A1C level.
agents, including insulin, if not contra-
type 2 diabetes who are symptom- Insulin has the advantage of being effec-
indicated and if tolerated. A
atic and/or have A1C $10% (86 tive where other agents may not be and
mmol/mol) and/or blood glucose should be considered as part of any com-
levels $300 mg/dL (16.7 mmol/L). E See Section 12 for recommendations bination regimen when hyperglycemia is
c Consider initiating dual therapy in specific for children and adolescents severe, especially if catabolic features
patients with newly diagnosed with type 2 diabetes. The use of metfor- (weight loss, ketosis) are present. Con-
type 2 diabetes who have A1C min as first-line therapy was supported by sider initiating combination insulin in-
$9% (75 mmol/mol). E findings from a large meta-analysis, with jectable therapy (Fig. 8.2) when blood
c In patients without atherosclerotic selection of second-line therapies based glucose is $300 mg/dL (16.7 mmol/L) or
cardiovascular disease, if mono- on patient-specific considerations (30). A1C is $10% (86 mmol/mol) or if the pa-
therapy or dual therapy does not An ADA/European Association for the Study tient has symptoms of hyperglycemia
achieve or maintain the A1C goal of Diabetes position statement “Manage- (i.e., polyuria or polydipsia). As the pa-
over 3 months, add an additional ment of Hyperglycemia in Type 2 Diabe- tient’s glucose toxicity resolves, the regi-
antihyperglycemic agent based on tes, 2015: A Patient-Centered Approach” men may, potentially, be simplified.
drug-specific and patient factors (31) recommended a patient-centered ap-
(Table 8.1). A proach, including assessment of efficacy, Combination Therapy
c A patient-centered approach should hypoglycemia risk, impact on weight, side Although there are numerous trials
be used to guide the choice of effects, costs, and patient preferences. Re- comparing dual therapy with metformin
pharmacologic agents. Consider- nal effects may also be considered when alone, few directly compare drugs as add-
ations include efficacy, hypoglyce- selecting glucose-lowering medications for on therapy. A comparative effectiveness
mia risk, history of atherosclerotic individual patients. Lifestyle modifications meta-analysis (36) suggests that each
cardiovascular disease, impact on that improve health (see Section 4 “Lifestyle new class of noninsulin agents added to
weight, potential side effects, re- Management”) should be emphasized initial therapy generally lowers A1C ap-
nal effects, delivery method (oral along with any pharmacologic therapy. proximately 0.7–1.0%. If the A1C target
versus subcutaneous), cost, and is not achieved after approximately 3 months
patient preferences. E Initial Therapy and patient does not have atherosclerotic
c In patients with type 2 diabetes and Metformin monotherapy should be cardiovascular disease (ASCVD), consider
established atherosclerotic cardio- started at diagnosis of type 2 diabetes un- a combination of metformin and any one
vascular disease, antihyperglycemic less there are contraindications. Metfor- of the preferred six treatment options:
min is effective and safe, is inexpensive, sulfonylurea, thiazolidinedione, DPP-4
S76 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 41, Supplement 1, January 2018

Figure 8.1—Antihyperglycemic therapy in type 2 diabetes: general recommendations. *If patient does not tolerate or has contraindications to metformin,
consider agents from another class in Table 8.1. #GLP-1 receptor agonists and DPP-4 inhibitors should not be prescribed in combination. If a patient with
ASCVD is not yet on an agent with evidence of cardiovascular risk reduction, consider adding.

inhibitor, SGLT2 inhibitor, GLP-1 receptor second agent with evidence of cardiovas- dual therapy, proceed to a three-drug
agonist, or basal insulin (Fig. 8.1); the choice cular risk reduction after consideration of combination (Fig. 8.1). Again, if A1C target
of which agent to add is based on drug- drug-specific and patient factors (see p. S77 is not achieved after ;3 months of triple
specific effects and patient factors (Table CARDIOVASCULAR OUTCOMES TRIALS). If A1C target therapy, proceed to combination injectable
8.1). For patients with ASCVD, add a is still not achieved after ;3 months of therapy (Fig. 8.2). Drug choice is based on
Pharmacologic Approaches to Glycemic Treatment

Table 8.1—Drug-specific and patient factors to consider when selecting antihyperglycemic treatment in adults with type 2 diabetes

*See ref. 31 for description of efficacy. †FDA approved for CVD benefit. CVD, cardiovascular disease; DKA, diabetic ketoacidosis; DKD, diabetic kidney disease; NASH, nonalcoholic steatohepatitis;
RAs, receptor agonists; SQ, subcutaneous; T2DM, type 2 diabetes.
S78 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 41, Supplement 1, January 2018

Figure 8.2—Combination injectable therapy for type 2 diabetes. FBG, fasting blood glucose; hypo, hypoglycemia. Adapted with permission from Inzucchi
et al. (31).

patient preferences (37), as well as various dual therapy, with continuous reevalu- Of note, prices listed are average whole-
patient, disease, and drug characteristics, ation of patient factors to guide treat- sale prices (AWP) (39) and National Aver-
with the goal of reducing blood glucose ment (Table 8.1). age Drug Acquisition Costs (NADAC) (40)
levels while minimizing side effects, espe- Table 8.2 lists drugs commonly used in and do not account for discounts, re-
cially hypoglycemia. If not already in- the U.S. Cost-effectiveness models of the bates, or other price adjustments often
cluded in the treatment regimen, addition newer agents based on clinical utility and involved in prescription sales that affect
of an agent with evidence of cardiovas- glycemic effect have been reported (38). the actual cost incurred by the patient.
cular risk reduction should be consid- Table 8.3 provides cost information for While there are alternative means to esti-
ered in patients with ASCVD beyond currently approved noninsulin therapies. mate medication prices, AWP and NADAC
Table 8.2—Pharmacology of available glucose-lowering agents in the U.S. for the treatment of type 2 diabetes
Class Compound(s) Cellular mechanism(s) Primary physiological action(s) Renal dosing recommendations (63–66)*
Biguanides c Metformin Activates AMP kinase (? other) ↓ Hepatic glucose production c No dose adjustment if eGFR .45;
do not initiate OR assess risk/benefit if currently on metformin if eGFR 30–45;
discontinue if eGFR ,30
Sulfonylureas (2nd c Glyburide Closes KATP channels on b-cell ↑ Insulin secretion c Avoid use in patients with renal impairment

generation) c Glipizide plasma membranes c Initiate conservatively at 2.5 mg daily to avoid hypoglycemia
c Glimepiride c Initiate conservatively at 1 mg daily to avoid hypoglycemia

Meglitinides c Repaglinide Closes KATP channels on b-cell ↑ Insulin secretion c Initiate conservatively at 0.5 mg with meals if eGFR ,30
(glinides) c Nateglinide plasma membranes c Initiate conservatively at 60 mg with meals if eGFR ,30
Thiazolidinediones c Pioglitazone Activates the nuclear ↑ Insulin sensitivity c No dose adjustment required
c Rosiglitazone§ transcription factor PPAR-g c No dose adjustment required
a-Glucosidase c Acarbose Inhibits intestinal a-glucosidase Slows intestinal carbohydrate c Avoid if eGFR ,30
inhibitors c Miglitol digestion/absorption c Avoid if eGFR ,25

DPP-4 inhibitors c Sitagliptin Inhibits DPP-4 activity, ↑ Insulin secretion (glucose c 100 mg daily if eGFR .50;
increasing postprandial incretin dependent); 50 mg daily if eGFR 30–50;
(GLP-1, GIP) concentrations ↓ Glucagon secretion (glucose 25 mg daily if eGFR ,30
c Saxagliptin c 5 mg daily if eGFR .50;
2.5 mg daily if eGFR #50
c Linagliptin c No dose adjustment required

c Alogliptin c 25 mg daily if eGFR .60;
12.5 mg daily if eGFR 30–60;
6.25 mg daily if eGFR ,30
Bile acid c Colesevelam Binds bile acids in intestinal ? ↓ Hepatic glucose production; c No specific dose adjustment recommended by manufacturer
sequestrants tract, increasing hepatic bile ? ↑ Incretin levels
acid production
Dopamine-2 c Bromocriptine (quick Activates dopaminergic receptors Modulates hypothalamic regulation c No specific dose adjustment recommended by manufacturer
agonists release)§ of metabolism;
↑ Insulin sensitivity
SGLT2 inhibitors c Canagliflozin Inhibits SGLT2 in the proximal Blocks glucose reabsorption by the c No dose adjustment required if eGFR $60;
nephron kidney, increasing glucosuria 100 mg daily if eGFR 45–59;
avoid use and discontinue in patients with eGFR persistently ,45
c Dapagliflozin c Avoid initiating if eGFR ,60;
not recommended with eGFR 30–60;
contraindicated with eGFR ,30
c Empagliflozin c Contraindicated with eGFR ,30

GLP-1 receptor c Exenatide Activates GLP-1 ↑ Insulin secretion (glucose c Not recommended with eGFR ,30
agonists c Exenatide extended receptors dependent) c Not recommended with eGFR ,30
Continued on p. S80
Pharmacologic Approaches to Glycemic Treatment

Table 8.2—Continued
Class Compound(s) Cellular mechanism(s) Primary physiological action(s) Renal dosing recommendations (63–66)*
c Liraglutide ↓ Glucagon secretion (glucose c No specific dose adjustment recommended by the manufacturer; limited
dependent); experience in patients with severe renal impairment
c Albiglutide Slows gastric emptying; c No dose adjustment required for eGFR 15–89 per manufacturer; limited
↑ Satiety experience in patients with severe renal impairment
c Lixisenatide c No dose adjustment required for eGFR 60–89;
no dose adjustment required for eGFR 30–59, but patients should be
monitored for adverse effects and changes in kidney function;
Pharmacologic Approaches to Glycemic Treatment

clinical experience is limited with eGFR 15–29; patients should be monitored
for adverse effects and changes in kidney function;
avoid if eGFR ,15
c Dulaglutide c No specific dose adjustment recommended by the manufacturer; limited
experience in patients with severe renal impairment
Amylin mimetics c Pramlintide§ Activates amylin receptors ↓ Glucagon secretion; c No specific dose adjustment recommended by manufacturer
Slows gastric emptying;
↑ Satiety
Insulins c Rapid-acting analogs Activates insulin receptors ↑ Glucose disposal; c Lower insulin doses required with a decrease in eGFR; titrate per clinical
Lispro ↓ Hepatic glucose production; response
Aspart Suppresses ketogenesis
Inhaled insulin
c Short-acting analogs
Human Regular
c Intermediate-acting analogs
Human NPH
c Basal insulin analogs
c Premixed insulin products
NPH/Regular 70/30
70/30 aspart mix
75/25 lispro mix
50/50 lispro mix
*eGFR is given in mL/min/1.73 m2. §Not licensed in Europe for type 2 diabetes. GIP, glucose-dependent insulinotropic peptide; PPAR-g, peroxisome proliferator–activated receptor g.
Diabetes Care Volume 41, Supplement 1, January 2018 Pharmacologic Approaches to Glycemic Treatment S81

Table 8.3—Median monthly 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, $93) $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 ($82, $6,671) $5 ($5, $3,630) 2,000 mg
750 mg (ER) $72 ($65, $92) $5 1,500 mg
1,000 mg (ER) $1,028 ($1,028, $539 ($539, $5,189) 2,000 mg
Sulfonylureas c Glyburide 5 mg $93 ($63, $103) $17 20 mg
(2nd generation) 6 mg (micronized) $50 ($48, $71) $12 12 mg (micronized)
c Glipizide 10 mg (IR) $75 ($67, $97) $4 40 mg (IR)
10 mg (XL) $48 $16 20 mg (XL)
c Glimepiride 4 mg $71 ($71, $198) $7 8 mg
Meglitinides (glinides) c Repaglinide 2 mg $659 ($122, $673) $40 16 mg
c Nateglinide 120 mg $155 $56 360 mg
Thiazolidinediones c Pioglitazone 45 mg $348 ($283, $349) $5 45 mg
c Rosiglitazone 4 mg $387 $314 8 mg
a-Glucosidase c Acarbose 100 mg $104 ($104, $106) $25 300 mg
inhibitors c Miglitol 100 mg $241 N/A†† 300 mg
DPP-4 inhibitors c Sitagliptin 100 mg $477 $382 100 mg
c Saxagliptin 5 mg $462 $370 5 mg
c Linagliptin 5 mg $457 $367 5 mg
c Alogliptin 25 mg $449 $357 25 mg
Bile acid sequestrants c Colesevelam 625 mg tabs $713 $570 3.75 g
1.875 g suspension $1,426 $572 3.75 g
Dopamine-2 agonists c Bromocriptine 0.8 mg $784 $629 4.8 mg
SGLT2 inhibitors c Canagliflozin 300 mg $512 $411 300 mg
c Dapagliflozin 10 mg $517 $413 10 mg
c Empagliflozin 25 mg $517 $415 25 mg
GLP-1 receptor c Exenatide 10 mg pen $802 $642 20 mg
agonists c Lixisenatide 20 mg pen $669 N/A†† 20 mg
c Liraglutide 18 mg/3 mL pen $968 $775 1.8 mg
c Exenatide (extended 2 mg powder for $747 $600 2 mg**
release) suspension or pen
c Albiglutide 50 mg pen $626 $500 50 mg**
c Dulaglutide 1.5/0.5 mL pen $811 $648 1.5 mg**
Amylin mimetics c Pramlintide 120 mg pen $2,336 N/A†† 120 mg/injection†††
ER and XL, extended release; IR, immediate release. †Calculated for 30-day supply (AWP or NADAC 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. ††Not applicable; data not available. **Administered once weekly. †††AWP
and NADAC calculated based on 120 mg three times daily.

were utilized to provide two separate mea- late postprandial hypoglycemia when The empagliflozin and liraglutide trials
sures to allow for a comparison of drug taking a sulfonylurea. Other drugs not demonstrated significant reductions in
prices with the primary goal of highlighting shown in Table 8.1 (e.g., inhaled insulin, cardiovascular death. Exenatide once-
the importance of cost considerations a-glucosidase inhibitors, colesevelam, bro- weekly did not have statistically sig-
when prescribing antihyperglycemic treat- mocriptine, and pramlintide) may be tried nificant reductions in major adverse
ments. The ongoing Glycemia Reduction in specific situations but considerations cardiovascular events or cardiovascu-
Approaches in Diabetes: A Comparative Ef- include modest efficacy in type 2 diabetes, lar mortality but did have a significant
fectiveness Study (GRADE) will compare frequency of administration, potential for reduction in all-cause mortality. In con-
four drug classes (sulfonylurea, DPP-4 in- drug interactions, cost, and/or side effects. trast, other GLP-1 receptor agonists
hibitor, GLP-1 receptor agonist, and basal have not shown similar reductions in
insulin) when added to metformin therapy Cardiovascular Outcomes Trials cardiovascular events (Table 9.4).
over 4 years on glycemic control and other There are now three large randomized Whether the benefits of GLP-1 receptor
medical, psychosocial, and health economic controlled trials reporting statistically sig- agonists are a class effect remains to be
outcomes (41). nificant reductions in cardiovascular events definitively established. See ANTIHYPERGLYCEMIC
Rapid-acting secretagogues (meglitinides) for two SGLT2 inhibitors (empagliflozin THERAPIES AND CARDIOVASCULAR OUTCOMES in
may be used instead of sulfonylureas in and canagliflozin) and one GLP-1 receptor Section 9 “Cardiovascular Disease and
patients with sulfa allergies or irregular agonist (liraglutide) where the majority, if Risk Management” and Table 9.4 for a de-
meal schedules or in those who develop not all patients, in the trial had ASCVD. tailed description of these cardiovascular
S82 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 41, Supplement 1, January 2018

Table 8.4—Median cost of insulin products in the U.S. calculated as AWP (39) and NADAC (40) per 1,000 units of specified dosage
Median AWP Median NADAC
Insulins Compounds Dosage form/product (min, max)* (min, max)*
Rapid-acting c Lispro U-100 vial; $330 $264
analogs U-100 3 mL cartridges; $408 $326
U-100 prefilled pen; U-200 prefilled pen $424 $339
c Aspart U-100 vial; $331 $265
U-100 3 mL cartridges; $410 $330
U-100 prefilled pen $426 $341
c Glulisine U-100 vial; $306 $245
U-100 prefilled pen $394 $315
c Inhaled insulin Inhalation cartridges $725 ($544, $911) N/A†
Short-acting analogs c Human Regular U-100 vial $165 ($165, $178) $135 ($135, $145)
Intermediate-acting analogs c Human NPH U-100 vial; $165 ($165, $178) $135 ($135, $145)
U-100 prefilled pen $377 $305
Concentrated Human c U-500 Human U-500 vial; $178 $143
Regular insulin Regular insulin U-500 prefilled pen $230 $184
Basal analogs c Glargine U-100 vial; U-100 prefilled pen; $298 $239 ($239, $241)
U-300 prefilled pen
c Glargine biosimilar U-100 prefilled pen $253 $203
c Detemir U-100 vial; U-100 prefilled pen $323 $259
c Degludec U-100 prefilled pen; U-200 prefilled pen $355 $285
Premixed insulin products c NPH/Regular 70/30 U-100 vial; $165 ($165, $178) $134 ($134, $146)
U-100 prefilled pen $377 $305
c Lispro 50/50 U-100 vial; $342 $278
U-100 prefilled pen $424 $339
c Lispro 75/25 U-100 vial; $342 $273
U-100 prefilled pen $424 $340
c Aspart 70/30 U-100 vial; $343 $275
U-100 prefilled pen $426 $341
Premixed insulin/GLP-1 c Degludec/Liraglutide 100/3.6 prefilled pen $763 N/A†
receptor agonist products c Glargine/Lixisenatide 100/33 prefilled pen $508 $404
*AWP or NADAC calculated as in Table 8.3; median listed alone when only one product and/or price. †Not applicable; data not available.

outcomes trials. Additional large random- avoid using insulin as a threat or de- to reduce the risk of symptomatic and noc-
ized trials of other agents in these classes scribing it as a sign of personal failure turnal hypoglycemia (43–48). Longer-
are ongoing. or punishment. acting basal analogs (U-300 glargine or
Of note, these studies examined the Equipping patients with an algorithm for degludec) may additionally convey a
drugs in combination with metformin self-titration of insulin doses based on self- lower hypoglycemia risk compared with
(Table 9.4) in the great majority of pa- monitoring of blood glucose improves U-100 glargine when used in combination
tients for whom metformin was not con- glycemic control in patients with type 2 di- with oral antihyperglycemic agents (49–
traindicated or not tolerated. For patients abetes initiating insulin (42). Comprehen- 55). While there is evidence for reduced
with type 2 diabetes who have ASCVD, on sive education regarding self-monitoring hypoglycemia with newer, longer-acting
lifestyle and metformin therapy, it is rec- of blood glucose, diet, and the avoidance basal insulin analogs, people without a
ommended to incorporate an agent with of and appropriate treatment of hypogly- history of hypoglycemia are at decreased
strong evidence for cardiovascular risk re- cemia are critically important in any pa- risk and could potentially be switched to
duction especially those with proven ben- tient using insulin. human insulin safely. Thus, due to high
efit on both major adverse cardiovascular costs of analog insulins, use of human in-
events and cardiovascular death after con- Basal Insulin sulin may be a practical option for some
sideration of drug-specific patient factors Basal insulin alone is the most convenient patients, and clinicians should be familiar
(Table 8.1). See Fig. 8.1 for additional rec- initial insulin regimen, beginning at 10 units with its use (56). Table 8.4 provides AWP
ommendations on antihyperglycemic per day or 0.1–0.2 units/kg/day, depend- (39) and NADAC (40) information (cost
treatment in adults with type 2 diabetes. ing on the degree of hyperglycemia. Basal per 1,000 units) for currently available in-
insulin is usually prescribed in conjunc- sulin and insulin combination products
Insulin Therapy tion with metformin and sometimes one in the U.S. There have been substantial
Many patients with type 2 diabetes even- additional noninsulin agent. When basal increases in the price of insulin over the
tually require and benefit from insulin insulin is added to antihyperglycemic past decade and the cost-effectiveness
therapy. The progressive nature of type 2 agents in patients with type 2 diabetes, of different antihyperglycemic agents is
diabetes should be regularly and objectively long-acting basal analogs (U-100 glargine an important consideration in a patient-
explained to patients. Providers should or detemir) can be used instead of NPH centered approach to care, along with Pharmacologic Approaches to Glycemic Treatment S83

efficacy, hypoglycemia risk, weight, and pulmonary disease and is not recommended insulin (NPH/Regular 70/30, 70/30 aspart
other patient and drug-specific factors in patients who smoke or who recently stop- mix, 75/25 or 50/50 lispro mix) twice
(Table 8.1) (57). ped smoking. It requires spirometry (FEV1) daily, usually before breakfast and before
Bolus Insulin
testing to identify potential lung disease in all dinner. Each approach has its advan-
Many individuals with type 2 diabetes patients prior to and after starting therapy. tages and disadvantages. For example,
may require mealtime bolus insulin dos- providers may wish to consider regimen
ing in addition to basal insulin. Rapid- Combination Injectable Therapy flexibility when devising a plan for the ini-
acting analogs are preferred due to their If basal insulin has been titrated to an ac- tiation and adjustment of insulin therapy
prompt onset of action after dosing. In ceptable fasting blood glucose level (or if in people with type 2 diabetes, with rapid-
September 2017, the FDA approved a new the dose is .0.5 units/kg/day) and A1C re- acting insulin offering greater flexibility in
faster-acting formulation of insulin aspart. mains above target, consider advancing terms of meal planning than premixed in-
The recommended starting dose of meal- to combination injectable therapy (Fig. sulin. If one regimen is not effective (i.e.,
time insulin is 4 units, 0.1 units/kg, or 10% 8.2). When initiating combination inject- basal insulin plus GLP-1 receptor agonist),
of the basal dose. If A1C is ,8% (64 mmol/ able therapy, metformin therapy should consider switching to another regimen to
mol) when starting mealtime bolus in- be maintained while other oral agents achieve A1C targets (i.e., basal insulin plus
sulin, consideration should be given to may be discontinued on an individual ba- single injection of rapid-acting insulin or pre-
decreasing the basal insulin dose. sis to avoid unnecessarily complex or mixed insulin twice daily) (60,61). Regular
costly regimens (i.e., adding a fourth anti- human insulin and human NPH/Regular
Premixed Insulin
hyperglycemic agent). In general, GLP-1 premixed formulations (70/30) are less
Premixed insulin products contain both a receptor agonists should not be discon- costly alternatives to rapid-acting insulin
basal and prandial component, allowing tinued with the initiation of basal insulin. analogs and premixed insulin analogs,
coverage of both basal and prandial needs Sulfonylureas, DPP-4 inhibitors, and GLP- respectively, but their pharmacody-
with a single injection. NPH/Regular 70/30 1 receptor agonists are typically stopped namic profiles may make them less optimal.
insulin, for example, is composed of 70% once more complex insulin regimens be- Fig. 8.2 outlines these options, as well
NPH insulin and 30% regular insulin. The use yond basal are used. In patients with sub- as recommendations for further intensifi-
of premixed insulin products has its advan- optimal blood glucose control, especially cation, if needed, to achieve glycemic
tages and disadvantages, as discussed be- those requiring large insulin doses, adjunc- goals. If a patient is still above the A1C
low in COMBINATION INJECTABLE THERAPY. tive use of a thiazolidinedione or SGLT2 target on premixed insulin twice daily,
Concentrated Insulin Products inhibitor may help to improve control consider switching to premixed analog in-
Several concentrated insulin preparations and reduce the amount of insulin needed, sulin three times daily (70/30 aspart mix,
are currently available. U-500 regular insu- though potential side effects should be 75/25 or 50/50 lispro mix). In general,
lin, by definition, is five times as concen- considered. Once an insulin regimen is ini- three times daily premixed analog insu-
trated as U-100 regular insulin and has a tiated, dose titration is important with ad- lins have been found to be noninferior
delayed onset and longer duration of ac- justments made in both mealtime and to basal-bolus regimens with similar rates
tion than U-100 regular, possessing both basal insulins based on the blood glucose of hypoglycemia (62). If a patient is still
prandial and basal properties. U-300 glar- levels and an understanding of the phar- above the A1C target on basal insulin
gine and U-200 degludec are three and macodynamic profile of each formulation plus single injection of rapid-acting insulin
two times as concentrated as their U-100 (pattern control). before the largest meal, advance to a
formulations and allow higher doses of basal Studies have demonstrated the non- basal-bolus regimen with $2 injections
insulin administration per volume used. inferiority of basal insulin plus a single of rapid-acting insulin before meals. Con-
U-300 glargine has a longer duration of ac- injection of rapid-acting insulin at the larg- sider switching patients from one regimen
tion than U-100 glargine. The FDA has also est meal relative to basal insulin plus a to another (i.e., premixed analog insulin
approved a concentrated formulation of GLP-1 receptor agonist relative to two three times daily to basal-bolus regimen
rapid-acting insulin lispro, U-200 (200 daily injections of premixed insulins or vice-versa) if A1C targets are not being
units/mL). These concentrated preparations (Fig. 8.2). Basal insulin plus GLP-1 recep- met and/or depending on other patient
may be more comfortable for the patient tor agonists are associated with less hy- considerations (60,61). Metformin should
and may improve adherence for patients poglycemia and with weight loss instead be continued in patients on combination
with insulin resistance who require large of weight gain but may be less tolerable injectable insulin therapy, if not contra-
doses of insulin. While U-500 regular insulin and have a greater cost (58,59). In No- indicated and if tolerated, for further gly-
is available in both prefilled pens and vials (a vember 2016, the FDA approved two dif- cemic benefits.
dedicated syringe was FDA approved in July ferent once-daily fixed-dual combination
2016), other concentrated insulins are avail- products containing basal insulin plus a
able only in prefilled pens to minimize the GLP-1 receptor agonist: insulin glargine 1. Peters AL, Laffel L, Eds. American Diabetes
risk of dosing errors. plus lixisenatide and insulin degludec Association/JDRF Type 1 Diabetes Sourcebook.
plus liraglutide. Other options for treat- Alexandria, VA, American Diabetes Association,
Inhaled Insulin ment intensification include adding a sin- 2013
Inhaled insulin is available for prandial use gle injection of rapid-acting insulin analog 2. Chiang JL, Kirkman MS, Laffel LMB, Peters AL;
Type 1 Diabetes Sourcebook Authors. Type 1 di-
with a more limited dosing range. It is contra- (lispro, aspart, or glulisine) before the abetes through the life span: a position statement
indicated in patients with chronic lung dis- largest meal or stopping the basal insulin of the American Diabetes Association. Diabetes
ease such as asthma and chronic obstructive and initiating a premixed (or biphasic) Care 2014;37:2034–2054
S84 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 41, Supplement 1, January 2018

3. Wolpert HA, Atakov-Castillo A, Smith SA, Steil with type 1 diabetes: systematic review and net- 30. Palmer SC, Mavridis D, Nicolucci A, et al. Com-
GM. Dietary fat acutely increases glucose con- work meta-analysis. BMJ 2014;349:g5459 parison of clinical outcomes and adverse events
centrations and insulin requirements in pa- 17. Bartley PC, Bogoev M, Larsen J, Philotheou A. associated with glucose-lowering drugs in patients
tients with type 1 diabetes: implications for Long-term efficacy and safety of insulin detemir with type 2 diabetes: a meta-analysis. JAMA 2016;
carbohydrate-based bolus dose calculation compared to Neutral Protamine Hagedorn insulin 316:313–324
and intensive diabetes management. Diabetes in patients with type 1 diabetes using a treat-to- 31. Inzucchi SE, Bergenstal RM, Buse JB, et al.
Care 2013;36:810–816 target basal-bolus regimen with insulin aspart at Management of hyperglycemia in type 2 diabe-
4. Bell KJ, Toschi E, Steil GM, Wolpert HA. Opti- meals: a 2-year, randomized, controlled trial. Dia- tes, 2015: a patient-centered approach: update
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in type 1 diabetes: application of a model-based 18. DeWitt DE, Hirsch IB. Outpatient insulin ther- tes Association and the European Association
approach to derive insulin doses for open-loop apy in type 1 and type 2 diabetes mellitus: scien- for the Study of Diabetes. Diabetes Care 2015;
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1631–1634 19. Lane W, Bailey TS, Gerety G, et al.; SWITCH 1. 32. Holman RR, Paul SK, Bethel MA, Matthews
5. Bell KJ, Smart CE, Steil GM, Brand-Miller JC, Effect of insulin degludec vs insulin glargine U100 DR, Neil HAW. 10-year follow-up of intensive glu-
King B, Wolpert HA. Impact of fat, protein, and on hypoglycemia in patients with type 1 diabetes: cose control in type 2 diabetes. N Engl J Med 2008;
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S86 Diabetes Care Volume 41, Supplement 1, January 2018

American Diabetes Association
9. Cardiovascular Disease and Risk
Management: Standards of
Medical Care in Diabetesd2018
Diabetes Care 2018;41(Suppl. 1):S86–S104 |

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes”
includes 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, 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. Readers who wish to comment on the Standards of Care are invited to
do so at

For prevention and management of diabetes complications in children and
adolescents, please refer to Section 12 “Children and Adolescents.”
Atherosclerotic cardiovascular disease (ASCVD)ddefined as coronary heart
disease, cerebrovascular disease, or peripheral arterial disease presumed to be of
atherosclerotic origindis the leading cause of morbidity and mortality for individuals
with diabetes and is the largest contributor to the direct and indirect costs of
diabetes. Common conditions coexisting with type 2 diabetes (e.g., hypertension
and dyslipidemia) are clear risk factors for ASCVD, and diabetes itself confers in-
dependent risk. Numerous studies have shown the efficacy of controlling individual
cardiovascular risk factors in preventing or slowing ASCVD in people with diabetes.
Furthermore, large benefits are seen when multiple cardiovascular risk factors are
addressed simultaneously. Under the current paradigm of aggressive risk factor
modification in patients with diabetes, there is evidence that measures of 10-year
coronary heart disease (CHD) risk among U.S. adults with diabetes have improved
significantly over the past decade (1) and that ASCVD morbidity and mortality have
decreased (2–4).
Therefore, cardiovascular risk factors should be systematically assessed at least
annually in all patients with diabetes. These risk factors include hypertension, dyslipi-
demia, smoking, a family history of premature coronary disease, chronic kidney dis-
ease, and the presence of albuminuria. Modifiable abnormal risk factors should be Suggested citation: American Diabetes Association.
treated as described in these guidelines. 9. Cardiovascular disease and risk management:
Standards of Medical Care in Diabetesd2018.
HYPERTENSION/BLOOD PRESSURE CONTROL Diabetes Care 2018;41(Suppl. 1):S86–S104
Hypertension, defined as a sustained blood pressure $140/90 mmHg, is common © 2017 by the American Diabetes Association.
among patients with either type 1 or type 2 diabetes. Hypertension is a major risk Readers may use this article as long as the work
is properly cited, the use is educational and not
factor for both ASCVD and microvascular complications. Moreover, numerous studies for profit, and the work is not altered. More infor-
have shown that antihypertensive therapy reduces ASCVD events, heart failure, and mation is available at http://www.diabetesjournals
microvascular complications. Please refer to the American Diabetes Association (ADA) .org/content/license. Cardiovascular Disease and Risk Management S87

position statement “Diabetes and Hyper- patients who have been educated about
c Lower systolic and diastolic blood
tension” for a detailed review of the epi- added treatment burden, side effects, and
pressure targets, such as 130/80
demiology, diagnosis, and treatment of costs, as discussed below.
mmHg, may be appropriate for
hypertension (5). Additional studies, such as the Systolic
individuals at high risk of cardio-
Blood Pressure Intervention Trial (SPRINT)
vascular disease, if they can be
Screening and Diagnosis and the Hypertension Optimal Treatment
achieved without undue treat-
(HOT) trial, also examined effects of inten-
Recommendations ment burden. C
sive versus standard control (Table 9.1),
c Blood pressure should be measured c In pregnant patients with diabetes
though the relevance of their results to
at every routine clinical visit. Pa- and preexisting hypertension who
people with diabetes is less clear. The
tients found to have elevated blood are treated with antihypertensive
Action in Diabetes and Vascular Disease:
pressure ($140/90) should have therapy, blood pressure targets of
Preterax and Diamicron MR Controlled
blood pressure confirmed using 120–160/80–105 mmHg are sug-
gested in the interest of optimiz- Evaluation–Blood Pressure (ADVANCE
multiple readings, including meas-
ing long-term maternal health BP) trial did not explicitly test blood pres-
urments on a separate day, to diag-
nose hypertension. B and minimizing impaired fetal sure targets (17); the achieved blood
c All hypertensive patients with dia- growth. E pressure in the intervention group was
betes should monitor their blood higher than that achieved in the ACCORD
pressure at home. B Randomized clinical trials have demon- BP intensive arm and would be consistent
strated unequivocally that treatment of with a target blood pressure of ,140/90
Blood pressure should be measured by a hypertension to blood pressure ,140/90 mmHg. Notably, ACCORD BP and SPRINT
trained individual and should follow the mmHg reduces cardiovascular events measured blood pressure using auto-
guidelines established for the general as well as microvascular complications mated office blood pressure measure-
population: measurement in the seated (9–15). Therefore, patients with type 1 ments, which yields values that are
position, with feet on the floor and arm or type 2 diabetes who have hypertension generally lower than typical office blood
supported at heart level, after 5 min of should, at a minimum, be treated to blood pressure readings by approximately
5–10 mmHg (18), suggesting that imple-
rest. Cuff size should be appropriate for pressure targets of ,140/90 mmHg. In-
the upper-arm circumference. Elevated menting the ACCORD BP or SPRINT pro-
tensification of antihypertensive ther-
values should be confirmed on a separate tocols in an outpatient clinic might require
apy to target blood pressures lower
a systolic blood pressure target higher
day. Postural changes in blood pressure than ,140/90 mmHg (e.g., ,130/80 or
and pulse may be evidence of autonomic than ,120 mmHg.
,120/80 mmHg) may be beneficial for
neuropathy and therefore require adjust- selected patients with diabetes such as Meta-analyses of Trials
ment of blood pressure targets. Orthostatic those with a high risk of cardiovascular To clarify optimal blood pressure targets
blood pressure measurements should be disease. Such intensive blood pressure in patients with diabetes, meta-analyses
checked on initial visit and as indicated. control has been evaluated in large ran- have stratified clinical trials by mean
Home blood pressure self-monitoring domized clinical trials and meta-analyses baseline blood pressure or mean blood
and 24-h ambulatory blood pressure of clinical trials. pressure attained in the intervention (or
monitoring may provide evidence of intensive treatment) arm. Based on these
white coat hypertension, masked hyper- Randomized Controlled Trials of Intensive analyses, antihypertensive treatment ap-
tension, or other discrepancies between Versus Standard Blood Pressure Control pears to be beneficial when mean base-
office and “true” blood pressure (5). In The Action to Control Cardiovascular Risk line blood pressure is $140/90 mmHg or
addition to confirming or refuting a diag- in Diabetes blood pressure (ACCORD BP) mean attained intensive blood pressure
nosis of hypertension, home blood pres- trial provides the strongest direct assess- is $130/80 mmHg (5,9,12–14). Among
sure assessment may be useful to monitor ment of the benefits and risks of intensive trials with lower baseline or attained
antihypertensive treatment. Studies of indi- blood pressure control among people blood pressure, antihypertensive treat-
viduals without diabetes found that home with type 2 diabetes (16). In ACCORD BP, ment reduced the risk of stroke, reti-
measurements may better correlate with compared with standard blood pres- nopathy, and albuminuria, but effects
ASCVD risk than office measurements sure control (target systolic blood pres- on other ASCVD outcomes and heart
(6,7). Moreover, home blood pressures sure ,140 mmHg), intensive blood failure were not evident. Taken to-
may improve patient medication adherence pressure control (target systolic blood gether, these meta-analyses consis-
and thus help reduce cardiovascular risk (8). pressure ,120 mmHg) did not reduce to- tently show that treating patients with
tal major atherosclerotic cardiovascular baseline blood pressure $140 mmHg to
Treatment Goals events but did reduce the risk of stroke, targets ,140 mmHg is beneficial, while
at the expense of increased adverse more intensive targets may offer addi-
events (Table 9.1). The ACCORD BP re- tional, though probably less robust, ben-
c Most patients with diabetes and efits.
sults suggest that blood pressure targets
hypertension should be treated
more intensive than ,140/90 mmHg are Individualization of Treatment Targets
to a systolic blood pressure goal of
not likely to improve cardiovascular out- Patients and clinicians should engage in a
,140 mmHg and a diastolic blood
comes among most people with type 2 di- shared decision-making process to deter-
pressure goal of ,90 mmHg. A
abetes but may be reasonable in selected mine individual blood pressure targets,
S88 Cardiovascular Disease and Risk Management Diabetes Care Volume 41, Supplement 1, January 2018

Table 9.1—Randomized controlled trials of intensive versus standard hypertension treatment strategies
Clinical trial Population Intensive Standard Outcomes
ACCORD BP (16) 4,733 participants with T2D Systolic blood Systolic blood pressure c No benefit in primary end point: composite of
aged 40–79 years with pressure target: target: 130–140 mmHg nonfatal MI, nonfatal stroke, and CVD death
prior evidence of CVD or ,120 mmHg
multiple cardiovascular Achieved (mean) Achieved (mean) c Stroke risk reduced 41% with intensive
risk factors systolic/diastolic: systolic/diastolic: control, not sustained through follow-up
119.3/64.4 133.5/70.5 mmHg beyond the period of active treatment
c Adverse events more common in intensive
group, particularly elevated serum creatinine
and electrolyte abnormalities
ADVANCE BP (17) 11,140 participants with T2D Intervention: Control: placebo c Intervention reduced risk of primary
aged 55 years and older a single-pill, composite end point of major macrovascular
with prior evidence of CVD fixed-dose and microvascular events (9%), death from
or multiple cardiovascular combination of any cause (14%), and death from CVD (18%)
risk factors perindopril and
Achieved (mean) Achieved (mean) c 6-year observational follow-up found
systolic/diastolic: systolic/diastolic: reduction in risk of death in intervention group
136/73 mmHg 141.6/75.2 mmHg attenuated but still significant (142)
HOT (143) 18,790 participants, Diastolic blood Diastolic blood pressure c In the overall trial, there was no cardiovascular
including 1,501 with pressure target: target: #90 mmHg benefit with more intensive targets
diabetes #80 mmHg c In the subpopulation with diabetes, an
intensive diastolic target was associated with
a significantly reduced risk (51%) of CVD events
SPRINT (144) 9,361 participants without Systolic blood Systolic blood pressure c Intensive systolic blood pressure target
diabetes pressure target: target: ,140 mmHg lowered risk of the primary composite
,120 mmHg outcome 25% (MI, ACS, stroke, heart failure,
and death due to CVD)
Achieved (mean): Achieved (mean): c Intensive target reduced risk of death 27%
121.4 mmHg 136.2 mmHg
c Intensive therapy increased risks of electrolyte
abnormalities and AKI
CVD, cardiovascular disease; T2D, type 2 diabetes. Data from this table can also be found in the ADA position statement “Diabetes and Hypertension” (5).

with the acknowledgment that the ben- adults, such as functional limitations,
overweight or obese; a Dietary
efits and risks of intensive blood pres- polypharmacy, and multimorbidity,
Approaches to Stop Hypertension–
sure targets are uncertain and may vary may be best suited for less intensive
style dietary pattern including reduc-
across patients (5). Similar to the factors blood pressure targets. Notably, there
ing sodium and increasing potassium
that influence management of hyper- is an absence of high-quality data avail-
intake; moderation of alcohol intake;
glycemia, factors that influence blood able to guide blood pressure targets in
and increased physical activity. B
pressure treatment targets may include type 1 diabetes.
risks of treatment (e.g., hypotension, Based on current evidence, ADA rec-
Lifestyle management is an important
drug adverse effects), life expectancy, co- ommends hypertension diagnosis and
component of hypertension treatment
morbidities including vascular compli- treatment as outlined, emphasizing individ-
because it lowers blood pressure, enhan-
cations, patient attitude and expected ualization of blood pressure targets. ADA
ces the effectiveness of some antihyper-
treatment efforts, and resources and is aware of hypertension recommendations
tensive medications, promotes other
support system (19). Specific factors to from other organizations (20a). The ADA
aspects of metabolic and vascular health,
consider are the absolute risk of car- Professional Practice Committee continu-
diovascular events (15,20), risk of pro- ously reviews and considers all studies, par- and generally leads to few adverse ef-
gressive kidney disease as reflected by ticularly high-quality trials including people fects. Lifestyle therapy consists of reduc-
albuminuria, adverse effects, age, and with diabetes, for potential incorporation ing excess body weight through caloric
overall treatment burden. Patients in future recommendations. restriction, restricting sodium intake
who have higher risk of cardiovascular (,2,300 mg/day), increasing consump-
events (particularly stroke) or albumin- Treatment Strategies tion of fruits and vegetables (8–10 serv-
uria and who are able to attain intensive Lifestyle Intervention ings per day) and low-fat dairy products
blood pressure control relatively easily (2–3 servings per day), avoiding excessive
and without substantial adverse effects alcohol consumption (no more than
c For patients with blood pressure
may be best suited for intensive blood 2 servings per day in men and no more
.120/80 mmHg, lifestyle inter-
pressure targets. In contrast, patients than 1 serving per day in women) (21),
vention consists of weight loss if
with conditions more common in older and increasing activity levels (22). Cardiovascular Disease and Risk Management S89

These lifestyle interventions are rea- Initial Number of Antihypertensive Medications. analysis of randomized clinical trials found a
sonable for individuals with diabetes Initial treatment for people with diabetes small benefit of evening versus morning
and mildly elevated blood pressure depends on the severity of hypertension dosing of antihypertensive medications
(systolic .120 mmHg or diastolic .80 (Fig. 9.1). Those with blood pressure be- with regard to blood pressure control but
mmHg) and should be initiated along with tween 140/90 mmHg and 159/99 mmHg had no data on clinical effects (35). In two
pharmacologic therapy when hypertension may begin with a single drug. For patients subgroup analyses of a single subsequent
is diagnosed (Fig. 9.1) (22). A lifestyle ther- with blood pressure $160/100 mmHg, randomized controlled trial, moving at
apy plan should be developed in collabo- initial pharmacologic treatment with least one antihypertensive medication
ration with the patient and discussed as two antihypertensive medications is rec- to bedtime significantly reduced cardio-
part of diabetes management. ommended in order to more effectively vascular events, but results were based
achieve adequate blood pressure control on a small number of events (36).
Pharmacologic Interventions (23,24). Single-pill antihypertensive com-
Hyperkalemia and AKI. Treatment with ACE
binations may improve medication ad-
Recommendations inhibitors or ARBs can cause AKI and hyper-
herence in some patients (25).
c Patients with confirmed office-based kalemia, while diuretics can cause AKI and
Classes of Antihypertensive Medications. Ini-
blood pressure $140/90 mmHg either hypokalemia or hyperkalemia (de-
tial treatment for hypertension should
should, in addition to lifestyle ther- pending on mechanism of action) (37,38).
include any of the drug classes demon-
apy, have prompt initiation and timely Detection and management of these ab-
strated to reduce cardiovascular events
titration of pharmacologic therapy to normalities is important because AKI and
in patients with diabetes: ACE inhibitors
achieve blood pressure goals. A hyperkalemia each increase the risks of
(26,27), angiotensin receptor blockers
c Patients with confirmed office-based cardiovascular events and death (39).
(ARBs) (26,27), thiazide-like diuretics
blood pressure $160/100 mmHg Therefore, serum creatinine and potassium
(28), or dihydropyridine calcium channel
should, in addition to lifestyle ther- should be monitored during treatment with
blockers (29). For patients with albumin-
apy, have prompt initiation and an ACE inhibitor, ARB, or diuretic, particu-
uria (urine albumin-to-creatinine ratio
timely titration of two drugs or a sin- larly among patients with reduced glomer-
[UACR] $30 mg/g), initial treatment
gle-pill combination of drugs dem- ular filtration who are at increased risk of
onstrated to reduce cardiovascular should include an ACE inhibitor or ARB
in order to reduce the risk of progressive hyperkalemia and AKI (37,38,40).
events in patients with diabetes. A
c Treatment for hypertension should kidney disease (5) (Fig. 9.1). In the ab-
Resistant Hypertension
include drug classes demonstrated sence of albuminuria, risk of progressive
to reduce cardiovascular events in pa- kidney disease is low, and ACE inhibitors Recommendation

tients with diabetes (ACE inhibitors, and ARBs have not been found to afford c Patients with hypertension who are
angiotensin receptor blockers, thiazide- superior cardioprotection when compared not meeting blood pressure targets
like diuretics, or dihydropyridine calcium with thiazide-like diuretics or dihydro- on three classes of antihypertensive
channel blockers). A pyridine calcium channel blockers(30). medications (including a diuretic)
c Multiple-drug therapy is generally b-Blockers may be used for the treatment should be considered for mineralocor-
required to achieve blood pressure of prior myocardial infarction (MI), ac- ticoid receptor antagonist therapy. B
targets. However, combinations of tive angina, or heart failure but have not
been shown to reduce mortality as blood Resistant hypertension is defined as
ACE inhibitors and angiotensin re-
pressure-lowering agents in the absence blood pressure $140/90 mmHg despite
ceptor blockers and combinations
of ACE inhibitors or angiotensin re- of these conditions (11,31). a therapeutic strategy that includes ap-
ceptor blockers with direct renin in- Multiple-Drug Therapy. Multiple-drug ther- propriate lifestyle management plus a di-
hibitors should not be used. A apy is often required to achieve blood uretic and two other antihypertensive
c An ACE inhibitor or angiotensin re- pressure targets (Fig. 9.1), particularly in drugs belonging to different classes at
ceptor blocker, at the maximumly the setting of diabetic kidney disease. adequate doses. Prior to diagnosing resis-
tolerated dose indicated for blood However, the use of both ACE inhibitors tant hypertension, a number of other
pressure treatment, is the recom- and ARBs in combination, or the combina- conditions should be excluded, including
mended first-line treatment for hy- tion of an ACE inhibitor or ARB and a direct medication nonadherence, white coat
pertension in patients with diabetes renin inhibitor, is not recommended given hypertension, and secondary hyperten-
and urinary albumin-to-creatinine the lack of added ASCVD benefit and in- sion. In general, barriers to medication
ratio $300 mg/g creatinine A or creased rate of adverse eventsdnamely, adherence (such as cost and side effects)
30–299 mg/g creatinine B. If one hyperkalemia, syncope, and acute kidney should be identified and addressed
class is not tolerated, the other injury (AKI) (32–34). Titration of and/or (Fig. 9.1). Mineralocorticoid receptor an-
should be substituted B. addition of further blood pressure medi- tagonists are effective for management of
c For patients treated with an ACE in- cations should be made in a timely fash- resistant hypertension in patients with
hibitor, angiotensin receptor blocker, ion to overcome clinical inertia in type 2 diabetes when added to existing
or diuretic, serum creatinine/estimated achieving blood pressure targets. treatment with a ACE inhibitor or ARB,
Bedtime Dosing. Growing evidence suggests thiazide-like diuretic, and dihydropyridine
glomerular filtration rate and serum
potassium levels should be monitored that there is an association between the calcium channel blocker (41). Miner-
at least annually. B absence of nocturnal blood pressure dip- alocorticoid receptor antagonists
ping and the incidence of ASCVD. A meta- also reduce albuminuria and have
S90 Cardiovascular Disease and Risk Management Diabetes Care Volume 41, Supplement 1, January 2018

Figure 9.1—Recommendations for the treatment of confirmed hypertension in people with diabetes. *An ACE inhibitor (ACEi) or ARB is suggested to treat
hypertension for patients with UACR 30–299 mg/g creatinine and strongly recommended for patients with UACR $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. BP, blood pressure. This figure can also be found in the ADA position statement “Diabetes and Hypertension” (5).

additional cardiovascular benefits monitoring for serum creatinine and po- Pregnancy and Antihypertensive Medications.
(42–45). However, adding a mineralocor- tassium in these patients, and long-term Since there is a lack of randomized con-
ticoid receptor antagonist to a regimen outcome studies are needed to better trolled trials of antihypertensive therapy
including an ACE inhibitor or ARB may evaluate the role of mineralocorticoid re- in pregnant women with diabetes, rec-
increase the risk for hyperkalemia, em- ceptor antagonists in blood pressure ommendations for the management of
phasizing the importance of regular management. hypertension in pregnant women with Cardiovascular Disease and Risk Management S91

diabetes should be similar to those for all LIPID MANAGEMENT In adults with diabetes, it is reasonable to
pregnant women. The American College Lifestyle Intervention obtain a lipid profile (total cholesterol,
of Obstetricians and Gynecologists (ACOG) LDL cholesterol, HDL cholesterol, and tri-
has recommended that women with mild to Recommendations glycerides) at the time of diagnosis, at the
c Lifestyle modification focusing on
moderate gestational hypertension (systolic initial medical evaluation, and at least ev-
blood pressure ,160 mmHg or diastolic weight loss (if indicated); the reduc- ery 5 years thereafter in patients under
blood pressure ,110 mmHg) do not need tion of saturated fat, trans fat, and the age of 40 years. In younger patients
to be treated with antihypertensive med- cholesterol intake; increase of die- with longer duration of disease (such as
ications as there is no benefit identified tary n-3 fatty acids, viscous fiber, those with youth-onset type 1 diabetes),
that clearly outweighs potential risks of and plant stanols/sterols intake; more frequent lipid profiles may be rea-
therapy (46). A 2014 Cochrane systematic and increased physical activity sonable. A lipid panel should also be ob-
review of antihypertensive therapy for should be recommended to im- tained immediately before initiating
mild to moderate chronic hypertension prove the lipid profile in patients statin therapy. Once a patient is taking a
that included 49 trials and over 4,700 with diabetes. A statin, LDL cholesterol levels should be
c Intensify lifestyle therapy and opti-
women did not find any conclusive evi- assessed 4–12 weeks after initiation of
dence for or against blood pressure treat- mize glycemic control for patients statin therapy, after any change in dose,
ment to reduce the risk of preeclampsia with elevated triglyceride levels and on an individual basis (e.g., to moni-
for the mother or effects on perinatal ($150 mg/dL [1.7 mmol/L]) and/ tor for medication adherence and effi-
outcomes such as preterm birth, small- or low HDL cholesterol (,40 mg/dL cacy). In cases where patients are
for-gestational-age infants, or fetal death [1.0 mmol/L] for men, ,50 mg/dL adherent but the LDL cholesterol level is
(47). For pregnant women who require [1.3 mmol/L] for women). C not responding, clinical judgment is rec-
antihypertensive therapy, systolic blood ommended to determine the need for
pressure levels of 120–160 mmHg and di- Lifestyle intervention, including weight and timing of lipid panels. In individual
astolic blood pressure levels of 80–105 loss, increased physical activity, and med- patients, the highly variable LDL choles-
mmHg are suggested to optimize mater- ical nutrition therapy, allows some pa- terol–lowering response seen with statins
nal health without risking fetal harm. tients to reduce ASCVD risk factors. is poorly understood (50). Clinicians
Lower targets (systolic blood pressure Nutrition intervention should be tailored should attempt to find a dose or alterna-
110–119 mmHg and diastolic blood pres- according to each patient’s age, diabetes tive statin that is tolerable, if side effects
sure 65–79 mmHg) may contribute to im- type, pharmacologic treatment, lipid lev- occur. There is evidence for benefit from
proved long-term maternal health; however, els, and medical conditions. even extremely low, less than daily statin
they may be associated with impaired fetal Recommendations should focus on re- doses (51).
growth. Pregnant women with hypertension ducing saturated fat, cholesterol, and trans
and evidence of end-organ damage from fat intake and increasing plant stanols/ Statin Treatment
cardiovascular and/or renal disease may sterols, n-3 fatty acids, and viscous fiber
be considered for lower blood pressure (such as in oats, legumes, and citrus) in-
c For patients of all ages with diabe-
targets to avoid progression of these con- take. Glycemic control may also beneficially
tes and atherosclerotic cardiovas-
ditions during pregnancy. modify plasma lipid levels, particularly in
cular disease, high-intensity statin
During pregnancy, treatment with ACE patients with very high triglycerides and
therapy should be added to lifestyle
inhibitors, ARBs, and spironolactone are poor glycemic control. See Section 4 therapy. A
contraindicated as they may cause fetal “Lifestyle Management” for additional c For patients with diabetes aged
damage. Antihypertensive drugs known to nutrition information. ,40 years with additional athero-
be effective and safe in pregnancy include
sclerotic cardiovascular disease
methyldopa, labetalol, and long-acting
Ongoing Therapy and Monitoring With risk factors, the patient and provider
nifedipine, while hydralzine may be consid-
Lipid Panel should consider using moderate-
ered in the acute management of hyperten-
intensity statin in addition to lifestyle
sion in pregnancy or severe preeclampsia Recommendations
therapy. C
(46). Diuretics are not recommended for c In adults not taking statins or other c For patients with diabetes aged 40–
blood pressure control in pregnancy but lipid-lowering therapy, it is reasonable 75 years A and .75 years B without
may be used during late-stage pregnancy to obtain a lipid profile at the time of atherosclerotic cardiovascular dis-
if needed for volume control (46,48). diabetes diagnosis, at an initial medi- ease, use moderate-intensity statin
ACOG also recommends that postpartum cal evaluation, and every 5 years in addition to lifestyle therapy.
patients with gestational hypertension, pre- thereafter if under the age of 40 years, c In clinical practice, providers may
eclampsia, and superimposed preeclampsia or more frequently if indicated. E need to adjust the intensity of statin
have their blood pressures observed for 72 h c Obtain a lipid profile at initiation of therapy based on individual patient
in the hospital and for 7–10 days postpar- statins or other lipid-lowering ther- response to medication (e.g., side
tum. Long-term follow-up is recommended
apy, 4–12 weeks after initiation or a effects, tolerability, LDL cholesterol
for these women as they have increased life-
change in dose, and annually thereafter levels, or percent LDL reduction on
time cardiovascular risk (49). See Section 13
as it may help to monitor the response statin therapy). For patients who do
“Management of Diabetes in Pregnancy”
to therapy and inform adherence. E not tolerate the intended intensity
for additional information.
S92 Cardiovascular Disease and Risk Management Diabetes Care Volume 41, Supplement 1, January 2018

of statin, the maximally tolerated Table 9.2—Recommendations for statin and combination treatment in adults with
statin dose should be used. E diabetes
c For patients with diabetes and ath- Recommended statin intensity^and
Age ASCVD combination treatment*
erosclerotic cardiovascular disease, if
LDL cholesterol is $70 mg/dL on ,40 years No None†
maximally tolerated statin dose, Yes High
c If LDL cholesterol $70 mg/dL despite maximally tolerated statin
consider adding additional LDL-
dose, consider adding additional LDL-lowering therapy (such as
lowering therapy (such as ezetimibe ezetimibe or PCSK9 inhibitor)#
or PCSK9 inhibitor) after evaluating $40 years No Moderate‡
the potential for further athero- Yes High
sclerotic cardiovascular disease c If LDL cholesterol $70 mg/dL despite maximally tolerated statin
risk reduction, drug-specific ad- dose, consider adding additional LDL-lowering therapy (such as
verse effects, and patient preferen- ezetimibe or PCSK9 inhibitor)
ces. Ezetimibe may be preferred ^
*In addition to lifestyle therapy. For patients who do not tolerate the intended intensity of statin,
due to lower cost. A the maximally tolerated statin dose should be used. †Moderate-intensity statin may be considered
c Statin therapy is contraindicated in based on risk-benefit profile and presence of ASCVD risk factors. ASCVD risk factors include LDL cholesterol
$100 mg/dL (2.6 mmol/L), high blood pressure, smoking, chronic kidney disease, albuminuria, and
pregnancy. B family history of premature ASCVD. ‡High-intensity statin may be considered based on risk-benefit
profile and presence of ASCVD risk factors. #Adults aged ,40 years with prevalent ASCVD were not
well represented in clinical trials of non-statin–based LDL reduction. Before initiating combination
Initiating Statin Therapy Based on Risk lipid-lowering therapy, consider the potential for further ASCVD risk reduction, drug-specific adverse
Patients with type 2 diabetes have an in- effects, and patient preferences.
creased prevalence of lipid abnormalities,
contributing to their high risk of ASCVD.
Multiple clinical trials have demonstrated death and nonfatal MI) are greatest in The Risk Calculator
the beneficial effects of statin therapy on people with high baseline ASCVD risk The American College of Cardiology/
ASCVD outcomes in subjects with and (known ASCVD and/or very high LDL cho- American Heart Association ASCVD risk
without CHD (52,53). Subgroup analyses lesterol levels), but the overall benefits of calculator is generally a useful tool to esti-
of patients with diabetes in larger trials statin therapy in people with diabetes at mate 10-year ASCVD risk (my.americanheart
(54–58) and trials in patients with diabe- moderate or even low risk for ASCVD are .org). However, as diabetes itself confers
tes (59,60) showed significant primary convincing (62,63). The relative benefit of increased risk for ASCVD and risk calcula-
and secondary prevention of ASCVD lipid-lowering therapy has been uniform tors in general do not account for the
events and CHD death in patients with across most subgroups tested (53,61), in- duration of diabetes or the presence of
diabetes. Meta-analyses, including data cluding subgroups that varied with re- other complications such as albuminuria,
from over 18,000 patients with diabetes spect to age and other risk factors. the risk calculator has limited use for as-
from 14 randomized trials of statin therapy sessing cardiovascular risk in individuals
(mean follow-up 4.3 years), demonstrate a Risk Stratification with diabetes.
9% proportional reduction in all-cause Two broad groups of patients exist for Recently, risk scores and other cardio-
mortality and 13% reduction in vascular management of cardiovascular risk: those vascular biomarkers have been devel-
mortality for each mmol/L (39 mg/dL) re- with documented ASCVD (as defined oped for risk stratification of secondary
duction in LDL cholesterol (61). above) and those without; treatment is prevention patients (i.e., those who are
Accordingly, statins are the drugs of often referred to as “secondary” and “pri- already high risk because they have
choice for LDL cholesterol lowering and mary” prevention, respectively. Because ASCVD) but are not yet in widespread
cardioprotection. Table 9.2 shows recom- risk is higher in patients with ASCVD, use (67,68). With newer, more expensive
mended lipid-lowering strategies, and Ta- more intensive therapy is indicated and lipid-lowering therapies now available,
ble 9.3 shows the two statin dosing has been shown to be of benefit in mul- use of these risk assessments may help
intensities that are recommended for tiple large randomized cardiovascular target these new therapies to “higher
use in clinical practice: high-intensity outcomes trials (61,64–66). risk” ASCVD patients in the future.
statin therapy will achieve approxi-
mately a 50% reduction in LDL choles-
Table 9.3—High-intensity and moderate-intensity statin therapy*
terol, and moderate-intensity statin
regimens achieve 30–50% reductions in High-intensity statin therapy (lowers LDL Moderate-intensity statin therapy
cholesterol by $50%) (lowers LDL cholesterol by 30% to 50%)
LDL cholesterol. Low-dose statin therapy
is generally not recommended in patients Atorvastatin 40–80 mg Atorvastatin 10–20 mg
with diabetes but is sometimes the only Rosuvastatin 20–40 mg Rosuvastatin 5–10 mg
Simvastatin 20–40 mg
dose of statin that a patient can tolerate.
Pravastatin 40–80 mg
For patients who do not tolerate the Lovastatin 40 mg
intended intensity of statin, the maximally Fluvastatin XL 80 mg
tolerated statin dose should be used. Pitavastatin 2–4 mg
As in those without diabetes, absolute *Once-daily dosing. XL, extended release.
reductions in ASCVD outcomes (CHD Cardiovascular Disease and Risk Management S93

Primary Prevention (Patients Without ASCVD) Association and American Diabetes Asso- diabetes (27% of participants), the com-
For primary prevention, moderate-dose ciation” (69) for additional discussion. bination of moderate-intensity simvasta-
statin therapy is recommended for those tin (40 mg) and ezetimibe (10 mg)
Secondary Preventions (Patients With
40 years and older (55,62,63), though ASCVD) showed a significant reduction of major
high-intensity therapy may be considered High-intensity statin therapy is recommen- adverse cardiovascular events with an ab-
on an individual basis in the context of ad- ded for all patients with diabetes and solute risk reduction of 5% (40% vs. 45%)
ditional ASCVD risk factors. The evidence is ASCVD. This recommendation is based on and relative risk reduction of 14% (RR
strong for patients with diabetes aged 40– the Cholesterol Treatment Trialists’ Collab- 0.86 [95% CI 0.78–0.94]) over moderate-
75 years, an age-group well represented oration involving 26 statin trials, of which intensity simvastatin (40 mg) alone (65).
in statin trials showing benefit. 5 compared high-intensity versus moderate- Statins and PCSK9 Inhibitors
The evidence is lower for patients intensity statins. Together, they found re- Placebo-controlled trials evaluating the
aged .75 years; relatively few older pa- ductions in nonfatal cardiovascular events addition of the PCSK9 inhibitors evolo-
tients with diabetes have been enrolled in with more intensive therapy, in patients cumab and alirocumab to maximally
primary prevention trials. However, het- with and without diabetes (53,57,64). tolerated doses of statin therapy in par-
erogeneity by age has not been seen in Over the past few years, there have ticipants who were at high risk for ASCVD
the relative benefit of lipid-lowering ther- been multiple large randomized trials in- demonstrated an average reduction in
apy in trials that included older partici- vestigating the benefits of adding nonsta- LDL cholesterol ranging from 36 to 59%.
pants (53,60,61), and because older age tin agents to statin therapy, including These agents have been approved as ad-
confers higher risk, the absolute benefits three that evaluated further lowering of junctive therapy for patients with ASCVD
are actually greater (53,65). Moderate- LDL cholesterol with ezetimibe (65), or familial hypercholesterolemia who are
intensity statin therapy is recommended PCSK9 inhibitors (66), and, cholesteryl es- receiving maximally tolerated statin ther-
in patients with diabetes that are 75 years ter transfer protein [CETP] inhibitors, an apy but require additional lowering of LDL
or older. However, the risk-benefit profile investigational class of drugs with some cholesterol (71,72).
should be routinely evaluated in this pop- recent supportive data (70). Each trial The effects of PCSK9 inhibition on
ulation, with downward titration of dose found a significant benefit in the reduc- ASCVD outcomes was investigated in
performed as needed. See Section 11 tion of ASCVD events that was directly the Further Cardiovascular Outcomes Re-
“Older Adults” for more details on clinical related to the degree of further LDL cho- search With PCSK9 Inhibition in Subjects
considerations for this population. lesterol lowering. These three large trials With Elevated Risk (FOURIER) trial, which
Age <40 Years and/or Type 1 Diabetes. Very comprised over 75,000 patients and enrolled 27,564 patients with prior
little clinical trial evidence exists for pa- 250,000 patient-years of follow-up, and ASCVD and an additional high-risk feature
tients with type 2 diabetes under the age approximately one-third of participants who were receiving their maximally toler-
of 40 years or for patients with type 1 di- had diabetes. For patients with ASCVD ated statin therapy (two-thirds were on
abetes of any age. In the Heart Protection who are on high-intensity (and maximally high-intensity statin) but who still had an
Study (lower age limit 40 years), the sub- tolerated) statin therapy and have an LDL LDL cholesterol $70 mg/dL or a non-HDL
group of ;600 patients with type 1 dia- cholesterol $70 mg/dL, the addition of cholesterol $100 mg/dL (66). Patients
betes had a proportionately similar, nonstatin LDL-lowering therapy is recom- were randomized to receive subcutane-
although not statistically significant, re- mended after considering the potential for ous injections of evolocumab (either
duction in risk as patients with type 2 di- further ASCVD risk reduction, drug-specific 140 mg every 2 weeks or 420 mg every
abetes (55). Even though the data are not adverse effects, and patient preferences. month based on patient preference) ver-
definitive, similar statin treatment ap- Combination Therapy for LDL
sus placebo. Evolocumab reduced LDL
proaches should be considered for pa- Cholesterol Lowering
cholesterol by 59% from a median of
tients with type 1 or type 2 diabetes, 92 to 30 mg/dL in the treatment arm.
Statins and Ezetimibe
particularly in the presence of other car- During the median follow-up of 2.2
The IMProved Reduction of Outcomes:
diovascular risk factors. Patients below years, the composite outcome of cardio-
Vytorin Efficacy International Trial
the age of 40 have lower risk of devel- vascular death, MI, stroke, hospitalization
(IMPROVE-IT) was a randomized con-
oping a cardiovascular event over a for angina, or revascularization occurred
trolled trial in 18,144 patients comparing
10-year horizon; however, their lifetime in 11.3% vs. 9.8% of the placebo and evo-
the addition of ezetimibe to simvastatin
risk of developing cardiovascular disease locumab groups, respectively, represent-
therapy versus simvastatin alone. Individuals
ing a 15% relative risk reduction (P ,
and suffering an MI, stroke, or cardiovas- were $50 years of age, had experienced a
cular death is high. For patients under the 0.001). The combined end point of cardio-
recent acute coronary syndrome (ACS),
age of 40 years and/or who have type 1 vascular death, MI, or stroke was reduced
and were treated for an average of
diabetes with other ASCVD risk factors, by 20%, from 7.4 to 5.9% (P , 0.001).
6 years. Overall, the addition of ezetimibe
we recommend that the patient and Importantly, similar benefits were seen
led to a 6.4% relative benefit and a 2% ab-
health care provider discuss the relative in prespecified subgroup of patients
solute reduction in major adverse cardiovas-
with diabetes, comprising 11,031 patients
benefits and risks and consider the use cular events, with the degree of benefit
(40% of the trial) (73).
of moderate-intensity statin therapy. being directly proportional to the change
Please refer to “Type 1 Diabetes Mellitus in LDL cholesterol, which was 70 mg/dL in Statins and CETP Inhibitors
and Cardiovascular Disease: A Scientific the statin group on average and 54 mg/dL in Inhibition of CETP increases HDL choles-
Statement From the American Heart the combination group (65). In those with terol and further reduces LDL cholesterol.
S94 Cardiovascular Disease and Risk Management Diabetes Care Volume 41, Supplement 1, January 2018

This class of drugs is not likely to be avail- dyslipidemia in individuals with type 2 di- (1.7–4.5 mmol/L) to statin therapy plus
able for clinical use, but studies pro- abetes. However, the evidence for the extended-release niacin or placebo. The
vide further insight into the effects of use of drugs that target these lipid frac- trial was halted early due to lack of effi-
LDL cholesterol lowering on cardiovascular tions is substantially less robust than that cacy on the primary ASCVD outcome (first
events. for statin therapy (78). In a large trial in event of the composite of death from
A total of four trials have been con- patients with diabetes, fenofibrate failed CHD, nonfatal MI, ischemic stroke, hospi-
ducted, three of which failed to show to reduce overall cardiovascular out- talization for an ACS, or symptom-driven
benefit (74–76). Of these, one showed comes (79). coronary or cerebral revascularization)
harm and two were stopped after approx- and a possible increase in ischemic stroke
imately 2 years and thus did not have Other Combination Therapy
in those on combination therapy (82).
sufficient time or power to identify the The much larger Heart Protection
benefit. The final study, the Randomized Recommendations Study 2–Treatment of HDL to Reduce
Evaluation of the Effects of Anacetrapib c Combination therapy (statin/fibrate) the Incidence of Vascular Events (HPS2-
Through Lipid-modification (REVEAL) trial has not been shown to improve ath- THRIVE) trial also failed to show a benefit
enrolled 30,449 patients with ASCVD (70). erosclerotic cardiovascular disease of adding niacin to background statin
All patients received intensive atorvasta- outcomes and is generally not rec- therapy (83). A total of 25,673 patients
tin therapy and were randomized to ana- ommended. A with prior vascular disease were random-
cetrapib or placebo. c Combination therapy (statin/niacin) ized to receive 2 g of extended-release
During the median follow-up of 4.1 has not been shown to provide addi- niacin and 40 mg of laropiprant (an antag-
years, the primary outcome (coronary tional cardiovascular benefit above onist of the prostaglandin D2 receptor
death, MI, or coronary revascularization) statin therapy alone, may increase DP1 that has been shown to improve ad-
was significantly reduced with the addi- the risk of stroke with additional herence to niacin therapy) versus a
tion of anacetrapib from 11.8 to 10.8%, side effects, and is generally not matching placebo daily and followed
with a hazard ratio (HR) of 0.91 (P 5 recommended. A for a median follow-up period of 3.9
0.004). The relative difference in risk years. There was no significant difference
was similar across multiple prespecified Statin and Fibrate in the rate of coronary death, MI, stroke,
subgroups, including among 11,320 pa- Combination therapy (statin and fibrate) or coronary revascularization with the ad-
tients with diabetes (37% of the trial). is associated with an increased risk for dition of niacin–laropiprant versus pla-
The benefit appeared to be related to abnormal transaminase levels, myositis, cebo (13.2% vs. 13.7%; rate ratio, 0.96;
the reduction in LDL (and more broadly and rhabdomyolysis. The risk of rhabdo- P 5 0.29). Niacin–laropiprant was associ-
non-HDL) as opposed to the raising of myolysis is more common with higher ated with an increased incidence of new-
HDL. The mean achieved LDL cholesterol doses of statins and renal insufficiency onset diabetes (absolute excess, 1.3
was 63 mg/dL vs. 53 mg/dL at the trial and appears to be higher when statins percentage points; P , 0.001) and distur-
midpoint in the placebo and anacetrapib are combined with gemfibrozil (com- bances in diabetes control among those
groups, respectively. This study reaffirms pared with fenofibrate) (80). with diabetes. In addition, there was an
the benefit of further lowering of LDL In the ACCORD study, in patients with increase in serious adverse events associ-
cholesterol on reducing cardiovascular type 2 diabetes who were at high risk for ated with the gastrointestinal system,
events. ASCVD, the combination of fenofibrate musculoskeletal system, skin, and, unex-
and simvastatin did not reduce the rate pectedly, infection and bleeding.
of fatal cardiovascular events, nonfatal Therefore, combination therapy with a
Treatment of Other Lipoprotein MI, or nonfatal stroke as compared with statin and niacin is not recommended
Fractions or Targets simvastatin alone. Prespecified subgroup given the lack of efficacy on major ASCVD
analyses suggested heterogeneity in outcomes and side effects.
c For patients with fasting triglyceride treatment effects with possible benefit
levels $500 mg/dL (5.7 mmol/L), for men with both a triglyceride level Diabetes With Statin Use
evaluate for secondary causes of $204 mg/dL (2.3 mmol/L) and an HDL Several studies have reported a modestly
hypertriglyceridemia and consider cholesterol level #34 mg/dL (0.9 mmol/L) increased risk of incident diabetes with
medical therapy to reduce the risk (81). statin use (84,85), which may be limited
of pancreatitis. C Statin and Niacin to those with diabetes risk factors. An
The Atherothrombosis Intervention in analysis of one of the initial studies
Hypertriglyceridemia should be ad- Metabolic Syndrome With Low HDL/High suggested that although statin use was
dressed with dietary and lifestyle changes Triglycerides: Impact on Global Health associated with diabetes risk, the cardio-
including abstinence from alcohol (77). Outcomes (AIM-HIGH) trial randomized vascular event rate reduction with statins
Severe hypertriglyceridemia (.1,000 over 3,000 patients (about one-third far outweighed the risk of incident diabe-
mg/dL) may warrant pharmacologic ther- with diabetes) with established ASCVD, tes even for patients at highest risk for
apy (fibric acid derivatives and/or fish oil) low LDL cholesterol levels (,180 mg/dL diabetes (86). The absolute risk increase
to reduce the risk of acute pancreatitis. [4.7 mmol/L]), low HDL cholesterol levels was small (over 5 years of follow-up,
Low levels of HDL cholesterol, often (men ,40 mg/dL [1.0 mmol/L] and 1.2% of participants on placebo devel-
associated with elevated triglyceride women ,50 mg/dL [1.3 mmol/L]), and oped diabetes and 1.5% on rosuvastatin
levels, are the most prevalent pattern of triglyceride levels of 150–400 mg/dL developed diabetes) (86). A meta-analysis Cardiovascular Disease and Risk Management S95

of 13 randomized statin trials with 91,140 Risk Reduction greater than the number of episodes of
participants showed an odds ratio of 1.09 Aspirin has been shown to be effective in bleeding induced, although these compli-
for a new diagnosis of diabetes, so that reducing cardiovascular morbidity and cations do not have equal effects on long-
(on average) treatment of 255 patients mortality in high-risk patients with previ- term health (94).
with statins for 4 years resulted in one ous MI or stroke (secondary prevention).
additional case of diabetes while simulta- Its net benefit in primary prevention Treatment Considerations
neously preventing 5.4 vascular events among patients with no previous cardio- In 2010, a position statement of the ADA,
among those 255 patients (85). vascular events is more controversial the American Heart Association, and the
both for patients with diabetes and for American College of Cardiology Foun-
Statins and Cognitive Function patients without diabetes (89,90). Previ- dation recommended that low-dose
A recent systematic review of the U.S. ous randomized controlled trials of aspi- (75–162 mg/day) aspirin for primary pre-
Food and Drug Administration’s (FDA’s) rin specifically in patients with diabetes vention is reasonable for adults with di-
postmarketing surveillance databases, failed to consistently show a significant abetes and no previous history of vascular
randomized controlled trials, and cohort, reduction in overall ASCVD end points, disease who are at increased ASCVD risk
case-control, and cross-sectional studies raising questions about the efficacy of as- and who are not at increased risk for
evaluating cognition in patients receiving pirin for primary prevention in people bleeding (95). This now out-of-date state-
statins found that published data do not re- with diabetes, although some sex differ- ment included sex-specific recommenda-
veal an adverse effect of statins on cognition ences were suggested (91–93). tions for use of aspirin therapy as primary
(87). In addition, no change in cognitive The Antithrombotic Trialists’ Collabora- prevention in persons with diabetes (95).
function has been reported in studies with tion published an individual patient–level However, since that time, multiple recent
the addition of ezetimibe (65) or PCSK9 meta-analysis (89) of the six large trials of well-conducted studies and meta-analyses
inhibitors (66,88) to statin therapy, includ- aspirin for primary prevention in the gen- have reported a risk of heart disease and
ing among patients treated to very low LDL eral population. These trials collectively stroke that is equivalent if not higher in
cholesterol levels. Therefore, a concern that enrolled over 95,000 participants, includ- women compared with men with diabe-
statins or other lipid-lowering agents might ing almost 4,000 with diabetes. Overall, tes, including among nonelderly adults.
cause cognitive dysfunction or dementia is they found that aspirin reduced the risk Thus, current recommendations for using
not currently supported by evidence and of serious vascular events by 12% (RR aspirin as primary prevention include both
should not deter their use in individuals 0.88 [95% CI 0.82–0.94]). The largest re- men and women aged $50 years with
with diabetes at high risk for ASCVD (87). duction was for nonfatal MI, with little diabetes and at least one additional major
effect on CHD death (RR 0.95 [95% CI risk factor (family history of premature
ANTIPLATELET AGENTS 0.78–1.15]) or total stroke. There was ASCVD, hypertension, dyslipidemia,
some evidence of a difference in aspirin smoking, or chronic kidney disease/
effect by sex: aspirin significantly reduced albuminuria) who are not at increased
c Use aspirin therapy (75–162 mg/day)
ASCVD events in men but not in women. risk of bleeding (e.g., older age, anemia,
as a secondary prevention strategy
Conversely, aspirin had no effect on renal disease) (96–99). While risk calcu-
in those with diabetes and a history
stroke in men but significantly reduced lators such as those from the American
of atherosclerotic cardiovascular
stroke in women. However, there was College of Cardiology/American Heart As-
disease. A
no heterogeneity of effect by sex in the sociation ( may
c For patients with atherosclerotic
risk of serious vascular events (P 5 0.9). be a useful tool to estimate 10-year
cardiovascular disease and docu-
Sex differences in the effects of aspirin ASCVD risk, diabetes itself confers in-
mented aspirin allergy, clopidogrel
have not been observed in studies of sec- creased risk for ASCVD. As a result, such
(75 mg/day) should be used. B
ondary prevention (89). In the six trials risk calculators have limited utility in help-
c Dual antiplatelet therapy (with low-
examined by the Antithrombotic Trialists’ ing to assess the potential benefits of as-
dose aspirin and a P2Y12 inhibitor)
Collaboration, the effects of aspirin on pirin therapy in individuals with diabetes.
is reasonable for a year after an acute
major vascular events were similar for pa- Noninvasive imaging techniques such as
coronary syndrome A and may have
tients with or without diabetes: RR 0.88 coronary computed tomography angiog-
benefits beyond this period. B
(95% CI 0.67–1.15) and RR 0.87 (95% CI raphy may potentially help further tai-
c Aspirin therapy (75–162 mg/day)
0.79–0.96), respectively. The CI was wider lor aspirin therapy, particularly in those
may be considered as a primary pre-
for those with diabetes because of at low risk (100), but are not generally
vention strategy in those with type 1
smaller numbers. recommended. Sex differences in the
or type 2 diabetes who are at in-
Aspirin appears to have a modest ef- antiplatelet effect of aspirin have been sug-
creased cardiovascular risk. This
fect on ischemic vascular events, with the gested in the general population (101);
includes most men and women with
absolute decrease in events depending however, further studies are needed to
diabetes aged $50 years who have
on the underlying ASCVD risk. The main investigate the presence of such differen-
at least one additional major risk
adverse effect is an increased risk of gas- ces in individuals with diabetes.
factor (family history of premature
trointestinal bleeding. The excess risk may
atherosclerotic cardiovascular dis-
be as high as 5 per 1,000 per year in real- Aspirin Use in People <50 Years of Age
ease, hypertension, dyslipidemia,
world settings. In adults with ASCVD Aspirin is not recommended for those at
smoking, or albuminuria) and are
risk .1% per year, the number of ASCVD low risk of ASCVD (such as men and women
not at increased risk of bleeding. C
events prevented will be similar to or aged ,50 years with diabetes with no
S96 Cardiovascular Disease and Risk Management Diabetes Care Volume 41, Supplement 1, January 2018

other major ASCVD risk factors) as the low adding ticagrelor to aspirin significantly
disease, after lifestyle management
benefit is likely to be outweighed by the reduces the risk of recurrent ischemic
and metformin, the antihyperglyce-
risks of bleeding. Clinical judgment should events including cardiovascular and coro-
mic agent canagliflozin may be con-
be used for those at intermediate risk nary heart disease death (108). More
sidered to reduce major adverse
(younger patients with one or more risk studies are needed to investigate the
cardiovascular events, based on
factors or older patients with no risk fac- longer-term benefits of these therapies
drug-specific and patient factors
tors) until further research is available. after ACS among patients with diabetes.
(see Table 8.1). C
Patients’ willingness to undergo long-
term aspirin therapy should also be con- CORONARY HEART DISEASE
sidered (102). Aspirin use in patients Recommendations Cardiac Testing
aged ,21 years is generally contraindi- Candidates for advanced or invasive car-
cated due to the associated risk of Reye Screening diac testing include those with 1) typical
syndrome. c In asymptomatic patients, routine or atypical cardiac symptoms and 2) an ab-
screening for coronary artery dis- normal resting electrocardiogram (ECG).
Aspirin Dosing ease is not recommended as it Exercise ECG testing without or with echo-
Average daily dosages used in most clini- does not improve outcomes as long cardiography may be used as the initial test.
cal trials involving patients with diabetes as atherosclerotic cardiovascular dis- In adults with diabetes $40 years of age,
ranged from 50 mg to 650 mg but were ease risk factors are treated. A measurement of coronary artery calcium
mostly in the range of 100–325 mg/day. c Consider investigations for coronary is also reasonable for cardiovascular risk
There is little evidence to support any artery disease in the presence of any assessment. Pharmacologic stress echo-
specific dose, but using the lowest possi- of the following: atypical cardiac cardiography or nuclear imaging should
ble dose may help to reduce side effects symptoms (e.g., unexplained dyspnea, be considered in individuals with diabetes
(103). In the U.S., the most common low- chest discomfort); signs or symptoms in whom resting ECG abnormalities pre-
dose tablet is 81 mg. Although platelets of associated vascular disease includ- clude exercise stress testing (e.g., left
from patients with diabetes have altered ing carotid bruits, transient ischemic bundle branch block or ST-T abnormali-
function, it is unclear what, if any, effect attack, stroke, claudication, or periph- ties). In addition, individuals who require
that finding has on the required dose of eral arterial disease; or electrocardio- stress testing and are unable to exercise
aspirin for cardioprotective effects in the gram abnormalities (e.g., Q waves). E should undergo pharmacologic stress
patient with diabetes. Many alternate echocardiography or nuclear imaging.
pathways for platelet activation exist Treatment
that are independent of thromboxane c In patients with known atheroscle-
Screening Asymptomatic Patients
A2 and thus not sensitive to the effects rotic cardiovascular disease, con-
The screening of asymptomatic patients
of aspirin (104). “Aspirin resistance” has sider ACE inhibitor or angiotensin
with high ASCVD risk is not recommended
been described in patients with diabetes receptor blocker therapy to reduce
(109), in part because these high-risk pa-
when measured by a variety of ex vivo the risk of cardiovascular events. B
tients should already be receiving inten-
and in vitro methods (platelet aggregom- c In patients with prior myocardial in-
sive medical therapydan approach that
etry, measurement of thromboxane B2) farction, b-blockers should be con-
provides similar benefit as invasive revas-
(101), but other studies suggest no impair- tinued for at least 2 years after the
cularization (110,111). There is also some
ment in aspirin response among patients event. B
evidence that silent MI may reverse over
with diabetes (105). A recent trial suggested c In patients with type 2 diabetes with
time, adding to the controversy concern-
that more frequent dosing regimens of aspi- stable congestive heart failure,
ing aggressive screening strategies (112).
rin may reduce platelet reactivity in individ- metformin may be used if estimated
In prospective studies, coronary artery
uals with diabetes (106); however, these glomerular filtration rate remains
calcium has been established as an in-
observations alone are insufficient to em- .30 mL/min but should be avoided
dependent predictor of future ASCVD events
pirically recommend that higher doses of in unstable or hospitalized patients
in patients with diabetes and is consistently
aspirin be used in this group at this time. with congestive heart failure. B
superior to both the UK Prospective Diabetes
It appears that 75–162 mg/day is optimal. c In patients with type 2 diabetes and
Study (UKPDS) risk engine and the Framing-
established atherosclerotic cardio-
ham Risk Score in predicting risk in this
vascular disease, antihyperglycemic
Indications for P2Y12 Use population (113–115). However, a random-
therapy should begin with lifestyle
A P2Y12 receptor antagonist in combina- ized observational trial demonstrated no
management and metformin and
tion with aspirin should be used for at clinical benefit to routine screening of
subsequently incorporate an agent
least 1 year in patients following an asymptomatic patients with type 2 dia-
proven to reduce major adverse car-
ACS and may have benefits beyond this betes and normal ECGs (116). Despite
diovascular events and cardiovascular
period. Evidence supports use of either abnormal myocardial perfusion imaging
mortality (currently empagliflozin
ticagrelor or clopidogrel if no percutane- in more than one in five patients, cardiac
and liraglutide), after considering
ous coronary intervention was performed outcomes were essentially equal (and
drug-specific and patient factors
and clopidogrel, ticagrelor, or prasugrel very low) in screened versus unscreened
(see Table 8.1). A
if a percutaneous coronary intervention patients. Accordingly, indiscriminate
c In patients with type 2 diabetes and es-
was performed (107). In patients with di- screening is not considered cost-effective.
abetes and prior MI (1–3 years before), Studies have found that a risk factor–
Table 9.4—CVOTs completed after issuance of the FDA 2008 guidance
DPP-4 inhibitors GLP-1 receptor agonists SGLT2 inhibitors
(129) (145) (132) (140) (138) (139)* (141) OUTCOME (133) (135) (135)
(n 5 16,492) (n 5 5,380) (n 5 14,671) (n 5 6,068) (n 5 9,340) (n 5 3,297) (n 5 14,752) (n 5 7,020) (n 5 4,330) (n 5 5,812)
Intervention Saxagliptin/ Alogliptin/ Sitagliptin/ Lixisenatide/ Liraglutide/ Semaglutide/ Exenatide QW/ Empagliflozin/ Canagliflozin/placebo

placebo placebo placebo placebo placebo placebo placebo placebo
Main inclusion criteria Type 2 diabetes Type 2 diabetes Type 2 Type 2 Type 2 Type 2 Type 2 diabetes Type 2 diabetes Type 2 diabetes and preexisting
and history of and ACS diabetes and diabetes and diabetes and diabetes and with or without and preexisting CVD at $30 years of age or $2
or multiple within 15–90 preexisting history of ACS preexisting preexisting preexisting CVD CVD with BMI cardiovascular risk factors at $50
risk factors for days before CVD (,180 days) CVD, kidney CVD, HF, or #45 kg/m2 and years of age
CVD randomization disease, or HF CKD at $50 eGFR $30
at $50 years of years of age or mL/min/1.73 m2
age or cardiovascular
cardiovascular risk at $60
risk at $60 years of age
years of age
A1C inclusion criteria (%) $6.5 6.5–11.0 6.5–8.0 5.5–11.0 $7.0 $7.0 6.5–10.0 7.0–10.0 7.0–10.5
Age (years)†† 65.1 61.0 65.4 60.3 64.3 64.6 62 63.1 63.3
Diabetes duration (years)†† 10.3 7.1 11.6 9.3 12.8 13.9 12 57% .10 13.5
Median follow-up (years) 2.1 1.5 3.0 2.1 3.8 2.1 3.2 3.1 5.7 2.1
Statin use (%) 78 91 80 93 72 73 74 77 75
Metformin use (%) 70 66 82 66 76 73 77 74 77
Prior CVD/CHF (%) 78/13 100/28 74/18 100/22 81/18 60/24 73.1/16.2 99/10 65.6/14.4
Mean baseline A1C (%) 8.0 8.0 7.2 7.7 8.7 8.7 8.0 8.1 8.2
Mean difference in A1C
between groups at
end of treatment (%) 20.3 ^ 20.3 ^ 20.3 ^ 20.3 ^ 20.4 ^ 20.7 or 21.0 †
^ 20.53 ^ 20.3 ‡
^ 20.58^
Year started/reported 2010/2013 2009/2013 2008/2015 2010/2015 2010/2016 2013/2016 2010/2017 2010/2015 2009/2017
Primary outcome§ 3-point MACE 3-point MACE 4-point MACE 4-point MACE 3-point MACE 3-point MACE 3-point MACE 3-point MACE 3-point MACE Progression to
1.00 0.96 (95% 0.98 1.02 0.87 0.74 0.91 0.86 0.86 0.73
(0.89–1.12) UL #1.16) (0.89–1.08) (0.89–1.17) (0.78–0.97) (0.58–0.95) (0.83–1.00) (0.74–0.99) (0.75–0.97)§ (0.47–0.77)
Key secondary outcome§ Expanded MACE 4-point MACE 3-point MACE Expanded Expanded Expanded Individual 4-point MACE All-cause and 40% reduction in
MACE MACE MACE components cardiovascular composite eGFR,
of MACE (see mortality (see renal replacement,
below) below) renal death
1.02 0.95 0.99 1.00 0.88 0.74 0.89 0.60
(0.94–1.11) (95% UL # 1.14) (0.89–1.10) (0.90–1.11) (0.81–0.96) (0.62–0.89) (0.78–1.01) (0.47–0.77)
Continued on p. S98
Cardiovascular Disease and Risk Management

Table 9.4—Continued
DPP-4 inhibitors GLP-1 receptor agonists SGLT2 inhibitors
(129) (145) (132) (140) (138) (139)* (141) OUTCOME (133) (135) (135)
(n 5 16,492) (n 5 5,380) (n 5 14,671) (n 5 6,068) (n 5 9,340) (n 5 3,297) (n 5 14,752) (n 5 7,020) (n 5 4,330) (n 5 5,812)
Cardiovascular Disease and Risk Management

Cardiovascular death§ 1.03 0.85 1.03 0.98 0.78 0.98 0.88 0.62 0.96 (0.77–1.18)¶
(0.87–1.22) (0.66–1.10) (0.89–1.19) (0.78–1.22) (0.66–0.93) (0.65–1.48) (0.76–1.02) (0.49–0.77) 0.87 (0.72–1.06)#
MI§ 0.95 1.08 0.95 1.03 0.86 0.74 0.97 0.87 0.85 0.85
(0.80–1.12) (0.88–1.33) (0.81–1.11) (0.87–1.22) (0.73–1.00) (0.51–1.08) (0.85–1.10) (0.70–1.09) (0.65–1.11) (0.61–1.19)
Stroke§ 1.11 0.91 0.97 1.12 0.86 0.61 0.85 1.18 0.97 0.82
(0.88–1.39) (0.55–1.50) (0.79–1.19) (0.79–1.58) (0.71–1.06) (0.38–0.99) (0.70–1.03) (0.89–1.56) (0.70–1.35) (0.57–1.18)
HF hospitalization§ 1.27 1.19 1.00 0.96 0.87 1.11 0.94 0.65 0.77 HR 0.56
(1.07–1.51) (0.90–1.58) (0.83–1.20) (0.75–1.23) (0.73–1.05) (0.77–1.61) (0.78–1.13) (0.50–0.85) (0.55–1.08) (0.38–0.83)
Unstable angina 1.19 0.90 0.90 1.11 0.98 0.82 1.05 0.99
hospitalization§ (0.89–1.60) (0.60–1.37) (0.70–1.16) (0.47–2.62) (0.76–1.26) (0.47–1.44) (0.94–1.18) (0.74–1.34)
All-cause mortality§ 1.11 0.88 1.01 0.94 0.85 1.05 0.86 0.68 0.87 (0.74–1.01)‡‡
(0.96–1.27) (0.71–1.09) (0.90–1.14) (0.78–1.13) (0.74–0.97) (0.74–1.50) (0.77–0.97) (0.57–0.82) 0.90 (0.76–1.07)##
Worsening 1.08 0.78 0.64 0.61 0.60 (0.47–0.77)
d d d d
nephropathy§| (0.88–1.32) (0.67–0.92) (0.46–0.88) (0.53–0.70)
d, not assessed/reported; CANVAS-R, CANVAS-Renal; CHF, congestive heart failure; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; MACE, major adverse cardiac event; UL, upper limit. Data from
this table was adapted from Cefalu et al. (146) in the January 2018 issue of Diabetes Care. *Powered to rule out an HR of 1.8; superiority hypothesis not prespecified. **On the basis of prespecified outcomes, the
renal outcomes are not viewed as statistically significant. ††Age was reported as means in all trials except EXAMINE, which reported medians; diabetes duration was reported as means in all but four trials,with SAVOR-
TIMI 58, EXAMINE, and EXSCEL reporting medians and EMPA-REG OUTCOME reporting as percentage of population with diabetes duration .10 years. †A1C change of 0.66% with 0.5 mg and 1.05% with 1 mg dose of
semaglutide. ‡A1C 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 HR (95% CI). |Worsening
nephropathy is defined as the new onset of UACR .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, LEADER, and SUSTAIN-6 and 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, LEADER, and SUSTAIN-6 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).
Diabetes Care Volume 41, Supplement 1, January 2018 Cardiovascular Disease and Risk Management S99

based approach to the initial diagnostic Recent studies have also examined the SGLT2 inhibitors (particularly the preven-
evaluation and subsequent follow-up for relationship between dipeptidyl pep- tion of heart failure), are being followed
coronary artery disease fails to identify tidase 4 (DPP-4) inhibitors and heart up with new outcomes trials in patients
which patients with type 2 diabetes will failure and have had mixed results. with established heart failure, both with
have silent ischemia on screening tests The Saxagliptin Assessment of Vascular and without diabetes, to determine their
(117,118). Any benefit of newer nonin- Outcomes Recorded in Patients with Di- efficacy in treatment of heart failure.
vasive coronary artery disease screening abetes Mellitus–Thrombolysis in Myocar-
methods, such as computed tomography dial Infarction 53 (SAVOR-TIMI 53) study Antihyperglycemic Therapies and
and computed tomography angiography, showed that patients treated with Cardiovascular Outcomes
to identify patient subgroups for different saxagliptin (a DPP-4 inhibitor) were more In 2008, the FDA issued a guidance for
treatment strategies remains unproven. likely to be hospitalized for heart failure industry to perform cardiovascular out-
Although asymptomatic patients with di- than were those given placebo (3.5% vs. comes trials for all new medications for
abetes with higher coronary disease bur- 2.8%, respectively) (129). Two other re- the treatment for type 2 diabetes amid
den have more future cardiac events cent multicenter, randomized, double- concerns of increased cardiovascular risk
(113,119,120), the role of these tests be- blind, noninferiority trials, Examination of (137). Previously approved diabetes med-
yond risk stratification is not clear. Their rou- Cardiovascular Outcomes with Alogliptin ications were not subject to the guidance.
tine use leads to radiation exposure and may versus Standard of Care (EXAMINE) and Recently published cardiovascular outcomes
result in unnecessary invasive testing such as Trial Evaluating Cardiovascular Outcomes trials have provided additional data on car-
coronary angiography and revascularization with Sitagliptin (TECOS), did not show asso- diovascular outcomes in patients with type 2
procedures. The ultimate balance of bene- ciations between DPP-4 inhibitor use and diabetes with cardiovascular disease or at
fit, cost, and risks of such an approach in heart failure. The FDA reported that the hos- high risk for cardiovascular disease (see Table
asymptomaticpatients remains controversial, pital admission rate for heart failure in 9.4). Cardiovascular outcomes trials of
particularly in the modern setting of aggres- EXAMINE was 3.9% for patients randomly DPP-4 inhibitors have all, so far, not shown
sive ASCVD risk factor control. assigned to alogliptin compared with cardiovascular benefits relative to placebo.
3.3% for those randomly assigned to However, results from other new agents
Lifestyle and Pharmacologic placebo (130). Alogliptin had no effect have provided a mix of results.
Interventions on the composite end point of cardiovas- EMPA-REG OUTCOME trial was a ran-
Intensive lifestyle intervention focusing cular death and hospital admission for domized, double-blind trial that assessed
on weight loss through decreased caloric heart failure in the post hoc analysis (HR the effect of empagliflozin, a SGLT2 inhib-
intake and increased physical activity as 1.00 [95% CI 0.82–1.21]) (131). TECOS itor, versus placebo on cardiovascular
performed in the Action for Health in Di- showed no difference in the rate of heart outcomes in 7,020 patients with type 2
abetes (Look AHEAD) trial may be con- failure hospitalization for the sitagliptin diabetes and existing cardiovascular dis-
sidered for improving glucose control, group (3.1%; 1.07 per 100 person-years) ease. Study participants had a mean age
fitness, and some ASCVD risk factors compared with the placebo group (3.1%; of 63 years, 57% had diabetes for more
(121). Patients at increased ASCVD risk 1.09 per 100 person-years) (132). than 10 years, and 99% had established
should receive aspirin and a statin and A benefit on the incidence of heart fail- cardiovascular disease.EMPA-REGOUTCOME
ACE inhibitor or ARB therapy if the patient ure has been observed with the use of showed that over a median follow-up of
has hypertension, unless there are con- some sodium–glucose cotransporter 3.1 years, treatment reduced the compos-
traindications to a particular drug class. 2 (SGLT2) inhibitors. In the BI 10773 ite outcome of MI, stroke, and cardiovas-
While clear benefit exists for ACE inhibitor (Empagliflozin) Cardiovascular Outcome cular death by 14% (absolute rate 10.5%
or ARB therapy in patients with diabetic Event Trial in Type 2 Diabetes Mellitus vs. 12.1% in the placebo group, HR in the
kidney disease or hypertension, the bene- Patients (EMPA-REG OUTCOME), the ad- empagliflozin group 0.86; 95% CI 0.74–
fits in patients with ASCVD in the absence dition of empagliflozin to standard care 0.99; P = 0.04 for superiority) and cardio-
of these conditions are less clear, espe- led to a significant 35% reduction in the vascular death by 38% (absolute rate
cially when LDL cholesterol is concomi- hospitalization for heart failure compared 3.7% vs. 5.9%, HR 0.62; 95% CI 0.49–
tantly controlled (122,123). In patients with placebo (133). Although the majority 0.77; P , 0.001) (133). The FDA recently
with prior MI, active angina, or heart fail- of patients in the study did not have heart added a new indication for empagliflozin,
ure, b-blockers should be used (124). failure at baseline, this benefit was con- to reduce the risk of major adverse car-
sistent in patients with and without a diovascular death in adults with type 2
Diabetes and Heart Failure prior history of heart failure (134). Simi- diabetes and cardiovascular disease.
As many as 50% of patients with type 2 larly, in the Canagliflozin Cardiovascu- A second large cardiovascular out-
diabetes may develop heart failure (125). lar Assessment Study (CANVAS), there comes trial program of an SGLT2 inhibi-
Data on the effects of glucose-lowering was a 33% reduction in hospitalization tor, canagliflozin, has been reported
agents on heart failure outcomes have for heart failure with canagliflozin versus (135). The CANVAS Program integrated
demonstrated that thiazolidinediones placebo (135). Although heart failure hos- data from two trials, including the CANVAS
have a strong and consistent relation- pitalizations were prospectively adjudicated trial that started in 2009 before the ap-
ship with increased risk of heart failure in both trials, the type(s) of heart failure proval of canagliflozin and the CANVAS-R
(126–128). Therefore, thiazolidinedione events prevented were not characterized. trial that started in 2014 after the approval
use should be avoided in patients with These preliminary findings, which strongly of canagliflozin. Combining both these trials,
symptomatic heart failure. suggest heart failure–related benefits of 10,142 participants with type 2 diabetes and
S100 Cardiovascular Disease and Risk Management Diabetes Care Volume 41, Supplement 1, January 2018

high cardiovascular risk were randomized to stroke and cardiovascular death, in adults significant (141). A total of 14,752 pa-
canagliflozin or placebo and were followed with type 2 diabetes and established car- tients with type 2 diabetes (of whom
for an average 3.6 years. The mean age of diovascular disease. 10,782 [73.1%] had previous cardiovascu-
patients was 63 years and 66% had a history Results from a moderate-sized trial of an- lar disease) were randomized to receive
of cardiovascular disease. The combined other GLP-1 receptor agonist, semaglutide, extended-release exenatide 2 mg or pla-
analysis of the two trials found that were consistent with the LEADER trial cebo and followed for a median of 3.2
canagliflozin significantly reduced the com- (139). Semaglutide, a once-weekly GLP-1 years. The primary end point of cardio-
posite outcome of cardiovascular death, receptor agonist, has not yet been ap- vascular death, MI, or stroke occurred
MI, or stroke versus placebo (occurring in proved by the FDA for the treatment of in 839 patients (11.4%; 3.7 events per
26.9 vs. 31.5 participants per 1,000 patient- type 2 diabetes. The preapproval Trial to 100 person-years) in the exenatide group
years; HR 0.86 [95% CI 0.75–0.97]; Evaluate Cardiovascular and Other Long- and in 905 patients (12.2%; 4.0 events per
P , 0.001 for noninferiority; P 5 0.02 term Outcomes with Semaglutide in Sub- 100 person-years) in the placebo group
for superiority). The specific estimates jects With Type 2 Diabetes (SUSTAIN-6) (HR 0.91 [95% CI 0.83–1.00]; P , 0.001
for canagliflozin versus placebo on the was the initial randomized trial powered for noninferiority) but was not superior to
primary composite cardiovascular out- to test noninferiority of semaglutide for placebo with respect to the primary end
come were HR 0.88 (0.75–1.03) for the the purpose of initial regulatory approval. point (P 5 0.06 for superiority). However,
CANVAS trial, and 0.82 (0.66–1.01) for In this study, 3,297 patients with type 2 di- all-cause mortality was lower in the exe-
the CANVAS-R, with no heterogeneity abetes were randomized to receive once- natide group (HR 0.86 [95% CI 0.77–0.97].
found between trials. In the combined weekly semaglutide (0.5 mg or 1.0 mg) or The incidence of acute pancreatitis, pan-
analysis, there was not a statistically sig- placebo for 2 years. The primary outcome creatic cancer, medullary thyroid carci-
nificant difference in cardiovascular death (the first occurrence of cardiovascular noma, and serious adverse events did
(HR 0.87 [95% CI 0.72–1.06]). The initial death, nonfatal MI, or nonfatal stroke) not differ significantly between the two
CANVAS trial was partially unblinded prior occurred in 108 patients (6.6%) in the groups.
to completion because of the need to file semaglutide group vs. 146 patients (8.9%) In summary, there are now large
interim cardiovascular outcome data for in the placebo group (HR 0.74 [95% CI randomized controlled trials reporting
regulatory approval of the drug (136). Of 0.58–0.95]; P , 0.001). More patients dis- statistically significant reductions in car-
note, there was an increased risk of am- continued treatment in the semaglutide diovascular events for two of the FDA-
putation with canaglifozin (6.3 vs. 3.4 par- group because of adverse events, mainly approved SGLT2 inhibitors (empagliflozin
ticipants per 1,000 patient-years; HR 1.97 gastrointestinal. and canagliflozin) and one of the FDA-
[95% CI 1.41–2.75]) (135). The Evaluation of Lixisenatide in Acute approved GLP-1 receptor agonists (liraglutide)
The Liraglutide Effect and Action in Di- Coronary Syndrome (ELIXA) trial studied where the majority, if not all, patients in
abetes: Evaluation of Cardiovascular the once-daily GLP-1 receptor agonist the trial had ASCVD. The empagliflozin
Outcome ResultsdA Long Term Evalua- lixisenatide on cardiovascular outcomes and liraglutide trials further demon-
tion (LEADER) trial was a randomized, in patients with type 2 diabetes who strated significant reductions in cardio-
double-blind trial that assessed the effect had had a recent acute coronary event vascular death. Once-weekly exenatide
of liraglutide, a glucagon-like peptide (140). A total of 6,068 patients with type 2 did not have statistically significant re-
1 (GLP-1) receptor agonist, versus placebo diabetes with a recent hospitalization for ductions in major adverse cardiovascu-
on cardiovascular outcomes in 9,340 pa- MI or unstable angina within the previ- lar events or cardiovascular mortality
tients with type 2 diabetes at high risk for ous 180 days were randomized to re- but did have a significant reduction in
cardiovascular disease or with cardiovascu- ceive lixisenatide or placebo in addition all-cause mortality. In contrast, other
lar disease. Study participants with a mean to standard care and were followed for GLP-1 receptor agonists have not
age of 64 years and a mean duration of a median of approximately 2.1 years. shown similar reductions in cardiovas-
diabetes of nearly 13 years. Over 80% of The primary outcome of cardiovascular cular events (Table 9.4). Whether the
study participants had established cardio- death, MI, stroke, or hospitalization for benefits of GLP-1 receptor agonists are a
vascular disease. After a median follow-up unstable angina occurred in 406 patients class effect remains to be definitively
of 3.8 years, LEADER showed that the pri- (13.4%) in the lixisenatide group vs. established. Additional large randomized
mary composite outcome (MI, stroke, or 399 (13.2%) in the placebo group (HR trials of other agents in these classes are
cardiovascular death) occurred in fewer 1.02 [95% CI 0.89–1.17]), which demon- ongoing.
participants in the treatment group strated the noninferiority of lixisenatide Of note, these studies examined the
(13.0%) when compared with the placebo to placebo (P , 0.001) but did not show drugs in combination with metformin (Ta-
group (14.9%) (HR 0.87; 95% CI 0.78–0.97; superiority (P 5 0.81). ble 9.4) in the great majority of patients
P , 0.001 for noninferiority; P = 0.01 for Most recently, the Exenatide Study of for whom metformin was not contraindi-
superiority). Deaths from cardiovascular Cardiovascular Event Lowering (EXSCEL) cated or was tolerated. For patients with
causes in the were significantly reduced trial also reported results with the once- type 2 diabetes who have ASCVD, on life-
in the liraglutide group (4.7%) compared weekly GLP-1 receptor agonist extended- style and metformin therapy, it is recom-
to the placebo group (6.0%) (HR 0.78; release exenatide and found that major mended to incorporate an agent with
95% CI 0.66–0.93; P = 0.007) (138). The adverse cardiovascular events were nu- strong evidence for cardiovascular risk
FDA recently approved use of liraglutide merically lower with use of extended- reduction, especially those with proven
to reduce the risk of major adverse car- release exenatide compared with placebo, benefit on both major adverse cardiovas-
diovascular events, including heart attack, although this difference was not statistically cular events and cardiovascular death, Cardiovascular Disease and Risk Management S101

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Diabetes Care Volume 41, Supplement 1, January 2018 S105

American Diabetes Association
10. Microvascular Complications
and Foot Care: Standards of
Medical Care in Diabetesd2018
Diabetes Care 2018;41(Suppl. 1):S105–S118 |

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes”
includes 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, 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 Introduc-
tion. Readers who wish to comment on the Standards of Care are invited to do so at


c At least once a year, assess urinary albumin (e.g., spot urinary albumin–to–creatinine
ratio) and estimated glomerular filtration rate in patients with type 1 diabetes
with duration of $5 years, in all patients with type 2 diabetes, and in all patients
with comorbid hypertension. B
c Optimize glucose control to reduce the risk or slow the progression of diabetic
kidney disease. A
c Optimize blood pressure control to reduce the risk or slow the progression of
diabetic kidney disease. A
c For people with nondialysis-dependent diabetic kidney disease, dietary protein
intake should be approximately 0.8 g/kg body weight per day (the recommended
daily allowance). For patients on dialysis, higher levels of dietary protein intake
should be considered. B
c In nonpregnant patients with diabetes and hypertension, either an ACE
inhibitor or an angiotensin receptor blocker is recommended for those Suggested citation: American Diabetes Association.
10. Microvascular complications and foot care:
with modestly elevated urinary albumin–to–creatinine ratio (30–299 mg/g
Standards of Medical Care in Diabetesd2018.
creatinine) B and is strongly recommended for those with urinary albumin–to– Diabetes Care 2018;41(Suppl. 1):S105–S118
creatinine ratio $300 mg/g creatinine and/or estimated glomerular filtration © 2017 by the American Diabetes Association.
rate ,60 mL/min/1.73 m2. A Readers may use this article as long as the work
c Periodically monitor serum creatinine and potassium levels for the development is properly cited, the use is educational and not
of increased creatinine or changes in potassium when ACE inhibitors, angiotensin for profit, and the work is not altered. More infor-
receptor blockers, or diuretics are used. B mation is available at http://www.diabetesjournals
S106 Microvascular Complications and Foot Care Diabetes Care Volume 41, Supplement 1, January 2018

collections are more burdensome and over time as the prevalence of diabetes in-
c Continued monitoring of urinary
add little to prediction or accuracy. Mea- creases in the U.S. (3,4,11,12).
albumin–to–creatinine ratio in pa-
surement of a spot urine sample for albumin An active urinary sediment (containing
tients with albuminuria treated with
alone (whether by immunoassay or by using red or white blood cells or cellular casts),
an ACE inhibitor or an angiotensin re-
a sensitive dipstick test specific for albu- rapidly increasing albuminuria or nephrotic
ceptor blocker is reasonable to assess
minuria) without simultaneously measur- syndrome, rapidly decreasing eGFR, or the
the response to treatment and pro-
ing urine creatinine (Cr) is less expensive but absence of retinopathy (in type 1 diabe-
gression of diabetic kidney disease. E
susceptible to false-negative and false- tes) may suggest alternative or additional
c An ACE inhibitor or an angiotensin
positive determinations as a result of varia- causes of kidney disease. For patients
receptor blocker is not recom-
tion in urine concentration due to hydration. with these features, referral to a nephrol-
mended for the primary prevention
Normal UACR is generally defined ogist for further diagnosis, including the
of diabetic kidney disease in pa-
as ,30 mg/g Cr, and increased urinary possibility of kidney biopsy, should be
tients with diabetes who have nor-
albumin excretion is defined as $30 considered. It is rare for patients with
mal blood pressure, normal urinary
mg/g Cr. However, UACR is a continuous type 1 diabetes to develop kidney disease
albumin–to–creatinine ratio (,30
measurement, and differences within the without retinopathy. In type 2 diabetes,
mg/g creatinine), and normal esti-
normal and abnormal ranges are associ- retinopathy is only moderately sensitive
mated glomerular filtration rate. B
ated with renal and cardiovascular out- and specific for CKD caused by diabetes,
c When estimated glomerular filtration
comes (7–9). Furthermore, because of as confirmed by kidney biopsy (13).
rate is ,60 mL/min/1.73 m2, evalu-
biological variability in urinary albumin Stage 1–2 CKD has been defined by
ate and manage potential complica-
excretion, two of three specimens of evidence of kidney damage (usually albu-
tions of chronic kidney disease. E
UACR collected within a 3- to 6-month minuria) with eGFR $60 mL/min/1.73 m2,
c Patients should be referred for
period should be abnormal before con- while stages 3–5 CKD have been de-
evaluation for renal replacement
sidering a patient to have albuminuria. fined by progressively lower ranges of
treatment if they have an estimated
Exercise within 24 h, infection, fever, eGFR (14) (Table 10.1). More recently,
glomerular filtration rate ,30
congestive heart failure, marked hyper- Kidney Disease: Improving Global Out-
mL/min/1.73 m2. A
glycemia, menstruation, and marked comes (KDIGO) recommended a more
c Promptly refer to a physician expe-
hypertension may elevate UACR inde- comprehensive CKD staging that incor-
rienced in the care of kidney disease
for uncertainty about the etiology of pendently of kidney damage. porates albuminuria and is more closely
kidney disease, difficult management eGFR should be calculated from serum associated with risks of cardiovascular
Cr using a validated formula. The Chronic disease (CVD) and CKD progression (2).
issues, and rapidly progressing kidney
disease. B Kidney Disease Epidemiology Collabora- It has not been determined whether ap-
tion (CKD-EPI) equation is generally pre- plication of the more complex system aids
Epidemiology of Diabetic Kidney ferred (2). eGFR is routinely reported by clinical care or improves health outcomes.
Disease laboratories with serum Cr, and eGFR cal-
Chronic kidney disease (CKD) is diagnosed culators are available from http://www Acute Kidney Injury
by the persistent presence of elevated An eGFR ,60 mL/min/ Acute kidney injury (AKI) is usually diag-
urinary albumin excretion (albuminuria), 1.73 m2 is generally considered abnormal, nosed by a rapid increase in serum Cr,
low estimated glomerular filtration rate though optimal thresholds for clinical di- which is also reflected as a rapid decrease
(eGFR), or other manifestations of kidney agnosis are debated (10). in eGFR, over a relatively short period of
damage (1,2). Diabetic kidney disease, or Urinary albumin excretion and eGFR time. People with diabetes are at higher
CKD attributed to diabetes, occurs in 20– each vary within people over time, and risk of AKI than those without diabetes
40% of patients with diabetes (1,3–5). Di- abnormal results should be confirmed to (15). Other risk factors for AKI include
abetic kidney disease typically develops stage CKD (1,2). preexisting CKD, the use of medications
after diabetes duration of 10 years in that cause kidney injury (e.g., nonsteroi-
type 1 diabetes, but may be present at Diagnosis of Diabetic Kidney Disease dal anti-inflammatory drugs), and the use
diagnosis of type 2 diabetes. Diabetic kid- Diabetic kidney disease is usually a clinical of medications that alter renal blood flow
ney disease can progress to end-stage re- diagnosis made based on the presence of and intrarenal hemodynamics. In particu-
nal disease (ESRD) requiring dialysis or albuminuria and/or reduced eGFR in the lar, many antihypertensive medications
kidney transplantation and is the leading absence of signs or symptoms of other (e.g., diuretics, ACE inhibitors, and angio-
cause of ESRD in the United States (6). In primary causes of kidney damage. The typ- tensin receptor blockers [ARBs]) can re-
addition, among people with type 1 or ical presentation of diabetic kidney disease duce intravascular volume, renal blood
2 diabetes, the presence of CKD markedly is considered to include a long-standing flow, and/or glomerular filtration. There
increases cardiovascular risk (7). duration of diabetes, retinopathy, albumin- is a concern that sodium–glucose cotrans-
uria without hematuria, and gradually pro- porter 2 (SGLT2) inhibitors may promote
Assessment of Albuminuria and gressive kidney disease. However, signs of AKI through volume depletion, particu-
Estimated Glomerular Filtration Rate CKD may be present at diagnosis or without larly when combined with diuretics or
Screening for albuminuria can be most retinopathy in type 2 diabetes, and reduced other medications that reduce glomeru-
easily performed by urinary albumin–to– eGFR without albuminuria has been fre- lar filtration. However, existing evidence
creatinine ratio (UACR) in a random spot quently reported in type 1 and type 2 di- from clinical trials and observational stud-
urine collection (1,2). Timed or 24-h abetes and is becoming more common ies suggests that SGLT2 inhibitors do not Microvascular Complications and Foot Care S107

Table 10.1—CKD stages and corresponding focus of kidney-related care
CKD stage† Focus of kidney-related care
Evidence of Diagnose Evaluate and treat Evaluate and
eGFR kidney cause of risk factors for CKD treat CKD Prepare for renal
Stage (mL/min/1.73 m2) damage* kidney injury progression** complications*** replacement therapy
No clinical
evidence of
CKD $60 d
1 $90 1 ! !
2 60–89 1 ! !
3 30–59 1/2 ! ! !
4 15–29 1/2 ! ! !
5 ,15 1/2 ! !
†CKD stages 1 and 2 are defined by evidence of kidney damage (1), while CKD stages 3–5 are defined by reduced eGFR with or without evidence of kidney
damage (1/2). *Kidney damage is most often manifest as albuminuria (UACR $30 mg/g Cr) but can also include glomerular hematuria, other
abnormalities of the urinary sediment, radiographic abnormalities, and other presentations. **Risk factors for CKD progression include elevated blood
pressure, glycemia, and albuminuria. ***See Table 10.2.

significantly increase AKI (16,17). Timely to therapy and disease progression and Comorbidities” for further information
identification and treatment of AKI are may aid in assessing adherence to ACE in- on immunization).
important because AKI is associated hibitor or ARB therapy. In addition, in clin- Interventions
with increased risks of progressive CKD ical trials of ACE inhibitors or ARB therapy Nutrition
and other poor health outcomes (18). in type 2 diabetes, reducing albuminuria For people with nondialysis-dependent di-
from levels $300 mg/g Cr has been asso- abetic kidney disease, dietary protein intake
Surveillance ciated with improved renal and cardiovas- should be approximately 0.8 g/kg body
Albuminuria and eGFR should be moni- cular outcomes, leading some to suggest weight per day (the recommended daily al-
tored regularly to enable timely diagnosis that medications should be titrated to min- lowance) (1). Compared with higher levels
of diabetic kidney disease, monitor pro- imize UACR. However, this approach has of dietary protein intake, this level slowed
gression of diabetic kidney disease, not been formally evaluated in prospec- GFR decline with evidence of a greater ef-
detect superimposed kidney diseases in- tive trials. In type 1 diabetes, remission of fect over time. Higher levels of dietary pro-
cluding AKI, assess risk of CKD compli- albuminuria may occur spontaneously tein intake (.20% of daily calories from
cations, dose drugs appropriately, and and cohort studies evaluating associa- protein or .1.3 g/kg/day) have been as-
determine whether nephrology referral tions of change in albuminuria with clini- sociated with increased albuminuria, more
is needed. Among people with existing cal outcomes have reported inconsistent rapid kidney function loss, and CVD mor-
kidney disease, albuminuria and eGFR results (22,23). tality and therefore should be avoided.
may change due to progression of dia- The prevalence of CKD complications Reducing the amount of dietary protein
betic kidney disease, development of a correlates with eGFR. When eGFR is below the recommended daily allowance
separate superimposed cause of kidney
,60 mL/min/1.73 m2, screening for com- of 0.8 g/kg/day is not recommended be-
disease, AKI, or other effects of medica-
plications of CKD is indicated (Table 10.2). cause it does not alter glycemic measures,
tions, as noted above. Serum potassium
Early vaccination against hepatitis B virus cardiovascular risk measures, or the
should also be monitored for patients
is indicated in patients likely to progress course of GFR decline. In dialysis, protein-
treated with ACE inhibitors, ARBs, and di-
to ESRD (see Section 3 “Comprehensive energy wasting is common, and in-
uretics because these medications can
Medical Evaluation and Assessment of creased dietary protein intake may be
cause hyperkalemia or hypokalemia,
which are associated with cardiovascular
risk and mortality (19–21). For patients Table 10.2—Selected complications of CKD
with eGFR ,60 mL/min/1.73 m2, appro- Complication Medical and laboratory evaluation
priate medication dosing should be veri- Elevated blood pressure Blood pressure, weight
fied, exposure to nephrotoxins (e.g., Volume overload History, physical examination, weight
nonsteroidal anti-inflammatory drugs Electrolyte abnormalities Serum electrolytes
and iodinated contrast) should be mini- Metabolic acidosis Serum electrolytes
mized, and potential CKD complications Anemia Hemoglobin; iron testing if indicated
should be evaluated. Metabolic bone disease Serum calcium, phosphate, PTH, vitamin 25(OH)D
The need for annual quantitative assess-
Complications of CKD generally become prevalent when eGFR falls below 60 mL/min/1.73 m2 (stage
ment of albumin excretion after diagnosis 3 CKD or greater) and become more common and severe as CKD progresses. Evaluation of elevated
of albuminuria, institution of ACE inhibitors blood pressure and volume overload should occur at every possible clinical contact; laboratory
or ARB therapy, and achieving blood pres- evaluations are generally indicated every 6–12 months for stage 3 CKD, every 3–5 months for stage
sure control is a subject of debate. Contin- 4 CKD, and every 1–3 months for stage 5 CKD, or as indicated to evaluate symptoms or changes in
therapy. PTH, parathyroid hormone; 25(OH)D, 25-hydroxyvitamin D.
ued surveillance can assess both response
S108 Microvascular Complications and Foot Care Diabetes Care Volume 41, Supplement 1, January 2018

necessary to help preserve muscle mass tubular glucose reabsorption, weight, sys- Disease and Risk Management” for fur-
and function. temic blood pressure, intraglomerular ther discussion). All of these trials included
For some patients with diabetes, restric- pressure, and albuminuria and slow GFR large numbers of people with kidney dis-
tion of dietary sodium may be useful to loss through mechanisms that appear ease (for example, the baseline prevalence
control blood pressure and reduce cardio- independent of glycemia (17,38–40). of albuminuria in EMPA-REG OUTCOME
vascular risk (24), and restriction of dietary Glucagon-like peptide 1 receptor agonists was 53%), and some of the cardiovascular
potassium may be necessary to control and dipeptidyl peptidase 4 inhibitors also outcomes trials (CANVAS and LEADER)
serum potassium concentration (15,19– have direct effects on the kidney and have were enriched with patients with kidney
21). These interventions may be most im- been reported to improve renal outcomes disease through eligibility criteria based on
portant for patients with reduced eGFR, compared with placebo (41–44). albuminuria or reduced eGFR. The glucose-
for whom urinary excretion of sodium and A number of large cardiovascular out- lowering effects of SGLT2 inhibitors are
potassium may be impaired. Recommen- comes trials in patients with type 2 diabetes blunted with eGFR (17,45). However, the
dations for dietary sodium and potassium at high risk for cardiovascular disease or with cardiovascular benefits of empagliflozin,
intake should be individualized on the basis existing cardiovascular disease (EMPA-REG canagliflozin, and liraglutide were similar
of comorbid conditions, medication use, OUTCOME [BI 10773 (Empagliflozin) Car- among participants with and without kid-
blood pressure, and laboratory data. diovascular Outcome Event Trial in Type 2 ney disease at baseline (40,41,45,46).
Diabetes Mellitus Patients], CANVAS With reduced eGFR, drug dosing may
[Canagliflozin Cardiovascular Assessment require modification (1). The U.S. Food
Intensive glycemic control with the goal
Study], LEADER [Liraglutide Effect and and Drug Administration (FDA) revised
of achieving near-normoglycemia has been
Action in Diabetes: Evaluation of Cardio- guidance for the use metformin in dia-
shown in large prospective randomized
vascular Outcome ResultsdA Long Term betic kidney disease in 2016 (47), recom-
studies to delay the onset and progression
Evaluation], and SUSTAIN-6 [Trial to Eval- mending use of eGFR instead of serum Cr
of albuminuria and reduced eGFR in patients
uate Cardiovascular and Other Long-term to guide treatment and expanding the
with type 1 diabetes (25,26) and type 2 di-
Outcomes With Semaglutide in Subjects With pool of patients with kidney disease for
abetes (1,27–32). Insulin alone was used
Type 2 Diabetes]) examined kidney effects whom metformin treatment should be
to lower blood glucose in the Diabetes
as secondary outcomes (40,41,44,45). considered. Revised FDA guidance states
Control and Complications Trial (DCCT)/
Specifically, compared with placebo, that metformin is contraindicated in patients
Epidemiology of Diabetes Interventions
empagliflozin reduced the risk of incident with an eGFR ,30 mL/min/ 1.73 m2, eGFR
and Complications (EDIC) study of type 1
or worsening nephropathy (a composite of should be monitored while taking metfor-
diabetes, while a variety of agents were
progression to UACR .300 mg/g Cr, dou- min, the benefits and risks of continuing
used in clinical trials of type 2 diabetes,
bling of serum Cr, ESRD, or death from treatment should be reassessed when
supporting the conclusion that glycemic
ESRD) by 39% and the risk of doubling of eGFR falls ,45 mL/min/1.73 m2, metfor-
control itself helps prevent diabetic kidney
serum Cr accompanied by eGFR #45 mL/ min should not be initiated for patients
disease and its progression. The effects of
min/1.73 m2 by 44%; canagliflozin reduced with an eGFR ,45 mL/min/1.73 m2, and
glucose-lowering therapies on diabetic
the risk of progression of albuminuria by metformin should be temporarily discon-
kidney disease have helped define A1C
27% and the risk of reduction in eGFR, tinued at the time of or before iodinated
targets (see Table 6.2).
ESRD, or death from ESRD by 40%; liraglu- contrast imaging procedures in patients
The presence of diabetic kidney dis-
tide reduced the risk of new or worsening with eGFR 30–60 mL/min/ 1.73 m2. Other
ease affects the risks and benefits of in-
nephropathy (a composite of persistent glucose-lowering medications also re-
tensive glycemic control and a number of
UACR .300 mg/g Cr, doubling of serum quire dose adjustment or discontinuation
specific glucose-lowering medications. In
Cr, ESRD, or death from ESRD) by 22%; and at low eGFR (see Table 8.2) (1).
the Action to Control Cardiovascular Risk
semaglutide reduced the risk of new or
in Diabetes (ACCORD) trial of type 2 di-
worsening nephropathy (a composite of Cardiovascular Disease and Blood Pressure
abetes, adverse effects of intensive glyce-
persistent UACR .300 mg/g Cr, doubling Hypertension is a strong risk factor for the
mic control (hypoglycemia and mortality)
of serum Cr, or ESRD) by 36% (each P , development and progression of diabetic
were increased among patients with
0.01). Additional trials with primary kid- kidney disease (48). Antihypertensive ther-
kidney disease at baseline (33,34). More-
ney outcomes are needed to definitively apy reduces the risk of albuminuria (49–
over, there is a lag time of at least 2 years
determine whether specific glucose-low- 52), and among patients with type 1 or
in type 2 diabetes to over 10 years in type 1
ering drugs improve renal outcomes. 2 diabetes with established diabetic kid-
diabetes for the effects of intensive glucose
Patients with diabetic kidney disease ney disease (eGFR ,60 mL/min/1.73 m2
control to manifest as improved eGFR out-
are at high risk of cardiovascular events, and UACR $300 mg/g Cr), ACE inhibitor
comes (31,35,36). Therefore, in some pa-
and some SGLT2 inhibitors and glucagon- or ARB therapy reduces the risk of pro-
tients with prevalent diabetic kidney
like peptide 1 receptor agonists have gression to ESRD (53–55). Moreover, an-
disease and substantial comorbidity, target
demonstrated cardiovascular benefits. tihypertensive therapy reduces risks of
A1C levels may be less intensive (1,37).
Namely, in EMPA-REG OUTCOME, CANVAS, cardiovascular events (49).
Specific Glucose-Lowering Medications and LEADER, empagliflozin, canagliflozin, Blood pressure levels ,140/90 mmHg
Some glucose-lowering medications also and liraglutide, respectively, each re- are generally recommended to reduce
have effects on the kidney that are direct, duced cardiovascular events, evaluated CVD mortality and slow CKD progression
i.e., not mediated through glycemia. For as primary outcomes, compared with among people with diabetes (52). Lower
example, SGLT2 inhibitors reduce renal placebo (see Section 9 “Cardiovascular blood pressure targets (e.g., ,130/80 Microvascular Complications and Foot Care S109

mmHg) may be considered for patients are effective for management of resistant
c If there is no evidence of retinopathy
based on individual anticipated benefits hypertension, have been shown to reduce
for one or more annual eye exam and
and risks. Patients with diabetic kidney dis- albuminuria in short-term studies of dia-
glycemia is well controlled, then
ease are at increased risk of CKD progression betic kidney disease, and may have addi-
exams every 1–2 years may be con-
(particularly those with albuminuria) and tional cardiovascular benefits (65–67).
sidered. If any level of diabetic ret-
CVD and therefore may be suitable in There has been, however, an increase in
inopathy is present, subsequent
some cases for lower blood pressure targets. hyperkalemic episodes in those on dual
dilated retinal examinations should
ACE inhibitors or ARBs are the pre- therapy, and larger, longer trials with clin-
be repeated at least annually by an
ferred first-line agent for blood pressure ical outcomes are needed before recom-
ophthalmologist or optometrist. If
treatment among patients with diabetes, mending such therapy.
retinopathy is progressing or sight-
hypertension, eGFR ,60 mL/min/1.73 m2, Referral to a Nephrologist threatening, then examinations will
and UACR $300 mg/g Cr because of their Consider referral to a physician expe- be required more frequently. B
proven benefits for prevention of CKD rienced in the care of kidney disease c While retinal photography may
progression (53–56). In general, ACE inhibi- when there is uncertainty about the eti- serve as a screening tool for reti-
tors and ARBs are considered to have similar ology of kidney disease, difficult man- nopathy, it is not a substitute for a
benefits (57,58) and risks. In the setting of agement issues (anemia, secondary comprehensive eye exam. E
lower levels of albuminuria (30–299 mg/g hyperparathyroidism, metabolic bone c Women with preexisting type 1 or
Cr), ACE inhibitor or ARB therapy has been disease, resistant hypertension, or elec- type 2 diabetes who are planning
demonstrated to reduce progression to trolyte disturbances), or advanced kidney pregnancy or who are pregnant
more advanced albuminuria ($300 mg/g disease (eGFR ,30 mL/min/1.73 m2) re- should be counseled on the risk of
Cr) and cardiovascular events but not pro- quiring discussion of renal replacement development and/or progression of
gression to ESRD (56,59). While ACE inhib- therapy for ESRD. The threshold for re- diabetic retinopathy. B
itors or ARBs are often prescribed for ferral may vary depending on the fre- c Eye examinations should occur be-
albuminuria without hypertension, clini- quency with which a provider encounters fore pregnancy or in the first trimes-
cal trials have not been performed in patients with diabetes and kidney dis- ter in patients with preexisting
this setting to determine whether this im- ease. Consultation with a nephrologist type 1 or type 2 diabetes, and then
proves renal outcomes. when stage 4 CKD develops (eGFR #30 patients should be monitored every
Absent kidney disease, ACE inhibitors mL/min/1.73 m2) has been found to re- trimester and for 1 year postpartum
or ARBs are useful to control blood pres- duce cost, improve quality of care, and as indicated by the degree of reti-
sure but may not be superior to alterna- delay dialysis (68). However, other spe- nopathy. B
tive proven classes of antihypertensive cialists and providers should also educate
therapy, including thiazide-like diuretics their patients about the progressive na- Treatment
and dihydropyridine calcium channel ture of diabetic kidney disease, the kidney c Promptly refer patients with any
blockers (60). In a trial of people with preservation benefits of proactive treat- level of macular edema, severe
type 2 diabetes and normal urine albumin ment of blood pressure and blood glu- nonproliferative diabetic retinopa-
excretion, an ARB reduced or suppressed cose, and the potential need for renal thy (a precursor of proliferative
the development of albuminuria but in- replacement therapy. diabetic retinopathy), or any prolif-
creased the rate of cardiovascular events
erative diabetic retinopathy to an
(61). In a trial of people with type 1 di- DIABETIC RETINOPATHY ophthalmologist who is knowledge-
abetes exhibiting neither albuminuria nor
Recommendations able and experienced in the man-
hypertension, ACE inhibitors or ARBs did
c Optimize glycemic control to re- agement of diabetic retinopathy. A
not prevent the development of diabetic
duce the risk or slow the progres- c The traditional standard treatment,
glomerulopathy assessed by kidney bi-
opsy (62). Therefore, ACE inhibitors or sion of diabetic retinopathy. A panretinal laser photocoagulation
c Optimize blood pressure and serum therapy, is indicated to reduce the
ARBs are not recommended for patients
lipid control to reduce the risk or risk of vision loss in patients with
without hypertension to prevent the de-
slow the progression of diabetic ret- high-risk proliferative diabetic retinop-
velopment of diabetic kidney disease.
Two clinical trials studied the combina- inopathy. A athy and, in some cases, severe non-
proliferative diabetic retinopathy. A
tions of ACE inhibitors and ARBs and found
Screening c Intravitreous injections of anti–
no benefits on CVD or diabetic kidney dis-
c Adults with type 1 diabetes should vascular endothelial growth factor
ease, and the drug combination had higher
have an initial dilated and compre- ranibizumab are not inferior to tradi-
adverse event rates (hyperkalemia and/or
hensive eye examination by an oph- tional panretinal laser photocoagula-
AKI) (63,64). Therefore, the combined use
thalmologist or optometrist within tion and are also indicated to reduce
of ACE inhibitors and ARBs should be
5 years after the onset of diabetes. B the risk of vision loss in patients with
c Patients with type 2 diabetes should proliferative diabetic retinopathy. A
Mineralocorticoid receptor antagonists
have an initial dilated and compre- c Intravitreous injections of anti–
(spironolactone, eplerenone, and finere-
hensive eye examination by an oph- vascular endothelial growth factor
none) in combination with ACE inhibitors
thalmologist or optometrist at the are indicated for central-involved di-
or ARBs remain an area of great interest.
time of the diabetes diagnosis. B abetic macular edema, which occurs
Mineralocorticoid receptor antagonists
S110 Microvascular Complications and Foot Care Diabetes Care Volume 41, Supplement 1, January 2018

in diagnosing diabetic retinopathy should diagnosis should have an initial dilated
beneath the foveal center and may
perform the examinations. Youth with and comprehensive eye examination at
threaten reading vision. A
type 1 or type 2 diabetes are also at the time of diagnosis.
c The presence of retinopathy is not a
risk for complications and need to be
contraindication to aspirin therapy Pregnancy
screened for diabetic retinopathy (80). If
for cardioprotection, as aspirin does Pregnancy is associated with a rapid pro-
diabetic retinopathy is present, prompt
not increase the risk of retinal hem- gression of diabetic retinopathy (87,88).
referral to an ophthalmologist is recom-
orrhage. A Women with preexisting type 1 or type 2
mended. Subsequent examinations for
diabetes who are planning pregnancy or
patients with type 1 or type 2 diabetes
Diabetic retinopathy is a highly specific who have become pregnant should be
are generally repeated annually for pa-
vascular complication of both type 1 and counseled on the risk of development
tients with minimal to no retinopathy. Ex-
type 2 diabetes, with prevalence strongly and/or progression of diabetic retinopa-
ams every 1–2 years may be cost-effective
related to both the duration of diabetes thy. In addition, rapid implementation of
after one or more normal eye exams,
and the level of glycemic control (69). Di- intensive glycemic management in the
and in a population with well-controlled
abetic retinopathy is the most frequent setting of retinopathy is associated with
type 2 diabetes, there was essentially no
cause of new cases of blindness among early worsening of retinopathy (79). Women
risk of development of significant retinop-
adults aged 20–74 years in developed who develop gestational diabetes melli-
athy with a 3-year interval after a normal
countries. Glaucoma, cataracts, and other tus do not require eye examinations dur-
examination (81). Less frequent intervals
disorders of the eye occur earlier and ing pregnancy and do not appear to be at
have been found in simulated modeling
more frequently in people with diabetes. increased risk of developing diabetic ret-
to be potentially effective in screening for
In addition to diabetes duration, factors inopathy during pregnancy (89).
diabetic retinopathy in patients without
that increase the risk of, or are associated
diabetic retinopathy (82). More frequent
with, retinopathy include chronic hypergly- Treatment
examinations by the ophthalmologist will Two of the main motivations for screen-
cemia (70), diabetic kidney disease (71),
be required if retinopathy is progressing. ing for diabetic retinopathy are to prevent
hypertension (72), and dyslipidemia (73).
Retinal photography with remote read- loss of vision and to intervene with treat-
Intensive diabetes management with the
ing by experts has great potential to pro- ment when vision loss can be prevented
goal of achieving near-normoglycemia
vide screening services in areas where or reversed.
has been shown in large prospective ran-
qualified eye care professionals are not
domized studies to prevent and/or delay Photocoagulation Surgery
readily available (83,84). High-quality fun-
the onset and progression of diabetic ret- Two large trials, the Diabetic Retinopathy
dus photographs can detect most clinically
inopathy and potentially improve patient- Study (DRS) in patients with PDR and the
significant diabetic retinopathy. Interpreta-
reported visual function (28,74–76). Early Treatment Diabetic Retinopathy
tion of the images should be performed
Lowering blood pressure has been Study (ETDRS) in patients with macular
by a trained eye care provider. Retinal pho-
shown to decrease retinopathy progres- edema, provide the strongest support
tography may also enhance efficiency and
sion, although tight targets (systolic blood for the therapeutic benefits of photoco-
reduce costs when the expertise of ophthal-
pressure ,120 mmHg) do not impart ad- agulation surgery. The DRS (90) showed in
mologists can be used for more complex
ditional benefit (75). ACE inhibitors and 1978 that panretinal photocoagulation
examinations and for therapy (85). In-person
ARBs are both effective treatments in di- surgery reduced the risk of severe vision
exams are still necessary when the retinal
abetic retinopathy (77). In patients with loss from PDR from 15.9% in untreated eyes
photos are of unacceptable quality and for
dyslipidemia, retinopathy progression to 6.4% in treated eyes with the greatest
follow-up if abnormalities are detected. Ret-
may be slowed by the addition of fenofi- benefit ratio in those with more advanced
inal photos are not a substitute for compre-
brate, particularly with very mild nonpro- baseline disease (disc neovascularization
hensive eye exams, which should be
liferative diabetic retinopathy (NPDR) at or vitreous hemorrhage). In 1985, the
performed at least initially and at intervals
baseline (73). Several case series and a ETDRS also verified the benefits of panreti-
thereafter as recommended by an eye care
controlled prospective study suggest nal photocoagulation for high-risk PDR
professional. Results of eye examinations
that pregnancy in patients with type 1 di- and in older-onset patients with severe
should be documented and transmitted
abetes may aggravate retinopathy and NPDR or less-than-high-risk PDR. Panreti-
to the referring health care professional.
threaten vision, especially when glycemic nal laser photocoagulation is still com-
control is poor at the time of conception Type 1 Diabetes
monly used to manage complications of
(78,79). Laser photocoagulation surgery Because retinopathy is estimated to take diabetic retinopathy that involve retinal
can minimize the risk of vision loss (79). at least 5 years to develop after the onset neovascularization and its complications.
of hyperglycemia, patients with type 1 di-
Screening Anti–Vascular Endothelial Growth Factor
abetes should have an initial dilated and
The preventive effects of therapy and Treatment
comprehensive eye examination within
the fact that patients with proliferative Recent data from the Diabetic Retinopa-
5 years after the diagnosis of diabetes (86).
diabetic retinopathy (PDR) or macular thy Clinical Research Network and others
edema may be asymptomatic provide Type 2 Diabetes demonstrate that intravitreal injections
strong support for screening to detect di- Patients with type 2 diabetes who may of anti–vascular endothelial growth fac-
abetic retinopathy. have had years of undiagnosed diabe- tor (anti-VEGF) agent, specifically ranibi-
An ophthalmologist or optometrist tes and have a significant risk of preva- zumab, resulted in visual acuity outcomes
who is knowledgeable and experienced lent diabetic retinopathy at the time of that were not inferior to those observed Microvascular Complications and Foot Care S111

in patients treated with panretinal laser at control can effectively prevent DPN and
starting at diagnosis of type 2 di-
2 years of follow-up (91). In addition, it was cardiac autonomic neuropathy (CAN) in
abetes and 5 years after the di-
observed that patients treated with ranibi- type 1 diabetes (97,98) and may modestly
agnosis of type 1 diabetes and at
zumab tended to have less peripheral visual slow their progression in type 2 diabetes
least annually thereafter. B
field loss, fewer vitrectomy surgeries for sec- (30), but does not reverse neuronal loss.
c Assessment for distal symmetric poly-
ondary complications from their prolifera- Therapeutic strategies (pharmacologic
neuropathy should include a careful
tive disease, and a lower risk of developing and nonpharmacologic) for the relief of
history and assessment of either tem-
diabetic macular edema. However, a po- painful DPN and symptoms of autonomic
perature or pinprick sensation (small-
tential drawback in using anti-VEGF ther- neuropathy can potentially reduce pain
fiber function) and vibration sensation
apy to manage proliferative disease is that (99) and improve quality of life.
using a 128-Hz tuning fork (for large-
patients were required to have a greater
fiber function). All patients should
number of visits and received a greater
have annual 10-g monofilament test- Diagnosis
number of treatments than is typically re-
ing to identify feet at risk for ulcera- Diabetic Peripheral Neuropathy
quired for management with panretinal la-
tion and amputation. B Patients with type 1 diabetes for 5 or
ser, which may not be optimal for some
c Symptoms and signs of autonomic more years and all patients with type 2
patients. Other emerging therapies for ret-
neuropathy should be assessed in diabetes should be assessed annually for
inopathy that may use sustained intravitreal
patients with microvascular compli- DPN using the medical history and simple
delivery of pharmacologic agents are cur-
cations. E clinical tests. Symptoms vary according to
rently under investigation. In April, the
FDA approved ranibizumab for the treat- the class of sensory fibers involved. The
ment of diabetic retinopathy. most common early symptoms are in-
c Optimize glucose control to prevent
While the ETDRS (92) established the duced by the involvement of small fibers
or delay the development of neu-
benefit of focal laser photocoagulation ropathy in patients with type 1 and include pain and dysesthesias (un-
surgery in eyes with clinically significant diabetes A and to slow the pro- pleasant sensations of burning and tin-
macular edema (defined as retinal edema gression of neuropathy in patients gling). The involvement of large fibers
located at or within 500 mm of the center with type 2 diabetes. B may cause numbness and loss of protec-
of the macula), current data from well- c Assess and treat patients to reduce tive sensation (LOPS). LOPS indicates the
designed clinical trials demonstrate that pain related to diabetic peripheral presence of distal sensorimotor poly-
intravitreal anti-VEGF agents provide a neuropathy B and symptoms of au- neuropathy and is a risk factor for di-
more effective treatment regimen for tonomic neuropathy and to im- abetic foot ulceration. The following
central-involved diabetic macular edema prove quality of life. E clinical tests may be used to assess small-
than monotherapy or even combination c Either pregabalin or duloxetine are and large-fiber function and protective
therapy with laser (93–95). There are cur- recommended as initial pharmaco- sensation:
rently three anti-VEGF agents commonly logic treatments for neuropathic pain
used to treat eyes with central-involved in diabetes. A 1. Small-fiber function: pinprick and tem-
diabetic macular edemadbevacizumab, perature sensation
ranibizumab, and aflibercept (69). The diabetic neuropathies are a heteroge- 2. Large-fiber function: vibration percep-
In both DRS and ETDRS, laser photoco- neous group of disorders with diverse clini- tion and 10-g monofilament
agulation surgery was beneficial in re- cal manifestations. The early recognition 3. Protective sensation: 10-g monofilament
ducing the risk of further visual loss in and appropriate management of neuropa-
affected patients, but generally not benefi- thy in the patient with diabetes is important. These tests not only screen for the pres-
cial in reversing already diminished acuity. ence of dysfunction but also predict
1. Diabetic neuropathy is a diagnosis of future risk of complications. Electrophys-
Anti-VEGF therapy improves vision and has
exclusion. Nondiabetic neuropathies iological testing or referral to a neurolo-
replaced the need for laser photocoagula-
may be present in patients with diabe- gist is rarely needed, except in situations
tion in the vast majority of patients with
tes and may be treatable. where the clinical features are atypical or
diabetic macular edema (96). Most pa-
2. Numerous treatment options exist for
tients require near-monthly administration the diagnosis is unclear.
symptomatic diabetic neuropathy.
of intravitreal therapy with anti-VEGF In all patients with diabetes and DPN,
3. Up to 50% of diabetic peripheral neu-
agents during the first 12 months of treat- ropathy (DPN) may be asymptomatic.
causes of neuropathy other than diabetes
ment, with fewer injections needed in sub- should be considered, including toxins
If not recognized and if preventive foot
sequent years to maintain remission from (alcohol), neurotoxic medications (che-
care is not implemented, patients are
central-involved diabetic macular edema. motherapy), vitamin B12 deficiency, hypo-
at risk for injuries to their insensate feet.
thyroidism, renal disease, malignancies
4. Recognition and treatment of autonomic
NEUROPATHY neuropathy may improve symptoms, re- (multiple myeloma, bronchogenic carci-
duce sequelae, and improve quality of noma), infections (HIV), chronic inflamma-
Recommendations tory demyelinating neuropathy, inherited
neuropathies, and vasculitis (100). See
Specific treatment for the underlying nerve American Diabetes Association position
c All patients should be assessed for
damage, other than improved glycemic statement “Diabetic Neuropathy” for
diabetic peripheral neuropathy
control, is currently not available. Glycemic more details (99).
S112 Microvascular Complications and Foot Care Diabetes Care Volume 41, Supplement 1, January 2018

Diabetic Autonomic Neuropathy and inadequate lubrication (103). Lower medication side effects is recommended
The symptoms and signs of autonomic urinary tract symptoms manifest as uri- to achieve pain reduction and improve
neuropathy should be elicited carefully nary incontinence and bladder dysfunction quality of life (113–115).
during the history and physical examination. (nocturia, frequent urination, urination ur- Pregabalin, a calcium channel a2-d
Major clinical manifestations of diabetic au- gency, and weak urinary stream). Evaluation subunit ligand, is the most extensively
tonomic neuropathy include hypoglycemia of bladder function should be performed for studied drug for DPN. The majority of
unawareness, resting tachycardia, ortho- individuals with diabetes who have recur- studies testing pregabalin have reported
static hypotension, gastroparesis, constipa- rent urinary tract infections, pyelonephritis, favorable effects on the proportion of
tion, diarrhea, fecal incontinence, erectile incontinence, or a palpable bladder. participants with at least 30–50% im-
dysfunction, neurogenic bladder, and sudo- provement in pain (112,114,116–119).
motor dysfunction with either increased or Treatment However, not all trials with pregabalin
decreased sweating. Glycemic Control have been positive (112,114,120,121), es-
Cardiac Autonomic Neuropathy. CAN is as- Near-normal glycemic control, imple- pecially when treating patients with ad-
sociated with mortality independently of mented early in the course of diabetes, vanced refractory DPN (118). Adverse
other cardiovascular risk factors (101,102). has been shown to effectively delay or effects may be more severe in older pa-
In its early stages, CAN may be completely prevent the development of DPN and tients (122) and may be attenuated by
asymptomatic and detected only by de- CAN in patients with type 1 diabetes lower starting doses and more gradual
creased heart rate variability with deep (104–107). Although the evidence for titration.
breathing. Advanced disease may be the benefit of near-normal glycemic con- Duloxetine is a selective norepineph-
associated with resting tachycardia trol is not as strong for type 2 diabetes, rine and serotonin reuptake inhibitor.
(.100 bpm) and orthostatic hypotension some studies have demonstrated a mod- Doses of 60 and 120 mg/day showed
(a fall in systolic or diastolic blood pres- est slowing of progression without re- efficacy in the treatment of pain associ-
sure by .20 mmHg or .10 mmHg, re- versal of neuronal loss (30,108). Specific ated with DPN in multicenter random-
spectively, upon standing without an glucose-lowering strategies may have dif- ized trials, although some of these had
appropriate increase in heart rate). CAN ferent effects. In a post hoc analysis, par- high drop-out rates (112,114,119,121).
treatment is generally focused on allevi- ticipants, particularly men, in the Bypass Duloxetine also appeared to improve
ating symptoms. Angioplasty Revascularization Investi- neuropathy-related quality of life (123).
Gastrointestinal Neuropathies. Gastrointes- gation in Type 2 Diabetes (BARI 2D) trial In longer-term studies, a small increase
tinal neuropathies may involve any por- treated with insulin sensitizers had a in A1C was reported in people with dia-
tion of the gastrointestinal tract with lower incidence of distal symmetric pol- betes treated with duloxetine compared
manifestations including esophageal yneuropathy over 4 years than those with placebo (124). Adverse events may
dysmotility, gastroparesis, constipation, treated with insulin/sulfonylurea (109). be more severe in older people, but may
diarrhea, and fecal incontinence. Gastro- Neuropathic Pain be attenuated with lower doses and
paresis should be suspected in individuals Neuropathic pain can be severe and can slower titrations of duloxetine.
with erratic glycemic control or with up- impact quality of life, limit mobility, and Tapentadol is a centrally acting opioid
per gastrointestinal symptoms without contribute to depression and social dys- analgesic that exerts its analgesic effects
another identified cause. Exclusion of or- function (110). No compelling evidence through both m-opioid receptor agonism
ganic causes of gastric outlet obstruction exists in support of glycemic control or and noradrenaline reuptake inhibition.
or peptic ulcer disease (with esophago- lifestyle management as therapies for Extended-release tapentadol was ap-
gastroduodenoscopy or a barium study neuropathic pain in diabetes or prediabe- proved by the FDA for the treatment of
of the stomach) is needed before consider- tes, which leaves only pharmaceutical in- neuropathic pain associated with diabe-
ing a diagnosis of or specialized testing for terventions (111). tes based on data from two multicenter
gastroparesis. The diagnostic gold standard Pregabalin and duloxetine have re- clinical trials in which participants ti-
for gastroparesis is the measurement of ceived regulatory approval by the FDA, trated to an optimal dose of tapentadol
gastric emptying with scintigraphy of di- Health Canada, and the European Medi- were randomly assigned to continue
gestible solids at 15-min intervals for 4 h cines Agency for the treatment of neu- that dose or switch to placebo (125,126).
after food intake. The use of 13C octanoic ropathic pain in diabetes. The opioid However, both used a design enriched for
acid breath test is emerging as a viable tapentadol has regulatory approval in patients who responded to tapentadol
alternative. the U.S. and Canada, but the evidence and therefore their results are not gener-
Genitourinary Disturbances. Diabetic auto- of its use is weaker (112). Comparative alizable. A recent systematic review and
nomic neuropathy may also cause genito- effectiveness studies and trials that in- meta-analysis by the Special Interest
urinary disturbances, including sexual clude quality-of-life outcomes are rare, Group on Neuropathic Pain of the Inter-
dysfunction and bladder dysfunction. In so treatment decisions must consider national Association for the Study of Pain
men, diabetic autonomic neuropathy each patient’s presentation and comor- found the evidence supporting the effec-
may cause erectile dysfunction and/or bidities and often follow a trial-and-error tiveness of tapentadol in reducing neu-
retrograde ejaculation (99). Female sexual approach. Given the range of partially ef- ropathic pain to be inconclusive (112).
dysfunction occurs more frequently in fective treatment options, a tailored and Therefore, given the high risk for addic-
those with diabetes and presents as de- stepwise pharmacologic strategy with tion and safety concerns compared with
creased sexual desire, increased pain dur- careful attention to relative symptom im- the relatively modest pain reduction, the
ing intercourse, decreased sexual arousal, provement, medication adherence, and use of extended-release tapentadol is Microvascular Complications and Foot Care S113

not generally recommended as a first- intraurethral prostaglandins, vacuum de- Foot ulcers and amputation, which are
or second-line therapy. vices, or penile prostheses. As with DPN consequences of diabetic neuropathy
Tricyclic antidepressants, gabapentin, treatments, these interventions do not and/or peripheral arterial disease (PAD),
venlafaxine, carbamazepine, tramadol, change the underlying pathology and nat- are common and represent major causes
and topical capsaicin, although not ap- ural history of the disease process but of morbidity and mortality in people with
proved for the treatment of painful DPN, may improve the patient’s quality of life. diabetes. Early recognition and treatment
may be effective and considered for the of patients with diabetes and feet at risk
treatment of painful DPN (99,112,114). for ulcers and amputations can delay or
Orthostatic Hypotension Recommendations prevent adverse outcomes.
Treating orthostatic hypotension is chal- c Perform a comprehensive foot eval- The risk of ulcers or amputations is in-
lenging. The therapeutic goal is to mini- uation at least annually to identify creased in people who have the following
mize postural symptoms rather than to risk factors for ulcers and amputa- risk factors:
restore normotension. Most patients re- tions. B
quire both nonpharmacologic measures c All patients with diabetes should + Poor glycemic control
(e.g., ensuring adequate salt intake, avoid- have their feet inspected at every + Peripheral neuropathy with LOPS
ing medications that aggravate hypoten- visit. C + Cigarette smoking
sion, or using compressive garments over c Obtain a prior history of ulceration, + Foot deformities
the legs and abdomen) and pharmacologic amputation, Charcot foot, angio- + Preulcerative callus or corn
measures. Physical activity and exercise plasty or vascular surgery, cigarette + PAD
should be encouraged to avoid decondi- smoking, retinopathy, and renal dis- + History of foot ulcer
tioning, which is known to exacerbate or- ease and assess current symptoms + Amputation
thostatic intolerance, and volume repletion of neuropathy (pain, burning, numb- + Visual impairment
with fluids and salt is critical. Midodrine and ness) and vascular disease (leg fa- + Diabetic kidney disease (especially pa-
droxidopa are approved by the FDA for the tigue, claudication). B tients on dialysis)
treatment of orthostatic hypotension. c The examination should include in-
spection of the skin, assessment Clinicians are encouraged to review
Gastroparesis American Diabetes Association screening
Treatment for diabetic gastroparesis may of foot deformities, neurological
assessment (10-g monofilament recommendations for further details and
be very challenging. Dietary changes may practical descriptions of how to perform
be useful, such as eating multiple small testing with at least one other as-
sessment: pinprick, temperature, components of the comprehensive foot
meals and decreasing dietary fat and fiber examination (129).
intake. Withdrawing drugs with adverse vibration), and vascular assessment
effects on gastrointestinal motility includ- including pulses in the legs and
ing opioids, anticholinergics, tricyclic an- feet. B Evaluation for Loss of Protective
c Patients with symptoms of claudi- Sensation
tidepressants, glucagon-like peptide 1 All adults with diabetes should undergo a
receptor agonists, pramlintide, and pos- cation or decreased or absent pedal
pulses should be referred for ankle- comprehensive foot evaluation at least
sibly dipeptidyl peptidase 4 inhibitors, annually. Detailed foot assessments may
may also improve intestinal motility (127, brachial index and for further vas-
cular assessment as appropriate. C occur more frequently in patients with
128). In cases of severe gastroparesis, histories of ulcers or amputations, foot
pharmacologic interventions are needed. c A multidisciplinary approach is rec-
deformities, insensate feet, and PAD
Only metoclopramide, a prokinetic agent, ommended for individuals with foot
(130). Foot inspections should occur at
is approved by the FDA for the treatment ulcers and high-risk feet (e.g., dialysis
every visit in all patients with diabetes.
of gastroparesis. However, the level of patients and those with Charcot foot,
To assess risk, clinicians should ask about
evidence regarding the benefits of meto- prior ulcers, or amputation). B
history of foot ulcers or amputation, neu-
clopramide for the management of gas- c Refer patients who smoke or who
ropathic and peripheral vascular symp-
troparesis is weak, and given the risk for have histories of prior lower-extremity
toms, impaired vision, renal disease,
serious adverse effects (extrapyramidal complications, loss of protective sen-
tobacco use, and foot care practices. A
signs such as acute dystonic reactions, sation, structural abnormalities, or pe-
general inspection of skin integrity and
drug-induced parkinsonism, akathisia, ripheral arterial disease to foot care
musculoskeletal deformities should be
and tardive dyskinesia), its use in the treat- specialists for ongoing preventive
performed. Vascular assessment should
ment of gastroparesis beyond 5 days is no care and life-long surveillance. C
include inspection and palpation of pedal
longer recommended by the FDA or the c Provide general preventive foot
European Medicines Agency. It should be self-care education to all patients
The neurological exam performed as
reserved for severe cases that are unre- with diabetes. B
part of the foot examination is designed
sponsive to other therapies (128). c The use of specialized therapeutic
to identify LOPS rather than early neurop-
footwear is recommended for high-
Erectile Dysfunction athy. The 10-g monofilament is the most
risk patients with diabetes includ-
In addition to treatment of hypogonad- useful test to diagnose LOPS. Ideally, the
ing those with severe neuropathy,
ism if present, treatments for erectile 10-g monofilament test should be per-
foot deformities, or history of am-
dysfunction may include phosphodiester- formed with at least one other assess-
putation. B
ase type 5 inhibitors, intracorporeal or ment (pinprick, temperature or vibration
S114 Microvascular Complications and Foot Care Diabetes Care Volume 41, Supplement 1, January 2018

sensation using a 128-Hz tuning fork, or when patients with neuropathy present healing compared to comprehensive
ankle reflexes). Absent monofilament with the acute onset of a red, hot, swollen wound care in patients with chronic di-
sensation suggests LOPS, while at least foot or ankle, and Charcot neuroarthrop- abetic foot ulcers (138). A systematic re-
two normal tests (and no abnormal test) athy should be excluded. Early diagnosis view by the International Working Group
rules out LOPS. and treatment of Charcot neuroarthrop- on the Diabetic Foot of interventions
athy is the best way to prevent defor- to improve the healing of chronic dia-
Evaluation for Peripheral Arterial mities that increase the risk of ulceration betic foot ulcers concluded that analysis of
Disease and amputation. The routine prescription the evidence continues to present meth-
Initial screening for PAD should include a of therapeutic footwear is not generally odological challenges as randomized con-
history of decreased walking speed, leg recommended. However, patients should trolled studies remain few with a majority
fatigue, claudication, and an assessment be provided adequate information to aid being of poor quality (135). HBOT also
of the pedal pulses. Ankle-brachial index in selection of appropriate footwear. Gen- does not seem to have a significant effect
testing should be performed in patients eral footwear recommendations include a on health-related quality of life in patients
with symptoms or signs of PAD. broad and square toe box, laces with three with diabetic foot ulcers (139,140). A re-
or four eyes per side, padded tongue, qual- cent review concluded that the evidence
Patient Education
All patients with diabetes and particularly ity lightweight materials, and sufficient to date remains inconclusive regarding
those with high-risk foot conditions (his- size to accommodate a cushioned insole. the clinical and cost-effectiveness of
tory of ulcer or amputation, deformity, Use of custom therapeutic footwear can HBOT as an adjunctive treatment to stan-
LOPS, or PAD) and their families should help reduce the risk of future foot ulcers in dard wound care for diabetic foot ulcers
be provided general education about risk high-risk patients (130,132). (141). Results from the recently published
factors and appropriate management Most diabetic foot infections are poly- Dutch DAMOCLES (Does Applying More
(131). Patients at risk should understand microbial, with aerobic gram-positive Oxygen Cure Lower Extremity Sores?)
the implications of foot deformities, LOPS, cocci. staphylococci and streptococci are trial demonstrated that HBOT in patients
and PAD; the proper care of the foot, in- the most common causative organisms. with diabetes and ischemic wounds did
cluding nail and skin care; and the impor- Wounds without evidence of soft tissue not significantly improve complete
tance of foot monitoring on a daily basis. or bone infection do not require antibiotic wound healing and limb salvage (142).
Patients with LOPS should be educated on therapy. Empiric antibiotic therapy can be The Centers for Medicare & Medicaid Ser-
ways to substitute other sensory modalities narrowly targeted at gram-positive cocci vices currently covers HBOT for diabetic
(palpation or visual inspection using an un- in many patients with acute infections, but foot ulcers that have failed a standard
breakable mirror) for surveillance of early those at risk for infection with antibiotic- course of wound therapy when there
foot problems. resistant organisms or with chronic, previ- are no measurable signs of healing for
The selection of appropriate footwear ously treated, or severe infections require at least 30 consecutive days (143). HBOT
and footwear behaviors at home should broader-spectrum regimens and should be should be a topic of shared decision-
also be discussed. Patients’ understand- referred to specialized care centers (133). making before treatment is considered
ing of these issues and their physical abil- Foot ulcers and wound care may re- for selected patients with diabetic foot
ity to conduct proper foot surveillance quire care by a podiatrist, orthopedic or ulcers (143).
and care should be assessed. Patients vascular surgeon, or rehabilitation spe-
with visual difficulties, physical constraints cialist experienced in the management
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preventing movement, or cognitive prob- of individuals with diabetes (133). kidney disease: a report from an ADA Consensus
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appropriate responses will need other peo- agement of chronic kidney disease. Kidney Int
ple, such as family members, to assist with adjunctive treatment to enhance wound
Suppl 2013;3:1–150
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136). In a relatively high-quality double- manifestations of kidney disease among US adults
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Diabetes Care Volume 41, Supplement 1, January 2018 S119

American Diabetes Association
11. Older Adults: Standards of
Medical Care in Diabetesd2018
Diabetes Care 2018;41(Suppl. 1):S119–S125 |

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes”
includes 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, 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.
Readers who wish to comment on the Standards of Care are invited to do so at

c Consider the assessment of medical, psychological, functional, and social geriatric
domains in older adults to provide a framework to determine targets and ther-
apeutic approaches for diabetes management. C
c Screening for geriatric syndromes may be appropriate in older adults expe-
riencing limitations in their basic and instrumental activities of daily living as
they may affect diabetes self-management and be related to health-related
quality of life. C

Diabetes is an important health condition for the aging population; approximately one-
quarter of people over the age of 65 years have diabetes and one-half of older adults
have prediabetes (1), and this proportion is expected to increase rapidly in the coming
decades. Older individuals with diabetes have higher rates of premature death, func-
tional disability, accelerated muscle loss, and coexisting illnesses, such as hypertension,
coronary heart disease, and stroke, than those without diabetes. Older adults with
diabetes also are at greater risk than other older adults for several common geriatric
syndromes, such as polypharmacy, cognitive impairment, urinary incontinence, injuri-
ous falls, and persistent pain. These conditions may impact older adults’ diabetes self-
management abilities (2).
Screening for diabetes complications in older adults should be individualized and
periodically revisited, as the results of screening tests may impact therapeutic ap- Suggested citation: American Diabetes Associa-
proaches and targets (2–4). Older adults are at increased risk for depression and should tion. 11. Older adults: Standards of Medical Care in
therefore be screened and treated accordingly (5). Diabetes management may require Diabetesd2018. Diabetes Care 2018;41(Suppl. 1):
assessment of medical, psychological, functional, and social domains. This may S119–S125
provide a framework to determine targets and therapeutic approaches. Particular © 2017 by the American Diabetes Association.
attention should be paid to complications that can develop over short periods of Readers may use this article as long as the work
is properly cited, the use is educational and not
time and/or that would significantly impair functional status, such as visual and for profit, and the work is not altered. More infor-
lower-extremity complications. Please refer to the American Diabetes Association mation is available at http://www.diabetesjournals
(ADA) consensus report “Diabetes in Older Adults” for details (2). .org/content/license.
S120 Older Adults Diabetes Care Volume 41, Supplement 1, January 2018

NEUROCOGNITIVE FUNCTION Older adults with diabetes should be and, conversely, severe hypoglycemia
carefully screened and monitored for cog- has been linked to increased risk of de-
nitive impairment (2). Several organiza- mentia. Therefore, it is important to rou-
c Screening for early detection of
tions have released simple assessment tinely screen older adults for cognitive
mild cognitive impairment or de-
tools, such as the Mini-Mental State Ex- dysfunction and discuss findings with the
mentia and depression i