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TH E J O U R NAL O F C LI N ICA L A N D A PPLI ED R ESEA RC H A N D EDU CATI O N VOLUME 39 | SUPPLEMENT 1

WWW.DIABETES.ORG/DIABETESCARE JANUARY 2016

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A M E R I C A N D I A B E T E S A S S O C I AT I O N

STANDARDS OF
MEDICAL CARE
IN DIABETES—2016

ISSN 0149-5992
American Diabetes Association
Standards of
Medical Care in
Diabetesd2016
January 2016 Volume 39, 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
EDITOR IN CHIEF

William T. Cefalu, MD

ASSOCIATE EDITORS EDITORIAL BOARD

George Bakris, MD Nicola Abate, MD Rita Rastogi Kalyani, MD, MHS, FACP
Lawrence Blonde, MD, FACP Silva Arslanian, MD Rory J. McCrimmon, MBChB, MD, FRCP
Andrew J.M. Boulton, MD Angelo Avogaro, MD, PhD Harold David McIntyre, MD, FRACP
David D’Alessio, MD Ananda Basu, MD, FRCP Gianluca Perseghin, MD
Sherita Hill Golden, MD, MHS, FAHA John B. Buse, MD, PhD Anne L. Peters, MD
Mary de Groot, PhD Sonia Caprio, MD Jonathan Q. Purnell, MD
Eddie L. Greene, MD Robert Chilton, DO Peter Reaven, MD
Frank B. Hu, MD, MPH, PhD Kenneth Cusi, MD, FACP, FACE Helena Wachslicht Rodbard, MD
Derek LeRoith, MD, PhD Paresh Dandona, MD, PhD David J. Schneider, MD
Robert G. Moses, MD Stefano Del Prato, MD Elizabeth R. Seaquist, MD
Stephen Rich, PhD Dariush Elahi, PhD Norbert Stefan, MD
Matthew C. Riddle, MD Franco Folli, MD, PhD Jeff Unger, MD
Julio Rosenstock, MD Robert G. Frykberg, DPM, MPH Ram Weiss, MD, PhD
William V. Tamborlane, MD W. Timothy Garvey, MD Deborah J. Wexler, MD, MSc
Katie Weinger, EdD, RN Ronald B. Goldberg, MD Joseph Wolfsdorf, MD, BCh
Judith Wylie-Rosett, EdD, RD Margaret Grey, DrPH, RN, FAAN Tien Yin Wong, MBBS, FRCSE, FRANZCO,
Richard Hellman, MD MPH, PhD

AMERICAN DIABETES ASSOCIATION OFFICERS


CHAIR OF THE BOARD PRESIDENT-ELECT, MEDICINE & SCIENCE
Robin J. Richardson Alvin C. Powers, MD
PRESIDENT, MEDICINE & SCIENCE PRESIDENT-ELECT, HEALTH CARE &
Desmond Schatz, MD EDUCATION
Brenda Montgomery, RN, MSHS, CDE
PRESIDENT, HEALTH CARE & EDUCATION
Margaret A. Powers, PhD, RD, CDE SECRETARY/TREASURER-ELECT
Umesh Verma
SECRETARY/TREASURER
Lorrie Welker Liang CHIEF EXECUTIVE OFFICER
Kevin L. Hagan
CHAIR OF THE BOARD-ELECT
David A. DeMarco, PhD CHIEF SCIENTIFIC & MEDICAL OFFICER
Robert E. Ratner, MD, FACP, FACE

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.
More information about the journal can be found online at care.diabetesjournals.org.
Copyright © 2016 by the American Diabetes Association, Inc. All rights reserved. Printed in
the USA. Requests for permission to reuse content should be sent to Copyright Clearance
Center at www.copyright.com or 222 Rosewood Dr., Danvers, MA 01923; phone: (978)
750-8400; fax: (978) 646-8600. Requests for permission to translate should be sent to
Permissions Editor, American Diabetes Association, at permissions@diabetes.org.
The American Diabetes Association reserves the right to reject any advertisement for
any reason, which need not be disclosed to the party submitting the advertisement.
Commercial reprint orders should be directed to Sheridan Content Services,
(800) 635-7181, ext. 8065.
Single issues of Diabetes Care can be ordered by calling toll-free (800) 232-3472, 8:30 A.M.
to 5:00 P.M. EST, Monday through Friday. Outside the United States, call (703) 549-1500.
Rates: $75 in the United States, $95 in Canada and Mexico, and $125 for all other countries.
Diabetes Care is available online at care.diabetesjournals.org. Please call the
numbers listed above, e-mail membership@diabetes.org, or visit the online journal for
PRINT ISSN 0149-5992 more information about submitting manuscripts, publication charges, ordering reprints,
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PRINTED IN THE USA content, and the journal’s publication policies.

AMERICAN DIABETES ASSOCIATION PERSONNEL AND CONTACTS


EDITORIAL OFFICE DIRECTOR PRODUCTION MANAGER DIRECTOR, MEMBERSHIP/SUBSCRIPTION
Lyn Reynolds Amy S. Gavin SERVICES
Donald Crowl
PEER REVIEW MANAGER TECHNICAL EDITOR PHARMACEUTICAL DIGITAL ADVERTISING
Shannon Potts Oedipa Rice e-Healthcare Solutions
John Burke
EDITORIAL OFFICE SECRETARIES
MANAGING DIRECTOR, MEDIA SALES Chief Revenue Officer
Raquel Castillo sales@ehsmail.com
Clare Liberis
Joan Garrett
cliberis@diabetes.org (609) 882-8887, ext. 149
MANAGING DIRECTOR, SCHOLARLY (212) 725-4925, ext. 3448
PHARMACEUTICAL PRINT ADVERTISING
JOURNAL PUBLISHING
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Heather Norton Blackburn Paul Nalbandian
(703) 299-5511 paulnalbandian@jacksongaeta.com
EDITORIAL MANAGERS Tina Auletta
Valentina Such ASSOCIATE DIRECTOR, BILLING & COLLECTIONS tinaauletta@jacksongaeta.com
Nancy C. Baldino Laurie Ann Hall (973) 403-7677
January 2016 Volume 39, Supplement 1

Standards of Medical Care in Diabetes—2016


S1 Introduction S60 8. Cardiovascular Disease and Risk
S3 Professional Practice Committee Management
S4 Standards of Medical Care in Diabetes—2016: Hypertension/Blood Pressure Control
Summary of Revisions Lipid Management
S6 1. Strategies for Improving Care Antiplatelet Agents
Coronary Heart Disease
Diabetes Care Concepts
Care Delivery Systems S72 9. Microvascular Complications and Foot Care
When Treatment Goals Are Not Met
Diabetic Kidney Disease
Tailoring Treatment to Vulnerable Populations
Diabetic Retinopathy
S13 2. Classification and Diagnosis of Diabetes Neuropathy
Classification Foot Care
Diagnostic Tests for Diabetes S81 10. Older Adults
Categories of Increased Risk for Diabetes (Prediabetes)
Type 1 Diabetes Overview
Type 2 Diabetes Neurocognitive Function
Gestational Diabetes Mellitus Hypoglycemia
Monogenic Diabetes Syndromes Treatment Goals
Cystic Fibrosis–Related Diabetes Pharmacological Therapy
Treatment in Skilled Nursing Facilities
S23 3. Foundations of Care and Comprehensive Medical and Nursing Homes
Evaluation End-of-Life Care
Foundations of Care S86 11. Children and Adolescents
Basis for Initial Care
Ongoing Care Management Type 1 Diabetes
Diabetes Self-management Education and Support Type 2 Diabetes
Medical Nutrition Therapy Transition From Pediatric to Adult Care
Physical Activity S94 12. Management of Diabetes in Pregnancy
Smoking Cessation: Tobacco and e-Cigarettes
Immunization Diabetes in Pregnancy
Psychosocial Issues Preconception Counseling
Comprehensive Medical Evaluation Glycemic Targets in Pregnancy
Comorbidities Management of Gestational Diabetes Mellitus
Management of Pregestational Type 1 Diabetes
S36 4. Prevention or Delay of Type 2 Diabetes and Type 2 Diabetes in Pregnancy
Lifestyle Modification Postpartum Care
Pharmacological Interventions Pregnancy and Antihypertensive Drugs
Diabetes Self-management Education and Support S99 13. Diabetes Care in the Hospital
S39 5. Glycemic Targets Hospital Care Delivery Standards
Assessment of Glycemic Control Considerations on Admission
A1C Testing Glycemic Targets in Hospitalized Patients
A1C Goals Antihyperglycemic Agents in Hospitalized
Hypoglycemia Patients
Intercurrent Illness Standards for Special Situations
Treating and Preventing Hypoglycemia
S47 6. Obesity Management for the Treatment of Type 2 Self-management in the Hospital
Diabetes Medical Nutrition Therapy in the Hospital
Look AHEAD Transition From the Acute Care Setting
Assessment Diabetes Care Providers in the Hospital
Diet, Physical Activity, and Behavioral Therapy Bedside Blood Glucose Monitoring
Pharmacotherapy S105 14. Diabetes Advocacy
Bariatric Surgery
Advocacy Position Statements
S52 7. Approaches to Glycemic Treatment
Pharmacological Therapy for Type 1 Diabetes S107 Professional Practice Committee for the Standards
Pharmacological Therapy for Type 2 Diabetes of Medical Care in Diabetes—2016
Bariatric Surgery S109 Index

This issue is freely accessible online at care.diabetesjournals.org.

Keep up with the latest information for Diabetes Care and other ADA titles via Facebook (/ADAJournals) and Twitter (@ADA_Journals).
Diabetes Care Volume 39, Supplement 1, January 2016 S1

INTRODUCTION
Introduction
Diabetes Care 2016;39(Suppl. 1):S1–S2 | DOI: 10.2337/dc16-S001

Diabetes is a complex, chronic illness re- diabetes care standards, guidelines, and to diabetes. Workgroup reports fall into
quiring continuous medical care with related documents for over 25 years. this category. Scientific statements are
multifactorial risk-reduction strategies ADA’s clinical practice recommenda- published in the ADA journals and other
beyond glycemic control. Ongoing patient tions are viewed as important resources scientific/medical publications, as ap-
self-management education and support for health care professionals who care propriate. Scientific statements also
are critical to preventing acute complica- for people with diabetes. ADA’s “Stan- undergo a formal review process.
tions and reducing the risk of long-term dards of Medical Care in Diabetes,”
complications. Significant evidence exists position statements, and scientific Consensus Report
that supports a range of interventions to statements undergo a formal review A consensus report contains a compre-
improve diabetes outcomes. process by ADA’s Professional Practice hensive examination by an expert panel
The American Diabetes Association’s Committee (PPC) and the Executive (i.e., consensus panel) of a scientific or
(ADA’s) “Standards of Medical Care in Committee of the Board of Directors. medical issue related to diabetes. A con-
Diabetes” is intended to provide clini- The Standards and all ADA position sensus report is not an ADA position and
cians, patients, researchers, payers, statements, scientific statements, and represents expert opinion only. The cat-
and other interested individuals with consensus reports are available on the As- egory may also include task force and
the components of diabetes care, gen- sociation’s Web site at http://professional expert committee reports. The need
eral treatment goals, and tools to eval- .diabetes.org/adastatements. for a consensus report arises when clini-
uate the quality of care. The Standards cians or scientists desire guidance on a
of Care recommendations are not in- “Standards of Medical Care in subject for which the evidence is contra-
tended to preclude clinical judgment Diabetes” dictory or incomplete. A consensus re-
and must be applied in the context of Standards of Care: ADA position state- port is developed following a consensus
excellent clinical care, with adjustments ment that provides key clinical practice conference where the controversial issue
for individual preferences, comorbid- recommendations. The PPC performs an is extensively discussed. The report
ities, and other patient factors. For extensive literature search and updates represents the panel’s collective anal-
more detailed information about man- the Standards annually based on the ysis, evaluation, and opinion at that
agement of diabetes, please refer to quality of new evidence. point in time based in part on the con-
Medical Management of Type 1 Diabe- ference proceedings. A consensus re-
ADA Position Statement
tes (1) and Medical Management of port does not undergo a formal ADA
A position statement is an official ADA
Type 2 Diabetes (2). review process.
point of view or belief that contains clin-
The recommendations include ical or research recommendations. Posi-
GRADING OF SCIENTIFIC EVIDENCE
screening, diagnostic, and therapeutic tion statements are issued on scientific
actions that are known or believed to or medical issues related to diabetes. Since the ADA first began publishing
favorably affect health outcomes of pa- They are published in the ADA journals practice guidelines, there has been con-
tients with diabetes. Many of these in- and other scientific/medical publica- siderable evolution in the evaluation of
terventions have also been shown to be tions. ADA position statements are typ- scientific evidence and in the develop-
cost-effective (3). ically based on a systematic review or ment of evidence-based guidelines. In
The ADA strives to improve and up- other review of published literature. 2002, the ADA developed a classification
date the Standards of Care to ensure Position statements undergo a formal system to grade the quality of scientific
that clinicians, health plans, and policy- review process. They are updated every evidence supporting ADA recommenda-
makers can continue to rely on them as 5 years or as needed. tions for all new and revised ADA posi-
the most authoritative and current tion statements. A recent analysis of the
guidelines for diabetes care. ADA Scientific Statement evidence cited in the Standards of Care
A scientific statement is an official ADA found steady improvement in quality
ADA STANDARDS, STATEMENTS, point of view or belief that may or may over the past 10 years, with the 2014
AND REPORTS not contain clinical or research recom- Standards for the first time having the
The ADA has been actively involved in mendations. Scientific statements con- majority of bulleted recommendations
the development and dissemination of tain scholarly synopsis of a topic related supported by A- or B-level evidence

“Standards of Medical Care in Diabetes” was originally approved in 1988. Most recent review/revision: November 2015.
© 2016 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.
S2 Introduction Diabetes Care Volume 39, Supplement 1, January 2016

Table 1—ADA evidence-grading system for “Standards of Medical Care in Diabetes” dence may be equally important but
Level of
are not as well supported. Of course,
evidence Description evidence is only one component of clin-
ical decision making. Clinicians care for
A Clear evidence from well-conducted, generalizable randomized controlled trials
that are adequately powered, including
patients, not populations; guidelines
c Evidence from a well-conducted multicenter trial must always be interpreted with the in-
c Evidence from a meta-analysis that incorporated quality ratings in the dividual patient in mind. Individual cir-
analysis cumstances, such as comorbid and
Compelling nonexperimental evidence, i.e., “all or none” rule developed by the coexisting diseases, age, education, dis-
Centre for Evidence-Based Medicine at the University of Oxford ability, and, above all, patients’ values
Supportive evidence from well-conducted randomized controlled trials that are
and preferences, must be considered
adequately powered, including
c Evidence from a well-conducted trial at one or more institutions
and may lead to different treatment tar-
c Evidence from a meta-analysis that incorporated quality ratings in the gets and strategies. Furthermore, con-
analysis ventional evidence hierarchies, such as
B Supportive evidence from well-conducted cohort studies the one adapted by the ADA, may miss
c Evidence from a well-conducted prospective cohort study or registry nuances important in diabetes care. For
c Evidence from a well-conducted meta-analysis of cohort studies example, although there is excellent ev-
Supportive evidence from a well-conducted case-control study idence from clinical trials supporting
C Supportive evidence from poorly controlled or uncontrolled studies the importance of achieving multiple
c Evidence from randomized clinical trials with one or more major or three or
risk factor control, the optimal way to
more minor methodological flaws that could invalidate the results
c Evidence from observational studies with high potential for bias (such as
achieve this result is less clear. It is dif-
case series with comparison with historical controls) ficult to assess each component of
c Evidence from case series or case reports such a complex intervention.
Conflicting evidence with the weight of evidence supporting the
recommendation References
E Expert consensus or clinical experience 1. American Diabetes Association. Medical
Management of Type 1 Diabetes. 6th ed.
Kaufman FR, Ed. Alexandria, VA, American Di-
abetes Association, 2012
2. American Diabetes Association. Medical
(4). A grading system (Table 1) devel- in which clinical trials may be impracti- Management of Type 2 Diabetes. 7th ed.
oped by the ADA and modeled after ex- cal, or in which there is conflicting evi- Burant CF, Young LA, Eds. Alexandria, VA, Amer-
ican Diabetes Association, 2012
isting methods was used to clarify and dence. Recommendations with an A 3. Li R, Zhang P, Barker LE, Chowdhury FM,
codify the evidence that forms the basis rating are based on large well-designed Zhang X. Cost-effectiveness of interventions to
for the recommendations. ADA recom- clinical trials or well-done meta-analyses. prevent and control diabetes mellitus: a sys-
mendations are assigned ratings of A, B, Generally, these recommendations tematic review. Diabetes Care 2010;33:1872–
or C, depending on the quality of evi- have the best chance of improving out- 1894
4. Grant RW, Kirkman MS. Trends in the evi-
dence. Expert opinion E is a separate comes when applied to the population dence level for the American Diabetes Associa-
category for recommendations in which to which they are appropriate. Recom- tion’s “Standards of Medical Care in Diabetes”
there is no evidence from clinical trials, mendations with lower levels of evi- from 2005 to 2014. Diabetes Care 2015;38:6–8
Diabetes Care Volume 39, Supplement 1, January 2016

PROFESSIONAL PRACTICE COMMITTEE


S3

Professional Practice Committee


Diabetes Care 2016;39(Suppl. 1):S3 | DOI: 10.2337/dc16-S002

The Professional Practice Committee for human studies related to each sec- Emma Morton-Eggleston, MD, MPH;
(PPC) of the American Diabetes Associ- tion and published since 1 January Margaret A. Powers, PhD, RD, CDE;
ation (ADA) is responsible for the “Stan- 2015. Recommendations were revised Robert E. Ratner, MD; Erinn Rhodes,
dards of Medical Care in Diabetes” based on new evidence or, in some MD, MPH; Amy Rothberg, MD; Sharon
position statement, referred to as the cases, to clarify the prior recommenda- D. Solomon, MD; Guillermo E. Umpierrez,
“Standards of Care.” The PPC is a multi- tion or match the strength of the word- MD; Willy Valencia, MD; and Kristina F.
disciplinary expert committee com- ing to the strength of the evidence. A Zdanys, MD.
prised of physicians, diabetes educators, table linking the changes in recommen-
registered dietitians, and others who dations to new evidence can be re-
have expertise in a range of areas, in- viewed at http://professional.diabetes Members of the PPC
cluding adult and pediatric endocrinol- .org/SOC. As for all position statements,
William H. Herman, MD, MPH (Chair)*
ogy, epidemiology, public health, lipid the Standards of Care position state-
research, hypertension, preconception ment was reviewed and approved by Thomas W. Donner, MD
planning, and pregnancy care. Appoint- the Executive Committee of ADA’s R. James Dudl, MD
ment to the PPC is based on excellence Board of Directors, which includes
Hermes J. Florez, MD, PhD, MPH*
in clinical practice and research. Al- health care professionals, scientists,
though the primary role of the PPC is and lay people. Judith E. Fradkin, MD
to review and update the Standards of Feedback from the larger clinical Charlotte A. Hayes, MMSc, MS, RD, CDE,
Care, it is also responsible for oversee- community was valuable for the 2016 ACSM CCEP
ing the review and revisions of ADA’s revision of the Standards of Care. Readers Rita Rastogi Kalyani, MD, MHS, FACP
position statements and scientific who wish to comment on the Standards
statements. of Medical Care in Diabetesd2016 are Suneil Koliwad, MD, PhD
The ADA adheres to the Institute of invited to do so at http://professional Joseph A. Stankaitis, MD, MPH*
Medicine Standards for Developing .diabetes.org/SOC. Tracey H. Taveira, PharmD, CDOE,
Trustworthy Clinical Practice Guidelines. The ADA funds development of the CVDOE*
All members of the PPC are required to Standards of Care and all ADA position
Deborah J. Wexler, MD, MSc*
disclose potential conflicts of interest statements out of its general revenues
with industry and/or other relevant or- and does not use industry support for Joseph Wolfsdorf, MB, BCh*
ganizations. These disclosures are dis- these purposes. The PPC would like to *Subgroup leaders
cussed at the onset of each Standards thank the following individuals who
of Care revision meeting. Members of the provided their expertise in reviewing
committee, their employer, and their dis- and/or consulting with the committee: ADA Staff
closed conflicts of interest are listed in Lloyd Paul Aiello, MD, PhD; Sheri Jane L. Chiang, MD
the “Professional Practice Committee Colberg-Ochs, PhD; Jo Ellen Condon, RD, (Corresponding author:
for the Standards of Medical Care in CDE; Donald R. Coustan, MD; Silvio E. jchiang@diabetes.org)
Diabetesd2016” table (see p. S107). Inzucchi, MD; George L. King, MD;
For the current revision, PPC mem- Shihchen Kuo, RPh, PhD; Ira B. Lamster, DDS, Erika Gebel Berg, PhD
bers systematically searched MEDLINE MMSc; Greg Maynard, MD, MSc, SFHM; Allison T. McElvaine, PhD

© 2016 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.
S4 Diabetes Care Volume 39, Supplement 1, January 2016
SUMMARY OF REVISIONS

Standards of Medical Care in Diabetesd2016:


Summary of Revisions
Diabetes Care 2016;39(Suppl. 1):S4–S5 | DOI: 10.2337/dc16-S003

GENERAL CHANGES screening recommendations. The rec- the ADA added the recommendation
In alignment with the American Diabe- ommendation is now to test all adults that people who use continuous glucose
tes Association’s (ADA’s) position that beginning at age 45 years, regardless monitoring and insulin pumps should
diabetes does not define people, the of weight. have continued access after they turn
word “diabetic” will no longer be used Testing is also recommended for 65 years of age.
when referring to individuals with dia- asymptomatic adults of any age who
Section 6. Obesity Management for
betes in the “Standards of Medical Care are overweight or obese and who have
one or more additional risk factors for the Treatment of Type 2 Diabetes
in Diabetes.” The ADA will continue to
This new section, which incorporates
use the term “diabetic” as an adjective diabetes. Please refer to Section 2 for
testing recommendations for gesta- prior recommendations related to bari-
for complications related to diabetes
tional diabetes mellitus. atric surgery, has new recommenda-
(e.g., diabetic retinopathy).
tions related to the comprehensive
Although levels of evidence for several For monogenic diabetes syndromes,
assessment of weight in diabetes and
recommendations have been updated, there is specific guidance and text on
to the treatment of overweight/obesity
these changes are not included below as testing, diagnosing, and evaluating indi-
with behavior modification and pharma-
the clinical recommendations have re- viduals and their family members.
cotherapy.
mained the same. Changes in evidence
Section 3. Foundations of Care and This section also includes a new table
level from, for example, C to E are not
Comprehensive Medical Evaluation of currently approved medications for
noted below. The “Standards of Medical
Section 3 “Initial Evaluation and Diabe- the long-term treatment of obesity.
Care in Diabetesd2016” contains, in addi-
tes Management Planning” and Section
tion to many minor changes that clarify Section 7. Approaches to Glycemic
4 “Foundations of Care: Education, Nu-
recommendations or reflect new evidence, Treatment
trition, Physical Activity, Smoking Cessa-
the following more substantive revisions. Bariatric surgery was removed from this
tion, Psychosocial Care, and Immunization”
from the 2015 Standards were com- section and placed in a new section en-
SECTION CHANGES titled “Obesity Management for the
bined into one section for 2016 to re-
Section 1. Strategies for Improving Care Treatment of Type 2 Diabetes.”
flect the importance of integrating
This section was revised to include rec-
medical evaluation, patient engage- Section 8. Cardiovascular Disease and
ommendations on tailoring treatment
ment, and ongoing care that highlight Risk Management
to vulnerable populations with diabetes,
the importance of lifestyle and behav- “Atherosclerotic cardiovascular disease”
including recommendations for those
ioral modification. The nutrition and (ASCVD) has replaced the former term
with food insecurity, cognitive dysfunc-
vaccination recommendations were “cardiovascular disease” (CVD), as
tion and/or mental illness, and HIV,
streamlined to focus on those aspects ASCVD is a more specific term.
and a discussion on disparities related
of care most important and most rele- A new recommendation for pharma-
to ethnicity, culture, sex, socioeconomic
vant to people with diabetes. cological treatment of older adults was
differences, and disparities.
Section 4. Prevention or Delay of added.
Section 2. Classification and Diagnosis Type 2 Diabetes To reflect new evidence on ASCVD
of Diabetes To reflect the changing role of technology risk among women, the recommenda-
The order and discussion of diagnostic in the prevention of type 2 diabetes, a re- tion to consider aspirin therapy in
tests (fasting plasma glucose, 2-h plasma commendation was added encouraging women aged .60 years has been
glucose after a 75-g oral glucose tolerance the use of new technology such as apps changed to include women aged $50
test, and A1C criteria) were revised to and text messaging to affect lifestyle years. A recommendation was also
make it clear that no one test is preferred modification to prevent diabetes. added to address antiplatelet use in pa-
over another for diagnosis. tients aged ,50 years with multiple risk
To clarify the relationship between Section 5. Glycemic Targets factors.
age, BMI, and risk for type 2 diabetes Because of the growing number of older A recommendation was made to re-
and prediabetes, the ADA revised the adults with insulin-dependent diabetes, flect new evidence that adding ezetimibe

© 2016 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.
care.diabetesjournals.org Summary of Revisions S5

to moderate-intensity statin provides ad- includes neurocognitive function, hypo- from a recommendation of ,6% (42
ditional cardiovascular benefits for select glycemia, treatment goals, care in skilled mmol/mol) to a target of 6–6.5% (42–
individuals with diabetes and should be nursing facilities/nursing homes, and 48 mmol/mol), although depending on
considered. end-of-life considerations. hypoglycemia risk the target may be
A new table provides efficacy and tightened or relaxed.
Section 11. Children and Adolescents
dose details on high- and moderate- Glyburide in gestational diabetes
The scope of this section is more com-
intensity statin therapy. mellitus was deemphasized based on
prehensive, capturing the nuances of di-
new data suggesting that it may be in-
abetes care in the pediatric population.
Section 9. Microvascular ferior to insulin and metformin.
This includes new recommendations
Complications and Foot Care
addressing diabetes self-management
“Nephropathy” was changed to “dia- Section 13. Diabetes Care in the
education and support, psychosocial
betic kidney disease” to emphasize Hospital
issues, and treatment guidelines for
that, while nephropathy may stem This section was revised to focus solely
type 2 diabetes in youth.
from a variety of causes, attention is on diabetes care in the hospital setting.
The recommendation to obtain a fast-
placed on kidney disease that is directly This comprehensive section addresses
ing lipid profile in children starting at
related to diabetes. There are several hospital care delivery standards, more
age 2 years has been changed to age
minor edits to this section. The signifi- detailed information on glycemic tar-
10 years, based on a scientific statement
cant ones, based on new evidence, are gets and antihyperglycemic agents,
on type 1 diabetes and cardiovascular
as follows: standards for special situations, and
disease from the American Heart Asso-
Diabetic kidney disease: guidance was transitions from the acute care setting.
ciation and the ADA.
added on when to refer for renal re- This section also includes a new table
placement treatment and when to refer on basal and bolus dosing recommenda-
Section 12. Management of Diabetes
to physicians experienced in the care of tions for continuous enteral, bolus en-
in Pregnancy
diabetic kidney disease. teral, and parenteral feedings.
The scope of this section is more com-
Diabetic retinopathy: guidance was
prehensive, providing new recommen-
added on the use of intravitreal anti-
dations on pregestational diabetes, Section 14. Diabetes Advocacy
VEGF agents for the treatment of
gestational diabetes mellitus, and gen- “Diabetes Care in the School Setting: A
center-involved diabetic macular edema,
eral principles for diabetes management Position Statement of the American Di-
as they were more effective than mono-
in pregnancy. abetes Association” was revised in 2015.
therapy or combination therapy with
A new recommendation was added to This position statement was previously
laser.
highlight the importance of discussing fam- called “Diabetes Care in the School and
Section 10. Older Adults ily planning and effective contraception Day Care Setting.” The ADA intentionally
The scope of this section is more compre- with women with preexisting diabetes. separated these two populations be-
hensive, capturing the nuances of diabe- A1C recommendations for pregnant cause of the significant differences in di-
tes care in the older adult population. This women with diabetes were changed, abetes care between the two cohorts.
S6 Diabetes Care Volume 39, Supplement 1, January 2016

American Diabetes Association


1. Strategies for Improving Care
Diabetes Care 2016;39(Suppl. 1):S6–S12 | DOI: 10.2337/dc16-S004

Recommendations
c A patient-centered communication style that incorporates patient prefer-
ences, assesses literacy and numeracy, and addresses cultural barriers to
care should be used. B
c Treatment decisions should be timely and based on evidence-based guide-
lines that are tailored to individual patient preferences, prognoses, and co-
morbidities. B
c Care should be aligned with components of the Chronic Care Model to ensure
productive interactions between a prepared proactive practice team and an
1. STRATEGIES FOR IMPROVING CARE

informed activated patient. A


c When feasible, care systems should support team-based care, community
involvement, patient registries, and decision support tools to meet patient
needs. B

DIABETES CARE CONCEPTS


In the following sections, different components of the clinical management of
patients with (or at risk for) diabetes are reviewed. Clinical practice guidelines are
key to improving population health; however, for optimal outcomes, diabetes care
must be individualized for each patient. The American Diabetes Association high-
lights the following three themes that clinicians, policymakers, and advocates
should keep in mind:

1. Patient-Centeredness: Practice recommendations, whether based on evi-


dence or expert opinion, are intended to guide an overall approach to
care. The science and art of medicine come together when the clinician is
faced with making treatment recommendations for a patient who would not
have met eligibility criteria for the studies on which guidelines were based.
Recognizing that one size does not fit all, these Standards provide guid-
ance for when and how to adapt recommendations. Because patients with
diabetes have greatly increased risk for cardiovascular disease, a patient-
centered approach should include a comprehensive plan to reduce cardio-
vascular risk by addressing blood pressure and lipid control, smoking prevention
and cessation, weight management, physical activity, and healthy lifestyle
choices.
2. Diabetes Across the Life Span: An increasing proportion of patients with type 1
diabetes are adults. For less salutary reasons, the incidence of type 2 diabetes is
increasing in children and young adults. Patients with type 1 diabetes and those
with type 2 diabetes are living well into older age, a stage of life for which there is
little evidence from clinical trials to guide therapy. All these demographic
changes highlight another challenge to high-quality diabetes care, which is the
need to improve coordination between clinical teams as patients transition
through different stages of the life span.
3. Advocacy for Patients With Diabetes: Advocacy can be defined as active support
and engagement to advance a cause or policy. Advocacy is needed to improve
the lives of patients with (or at risk for) diabetes. Given the tremendous toll that Suggested citation: American Diabetes Associa-
obesity, physical inactivity, and smoking have on the health of patients with tion. Strategies for improving care. Sec. 1. In
Standards of Medical Care in Diabetesd2016.
diabetes, efforts are needed to address and change the societal determinants
Diabetes Care 2016;39(Suppl. 1):S6–S12
at the root of these problems. Within the narrower domain of clinical practice
© 2016 by the American Diabetes Association.
guidelines, the application of evidence level grading to practice recommenda- Readers may use this article as long as the work
tions can help to identify areas that require more research (1). Refer to Section is properly cited, the use is educational and not
14 “Diabetes Advocacy.” for profit, and the work is not altered.
care.diabetesjournals.org Strategies for Improving Care S7

CARE DELIVERY SYSTEMS 2. Self-management support 1. Healthy lifestyle choices (physical


There has been steady improvement in 3. Decision support (basing care on activity, healthy eating, tobacco ces-
the proportion of patients with diabetes evidence-based, effective care guide- sation, weight management, and ef-
treated with statins and achieving recom- lines) fective coping)
mended levels of A1C, blood pressure, 4. Clinical information systems (using 2. Disease self-management (taking
and LDL cholesterol in the last 10 years registries that can provide patient- and managing medications and, when
(2). The mean A1C nationally has declined specific and population-based sup- clinically appropriate, self-monitoring
from 7.6% (60 mmol/mol) in 1999–2002 port to the care team) of glucose and blood pressure)
to 7.2% (55 mmol/mol) in 2007–2010 5. Community resources and policies 3. Prevention of diabetes complica-
based on the National Health and Nutri- (identifying or developing resources tions (self-monitoring of foot health;
tion Examination Survey (NHANES), with to support healthy lifestyles) active participation in screening for
younger adults less likely to meet treat- 6. Health systems (to create a quality- eye, foot, and renal complications;
ment targets compared with older adults oriented culture) and immunizations)
(2). This has been accompanied by im-
provements in cardiovascular outcomes Redefining the roles of the health care High-quality diabetes self-management
and has led to substantial reductions in delivery team and promoting self- education (DSME) has been shown to
end-stage microvascular complications. management on the part of the patient improve patient self-management,
Nevertheless, 33–49% of patients still are fundamental to the successful imple- satisfaction, and glucose control. Na-
do not meet targets for glycemic, blood mentation of the CCM (8). Collaborative, tional DSME standards call for an inte-
pressure, or cholesterol control, and multidisciplinary teams are best suited to grated approach that includes clinical
only 14% meet targets for all three mea- provide care for people with chronic con- content and skills, behavioral strategies
sures and nonsmoking status (2). Evi- ditions such as diabetes and to facilitate (goal setting, problem solving), and en-
dence also suggests that progress in patients’ self-management (9–11). gagement with psychosocial concerns
cardiovascular risk factor control (par- (23).
Key Objectives
ticularly tobacco use) may be slowing The National Diabetes Education Pro- Objective 3: Change the Care System
(2,3). Certain patient groups, such as gram (NDEP) maintains an online re- An institutional priority in most success-
young adults and patients with complex source (www.betterdiabetescare.nih ful care systems is providing high quality
comorbidities, financial or other social .gov) to help health care professionals of care (24). Changes that have been
hardships, and/or limited English profi- to design and implement more effective shown to increase quality of diabetes
ciency, may present particular chal- health care delivery systems for those care include basing care on evidence-
lenges to goal-based care (4–6). Even with diabetes. Three specific objectives, based guidelines (18); expanding the
after adjusting for patient factors, with references to literature outlining role of teams to implement more inten-
the persistent variation in quality of di- practical strategies to achieve each, are sive disease management strategies
abetes care across providers and prac- as follows: (6,21,25); redesigning the care process
tice settings indicates that there is
potential for substantial system-level
Objective 1 : Optimize Provider and Team (26); implementing electronic health
improvements.
Behavior record tools (27,28); activating and
The care team should prioritize timely educating patients (29,30); removing fi-
Chronic Care Model and appropriate intensification of life- nancial barriers and reducing patient
Numerous interventions to improve ad- style and/or pharmacological therapy out-of-pocket costs for diabetes educa-
herence to the recommended standards for patients who have not achieved ben- tion, eye exams, self-monitoring of
have been implemented. However, a ma- eficial levels of glucose, blood pressure, blood glucose, and necessary medica-
jor barrier to optimal care is a delivery or lipid control (12). Strategies such as tions (6); and identifying/developing/
system that is often fragmented, lacks explicit goal setting with patients (13); engaging community resources and
clinical information capabilities, dupli- identifying and addressing language, nu- public policy that support healthy life-
cates services, and is poorly designed for meracy, or cultural barriers to care (14– styles (31).
the coordinated delivery of chronic care. 17); integrating evidence-based guide- Initiatives such as the Patient-Centered
The Chronic Care Model (CCM) has been lines and clinical information tools into Medical Home show promise for improv-
shown to be an effective framework for the process of care (18–20); and incor- ing outcomes through coordinated pri-
improving the quality of diabetes care (7). porating care management teams in- mary care and offer new opportunities
Six Core Elements
cluding nurses, pharmacists, and other for team-based chronic disease care
The CCM includes six core elements for providers (21,22) have each been shown (32). Additional strategies to improve di-
the provision of optimal care of patients to optimize provider and team behavior abetes care include reimbursement
with chronic disease: and thereby catalyze reductions in A1C, structures that, in contrast to visit-based
blood pressure, and LDL cholesterol. billing, reward the provision of appropriate
1. Delivery system design (moving Objective 2: Support Patient Behavior and high-quality care (33), and incen-
from a reactive to a proactive care Change tives that accommodate personalized
delivery system where planned visits Successful diabetes care requires a sys- care goals (6,34).
are coordinated through a team- tematic approach to supporting patients’ Optimal diabetes management re-
based approach) behavior change efforts, including quires an organized, systematic approach
S8 Strategies for Improving Care Diabetes Care Volume 39, Supplement 1, January 2016

and the involvement of a coordinated pressure, or lipids (40). Although there TAILORING TREATMENT TO
team of dedicated health care profes- are many ways to measure adherence VULNERABLE POPULATIONS
sionals working in an environment where (40), Medicare uses percent of days cov- Health Disparities
patient-centered high-quality care is a ered (PDC), which is a measure of the The causes of health disparities are com-
priority (6). number of pills prescribed divided by plex and include societal issues such as
the days between first and last prescrip- institutional racism, discrimination, socio-
WHEN TREATMENT GOALS ARE tions. “Adequate” adherence is defined economic status, poor access to health
NOT MET as 80% (40). This metric can be used to care, and lack of health insurance. Disparities
In general, providers should seek evidence- find and track poor adherence and help are particularly well documented for car-
based approaches that improve the to guide system improvement efforts to diovascular disease.
clinical outcomes and quality of life of pa- overcome the barriers to adherence.
tients with diabetes. Recent reviews of Barriers to adherence may include pa- Ethnic/Cultural/Sex/Socioeconomic
quality improvement strategies in diabe- tient factors (remembering to obtain Differences
tes care (24,35,36) have not identified a or take medications, fears, depression, Ethnic, cultural, religious, and sex differ-
particular approach that is more effective or health beliefs), medication factors ences and socioeconomic status may
than others. However, the Translating Re- (complexity, multiple daily dosing, affect diabetes prevalence and out-
search Into Action for Diabetes (TRIAD) cost, or side effects), and system factors comes. Type 2 diabetes develops more
study provided objective data from large (inadequate follow-up or support). frequently in women with prior gesta-
managed care systems demonstrating ef- tional diabetes mellitus (42), in individu-
fective tools for specific targets (6). TRIAD Improving Adherence als with hypertension or dyslipidemia,
found it useful to divide interventions into Simplifying a complex treatment regi- and in certain racial/ethnic groups
those that affected processes of care and men may improve adherence. Nurse- (African American, Native American,
intermediate outcomes. directed interventions, home aides, Hispanic/Latino, and Asian American) (43).
diabetes education, and pharmacy-
Processes of Care Access to Health Care
derived interventions improved ad-
Processes of care included periodic test- Ethnic, cultural, religious, sex, and socio-
herence but had a very small effect on
ing of A1C, lipids, and urinary albumin; economic differences affect health care
outcomes, including metabolic control
examining the retina and feet; advising access and complication risk in people
(41). Success in overcoming barriers
on aspirin use; and smoking cessation. with diabetes. Recent studies have rec-
may be achieved if the patient and pro- ommended lowering the BMI cut point
TRIAD results suggest that providers vider agree on a targeted treatment
control these activities. Performance for testing for Asian Americans to $23
for a specific barrier. For example, one kg/m2 (44). Women with diabetes, com-
feedback, reminders, and structured study found that when depression was
care (e.g., guidelines, formal case man- pared with men with diabetes, have a
identified as a barrier, agreement on 40% greater risk of incident coronary
agement, and patient education re- antidepressant treatment subsequently
sources) may influence providers to heart disease (45). Socioeconomic and
allowed for improvements in A1C, ethnic inequalities exist in the provision
improve processes of care (6). blood pressure, and lipid control (10). of health care to individuals with diabe-
Intermediate Outcomes and
Thus, to improve adherence, systems tes (46). As a result, children with type 1
Treatment Intensification should continually monitor and prevent diabetes from racial/ethnic populations
For intermediate outcomes, such as or treat poor adherence by identifying with lower socioeconomic status are at
A1C, blood pressure, and lipid goals, barriers and implementing treatments risk for poor metabolic control and poor
tools that improved processes of care that are barrier specific and effective. emotional functioning (47). Significant
did not perform as well in addressing A systematic approach to achieving in- racial differences and barriers exist in
barriers to treatment intensification termediate outcomes involves three steps: self-monitoring and outcomes (48).
and adherence (6). In 35% of cases, un-
controlled A1C, blood pressure, or lipids 1. Assess adherence. Adherence should Addressing Disparities
were associated with a lack of treatment be addressed as the first priority. If Therefore, diabetes management re-
intensification, defined as a failure to adherence is 80% or above, then treat- quires individualized, patient-centered,
either increase a drug dose or change a ment intensification should be consid- and culturally appropriate strategies. To
drug class (37). Treatment intensifica- ered (e.g., up-titration). If medication overcome disparities, community health
tion was associated with improvement up-titration is not a viable option, then workers (49), peers (50,51), and lay lead-
in A1C, hypertension, and hyperlipid- consider initiating or changing to a dif- ers (52) may assist in the delivery of
emia control (38). A large multicenter ferent medication class. DSME and diabetes self-management
study confirmed the strong association 2. Explore barriers to adherence with support services (53). Strong social sup-
between treatment intensification and the patient/caregiver and find a mutu- port leads to improved clinical outcomes,
improved A1C (39). ally agreeable approach to overcom- reduced psychosocial symptomatology,
ing the barriers. and adoption of healthier lifestyles (54).
Intermediate Outcomes and 3. Establish a follow-up plan that con- Structured interventions, tailored to eth-
Adherence firms the planned treatment change nic populations that integrate culture,
In 23% of cases, poor adherence was and assess progress in reaching the language, religion, and literacy skills, pos-
associated with uncontrolled A1C, blood target. itively influence patient outcomes (55).
care.diabetesjournals.org Strategies for Improving Care S9

To decrease disparities, all providers and Providers should recognize that FI com- Additionally, homeless patients with dia-
groups are encouraged to use the National plicates diabetes management and seek betes need secure places to keep their
Quality Forum’s National Voluntary Con- local resources that can help patients and diabetes supplies and refrigerator access
sensus Standards for Ambulatory Cared the parents of patients with diabetes to to properly store their insulin.
Measuring Healthcare Disparities (56). more regularly obtain nutritious food (59). Literacy and Numeracy Deficiencies. FI and

Lack of Health Insurance Food Insecurity and Hyperglycemia. Hy- diabetes are more common among non-
Not having health insurance affects the perglycemia is more common in those English speaking individuals and those
processes and outcomes of diabetes with diabetes and FI. Reasons for this with poor literacy and numeracy skills.
care. Individuals without insurance include the steady consumption of Therefore, it is important to consider
coverage for blood glucose monitoring carbohydrate-rich processed foods, screening for FI, proper housing, and di-
supplies have a 0.5% higher A1C than binge eating, not filling antidiabetes med- abetes in this population. Programs that
those with coverage (57). The afford- ication prescriptions owing to financial see such patients should work to develop
able care act has improved access to constraint, and anxiety/depression that services in multiple languages with the
health care; however, many remain lead to poor diabetes self-care behaviors. specific goal of preventing diabetes and
without coverage. In a recent study of Providers should be well versed in these building diabetes awareness in people
predominantly African American or risk factors for hyperglycemia and take who cannot easily read or write in English.
Hispanic uninsured patients with dia- practical steps to alleviate them in order
Cognitive Dysfunction
betes, 50–60% were hypertensive, but to improve glucose control.
only 22–37% had systolic blood pres- Recommendations
Food Insecurity and Hypoglycemia
sure controlled by treatments to under c Intensive glucose control is not ad-
130 mmHg (58). Type 1 Diabetes. Individuals with type 1 vised for the improvement of poor
diabetes and FI may develop hypoglycemia cognitive function in hyperglycemic
Food Insecurity as a result of inadequate or erratic carbo- individuals with type 2 diabetes. B
Recommendations hydrate consumption following insulin c In individuals with poor cognitive
c Providers should evaluate hyper- administration. Long-acting insulin, as op- function or severe hypoglycemia,
glycemia and hypoglycemia in the posed to shorter-acting insulin that may glycemic therapy should be tailored
context of food insecurity and pro- peak when food is not available, may to avoid significant hypoglycemia. C
pose solutions accordingly. A lower the risk for hypoglycemia in those c In individuals with diabetes at high
c Providers should recognize that with FI. Short-acting insulin analogs, cardiovascular risk, the cardiovascular
homelessness, poor literacy, and preferably delivered by a pen, may be benefits of statin therapy outweigh
poor numeracy often occur with used immediately after consumption the risk of cognitive dysfunction. A
food insecurity, and appropriate of a meal, whenever food becomes c If a second-generation antipsychotic
resources should be made avail- available. Unfortunately, the greater medication is prescribed, changes in
able for patients with diabetes. A cost of insulin analogs should be weighed weight, glycemic control, and cho-
against their potential advantages. Caring lesterol levels should be carefully
Food insecurity (FI) is the unreliable for those with type 1 diabetes in the set- monitored and the treatment regi-
availability of nutritious food and the ting of FI may mirror “sick day” manage- men should be reassessed. C
inability to consistently obtain food ment protocols.
without resorting to socially unaccept- Dementia
Type 2 Diabetes. Those with type 2 diabe- The most severe form of cognitive
able practices. Over 14% (or one out of
tes and FI can develop hypoglycemia for dysfunction is dementia. A recent meta-
every seven people in the U.S.) are food
similar reasons after taking certain oral analysis of prospective observational stud-
insecure. The rate is higher in some
hypoglycemic agents. If using a sulfonyl- ies in people with diabetes showed a 73%
racial/ethnic minority groups including
urea, glipizide is the preferred choice increased risk of all types of dementia, a
African American and Latino popula-
due to the shorter half-life. Glipizide 56% increased risk of Alzheimer dementia,
tions, in low-income households, and
can be taken immediately before meal and 127% increased risk of vascular de-
in homes headed by a single mother. FI
may involve a tradeoff between purchas- consumption, thus limiting its tendency mentia compared with individuals without
ing nutritious food for inexpensive and to produce hypoglycemia as compared diabetes (60). The reverse is also true: peo-
more energy- and carbohydrate-dense with longer-acting sulfonylureas (e.g., ple with Alzheimer dementia are more
processed foods. glyburide). likely to develop diabetes than people
In people with FI, interventions should Homelessness. Homelessness often ac- without Alzheimer dementia.
focus on preventing diabetes and, in companies the most severe form of FI. Hyperglycemia. In those with type 2
those with diabetes, limiting hyperglyce- Therefore, providers who care for those diabetes, the degree and duration of
mia and preventing hypoglycemia. The with FI who are uninsured and homeless hyperglycemia are related to dementia.
risk for type 2 diabetes is increased two- and individuals with poor literacy and nu- More rapid cognitive decline is associated
fold in those with FI. The risks of uncontrolled meracy should be well versed or have with both increased A1C and longer du-
hyperglycemia and severe hypoglycemia access to social workers to facilitate tem- ration of diabetes (61). The Action to
are increased in those with diabetes who porary housing for their patients as a Control Cardiovascular Risk in Diabetes
are also food insecure. means to prevent and control diabetes. (ACCORD) study found that each 1%
S10 Strategies for Improving Care Diabetes Care Volume 39, Supplement 1, January 2016

higher A1C level was associated with analysis showed a significantly increased progression toward diabetes. Among
lower cognitive function in individuals risk of incident depression (relative risk HIV patients with diabetes, preventive
with type 2 diabetes (62). However, the [RR] 5 1.15), and, in turn, depression was health care using an approach similar
ACCORD study found no difference in associated with a significantly increased to that used in patients without HIV is
cognitive outcomes between intensive risk of diabetes (RR 5 1.6) (71). Depression critical to reduce the risks of microvas-
and standard glycemic control, support- and psychosocial issues are discussed cular and macrovascular complications.
ing the recommendation that intensive more extensively in Section 3 “Founda- For patients with HIV and ARV-
glucose control should not be advised for tions of Care and Comprehensive Medical associated hyperglycemia, it may be
the improvement of cognitive function in Evaluation.” appropriate to consider discontinuing
individuals with type 2 diabetes (63). the problematic ARV agents if safe and
Medications effective alternatives are available (76).
Hypoglycemia. In type 2 diabetes, severe Diabetes medications are effective, re-
hypoglycemia is associated with reduced Before making ARV substitutions, carefully
gardless of mental health status. Treat- consider the possible effect on HIV viro-
cognitive function, and those with poor ments for depression are effective in
cognitive function have more severe hy- logical control and the potential adverse
patients with diabetes, and treating de- effects of new ARV agents. In some cases,
poglycemia. In a long-term study of older pression may improve short-term glyce-
patients with type 2 diabetes, individuals antidiabetes agents may still be necessary.
mic control (72). If a second-generation
with one or more recorded episode of antipsychotic medication is prescribed, References
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port systems on practitioner performance and sus nurse care management: a randomized trial.
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2005;293:1223–1238 51. Long JA, Jahnle EC, Richardson DM,
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and Quality, 2004 (Report no. 04-0051-2. AHRQ
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37. Schmittdiel JA, Uratsu CS, Karter AJ, et al.
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Why don’t diabetes patients achieve recom-
21. Jaffe MG, Lee GA, Young JD, Sidney S, Go Griffiths CJ. Self-management education pro-
mended risk factor targets? Poor adherence
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versus lack of treatment intensification. J Gen
with a large-scale hypertension program. JAMA Intern Med 2008;23:588–594 conditions. Cochrane Database Syst Rev 2007;4:
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nitoring in veterans with type 2 diabetes: the Med Care 2009;47:395–402 port in primary care? Findings from a random-
DiaTel randomized controlled trial. Diabetes 39. Raebel MA, Ellis JL, Schroeder EB, et al. In- ized controlled trial. Diabetes Educ 2013;39:
Care 2010;33:478–484 tensification of antihyperglycemic therapy among 705–713
23. Powers MA, Bardsley J, Cypress M, et al. patients with incident diabetes: a Surveillance 54. Strom JL, Egede LE. The impact of social
Diabetes self-management education and sup- Prevention and Management of Diabetes Mellitus support on outcomes in adult patients with
port in type 2 diabetes: a joint position state- (SUPREME-DM) study. Pharmacoepidemiol Drug type 2 diabetes: a systematic review. Curr
ment of the American Diabetes Association, the Saf 2014;23:699–710 Diab Rep 2012;12:769–781
American Association of Diabetes Educators, 40. Raebel MA, Schmittdiel J, Karter AJ, 55. Zeh P, Sandhu HK, Cannaby AM, Sturt JA.
and the Academy of Nutrition and Dietetics. Di- Konieczny JL, Steiner JF. Standardizing terminol- The impact of culturally competent diabetes
abetes Care 2015;38:1372–1382 ogy and definitions of medication adherence and care interventions for improving diabetes-
24. Tricco AC, Ivers NM, Grimshaw JM, et al. persistence in research employing electronic da- related outcomes in ethnic minority groups: a
Effectiveness of quality improvement strategies tabases. Med Care 2013;51(Suppl. 3):S11–S21 systematic review. Diabet Med 2012;29:1237–
on the management of diabetes: a systematic 41. Vermeire E, Wens J, Van Royen P, Biot Y, 1252
review and meta-analysis. Lancet 2012;379: Hearnshaw H, Lindenmeyer A. Interventions 56. National Quality Forum. National Voluntary
2252–2261 for improving adherence to treatment recom- Consensus Standards for Ambulatory Cared
25. Peikes D, Chen A, Schore J, Brown R. Effects mendations in people with type 2 diabetes mel- Measuring Healthcare Disparities [Internet],
of care coordination on hospitalization, quality litus. Cochrane Database Syst Rev 2005;2: 2008. Available from https://www.qualityforum
of care, and health care expenditures among CD003638 .org/Publications/2008/03/National_Voluntary_
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26. Feifer C, Nemeth L, Nietert PJ, et al. Differ- systematic review. Diabetes Care 2002;25: .aspx. Accessed 2 September 2015
ent paths to high-quality care: three archetypes 1862–1868 57. Bowker SL, Mitchell CG, Majumdar SR, Toth
of top-performing practice sites. Ann Fam Med 43. Hutchinson RN, Shin S. Systematic review of EL, Johnson JA. Lack of insurance coverage for
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glycemic control in patients with type 2 diabe- 64. Whitmer RA, Karter AJ, Yaffe K, Quesenberry depression and bipolar disorder. World Psychi-
tes. CMAJ 2004;171:39–43 CP Jr, Selby JV. Hypoglycemic episodes and risk of atry 2015;14:119–136
58. Baumann LC, Chang M-W, Hoebeke R. Clinical dementia in older patients with type 2 diabetes 71. Mezuk B, Eaton WW, Albrecht S, Golden SH.
outcomes for low-income adults with hyperten- mellitus. JAMA 2009;301:1565–1572 Depression and type 2 diabetes over the lifespan: a
sion and diabetes. Nurs Res 2002;51:191–198 65. Punthakee Z, Miller ME, Launer LJ, et al.; meta-analysis. Diabetes Care 2008;31:2383–2390
59. Seligman HK, Schillinger D. Hunger and so- ACCORD Group of Investigators; ACCORD- 72. Baumeister H, Hutter N, Bengel J. Psycho-
cioeconomic disparities in chronic disease. N MIND Investigators. Poor cognitive function logical and pharmacological interventions for
Engl J Med 2010;363:6–9 and risk of severe hypoglycemia in type 2 dia- depression in patients with diabetes mellitus
60. Gudala K, Bansal D, Schifano F, Bhansali A. betes: post hoc epidemiologic analysis of the and depression. Cochrane Database Syst Rev
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analysis of prospective observational studies. J 66. Scarmeas N, Stern Y, Mayeux R, Manly JJ, 73. American Diabetes Association; American
Diabetes Investig 2013;4:640–650 Schupf N, Luchsinger JA. Mediterranean diet Psychiatric Association; American Association
61. Rawlings AM, Sharrett AR, Schneider AL, and mild cognitive impairment. Arch Neurol of Clinical Endocrinologists; North American As-
et al. Diabetes in midlife and cognitive change 2009;66:216–225 sociation for the Study of Obesity. Consensus
over 20 years: a cohort study. Ann Intern Med 67. Ooi CP, Loke SC, Yassin Z, Hamid T-A. Car- development conference on antipsychotic
bohydrates for improving the cognitive per- drugs and obesity and diabetes. Diabetes Care
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62. Cukierman-Yaffe T, Gerstein HC, Williamson
with normal cognition or mild cognitive impair- 74. Dubé MP. Disorders of glucose metabo-
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baseline glycemic control and cognitive func- Statins and cognitive function: a systematic re- 75. Schambelan M, Benson CA, Carr A, et al.;
tion in individuals with type 2 diabetes and view. Ann Intern Med 2013;159:688–697 International AIDS Society-USA. Management
other cardiovascular risk factors: the action to 69. Osborn DPJ, Wright CA, Levy G, King MB, of metabolic complications associated with
control cardiovascular risk in diabetes-memory Deo R, Nazareth I. Relative risk of diabetes, dys- antiretroviral therapy for HIV-1 infection: rec-
in diabetes (ACCORD-MIND) trial. Diabetes lipidaemia, hypertension and the metabolic syn- ommendations of an International AIDS Society-
Care 2009;32:221–226 drome in people with severe mental illnesses: USA panel. J Acquir Immune Defic Syndr 2002;31:
63. Launer LJ, Miller ME, Williamson JD, et al.; systematic review and metaanalysis. BMC Psy- 257–275
ACCORD MIND investigators. Effects of intensive chiatry 2008;8:84 76. Wohl DA, McComsey G, Tebas P, et al.
glucose lowering on brain structure and function 70. Correll CU, Detraux J, De Lepeleire J, De Current concepts in the diagnosis and man-
in people with type 2 diabetes (ACCORD MIND): a Hert M. Effects of antipsychotics, antidepres- agement of metabolic complications of HIV
randomised open-label substudy. Lancet Neurol sants and mood stabilizers on risk for physi- infection and its therapy. Clin Infect Dis
2011;10:969–977 cal diseases in people with schizophrenia, 2006;43:645–653
Diabetes Care Volume 39, Supplement 1, January 2016 S13

American Diabetes Association


2. Classification and Diagnosis of
Diabetes
Diabetes Care 2016;39(Suppl. 1):S13–S22 | DOI: 10.2337/dc16-S005

CLASSIFICATION
Diabetes can be classified into the following general categories:

1. Type 1 diabetes (due to b-cell destruction, usually leading to absolute insulin


deficiency)

2. CLASSIFICATION AND DIAGNOSIS OF DIABETES


2. Type 2 diabetes (due to a progressive loss of insulin secretion on the background
of insulin resistance)
3. Gestational diabetes mellitus (GDM) (diabetes diagnosed in the second or third
trimester of pregnancy that is not clearly overt diabetes)
4. Specific types of diabetes due to other causes, e.g., monogenic diabetes syn-
dromes (such as neonatal diabetes and maturity-onset diabetes of the young
[MODY]), diseases of the exocrine pancreas (such as cystic fibrosis), and drug- or
chemical-induced diabetes (such as with glucocorticoid use, in the treatment 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 im-
portant for determining therapy, but some individuals cannot be clearly classified as
having type 1 or type 2 diabetes at the time of diagnosis. The traditional paradigms
of type 2 diabetes occurring only in adults and type 1 diabetes only in children are no
longer accurate, as both diseases occur in both cohorts. Occasionally, patients with
type 2 diabetes may present with diabetic ketoacidosis (DKA). Children with type 1
diabetes typically present with the hallmark symptoms of polyuria/polydipsia and
approximately one-third with DKA (2). The onset of type 1 diabetes may be more
variable in adults, and they may not present with the classic symptoms seen in
children. Although difficulties in distinguishing diabetes type may occur in all age-
groups at onset, the true diagnosis becomes more obvious over time.
DIAGNOSTIC TESTS FOR DIABETES
Diabetes may be diagnosed based on the plasma glucose criteria, either the fasting
plasma glucose (FPG) or the 2-h plasma glucose (2-h PG) value after a 75-g oral
glucose tolerance test (OGTT) or the A1C criteria (1,3) (Table 2.1).
The same tests are used to screen for and diagnose diabetes and to detect individ-
uals with prediabetes. Diabetes may be identified anywhere along the spectrum of
clinical scenarios: in seemingly low-risk individuals who happen to have glucose testing,
in individuals tested based on diabetes risk assessment, and in symptomatic patients.
Fasting and 2-Hour Plasma Glucose
Suggested citation: American Diabetes Associa-
The FPG and 2-h PG may be used to diagnose diabetes (Table 2.1). The concordance
tion. Classification and diagnosis of diabetes.
between the FPG and 2-h PG tests is imperfect, as is the concordance between A1C Sec. 2. In Standards of Medical Care in
and either glucose-based test. Numerous studies have confirmed that, compared Diabetesd2016. Diabetes Care 2016;39(Suppl. 1):
with FPG cut points and A1C, the 2-h PG value diagnoses more people with diabetes. S13–S22
© 2016 by the American Diabetes Association.
A1C Readers may use this article as long as the work
The A1C test should be performed using a method that is certified by the NGSP is properly cited, the use is educational and not
(www.ngsp.org) and standardized or traceable to the Diabetes Control and for profit, and the work is not altered.
S14 Classification and Diagnosis of Diabetes Diabetes Care Volume 39, Supplement 1, January 2016

Table 2.1—Criteria for the diagnosis of diabetes the test result that is above the diagnos-
FPG $126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 h.*
tic cut point should be repeated. The di-
OR
agnosis is made on the basis of the
confirmed test. For example, if a patient
2-h PG $200 mg/dL (11.1 mmol/L) during an OGTT. The test should be performed as described by
the WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in meets the diabetes criterion of the A1C
water.* (two results $6.5% [48 mmol/mol]) but not
OR FPG (,126 mg/dL [7.0 mmol/L]), that
A1C $6.5% (48 mmol/mol). The test should be performed in a laboratory using a method that is person should nevertheless be consid-
NGSP certified and standardized to the DCCT assay.* ered to have diabetes.
OR Since all the tests have preanalytic and
In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma analytic variability, it is possible that an
glucose $200 mg/dL (11.1 mmol/L). abnormal result (i.e., above the diagnostic
*In the absence of unequivocal hyperglycemia, results should be confirmed by repeat testing.
threshold), when repeated, will produce a
value below the diagnostic cut point. This
scenario is least likely for A1C, more likely
Complications Trial (DCCT) reference as- of fructosamine and glycated albumin and for FPG, and most likely for the 2-h PG,
say. Although point-of-care A1C assays lower levels of 1,5-anhydroglucitol, sug- especially if the glucose samples remain
may be NGSP certified, proficiency testing gesting that their glycemic burden (partic- at room temperature and are not centri-
is not mandated for performing the test, ularly postprandially) may be higher (8). fuged promptly. Barring laboratory error,
so use of point-of-care assays for diagnos- Moreover, the association of A1C with such patients will likely have test results
tic purposes is not recommended. risk for complications is similar in African near the margins of the diagnostic thresh-
The A1C has several advantages com- Americans and non-Hispanic whites (9). old. The health care professional should
pared with the FPG and OGTT, including follow the patient closely and repeat the
Hemoglobinopathies/Anemias
greater convenience (fasting not re- test in 3–6 months.
Interpreting A1C levels in the presence of
quired), greater preanalytical stability, certain hemoglobinopathies and anemia
and less day-to-day perturbations during CATEGORIES OF INCREASED RISK
may be problematic. For patients with an FOR DIABETES (PREDIABETES)
stress and illness. However, these advan- abnormal hemoglobin but normal red blood
tages may be offset by the lower sensitiv- cell turnover, such as those with the sickle Recommendations
ity of A1C at the designated cut point, c Testing to assess risk for future di-
cell trait, an A1C assay without interference
greater cost, limited availability of A1C from abnormal hemoglobins should be abetes in asymptomatic people
testing in certain regions of the develop- used. An updated list of interferences is should be considered in adults of
ing world, and the imperfect correlation available at www.ngsp.org/interf.asp. any age who are overweight or
between A1C and average glucose in cer- obese (BMI $25 kg/m 2 or $23
Red Blood Cell Turnover kg/m 2 in Asian Americans) and
tain individuals. National Health and
Nutrition Examination Survey (NHANES) In conditions associated with increased who have one or more additional
data indicate that an A1C cut point of red blood cell turnover, such as pregnancy risk factors for diabetes. B
$6.5% (48 mmol/mol) identifies one- (second and third trimesters), recent blood c For all patients, testing should begin
third fewer cases of undiagnosed diabe- loss or transfusion, erythropoietin therapy, at age 45 years. B
tes than a fasting glucose cut point of or hemolysis, only blood glucose criteria c If tests are normal, repeat testing
$126 mg/dL (7.0 mmol/L) (4). should be used to diagnose diabetes. carried out at a minimum of 3-year
It is important to take age, race/ intervals is reasonable. C
ethnicity, and anemia/hemoglobinop- Confirming the Diagnosis c To test for prediabetes, fasting
athies into consideration when using Unless there is a clear clinical diagnosis plasma glucose, 2-h plasma glucose
the A1C to diagnose diabetes. (e.g., patient in a hyperglycemic crisis or after 75-g oral glucose tolerance test,
Age
with classic symptoms of hyperglycemia and A1C are equally appropriate. B
and a random plasma glucose $200 c In patients with prediabetes, iden-
The epidemiological studies that formed
mg/dL [11.1 mmol/L]), a second test is re- tify and, if appropriate, treat other
the basis for recommending A1C to di-
agnose diabetes included only adult
quired for confirmation. It is recom- cardiovascular disease risk factors. B
mended that the same test be repeated c Testing to detect prediabetes should
populations. Therefore, it remains un-
without delay using a new blood sample be considered in children and ado-
clear if A1C and the same A1C cut point
for confirmation because there will be a lescents who are overweight or
should be used to diagnose diabetes in
greater likelihood of concurrence. For ex- obese and who have two or more
children and adolescents (4,5).
ample, if the A1C is 7.0% (53 mmol/mol) additional risk factors for diabetes. E
Race/Ethnicity and a repeat result is 6.8% (51 mmol/mol),
A1C levels may vary with patients’ race/ the diagnosis of diabetes is confirmed. If
ethnicity (6,7). For example, African Amer- two different tests (such as A1C and FPG) Description
icans may have higher A1C levels than are both above the diagnostic threshold, In 1997 and 2003, the Expert Committee
non-Hispanic whites despite similar fast- this also confirms the diagnosis. On the on the Diagnosis and Classification of Di-
ing and postglucose load glucose levels. other hand, if a patient has discordant abetes Mellitus (10,11) recognized a
African Americans also have higher levels results from two different tests, then group of individuals whose glucose
care.diabetesjournals.org Classification and Diagnosis of Diabetes S15

levels did not meet the criteria for di- Hence, it is reasonable to consider an islet cell autoantibodies and autoanti-
abetes but were too high to be consid- A1C range of 5.7–6.4% (39–46 mmol/mol) bodies to insulin, GAD (GAD65), the ty-
ered normal. “Prediabetes” is the term as identifying individuals with prediabe- rosine phosphatases IA-2 and IA-2b, and
used for individuals with impaired fast- tes. As with those with IFG and/or IGT, ZnT8. Type 1 diabetes is defined by one
ing glucose (IFG) and/or impaired glu- individuals with an A1C of 5.7–6.4% or more of these autoimmune markers.
cose tolerance (IGT) and indicates an (39–46 mmol/mol) should be informed The disease has strong HLA associations,
increased risk for the future develop- of their increased risk for diabetes and with linkage to the DQA and DQB genes.
ment of diabetes. IFG and IGT should CVD and counseled about effective strate- These HLA-DR/DQ alleles can be either
not be viewed as clinical entities in their gies to lower their risks (see Section 4 “Pre- predisposing or protective.
own right but rather risk factors for di- vention or Delay of Type 2 Diabetes”). The rate of b-cell destruction is quite
abetes (Table 2.2) and cardiovascular Similar to glucose measurements, the con- variable, being rapid in some individu-
disease (CVD). IFG and IGT are associ- tinuum of risk is curvilinear, so as A1C rises, als (mainly infants and children) and
ated with obesity (especially abdominal the diabetes risk rises disproportionately slow in others (mainly adults). Children
or visceral obesity), dyslipidemia with (12). Aggressive interventions and vigilant and adolescents may present with ke-
high triglycerides and/or low HDL cho- follow-up should be pursued for those toacidosis as the first manifestation of
lesterol, and hypertension. considered at very high risk (e.g., those the disease. Others have modest fast-
with A1C .6.0% [42 mmol/mol]). ing hyperglycemia that can rapidly
Diagnosis Table 2.3 summarizes the categories change to severe hyperglycemia and/or
In 1997 and 2003, the Expert Committee of prediabetes and Table 2.2 the criteria ketoacidosis with infection or other
on the Diagnosis and Classification of Di- for prediabetes testing. For recommen- stress. Adults may retain sufficient b-cell
abetes Mellitus (10,11) defined IFG as dations regarding risk factors and function to prevent ketoacidosis for
FPG levels 100–125 mg/dL (5.6–6.9 screening for prediabetes, see pp. S17– many years; such individuals eventually
mmol/L) and IGT as 2-h PG after 75-g S18 (“Testing for Type 2 Diabetes and Pre- become dependent on insulin for survival
OGTT levels 140–199 mg/dL (7.8–11.0 diabetes in Asymptomatic Adults” and and are at risk for ketoacidosis. At this
mmol/L). It should be noted that the “Testing for Type 2 Diabetes and Pre- latter stage of the disease, there is little
World Health Organization (WHO) and diabetes in Children and Adolescents”). or no insulin secretion, as manifested by
numerous diabetes organizations define low or undetectable levels of plasma C-
the IFG cutoff at 110 mg/dL (6.1 mmol/L). TYPE 1 DIABETES peptide. Immune-mediated diabetes
As with the glucose measures, several Recommendations commonly occurs in childhood and ado-
prospective studies that used A1C to c Blood glucose rather than A1C should lescence, but it can occur at any age, even
predict the progression to diabetes be used to diagnose acute onset of in the 8th and 9th decades of life.
demonstrated a strong, continuous as- type 1 diabetes in individuals with Autoimmune destruction of b-cells
sociation between A1C and subsequent symptoms of hyperglycemia. E has multiple genetic predispositions
diabetes. In a systematic review of c Inform the relatives of patients with and is also related to environmental fac-
44,203 individuals from 16 cohort stud- type 1 diabetes of the opportunity tors that are still poorly defined. Al-
ies with a follow-up interval averaging to be tested for type 1 diabetes risk, though patients are not typically obese
5.6 years (range 2.8–12 years), those but only in the setting of a clinical when they present with type 1 diabetes,
with an A1C between 5.5–6.0% (37–42 research study. E obesity should not preclude the diagno-
mmol/mol) had a substantially in- sis. These patients are also prone to
creased risk of diabetes (5-year inci- other autoimmune disorders such as
Diagnosis
dence from 9% to 25%). An A1C range Hashimoto thyroiditis, celiac disease,
In a patient with acute symptoms, mea-
of 6.0–6.5% (42–48 mmol/mol) had a Graves disease, Addison disease, viti-
surement of blood glucose is part of the
5-year risk of developing diabetes be- ligo, autoimmune hepatitis, myasthenia
definition of diabetes (classic symptoms of
tween 25% and 50% and a relative gravis, and pernicious anemia.
hyperglycemia or hyperglycemic crisis plus
risk 20 times higher compared with an
a random plasma glucose $200 mg/dL
A1C of 5.0% (31 mmol/mol) (12). In a Idiopathic Type 1 Diabetes
[11.1 mmol/L]). In these cases, knowing
community-based study of African Some forms of type 1 diabetes have no
the blood glucose level is critical because,
American and non-Hispanic white adults known etiologies. These patients have
in addition to confirming that symptoms
without diabetes, baseline A1C was a permanent insulinopenia and are prone
are due to diabetes, this will inform man-
stronger predictor of subsequent diabe- to ketoacidosis, but have no evidence of
agement decisions. Some providers may
tes and cardiovascular events than fast- b-cell autoimmunity. Although only a
also want to know the A1C to determine
ing glucose (13). Other analyses suggest minority of patients with type 1 diabetes
how long a patient has had hyperglycemia.
that an A1C of 5.7% (39 mmol/mol) is fall into this category, of those who do,
associated with a diabetes risk similar Immune-Mediated Diabetes most are of African or Asian ancestry.
to that of the high-risk participants in This form, previously called “insulin- Individuals with this form of diabetes
the Diabetes Prevention Program (DPP) dependent diabetes” or “juvenile-onset suffer from episodic ketoacidosis and
(14), and A1C at baseline was a strong diabetes,” accounts for 5–10% of diabe- exhibit varying degrees of insulin defi-
predictor of the development of glucose- tes and is due to cellular-mediated auto- ciency between episodes. This form of
defined diabetes during the DPP and its immune destruction of the pancreatic diabetes is strongly inherited and is not
follow-up (15). b-cells. Autoimmune markers include HLA associated. An absolute requirement
S16 Classification and Diagnosis of Diabetes Diabetes Care Volume 39, Supplement 1, January 2016

Table 2.2—Criteria for testing for diabetes or prediabetes in asymptomatic adults being conducted to test various meth-
1. Testing should be considered in all adults who are overweight (BMI $25 kg/m or $23 kg/m in
2 2 ods of preventing type 1 diabetes in
Asian Americans) and have additional risk factors: those with evidence of autoimmunity
c physical inactivity (www.clinicaltrials.gov).
c first-degree relative with diabetes
c high-risk race/ethnicity (e.g., African American, Latino, Native American, Asian American,
TYPE 2 DIABETES
Pacific Islander)
c women who delivered a baby weighing .9 lb or were diagnosed with GDM Recommendations
c hypertension ($140/90 mmHg or on therapy for hypertension) c Testing to detect type 2 diabetes in
c HDL cholesterol level ,35 mg/dL (0.90 mmol/L) and/or a triglyceride level .250 mg/dL asymptomatic people should be con-
(2.82 mmol/L) sidered in adults of any age who are
c women with polycystic ovary syndrome
overweight or obese (BMI $25
c A1C $5.7% (39 mmol/mol), IGT, or IFG on previous testing
c other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis
kg/m2 or $23 kg/m2 in Asian Amer-
nigricans) icans) and who have one or more
c history of CVD additional risk factors for diabetes. B
2. For all patients, testing should begin at age 45 years. c For all patients, testing should be-
3. If results are normal, testing should be repeated at a minimum of 3-year intervals, with gin at age 45 years. B
consideration of more frequent testing depending on initial results (e.g., those with c If tests are normal, repeat testing
prediabetes should be tested yearly) and risk status. carried out at a minimum of 3-year
intervals is reasonable. C
c To test for type 2 diabetes, fasting
for insulin replacement therapy in af- type 1 diabetes within 10 years and 84% plasma glucose, 2-h plasma glucose
fected patients may be intermittent. within 15 years (19,20). These findings are after 75-g oral glucose tolerance test,
highly significant because, while the and A1C are equally appropriate. B
Testing for Type 1 Diabetes Risk German group was recruited from off- c In patients with diabetes, identify
The incidence and prevalence of type 1 spring of parents with type 1 diabetes, and, if appropriate, treat other car-
diabetes is increasing (16). Patients with the Finnish and American groups were diovascular disease risk factors. B
type 1 diabetes often present with acute recruited from the general population. c Testing to detect type 2 diabetes
symptoms of diabetes and markedly el- Remarkably, the findings in all three should be considered in children
evated blood glucose levels, and ap- groups were the same, suggesting that and adolescents who are overweight
proximately one-third are diagnosed the same sequence of events led to clin- or obese and who have two or more
with life-threatening ketoacidosis (2). ical disease in both “sporadic” and famil- additional risk factors for diabetes. E
Several studies indicate that measuring ial cases of type 1 diabetes.
islet autoantibodies in relatives of those Although there is currently a lack of
Description
with type 1 diabetes may identify individ- accepted screening programs, one Type 2 diabetes, previously referred to
uals who are at risk for developing type 1 should consider referring relatives of as “non–insulin-dependent diabetes” or
diabetes (17). Such testing, coupled with those with type 1 diabetes for antibody “adult-onset diabetes,” accounts for
education about diabetes symptoms and testing for risk assessment in the setting 90–95% of all diabetes. This form en-
close follow-up in an observational clini- of a clinical research study (http://www2 compasses individuals who have insulin
cal study, may enable earlier identifica- .diabetestrialnet.org). Widespread clini- resistance and usually relative (rather
tion of type 1 diabetes onset (18). There cal testing of asymptomatic low-risk in- than absolute) insulin deficiency. At
is evidence to suggest that early diagnosis dividuals is not currently recommended least initially, and often throughout
may limit acute complications (19). due to lack of approved therapeutic in- their lifetime, these individuals may
A recent study reported the risk of pro- terventions. Higher-risk individuals may not need insulin treatment to survive.
gression to type 1 diabetes from the be tested, but only in the context of a There are various causes of type 2 di-
time of seroconversion to autoantibody clinical research setting. Individuals abetes. Although the specific etiologies
positivity in three pediatric cohorts from who test positive will be counseled are not known, autoimmune destruction
Finland, Germany, and the U.S. Of the 585 about the risk of developing diabetes, of b-cells does not occur, and patients do
children who developed more than two diabetes symptoms, and DKA preven- not have any of the other known causes
autoantibodies, nearly 70% developed tion. Numerous clinical studies are of diabetes. Most, but not all, patients
with type 2 diabetes are overweight or
Table 2.3—Categories of increased risk for diabetes (prediabetes)* obese. Excess weight itself causes some
FPG 100 mg/dL (5.6 mmol/L) to 125 mg/dL (6.9 mmol/L) (IFG) degree of insulin resistance. Patients who
OR are not obese or overweight by traditional
2-h PG in the 75-g OGTT 140 mg/dL (7.8 mmol/L) to 199 mg/dL (11.0 mmol/L) (IGT) weight criteria may have an increased
OR
percentage of body fat distributed pre-
dominantly in the abdominal region.
A1C 5.7–6.4% (39–46 mmol/mol)
Ketoacidosis seldom occurs sponta-
*For all three tests, risk is continuous, extending below the lower limit of the range and neously in type 2 diabetes; when seen,
becoming disproportionately greater at the higher end of the range.
it usually arises in association with the
care.diabetesjournals.org Classification and Diagnosis of Diabetes S17

stress of another illness such as infec- individuals to identify those with predi- (sensitivity of 80%) for nearly all Asian
tion. Type 2 diabetes frequently goes abetes or diabetes might seem reason- American subgroups (with levels slightly
undiagnosed for many years because hy- able, rigorous clinical trials to prove the lower for Japanese Americans). This
perglycemia develops gradually and, at effectiveness of such screening have not makes a rounded cut point of 23 kg/m2
earlier stages, is often not severe enough been conducted and are unlikely to occur. practical. In determining a single BMI cut
for the patient to notice the classic diabe- A large European randomized con- point, it is important to balance sensitivity
tes symptoms. Nevertheless, even undi- trolled trial compared the impact of and specificity so as to provide a valuable
agnosed patients are at increased risk of screening for diabetes and intensive screening tool without numerous false
developing macrovascular and microvas- multifactorial intervention with that of positives. An argument can be made to
cular complications. screening and routine care (22). General push the BMI cut point to lower than
Whereas patients with type 2 diabetes practice patients between the ages of 23 kg/m2 in favor of increased sensitivity;
may have insulin levels that appear nor- 40–69 years were screened for diabetes however, this would lead to an unaccept-
mal or elevated, the higher blood glucose and randomly assigned by practice to ably low specificity (13.1%). Data from the
levels in these patients would be expected intensive treatment of multiple risk fac- WHO also suggest that a BMI $23 kg/m2
to result in even higher insulin values had tors or routine diabetes care. After 5.3 should be used to define increased risk
their b-cell function been normal. Thus, years of follow-up, CVD risk factors were in Asian Americans (27). The finding
insulin secretion is defective in these pa- modestly but significantly improved that half of diabetes in Asian Americans
tients and insufficient to compensate for with intensive treatment compared is undiagnosed suggests that testing is not
insulin resistance. Insulin resistance may with routine care, but the incidence of occurring at lower BMI thresholds (21).
improve with weight reduction and/or first CVD events or mortality was not Evidence also suggests that other
pharmacological treatment of hypergly- significantly different between the populations may benefit from lower
cemia but is seldom restored to normal. groups (22). The excellent care provided BMI cut points. For example, in a large
The risk of developing type 2 diabetes to patients in the routine care group and multiethnic cohort study, for an equiva-
increases with age, obesity, and lack of the lack of an unscreened control arm lent incidence rate of diabetes, a BMI of
physical activity. It occurs more fre- limited the authors’ ability to prove that 30 kg/m2 in non-Hispanic whites was
quently in women with prior GDM, in screening and early intensive treatment equivalent to a BMI of 26 kg/m2 in Afri-
those with hypertension or dyslipidemia, impact outcomes. Mathematical model- can Americans (28).
and in certain racial/ethnic subgroups ing studies suggest that major benefits
Medications
(African American, American Indian, are likely to accrue from the early diag-
Certain medications, such as glucocorti-
Hispanic/Latino, and Asian American). It nosis and treatment of glycemia and car-
coids, thiazide diuretics, and atypical an-
is often associated with a strong genetic diovascular risk factors in type 2 diabetes
tipsychotics (29), are known to increase
predisposition, more so than type 1 dia- (23); moreover, screening, beginning at
the risk of diabetes and should be con-
betes. However, the genetics of type 2 age 30 or 45 years and independent
sidered when ascertaining a diagnosis.
diabetes is poorly understood. of risk factors, may be cost-effective
(,$11,000 per quality-adjusted life- Diagnostic Tests
Testing for Type 2 Diabetes and year gained) (24). FPG, 2-h PG after 75-g OGTT, and A1C
Prediabetes in Asymptomatic Adults Additional considerations regarding are equally appropriate for testing. It
Prediabetes and type 2 diabetes meet cri- testing for type 2 diabetes and predia- should be noted that the tests do not
teria for conditions in which early detec- betes in asymptomatic patients include necessarily detect diabetes in the same
tion is appropriate. Both conditions are the following: individuals. The efficacy of interventions
common and impose significant clinical Age for primary prevention of type 2 diabe-
and public health burdens. There is often Testing recommendations for diabetes tes (30,31) has primarily been demon-
a long presymptomatic phase before the in asymptomatic adults are listed in strated among individuals with IGT, not
diagnosis of type 2 diabetes. Simple tests Table 2.2. Age is a major risk factor for for individuals with isolated IFG or for
to detect preclinical disease are readily diabetes. Testing should begin at age 45 those with prediabetes defined by A1C
available. The duration of glycemic burden years for all patients. criteria.
is a strong predictor of adverse outcomes.
Testing Interval
There are effective interventions that pre- BMI and Ethnicity
The appropriate interval between tests is
vent progression from prediabetes to dia- Testing should be considered in adults
not known (32). The rationale for the
betes (see Section 4 “Prevention or Delay of any age with BMI $25 kg/m2 and one
3-year interval is that with this interval,
of Type 2 Diabetes”) and reduce the risk of or more additional risk factors for dia-
the number of false-positive tests that re-
diabetes complications (see Section 8 betes. However, recent data (25) and
quire confirmatory testing will be reduced
“Cardiovascular Disease and Risk Man- evidence from the ADA position state-
and individuals with false-negative tests
agement” and Section 9 “Microvascular ment “BMI Cut Points to Identify At-Risk
will be retested before substantial time
Complications and Foot Care”). Asian Americans for Type 2 Diabetes
elapses and complications develop (32).
Approximately one-quarter of people Screening” (26) suggest that the BMI
with diabetes in the U.S. and nearly half cut point should be lower for the Asian Community Screening
of Asian and Hispanic Americans with American population. For diabetes Ideally, testing should be carried out
diabetes are undiagnosed (21). Al- screening purposes, the BMI cut points within a health care setting because of
though screening of asymptomatic fall consistently between 23 and 24 kg/m2 the need for follow-up and treatment.
S18 Classification and Diagnosis of Diabetes Diabetes Care Volume 39, Supplement 1, January 2016

Community testing outside a health care 1. “One-step” 75-g OGTT or


using the oral glucose tolerance
setting is not recommended because 2. “Two-step” approach with a 50-g (non-
test and clinically appropriate non-
people with positive tests may not fasting) screen followed by a 100-g
pregnancy diagnostic criteria. E
seek, or have access to, appropriate OGTT for those who screen positive
c Women with a history of gesta-
follow-up testing and care. Community
tional diabetes mellitus should
testing may also be poorly targeted; i.e., Different diagnostic criteria will identify
have lifelong screening for the de-
it may fail to reach the groups most at different degrees of maternal hyperglyce-
velopment of diabetes or predia-
risk and inappropriately test those at mia and maternal/fetal risk, leading some
betes at least every 3 years. B
very low risk or even those who have experts to debate, and disagree on, opti-
c Women with a history of gesta-
already been diagnosed. mal strategies for the diagnosis of GDM.
tional diabetes mellitus found to
Testing for Type 2 Diabetes and
have prediabetes should receive
One-Step Strategy
Prediabetes in Children and
lifestyle interventions or metfor-
In the 2011 Standards of Care (39), the
min to prevent diabetes. A
Adolescents ADA for the first time recommended
In the last decade, the incidence and that all pregnant women not known to
prevalence of type 2 diabetes in ado- have prior diabetes undergo a 75-g
Definition
lescents has increased dramatically, es- For many years, GDM was defined as any OGTT at 24–28 weeks of gestation, based
pecially in ethnic populations (16). degree of glucose intolerance that was first on a recommendation of the Interna-
Recent studies question the validity of recognized during pregnancy (10), regard- tional Association of the Diabetes and
A1C in the pediatric population, espe- less of whether the condition may have pre- Pregnancy Study Groups (IADPSG) (40).
cially among certain ethnicities, and dated the pregnancy or persisted after the The IADPSG defined diagnostic cut points
suggest OGTT or FPG as more suitable pregnancy. This definition facilitated a uni- for GDM as the average glucose values
diagnostic tests (33). However, many of form strategy for detection and classification (fasting, 1-h, and 2-h PG) in the HAPO
these studies do not recognize that di- of GDM, but it was limited by imprecision. study at which odds for adverse out-
abetes diagnostic criteria are based on The ongoing epidemic of obesity and comes reached 1.75 times the estimated
long-term health outcomes, and valida- diabetes has led to more type 2 diabetes odds of these outcomes at the mean glu-
tions are not currently available in the in women of childbearing age, with an in- cose levels of the study population. This
pediatric population (34). The ADA ac- crease in the number of pregnant women one-step strategy was anticipated to sig-
knowledges the limited data support- with undiagnosed type 2 diabetes (37). Be- nificantly increase the incidence of GDM
ing A1C for diagnosing type 2 diabetes cause of the number of pregnant women (from 5–6% to 15–20%), primarily be-
in children and adolescents. Although with undiagnosed type 2 diabetes, it is rea- cause only one abnormal value, not two,
A1C is not recommended for diagnosis sonable to test women with risk factors for became sufficient to make the diagnosis.
of diabetes in children with cystic fibro- type 2 diabetes (Table 2.2) at their initial The ADA recognized that the anticipated
sis or symptoms suggestive of acute on- prenatal visit, using standard diagnostic increase in the incidence of GDM would
set of type 1 diabetes and only A1C criteria (Table 2.1). Women with diabetes have significant impact on the costs, med-
assays without interference are appro- in the first trimester would be classified as ical infrastructure capacity, and potential
priate for children with hemoglobinopa- having type 2 diabetes. GDM is diabetes for increased “medicalization” of preg-
thies, the ADA continues to recommend diagnosed in the second or third trimester nancies previously categorized as normal,
A1C for diagnosis of type 2 diabetes in of pregnancy that is not clearly either but recommended these diagnostic crite-
this cohort (35,36). The modified recom- type 1 or type 2 diabetes (see Section 12 ria changes in the context of worrisome
mendations of the ADA consensus “Management of Diabetes in Pregnancy”). worldwide increases in obesity and diabe-
report “Type 2 Diabetes in Children tes rates with the intent of optimizing
and Adolescents” are summarized in Diagnosis gestational outcomes for women and
Table 2.4. GDM carries risks for the mother and ne- their offspring.
onate. Not all adverse outcomes are of The expected benefits to these preg-
GESTATIONAL DIABETES equal clinical importance. The Hypergly- nancies and offspring are inferred from
MELLITUS cemia and Adverse Pregnancy Outcome intervention trials that focused on
(HAPO) study (38), a large-scale (25,000 women with lower levels of hyperglyce-
Recommendations
pregnant women) multinational cohort mia than identified using older GDM di-
c Test for undiagnosed type 2 diabe-
study, demonstrated that risk of adverse agnostic criteria and that found modest
tes at the first prenatal visit in
maternal, fetal, and neonatal outcomes benefits including reduced rates of
those with risk factors, using stan-
continuously increased as a function of large-for-gestational-age births and pre-
dard diagnostic criteria. B
maternal glycemia at 24–28 weeks, even eclampsia (41,42). It is important to
c Test for gestational diabetes mel-
within ranges previously considered nor- note that 80–90% of women being
litus at 24–28 weeks of gestation
mal for pregnancy. For most complica- treated for mild GDM in two random-
in pregnant women not previously
tions, there was no threshold for risk. ized controlled trials (whose glucose val-
known to have diabetes. A
These results have led to careful reconsid- ues overlapped with the thresholds
c Screen women with gestational di-
eration of the diagnostic criteria for GDM. recommended by the IADPSG) could
abetes mellitus for persistent diabe-
GDM diagnosis (Table 2.5) can be accom- be managed with lifestyle therapy
tes at 6–12 weeks postpartum,
plished with either of two strategies: alone. Data are lacking on how the
care.diabetesjournals.org Classification and Diagnosis of Diabetes S19

Table 2.4—Testing for type 2 diabetes or prediabetes in asymptomatic children* c Because a diagnosis of maturity-
Criteria onset diabetes of the young may
c Overweight (BMI .85th percentile for age and sex, weight for height .85th percentile, or
impact therapy and lead to identi-
weight .120% of ideal for height)
fication of other affected family
Plus any two of the following risk factors: members, consider referring indi-
c Family history of type 2 diabetes in first- or second-degree relative
c Race/ethnicity (Native American, African American, Latino, Asian American, Pacific Islander)
viduals with diabetes not typical of
c Signs of insulin resistance or conditions associated with insulin resistance (acanthosis
type 1 or type 2 diabetes and oc-
nigricans, hypertension, dyslipidemia, polycystic ovary syndrome, or small-for-gestational- curing in successive generations
age birth weight) (suggestive of an autosomal dom-
c Maternal history of diabetes or GDM during the child’s gestation inant pattern of inheritance) to a
Age of initiation: age 10 years or at onset of puberty, if puberty occurs at a younger age specialist for further evaluation. E
Frequency: every 3 years
*Persons aged #18 years. Monogenic defects that cause b-cell
dysfunction, such as neonatal diabetes
treatment of lower levels of hyperglyce- its guidelines in 2013 and supported the and MODY, represent a small fraction of
mia affects a mother’s risk for the devel- two-step approach (45). patients with diabetes (,5%). These
opment of type 2 diabetes in the future forms of diabetes are frequently charac-
Future Considerations
and her offspring’s risk for obesity, di- terized by onset of hyperglycemia at an
The conflicting recommendations from early age (generally before age 25 years).
abetes, and other metabolic dysfunc- expert groups underscore the fact that
tion. Additional well-designed clinical there are data to support each strategy. Neonatal Diabetes
studies are needed to determine the op- The decision of which strategy to imple- Neonatal diabetes is a monogenic form of
timal intensity of monitoring and treat- ment must therefore be made based on diabetes with onset in the first 6 months of
ment of women with GDM diagnosed by the relative values placed on factors that life. It can be mistaken for the more com-
the one-step strategy. have yet to be measured (e.g., cost–benefit mon type 1 diabetes, but type 1 diabetes
estimation, willingness to change prac- rarely occurs before 6 months of age. Neo-
Two-Step Strategy
tice based on correlation studies rather natal diabetes can either be transient or
In 2013, the National Institutes of Health
than clinical intervention trial results, rel- permanent. The most common genetic
(NIH) convened a consensus develop-
ative role of cost considerations, and avail- defect causing transient disease is a defect
ment conference on diagnosing GDM.
able infrastructure locally, nationally, and on ZAC/HYAMI imprinting, whereas per-
The 15-member panel had representatives
internationally). manent neonatal diabetes is most com-
from obstetrics/gynecology, maternal-
As the IADPSG criteria have been adop- monly an autosomal dominant defect in
fetal medicine, pediatrics, diabetes re-
ted internationally, further evidence has the gene encoding the Kir6.2 subunit of
search, biostatistics, and other related
emerged to support improved pregnancy the b-cell KATP channel. Correct diagnosis
fields to consider diagnostic criteria (43).
outcomes with cost savings (46) and may has important implications, because chil-
The panel recommended the two-step
be the preferred approach. In addition, dren with neonatal diabetes due to muta-
approach of screening with a 1-h 50-g
pregnancies complicated by GDM per tions affecting Kir6.2 should be treated
glucose load test (GLT) followed by a 3-h
IADPSG criteria, but not recognized as with sulfonylureas rather than insulin.
100-g OGTT for those who screen posi-
such, have comparable outcomes to preg-
tive, a strategy commonly used in the U.S. Maturity-Onset Diabetes of the Young
nancies diagnosed as GDM by the more
Key factors reported in the NIH pan- MODY is characterized by impaired insulin
stringent two-step criteria (47). There
el’s decision-making process were the secretion with minimal or no defects in
remains strong consensus that estab-
lack of clinical trial interventions dem- insulin action. It is inherited in an autoso-
lishing a uniform approach to diagnosing
onstrating the benefits of the one-step mal dominant pattern. Abnormalities at
GDM will benefit patients, caregivers,
strategy and the potential negative con- six genetic loci on different chromosomes
and policymakers. Longer-term outcome
sequences of identifying a large new have been identified to date. The most
studies are currently under way.
group of women with GDM, including common form (MODY 3) is associated
medicalization of pregnancy with in- MONOGENIC DIABETES with mutations on chromosome 12 in a
creased interventions and costs. More- SYNDROMES hepatic transcription factor referred to as
over, screening with a 50-g GLT does not hepatocyte nuclear factor (HNF)-1a and
Recommendations
require fasting and is therefore easier to also referred to as transcription factor-1
c All children diagnosed with diabe-
accomplish for many women. Treat- (TCF-1). The second most common form
tes in the first 6 months of life
ment of higher threshold maternal (MODY 2) is associated with mutations in
should have genetic testing. B
hyperglycemia, as identified by the two- the glucokinase gene on chromosome 7p
c Maturity-onset diabetes of the
step approach, reduces rates of neonatal and results in a defective glucokinase mol-
young should be considered in indi-
macrosomia, large-for-gestational-age ecule. Glucokinase converts glucose to
viduals who have mild stable fasting
births (44), and shoulder dystocia, with- glucose-6-phosphate, the metabolism of
hyperglycemia and multiple family
out increasing small-for-gestational-age which, in turn, stimulates insulin secretion
members with diabetes not charac-
births. The American College of Obstetri- by the b-cell. The less common forms of
teristic of type 1 or type 2 diabetes. E
cians and Gynecologists (ACOG) updated MODY result from mutations in other
S20 Classification and Diagnosis of Diabetes Diabetes Care Volume 39, Supplement 1, January 2016

Table 2.5—Screening for and diagnosis of GDM occurring in about 20% of adolescents
One-step strategy
and 40–50% of adults. Diabetes in this
Perform a 75-g OGTT, with plasma glucose measurement when patient is fasting and at 1 and
population, compared with individuals
2 h, at 24–28 weeks of gestation in women not previously diagnosed with overt diabetes. with type 1 or type 2 diabetes, is asso-
The OGTT should be performed in the morning after an overnight fast of at least 8 h. ciated with worse nutritional status,
The diagnosis of GDM is made when any of the following plasma glucose values are met or more severe inflammatory lung dis-
exceeded: ease, and greater mortality. Insulin in-
c Fasting: 92 mg/dL (5.1 mmol/L) sufficiency is the primary defect in
c 1 h: 180 mg/dL (10.0 mmol/L) CFRD. Genetically determined b-cell
c 2 h: 153 mg/dL (8.5 mmol/L) function and insulin resistance associ-
Two-step strategy ated with infection and inflammation
Step 1: Perform a 50-g GLT (nonfasting), with plasma glucose measurement at 1 h, at 24–28 may also contribute to the develop-
weeks of gestation in women not previously diagnosed with overt diabetes. ment of CFRD. Milder abnormalities
If the plasma glucose level measured 1 h after the load is $140 mg/dL* (7.8 mmol/L), proceed of glucose tolerance are even more
to a 100-g OGTT.
common and occur at earlier ages
Step 2: The 100-g OGTT should be performed when the patient is fasting. than CFRD. Although screening for di-
The diagnosis of GDM is made if at least two of the following four plasma glucose levels abetes before the age of 10 years can
(measured fasting and 1 h, 2 h, 3 h after the OGTT) are met or exceeded:
identify risk for progression to CFRD
Carpenter/Coustan (55) or NDDG (56) in those with abnormal glucose toler-
cFasting 95 mg/dL (5.3 mmol/L) 105 mg/dL (5.8 mmol/L) ance, no benefit has been established
c1h 180 mg/dL (10.0 mmol/L) 190 mg/dL (10.6 mmol/L) with respect to weight, height, BMI,
c2h 155 mg/dL (8.6 mmol/L) 165 mg/dL (9.2 mmol/L) or lung function. Continuous glucose
c3h 140 mg/dL (7.8 mmol/L) 145 mg/dL (8.0 mmol/L) monitoring may be more sensitive
NDDG, National Diabetes Data Group. *The ACOG recommends a lower threshold of 135 mg/dL than OGTT to detect risk for progres-
(7.5 mmol/L) in high-risk ethnic populations with higher prevalence of GDM; some experts also sion to CFRD, but evidence linking
recommend 130 mg/dL (7.2 mmol/L). continuous glucose monitoring results
to long-term outcomes is lacking
transcription factors, including HNF-4a, without typical clinical features of and its use is not recommended for
HNF-1b, insulin promoter factor-1 (IPF-1), type 2 diabetes screening (50).
and NeuroD1. CRFD mortality has significantly de-
Diagnosis CYSTIC FIBROSIS–RELATED creased over time, and the gap in mor-
A diagnosis of MODY should be consid- DIABETES tality between cystic fibrosis patients
ered in individuals who have atypical di- Recommendations with and without diabetes has consider-
abetes and multiple family members c Annual screening for cystic fibrosis– ably narrowed (51). There are limited
with diabetes not characteristic of related diabetes with oral glucose clinical trial data on therapy for CFRD.
type 1 or type 2 diabetes. These individ- tolerance test should begin by age The largest study compared three regi-
uals should be referred to a specialist for 10 years in all patients with cystic mens: premeal insulin aspart, repagli-
further evaluation. Readily available fibrosis who do not have cystic nide, or oral placebo in cystic fibrosis
commercial genetic testing now enables fibrosis–related diabetes. B patients with diabetes or abnormal
a genetic diagnosis. It is important to cor- c A1C as a screening test for cystic glucose tolerance. Participants all had
rectly diagnose one of the monogenic fibrosis–related diabetes is not weight loss in the year preceding treat-
forms of diabetes because these patients recommended. B ment; however, in the insulin-treated
may be incorrectly diagnosed with type 1 c Patients with cystic fibrosis–related group, this pattern was reversed, and
or type 2 diabetes, leading to suboptimal diabetes should be treated with patients gained 0.39 (6 0.21) BMI units
treatment regimens and delays in diag- insulin to attain individualized gly- (P 5 0.02). The repaglinide-treated
nosing other family members (48,49). cemic goals. A group had initial weight gain, but this
The diagnosis of monogenic diabetes c In patients with cystic fibrosis and was not sustained by 6 months. The pla-
should be considered in children with impaired glucose tolerance with- cebo group continued to lose weight
the following findings: out confirmed diabetes, prandial (52). Insulin remains the most widely
insulin therapy should be consid- used therapy for CFRD (53).
○ Diabetes diagnosed within the first ered to maintain weight. B Recommendations for the clinical
6 months of life c Beginning 5 years after the diagnosis management of CFRD can be found in
○ Strong family history of diabetes but with- of cystic fibrosis–related diabetes, the ADA position statement “Clinical
out typical features of type 2 diabetes annual monitoring for complications Care Guidelines for Cystic Fibrosis–
(nonobese, low-risk ethnic group) of diabetes is recommended. E Related Diabetes: A Position Statement
○ Mild fasting hyperglycemia (100–150 of the American Diabetes Association
mg/dL [5.5–8.5 mmol/L]), especially if and a Clinical Practice Guideline of
young and nonobese Cystic fibrosis–related diabetes the Cystic Fibrosis Foundation, En-
○ Diabetes with negative diabetes- (CFRD) is the most common comor- dorsed by the Pediatric Endocrine
associated autoantibodies and bidity in people with cystic fibrosis, Society” (54).
care.diabetesjournals.org Classification and Diagnosis of Diabetes S21

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3160–3167 type 2 diabetes. Diabetes Care 2015;38:814–820 on the diagnosis and classification of hyper-
12. Zhang X, Gregg EW, Williamson DF, et al. 26. Hsu WC, Araneta MR, Kanaya AM, Chiang glycemia in pregnancy. Diabetes Care 2010;
A1C level and future risk of diabetes: a system- JL, Fujimoto W. BMI cut points to identify at-risk 33:676–682
atic review. Diabetes Care 2010;33:1665–1673 Asian Americans for type 2 diabetes screening. 41. Landon MB, Spong CY, Thom E, et al.; Eunice
13. Selvin E, Steffes MW, Zhu H, et al. Glycated Diabetes Care 2015;38:150–158 Kennedy Shriver National Institute of Child
hemoglobin, diabetes, and cardiovascular risk 27. WHO Expert Consultation. Appropriate Health and Human Development Maternal-Fetal
in nondiabetic adults. N Engl J Med 2010;362: body-mass index for Asian populations and its Medicine Units Network. A multicenter, ran-
800–811 implications for policy and intervention strate- domized trial of treatment for mild gestational
14. Ackermann RT, Cheng YJ, Williamson DF, gies. Lancet 2004;363:157–163 diabetes. N Engl J Med 2009;361:1339–1348
Gregg EW. Identifying adults at high risk for di- 28. Chiu M, Austin PC, Manuel DG, Shah BR, Tu 42. Crowther CA, Hiller JE, Moss JR, McPhee AJ,
abetes and cardiovascular disease using hemo- JV. Deriving ethnic-specific BMI cutoff points for Jeffries WS, Robinson JS; Australian Carbohy-
globin A1c National Health and Nutrition assessing diabetes risk. Diabetes Care 2011;34: drate Intolerance Study in Pregnant Women
Examination Survey 2005-2006. Am J Prev 1741–1748 (ACHOIS) Trial Group. Effect of treatment of
Med 2011;40:11–17 29. Erickson SC, Le L, Zakharyan A, et al. New- gestational diabetes mellitus on pregnancy out-
15. Diabetes Prevention Program Research onset treatment-dependent diabetes mellitus comes. N Engl J Med 2005;352:2477–2486
Group. HbA1c as a predictor of diabetes and and hyperlipidemia associated with atypical an- 43. Vandorsten JP, Dodson WC, Espeland MA,
as an outcome in the Diabetes Prevention Pro- tipsychotic use in older adults without schizo- et al. NIH consensus development confer-
gram: a randomized clinical trial. Diabetes Care phrenia or bipolar disorder. J Am Geriatr Soc ence: diagnosing gestational diabetes melli-
2015;38:51–58 2012;60:474–479 tus. NIH Consens State Sci Statements 2013;
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SEARCH for Diabetes in Youth Study. Prevalence et al.; Diabetes Prevention Program Research 44. Horvath K, Koch K, Jeitler K, et al. Effects of
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311:1778–1786 N Engl J Med 2002;346:393–403 BMJ 2010;340:c1395
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45. Committee on Practice Bulletins–Obstetrics. 49. Rubio-Cabezas O, Hattersley AT, Njølstad Therapy trial. Diabetes Care 2009;32:1783–
Practice Bulletin No. 137: gestational diabetes PR, et al.; International Society for Pediatric 1788
mellitus. Obstet Gynecol 2013;122:406–416 and Adolescent Diabetes. ISPAD Clinical Practice 53. Onady GM, Stolfi A. Insulin and oral agents
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diagnosis of gestational diabetes mellitus re- and adolescents. Pediatr Diabetes 2014;15 54. Moran A, Brunzell C, Cohen RC, et al.; CFRD
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lower cost in a large cohort of pregnant women: 50. Ode KL, Moran A. New insights into cystic for cystic fibrosis-related diabetes: a position
the St. Carlos Gestational Diabetes Study. fibrosis-related diabetes in children. Lancet Di- statement of the American Diabetes Associa-
Diabetes Care 2014;37:2442–2450 abetes Endocrinol 2013;1:52–58 tion and a clinical practice guideline of the Cystic
47. Ethridge JK Jr, Catalano PM, Waters TP. Peri- 51. Moran A, Dunitz J, Nathan B, Saeed A, Fibrosis Foundation, endorsed by the Pediatric
natal outcomes associated with the diagnosis of Holme B, Thomas W. Cystic fibrosis-related di- Endocrine Society. Diabetes Care 2010;33:
gestational diabetes made by the International abetes: current trends in prevalence, incidence, 2697–2708
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48. Hattersley A, Bruining J, Shield J, Njolstad P, Fibrosis Related Diabetes Therapy Study Group. 56. National Diabetes Data Group. Classifica-
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Pediatr Diabetes 2009;10(Suppl. 12):33–42 results of the Cystic Fibrosis Related Diabetes tes 1979;28:1039–1057
Diabetes Care Volume 39, Supplement 1, January 2016 S23

American Diabetes Association


3. Foundations of Care and
Comprehensive Medical
Evaluation
Diabetes Care 2016;39(Suppl. 1):S23–S35 | DOI: 10.2337/dc16-S006

The foundations of care include self-management education, nutrition, counseling,


physical activity, smoking cessation, immunizations, psychosocial care, and med-
ications (covered in other sections). The comprehensive medical evaluation in-
cludes the initial and ongoing evaluations, assessment of complications,
management of comorbid conditions, and engagement of the patient throughout
the process.

3. FOUNDATIONS OF CARE
FOUNDATIONS OF CARE
Optimal diabetes management starts with laying down the foundations of care. The
health care provider must take a holistic approach in providing care, accounting for
all aspects of the patient’s life circumstances. A team approach to diabetes man-
agement facilitates a comprehensive assessment and development of a plan that
addresses the patient’s values and circumstances. The investment of time and
collaboration can facilitate, and potentially expedite, care delivery and achieve
and maintain outcomes.
The initial clinical evaluation should be as comprehensive as possible as the pa-
tient will now have to address behavioral, dietary, lifestyle, and pharmaceutical
interventions to effectively manage this newly identified chronic condition. The
components for the comprehensive medical evaluation (Table 3.1) will provide
the health care team with information necessary to optimally support a patient
with diabetes. In addition to the medical history and physical examination, labora-
tory tests, nutrition, and psychosocial assessments should be obtained.
Patient Engagement
As discussed in Section 1 “Strategies for Improving Care,” the Chronic Care Model
(CCM) has been shown to be an effective framework for improving the quality of
diabetes care (1–3). This is a patient-centered approach to care that requires a close
working relationship between the patient and clinicians involved in care planning
and delivery. The foundation of successful diabetes management includes ongoing
individual lifestyle and behavioral changes, engagement of the patient, and assess-
ment of the patient’s level of understanding about the disease and level of pre-
paredness for self-management.

BASIS FOR INITIAL CARE


Diabetes self-management education (DSME), diabetes self-management sup-
port (DSMS), medical nutrition therapy (MNT), counseling on smoking cessa-
tion, education on physical activity, guidance on routine immunizations, and
psychosocial care are the cornerstone of diabetes management. Patients
should be referred for such services if not readily available in the clinical
care setting, i.e., referral for DSME, DSMS, MNT, and emotional health con-
cerns. Additionally, specialty and lifestyle change services and programs may Suggested citation: American Diabetes Associa-
be beneficial (Table 3.2). Patients should also receive recommended preven- tion. Foundations of care and comprehensive
tive care services (e.g., cancer screening and immunizations); referral for smok- medical evaluation. Sec. 3. In Standards of Med-
ical Care in Diabetesd2016. Diabetes Care
ing cessation, if needed; and podiatric, ophthalmological, and dental referrals.
2016;39(Suppl. 1):S23–S35
Clinicians should ensure that individuals with diabetes are screened for com-
© 2016 by the American Diabetes Association.
plications and comorbidities. Identifying and implementing the initial approach Readers may use this article as long as the work
to glycemic control with the patient is one part, not the sole aspect, of the is properly cited, the use is educational and not
comprehensive care strategy. for profit, and the work is not altered.
S24 Foundations of Care and Comprehensive Medical Evaluation Diabetes Care Volume 39, Supplement 1, January 2016

Table 3.1—Components of the comprehensive diabetes medical evaluation psychosocial care). Various strategies
Medical history and techniques should be used to enable
c Age and characteristics of onset of diabetes (e.g., diabetic ketoacidosis, asymptomatic patients to self-manage diabetes, includ-
laboratory finding) ing providing education on problem-
c Eating patterns, nutritional status, weight history, and physical activity habits; nutrition solving skills for all aspects of diabetes
education and behavioral support history and needs management. Treatment goals and plans
c Presence of common comorbidities, psychosocial problems, and dental disease
c Screen for depression using PHQ-2 (PHQ-9 if PHQ-2 is positive) or Edinburgh Postnatal
should be individualized and take patient
Depression Scale (EPDS) preferences into account. In developing
c Screen for diabetes distress using DDS or PAID-1 the plan, health care providers should
c History of smoking, alcohol consumption, and substance use consider the patient’s age, school/work
c Diabetes education, self-management, and support history and needs schedule and conditions, physical activ-
c Review of previous treatment regimens and response to therapy (A1C records) ity, eating patterns, social situation, cul-
c Results of glucose monitoring and patient’s use of data
tural factors, diabetes complications,
c Diabetic ketoacidosis frequency, severity, and cause
c Hypoglycemia episodes, awareness, and frequency and causes
health priorities, other medical condi-
c History of increased blood pressure, increased lipids, and tobacco use tions, preferences for care and self-
c Microvascular complications: retinopathy, nephropathy, and neuropathy (sensory, management, and life expectancy.
including history of foot lesions; autonomic, including sexual dysfunction and
gastroparesis)
c Macrovascular complications: coronary heart disease, cerebrovascular disease, and DIABETES SELF-MANAGEMENT
peripheral arterial disease EDUCATION AND SUPPORT
Physical examination
Recommendations
c Height, weight, and BMI; growth and pubertal development in children and adolescents
c In accordance with the national
c Blood pressure determination, including orthostatic measurements when indicated
c Fundoscopic examination standards for diabetes self-man-
c Thyroid palpation agement education (DSME) and
c Skin examination (e.g., for acanthosis nigricans, insulin injection or infusion set insertion support (DSMS), all people with di-
sites) abetes should participate in DSME
c Comprehensive foot examination
to facilitate the knowledge, skills,
c Inspection
c Palpation of dorsalis pedis and posterior tibial pulses
and ability necessary for diabetes
c Presence/absence of patellar and Achilles reflexes self-care and in DSMS to assist with
c Determination of proprioception, vibration, and monofilament sensation implementing and sustaining skills
Laboratory evaluation and behaviors needed for ongoing
c A1C, if the results are not available within the past 3 months self-management, both at diagnosis
c If not performed/available within the past year and as needed thereafter. B
c Fasting lipid profile, including total, LDL, and HDL cholesterol and triglycerides, as needed c Effective self-management, im-
c Liver function tests
proved clinical outcomes, health
c Spot urinary albumin–to–creatinine ratio
c Serum creatinine and estimated glomerular filtration rate
status, and quality of life are key
c Thyroid-stimulating hormone in patients with type 1 diabetes or dyslipidemia or women
outcomes of DSME and DSMS and
aged .50 years should be measured and moni-
tored as part of care. C
c DSME and DSMS should be patient
centered, respectful, and respon-
ONGOING CARE MANAGEMENT with diabetes must assume an active
sive to individual patient prefer-
People with diabetes should receive role in their care. ences, needs, and values, which
medical care from a collaborative, inte- The patient, family, physician, and should guide clinical decisions. A
grated team with diabetes expertise. other members of the health care team c DSME and DSMS programs should
This team may include physicians, nurse should formulate the management plan. have the necessary elements in
practitioners, physician assistants, Integral components of the management their curricula that are needed to
nurses, dietitians, exercise specialists, plan include the foundations of care prevent the onset of diabetes.
pharmacists, dentists, podiatrists, and (DSME, DSMS, MNT, smoking cessation, DSME and DSMS programs should
mental health professionals. Individuals physical activity, immunizations, and therefore tailor their content spe-
cifically when prevention of diabe-
tes is the desired goal. B
Table 3.2—Referrals for initial care management c Because DSME and DSMS can re-
c Eye care professional for annual dilated eye exam sult in cost savings and improved
c Family planning for women of reproductive age outcomes B, DSME and DSMS
c Registered dietitian for MNT should be adequately reimbursed
c DSME/DSMS by third-party payers. E
c Dentist for comprehensive dental and periodontal examination
c Mental health professional, if indicated DSME and DSMS are the ongoing
processes of facilitating the knowledge,
care.diabetesjournals.org Foundations of Care and Comprehensive Medical Evaluation S25

skills, and ability necessary for diabetes (10,13), healthy coping (14,15), and types of diabetes and be supportive of
self-care. These processes incorporate lower costs (16,17). Better outcomes their implementation. See Table 3.3 for
the needs, goals, and life experiences were reported for DSME interventions specific nutrition recommendations.
of the person with diabetes. The overall that were longer (.10 h) and included
Goals of Medical Nutrition Therapy
objectives of DSME and DSMS are to follow-up support (DSMS) (18,19), were
for Adults With Diabetes
support informed decision making, culturally (20,21) and age appropriate
1. To promote and support healthful eat-
self-care behaviors, problem solving, (22,23), were tailored to individual
ing patterns, emphasizing a variety of
and active collaboration with the health needs and preferences, and addressed
nutrient-dense foods in appropriate
care team to improve clinical outcomes, psychosocial issues and incorporated
portion sizes, in order to improve
health status, and quality of life in a behavioral strategies (5,14,24,25). Both
overall health and specifically to
cost-effective manner (4). individual and group approaches have ○ Achieve and maintain body weight
DSME and DSMS are essential ele- been found effective (12,26). There is
goals
ments of diabetes care (5,6), and the growing evidence for the role of com- ○ Attain individualized glycemic,
current national standards for DSME munity health workers (27), as well as
blood pressure, and lipid goals
and DSMS (4) are based on the evidence peer (27–29) and lay (30) leaders, in pro- ○ Delay or prevent complications of
of their benefits. Education helps people viding ongoing support.
diabetes
with diabetes to initiate effective self- DSME is associated with increased pri-
2. To address individual nutrition needs
management and cope with diabetes mary and preventive service use
based on personal and cultural prefer-
when they are first diagnosed. Ongoing (16,31,32) and lower acute, inpatient hos-
ences, health literacy and numeracy,
DSMS helps people with diabetes to pital service use (11). Patients who partic-
access to healthful foods, willingness
maintain effective self-management ipate in DSME are more likely to follow
and ability to make behavioral changes,
throughout a lifetime of diabetes as best practice treatment recommenda-
and barriers to change
they face new challenges and as treat- tions, particularly among the Medicare
3. To maintain the pleasure of eating by
ment advances become available. population, and have lower Medicare
providing nonjudgmental messages
The DSME and DSMS algorithm de- and insurance claim costs (17,31).
about food choices
fines four critical time points for DSME
Reimbursement 4. To provide an individual with diabe-
and DSMS delivery (7):
DSME and DSMS, when provided by a tes with practical tools for develop-
1. At diagnosis program that meets the national stan- ing healthful eating patterns rather
2. Annually for assessment of educa- dards (4) and is recognized by the Amer- than focusing on individual macronu-
tion, nutrition, and emotional needs ican Diabetes Association (ADA) or other trients, micronutrients, or single
3. When new complicating factors arise approval bodies, are reimbursed as part foods
that influence self-management of the Medicare program as overseen by
4. When transitions in care occur the Centers for Medicare & Medicaid Ser- MNT is an integral component of diabe-
vices. DSME is also covered by most tes prevention, management, and self-
Current best practice of DSME is a skill- health insurance plans. Although DSMS management education. All individuals
based approach that focuses on helping has been shown to be instrumental for with diabetes should receive individual-
those with diabetes to make informed improving outcomes and can be provided ized MNT, preferably provided by a reg-
self-management choices (4,5). DSME has via phone calls and telehealth, it currently istered dietitian who is knowledgeable
changed from a didactic approach that has limited reimbursement as compared and skilled in providing diabetes-specific
focused on providing information to em- with in-person follow-up to DSME. MNT. MNT delivered by a registered di-
powerment models that focus on helping etitian shows A1C decreases of 0.3–1%
those with diabetes to make informed self- MEDICAL NUTRITION THERAPY for people with type 1 diabetes (35–37)
management decisions (5). Diabetes care and 0.5–2% for people with type 2 di-
has shifted to an approach that is more For many individuals with diabetes, the
abetes (38–41).
patient centered and places the person most challenging part of the treatment
with diabetes and his or her family at the plan is determining what to eat. It is the Weight Management
center of the care model, working in col- position of the ADA that there is not a Intensive lifestyle programs with fre-
laboration with health care professionals. one-size-fits-all eating pattern for individ- quent follow-up are required to achieve
Patient-centered care is respectful of and uals with diabetes. The ADA recognizes significant reductions in excess body
responsive to individual patient prefer- the integral role of MNT in overall diabe- weight and improve clinical indicators.
ences, needs, and values. It ensures that tes management and recommends that There is strong and consistent evidence
patient values guide all decision making (8). each person with diabetes be actively en- that obesity management can delay pro-
gaged in self-management, education, gression from prediabetes to type 2 di-
and treatment planning with his or her abetes (42,43) and benefits type 2
Evidence for the Benefits health care team, including the collabora- diabetes treatment.
Studies have found that DSME is associ- tive development of an individualized In overweight and obese patients
ated with improved diabetes knowl- eating plan (33,34). Therefore, it is impor- with type 2 diabetes, modest weight
edge, improved self-care behaviors (4), tant that each member of the health care loss, defined as sustained reduction of
lower A1C (6,9,10), lower self-reported team be knowledgeable about nutrition 5% of initial body weight, has been
weight (11,12), improved quality of life therapy principles for people with all shown to improve glycemic control
S26 Foundations of Care and Comprehensive Medical Evaluation Diabetes Care Volume 39, Supplement 1, January 2016

Table 3.3—Nutrition therapy recommendations


Topic Recommendations Evidence rating
Effectiveness of nutrition therapy c An individualized MNT program, preferably provided by a registered dietitian, is A
recommended for all people with type 1 or type 2 diabetes.
c For people with type 1 diabetes or those with type 2 diabetes who are prescribed A
a flexible insulin therapy program, education on how to use carbohydrate
counting or estimation to determine mealtime insulin dosing can improve
glycemic control.
c For individuals whose daily insulin dosing is fixed, having a consistent pattern of B
carbohydrate intake with respect to time and amount can result in improved
glycemic control and a reduced risk of hypoglycemia.
c A simple and effective approach to glycemia and weight management C
emphasizing healthy food choices and portion control may be more helpful for
those with type 2 diabetes who are not taking insulin, who have limited health
literacy or numeracy, and who are elderly and prone to hypoglycemia.
c Because diabetes nutrition therapy can result in cost savings B and improved B, A, E
outcomes (e.g., A1C reduction) A, MNT should be adequately reimbursed by
insurance and other payers. E
Energy balance c Modest weight loss achievable by the combination of lifestyle modification and A
the reduction of energy intake benefits overweight or obese adults with type 2
diabetes and also those at risk for diabetes. Interventional programs to facilitate
this process are recommended.
Eating patterns and macronutrient c As there is no single ideal dietary distribution of calories among carbohydrates, E
distribution fats, and proteins for people with diabetes, macronutrient distribution should be
individualized while keeping total calorie and metabolic goals in mind.
c Carbohydrate intake from whole grains, vegetables, fruits, legumes, and dairy B
products, with an emphasis on foods higher in fiber and lower in glycemic load,
should be advised over other sources, especially those containing sugars.
c People with diabetes and those at risk should avoid sugar-sweetened beverages B, A
in order to control weight and reduce their risk for CVD and fatty liver B and
should minimize the consumption of sucrose-containing foods that have the
capacity to displace healthier, more nutrient-dense food choices. A
Protein c In individuals with type 2 diabetes, ingested protein appears to increase insulin B
response without increasing plasma glucose concentrations. Therefore,
carbohydrate sources high in protein should not be used to treat or prevent
hypoglycemia.
Dietary fat c Whereas data on the ideal total dietary fat content for people with diabetes are B
inconclusive, an eating plan emphasizing elements of a Mediterranean-style diet
rich in monounsaturated fats may improve glucose metabolism and lower CVD
risk and can be an effective alternative to a diet low in total fat but relatively high
in carbohydrates.
c Eating foods rich in long-chain omega-3 fatty acids, such as fatty fish (EPA and B, A
DHA) and nuts and seeds (ALA), is recommended to prevent or treat CVD B;
however, evidence does not support a beneficial role for omega-3 dietary
supplements. A
Micronutrients and herbal supplements c There is no clear evidence that dietary supplementation with vitamins, minerals, C
herbs, or spices can improve diabetes, and there may be safety concerns
regarding the long-term use of antioxidant supplements such as vitamins E and C
and carotene.
Alcohol c Adults with diabetes who drink alcohol should do so in moderation (no more C
than one drink per day for adult women and no more than two drinks per day for
adult men).
c Alcohol consumption may place people with diabetes at increased risk for B
delayed hypoglycemia, especially if taking insulin or insulin secretagogues.
Education and awareness regarding the recognition and management of delayed
hypoglycemia are warranted.
Sodium c As for the general population, people with diabetes should limit sodium B
consumption to ,2,300 mg/day, although further restriction may be indicated
for those with both diabetes and hypertension.
care.diabetesjournals.org Foundations of Care and Comprehensive Medical Evaluation S27

and to reduce the need for glucose- from meal to meal and improving glycemic omega-3 fatty acids did not improve glyce-
lowering medications (44–46). Weight control (36,51,57,58). For individuals on a mic control in individuals with type 2 di-
loss can be attained with lifestyle programs fixed daily insulin schedule, meal planning abetes (53). Randomized controlled trials
that achieve a 500–750 kcal/day energy should emphasize a relatively fixed carbo- also do not support recommending
deficit or provide ;1,200–1,500 kcal/day hydrate consumption pattern with respect omega-3 supplements for primary or sec-
for women and 1,500–1,800 kcal/day for to both time and amount (34). By ondary prevention of CVD (69–73). People
men, adjusted for the individual’s baseline contrast, a simpler diabetes meal planning with diabetes should be advised to follow
body weight. Although benefits may be approach emphasizing portion control and the guidelines for the general population
seen with as little as 5% weight loss, sus- healthful food choices may be better for the recommended intakes of saturated
tained weight loss of $7% is optimal. suited for some elderly individuals, those fat, dietary cholesterol, and trans fat (64).
These diets may differ in the types of with cognitive dysfunction, and those for In general, trans fats should be avoided.
foods they restrict (such as high-fat or whom there are concerns over health lit-
high-carbohydrate foods) but are effec- eracy and numeracy (34–36,38,51,57). Sodium
tive if they create the necessary energy As for the general population, people with
deficit (47–50). The diet choice should diabetes should limit their sodium con-
Protein
be based on the patients’ health status sumption to ,2,300 mg/day. Lowering
For individuals without evidence of dia-
and preferences. sodium intake (i.e., 1,500 mg/day) may
betic kidney disease, the evidence is incon-
benefit blood pressure in certain circum-
clusive about recommending an ideal
Carbohydrates stances (74). The American Heart Associa-
amount of protein for optimizing glycemic
Studies examining the ideal amount of tion recommends 1,500 mg/day for
control or for improving one or more CVD
carbohydrate intake for people with dia- African Americans; people diagnosed
risk measures (53). Therefore, these goals
betes are inconclusive, although monitor- with hypertension, diabetes, or chronic
should be individualized. For those with di-
ing carbohydrate intake and considering kidney disease; and people over 51 years
abetic kidney disease (with albuminuria,
the blood glucose response to dietary car- of age (75). However, other studies (76,77)
reduced estimated glomerular filtration
bohydrate are key for improving post- have recommended caution for universal
rate), dietary protein should be maintained
prandial glucose control (51,52). The sodium restriction to 1,500 mg in this pop-
at the recommended daily allowance of
literature concerning glycemic index and ulation. Sodium intake recommendations
0.8 g/kg body weight per day. Reducing
glycemic load in individuals with diabetes should take into account palatability, avail-
the amount of dietary protein below
is complex. Although in some studies low- ability, affordability, and the difficulty of
the recommended daily allowance is
ering the glycemic load of consumed achieving low-sodium recommendations
not recommended because it does not
carbohydrates has demonstrated A1C in a nutritionally adequate diet (78).
alter glycemic measures, cardiovascular
reductions of 20.2% to 20.5% (53,54), a risk measures, or the rate at which glo-
For complete discussion and refer-
systematic review (53) found that whole- ences of all recommendations, see the
merular filtration rate declines (59,60).
grain consumption was not associated ADA position statement “Nutrition Ther-
In individuals with type 2 diabetes, in-
with improvements in glycemic control apy Recommendations for the Manage-
gested protein may enhance the insulin
in type 2 diabetes. One study did find a response to dietary carbohydrates (61).
ment of Adults With Diabetes” (34).
potential benefit of whole-grain intake in Therefore, carbohydrate sources high in
reducing mortality and cardiovascular dis- protein should not be used to treat or pre- PHYSICAL ACTIVITY
ease (CVD) among individuals with type 2 vent hypoglycemia. The effects of protein Recommendations
diabetes (55). As for all Americans, indi- intake on blood glucose levels in type 1 c Children with diabetes or predia-
viduals with diabetes should be encour- diabetes are less clear. betes should be encouraged to en-
aged to replace refined carbohydrates
gage in at least 60 min of physical
and added sugars with whole grains, Fats
activity each day. B
legumes, vegetables, and fruits. The con- Limited research exists concerning the
c Adults with diabetes should be ad-
sumption of sugar-sweetened beverages ideal amount of fat for individuals with di-
vised to perform at least 150 min/
and “low-fat” or “nonfat” products with abetes. The Institute of Medicine has
week of moderate-intensity aerobic
high amounts of refined grains and added defined an acceptable macronutrient dis-
physical activity (50–70% of maxi-
sugars should be discouraged (56). tribution range for all adults for total fat of
mum heart rate), spread over at least
Individuals with type 1 or type 2 diabe- 20–35% of energy with no tolerable upper
3 days/week with no more than 2
tes taking insulin at mealtimes should be intake level defined (62). The type of fatty
consecutive days without exercise. A
offered intensive education on coupling acids consumed is more important than
c All individuals, including those with
insulin administration with carbohydrate total amount of fat when looking at meta-
diabetes, should be encouraged to
intake. For people whose meal schedules bolic goals and CVD risk (63–65). Multiple
reduce sedentary time, particularly
or carbohydrate consumption is variable, randomized controlled trials including pa-
by breaking up extended amounts
regular counseling to help them to under- tients with type 2 diabetes have reported
of time (.90 min) spent sitting. B
stand the complex relationship between that a Mediterranean-style eating pattern
c In the absence of contraindications,
carbohydrate intake and insulin needs, as (63,66–68), rich in monounsaturated fats,
adults with type 2 diabetes should be
well as the carbohydrate-counting ap- can improve both glycemic control and
encouraged to perform resistance
proach to meal planning, can assist them blood lipids. However, a systematic review
training at least twice per week. A
with effectively modifying insulin dosing concluded that dietary supplements with
S28 Foundations of Care and Comprehensive Medical Evaluation Diabetes Care Volume 39, Supplement 1, January 2016

Physical activity is a general term that over age 18 years do 150 min/week of careful history being aware of the atyp-
includes all movement that increases en- moderate-intensity or 75 min/week of ical presentation of coronary artery dis-
ergy use and is an important part of the vigorous-intensity aerobic physical activ- ease in patients with diabetes and assess
diabetes management plan. Exercise is a ity, or an equivalent combination of the other cardiovascular risk factors. Cer-
more specific form of physical activity two. In addition, the guidelines suggest tainly, high-risk patients should be en-
that is structured and designed to im- that adults do muscle-strengthening activ- couraged to start with short periods of
prove physical fitness. Although both ities that involve all major muscle groups 2 low-intensity exercise and slowly in-
are important, exercise has been shown or more days/week. The guidelines sug- crease the intensity and duration. Pro-
to improve blood glucose control, reduce gest that adults over age 65 years or those viders should assess patients for
cardiovascular risk factors, contribute to with disabilities follow the adult guide- conditions that might contraindicate
weight loss, and improve well-being. lines if possible or, if this is not possible, certain types of exercise or predis-
Physical activity is as important for those be as physically active as they are able. pose to injury, such as uncontrolled
with type 1 diabetes as it is for the general Recent evidence supports that all indi- hypertension, autonomic neuropathy,
population, but its specific role in pre- viduals, including those with diabetes, peripheral neuropathy, a history of
venting diabetes complications and con- should be encouraged to reduce the foot lesions, and untreated proliferative
trolling blood glucose is not as clear as it is amount of time spent being sedentary retinopathy. The patient’s age and pre-
for those with type 2 diabetes. (e.g., working at a computer, watching vious physical activity level should be
Furthermore, regular exercise may TV), particularly, by breaking up extended considered. The provider should cus-
prevent type 2 diabetes in high-risk in- amounts of time (.90 min) spent sitting tomize the exercise regimen to the
dividuals (43,79,80) (see Section 4 “Pre- by briefly standing or walking (87). individual’s needs. Those with compli-
vention or Delay of Type 2 Diabetes”). cations may require a more thorough
Structured exercise interventions of at Physical Activity and Glycemic evaluation (81).
least 8 weeks’ duration have been Control
shown to lower A1C by an average of Hypoglycemia
On the basis of physical activity studies
0.66% in people with type 2 diabetes, In individuals taking insulin and/or insu-
that include people with diabetes, it is
even with no significant change in BMI lin secretagogues, physical activity may
reasonable to recommend that people
(80). There are also considerable data cause hypoglycemia if the medication
with diabetes will specifically benefit
for the health benefits (e.g., increased dose or carbohydrate consumption is
from following the U.S. Department of
cardiovascular fitness, muscle strength, Health and Human Services’ physical ac-
not altered. Individuals on these thera-
improved insulin sensitivity, etc.) of reg- pies may need to ingest some added
tivity guidelines. For example, studies in-
ular exercise for those with type 1 dia- carbohydrate if pre-exercise glucose lev-
cluded in the meta-analysis of the effects
betes (81). Higher levels of exercise els are ,100 mg/dL (5.6 mmol/L), de-
of exercise interventions on glycemic con-
intensity are associated with greater im- pending on whether they can lower
trol (80) reported a mean of 3.4 sessions/
provements in A1C and in fitness (82). week, with a mean of 49 min/session.
insulin levels during the workout (such
Other benefits include slowing the de- as with an insulin pump or reduced pre-
Clinical trials have provided strong evi-
cline in mobility among overweight pa- exercise insulin dosage), the time of day
dence for the A1C-lowering value of resis-
tients with diabetes (83). “Exercise and tance training in older adults with type 2
exercise is done, and the intensity and
Type 2 Diabetes: The American College duration of the activity. Hypoglycemia is
diabetes (84) and for an additive benefit of
of Sports Medicine and the American less common in patients with diabetes
combined aerobic and resistance exercise
Diabetes Association: Joint Position who are not treated with insulin or in-
in adults with type 2 diabetes (88,89). If
Statement” (84) reviews the evidence sulin secretagogues, and no preventive
not contraindicated, patients with type 2
for the benefits of exercise in people measures for hypoglycemia are usually
diabetes should be encouraged to do at
with type 2 diabetes. advised in these cases. Intense activities
least two weekly sessions of resistance ex-
may actually raise blood glucose levels
ercise (exercise with free weights or
Exercise and Children instead of lowering them (91).
weight machines), with each session con-
As is recommended for all children, chil-
sisting of at least one set of five or more
dren with diabetes or prediabetes should Exercise in the Presence of Specific
different resistance exercises involving the
be encouraged to engage in at least 60 Long-term Complications of Diabetes
large muscle groups (84).
min of physical activity each day. Included Retinopathy
in the 60 min each day, children should Pre-exercise Evaluation If proliferative diabetic retinopathy or se-
engage in vigorous-intensity aerobic ac- As discussed more fully in Section 8 “Car- vere nonproliferative diabetic retinopa-
tivity, muscle-strengthening activities, diovascular Disease and Risk Manage- thy is present, then vigorous-intensity
and bone-strengthening activities at least ment,” the best protocol for screening aerobic or resistance exercise may be
3 of those days (85). asymptomatic patients with diabetes contraindicated because of the risk of
for coronary artery disease remains triggering vitreous hemorrhage or retinal
Frequency and Type of Physical unclear. The ADA consensus report detachment (92).
Activity “Screening for Coronary Artery Disease Peripheral Neuropathy
The U.S. Department of Health and Hu- in Patients With Diabetes” (90) con- Decreased pain sensation and a higher
man Services’ physical activity guidelines cluded that routine testing is not recom- pain threshold in the extremities result
for Americans (86) suggest that adults mended. Providers should perform a in an increased risk of skin breakdown,
care.diabetesjournals.org Foundations of Care and Comprehensive Medical Evaluation S29

infection, and Charcot joint destruction Results from epidemiological, case-control,


c Administer hepatitis B vaccine to
with some forms of exercise. There- and cohort studies provide convincing ev-
unvaccinated adults with diabetes
fore, a thorough assessment should idence to support the causal link between
who are aged 19–59 years. C
be done to ensure that neuropathy cigarette smoking and health risks (97).
c Consider administering hepatitis B
does not alter kinesthetic or propriocep- Other studies of individuals with diabetes
vaccine to unvaccinated adults
tive sensation during physical activity. consistently demonstrate that smokers
with diabetes who are aged $60
Studies have shown that moderate- (and people exposed to secondhand
years. C
intensity walking may not lead to an smoke) have a heightened risk of CVD,
increased risk of foot ulcers or reulcera- premature death, and microvascular
As for the general population, all chil-
tion in those with peripheral neuropa- complications. Smoking may have a role
dren and adults with diabetes should re-
thy who use proper footwear (93). In in the development of type 2 diabetes
ceive routine vaccinations (105,106)
addition, 150 min/week of moderate (98). One study in smokers with newly
according to age-specific recommenda-
exercise was reported to improve out- diagnosed type 2 diabetes found that
tions (see the adult vaccination sched-
comes in patients with milder forms smoking cessation was associated with
ule available from http://www.cdc.gov/
of neuropathy (94). All individuals with amelioration of metabolic parameters
vaccines/schedules/hcp/imz/adult.html
peripheral neuropathy should wear and reduced blood pressure and albumin-
and the child and adolescent vaccina-
proper footwear and examine their uria at 1 year (99).
tion schedule available from http://
feet daily to detect lesions early. Any- The routine and thorough assessment
www.cdc.gov/vaccines/schedules/hcp/
one with a foot injury or open sore of tobacco use is essential to prevent
imz/child-adolescent.html).
should be restricted to non–weight- smoking or encourage cessation. Nu-
The Centers for Disease Control and
bearing activities. merous large randomized clinical trials
Prevention (CDC) Advisory Committee
Autonomic Neuropathy have demonstrated the efficacy and cost-
on Immunization Practices recommends
Autonomic neuropathy can increase the effectiveness of brief counseling in smoking
influenza and pneumococcal vaccines
risk of exercise-induced injury or ad- cessation, including the use of telephone
for all individuals with diabetes (http://
verse events through decreased cardiac quit lines, in reducing tobacco use. For the
www.cdc.gov/vaccines/schedules).
responsiveness to exercise, postural hy- patient motivated to quit, the addition of
potension, impaired thermoregulation, pharmacological therapy to counseling Influenza
impaired night vision due to impaired is more effective than either treatment Influenza is a common, preventable in-
papillary reaction, and greater suscepti- alone. Special considerations should in- fectious disease associated with high
bility to hypoglycemia (95). Cardiovas- clude assessment of level of nicotine mortality and morbidity in vulnerable
cular autonomic neuropathy is also an dependence, which is associated with populations, such as the young and
independent risk factor for cardiovascu- difficulty in quitting and relapse (100). the elderly and people with chronic
lar death and silent myocardial ischemia Although some patients may gain weight diseases. Regardless of sex, race, and
(96). Therefore, individuals with dia- in the period shortly after smoking ces- socioeconomic status, adults with dia-
betic autonomic neuropathy should un- sation, recent research has demon- betes 25–64 years of age who died are
dergo cardiac investigation before strated that this weight gain does not four times more likely to have pneu-
beginning physical activity more intense diminish the substantial CVD benefit re- monia and influenza recorded on their
than that to which they are accustomed. alized from smoking cessation (101). death certificates than adults without
Nonsmokers should be advised not to diabetes who died at comparable ages
Albuminuria and Nephropathy
use e-cigarettes. (107). In a case-control series, the in-
Physical activity can acutely increase uri-
nary protein excretion. However, there
There are no rigorous studies that have fluenza vaccine was shown to reduce
demonstrated that e-cigarettes are a diabetes-related hospital admission
is no evidence that vigorous-intensity
exercise increases the rate of progres-
healthier alternative to smoking or that by as much as 79% during flu epidemics
e-cigarettes can facilitate smoking cessa- (108).
sion of diabetic kidney disease, and tion. More extensive research of their
there appears to be no need for specific short- and long-term effects is needed Pneumococcal Pneumonia
exercise restrictions for people with di- to determine their safety and their car- Like influenza, pneumococcal pneumo-
abetic kidney disease (92). diopulmonary effects in comparison nia is a common, preventable disease.
with smoking and standard approaches People with diabetes may be at in-
SMOKING CESSATION: TOBACCO to smoking cessation (102–104). creased risk for the bacteremic form of
AND e-CIGARETTES pneumococcal infection and have been
reported to have a high risk of nosoco-
Recommendations
IMMUNIZATION mial bacteremia, with a mortality rate
c Advise all patients not to use ciga-
as high as 50% (109). All patients with
rettes, other tobacco products, or Recommendations
diabetes 2 years of age and older should
e-cigarettes. A c Provide routine vaccinations for
receive the pneumococcal polysaccha-
c Include smoking cessation coun- children and adults with diabetes
ride vaccine 23 (PPSV23). There is suffi-
seling and other forms of treat- as for the general population ac-
cient evidence to support that people
ment as a routine component of cording to age-related recommen-
with diabetes have appropriate sero-
diabetes care. B dations. C
logic and clinical responses to these
S30 Foundations of Care and Comprehensive Medical Evaluation Diabetes Care Volume 39, Supplement 1, January 2016

vaccinations. The ADA endorses the appropriate services. A systematic re- with depression without significant
CDC advisory panel recommendation view and meta-analysis showed that DD, and those with DD without signifi-
that both pneumococcal conjugate vac- psychosocial interventions modestly cant depression. Understanding the
cine 13 (PCV13) and PPSV23 should be but significantly improved A1C (stan- category in which a particular patient
administered routinely in series to all dardized mean difference 20.29%) belongs facilitates a customized care
adults aged $65 years. and mental health outcomes. However, approach that may include DSME,
there was a limited association be- DSMS, cognitive therapy, or treatment
Hepatitis B tween the effects on A1C and mental for depression (psychotherapy and/
Compared with the general population, health, and no intervention characteris- or psychotropic medications). The
people with type 1 or type 2 diabetes tics predicted benefit on both outcomes screening of all patients with diabetes
have higher rates of hepatitis B. This (114). with the Patient Health Questionnaire-2
may be due to contact with infected (PHQ-2) and either the Diabetes Dis-
blood or through improper equipment Screening tress Scale (DDS) or Problem Areas in
use (glucose monitoring devices or in- Key opportunities for psychosocial Diabetes (PAID)-1 scale can help to
fected needles). Because of the higher screening occur at diabetes diagnosis, facilitate this (24,123,124).
likelihood of transmission, hepatitis B during regularly scheduled manage- Other issues known to affect self-
vaccine is recommended for adults ment visits, during hospitalizations, management and health outcomes
with diabetes. with new onset of complications, or include attitudes about the illness, ex-
when problems with glucose control, pectations for medical management and
PSYCHOSOCIAL ISSUES quality of life, or self-management are outcomes, anxiety, general and diabetes-
Recommendations identified. Patients are likely to exhibit related quality of life, resources (financial,
c The patient’s psychological and psychological vulnerability at diagnosis, social, and emotional) (125), and psychi-
social situation should be ad- when their medical status changes atric history (126).
dressed in the medical manage- (e.g., end of the honeymoon period),
ment of diabetes. B when the need for intensified treat- Referral to a Mental Health Specialist
c Psychosocial screening and follow- ment is evident, and when complica- Indications for referral to a mental
up may include, but are not lim- tions are discovered. Depression health specialist familiar with diabetes
ited to, attitudes about the illness, affects ;20–25% of people with diabe- management may include possibility of
expectations for medical man- tes (115). Individuals with both diabe- self-harm, gross disregard for the med-
agement and outcomes, affect/ tes and major depressive disorder ical regimen (by self or others) (127),
mood, general and diabetes-related have a twofold increased risk for new- depression, overall stress related to
quality of life, resources (financial, onset myocardial infarction compared work-life balance, debilitating anxiety
social, and emotional), and psy- with either disease state alone (116). (alone or with depression), indications
chiatric history. E There appears to be a bidirectional re- of an eating disorder (128), or cognitive
c Routinely screen for psychoso- lationship between both diabetes (117) functioning that significantly impairs
cial problems such as depression, and metabolic syndrome (118) and judgment. It is preferable to incorpo-
diabetes-related distress, anxiety, depression. rate psychological assessment and
eating disorders, and cognitive im- treatment into routine care rather
pairment. B Diabetes Distress than waiting for a specific problem or
c Older adults (aged $65 years) Diabetes-related distress (DD) is dis- deterioration in metabolic or psycho-
with diabetes should be consid- tinct from depressive disorders and is logical status (24,119). In the second Di-
ered for evaluation of cognitive very common (119–121) in people abetes Attitudes, Wishes and Needs
function and depression screening with diabetes and their family mem- (DAWN2) study, significant DD was re-
and treatment. B bers (113). DD refers to significant neg- ported by 45% of the participants, but
c Patients with comorbid diabetes ative psychological reactions related only 24% reported that their health care
and depression should receive a to emotional burdens and worries spe- team asked them how diabetes affected
stepwise collaborative care ap- cific to an individual’s experience in their life (119).
proach for the management of de- having to manage a severe, compli- Although the clinician may not feel
pression. A cated, and demanding chronic dis- qualified to treat psychological prob-
ease such as diabetes (120–122). Its lems (129), optimizing the patient–
Emotional well-being is an important part prevalence is reported to be 18–45%, provider relationship as a foundation
of diabetes care and self-management. with an incidence of 38–48% over 18 may increase the likelihood of the pa-
Psychological and social problems can months. High levels of distress are tient accepting referral for other ser-
impair the individual’s (110–112) or significantly linked to medication non- vices. Collaborative care interventions
family’s (113) ability to carry out adherence (122), higher A1C, lower and a team approach have demonstrated
diabetes care tasks and therefore com- self-efficacy, and poorer dietary and efficacy in diabetes and depression
promise health status. There are oppor- exercise behaviors (15,120). The clini- (130,131). Interventions to enhance
tunities for the clinician to routinely cian needs to understand that individuals self-management and address severe
assess psychosocial status in a timely may fall into one of three categories: distress have demonstrated efficacy
and efficient manner for referral for those with depression and DD, those in DD (15).
care.diabetesjournals.org Foundations of Care and Comprehensive Medical Evaluation S31

COMPREHENSIVE MEDICAL Obstructive Sleep Apnea For patients with type 2 diabetes with
EVALUATION Age-adjusted rates of obstructive sleep fracture risk factors, thiazolidinediones
apnea, a risk factor for CVD, are signifi- (148) and sodium–glucose cotransporter
Recommendations
cantly higher (4- to 10-fold) with obe- 2 inhibitors should be avoided as their use
A complete medical evaluation should sity, especially with central obesity has been associated with a higher risk of
be performed at the initial visit to (139). The prevalence of obstructive fractures (149).
c Confirm the diagnosis and classify sleep apnea in the population with
diabetes. B type 2 diabetes may be as high as 23% Low Testosterone in Men
c Detect diabetes complications and (140). In obese participants enrolled in Mean levels of testosterone are lower in
potential comorbid conditions. E the Action for Health in Diabetes (Look men with diabetes compared with age-
c Review previous treatment and AHEAD) trial, it exceeded 80% (141). matched men without diabetes, but
risk factor control in patients Sleep apnea treatment significantly im- obesity is a major confounder (150).
with established diabetes. E proves quality of life and blood pressure Treatment in asymptomatic men is con-
c Begin patient engagement in the control. The evidence for a treatment troversial. The evidence that testoster-
formulation of a care manage- effect on glycemic control is mixed one replacement affects outcomes is
ment plan. B (142). mixed, and recent guidelines do not rec-
c Develop a plan for continuing care. B ommend testing and treating men with-
Cancer out symptoms (151).
Diabetes (possibly only type 2 diabetes)
Besides assessing diabetes-related is associated with increased risk of Periodontal Disease
complications and comorbidities, clini- cancers of the liver, pancreas, endome- Periodontal disease is more severe, but
cians and their patients need to be trium, colon/rectum, breast, and blad- not necessarily more prevalent, in pa-
aware of other common conditions der (143). The association may result tients with diabetes than in those with-
that affect people with diabetes. Im- from shared risk factors between out (152). Current evidence suggests
proved disease prevention and treat- type 2 diabetes and cancer (older age, that periodontal disease adversely af-
ment mean that people with diabetes obesity, and physical inactivity) but fects diabetes outcomes, although evi-
are living longer and developing heart may also be due to hyperinsulinemia dence for treatment benefits remains
failure, fatty liver disease, obstructive or hyperglycemia (144). Patients with controversial (136).
sleep apnea, and arthritisdconditions diabetes should be encouraged to un-
dergo recommended age- and sex-ap- Hearing Impairment
that affect people with diabetes more
propriate cancer screenings and to Hearing impairment, both in high-frequency
often than age-matched people without
reduce their modifiable cancer risk fac- and low/mid-frequency ranges, is more
diabetes and that may complicate dia-
betes management (132–136). tors (smoking, obesity, and physical in- common in people with diabetes than
Adults who develop type 1 diabetes activity). in those without, perhaps due to neu-
may develop additional autoimmune dis- ropathy and/or vascular disease. In a
Fractures National Health and Nutrition Examina-
orders including thyroid or adrenal dys- Age-specific hip fracture risk is signifi-
function and celiac disease, although the tion Survey (NHANES) analysis, hearing
cantly increased in both type 1 (relative impairment was about twice as preva-
risk of coexisting autoimmunity is lower in risk 6.3) and type 2 (relative risk 1.7) di- lent in people with diabetes compared
adults than for youth with type 1 diabe- abetes in both sexes (145). Type 1 dia- with those without, after adjusting for
tes. For additional details on autoimmune betes is associated with osteoporosis, age and other risk factors for hearing
conditions, see Section 11 “Children and but in type 2 diabetes, an increased impairment (153).
Adolescents.” risk of hip fracture is seen despite higher
bone mineral density (BMD) (146). In Cognitive Impairment
COMORBIDITIES three large observational studies of Diabetes is associated with a signifi-
Fatty Liver Disease older adults, femoral neck BMD T-score cantly increased risk and rate of cogni-
Elevations of hepatic transaminase con- and the World Health Organization Frac- tive decline and an increased risk of
centrations are significantly associated ture Risk Assessment Tool (FRAX) score dementia (154,155). In a 15-year pro-
with higher BMI, waist circumference, were associated with hip and nonspine spective study of community-dwelling
and triglyceride levels and lower HDL fractures. Fracture risk was higher in people aged .60 years, the presence
cholesterol levels. In a prospective anal- participants with diabetes compared of diabetes at baseline significantly
ysis, diabetes was significantly associ- with those without diabetes for a given increased the age- and sex-adjusted
ated with incident nonalcoholic chronic T-score and age for a given FRAX score incidence of all-cause dementia, Alz-
liver disease and with hepatocellular (147). Providers should assess fracture heimer disease, and vascular dementia
carcinoma (137). Interventions that im- history and risk factors in older patients compared with rates in those with
prove metabolic abnormalities in pa- with diabetes and recommend measure- normal glucose tolerance (156). In a
tients with diabetes (weight loss, ment of BMD if appropriate for the pa- substudy of the Action to Control Car-
glycemic control, and treatment with tient’s age and sex. Fracture prevention diovascular Risk in Diabetes (ACCORD)
specific drugs for hyperglycemia or dys- strategies for people with diabetes are clinical trial, there were no differences
lipidemia) are also beneficial for fatty the same as for the general population in cognitive outcomes between the in-
liver disease (138). and include vitamin D supplementation. tensive and standard glycemic control
S32 Foundations of Care and Comprehensive Medical Evaluation Diabetes Care Volume 39, Supplement 1, January 2016

groups, although there was signifi- mellitus. Cochrane Database Syst Rev 2005;2: 30. Foster G, Taylor SJ, Eldridge SE, Ramsay J,
cantly less of a decrement in total brain CD003417 Griffiths CJ. Self-management education pro-
13. Cochran J, Conn VS. Meta-analysis of qual- grammes by lay leaders for people with chronic
volume, as measured by MRI, in partic- ity of life outcomes following diabetes self- conditions. Cochrane Database Syst Rev 2007;4:
ipants in the intensive arm (157). The management training. Diabetes Educ 2008;34: CD005108
effects of hyperglycemia and insulin on 815–823 31. Duncan I, Birkmeyer C, Coughlin S, Li QE,
the brain are areas of intense research 14. Thorpe CT, Fahey LE, Johnson H, Deshpande Sherr D, Boren S. Assessing the value of diabetes
interest. M, Thorpe JM, Fisher EB. Facilitating healthy education. Diabetes Educ 2009;35:752–760
coping in patients with diabetes: a systematic 32. Johnson TM, Murray MR, Huang Y. Associ-
review. Diabetes Educ 2013;39:33–52 ations between self-management education
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S36 Diabetes Care Volume 39, Supplement 1, January 2016

American Diabetes Association


4. Prevention or Delay of Type 2
Diabetes
Diabetes Care 2016;39(Suppl. 1):S36–S38| DOI: 10.2337/dc16-S007

Recommendations
c Patients with prediabetes should be referred to an intensive diet and physical
activity behavioral counseling program adhering to the tenets of the Diabetes
Prevention Program (DPP) targeting a loss of 7% of body weight and should
increase their moderate-intensity physical activity (such as brisk walking) to at
least 150 min/week. A
4. PREVENTION OR DELAY OF TYPE 2 DIABETES

c Follow-up counseling and maintenance programs should be offered for long-


term success in preventing diabetes. B
c Based on the cost-effectiveness of diabetes prevention, such programs should
be covered by third-party payers. B
c Metformin therapy for prevention of type 2 diabetes should be considered in
those with prediabetes, especially in those with BMI .35 kg/m2, those aged
,60 years, and women with prior gestational diabetes mellitus. A
c At least annual monitoring for the development of diabetes in those with
prediabetes is suggested. E
c Screening for and treatment of modifiable risk factors for cardiovascular dis-
ease is suggested. B
c Diabetes self-management education and support programs are appropriate
venues for people with prediabetes to receive education and support to de-
velop and maintain behaviors that can prevent or delay the onset of diabetes. B
c Technology-assisted tools including Internet-based social networks, distance
learning, DVD-based content, and mobile applications can be useful elements
of effective lifestyle modification to prevent diabetes. B
LIFESTYLE MODIFICATION
Randomized controlled trials have shown that individuals at high risk for develop-
ing type 2 diabetes (impaired fasting glucose, impaired glucose tolerance, or both)
can significantly decrease the rate of diabetes onset with particular interventions
(1–7). These include intensive lifestyle modification programs that have been
shown to be very effective (;58% reduction after 3 years). Follow-up of all three
large studies of lifestyle intervention has shown sustained reduction in the rate of
conversion to type 2 diabetes: 43% reduction at 20 years in the Da Qing study (8),
43% reduction at 7 years in the Finnish Diabetes Prevention Study (DPS) (9), and
34% reduction at 10 years in the U.S. Diabetes Prevention Program Outcomes Study
(DPPOS) (10).
A cost-effectiveness model suggested that lifestyle interventions in the Diabetes
Prevention Program (DPP) are cost-effective (11). Actual cost data from the DPP and
DPPOS also confirm this (12). Group delivery of DPP content into community
settings has the potential to reduce overall program costs while still producing
weight loss and diabetes risk reduction (13,14). The Centers for Disease Control
and Prevention (CDC) helps to coordinate the National Diabetes Prevention
Program, a resource designed to bring evidence-based lifestyle change programs
for preventing type 2 diabetes to communities (http://www.cdc.gov/diabetes/ Suggested citation: American Diabetes Associa-
prevention/index.htm). tion. Prevention or delay of type 2 diabetes. Sec.
4. In Standards of Medical Care in Diabetesd2016.
Given the clinical trial results and the known risks of progression from prediabetes
Diabetes Care 2016;39(Suppl. 1):S36–S38
to diabetes, people with an A1C 5.7–6.4% (39–46 mmol/mol), impaired glucose
© 2016 by the American Diabetes Association.
tolerance, or impaired fasting glucose should be counseled on lifestyle changes Readers may use this article as long as the work
with goals similar to those of the DPP (7% weight loss and moderate-intensity is properly cited, the use is educational and not
physical activity of at least 150 min/week). for profit, and the work is not altered.
care.diabetesjournals.org Prevention or Delay of Type 2 Diabetes S37

Nutrition health care providers should inform PHARMACOLOGICAL


As for people with diabetes (see Section 3 at-risk patients of these benefits in or- INTERVENTIONS
“Foundations of Care and Comprehen- der to motivate them to engage Pharmacological agents, such as metfor-
sive Medical Evaluation”), evidence sup- in regular moderate-intensity physical min, a-glucosidase inhibitors, orlistat,
ports the importance of maintaining a activity. and thiazolidinediones, have each
healthy diet in order to prevent diabetes Moderate exercise, such as brisk been shown to decrease incident dia-
onset. Unlike past recommendations walking or other activities of equivalent betes to various degrees. Metformin
that focused on simply reducing total di- intensity, has been also observed to im- has the strongest evidence base and
etary fat and cholesterol consumption, prove insulin sensitivity and reduce ab- demonstrated long-term safety as
more recent evidence argues against dominal fat content in children and pharmacological therapy for diabetes
the preventative effects of lowering fat young adults (22,23). The DPP included prevention (34). For other drugs, cost,
and cholesterol intake across the board 150 min/week of moderate-intensity ex- side effects, and durable efficacy re-
and supports instead that the quality of ercise and showed beneficial effect on quire consideration.
fats consumed in the diet is more impor- glycemia in those with prediabetes (1). Metformin was less effective than
tant than the total quantity of dietary fat. Both resistance training and endurance lifestyle modification in the DPP and
For example, recent work supports the exercise appear to have beneficial ef- DPPOS but may be cost-saving over a
Mediterranean diet, which is relatively fects on waist circumference, insulin 10-year period (12). It was as effective
rich in monounsaturated fats, as a means sensitivity, and thus diabetes risk as lifestyle modification in participants
to help to prevent type 2 diabetes (15). (24,25). The preventative effects of exer- with BMI $35 kg/m 2 but not signifi-
Studies evaluating glycemic index to cise appear to extend to the prevention cantly better than placebo in those
guide carbohydrate recommendations of gestational diabetes mellitus (GDM) over 60 years of age (1). In the DPP,
have been inconsistent (16,17); however, as well (26). for women with a history of GDM, met-
data suggest that consumption of a diet formin and intensive lifestyle modifica-
enriched in whole grains is helpful in pre- Prevention of Cardiovascular Disease tion led to an equivalent 50% reduction
venting type 2 diabetes (18). Finally, in- People with prediabetes often have other in diabetes risk (35), and both inter-
creased consumption of nuts (19) and cardiovascular risk factors, such as obe- ventions remained highly effective
berries (20) in the context of a diet high sity, hypertension, and dyslipidemia during a 10-year follow-up period
in vegetables and whole fruits has been and are at increased risk for cardiovas- (36). Metformin may be recommended
correlated with reduced diabetes risk. In- cular disease events. While treatment for high-risk individuals (e.g., those
dividualized medical nutrition therapy goals for people with prediabetes are with a history of GDM, those who are
(see Section 3 “Foundations of Care and the same as for the general population, very obese, and/or those with more
Comprehensive Medical Evaluation” for increased vigilance is warranted to severe or progressive hyperglycemia)
more detailed information) has been identify and treat these and other risk and/or those with rising A1C despite
shown to be effective in lowering A1C in factors (e.g., smoking). lifestyle intervention.
individuals diagnosed with prediabetes
(7). This indicates that nutritional inter- Technology Assistance to Deliver
ventions are potentially effective in stav- Lifestyle Modification DIABETES SELF-MANAGEMENT
ing off the progression toward type 2 Technology may be an effective means EDUCATION AND SUPPORT
diabetes (e.g., individuals showing signs to deliver the core components of the As for those with established diabetes, the
of metabolic syndrome). DPP (27,28). Initial studies have vali- standards for diabetes self-management
dated DVD-based content delivery education and support (see Section 3
Physical Activity and Exercise (29). This has been corroborated in a “Foundations of Care and Comprehen-
Physical activity and exercise are impor- primary care patient population (30). sive Medical Evaluation”) can also apply
tant for those living with diabetes (see Recent studies support content delivery to the education and support of people
Section 3 “Foundations of Care and Com- through virtual small groups (31), Internet- with prediabetes. Currently, there are
prehensive Medical Evaluation”), but they driven social networks (32,33), cellular significant barriers to the provision of
have also been evaluated for diabetes pre- phones, and other mobile devices. Mo- education and support to those with pre-
vention. Physical activity is a more general bile applications for weight loss and di- diabetes. However, the strategies for
term that covers all types of activity, abetes prevention have been validated supporting successful behavior change
whereas exercise refers to structured or for their ability to reduce A1C in the and the healthy behaviors recom-
planned activities. Although not well stud- setting of prediabetes (33). The CDC’s Di- mended for people with prediabetes
ied in isolation, exercise and physical ac- abetes Prevention Recognition Program are comparable to those for diabetes.
tivity have been validated to prevent or (DPRP) (http://www.cdc.gov/diabetes/ Although reimbursement remains a
delay diabetes development as part of a prevention/recognition/index.htm) has barrier, studies show that providers of
comprehensive approach to lifestyle mod- begun to certify electronic and mobile diabetes self-management education
ification (21). These studies suggest that health-based modalities as effective ve- and support are particularly well equip-
while exercise treatment programs may hicles for DPP-style prevention content ped to assist people with prediabetes in
not reduce body weight, programs of suf- that may be considered alongside more developing and maintaining behaviors
ficient intensity have been shown to de- traditional face-to-face and coach-driven that can prevent or delay the onset of
crease diabetes risk (21). Therefore, programs. diabetes (7,37).
S38 Prevention or Delay of Type 2 Diabetes Diabetes Care Volume 39, Supplement 1, January 2016

References 13. Ackermann RT, Finch EA, Brizendine E, in obese adolescent boys: a randomized, con-
1. Knowler WC, Barrett-Connor E, Fowler SE, Zhou H, Marrero DG. Translating the Diabetes trolled trial. Diabetes 2012;61:2787–2795
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2. Buchanan TA, Xiang AH, Peters RK, et al. Pittas AG, Remington PL. Combined diet and Obstet Gynecol 2015;125:576–582
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ical treatment of insulin resistance in high-risk a systematic review for the Community Preven- loss interventions in primary care: a systematic
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Karasik A, Laakso M; STOP-NIDDM Trial Re- 15. Salas-Salvadó J, Bulló M, Babio N, et al.; assisted weight management interventions:
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4. Lin JS, O’Connor E, Evans CV, Senger CA, nutrition intervention randomized trial. Diabe- novel approach to diabetes prevention: evalua-
Rowland MG, Groom HC. Behavioral counseling tes Care 2011;34:14–19 tion of the Group Lifestyle Balance program de-
to promote a healthy lifestyle in persons with 16. Bhupathiraju SN, Tobias DK, Malik VS, et al. livered via DVD. Diabetes Res Clin Pract 2010;
cardiovascular risk factors: a systematic review Glycemic index, glycemic load, and risk of type 2 90:e60–e63
for the U.S. Preventive Services Task Force. Ann diabetes: results from 3 large US cohorts and an 30. Ma J, Yank V, Xiao L, et al. Translating the
Intern Med 2014;161:568–578 updated meta-analysis. Am J Clin Nutr 2014; Diabetes Prevention Program lifestyle interven-
5. Paulweber B, Valensi P, Lindström J, et al. A 100:218–232 tion for weight loss into primary care: a random-
European evidence-based guideline for the pre- 17. Sacks FM, Carey VJ, Anderson CAM, et al. ized trial. JAMA Intern Med 2013;173:113–121
vention of type 2 diabetes. Horm Metab Res Effects of high vs low glycemic index of dietary 31. Azar KMJ, Aurora M, Wang EJ, Muzaffar A,
2010;42(Suppl. 1):S3–S36 carbohydrate on cardiovascular disease risk fac- Pressman A, Palaniappan LP. Virtual small
6. Diabetes Prevention Program Research tors and insulin sensitivity: the OmniCarb ran- groups for weight management: an innovative
Group. HbA1c as a predictor of diabetes and as domized clinical trial. JAMA 2014;312:2531–2541 delivery mechanism for evidence-based lifestyle
an outcome in the Diabetes Prevention Pro- 18. Montonen J, Knekt P, Järvinen R, Aromaa A, interventions among obese men. Transl Behav
gram: a randomized clinical trial. Diabetes Reunanen A. Whole-grain and fiber intake and Med 2015;5:37–44
Care 2015;38:51–58 the incidence of type 2 diabetes. Am J Clin Nutr 32. Sepah SC, Jiang L, Peters AL. Translating the
7. Parker AR, Byham-Gray L, Denmark R, Winkle 2003;77:622–629 Diabetes Prevention Program into an online so-
PJ. The effect of medical nutrition therapy by a 19. Afshin A, Micha R, Khatibzadeh S, cial network: validation against CDC standards.
registered dietitian nutritionist in patients with Mozaffarian D. Consumption of nuts and legumes Diabetes Educ 2014;40:435–443
prediabetes participating in a randomized con- and risk of incident ischemic heart disease, stroke, 33. Sepah SC, Jiang L, Peters AL. Long-term out-
trolled clinical research trial. J Acad Nutr Diet and diabetes: a systematic review and meta- comes of a Web-based diabetes prevention pro-
2014;114:1739–1748 analysis. Am J Clin Nutr 2014;100:278–288 gram: 2-year results of a single-arm longitudinal
8. Li G, Zhang P, Wang J, et al. The long-term 20. Mursu J, Virtanen JK, Tuomainen T-P, Nurmi study. J Med Internet Res 2015;17:e92
effect of lifestyle interventions to prevent dia- T, Voutilainen S. Intake of fruit, berries, and 34. Group TDPPR; Diabetes Prevention Pro-
betes in the China Da Qing Diabetes Prevention vegetables and risk of type 2 diabetes in Finnish gram Research Group. Long-term safety, tol-
Study: a 20-year follow-up study. Lancet 2008; men: the Kuopio Ischaemic Heart Disease Risk erability, and weight loss associated with
371:1783–1789 Factor Study. Am J Clin Nutr 2014;99:328–333 metformin in the Diabetes Prevention Pro-
9. Lindström J, Ilanne-Parikka P, Peltonen M, 21. Swift DL, Johannsen NM, Lavie CJ, Earnest gram Outcomes Study. Diabetes Care 2012;
et al.; Finnish Diabetes Prevention Study Group. CP, Church TS. The role of exercise and physical 35:731–737
Sustained reduction in the incidence of type 2 activity in weight loss and maintenance. Prog 35. Ratner RE, Christophi CA, Metzger BE, et al.;
diabetes by lifestyle intervention: follow-up of Cardiovasc Dis 2014;56:441–447 Diabetes Prevention Program Research Group.
the Finnish Diabetes Prevention Study. Lancet 22. Fedewa MV, Gist NH, Evans EM, Dishman Prevention of diabetes in women with a history
2006;368:1673–1679 RK. Exercise and insulin resistance in youth: a of gestational diabetes: effects of metformin
10. Knowler WC, Fowler SE, Hamman RF, et al.; meta-analysis. Pediatrics 2014;133:e163–e174 and lifestyle interventions. J Clin Endocrinol
Diabetes Prevention Program Research Group. 23. Davis CL, Pollock NK, Waller JL, et al. Exer- Metab 2008;93:4774–4779
10-year follow-up of diabetes incidence and cise dose and diabetes risk in overweight and 36. Aroda VR, Christophi CA, Edelstein SL, et al.;
weight loss in the Diabetes Prevention Program obese children: a randomized controlled trial. Diabetes Prevention Program Research Group.
Outcomes Study. Lancet 2009;374:1677–1686 JAMA 2012;308:1103–1112 The effect of lifestyle intervention and metfor-
11. Herman WH, Hoerger TJ, Brandle M, et al.; 24. Sigal RJ, Alberga AS, Goldfield GS, et al. Ef- min on preventing or delaying diabetes among
Diabetes Prevention Program Research Group. fects of aerobic training, resistance training, or women with and without gestational diabetes:
The cost-effectiveness of lifestyle modification both on percentage body fat and cardiometa- the Diabetes Prevention Program outcomes
or metformin in preventing type 2 diabetes in bolic risk markers in obese adolescents: the study 10-year follow-up. J Clin Endocrinol
adults with impaired glucose tolerance. Ann In- healthy eating aerobic and resistance training Metab 2015;100:1646–1653
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12. Diabetes Prevention Program Research 2014;168:1006–1014 Gohdes D, Helgerson SD, Harwell TS. Capacity
Group. The 10-year cost-effectiveness of life- 25. Lee S, Bacha F, Hannon T, Kuk JL, Boesch C, of diabetes education programs to provide both
style intervention or metformin for diabetes Arslanian S. Effects of aerobic versus resistance diabetes self-management education and to im-
prevention: an intent-to-treat analysis of the exercise without caloric restriction on abdomi- plement diabetes prevention services. J Public
DPP/DPPOS. Diabetes Care 2012;35:723–730 nal fat, intrahepatic lipid, and insulin sensitivity Health Manag Pract 2011;17:242–247
Diabetes Care Volume 39, Supplement 1, January 2016 S39

American Diabetes Association


5. Glycemic Targets
Diabetes Care 2016;39(Suppl. 1):S39–S46 | DOI: 10.2337/dc16-S008

ASSESSMENT OF GLYCEMIC CONTROL


Two primary techniques are available for health providers and patients to assess the
effectiveness of the management plan on glycemic control: patient self-monitoring
of blood glucose (SMBG) and A1C. Continuous glucose monitoring (CGM) or in-
terstitial glucose may be a useful adjunct to SMBG in selected patients.
Recommendations
c When prescribed as part of a broader educational context, self-monitoring of
blood glucose (SMBG) results may help to guide treatment decisions and/or
self-management for patients using less frequent insulin injections B or non-
insulin therapies. E
c When prescribing SMBG, ensure that patients receive ongoing instruction and

5. GLYCEMIC TARGETS
regular evaluation of SMBG technique, SMBG results, and their ability to use
SMBG data to adjust therapy. E
c Most patients on intensive insulin regimens (multiple-dose insulin or insulin
pump therapy) should consider SMBG prior to meals and snacks, occasionally
postprandially, at bedtime, 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 used properly, continuous glucose monitoring (CGM) in conjunction
with intensive insulin regimens is a useful tool to lower A1C in selected adults
(aged $25 years) with type 1 diabetes. A
c Although the evidence for A1C lowering is less strong in children, teens, and
younger adults, CGM may be helpful in these groups. Success correlates with
adherence to ongoing use of the device. B
c CGM may be a supplemental tool to SMBG in those with hypoglycemia un-
awareness and/or frequent hypoglycemic episodes. C
c Given variable adherence to CGM, assess individual readiness for continuing
CGM use prior to prescribing. E
c When prescribing CGM, robust diabetes education, training, and support are
required for optimal CGM implementation and ongoing use. E
c People who have been successfully using CGM should have continued access
after they turn 65 years of age. E
Self-monitoring of Blood Glucose
Major clinical trials of insulin-treated patients have included SMBG as part of the
multifactorial interventions to demonstrate the benefit of intensive glycemic con-
trol on diabetes complications. SMBG is thus an integral component of effective
therapy (1). SMBG allows patients to evaluate their individual response to therapy
and assess whether glycemic targets are being achieved. Integrating SMBG results
into diabetes management can be a useful tool for guiding medical nutrition therapy
and physical activity, preventing hypoglycemia, and adjusting medications (particularly
prandial insulin doses). Among patients with type 1 diabetes, there is a correlation
between greater SMBG frequency and lower A1C (2). The patient’s specific needs and
goals should dictate SMBG frequency and timing.
Suggested citation: American Diabetes Associa-
Optimization tion. Glycemic targets. Sec. 5. In Standards of
Medical Care in Diabetesd2016. Diabetes Care
SMBG accuracy is dependent on the instrument and user, so it is important to
2016;39(Suppl. 1):S39–S46
evaluate each patient’s monitoring technique, both initially and at regular intervals
© 2016 by the American Diabetes Association.
thereafter. Optimal use of SMBG requires proper review and interpretation of the Readers may use this article as long as the work
data, by both the patient and the provider. Among patients who check their blood is properly cited, the use is educational and not
glucose at least once daily, many report taking no action when results are high or for profit, and the work is not altered.
S40 Glycemic Targets Diabetes Care Volume 39, Supplement 1, January 2016

low. In a yearlong study of insulin-naı̈ve suggested that SMBG reduced A1C by automatic low glucose suspend feature
patients with suboptimal initial glycemic 0.25% at 6 months (13), but the effect was has been approved by the FDA. The Auto-
control, a group trained in structured attenuated at 12 months (14). A key con- mation to Simulate Pancreatic Insulin Re-
SMBG (a paper tool was used at least sideration is that performing SMBG alone sponse (ASPIRE) trial of 247 patients
quarterly to collect and interpret 7-point does not lower blood glucose levels. To be showed that sensor-augmented insulin
SMBG profiles taken on 3 consecutive useful, the information must be integrated pump therapy with a low glucose sus-
days) reduced their A1C by 0.3 percent- into clinical and self-management plans. pend significantly reduced nocturnal hy-
age points more than the control group poglycemia, without increasing A1C
(3). Patients should be taught how to use Continuous Glucose Monitoring levels for those over 16 years of age
SMBG data to adjust food intake, exer- Real-time CGM measures interstitial (23). These devices may offer the oppor-
cise, or pharmacological therapy to glucose (which correlates well with tunity to reduce severe hypoglycemia for
achieve specific goals. The ongoing need plasma glucose) and includes sophisti- those with a history of nocturnal hypo-
for and frequency of SMBG should be cated alarms for hypo- and hyperglycemic glycemia. Due to variable adherence, op-
reevaluated at each routine visit to avoid excursions, but the U.S. Food and Drug timal CGM use requires an assessment of
overuse (4–6). SMBG is especially impor- Administration (FDA) has not approved individual readiness for the technology
tant for insulin-treated patients to monitor these devices as a sole agent to monitor as well as initial and ongoing education
for and prevent asymptomatic hypoglyce- glucose. CGMs require calibration with and support (16,24). Additionally, providers
mia and hyperglycemia. SMBG, with the latter still required for need to provide robust diabetes education,
making acute treatment decisions. training, and support for optimal CGM
For Patients on Intensive Insulin Regimens
A 26-week randomized trial of 322 pa- implementation and ongoing use. As
Most patients on intensive insulin regimens tients with type 1 diabetes showed that people with type 1 or type 2 diabetes
(multiple-dose insulin or insulin pump ther- adults aged $25 years using intensive in- are living longer healthier lives, individu-
apy) should consider SMBG prior to meals sulin therapy and CGM experienced a 0.5% als who have been successfully using
and snacks, occasionally postprandially, at reduction in A1C (from ;7.6% to 7.1% CGM should have continued access after
bedtime, prior to exercise, when they sus- [;60 mmol/mol to 54 mmol/mol]), com- they turn 65 years of age.
pect low blood glucose, after treating low pared with those using intensive insulin
blood glucose until they are normoglyce- therapy with SMBG (15). Sensor use in A1C TESTING
mic, and prior to critical tasks such as driv- those aged ,25 years (children, teens, Recommendations
ing. For many patients, this will require and adults) did not result in significant c Perform the A1C test at least two
testing 6–10 (or more) times daily, al- A1C lowering, and there was no significant times a year in patients who are
though individual needs may vary. A data- difference in hypoglycemia in any group. meeting treatment goals (and who
base study of almost 27,000 children and The greatest predictor of A1C lowering have stable glycemic control). E
adolescents with type 1 diabetes showed for all age-groups was frequency of sensor c Perform the A1C test quarterly in
that, after adjustment for multiple con- use, which was highest in those aged $25 patients whose therapy has changed
founders, increased daily frequency of years and lower in younger age-groups. or who are not meeting glycemic
SMBG was significantly associated with A registry study of 17,317 participants goals. E
lower A1C (20.2% per additional test per confirmed that more frequent CGM use is c Point-of-care testing for A1C pro-
day) and with fewer acute complications. associated with lower A1C (16), whereas vides the opportunity for more
For Patients Using Basal Insulin or Oral another study showed that children with timely treatment changes. E
Agents .70% sensor use missed fewer school
The evidence is insufficient regarding days (17). Small randomized controlled A1C reflects average glycemia over
when to prescribe SMBG and how often trials in adults and children with baseline several months and has strong predic-
testing is needed for patients who do A1C 7.0–7.5% (53–58 mmol/mol) have tive value for diabetes complications
not use an intensive insulin regimen, confirmed favorable outcomes (A1C and (25,26). Thus, A1C testing should be
such as those with type 2 diabetes using hypoglycemia occurrence) in groups us- performed routinely in all patients with
oral agents or on basal insulin. For patients ing CGM, suggesting that CGM may pro- diabetesdat initial assessment and as
on basal insulin, lowering of A1C has been vide further benefit for individuals with part of continuing care. Measurement
demonstrated for those who adjust their type 1 diabetes who already have tight approximately every 3 months deter-
dose to attain a fasting glucose within a control (18,19). mines whether patients’ glycemic targets
targeted range (7,8). A meta-analysis suggests that, com- have been reached and maintained. The
For individuals with type 2 diabetes on pared with SMBG, CGM is associated frequency of A1C testing should depend
less intensive insulin therapy, more fre- with short-term A1C lowering of ;0.26% on the clinical situation, the treatment
quent SMBG (e.g., fasting, before/after (20). The long-term effectiveness of CGM regimen, and the clinician’s judgment. Pa-
meals) may be helpful, as increased fre- needs to be determined. This technology tients with type 2 diabetes with stable
quency has been shown to be inversely may be particularly useful in those with glycemia well within target may do well
correlated with glycemic control (9). hypoglycemia unawareness and/or fre- with testing only twice per year. Unstable or
Several randomized trials have called quent hypoglycemic episodes, although highly intensively managed patients (e.g.,
into question the clinical utility and cost- studies have not shown consistent re- pregnant women with type 1 diabetes)
effectiveness of routine SMBG in noninsulin- ductions in severe hypoglycemia (20– may require testing more frequently than
treated patients (10–12). A meta-analysis 22). A CGM device equipped with an every 3 months (27).
care.diabetesjournals.org Glycemic Targets S41

Table 5.1—Mean glucose levels for specified A1C levels (24,28)


Mean plasma glucose* Mean fasting glucose Mean premeal glucose Mean postmeal glucose Mean bedtime glucose
A1C
% (mmol/mol) mg/dL mmol/L mg/dL mmol/L mg/dL mmol/L mg/dL mmol/L mg/dL mmol/L
6 (42) 126 7.0
,6.5 (48) 122 6.8 118 6.5 144 8.0 136 7.5
6.5–6.99 (48–53) 142 7.9 139 7.7 164 9.1 153 8.5
7 (53) 154 8.6
.7.0–7.49 (53–58) 152 8.4 152 8.4 176 9.8 177 9.8
7.5–7.99 (58–64) 167 9.3 155 8.6 189 10.5 175 9.7
8 (64) 183 10.2
.8.0–8.5 (64–69) 178 9.9 179 9.9 206 11.4 222 12.3
9 (75) 212 11.8
10 (86) 240 13.4
11 (97) 269 14.9
12 (108) 298 16.5
A calculator for converting A1C results into eAG, in either mg/dL or mmol/L, is available at http://professional.diabetes.org/eAG.
*These estimates are 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 (28).

A1C Limitations type 2, and no diabetes (28), and an em- A1C GOALS
The A1C test is subject to certain limita- pirical study of the average blood glucose For glycemic goals in children, please refer
tions. Conditions that affect red blood levels at premeal, postmeal, and bedtime to Section 11 “Children and Adolescents.”
cell turnover (hemolysis, blood loss) associated with specified A1C levels using For glycemic goals in pregnant women,
and hemoglobin variants must be consid- data from the ADAG trial (24). The Amer- please refer to Section 12 “Management
ered, particularly when the A1C result does ican Diabetes Association (ADA) and the of Diabetes in Pregnancy.”
not correlate with the patient’s blood glu- American Association for Clinical Chemis-
cose levels. For patients in whom A1C/ try have determined that the correlation Recommendations
estimated average glucose (eAG) and (r 5 0.92) in the ADAG trial is strong c A reasonable A1C goal for many
measured blood glucose appear discrep- enough to justify reporting both the A1C nonpregnant adults is ,7% (53
ant, clinicians should consider the possi- result and the eAG result when a clinician mmol/mol). A
bilities of hemoglobinopathy or altered orders the A1C test. Clinicians should c Providers might reasonably sug-
red blood cell turnover and the options note that the mean plasma glucose num- gest more stringent A1C goals
of more frequent and/or different timing bers in the table are based on ;2,800 (such as ,6.5% [48 mmol/mol])
of SMBG or CGM use. Other measures of readings per A1C in the ADAG trial. for selected individual patients if
chronic glycemia such as fructosamine are this can be achieved without signif-
A1C Differences in Ethnic Populations and
available, but their linkage to average glu- icant hypoglycemia or other adverse
Children
cose and their prognostic significance are effects of treatment. Appropriate
In the ADAG study, there were no signif-
not as clear as for A1C (see Section 2 “Clas- patients might include those with
icant differences among racial and ethnic
sification and Diagnosis of Diabetes”). short duration of diabetes, type 2
groups in the regression lines between
A1C does not provide a measure of gly- diabetes treated with lifestyle or
A1C and mean glucose, although there
cemic variability or hypoglycemia. For metformin only, long life expec-
was a trend toward a difference between
patients prone to glycemic variability, es- tancy, or no significant cardiovascu-
the African/African American and non-
pecially patients with type 1 diabetes or lar disease. C
Hispanic white cohorts. A small study
type 2 diabetes with severe insulin defi- c Less stringent A1C goals (such as
comparing A1C to CGM data in children
ciency, glycemic control is best evaluated ,8% [64 mmol/mol]) may be ap-
with type 1 diabetes found a highly sta-
by the combination of results from SMBG propriate for patients with a his-
tistically significant correlation between
and A1C. A1C may also confirm the accu- tory of severe hypoglycemia,
A1C and mean blood glucose, although
racy of the patient’s meter (or the patient’s limited life expectancy, advanced
the correlation (r 5 0.7) was signifi-
reported SMBG results) and the adequacy microvascular or macrovascular
cantly lower than in the ADAG trial (29).
of the SMBG testing schedule. complications, extensive comor-
Whether there are significant differences
bid conditions, or long-standing
A1C and Mean Glucose in how A1C relates to average glucose in
diabetes in whom the general
Table 5.1 shows the correlation between children or in different ethnicities is an
goal is difficult to attain despite
A1C levels and mean glucose levels based area for further study (30,31). For the
diabetes self-management educa-
on two studies: the international A1C- time being, the question has not led to
tion, appropriate glucose monitor-
Derived Average Glucose (ADAG) trial, different recommendations about testing
ing, and effective doses of multiple
which based the correlation with A1C on A1C or to different interpretations of the
glucose-lowering agents including
frequent SMBG and CGM in 507 adults clinical meaning of given levels of A1C in
insulin. B
(83% non-Hispanic whites) with type 1, those populations.
S42 Glycemic Targets Diabetes Care Volume 39, Supplement 1, January 2016

A1C and Microvascular Complications poor control to fair/good control. These events (combined fatal or nonfatal MI
Type 1 Diabetes analyses also suggest that further lower- and sudden death) in the intensive glyce-
Hyperglycemia defines diabetes, and ing of A1C from 7% to 6% [53 mmol/mol mic control arm that did not reach statis-
glycemic control is fundamental to dia- to 42 mmol/mol] is associated with fur- tical significance (P 5 0.052), and there
betes management. The Diabetes Con- ther reduction in the risk of microvascular was no suggestion of benefit on other
trol and Complications Trial (DCCT) (1), a complications, although the absolute risk CVD outcomes (e.g., stroke). However, af-
prospective randomized controlled trial reductions become much smaller. Given ter 10 years of follow-up, those originally
of intensive versus standard glycemic the substantially increased risk of hypo- randomly assigned to intensive glycemic
control in patients with relatively recently glycemia in type 1 diabetes trials and control had significant long-term reduc-
diagnosed type 1 diabetes, showed defin- with polypharmacy in type 2 diabetes, tions in MI (15% with sulfonylurea or in-
itively that improved glycemic control is the risks of lower glycemic targets outweigh sulin as initial pharmacotherapy, 33%
associated with significantly decreased the potential benefits on microvascular with metformin as initial pharmacother-
rates of microvascular (retinopathy [32] complications. apy) and in all-cause mortality (13% and
and diabetic kidney disease) and neuro- The concerning mortality findings in 27%, respectively) (37).
pathic complications. Follow-up of the the ACCORD trial (42), discussed below, The ACCORD, ADVANCE, and VADT
DCCT cohorts in the Epidemiology of and the relatively intense efforts required suggested no significant reduction in
Diabetes Interventions and Complications to achieve near-euglycemia should also CVD outcomes with intensive glycemic
(EDIC) study (33) demonstrated persis- be considered when setting glycemic tar- control in participants followed for
tence of these microvascular benefits in gets. However, on the basis of physician 3.525.6 years who had more advanced
previously intensively treated subjects, judgment and patient preferences, select type 2 diabetes than UKPDS partici-
even though their glycemic control ap- patients, especially those with little co- pants. All three trials were conducted
proximated that of previous standard morbidity and long life expectancy, may in participants with more long-standing
arm subjects during follow-up. benefit from adopting more intensive gly- diabetes (mean duration 8–11 years)
cemic targets (e.g., A1C target ,6.5% and either known CVD or multiple car-
Type 2 Diabetes
[48 mmol/mol]) as long as significant hy- diovascular risk factors. The target
The Kumamoto Study (34) and UK Pro-
poglycemia does not become a barrier. A1C among intensive control subjects
spective Diabetes Study (UKPDS) (35,36)
was ,6% (42 mmol/mol) in ACCORD,
confirmed that intensive glycemic control A1C and Cardiovascular Disease ,6.5% (48 mmol/mol) in ADVANCE,
was associated with significantly de- Outcomes and a 1.5% reduction in A1C compared
creased rates of microvascular and neu- Cardiovascular Disease and Type 1 with control subjects in VADT, with
ropathic complications in patients with Diabetes achieved A1C of 6.4% versus 7.5%
type 2 diabetes. Long-term follow-up of Cardiovascular disease (CVD) is a more (46 mmol/mol vs. 58 mmol/mol) in
the UKPDS cohorts showed enduring ef- common cause of death than microvas- ACCORD, 6.5% versus 7.3% (48 mmol/mol
fects of early glycemic control on most cular complications in populations with vs. 56 mmol/mol) in ADVANCE, and
microvascular complications (37). diabetes. There is evidence for a cardio- 6.9% versus 8.4% (52 mmol/mol vs. 68
Therefore, achieving glycemic control vascular benefit of intensive glycemic mmol/mol) in VADT. Details of these
of A1C targets of ,7% (53 mmol/mol) control after long-term follow-up of studies are reviewed extensively in the
has been shown to reduce microvascular study cohorts treated early in the course ADA position statement “Intensive Glyce-
complications of diabetes and, in patients of type 1 and type 2 diabetes. In the mic Control and the Prevention of Cardio-
with type 1 diabetes, mortality. If imple- DCCT, there was a trend toward lower vascular Events: Implications of the
mented soon after the diagnosis of diabetes, risk of CVD events with intensive control. In ACCORD, ADVANCE, and VA Diabetes
this target is associated with long-term the 9-year post-DCCT follow-up of the EDIC Trials: A Position Statement of the Amer-
reduction in macrovascular disease. cohort, participants previously randomly ican Diabetes Association and a Scientific
ACCORD, ADVANCE, and VADT assigned to the intensive arm had a signif- Statement of the American College of
Three landmark trials (Action to Control icant 57% reduction in the risk of nonfatal Cardiology Foundation and the American
Cardiovascular Risk in Diabetes [ACCORD], myocardial infarction (MI), stroke, or CVD Heart Association” (46).
Action in Diabetes and Vascular Disease: death compared with those previously in The glycemic control comparison in
Preterax and Diamicron MR Controlled the standard arm (43). The benefit of in- ACCORD was halted early due to an in-
Evaluation [ADVANCE], and Veterans Af- tensive glycemic control in this cohort with creased mortality rate in the intensive
fairs Diabetes Trial [VADT]) showed that type 1 diabetes has been shown to persist compared with the standard arm
lower A1C levels were associated with for several decades (44) and to be associ- (1.41% vs. 1.14% per year; hazard ratio
reduced onset or progression of micro- ated with a modest reduction in all-cause 1.22 [95% CI 1.01–1.46]), with a similar
vascular complications (38–40). mortality (45). increase in cardiovascular deaths. Anal-
Epidemiological analyses of the DCCT Cardiovascular Disease and Type 2 ysis of the ACCORD data did not identify a
(1) and UKPDS (41) demonstrate a cur- Diabetes clear explanation for the excess mortality
vilinear relationship between A1C and In type 2 diabetes, there is evidence that in the intensive arm (42).
microvascular complications. Such analyses more intensive treatment of glycemia in Longer-term follow-up has shown no
suggest that, on a population level, the newly diagnosed patients may reduce evidence of cardiovascular benefit or
greatest number of complications will be long-term CVD rates. During the UKPDS harm in the ADVANCE trial (47), which is
averted by taking patients from very trial, there was a 16% reduction in CVD perhaps not unexpected given the narrow
care.diabetesjournals.org Glycemic Targets S43

separation in A1C between groups. The Table 5.2—Summary of glycemic recommendations for nonpregnant adults with
end-stage renal disease rate was lower diabetes
in the intensive group over follow-up. A1C ,7.0% (53 mmol/mol)*
However, 10-year follow-up of the VADT Preprandial capillary plasma glucose 80–130 mg/dL* (4.4–7.2 mmol/L)
cohort (48) showed a reduction in the risk Peak postprandial capillary plasma glucose† ,180 mg/dL* (10.0 mmol/L)
of cardiovascular events (52.7 [control
*More or less stringent glycemic goals may be appropriate for individual patients. Goals should
group] vs. 44.1 [intervention group] be individualized based on duration of diabetes, age/life expectancy, comorbid conditions,
events per 1,000 person-years) with no known CVD or advanced microvascular complications, hypoglycemia unawareness, and
benefit in cardiovascular or overall mor- individual patient considerations.
tality. Heterogeneity of mortality effects †Postprandial glucose may be targeted if A1C goals are not met despite reaching preprandial
glucose goals. Postprandial glucose measurements should be made 1–2 h after the beginning of
across studies was noted, which may re- the meal, generally peak levels in patients with diabetes.
flect differences in glycemic targets, ther-
apeutic approaches, and population
characteristics (49). of ,7% (53 mmol/mol). The issue of pre- and landmark glycemic control trials
Mortality findings in ACCORD (42) and prandial versus postprandial SMBG targets such as the DCCT and UKPDS relied
subgroup analyses of VADT (50) suggest is complex (54). Elevated postchallenge (2-h overwhelmingly on preprandial SMBG.
that the potential risks of intensive glyce- oral glucose tolerance test) glucose values Additionally, a randomized controlled
mic control may outweigh its benefits in have been associated with increased cardio- trial in patients with known CVD found
higher-risk patients. In all three trials, se- vascular risk independent of fasting plasma no CVD benefit of insulin regimens tar-
vere hypoglycemia was significantly more glucose in some epidemiological studies. In geting postprandial glucose compared
likely in participants who were randomly subjects with diabetes, surrogate measures with those targeting preprandial glucose
assigned to the intensive glycemic control of vascular pathology, such as endothelial (55). Therefore, it is reasonable for post-
arm. Those patients with long duration of dysfunction, are negatively affected by prandial testing to be recommended for
diabetes, a known history of severe hypo- postprandial hyperglycemia. It is clear that individuals who have premeal glucose val-
glycemia, advanced atherosclerosis, or postprandial hyperglycemia, like prepran- ues within target but have A1C values
advanced age/frailty may benefit from dial hyperglycemia, contributes to elevated above target. Taking postprandial plasma
less aggressive targets (51,52). A1C levels, with its relative contribution be- glucose measurements 1–2 h after the
Providers should be vigilant in pre- ing greater at A1C levels that are closer to start of a meal and using treatments aimed
venting severe hypoglycemia in patients 7% (53 mmol/mol). However, outcome at reducing postprandial plasma glucose
with advanced disease and should not studies have clearly shown A1C to be values to ,180 mg/dL (10.0 mmol/L)
aggressively attempt to achieve near- the primary predictor of complications, may help to lower A1C.
normal A1C levels in patients in whom
such targets cannot be safely and rea-
sonably achieved. Severe or frequent
hypoglycemia is an absolute indication
for the modification of treatment regi-
mens, including setting higher glycemic
goals. Many factors, including patient
preferences, should be taken into ac-
count when developing a patient’s indi-
vidualized goals (Table 5.2).

A1C and Glycemic Targets


Numerous aspects must be considered
when setting glycemic targets. The ADA
proposes optimal targets, but each target
must be individualized to the needs of
each patient and his or her disease factors.
When possible, such decisions should
be made with the patient, reflecting his
or her preferences, needs, and values.
Figure 5.1 is not designed to be applied
rigidly but to be used as a broad con-
struct to guide clinical decision making
(53), both in type 1 and type 2 diabetes.
Recommended glycemic targets for
many nonpregnant adults are shown in
Table 5.2. The recommendations in- Figure 5.1—Depicted are patient and disease factors used to determine optimal A1C targets.
clude blood glucose levels that appear Characteristics and predicaments toward the left justify more stringent efforts to lower A1C; those
to correlate with achievement of an A1C toward the right suggest less stringent efforts. Adapted with permission from Inzucchi et al. (53).
S44 Glycemic Targets Diabetes Care Volume 39, Supplement 1, January 2016

An analysis of data from 470 partici- (e.g., bedtime snack to prevent overnight
c Ongoing assessment of cognitive
pants of the ADAG study (237 with hypoglycemia), exercise management,
function is suggested with in-
type 1 diabetes and 147 with type 2 dia- medication adjustment, glucose monitor-
creased vigilance for hypoglyce-
betes) found that actual average glucose ing, and routine clinical surveillance may
mia by the clinician, patient, and
levels associated with conventional A1C improve patient outcomes (61). Docu-
caregivers if low cognition or de-
targets were higher than older DCCT and mented symptomatic hypoglycemia and
clining cognition is found. B
ADA targets (Table 5.1) (24,28). These find- asymptomatic hypoglycemia are defined
ings support that premeal glucose targets as occurring at a plasma glucose concen-
Hypoglycemia is the major limiting fac-
may be relaxed without undermining over- tration of #70 mg/dL (3.9 mmol/L) (61).
tor in the glycemic management of type
all glycemic control as measured by A1C. This level remains a general threshold for
1 and insulin-treated type 2 diabetes.
These data have prompted a revision in defining hypoglycemia.
Mild hypoglycemia may be inconve-
the ADA-recommended premeal target In 2014, the ADA changed its glycemic
nient or frightening to patients with
to 80–130 mg/dL (4.4–7.2 mmol/L). target to 80–130 mg/dL (4.4–7.2 mmol/L).
diabetes. Severe hypoglycemia is defined
This change reflects the results of the
HYPOGLYCEMIA as hypoglycemia requiring assistance
ADAG study, which demonstrated that
from another person. It is characterized
Recommendations
higher glycemic targets corresponded to
by cognitive impairment that may be rec-
c Individuals at risk for hypogly- A1C goals (24). An additional goal of rais-
ognized or unrecognized and can prog-
cemia should be asked about ing the lower range of the glycemic tar-
ress to loss of consciousness, seizure,
symptomatic and asymptomatic get was to limit overtreatment and
coma, or death, and it is reversed by ad-
hypoglycemia at each encoun- provide a safety margin in patients ti-
ministration of rapid-acting glucose. Se-
ter. C trating glucose-lowering drugs such as
vere hypoglycemia can cause acute insulin to glycemic targets.
c Glucose (15–20 g) is the preferred harm to the person with diabetes or
treatment for the conscious in- others, especially if it causes falls, motor Hypoglycemia Treatment
dividual with hypoglycemia, al- vehicle accidents, or other injury. A large Hypoglycemia treatment requires in-
though any form of carbohydrate cohort study suggested that among older gestion of glucose- or carbohydrate-
that contains glucose may be adults with type 2 diabetes, a history of containing foods. The acute glycemic
used. Fifteen minutes after treat- severe hypoglycemia was associated with response correlates better with the glu-
ment, if SMBG shows continued greater risk of dementia (56). Conversely, cose content of food than with the car-
hypoglycemia, the treatment in a substudy of the ACCORD trial, cogni- bohydrate content of food. Pure glucose
should be repeated. Once SMBG tive impairment at baseline or decline in is the preferred treatment, but any form
returns to normal, the individual cognitive function during the trial was sig- of carbohydrate that contains glucose
should consume a meal or snack nificantly associated with subsequent ep- will raise blood glucose. Added fat may
to prevent recurrence of hypogly- isodes of severe hypoglycemia (57). retard and then prolong the acute gly-
cemia. E Evidence from DCCT/EDIC, which in- cemic response. Ongoing insulin activity
c Glucagon should be prescribed for volved younger adults and adolescents or insulin secretagogues may lead to re-
all individuals at increased risk of current hypoglycemia unless further
with type 1 diabetes, found no associa-
severe hypoglycemia, defined as food is ingested after recovery.
tion between frequency of severe hypo-
hypoglycemia requiring assis- glycemia and cognitive decline (58), as Glucagon
tance, and caregivers, school per- discussed in Section 11 “Children and Those in close contact with, or having
sonnel, or family members of these Adolescents.” custodial care of, people with hypoglyce-
individuals should be instructed in Severe hypoglycemia was associated mia-prone diabetes (family members,
its administration. Glucagon admin- with mortality in participants in both the roommates, school personnel, child care
istration is not limited to health providers, correctional institution staff, or
standard and the intensive glycemia
care professionals. E coworkers) should be instructed on the use
arms of the ACCORD trial, but the relation-
c Hypoglycemia unawareness or of glucagon kits. An individual does not
ships between hypoglycemia, achieved
one or more episodes of severe need to be a health care professional to
A1C, and treatment intensity were not
hypoglycemia should trigger re- safely administer glucagon. Care should
straightforward. An association of severe
evaluation of the treatment regi- be taken to ensure that glucagon kits are
hypoglycemia with mortality was also
men. E not expired.
found in the ADVANCE trial (59). An asso-
c Insulin-treated patients with hy-
ciation between self-reported severe hy- Hypoglycemia Prevention
poglycemia unawareness or an ep-
poglycemia and 5-year mortality has also Hypoglycemia prevention is a critical
isode of severe hypoglycemia
been reported in clinical practice (60). component of diabetes management.
should be advised to raise their
Young children with type 1 diabetes SMBG and, for some patients, CGM are
glycemic targets to strictly avoid
and the elderly are noted as particularly essential tools to assess therapy and de-
further hypoglycemia for at least
vulnerable to severe hypoglycemia be- tect incipient hypoglycemia. Patients
several weeks in order to partially
cause of their reduced ability to recognize should understand situations that in-
reverse hypoglycemia unaware-
hypoglycemic symptoms and effectively crease their risk of hypoglycemia, such
ness and reduce risk of future ep-
communicate their needs. Individualized as fasting for tests or procedures, during
isodes. A
patient education, dietary intervention or after intense exercise, and during
care.diabetesjournals.org Glycemic Targets S45

sleep. Hypoglycemia may increase the hyperglycemic nonketotic hyperosmo- HbA1c by 0.25%. Ann Intern Med 2012;156:JC6–
risk of harm to self or others, such as lar state, please refer to the ADA con- JC12
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DR, Neil HAW. 10-year follow-up of intensive type 2 diabetes. N Engl J Med 2014;371:1392–1406 group of the American Diabetes Association
glucose control in type 2 diabetes. N Engl 48. Hayward RA, Reaven PD, Wiitala WL, et al.; and the Endocrine Society. Diabetes Care
J Med 2008;359:1577–1589 VADT Investigators. Follow-up of glycemic con- 2013;36:1384–1395
38. Duckworth W, Abraira C, Moritz T, et al.; trol and cardiovascular outcomes in type 2 62. Cryer PE. Diverse causes of hypoglycemia-
VADT Investigators. Glucose control and vascu- diabetes. N Engl J Med 2015;372:2197–2206 associated autonomic failure in diabetes. N Engl
lar complications in veterans with type 2 diabetes. 49. Turnbull FM, Abraira C, Anderson RJ, et al. J Med 2004;350:2272–2279
N Engl J Med 2009;360:129–139 Intensive glucose control and macrovascular 63. Kitabchi AE, Umpierrez GE, Miles JM, Fisher
39. Patel A, MacMahon S, Chalmers J, et al.; outcomes in type 2 diabetes. Diabetologia JN. Hyperglycemic crises in adult patients with
ADVANCE Collaborative Group. Intensive blood 2009;52:2288–2298 diabetes. Diabetes Care 2009;32:1335–1343
Diabetes Care Volume 39, Supplement 1, January 2016 S47

American Diabetes Association


6. Obesity Management for the
Treatment of Type 2 Diabetes
Diabetes Care 2016;39(Suppl. 1):S47–S51 | DOI: 10.2337/dc16-S009

There is strong and consistent evidence that obesity management can delay pro-
gression from prediabetes to type 2 diabetes (1,2) and may be beneficial in the
treatment of type 2 diabetes. 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 dem-
onstrated that in obese patients with type 2 diabetes more extreme dietary energy

6. OBESITY MANAGEMENT IN TYPE 2 DIABETES


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 pharmacological
therapy or ongoing procedures (6,7). 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 remains relatively preserved (5,8). Although the Action for Health
in Diabetes (Look AHEAD) trial did not show that an intensive lifestyle intervention
reduced cardiovascular events in overweight or obese adults with type 2 diabetes (9),
it did show the feasibility of achieving and maintaining long-term weight loss in
patients with type 2 diabetes.
LOOK AHEAD
In the Look AHEAD intensive lifestyle intervention group, mean weight loss was 4.7%
(SE 0.2) at 8 years (10). Approximately 50% of intensive lifestyle intervention par-
ticipants lost $5% and 27% lost $10% of their initial body weight at 8 years (10).
Participants randomly assigned to the intensive lifestyle group achieved equivalent
risk factor control but required fewer glucose-, blood pressure–, and lipid-lowering
medications than those randomly assigned to standard care. Secondary analyses of
the Look AHEAD trial and other large cardiovascular outcome studies document
other benefits of weight loss in patients with type 2 diabetes, including improve-
ments in mobility, physical and sexual functioning, and health-related quality of life
(11). The goal of this section is to provide evidence-based recommendations for
dietary, pharmacological, and surgical interventions for obesity management as
treatments for hyperglycemia in type 2 diabetes.

ASSESSMENT
Recommendation
c At each patient encounter, BMI should be calculated and documented in the
medical record. B

At each routine patient encounter, BMI should be calculated from the height and
weight. BMI should be classified to determine the presence of overweight or obesity,
discussed with the patient, and documented in the patient record (Table 6.1). In Asian
Americans, the BMI cutoff points to define overweight and obesity are lower: normal
(,23 kg/m2), overweight (23.0–27.4 kg/m2), obese (27.5–37.4 kg/m2), and extremely Suggested citation: American Diabetes Associa-
obese ($37.5 kg/m2) (12). Providers should advise overweight and obese patients that tion. Obesity management for the treatment of
higher BMIs increase the risk of cardiovascular disease and all-cause mortality. Providers type 2 diabetes. Sec. 6. In Standards of Medical
Care in Diabetesd2016. Diabetes Care 2016;
should assess each patient’s readiness to achieve weight loss and jointly determine
39(Suppl. 1):S47–S51
weight loss goals and intervention strategies. Strategies include diet, physical activity,
© 2016 by the American Diabetes Association.
behavioral therapy, pharmacological therapy, and bariatric surgery (Table 6.1). The latter Readers may use this article as long as the work
two strategies may be prescribed for carefully selected patients as adjuncts to diet, is properly cited, the use is educational and not
physical activity, and behavioral therapy. for profit, and the work is not altered.
S48 Obesity Management for the Treatment of Type 2 Diabetes Diabetes Care Volume 39, Supplement 1, January 2016

DIET, PHYSICAL ACTIVITY, AND control, and/or other obesity-related consumption of a reduced calorie diet,
BEHAVIORAL THERAPY medical conditions, lifestyle changes and participation in high levels of phys-
that result in modest and sustained ical activity (200–300 min/week). Some
Recommendations
weight loss produce clinically meaning- commercial and proprietary weight loss
c Diet, physical activity, and behavioral
ful reductions in blood glucose, A1C, and programs have shown promising weight
therapy designed to achieve 5%
triglycerides (3–5). Greater weight loss loss results (18).
weight loss should be prescribed
produces even greater benefits, including When provided by trained practi-
for overweight and obese patients
reductions in blood pressure, improve- tioners in medical care settings with
with type 2 diabetes ready to
ments in LDL and HDL cholesterol, and close medical monitoring, short-term
achieve weight loss. A
reductions in the need for medications (3-month) high-intensity lifestyle inter-
c Such interventions should be high in-
to control blood glucose, blood pressure, ventions that use very low-calorie diets
tensity ($16 sessions in 6 months)
and lipids (9,10). (defined as #800 kcal/day) and total
and focus on diet, physical activity,
meal replacements may achieve greater
and behavioral strategies to achieve
short-term weight loss (10–15%) than
a 500–750 kcal/day energy deficit. A Lifestyle Interventions
intensive behavioral lifestyle interven-
c Diets that provide the same caloric Weight loss can be attained with life-
tions that typically achieve 5% weight
restriction but differ in protein, style programs that achieve a 500–750
loss. Weight regain following the cessation
carbohydrate, and fat content are kcal/day energy deficit or provide ap-
of high-intensity lifestyle interventions is
equally effective in achieving proximately 1,200–1,500 kcal/day for
greater than following intensive behavioral
weight loss. A women and 1,500–1,800 kcal/day for
lifestyle interventions unless a long-term
c For patients who achieve short- men, adjusted for the individual’s base-
comprehensive weight loss maintenance
term weight loss goals, long-term line body weight. Although benefits may
program is provided (19,20).
($1-year) comprehensive weight be seen with as little as 5% weight loss,
maintenance programs should be sustained weight loss of $7% is optimal. PHARMACOTHERAPY
prescribed. Such programs should These diets may differ in the types of
Recommendations
provide at least monthly contact foods they restrict (such as high-fat or
c When choosing glucose-lowering
and encourage ongoing monitoring high-carbohydrate foods) but are effec-
medications for overweight or
of body weight (weekly or more fre- tive if they create the necessary energy
obese patients with type 2 diabetes,
quently), continued consumption deficit (13–16). The diet choice should
consider their effect on weight. E
of a reduced calorie diet, and par- be based on the patient’s health status
c Whenever possible, minimize the
ticipation in high levels of physical and preferences.
medications for comorbid condi-
activity (200–300 min/week). A Intensive behavioral lifestyle inter-
tions that are associated with weight
c To achieve weight loss of .5%, ventions should include $16 sessions
gain. E
short-term (3-month) high-intensity in 6 months and focus on diet, physical
c Weight loss medications may be
lifestyle interventions that use activity, and behavioral strategies to
effective as adjuncts to diet, physical
very low-calorie diets (#800 achieve an ;500–750 kcal/day energy
activity, and behavioral counseling
kcal/day) and total meal replace- deficit. Interventions should be pro-
for selected patients with type 2 di-
ments may be prescribed for vided by trained interventionists in ei-
abetes and BMI $27 kg/m2. Potential
carefully selected patients by ther individual or group sessions (17).
benefits must be weighed against the
trained practitioners in medical Overweight and obese patients with
potential risks of the medications. A
care settings with close medical type 2 diabetes who have lost weight
c If a patient’s response to weight loss
monitoring. To maintain weight during the 6-month intensive behavioral
medications is ,5% after 3 months
loss, such programs must incorpo- lifestyle intervention should be enrolled
or if there are any safety or tolerabil-
rate long-term comprehensive in long-term ($1-year) comprehensive
ity issues at any time, the medication
weight maintenance counseling. B weight loss maintenance programs
should be discontinued and alterna-
that provide at least monthly contact
tive medications or treatment ap-
Among overweight or obese patients with a trained interventionist and focus
proaches should be considered. A
with type 2 diabetes and inadequate on ongoing monitoring of body weight
glycemic, blood pressure and lipid (weekly or more frequently), continued
When considering pharmacological treat-
ments for overweight or obese patients
Table 6.1—Treatment for overweight and obesity in type 2 diabetes
with type 2 diabetes, providers should
BMI category (kg/m2)
first consider their choice of glucose-
lowering medications. Whenever possi-
Treatment 23.0* or 25.0–26.9 27.0–29.9 30.0–34.9 35.0–39.9 $40
ble, medications should be chosen to
Diet, physical activity, and
promote weight loss or to be weight neu-
behavioral therapy ┼ ┼ ┼ ┼ ┼
tral. Agents associated with weight loss
Pharmacotherapy ┼ ┼ ┼ ┼
Bariatric surgery ┼ ┼
include metformin, a-glucosidase inhibi-
tors, glucagon-like peptide 1 agonists,
┼Treatment may be indicated for selected motivated patients.
amylin mimetics, and sodium–glucose
*Cutoff points for Asian American individuals.
cotransporter 2 inhibitors. Dipeptidyl
care.diabetesjournals.org Obesity Management for the Treatment of Type 2 Diabetes S49

peptidase 4 inhibitors appear to be In general, pharmacological treatment education, lifestyle counseling, and
weight neutral. Unlike these agents, insu- of obesity has been limited by low adher- encouragement to participate in Weight
lin secretagogues, thiazolidinediones, and ence, modest efficacy, adverse effects, Watchers) in achieving a target A1C #6%
insulin have often been associated with and weight regain after medication cessa- (42 mmol/mol) at 3 years among obese
weight gain (see Section 7 “Approaches tion (21). patients with uncontrolled type 2 diabe-
to Glycemic Treatment”). tes (mean A1C 9.3% [78 mmol/mol]). This
BARIATRIC SURGERY A1C target was achieved by 38% (P ,
Concomitant Medications 0.001) in the gastric bypass group, 24%
Recommendations
Providers should carefully review the (P 5 0.01) in the sleeve gastrectomy
c Bariatric surgery may be considered
patient’s concomitant medications group, and 5% in the group that received
and, whenever possible, minimize or for adults with BMI .35 kg/m2 and
type 2 diabetes, especially if diabe- only medical therapy (26). Diabetes re-
provide alternatives for medications mission rates tend to be higher with pro-
that promote weight gain. The latter in- tes or associated comorbidities are
difficult to control with lifestyle and cedures that bypass portions of the small
clude atypical antipsychotics (clozapine, intestine and lower with procedures that
olanzapine, risperidone, etc.) and an- pharmacological therapy. B
c Patients with type 2 diabetes who only restrict the stomach.
tidepressants (tricyclic antidepressants, Younger age, shorter duration of
selective serotonin reuptake inhibitors, have undergone bariatric surgery
need lifelong lifestyle support type 2 diabetes, lower A1C, higher
and monoamine oxidase inhibitors), serum insulin levels, and nonuse of
glucocorticoids, oral contraceptives and annual medical monitoring,
at a minimum. B insulin have all been associated with
that contain progestins, anticonvulsants higher remission rates after bariatric
c Although small trials have shown a
including gabapentin, and a number of surgery (27).
antihistamines and anticholinergics. glycemic benefit of bariatric sur-
gery in patients with type 2 dia- Although bariatric surgery has been
Approved Medications betes and BMI 30–35 kg/m 2 , shown to improve the metabolic profiles
The U.S. Food and Drug Administration there is currently insufficient evi- of morbidly obese patients with type 1
(FDA) has approved five weight loss dence to generally recommend diabetes, the role of bariatric surgery in
medications (or combination medica- surgery in patients with BMI such patients will require larger and
tions) for long-term use by patients #35 kg/m2. E longer studies (28).
with BMI $27 kg/m2 with one or more
obesity-associated comorbid conditions Bariatric and metabolic surgeries, either Disadvantages
and by patients with BMI $30 kg/m2 gastric banding or procedures that involve Bariatric surgery is costly and has asso-
who are motivated to lose weight (21– resecting, bypassing, or transposing sec- ciated risks. Morbidity and mortality
23). Medications approved for long-term tions of the stomach and small intestine, rates directly related to the surgery
weight loss and weight loss mainte- can be effective weight loss treatments have decreased considerably in recent
nance and their advantages and disad- for severe obesity when performed as years, with 30-day mortality rates
vantages are summarized in Table 6.2. part of a comprehensive weight manage- now 0.2% for laparoscopic procedures,
The rationale for weight loss medica- ment program with lifelong lifestyle sup- similar to those for laparoscopic cholecys-
tions is to help patients to more consis- port and medical monitoring. In one tectomy, and 2.1% for open procedures
tently adhere to low-calorie diets and to meta-analysis, gastric banding resulted (29,30). Outcomes vary depending on
reinforce lifestyle changes including phys- in less weight loss than sleeve gastrec- the procedure and the experience of
ical activity. Providers should be knowl- tomy and Roux-en-Y gastric bypass the surgeon and center. Longer-term
edgeable about the product label and (1-year excess weight loss ;33% vs. concerns include dumping syndrome
should balance the potential benefits of ;70%) (24). National guidelines sup- (nausea, colic, diarrhea), vitamin and
successful weight loss against the poten- port consideration of bariatric surgery mineral deficiencies, osteoporosis, and,
tial risks of the medication for each pa- for people with type 2 diabetes with rarely, severe hypoglycemia from insulin
tient. All medications are FDA pregnancy BMI .35 kg/m2. hypersecretion. More recent studies also
category X. These medications are con- suggest that patients who undergo bari-
traindicated in women who are or may Advantages atric surgery may be at increased risk for
become pregnant. Women in their repro- Treatment with bariatric surgery has substance use, including drug and alcohol
ductive years must be cautioned to use a been shown to achieve near or complete use and cigarette smoking (31). Cohort
reliable method of contraception. normalization of glycemia 2 years follow- studies attempting to match surgical
ing surgery in 72% of patients (compared and nonsurgical subjects suggest that
Assessing Efficacy and Safety with 16% in a matched control group the procedure may reduce longer-term
Efficacy and safety should be assessed at treated with lifestyle and pharmacologi- mortality (25).
least monthly for the first 3 months of treat- cal interventions) (25). A study evaluated In contrast, a propensity score–
ment. If a patient’s response is deemed in- the effectiveness of surgical intervention adjusted analysis of older, severely obese
sufficient (weight loss ,5%) or if there are (Roux-en-Y gastric bypass or sleeve gas- patients in Veterans Affairs Medical Cen-
any safety or tolerability issues at any time, trectomy) and medical therapy compared ters found that bariatric surgery was not
the medication should be discontinued and with medical therapy alone (quarterly associated with decreased mortality com-
alternative medications or treatment ap- visits, pharmacological therapy, self- pared with usual care (mean follow-up
proaches should be considered. monitoring of blood glucose, diabetes 6.7 years) (32). Retrospective analyses
S50

Table 6.2—Medications approved by the FDA for the long-term treatment of obesity
1-Year weight change status2–5
Generic drug name, % Patients with $5% Adverse effects2,6–12
(proprietary name[s]) and Average wholesale Average weight loss loss of baseline
dosage strength and form Adult dosing frequency price (per month)1 relative to placebo weight Common7 Serious7
Lipase inhibitor
Orlistat (Alli) 60 mg caps or 60 mg or 120 mg t.i.d. $41–82 (60 mg) 2.5 kg (60 mg) 35–73% Abdominal pain/discomfort, oily Liver failure and oxalate
orlistat (Xenical) 120 mg caps (during or up to 1 h $615 (120 mg) 3.4 kg (120 mg) spotting/stool, fecal urgency, nephropathy
after a low-fat meal) 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 tabs 10 mg b.i.d. $263 3.2 kg 38–48% Hypoglycemia, headache, fatigue Serotonin syndrome or
NMS-like reactions, heart
valve disorder (,2.4%),
bradycardia
Sympathomimetic amine anorectic/antiepileptic combination
Obesity Management for the Treatment of Type 2 Diabetes

Phentermine/topiramate ER (Qsymia) Recommended dose: 3.75 mg/23 mg $239 (maximum 6.7 kg (7.5 mg/46 mg) 45–70% Paresthesia, xerostomia, constipation, Topiramate is teratogenic and
3.75 mg/23 mg caps, q.d. for 14 days, then increase to dose using the 8.9 kg (15 mg/92 mg) headache has been associated with
7.5 mg/46 mg caps, 7.5 mg/46 mg q.d. highest strength) cleft lip/palate
11.25 mg/69 mg caps, Maximum dose: 15 mg/92 mg q.d.
15 mg/92 mg caps
Opioid antagonist/aminoketone antidepressant combination
Naltrexone/bupropion (Contrave) Maximum dose: two tablets of Contrave $239 (maximum dose) 2.0–4.1 kg 36–57% Nausea, constipation, headache, Depression, precipitation
8 mg/90 mg tabs b.i.d. for a total daily dosage of naltrexone (32 mg/360 mg) vomiting of mania
32 mg/bupropion 360 mg
Acylated human glucagon-like peptide 1 receptor agonist
Liraglutide (Saxenda) Maintenance dose: 3 mg s.c. q.d. $1,282 5.8–5.9 kg 51–73% Hypoglycemia, nausea, vomiting, Pancreatitis, thyroid C-cell
6 mg/mL prefilled pen diarrhea, constipation, headache tumors in rodents,
contraindicated in patients
with personal/family history
of MTC or MEN2, acute renal
failure

All medications are FDA pregnancy category X; these 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; NMS, neuroleptic malignant syndrome; s.c., subcutaneous; tabs, tablets.
1
RED BOOK Online. Micromedex 2.0 (electronic version). Truven Health Analytics, Greenwood Village, CO.
2
Physicians’ Desk Reference. PDR Network, LLC (electronic version). Truven Health Analytics, Greenwood Village, CO.
3
Yanovski SZ, Yanovski JA. Long-term drug treatment for obesity: a systematic and clinical review. JAMA 2014;311:74–86.
4
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.
5
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.
6
DrugPoints System (electronic version). Truven Health Analytics, Greenwood Village, CO.
7
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.
8
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.
9
Data of common adverse effects for Belviq were derived from placebo-controlled clinical trials in patients with type 2 diabetes.
10
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.
11
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 diabetes.
12
Diabetes Care Volume 39, Supplement 1, January 2016

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 reported.
care.diabetesjournals.org Obesity Management for the Treatment of Type 2 Diabetes S51

and modeling studies suggest that bariat- intervention: the Look AHEAD study. Obesity 23. Pi-Sunyer X, Astrup A, Fujioka K, et al.;
ric surgery may be cost-effective or even (Silver Spring) 2014;22:5–13 SCALE Obesity and Prediabetes NN8022-1839
11. Wilding JPH. The importance of weight Study Group. A randomized, controlled trial of
cost-saving for patients with type 2 di- management in type 2 diabetes mellitus. Int J 3.0 mg of liraglutide in weight management.
abetes, but the results are largely de- Clin Pract 2014;68:682–691 N Engl J Med 2015;373:11–22
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of intensive lifestyle intervention in type 2 plus bupropion on weight loss in overweight 36. Courcoulas AP, Goodpaster BH, Eagleton JK,
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10. Look AHEAD Research Group. Eight-year mised, double-blind, placebo-controlled, phase diabetes mellitus: a randomized clinical trial.
weight losses with an intensive lifestyle 3 trial. Lancet 2010;376:595–605 JAMA Surg 2014;149:707–715
S52 Diabetes Care Volume 39, Supplement 1, January 2016

American Diabetes Association


7. Approaches to Glycemic
Treatment
Diabetes Care 2016;39(Suppl. 1):S52–S59 | DOI: 10.2337/dc16-S010

PHARMACOLOGICAL THERAPY FOR TYPE 1 DIABETES


Recommendations
c Most people with type 1 diabetes should be treated with multiple-dose insulin
injections (three to four injections per day of basal and prandial insulin) or
continuous subcutaneous insulin infusion. A
7. APPROACHES TO GLYCEMIC TREATMENT

c Consider educating individuals with type 1 diabetes on matching prandial insulin


dose to carbohydrate intake, premeal blood glucose, and anticipated activity. E
c Most individuals with type 1 diabetes should use insulin analogs to reduce
hypoglycemia risk. A
c Individuals who have been successfully using continuous subcutaneous insulin
infusion should have continued access after they turn 65 years of age. E

Insulin Therapy
Insulin is the mainstay of therapy for individuals with type 1 diabetes. There are
excellent reviews to guide the initiation and management of insulin therapy to
achieve desired glycemic goals (1). Although most studies of multiple-dose insulin
versus pump therapy have been small and of short duration, a systematic review and
meta-analysis concluded that there are minimal differences between the two forms
of intensive insulin therapy in A1C (combined mean between-group difference
favoring insulin pump therapy 20.30% [95% CI 20.58 to 20.02]) and severe hypo-
glycemia rates in children and adults (2). A large randomized trial in patients with
type 1 diabetes with nocturnal hypoglycemia reported that sensor-augmented in-
sulin pump therapy with the threshold suspend feature reduced nocturnal hypo-
glycemia, without increasing glycated hemoglobin values (3). Intensive
management through pump therapy/continuous glucose monitoring and active
patient/family participation should be strongly encouraged (4–6). Selected
individuals who have mastered carbohydrate counting should be educated that fat
increases glucose concentrations and insulin requirements (7).
The Diabetes Control and Complications Trial (DCCT) clearly showed that in-
tensive insulin therapy (three or more injections per day of insulin) or continuous
subcutaneous insulin infusion (CSII) (insulin pump therapy) was a key part of
improved glycemia and better outcomes (8,9). The study was carried out with
short-acting and intermediate-acting human insulins. Despite better microvascular,
macrovascular, and all-cause mortality outcomes, intensive insulin therapy was as-
sociated with a high rate of severe hypoglycemia (62 episodes per 100 patient-years
of therapy). Since the DCCT, a number of rapid-acting and long-acting insulin analogs
have been developed. These analogs are associated with less hypoglycemia in type 1
diabetes, while matching the A1C lowering of human insulins (10,11).
Rapid-acting inhaled insulin used before meals in type 1 diabetes leads to inferior
A1C lowering when compared with aspart insulin, with less hypoglycemia across all
A1C target categories (12). Suggested citation: American Diabetes Associa-
Postprandial glucose excursions can be better controlled by adjusting the timing tion. Approaches to glycemic treatment. Sec. 7.
In Standards of Medical Care in Diabetesd2016.
of prandial (bolus) insulin dose administration. The optimal time to inject prandial
Diabetes Care 2016;39(Suppl. 1):S52–S59
insulin varies, based on the type of insulin injected (regular, rapid-acting analog,
© 2016 by the American Diabetes Association.
inhaled, etc.), the measured blood glucose level, timing of meals, and carbohydrate Readers may use this article as long as the work
consumption. Recommendations for prandial insulin dose administration should is properly cited, the use is educational and not
therefore be individualized. for profit, and the work is not altered.
care.diabetesjournals.org Approaches to Glycemic Treatment S53

Recommended therapy for type 1 di- insulin requirements (6.6 units/day, P ,


c A patient-centered approach
abetes consists of the following: 0.001) and led to small reductions in
should be used to guide the choice
weight and total and LDL cholesterol but
of pharmacological agents. Con-
1. Multiple-dose insulin injections (three not to improved glycemic control (abso-
siderations include efficacy, cost,
to four injections per day of basal and lute A1C reduction 0.11%, P 5 0.42) (14).
potential side effects, weight, co-
prandial insulin) or CSII therapy. Incretin-Based Therapies morbidities, hypoglycemia risk,
2. Match prandial insulin to carbohy- Therapies approved for the treatment of and patient preferences. E
drate intake, premeal blood glucose, type 2 diabetes are currently being eval- c For patients with type 2 diabetes
and anticipated physical activity. uated in type 1 diabetes. Glucagon-like who are not achieving glycemic
3. For most patients (especially those at peptide 1 (GLP-1) agonists and dipep- goals, insulin therapy should not
elevated risk of hypoglycemia), use tidyl peptidase 4 (DPP-4) inhibitors are be delayed. B
insulin analogs. not currently FDA approved for those
4. For patients with frequent nocturnal with type 1 diabetes but are being stud- An American Diabetes Association/
hypoglycemia, recurrent severe hy- ied in this population. European Association for the Study of
poglycemia, and/or hypoglycemia
Sodium–Glucose Cotransporter 2 Diabetes position statement (17) evalu-
unawareness, a sensor-augmented
Inhibitors ated the data and developed recom-
low glucose threshold suspend pump
Sodium–glucose cotransporter 2 (SGLT2) mendations, including advantages and
may be considered.
inhibitors provide insulin-independent disadvantages, for antihyperglycemic
Pramlintide glucose lowering by blocking glucose re- agents for patients with type 2 diabetes.
Pramlintide, an amylin analog, is an absorption in the proximal renal tubule A patient-centered approach is stressed,
agent that delays gastric emptying, by inhibiting SGLT2. These agents including patient preferences, cost, and
blunts pancreatic secretion of glucagon, provide modest weight loss and blood potential side effects of each class, effects
and enhances satiety. It is a U.S. Food pressure reduction. There are three on body weight, and hypoglycemia risk.
and Drug Administration (FDA)-approved FDA-approved agents for use in patients Lifestyle modifications that improve
therapy for use in adults with type 1 di- with type 2 diabetes, but there are in- health (see Section 3 “Foundations of
abetes. It has been shown to induce sufficient data to recommend treatment Care and Comprehensive Medical Eval-
weight loss and lower insulin dose. Con- in type 1 diabetes (15). The FDA recently uation”) should be emphasized along
current reduction of prandial insulin issued a warning about the risk of keto- with any pharmacological therapy.
dosing is required to reduce the risk of acidosis with SGLT2 inhibitors in individ-
Initial Therapy
severe hypoglycemia. uals with type 1 or type 2 diabetes.
Most patients should begin with life-
Symptoms of ketoacidosis include nau-
Pancreas and Islet Cell Transplantation style changes, which may include life-
sea, vomiting, abdominal pain, tiredness,
Pancreas and islet cell transplantation style counseling, setting a physical
and dyspnea. Urinary tract infections
have been shown to normalize glucose activity goal of 150 min/week minimum,
leading to urosepsis and pyelonephritis
levels but require lifelong immunosup- and weight loss counseling to lose a min-
may also occur with SGLT2 inhibitors. Pa-
pression to prevent graft rejection and imum of 7% of body weight (for details
tients should stop taking their SGLT2 in-
recurrence of autoimmune islet destruc- on lifestyle therapy, see Section 6 “Obe-
hibitor and seek medical attention
tion. Given the potential adverse effects sity Management for the Treatment of
immediately if they have symptoms of
of immunosuppressive therapy, pan- Type 2 Diabetes”). When lifestyle efforts
ketoacidosis (16).
creas transplantation should be reserved alone do not achieve or maintain glyce-
for patients with type 1 diabetes under- PHARMACOLOGICAL THERAPY mic goals, metformin monotherapy
going simultaneous renal transplanta- FOR TYPE 2 DIABETES should be added at, or soon after, diag-
tion, following renal transplantation, nosis, unless there are contraindications
Recommendations
or for those with recurrent ketoacidosis or intolerance. Metformin has a long-
c Metformin, if not contraindicated
or severe hypoglycemia despite aggres- standing evidence base for efficacy and
and if tolerated, is the preferred
sive glycemic management (13). Islet safety, is inexpensive, and may reduce
initial pharmacological agent for
cell transplantation remains investiga- risk of cardiovascular events and death
type 2 diabetes. A
tional. Autoislet transplantation may (18). Accumulating observational data
c Consider initiating insulin therapy
be considered for patients requiring to- suggest that metformin may be safely
(with or without additional agents)
tal pancreatectomy who meet eligibility continued down to glomerular filtration
in patients with newly diagnosed
criteria. rate (GFR) of 45 mL/min/1.73 m2 or even
type 2 diabetes and markedly symp-
30 mL/min/1.73 m2 (19). If metformin is
tomatic and/or elevated blood glu-
Investigational Agents used in the lower GFR range, the dose
cose levels or A1C. E
Metformin should be reduced and patients should
c If noninsulin monotherapy at max-
Adding metformin to insulin therapy may be advised to stop the medication for nau-
imum tolerated dose does not
reduce insulin requirements and improve sea, vomiting, and dehydration. In patients
achieve or maintain the A1C target
metabolic control in overweight/obese with metformin intolerance or contraindi-
over 3 months, then add a second
patients with poorly controlled type 1 di- cations, consider an initial drug from other
oral agent, a glucagon-like peptide
abetes. In a meta-analysis, metformin in classes depicted in Fig. 7.1 under “Dual
1 receptor agonist, or basal insulin. A
type 1 diabetes was found to reduce therapy” and proceed accordingly.
S54 Approaches to Glycemic Treatment Diabetes Care Volume 39, Supplement 1, January 2016

Figure 7.1—Antihyperglycemic therapy in type 2 diabetes: general recommendations (17). The order in the chart was determined by historical
availability and the route of administration, with injectables to the right; it is not meant to denote any specific preference. Potential sequences of
antihyperglycemic therapy for patients with type 2 diabetes are displayed, with the usual transition moving vertically from top to bottom (although
horizontal movement within therapy stages is also possible, depending on the circumstances). DPP-4-i, DPP-4 inhibitor; fxs, fractures; GI, gastro-
intestinal; GLP-1-RA, GLP-1 receptor agonist; GU, genitourinary; HF, heart failure; Hypo, hypoglycemia; SGLT2-i, SGLT2 inhibitor; SU, sulfonylurea;
TZD, thiazolidinedione. *See ref. 17 for description of efficacy categorization. †Consider starting at this stage when A1C is $9% (75 mmol/mol).
‡Consider starting at this stage when blood glucose is $300–350 mg/dL (16.7–19.4 mmol/L) and/or A1C is $10–12% (86–108 mmol/mol), especially
if symptomatic or catabolic features are present, in which case basal insulin 1 mealtime insulin is the preferred initial regimen. §Usually a basal
insulin (NPH, glargine, detemir, degludec). Adapted with permission from Inzucchi et al. (17).

Combination Therapy medical, psychosocial, and health eco- may be low-value based on high cost and
Although there are numerous trials nomic outcomes (21). moderate glycemic effect (24).
comparing dual therapy with metformin If the A1C target is not achieved after Rapid-acting secretagogues (megliti-
alone, few directly compare drugs as approximately 3 months, consider a com- nides) may be used instead of sulfonyl-
add-on therapy. A comparative effec- bination of metformin and one of these six ureas in patients with irregular meal
tiveness meta-analysis (20) suggests treatment options: sulfonylurea, thiazolidi- schedules or those who develop late
that overall each new class of noninsulin nedione, DPP-4 inhibitors (22), SGLT2 in- postprandial hypoglycemia on a sulfo-
agents added to initial therapy lowers hibitors, GLP-1 receptor agonists, or basal nylurea. Other drugs not shown in the
A1C around 0.9–1.1%. A comprehensive insulin (Fig. 7.1). Drug choice is based on figure (e.g., a-glucosidase inhibitors, co-
listing, including the cost, is available in patient preferences (23), as well as various lesevelam, bromocriptine, pramlintide)
Table 7.1. The ongoing Glycemia Reduc- patient, disease, and drug characteristics, may be tried in specific situations, but
tion Approaches in Diabetes: A Compar- with the goal of reducing blood glucose are generally not favored due to modest
ative Effectiveness Study (GRADE) will levels while minimizing side effects, espe- efficacy, the frequency of administra-
compare the effect of four major drug cially hypoglycemia. Figure 7.1 emphasizes tion, and/or side effects.
classes (sulfonylurea, DPP-4 inhibitor, drugs commonly used in the U.S. and/or For all patients, consider initiating
GLP-1 analog, and basal insulin) over Europe. Cost-effectiveness models have therapy with a dual combination when
4 years on glycemic control and other suggested that some of the newer agents A1C is $9% (75 mmol/mol) to more
Table 7.1—Properties of available glucose-lowering agents in the U.S. and Europe that may guide individualized treatment choices in patients with type 2 diabetes (17)
Class Compound(s) Cellular mechanism(s) Primary physiological action(s) Advantages Disadvantages Cost*
Biguanides c Metformin Activates AMP-kinase (? other) c ↓ Hepatic glucose production c Extensive experience c Gastrointestinal side effects Low
c No hypoglycemia (diarrhea, abdominal cramping)
c ↓ CVD events (UKPDS) c Vitamin B12 deficiency
c Contraindications: CKD, acidosis,
hypoxia, dehydration, etc.
care.diabetesjournals.org

c Lactic acidosis risk (rare)


Sulfonylureas 2nd Generation Closes KATP channels on b-cell c ↑ Insulin secretion c Extensive experience c Hypoglycemia Low
c Glyburide/ plasma membranes c ↓ Microvascular risk c ↑ Weight
glibenclamide (UKPDS)
c Glipizide
c Gliclazide†
c Glimepiride

Meglitinides (glinides) c Repaglinide Closes KATP channels on b-cell c ↑ Insulin secretion c ↓ Postprandial glucose c Hypoglycemia Moderate
c Nateglinide plasma membranes excursions c ↑ Weight
c Dosing flexibility c Frequent dosing schedule

TZDs c Pioglitazone‡ Activates the nuclear c ↑ Insulin sensitivity c No hypoglycemia c ↑ Weight Low
c Rosiglitazone§ transcription factor PPAR-g c Durability c Edema/heart failure
c ↑ HDL-C c Bone fractures
c ↓ Triglycerides c ↑ LDL-C (rosiglitazone)
(pioglitazone) c ? ↑ MI (meta-analyses,
c ? ↓ CVD events rosiglitazone)
(PROactive,
pioglitazone)
a-Glucosidase inhibitors c Acarbose Inhibits intestinal a-glucosidase c Slows intestinal carbohydrate c No hypoglycemia c Generally modest A1C efficacy Low to
c Miglitol digestion/absorption c ↓ Postprandial glucose c Gastrointestinal side effects moderate
excursions (flatulence, diarrhea)
c ? ↓ CVD events (STOP- c Frequent dosing schedule
NIDDM)
c Nonsystemic

DPP-4 inhibitors c Sitagliptin Inhibits DPP-4 activity, increasing c ↑ Insulin secretion (glucose c No hypoglycemia c Angioedema/urticaria and other High
c Vildagliptin† postprandial active incretin dependent) c Well tolerated immune-mediated dermatological
c Saxagliptin (GLP-1, GIP) concentrations c ↓ Glucagon secretion (glucose effects
c Linagliptin dependent) c ? Acute pancreatitis
c Alogliptin c ? ↑ Heart failure hospitalizations

Bile acid sequestrants c Colesevelam Binds bile acids in intestinal tract, c ? ↓ Hepatic glucose production c No hypoglycemia c Generally modest A1C efficacy High
increasing hepatic bile acid c ? ↑ Incretin levels c ↓ LDL-C c Constipation
production c ↑ Triglycerides
c May ↓ absorption of other
medications
Dopamine-2 agonists c Bromocriptine Activates dopaminergic receptors c Modulates hypothalamic c No hypoglycemia c Generally modest A1C efficacy High
(quick release)§ regulation of metabolism c ? ↓ CVD events (Cycloset c Dizziness/syncope
c ↑ Insulin sensitivity Safety Trial) c Nausea
c Fatigue
c Rhinitis
Approaches to Glycemic Treatment

Continued on p. S56
S55
S56

Table 7.1—Continued
Class Compound(s) Cellular mechanism(s) Primary physiological action(s) Advantages Disadvantages Cost*
SGLT2 inhibitors c Canagliflozin Inhibits SGLT2 in the proximal c Blocks glucose reabsorption by c No hypoglycemia c Genitourinary infections High
c Dapagliflozin‡ nephron the kidney, increasing c ↓ Weight c Polyuria
c Empagliflozin glucosuria c ↓ Blood pressure c Volume depletion/hypotension/
c Effective at all stages of dizziness
type 2 diabetes c ↑ LDL-C
c Associated with lower c ↑ Creatinine (transient)
CVD event rate and c DKA, urinary tract infections
mortality in patients leading to urosepsis, pyelonephritis
Approaches to Glycemic Treatment

with CVD (EMPA-REG


OUTCOME)
GLP-1 receptor agonists c Exenatide Activates GLP-1 receptors c ↑ Insulin secretion (glucose c No hypoglycemia c Gastrointestinal side effects High
c Exenatide extended dependent) c ↓ Weight (nausea/vomiting/diarrhea)
release c ↓ Glucagon secretion (glucose c ↓ Postprandial glucose c ↑ Heart rate
c Liraglutide dependent) excursions c ? Acute pancreatitis
c Albiglutide c Slows gastric emptying c ↓ Some cardiovascular c C-cell hyperplasia/medullary
c Lixisenatide† c ↑ Satiety risk factors thyroid tumors in animals
c Dulaglutide c Injectable
c Training requirements

Amylin mimetics c Pramlintide§ Activates amylin receptors c ↓ Glucagon secretion c ↓ Postprandial glucose c Generally modest A1C efficacy High
c Slows gastric emptying excursions c Gastrointestinal side effects
c ↑ Satiety c ↓ Weight (nausea/vomiting)
c Hypoglycemia unless insulin dose is
simultaneously reduced
c Injectable
c Frequent dosing schedule
c Training requirements

Insulins c Rapid-acting analogs Activates insulin receptors c ↑ Glucose disposal c Nearly universal c Hypoglycemia Moderate to
- Lispro c ↓ Hepatic glucose production response c Weight gain high#
- Aspart c Theoretically unlimited c ? Mitogenic effects
- Glulisine c Suppresses ketogenesis efficacy c Training requirements
- Inhaled insulin c ↓ Microvascular risk c Patient reluctance
c Short-acting (UKPDS) c Injectable (except inhaled insulin)
- Human Regular c Pulmonary toxicity (inhaled insulin)
c Intermediate-acting
- Human NPH
c Basal insulin analogs
- Glargine
- Detemir
- Degludec†
c Premixed (several
types)
CKD, chronic kidney disease; CVD, cardiovascular disease; DKA, diabetic ketoacidosis; EMPA-REG OUTCOME, BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (31);
GIP, glucose-dependent insulinotropic peptide; HDL-C, HDL cholesterol; LDL-C, LDL cholesterol; MI, myocardial infarction; PPAR-g, peroxisome proliferator–activated receptor g; PROactive, Prospective
Pioglitazone Clinical Trial in Macrovascular Events (32); STOP-NIDDM, Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (33); TZD, thiazolidinedione; UKPDS, UK Prospective Diabetes Study (34,35).
Cycloset trial of quick-release bromocriptine (36). *Cost is based on lowest-priced member of the class (see ref. 17). †Not licensed in the U.S. ‡Initial concerns regarding bladder cancer risk are decreasing after
Diabetes Care Volume 39, Supplement 1, January 2016

subsequent study. §Not licensed in Europe for type 2 diabetes. #Cost is highly dependent on type/brand (analogs . human insulins) and dosage. Adapted with permission from Inzucchi et al. (17).
care.diabetesjournals.org Approaches to Glycemic Treatment S57

Figure 7.2—Approach to starting and adjusting insulin in type 2 diabetes (17). FBG, fasting blood glucose; GLP-1-RA, GLP-1 receptor agonist; hypo,
hypoglycemia; mod., moderate; PPG, postprandial glucose; #, number. Adapted with permission from Inzucchi et al. (17).

expeditiously achieve the target A1C elevated blood glucose levels or A1C. control in patients with type 2 diabetes
level. Insulin has the advantage of being Many patients with type 2 diabetes initiating insulin (25).
effective where other agents may not be eventually require and benefit from in- Basal Insulin
and should be considered as part of any sulin therapy. Providers may wish to Basal insulin alone is the most conve-
combination regimen when hyperglyce- consider regimen flexibility when de nient initial insulin regimen, beginning
mia is severe, especially if symptoms are vising a plan for the initiation and ad- at 10 units or 0.1–0.2 units/kg, depend-
present or any catabolic features (weight justment of insulin therapy in people
ing on the degree of hyperglycemia.
loss, ketosis) are present. Consider ini- with type 2 diabetes (Fig. 7.2). The pro-
Basal insulin is usually prescribed in con-
tiating combination insulin injectable gressive nature of type 2 diabetes and
junction with metformin and possibly
therapy when blood glucose is $300– its therapies should be regularly and ob-
one additional noninsulin agent. While
350 mg/dL (16.7–19.4 mmol/L) and/or jectively explained to patients. For pa-
A1C is $10–12% (86–108 mmol/mol). As tients with type 2 diabetes who are not there is evidence for reduced risk of hy-
the patient’s glucose toxicity resolves, the achieving glycemic goals, providers should poglycemia with newer, longer-acting,
regimen may, potentially, be simplified. promptly initiate insulin therapy. basal insulin analogs, people with type
Providers should avoid using insulin 2 diabetes without history of hypogly-
Insulin Therapy as a threat or describing it as a failure or cemia or severe hypoglycemia may use
Consider initiating insulin therapy (with punishment. Equipping patients with an NPH safely at much lower cost (24,26).
or without additional agents) in patients algorithm for self-titration of insulin Concentrated preparation of basal in-
with newly diagnosed type 2 diabetes doses based on self-monitoring of blood sulin such as U-500 regular is five times
and markedly symptomatic and/or glucose (SMBG) improves glycemic as potent per volume of insulin (i.e.,
S58 Approaches to Glycemic Treatment Diabetes Care Volume 39, Supplement 1, January 2016

0.01 mL ;5 units of U-100 regular) and current insulin dose and then providing of hypoglycemia. N Engl J Med 2013;369:224–
has a delayed onset and longer one-half of this amount as basal and 232
4. Wood JR, Miller KM, Maahs DM, et al.; T1D
duration of action than U-100 regular. one-half as mealtime insulin, the latter Exchange Clinic Network. Most youth with
U-300 glargine and U-200 degludec are split evenly between three meals. It is crit- type 1 diabetes in the T1D Exchange clinic reg-
three and two times, respectively, as ical that individuals who have been suc- istry do not meet American Diabetes Associa-
potent per volume, have a longer dura- cessfully using CSII should have continued tion or International Society for Pediatric and
tion of action, and may allow higher Adolescent Diabetes clinical guidelines. Diabe-
access after they turn 65 years of age (30). tes Care 2013;36:2035–2037
doses of insulin administration in 5. Kmietowicz Z. Insulin pumps improve control
Inhaled Insulin
smaller volumes. These concentrated and reduce complications in children with
Inhaled insulin is now available for pran-
preparations may be more comfortable type 1 diabetes. BMJ 2013;347:f5154
dial use with a more limited dosing 6. Phillip M, Battelino T, Atlas E, et al. Nocturnal
for the patient and allow better absorp- range and may require serial lung func- glucose control with an artificial pancreas at a dia-
tion. However, they are more expen- tion testing prior to and after starting betes camp. N Engl J Med 2013;368:824–833
sive, and accurate dosing may be more therapy. 7. Wolpert HA, Atakov-Castillo A, Smith SA,
complicated. Steil GM. Dietary fat acutely increases glucose
If basal insulin has been titrated to an Treatment Strategies concentrations and insulin requirements in
acceptable fasting blood glucose level, Figure 7.2 focuses solely on sequential patients with type 1 diabetes: implications for
but A1C remains above target, consider insulin strategies, describing the num- carbohydrate-based bolus dose calculation and
ber of injections and the relative com- intensive diabetes management. Diabetes Care
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ber 2015 with type 2 diabetes [Internet], 2014. Available 28:1568–1573
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Management of hyperglycemia in type 2 diabetes, uploads/2014/08/CEPAC-T2D-Final-Report- EMPA-REG OUTCOME Investigators. Empagli-
2015: a patient-centered approach. Update to a December-22.pdf. Accessed 6 November 2015 flozin, cardiovascular outcomes, and mortality
position statement of the American Diabetes As- 25. Blonde L, Merilainen M, Karwe V, Raskin P; in type 2 diabetes. N Engl J Med. 17 September
sociation and the European Association for the TITRATE Study Group. Patient-directed titration 2015 [Epub ahead of print]. DOI: 10.1056/
Study of Diabetes. Diabetes Care 2015;38:140– for achieving glycaemic goals using a once-daily NEJMoa1504720
149 basal insulin analogue: an assessment of two 32. Dormandy JA, Charbonnel B, Eckland DJA, et al.;
18. Holman RR, Paul SK, Bethel MA, Matthews different fasting plasma glucose targetsdthe PROactive Investigators. Secondary prevention
DR, Neil HA. 10-year follow-up of intensive glu- TITRATE study. Diabetes Obes Metab 2009;11: of macrovascular events in patients with type 2
cose control in type 2 diabetes. N Engl J Med 623–631 diabetes in the PROactive Study (PROspective
2008;359:1577–1589 26. Tricco AC, Ashoor HM, Soobiah C, et al. pioglitAzone Clinical Trial In macroVascular Events):
19. Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, Safety, effectiveness, and cost of long-acting a randomised controlled trial. Lancet 2005;366:
McGuire DK. Metformin in patients with versus intermediate-acting insulin for type 1 di- 1279–1289
type 2 diabetes and kidney disease: a systematic abetes: protocol for a systematic review and 33. Chiasson J-L, Josse RG, Gomis R, Hanefeld
review. JAMA 2014;312:2668–2675 network meta-analysis. Syst Rev 2013;2:73 M, Karasik A, Laakso M; STOP-NIDDM Trial Re-
20. Bennett WL, Maruthur NM, Singh S, et al. 27. Eng C, Kramer CK, Zinman B, Retnakaran R. search Group. Acarbose for prevention of type 2
Comparative effectiveness and safety of medi- Glucagon-like peptide-1 receptor agonist and diabetes mellitus: the STOP-NIDDM randomised
cations for type 2 diabetes: an update including basal insulin combination treatment for the trial. Lancet 2002;359:2072–2077
new drugs and 2-drug combinations. Ann Intern management of type 2 diabetes: a systematic 34. UK Prospective Diabetes Study (UKPDS) Group.
Med 2011;154:602–613 review and meta-analysis. Lancet 2014;384: Intensive blood-glucose control with sulphonylureas
21. Nathan DM, Buse JB, Kahn SE, et al.; GRADE 2228–2234 or insulin compared with conventional treatment
Study Research Group. Rationale and design of 28. Reznik Y, Cohen O, Aronson R, et al.; OpT2mise and risk of complications in patients with type 2 di-
the glycemia reduction approaches in diabetes: Study Group. Insulin pump treatment compared abetes (UKPDS 33). Lancet 1998;352:837–853
a comparative effectiveness study (GRADE). with multiple daily injections for treatment of 35. UK Prospective Diabetes Study (UKPDS)
Diabetes Care 2013;36:2254–2261 type 2 diabetes (OpT2mise): a randomised Group. Effect of intensive blood-glucose control
22. Green JB, Bethel MA, Armstrong PW, et al.; open-label controlled trial. Lancet 2014;384: with metformin on complications in overweight
TECOS Study Group. Effect of sitagliptin on car- 1265–1272 patients with type 2 diabetes (UKPDS 34). Lan-
diovascular outcomes in type 2 diabetes. N Engl 29. Johnson SL, McEwen LN, Newton CA, et al. The cet 1998;352:854–865
J Med 2015;373:232–242 impact of continuous subcutaneous insulin infusion 36. Gaziano JM, Cincotta AH, O’Connor CM,
23. Vijan S, Sussman JB, Yudkin JS, Hayward RA. and multiple daily injections of insulin on glucose et al. Randomized clinical trial of quick-
Effect of patients’ risks and preferences on variability in older adults with type 2 diabetes. release bromocriptine among patients with
health gains with plasma glucose level lowering J Diabetes Complications 2011;25:211–215 type 2 diabetes on overall safety and cardio-
in type 2 diabetes mellitus. JAMA Intern Med 30. Herman WH, Ilag LL, Johnson SL, et al. A vascular outcomes. Diabetes Care 2010;33:
2014;174:1227–1234 clinical trial of continuous subcutaneous insulin 1503–1508
S60 Diabetes Care Volume 39, Supplement 1, January 2016

American Diabetes Association


8. Cardiovascular Disease and Risk
Management
Diabetes Care 2016;39(Suppl. 1):S60–S71 | DOI: 10.2337/dc16-S011

For prevention and management of diabetes complications in children and adolescents,


please refer to Section 11 “Children and Adolescents.”
In all patients with diabetes, cardiovascular risk factors should be systematically as-
sessed at least annually. These risk factors include dyslipidemia, hypertension, smoking, a
family history of premature coronary disease, and the presence of albuminuria. Abnor-
mal risk factors should be treated as described elsewhere in these guidelines.
8. CARDIOVASCULAR DISEASE AND RISK MANAGEMENT

Atherosclerotic cardiovascular disease (ASCVD)ddefined as acute coronary


syndromes (ACSs), a history of myocardial infarction (MI), stable or unstable
angina, coronary or other arterial revascularization, stroke, transient ischemic
attack, 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. The common con-
ditions coexisting with type 2 diabetes (e.g., hypertension and dyslipidemia) are
clear risk factors for ASCVD, and diabetes itself confers independent risk. Numerous
studies have shown the efficacy of controlling individual cardiovascular risk factors
in preventing or slowing ASCVD in people with diabetes. Large benefits are seen
when multiple risk factors are addressed simultaneously. 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).
HYPERTENSION/BLOOD PRESSURE CONTROL
Recommendations

Screening and Diagnosis


c Blood pressure should be measured at every routine visit. Patients found to have
elevated blood pressure should have blood pressure confirmed on a separate day. B
Goals
Systolic Targets
c People with diabetes and hypertension should be treated to a systolic blood
pressure goal of ,140 mmHg. A
c Lower systolic targets, such as ,130 mmHg, may be appropriate for certain indi-
viduals with diabetes, such as younger patients, those with albuminuria, and/or
those with hypertension and one or more additional atherosclerotic cardiovascular
disease risk factors, if they can be achieved without undue treatment burden. C
Diastolic Targets
c Individuals with diabetes should be treated to a diastolic blood pressure goal
of ,90 mmHg. A
c Lower diastolic targets, such as ,80 mmHg, may be appropriate for certain indi-
viduals with diabetes, such as younger patients, those with albuminuria, and/or
those with hypertension and one or more additional atherosclerotic cardiovascular
disease risk factors, if they can be achieved without undue treatment burden. B Suggested citation: American Diabetes Associa-
tion. Cardiovascular disease and risk manage-
Treatment
ment. Sec. 8. In Standards of Medical Care in
c Patients with blood pressure .120/80 mmHg should be advised on lifestyle Diabetesd2016. Diabetes Care 2016;39(Suppl. 1):
changes to reduce blood pressure. B S60–S71
c Patients with confirmed office-based blood pressure .140/90 mmHg should, © 2016 by the American Diabetes Association.
in addition to lifestyle therapy, have prompt initiation and timely subsequent Readers may use this article as long as the work
titration of pharmacological therapy to achieve blood pressure goals. A is properly cited, the use is educational and not
for profit, and the work is not altered.
care.diabetesjournals.org Cardiovascular Disease and Risk Management S61

arm supported at heart level, after 5 min Diabetes and Vascular Disease: Preterax
c In older adults, pharmacological ther-
of rest. Cuff size should be appropriate for and Diamicron MR Controlled Evalua-
apy to achieve treatment goals of
the upper-arm circumference. Elevated tion–Blood Pressure (ADVANCE-BP), ex-
,130/70 mmHg is not recom-
values should be confirmed on a separate amined the benefit of tighter blood
mended; treating to systolic blood
day. Postural changes in blood pressure pressure control in patients with type 2
pressure ,130 mmHg has not been
and pulse may be evidence of autonomic diabetes.
shown to improve cardiovascular out-
neuropathy and therefore require adjust- ACCORD. The ACCORD trial examined
comes and treating to diastolic blood
ment of blood pressure targets. whether a lower SBP of ,120 mmHg in
pressure ,70 mmHg has been asso-
Home blood pressure self-monitoring
ciated with higher mortality. C patients with type 2 diabetes at high risk
and 24-h ambulatory blood pressure for ASCVD provided greater cardiovascular
c Lifestyle therapy for elevated blood
monitoring may provide evidence of protection than an SBP of 130–140 mmHg
pressure consists of weight loss, if
white-coat hypertension, masked hyper- (10). The study did not find a benefit in
overweight or obese; a Dietary Ap-
tension, or other discrepancies between primary end point (nonfatal MI, nonfatal
proaches to Stop Hypertension
office and “true” blood pressure. Studies stroke, and cardiovascular death) compar-
(DASH)-style dietary pattern includ-
in individuals without diabetes found ing intensive blood pressure treatment
ing reducing sodium and increasing
that home measurements may better (goal ,120 mmHg, average blood pres-
potassium intake; moderation of al-
correlate with ASCVD risk than office sure achieved 5 119/64 mmHg on 3.4
cohol intake; and increased physical
measurements (5,6). However, most of
activity. B medications) with standard treatment
the evidence of benefits of hyperten- (average blood pressure achieved 5
c Pharmacological therapy for patients
sion treatment in people with diabetes 143/70 mmHg on 2.1 medications). In
with diabetes and hypertension
is based on office measurements. ACCORD, there was no benefit of ag-
should comprise a regimen that in-
cludes either an ACE inhibitor or an Treatment Goals gressive blood pressure lowering, de-
angiotensin receptor blocker but not Epidemiological analyses show that spite the extra cost and efforts.
both. B If one class is not tolerated, blood pressure .115/75 mmHg is asso- ADVANCE. In ADVANCE, the active blood
the other should be substituted. C ciated with increased cardiovascular pressure intervention arm (a single-pill,
c Multiple-drug therapy (including a event rates and mortality in individuals fixed-dose combination of perindopril
thiazide diuretic and ACE inhibitor/ with diabetes and that systolic blood and indapamide) showed a significant
angiotensin receptor blocker, at pressure (SBP) .120 mmHg predicts reduction in the risk of the primary com-
maximal doses) is generally required long-term end-stage renal disease. posite end point (major macrovascular
to achieve blood pressure targets. B Randomized clinical trials have dem- or microvascular event) and significant
c If ACE inhibitors, angiotensin recep- onstrated the benefit (reduction of reductions in the risk of death from any
tor blockers, or diuretics are used, CHD events, stroke, and diabetic kidney cause and of death from cardiovascular
serum creatinine/estimated glomer- disease) of lowering blood pressure to causes (11). The baseline blood pres-
ular filtration rate and serum potas- ,140 mmHg systolic and ,90 mmHg sure among the study subjects was
sium levels should be monitored. E diastolic in individuals with diabetes 145/81 mmHg. Compared with the pla-
c In pregnant patients with diabetes (7). There is limited prespecified clinical cebo group, the patients treated with a
and chronic hypertension, blood trial evidence for the benefits of lower single-pill, fixed-dose combination of
pressure targets of 110–129/65–79 SBP or diastolic blood pressure (DBP) perindopril and indapamide experienced
mmHg are suggested in the interest targets (8). A meta-analysis of random- an average reduction of 5.6 mmHg in SBP
of optimizing long-term maternal ized trials of adults with type 2 diabetes and 2.2 mmHg in DBP. The final blood
health and minimizing impaired fetal comparing intensive blood pressure pressure in the treated group was
growth. E targets (upper limit of 130 mmHg systolic 136/73 mmHg, not quite the intensive
and 80 mmHg diastolic) with standard or tight control achieved in ACCORD.
Hypertension is a common diabetes comor- targets (upper limit of 140–160 mmHg Recently published 6-year follow-up
bidity that affects many patients, with the systolic and 85–100 mmHg diastolic) of the ADVANCE–Post-Trial Observational
prevalence depending on type of diabetes, found no significant reduction in mortal- Study (ADVANCE-ON) reported that the
age, BMI, and ethnicity. Hypertension is a ity or nonfatal MI. There was a statistically reductions in the risk of death from any
major risk factor for both ASCVD and micro- significant 35% relative risk (RR) reduc- cause and of death from cardiovascular
vascular complications. In type 1 diabetes, tion in stroke with intensive targets, but causes in the intervention group were
hypertension is often the result of under- the absolute risk reduction was only 1%, attenuated, but remained significant (12).
lying diabetic kidney disease, while in and intensive targets were associated
SPRINT. Systolic Blood Pressure Interven-
type 2 diabetes, it usually coexists with with an increased risk for adverse events
other cardiometabolic risk factors. tion Trial (SPRINT) was a multicenter, ran-
such as hypotension and syncope (9).
domized controlled trial that compared
Screening and Diagnosis ACCORD, ADVANCE, SPRINT, AND HOT two strategies for treating SBP with either
Blood pressure measurement should be Given the epidemiological relationship be- the standard target of ,140 mmHg or an
done by a trained individual and should tween lower blood pressure and better intensive target of ,120 mmHg; primary
follow the guidelines established for the long-term clinical outcomes, two landmark outcomes were MI, ACS, stroke, heart
general population: measurement in the trials, Action to Control Cardiovascular Risk failure, and death due to cardiovascular
seated position, with feet on the floor and in Diabetes (ACCORD) and Action in disease. Of note, patients with diabetes
S62 Cardiovascular Disease and Risk Management Diabetes Care Volume 39, Supplement 1, January 2016

were excluded from participating in this additional ASCVD risk factors such as dysli- antihypertensive agents, including ACE in-
trial, so the results have no direct impli- pidemia, smoking, or obesity (14). The hibitors, angiotensin receptor blockers
cations for blood pressure management 2016 American Diabetes Association (ARBs), b-blockers, diuretics, and calcium
in this population. The National Insti- (ADA) Standards of Care recommendations channel blockers, has been shown to be
tutes of Health halted this study early have been revised to reflect the higher- effective in reducing cardiovascular
because intensive therapy with a target quality evidence that exists to support a events. Several studies have suggested
SBP of 120 mmHg demonstrated a risk goal of DBP ,90 mmHg, although lower that ACE inhibitors may be superior to
reduction of cardiovascular events by targets may be appropriate for certain in- dihydropyridine calcium channel blockers
almost a third and the risk of death dividuals. These targets are in harmoniza- in reducing cardiovascular events (18–20).
by almost a quarter compared with a tion with a recent publication by the Eighth However, several studies have also shown
target SBP of 140 mmHg (13). Joint National Committee that recom- no specific advantage to ACE inhibitors as
HOT. The results from the ACCORD and
mended for individuals over 18 years of an initial treatment of hypertension in the
Hypertension Optimal Treatment (HOT) age with diabetes a DBP threshold of general hypertensive population, while
(14) trials support the recommendation ,90 mmHg and SBP ,140 mmHg (8). showing an advantage of initial therapy
to achieve blood pressure levels ,140/90 with low-dose thiazide diuretics on car-
mmHg and underscore the important Treatment Strategies diovascular outcomes (17,21,22).
clinical difference between patients who Lifestyle Modification Angiotensin Receptor Blockers. In people
are able to easily achieve lower blood Although there are no well-controlled with diabetes, inhibitors of the renin-
pressure levels (e.g., as seen in observa- studies of diet and exercise in the treat- angiotensin system (RAS) may have
tional epidemiological studies) and pa- ment of elevated blood pressure or unique advantages for initial or early
tients who require intensive medical hypertension in individuals with diabe- treatment of hypertension. In a trial of
management to achieve lower blood tes, the Dietary Approaches to Stop individuals at high risk for ASCVD,
pressure goals (e.g., the clinical trials). Hypertension (DASH) study evaluated including a large subset with diabetes,
the impact of healthy dietary patterns an ACE inhibitor reduced ASCVD out-
Systolic Blood Pressure comes (23). In patients with congestive
in individuals without diabetes and has
There is strong evidence that SBP .140 shown antihypertensive effects similar to heart failure, including subgroups with
mmHg is harmful, suggesting that clinicians those of pharmacological monotherapy. diabetes, ARBs have been shown to re-
should promptly initiate and titrate ther- Lifestyle therapy consists of reducing duce major ASCVD outcomes (24–27).
apy in an ongoing fashion to achieve and excess body weight, restricting sodium In patients with type 2 diabetes with
maintain SBP ,140 mmHg in most pa- intake (,2,300 mg/day), increasing con- significant diabetic kidney disease,
tients (see Section 10 “Older Adults”). A sumption of fruits and vegetables (8–10 ARBs were superior to calcium channel
recent systematic review and meta-anal- servings per day) and low-fat dairy blockers for reducing heart failure (28).
ysis evaluating SBP lowering in adults with products (2–3 servings per day), avoiding Although evidence for distinct advantages
type 2 diabetes showed that each 10-mmHg excessive alcohol consumption (no more of RAS inhibitors on ASCVD outcomes in
reduction of SBP was associated with signif- than 2 servings per day in men and no diabetes remains conflicting (11,22), the
icantly lower risk of mortality, cardiovascular more than 1 serving per day in women) high ASCVD risks associated with diabetes
events, CHD, stroke, albuminuria, and reti- (16), and increasing activity levels (17). and the high prevalence of undiagnosed
nopathy. However, when trials were strati- These lifestyle (nonpharmacological) ASCVD may still favor recommendations
fied by mean baseline SBP $140 mmHg or strategies may also positively affect for their use as first-line antihypertensive
,140 mmHg, blood pressure–lowering glycemia and lipid control and should be therapy in people with diabetes (17).
treatment was associated with lower risks encouraged in those with even mildly ele- However, the use of both ACE inhibitors
of stroke and albuminuria, regardless of vated blood pressure, although the impact and ARBs in combination is not recom-
initial SBP (15). Therefore, individuals in of lifestyle therapy on cardiovascular events mended given the lack of added ASCVD
whom stroke risk is a concern may, as part has not been established. Nonpharmaco- benefit and increased rate of adverse
of shared decision making, have lower logical therapy is reasonable in individuals eventsdnamely, hyperkalemia, syncope,
systolic targets such as ,130 mmHg. with diabetes and mildly elevated blood and renal dysfunction (29).
This is especially true if lower blood pres- pressure (SBP .120 mmHg or DBP .80 Other Pharmacological Interventions
sure can be achieved with few drugs and mmHg). If the blood pressure is confirmed
without side effects of therapy. The blood pressure arm of the ADVANCE
to be $140 mmHg systolic and/or $90 trial demonstrated that routine adminis-
Diastolic Blood Pressure mmHg diastolic, pharmacological therapy tration of a fixed combination of the ACE
Similarly, strong evidence from random- should be initiated along with nonpharma- inhibitor perindopril and the diuretic
ized clinical trials supports DBP targets cological therapy (17). To enable long-term indapamide significantly reduced com-
of ,90 mmHg. Prior recommendations for adherence, lifestyle therapy should be adap- bined microvascular and macrovascular
lower DBP targets (,80 mmHg) were based ted to suit the needs of the patient and outcomes, as well as death from cardio-
primarily on a post hoc analysis of the HOT discussed as part of diabetes management. vascular causes and total mortality.
trial (14). A DBP of ,80 mmHg may still be The improved outcomes could also
appropriate for patients with long life expec- Pharmacological Interventions have been due to lower achieved blood
tancy, those with chronic kidney disease, ACE Inhibitors. Lowering of blood pres- pressure in the perindopril–indapamide
elevated urinary albumin excretion, and sure with regimens based on a variety of arm (11). Another trial showed a decrease
care.diabetesjournals.org Cardiovascular Disease and Risk Management S63

in morbidity and mortality in those receiv- drugs known to be effective and safe in
c For patients with diabetes aged
ing benazepril and amlodipine versus be- pregnancy include methyldopa, labetalol,
40–75 years with additional ath-
nazepril and hydrochlorothiazide (HCTZ) diltiazem, clonidine, and prazosin. Chronic
erosclerotic cardiovascular dis-
(30). The compelling benefits of RAS in- diuretic use during pregnancy is not rec-
ease risk factors, consider using
hibitors in patients with diabetes and al- ommended as it has been associated with
high-intensity statin and lifestyle
buminuria or renal insufficiency provide restricted maternal plasma volume, which
therapy. B
additional rationale for the use of these may reduce uteroplacental perfusion (33).
c For patients with diabetes aged
agents (see Section 9 “Microvascular
LIPID MANAGEMENT .75 years without additional ath-
Complications and Foot Care”). If needed
erosclerotic cardiovascular dis-
to achieve blood pressure targets, amlo- Recommendations ease risk factors, consider using
dipine, HCTZ, or chlorthalidone can be c In adults not taking statins, it is moderate-intensity statin therapy
added. If estimated glomerular filtration reasonable to obtain a lipid profile and lifestyle therapy. B
rate is ,30 mL/min/1.73 m2, a loop di- at the time of diabetes diagnosis, at c For patients with diabetes aged
uretic, rather than HCTZ or chlorthali- an initial medical evaluation, and .75 years with additional athero-
done, should be prescribed. Titration of every 5 years thereafter, or more sclerotic cardiovascular disease risk
and/or addition of further blood pressure frequently if indicated. E factors, consider using moderate-
medications should be made in a timely c Obtain a lipid profile at initiation intensity or high-intensity statin
fashion to overcome clinical inertia in of statin therapy and periodically therapy and lifestyle therapy. B
achieving blood pressure targets. thereafter as it may help to mon- c In clinical practice, providers may
Bedtime Dosing itor the response to therapy and need to adjust intensity of statin
Growing evidence suggests that there is inform adherence. E therapy based on individual patient
an association between increase in sleep- c Lifestyle modification focusing on response to medication (e.g., side
time blood pressure and incidence of weight loss (if indicated); the reduc- effects, tolerability, LDL cholesterol
ASCVD events. A randomized controlled tion of saturated fat, trans fat, and levels). E
trial of 448 participants with type 2 di- cholesterol intake; increase of c The addition of ezetimibe to
abetes and hypertension demonstrated omega-3 fatty acids, viscous fiber, moderate-intensity statin therapy
reduced cardiovascular events and mor- and plant stanols/sterols intake; and has been shown to provide additional
tality with median follow-up of 5.4 years increased physical activity should be cardiovascular benefit compared
if at least one antihypertensive medica- recommended to improve the lipid with moderate-intensity statin ther-
tion was given at bedtime (31). Consider profile in patients with diabetes. A apy alone and may be considered
administering one or more antihyper- c Intensify lifestyle therapy and opti- for patients with a recent acute cor-
tensive medications at bedtime (32). mize glycemic control for patients onary syndrome with LDL cholesterol
Other Considerations with elevated triglyceride levels $50 mg/dL (1.3 mmol/L) or for those
An important caveat is that most patients ($150 mg/dL [1.7 mmol/L]) and/or patients who cannot tolerate high-
with diabetes with hypertension require low HDL cholesterol (,40 mg/dL intensity statin therapy. A
multiple-drug therapy to reach treatment [1.0 mmol/L] for men, ,50 mg/dL c Combination therapy (statin/fibrate)
goals (16). Identifying and addressing [1.3 mmol/L] for women). C has not been shown to improve ath-
barriers to medication adherence (such c For patients with fasting triglyceride erosclerotic cardiovascular disease
as cost and side effects) should rou- levels $500 mg/dL (5.7 mmol/L), outcomes and is generally not rec-
tinely be done. If blood pressure remains evaluate for secondary causes of ommended. A However, therapy
uncontrolled despite confirmed adher- hypertriglyceridemia and consider with statin and fenofibrate may be
ence to optimal doses of at least three medical therapy to reduce the risk considered for men with both tri-
antihypertensive agents of different clas- of pancreatitis. C glyceride level $204 mg/dL (2.3
ses, one of which should be a diuretic, c For patients of all ages with diabetes mmol/L) and HDL cholesterol
clinicians should consider an evaluation and atherosclerotic cardiovascular dis- level #34 mg/dL (0.9 mmol/L). B
for secondary causes of hypertension. ease, high-intensity statin therapy c Combination therapy (statin/niacin)
should be added to lifestyle therapy. A has not been shown to provide
Pregnancy and Antihypertensive c For patients with diabetes aged additional cardiovascular benefit
Medications
,40 years with additional athero- above statin therapy alone and
In a pregnancy complicated by diabetes sclerotic cardiovascular disease risk may increase the risk of stroke and
and chronic hypertension, target blood factors, consider using moderate- is not generally recommended. A
pressure goals of SBP 110–129 mmHg intensity or high-intensity statin c Statin therapy is contraindicated
and DBP 65–79 mmHg are reasonable, and lifestyle therapy. C in pregnancy. B
as they contribute to improved long- c For patients with diabetes aged
term maternal health. Lower blood 40–75 years without additional
pressure levels may be associated with atherosclerotic cardiovascular dis- Lifestyle Intervention
impaired fetal growth. During preg- ease risk factors, consider using Lifestyle intervention, including weight
nancy, treatment with ACE inhibitors moderate-intensity statin and life- loss, increased physical activity, and
and ARBs is contraindicated, as they style therapy. A medical nutrition therapy, allows some
may cause fetal damage. Antihypertensive patients to reduce ASCVD risk factors.
S64 Cardiovascular Disease and Risk Management Diabetes Care Volume 39, Supplement 1, January 2016

Nutrition intervention should be tailored Table 8.1—Recommendations for statin and combination treatment in people
according to each patient’s age, diabe- with diabetes
tes type, pharmacological treatment, Age Risk factors Recommended statin intensity*
lipid levels, and medical conditions.
,40 years None None
Recommendations should focus on re- ASCVD risk factor(s)** Moderate or high
ducing saturated fat, cholesterol, and ASCVD High
trans fat intake and increasing plant 40–75 None Moderate
stanols/sterols, omega-3 fatty acids, years ASCVD risk factors High
and viscous fiber (such as in oats, le- ASCVD High
gumes, and citrus). Glycemic control ACS and LDL cholesterol .50 mg/dL (1.3 mmol/L) Moderate plus ezetimibe
can also beneficially modify plasma lipid in patients who cannot tolerate high-dose statins
levels, particularly in patients with very .75 years None Moderate
high triglycerides and poor glycemic ASCVD risk factors Moderate or high
ASCVD High
control.
ACS and LDL cholesterol .50 mg/dL (1.3 mmol/L) in Moderate plus ezetimibe
patients who cannot tolerate high-dose statins
Statin Treatment
*In addition to lifestyle therapy.
Initiating Statin Therapy Based on Risk
**ASCVD risk factors include LDL cholesterol $100 mg/dL (2.6 mmol/L), high blood pressure,
Patients with type 2 diabetes have an smoking, overweight and obesity, and family history of premature ASCVD.
increased prevalence of lipid abnormal-
ities, contributing to their high risk of
ASCVD. Multiple clinical trials have The Risk Calculator. The American College Age >75 Years
demonstrated the beneficial effects of of Cardiology/American Heart Association For adults with diabetes over 75 years of
pharmacological (statin) therapy on ASCVD risk calculator may be a useful tool age, there are limited data regarding the
ASCVD outcomes in subjects with and to estimate 10-year ASCVD (http://my benefits and risks of statin therapy.
without CHD (34,35). Subgroup analy- .americanheart.org). As diabetes itself Statin therapy should be individualized
ses of patients with diabetes in larger confers increased risk for ASCVD, the based on risk profile. High-intensity
trials (36–40) and trials in patients risk calculator has limited use for statins, if well tolerated, are still appropri-
with diabetes (41,42) showed signifi- assessing cardiovascular risk in indi- ate and recommended for older adults
cant primary and secondary prevention viduals with diabetes. with ASCVD. High-intensity statin therapy
of ASCVD events and CHD death in may also be appropriate in adults with
Age ‡40 Years
diabetes .75 years of age with additional
patients with diabetes. Meta-analyses, In all patients with diabetes aged $40
including data from over 18,000 patients ASCVD risk factors. However, the risk–
years, moderate-intensity statin treat-
with diabetes from 14 randomized trials benefit profile should be routinely evalu-
ment should be considered in addition
of statin therapy (mean follow-up 4.3 ated in this population, with downward
to lifestyle therapy. Clinical trials in high-
years), demonstrate a 9% proportional re- titration (e.g., high to moderate intensity)
risk patients, such as those with ACS or
duction in all-cause mortality and 13% re- performed as needed. See Section 10
previous cardiovascular events (47–49),
duction in vascular mortality for each “Older Adults” for more details on clinical
have demonstrated that more aggressive
mmol/L (39 mg/dL) reduction in LDL cho- considerations for this population.
therapy with high doses of statins led to a
lesterol (43). significant reduction in further events. Age <40 Years and/or Type 1 Diabetes
As in those without diabetes, abso- Therefore, high-dose statins are recom- Very little clinical trial evidence exists
lute reductions in ASCVD outcomes mended in patients with increased car- for patients with type 2 diabetes under
(CHD death and nonfatal MI) are great- diovascular risk (e.g., LDL cholesterol the age of 40 years or for patients with
est in people with high baseline ASCVD $100 mg/dL [2.6 mmol/L], high blood type 1 diabetes of any age. In the Heart
risk (known ASCVD and/or very high LDL pressure, smoking, albuminuria, and Protection Study (lower age limit
cholesterol levels), but the overall ben- family history of premature ASCVD) or 40 years), the subgroup of ;600 patients
efits of statin therapy in people with di- with ASCVD. with type 1 diabetes had a proportionately
abetes at moderate or even low risk for
ASCVD are convincing (44,45). Statins
are the drugs of choice for LDL choles-
terol lowering and cardioprotection. Table 8.2—High-intensity and moderate-intensity statin therapy*
Most trials of statins and ASCVD out- High-intensity statin therapy Moderate-intensity statin therapy
comes tested specific doses of statins Lowers LDL cholesterol by $50% Lowers LDL cholesterol by 30% to ,50%
against placebo or other statins rather Atorvastatin 40–80 mg Atorvastatin 10–20 mg
than aiming for specific LDL cholesterol Rosuvastatin 20–40 mg Rosuvastatin 5–10 mg
goals (46). In light of this fact, the 2016 Simvastatin 20–40 mg
Pravastatin 40–80 mg
ADA Standards of Care position state-
Lovastatin 40 mg
ment was revised to recommend when Fluvastatin XL 80 mg
to initiate and intensify statin therapy Pitavastatin 2–4 mg
(high vs. moderate intensity) based on
*Once-daily dosing.
risk profile (Table 8.1 and Table 8.2).
care.diabetesjournals.org Cardiovascular Disease and Risk Management S65

similar, although not statistically signifi- be considered in adults with heterozygous levels, are the most prevalent pattern
cant, reduction in risk as patients with familial hypercholesterolemia who require of dyslipidemia in individuals with
type 2 diabetes (37). Even though the additional lowering of LDL cholesterol. type 2 diabetes. However, the evidence
data are not definitive, similar statin for the use of drugs that target these
treatment approaches should be consid- Combination Therapy for LDL lipid fractions is substantially less robust
ered for patients with type 1 or type 2 Cholesterol Lowering than that for statin therapy (57). In a
diabetes, particularly in the presence of Statins and Ezetimibe large trial in patients with diabetes,
other cardiovascular risk factors. Please The IMProved Reduction of Outcomes: fenofibrate failed to reduce overall
refer to “Type 1 Diabetes Mellitus and Vytorin Efficacy International Trial cardiovascular outcomes (58).
Cardiovascular Disease: A Scientific (IMPROVE-IT) was a randomized con- Combination Therapy
Statement From the American Heart As- trolled trial comparing the addition of
Statin and Fibrate
sociation and American Diabetes Associ- ezetimibe to simvastatin therapy versus
ation” (50) for additional discussion. Combination therapy (statin and fibrate)
simvastatin alone. Individuals were
is associated with an increased risk for
High-intensity statin therapy is recom- $50 years of age who experienced an
mended for all patients with diabetes and abnormal transaminase levels, myositis,
ACS within the preceding 10 days and
and rhabdomyolysis. The risk of rhabdo-
ASCVD. Treatment with a moderate dose had an LDL cholesterol level $50 mg/dL
of statin should be considered if the myolysis is more common with higher
(1.3 mmol/L). In those with diabetes
patient does not have ASCVD but has doses of statins and renal insufficiency
(27%), the combination of moderate-
additional ASCVD risk factors. and appears to be higher when statins
intensity simvastatin (40 mg) and ezetimibe
are combined with gemfibrozil (59)
(10 mg) showed a significant reduction
(compared with fenofibrate).
Ongoing Therapy and Monitoring of major adverse cardiovascular events
In the ACCORD study, in patients with
With Lipid Panel with an absolute risk reduction of
In adults with diabetes, it is reasonable to type 2 diabetes who were at high risk for
5% (40% vs. 45%) and RR reduction of
obtain a lipid profile (total cholesterol, ASCVD, the combination of fenofibrate
14% (RR 0.86 [95% CI 0.78–0.94]) over
LDL cholesterol, HDL cholesterol, and and simvastatin did not reduce the rate
moderate-intensity simvastatin (40 mg)
triglycerides) at the time of diagnosis, of fatal cardiovascular events, nonfatal
alone (53). Therefore, for people meeting
at the initial medical evaluation, and at MI, or nonfatal stroke as compared with
IMPROVE-IT eligibility criteria who can
least every 5 years thereafter. A lipid simvastatin alone. Prespecified subgroup
only tolerate a moderate-dose statin, the
panel should also be obtained immedi- analyses suggested heterogeneity in
addition of ezetimibe to statin therapy
ately before initiating statin therapy. treatment effects with possible benefit
should be considered.
Once a patient is taking a statin, testing for men with both a triglyceride level
for LDL cholesterol may be considered
Statins and PCSK9 Inhibitors $204 mg/dL (2.3 mmol/L) and an HDL
on an individual basis (e.g., to monitor
Placebo-controlled trials evaluating the cholesterol level #34 mg/dL (0.9
addition of the novel PCSK9 inhibitors, mmol/L) (60).
for adherence and efficacy). In cases
evolocumab and alirocumab, to maxi-
where patients are adherent, but the Statin and Niacin
mally tolerated doses of statin therapy
LDL cholesterol level is not responding, The Atherothrombosis Intervention
in participants who were at high risk for
clinical judgment is recommended to de- in Metabolic Syndrome With Low
ASCVD demonstrated an average reduc-
termine the need for and timing of lipid HDL/High Triglycerides: Impact on
tion in LDL cholesterol ranging from 36%
panels. In individual patients, the highly Global Health Outcomes (AIM-HIGH) tri-
to 59%. These agents may therefore
variable LDL cholesterol–lowering re- al randomized over 3,000 patients
be considered as adjunctive therapy
sponse seen with statins is poorly under- (about one-third with diabetes) with es-
for patients with diabetes at high risk for
stood (51). When maximally tolerated tablished ASCVD, low LDL cholesterol
ASCVD events who require additional low-
doses of statins fail to substantially lower levels (,180 mg/dL [4.7 mmol/L]), low
ering of LDL cholesterol or who require
LDL cholesterol (,30% reduction from HDL cholesterol levels (men ,40 mg/dL
but are intolerant to high-intensity statin
the patient’s baseline), there is no strong [1.0 mmol/L] and women ,50 mg/dL
therapy (54,55). It is important to note
evidence that combination therapy [1.3 mmol/L]), and triglyceride levels of
that the effects of this novel class of agents
should be used. Clinicians should attempt 150–400 mg/dL (1.7–4.5 mmol/L) to sta-
on ASCVD outcomes are unknown as
to find a dose or alternative statin that is tin therapy plus extended-release niacin
phase 4 studies are currently under way.
tolerable, if side effects occur. There is or placebo. The trial was halted early due
evidence for benefit from even extremely Treatment of Other Lipoprotein to lack of efficacy on the primary ASCVD
low, less than daily, statin doses (52). Fractions or Targets outcome (first event of the composite
Increased frequency of LDL cholesterol Hypertriglyceridemia should be addressed of death from CHD, nonfatal MI, ische-
monitoring should be considered for pa- with dietary and lifestyle changes includ- mic stroke, hospitalization for an ACS, or
tients with new-onset ACS. A recent ran- ing abstinence from alcohol (56). Severe symptom-driven coronary or cerebral re-
domized controlled trial evaluated the hypertriglyceridemia (.1,000 mg/dL) vascularization) and a possible increase
addition of ezetimibe to moderate- may warrant immediate pharmacological in ischemic stroke in those on combina-
intensity statin therapy and demon- therapy (fibric acid derivatives and/or fish tion therapy (61). Therefore, combina-
strated ASCVD risk benefit over statin oil) to reduce the risk of acute pancreatitis. tion therapy with a statin and niacin is
monotherapy (53). Increased frequency Low levels of HDL cholesterol, often not recommended given the lack of
of LDL cholesterol monitoring may also associated with elevated triglyceride efficacy on major ASCVD outcomes,
S66 Cardiovascular Disease and Risk Management Diabetes Care Volume 39, Supplement 1, January 2016

possible increase in risk of ischemic stroke. There was some evidence of a dif-
disease prevention for adults with
stroke, and side effects. ference in aspirin effect by sex: aspirin
diabetes at low atherosclerotic
Diabetes With Statin Use
significantly reduced ASCVD events in
cardiovascular disease risk (10-
Several studies have reported an increased men, but not in women. Conversely, as-
year atherosclerotic cardiovascu-
pirin had no effect on stroke in men but
risk of incident diabetes with statin use lar disease risk ,5%), such as in
(62,63), which may be limited to those significantly reduced stroke in women.
men or women with diabetes aged
However, there was no heterogeneity of
with diabetes risk factors. An analysis of ,50 years with no major additional
one of the initial studies suggested that effect by sex in the risk of serious vascular
atherosclerotic cardiovascular dis-
although statins were linked to diabetes events (P 5 0.9). Sex differences in
ease risk factors, as the potential
risk, the cardiovascular event rate reduc- aspirin’s effects have not been observed
adverse effects from bleeding likely
in studies of secondary prevention (66).
tion with statins far outweighed the risk of offset the potential benefits. C
In the six trials examined by the ATT
incident diabetes even for patients at high- c In patients with diabetes ,50 years
est risk for diabetes (64). The absolute risk collaborators, the effects of aspirin on
of age with multiple other risk fac-
increase was small (over 5 years of follow- major vascular events were similar for
tors (e.g., 10-year risk 5–10%), clin-
patients with or without diabetes: RR
up, 1.2% of participants on placebo devel- ical judgment is required. E
oped diabetes and 1.5% on rosuvastatin 0.88 (95% CI 0.67–1.15) and RR 0.87
c Use aspirin therapy (75–162 mg/day)
developed diabetes) (64). A meta-analysis (95% CI 0.79–0.96), respectively. The con-
as a secondary prevention strat-
of 13 randomized statin trials with 91,140 fidence interval was wider for those with
egy in those with diabetes and a
participants showed an odds ratio of 1.09 diabetes because of smaller numbers.
history of atherosclerotic cardio-
Aspirin appears to have a modest effect
for a new diagnosis of diabetes, so that vascular disease. A
(on average) treatment of 255 patients on ischemic vascular events with the
c For patients with atherosclerotic
with statins for 4 years resulted in one absolute decrease in events depending
cardiovascular disease and docu-
additional case of diabetes, while simul- on the underlying ASCVD risk. The main
mented aspirin allergy, clopidog-
adverse effects appear to be an increased
taneously preventing 5.4 vascular events rel (75 mg/day) should be used. B
among those 255 patients (63). risk of gastrointestinal bleeding. The excess
c Dual antiplatelet therapy is reason-
risk may be as high as 1–5 per 1,000 per
Statins and Cognitive Function able for up to a year after an acute
year in real-world settings. In adults with
A recent systematic review of the U.S. coronary syndrome. B
ASCVD risk .1% per year, the number of
Food and Drug Administration’s post- ASCVD events prevented will be similar to
marketing surveillance databases, ran- Risk Reduction or greater than the number of episodes of
domized controlled trials, and cohort, Aspirin has been shown to be effective bleeding induced, although these compli-
case-control, and cross-sectional stud- in reducing cardiovascular morbidity cations do not have equal effects on long-
ies evaluating cognition in patients re- and mortality in high-risk patients with term health (72).
ceiving statins found that published previous MI or stroke (secondary preven-
data do not reveal an adverse effect of Treatment Considerations
tion). Its net benefit in primary prevention
statins on cognition. Therefore, a con- In 2010, a position statement of the
among patients with no previous cardio-
cern that statins might cause cognitive ADA, the American Heart Association,
vascular events is more controversial,
dysfunction or dementia should not and the American College of Cardiology
both for patients with diabetes and for
prohibit their use in individuals with Foundation recommended that low-dose
patients without diabetes (66,67). Previ-
diabetes at high risk for ASCVD (65). (75–162 mg/day) aspirin for primary
ous randomized controlled trials of aspi-
prevention is reasonable for adults
rin specifically in patients with diabetes
ANTIPLATELET AGENTS with diabetes and no previous history
failed to consistently show a significant
of vascular disease who are at increased
Recommendations
reduction in overall ASCVD end points,
ASCVD risk (10-year risk of ASCVD events
c Consider aspirin therapy (75–162 raising questions about the efficacy of
over 10%) and who are not at increased
mg/day) as a primary prevention aspirin for primary prevention in people
risk for bleeding. This previous recom-
strategy in those with type 1 or with diabetes, although some sex differ-
mendation included most men over age
type 2 diabetes who are at increased ences were suggested (68–71).
50 years and women over age 60 years
cardiovascular risk (10-year risk The Antithrombotic Trialists’ (ATT)
who also have one or more of the follow-
.10%). This includes most men or collaborators published an individual
ing major risk factors: smoking, hyperten-
women with diabetes aged $50 patient-level meta-analysis of the six
sion, dyslipidemia, family history of
years who have at least one addi- large trials of aspirin for primary preven-
premature ASCVD, and albuminuria (73).
tional major risk factor (family his- tion in the general population. These tri-
tory of premature atherosclerotic als collectively enrolled over 95,000 Sex Considerations
cardiovascular disease, hyperten- participants, including almost 4,000 Multiple recent well-conducted studies
sion, smoking, dyslipidemia, or al- with diabetes. Overall, they found that and meta-analyses reported a risk of
buminuria) and are not at increased aspirin reduced the risk of serious vascular heart disease and stroke that is equiva-
risk of bleeding. C events by 12% (RR 0.88 [95% CI 0.82– lent if not higher in women compared
c Aspirin should not be recommended 0.94]). The largest reduction was for non- with men with diabetes, including among
for atherosclerotic cardiovascular fatal MI, with little effect on CHD death nonelderly adults. Thus, the recommen-
(RR 0.95 [95% CI 0.78–1.15]) or total dations for using aspirin as primary
care.diabetesjournals.org Cardiovascular Disease and Risk Management S67

prevention are now revised to include Indications for P2Y12 Use the initial test. In adults with diabetes
both men and women aged $50 years A P2Y12 receptor antagonist in combi- $40 years of age, measurement of cor-
with diabetes and one or more major nation with aspirin should be used for at onary artery calcium is also reasonable
risk factors to reflect these more recent least 1 year in patients following an ACS. for cardiovascular risk assessment.
findings (74–77). Sex differences in the Evidence supports use of either ticagrelor Pharmacological stress echocardiography
antiplatelet effect of aspirin have been or clopidogrel if no percutaneous cor- or nuclear imaging should be considered
suggested in the general population onary intervention was performed and in individuals with diabetes in whom rest-
(78); however, further studies are needed clopidogrel, ticagrelor, or prasugrel if a ing ECG abnormalities preclude exercise
to investigate the presence of such differ- percutaneous coronary intervention stress testing (e.g., left bundle branch
ences in individuals with diabetes. was performed (82). block or ST-T abnormalities). In addition,
individuals who require stress testing and
Aspirin Use in People <50 Years of Age CORONARY HEART DISEASE are unable to exercise should undergo
Aspirin is not recommended for those at
pharmacological stress echocardiography
low risk of ASCVD (such as men and Recommendations
or nuclear imaging.
women aged ,50 years with diabetes
Screening
with no other major ASCVD risk factors;
c In asymptomatic patients, routine Screening Asymptomatic Patients
10-year ASCVD risk ,5%) as the low
screening for coronary artery dis- The screening of asymptomatic patients
benefit is likely to be outweighed by
ease is not recommended as it with high ASCVD risk is not recommended
the risks of significant bleeding. Clinical
does not improve outcomes as (44), in part because these high-risk
judgment should be used for those at
long as atherosclerotic cardiovascu- patients should already be receiving
intermediate risk (younger patients
lar disease risk factors are treated. A intensive medical therapydan approach
with one or more risk factors or older
c Consider investigations for coro- that provides similar benefit as invasive
patients with no risk factors; those
nary artery disease in the presence revascularization (83,84). There is also
with 10-year ASCVD risk of 5–10%) until
of any of the following: atypical car- some evidence that silent MI may reverse
further research is available. Aspirin use
diac symptoms (e.g., unexplained over time, adding to the controversy con-
in patients aged ,21 years is contrain-
dyspnea, chest discomfort); signs cerning aggressive screening strategies
dicated due to the associated risk of
or symptoms of associated vascular (85). In prospective trials, coronary artery
Reye syndrome.
disease including carotid bruits, calcium has been established as an inde-
Aspirin Dosing transient ischemic attack, stroke, pendent predictor of future ASCVD
Average daily dosages used in most clini- claudication, or peripheral arterial events in patients with diabetes and
cal trials involving patients with diabetes disease; or electrocardiogram ab- is superior to both the UK Prospective
ranged from 50 mg to 650 mg but were normalities (e.g., Q waves). E Diabetes Study (UKPDS) risk engine
mostly in the range of 100–325 mg/day. and the Framingham Risk Score in pre-
Treatment
There is little evidence to support any dicting risk in this population (86–88).
c In patients with known atheroscle-
specific dose, but using the lowest However, a randomized observational
rotic cardiovascular disease, use as-
possible dose may help to reduce side trial demonstrated no clinical benefit
pirin and statin therapy (if not
effects (79). In the U.S., the most com- to routine screening of asymptomatic
contraindicated) A and consider
mon low-dose tablet is 81 mg. Although patients with type 2 diabetes and normal
ACE inhibitor therapy C to reduce
platelets from patients with diabetes ECGs (89). Despite abnormal myocardial
the risk of cardiovascular events.
have altered function, it is unclear what, perfusion imaging in more than one in
c In patients with prior myocardial in-
if any, effect that finding has on the five patients, cardiac outcomes were
farction, b-blockers should be con-
required dose of aspirin for cardiopro- essentially equal (and very low) in
tinued for at least 2 years after the
tective effects in the patient with dia- screened versus unscreened patients.
event. B
betes. Many alternate pathways for Accordingly, indiscriminate screening
c In patients with symptomatic
platelet activation exist that are inde- is not considered cost-effective. Studies
heart failure, thiazolidinedione
pendent of thromboxane A2 and thus have found that a risk factor–based
treatment should not be used. A
not sensitive to the effects of aspirin approach to the initial diagnostic eval-
c In patients with type 2 diabetes with
(80). “Aspirin resistance” appears higher uation and subsequent follow-up for
stable congestive heart failure, met-
in patients with diabetes when mea- coronary artery disease fails to identify
formin may be used if renal function
sured by a variety of ex vivo and in vitro which patients with type 2 diabetes will
is normal but should be avoided in
methods (platelet aggregometry, mea- have silent ischemia on screening tests
unstable or hospitalized patients
surement of thromboxane B2) (78). A re- (90,91). Any benefit of newer noninva-
with congestive heart failure. B
cent trial suggested that more frequent sive coronary artery disease screening
dosing regimens of aspirin may reduce Cardiac Testing methods, such as computed tomography
platelet reactivity in individuals with dia- Candidates for advanced or invasive and computed tomography angiography,
betes (81); however, these observations cardiac testing include those with 1) typ- to identify patient subgroups for different
alone are insufficient to empirically rec- ical or atypical cardiac symptoms and 2) treatment strategies remains unproven.
ommend that higher doses of aspirin be an abnormal resting electrocardiogram Although asymptomatic patients with di-
used in this group at this time. It appears (ECG). Exercise ECG testing without or abetes with higher coronary disease bur-
that 75–162 mg/day is optimal. with echocardiography may be used as den have more future cardiac events
S68 Cardiovascular Disease and Risk Management Diabetes Care Volume 39, Supplement 1, January 2016

(86,92,93), the role of these tests beyond Cardiovascular Outcomes with Sitagliptin other glucose-lowering treatments in
risk stratification is not clear. Their routine (TECOS), recent multicenter, randomized, patients with diabetes and congestive
use leads to radiation exposure and may double-blind, noninferiority trials, evalu- heart failure, even in those with reduced
result in unnecessary invasive testing such ated heart failure and mortality outcomes left ventricular ejection fraction or con-
as coronary angiography and revasculari- in patients with type 2 diabetes taking comitant chronic kidney disease; however,
zation procedures. The ultimate balance of different DPP-4 inhibitors, alogliptin metformin should be avoided in hospi-
benefit, cost, and risks of such an approach and sitagliptin, respectively, compared talized patients (105).
in asymptomatic patients remains contro- with placebo. EXAMINE reported that
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S72 Diabetes Care Volume 39, Supplement 1, January 2016

American Diabetes Association


9. Microvascular Complications
and Foot Care
Diabetes Care 2016;39(Suppl. 1):S72–S80 | DOI: 10.2337/dc16-S012

DIABETIC KIDNEY DISEASE

Recommendations
Screening
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,
9. MICROVASCULAR COMPLICATIONS AND FOOT CARE

and in all patients with comorbid hypertension. B


Treatment
c Optimize glucose control to reduce the risk or slow the progression of diabetic
kidney disease. A
c Optimize blood pressure control (,140/90 mmHg) to reduce the risk or slow
the progression of diabetic kidney disease. A
c For people with nondialysis-dependent diabetic kidney disease, dietary pro-
tein intake should be 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. A
c Either an ACE inhibitor or an angiotensin receptor blocker is recommended for
the treatment of nonpregnant patients with diabetes and modestly elevated
urinary albumin excretion (30–299 mg/day) B and is strongly recommended
for those with urinary albumin excretion $300 mg/day and/or estimated
glomerular filtration rate ,60 mL/min/1.73 m2. A
c Periodically monitor serum creatinine and potassium levels for the develop-
ment of increased creatinine or changes in potassium when ACE inhibitors,
angiotensin receptor blockers, or diuretics are used. E
c Continued monitoring of urinary albumin–to–creatinine ratio in patients with
albuminuria treated with an ACE inhibitor or an angiotensin receptor blocker is
reasonable to assess the response to treatment and progression of diabetic
kidney disease. E
c An ACE inhibitor or an angiotensin receptor blocker is not recommended for
the primary prevention of diabetic kidney disease in patients with diabetes
who have normal blood pressure, normal urinary albumin–to–creatinine ratio
(,30 mg/g), and normal estimated glomerular filtration rate. B
c When estimated glomerular filtration rate is ,60 mL/min/1.73 m2, evaluate
and manage potential complications of chronic kidney disease. E
c Patients should be referred for evaluation for renal replacement treatment if
they have estimated glomerular filtration rate ,30 mL/min/1.73 m2. A
c Promptly refer to a physician experienced in the care of kidney disease for
uncertainty about the etiology of kidney disease, difficult management issues,
and rapidly progressing kidney disease. B
Suggested citation: American Diabetes Associ-
Assessment of Albuminuria and Renal Function ation. Microvascular complications and foot
Diabetic kidney disease, or kidney disease attributed to diabetes, occurs in 20–40% care. Sec. 9. In Standards of Medical Care in
Diabetesd2016. Diabetes Care 2016;39(Suppl. 1):
of patients with diabetes and is the leading cause of end-stage renal disease
S72–S80
(ESRD) (1).
© 2016 by the American Diabetes Association.
Screening for kidney damage (albuminuria) can be most easily performed by Readers may use this article as long as the work
urinary albumin–to–creatinine ratio (UACR) in a random spot urine collection. is properly cited, the use is educational and not
Timed or 24-h collections are more burdensome and add little to prediction or for profit, and the work is not altered.
care.diabetesjournals.org Microvascular Complications and Foot Care S73

accuracy (2,3). Measurement of a spot blood pressure control is a subject of not progress to higher levels over 5–10
urine sample for albumin alone (whether debate. Continued surveillance can as- years of follow-up (5,9–11). Patients
by immunoassay or by using a sensitive sess both response to therapy and dis- with persistent and severely increased
dipstick test specific for albuminuria) ease progression and may aid in assessing ($300 mg/g Cr) levels of albuminuria
without simultaneously measuring urine adherence to ACE inhibitor or ARB ther- are likely to develop ESRD (12,13).
creatinine (Cr) is less expensive but sus- apy. Some suggest that reducing UACR to The presence of diabetic retinopathy
ceptible to false-negative and false- normal (,30 mg/g Cr) or near normal in patients with UACR $300 mg/g Cr
positive determinations as a result of may improve CKD and cardiovascular strongly suggests diabetic kidney dis-
variation in urine concentration due to disease (CVD) prognosis, but this ap- ease, and its absence in those with re-
hydration. proach has not been formally evaluated duced eGFR and UACR ,300 mg/g Cr
Normal UACR is defined as ,30 mg/g in prospective trials, and evidence suggests nondiabetic CKD. Other causes
Cr, and increased urinary albumin excre- demonstrates spontaneous remission of CKD should be considered in patients
tion is defined as $30 mg/g Cr. Because of albuminuria in up to 40% of patients with diabetes and CKD but without di-
of variability in urinary albumin excretion, with type 1 diabetes. abetic retinopathy and in those with an
two of three specimens of UACR collected Progression of Diabetic Kidney Disease active urine sediment, with rapidly in-
within a 3- to 6-month period should be Conversely, patients with increasing creasing proteinuria or nephrotic syn-
abnormal before considering a patient to UACR, declining eGFR, retinopathy, in- drome with low or rapidly decreasing
have albuminuria. Exercise within 24 h, creasing blood pressure, macrovascular eGFR, with .30% reduction in eGFR
infection, fever, congestive heart failure, disease, elevated lipids and/or uric acid within 2–3 months of initiating ACE in-
marked hyperglycemia, menstruation, concentrations, or a family history of hibitor or ARB therapy, with refractory
and marked hypertension may elevate CKD are more likely to experience a pro- hypertension, or with signs or symp-
UACR independently of kidney damage. gression of diabetic kidney disease (5). toms of other systemic diseases.
Estimated Glomerular Filtration Rate
Complications of kidney disease cor- Interventions
Serum Cr should be used to estimate relate with level of kidney function. Nutrition
glomerular filtration rate (GFR). Esti- When eGFR is ,60 mL/min/1.73 m2, For people with nondialysis-dependent
mated GFR (eGFR) is commonly report- screening for complications of CKD is in- diabetic kidney disease, dietary protein
ed by laboratories or can be estimated dicated (Table 9.2). Early vaccination intake should be 0.8 g/kg body weight
using formulae such as the Modification against hepatitis B virus is indicated in per day (the recommended daily allow-
of Diet in Renal Disease (MDRD) study patients likely to progress to ESRD. ance). Compared with higher levels of
equation (4) or the Chronic Kidney Identifying and monitoring diabetic dietary protein intake, this level slowed
Disease Epidemiology Collaboration kidney disease relies on assessments of GFR decline with evidence of a greater
(CKD-EPI) equation. The latter is the pre- kidney damage (albuminuria) and kid- effect over time. Higher levels of dietary
ferred GFR estimating equation. GFR ney function (eGFR). Persistently in- protein intake (.20% of daily calories
calculators are available at http:// creased UACR in the range of UACR from protein or .1.3 g/kg/day) have
www.nkdep.nih.gov. 30–299 mg/g Cr is an early indicator of been associated with increased albu-
Abnormal urinary albumin excretion diabetic kidney disease in type 1 diabe- minuria, more rapid kidney function
and eGFR may be used to stage chronic tes and a marker for development of di- loss, and CVD mortality and therefore
kidney disease (CKD). The National Kid- abetic kidney disease in type 2 diabetes. should be avoided. Reducing the
ney Foundation classification (Table 9.1) It is also a well-established marker of amount of dietary protein below the
is based on both kidney damage (UACR increased CVD risk (6–8). recommended daily allowance of 0.8
$30 mg/g Cr) and eGFR. Not all people with diabetes, kidney g/kg/day is not recommended because
disease, and reduced eGFR have albumin- it does not alter glycemic measures, car-
Surveillance uria. In addition, there is increasing evi- diovascular risk measures, or the course
The need for annual quantitative as- dence that up to 40% of patients with of GFR decline.
sessment of albumin excretion after di- type 1 diabetes and UACR levels 30–299
agnosis of albuminuria, institution of mg/g Cr have spontaneous remissions Glycemia

ACE inhibitor or angiotensin receptor and approximately 30–40% remain with A number of interventions have been
blocker (ARB) therapy, and achieving UACR levels of 30–299 mg/g Cr and do demonstrated to reduce the risk and
slow the progression of diabetic kidney
disease. Intensive diabetes manage-
Table 9.1—Stages of CKD ment with the goal of achieving near-
Stage Description GFR (mL/min/1.73 m2) normoglycemia has been shown in large
1 Kidney damage* with normal or increased eGFR $90 prospective randomized studies to delay
2 Kidney damage* with mildly decreased eGFR 60–89 the onset and progression of increased
3 Moderately decreased eGFR 30–59 urinary albumin excretion and reduced
4 Severely decreased eGFR 15–29
eGFR in patients with type 1 diabetes
(13) and type 2 diabetes (1,14–17).
5 Kidney failure ,15 or dialysis
Despite prior concerns and published
*Kidney damage is defined as abnormalities on pathological, urine, blood, or imaging tests. case reports, current data indicate that
Adapted from Levey et al. (3).
the overall risk of metformin-associated
S74 Microvascular Complications and Foot Care Diabetes Care Volume 39, Supplement 1, January 2016

Table 9.2—Management of CKD in diabetes in hyperkalemic episodes in those on dual


GFR (mL/min/1.73 m )2
Recommended management
therapy, and larger trials are needed be-
fore recommending such therapy.
All patients Yearly measurement of Cr, UACR, potassium
Diuretics, calcium channel blockers,
45–60 Referral to a nephrologist if possibility for nondiabetic kidney and b-blockers can be used as add-on
disease exists (duration of type 1 diabetes ,10 years,
persistent albuminuria, abnormal findings on renal
therapy to achieve blood pressure goals
ultrasound, resistant hypertension, rapid fall in eGFR, or in patients treated with maximum doses
active urinary sediment on urine microscopic examination) of ACE inhibitors or ARBs (26) or as alter-
Consider the need for dose adjustment of medications nate therapy in the rare individual unable
Monitor eGFR every 6 months to tolerate ACE inhibitors and ARBs.
Monitor electrolytes, bicarbonate, hemoglobin, calcium,
phosphorus, and parathyroid hormone at least yearly Referral to a Nephrologist
Assure vitamin D sufficiency Consider referral to a physician experi-
Consider bone density testing enced in the care of kidney disease when
Referral for dietary counseling there is uncertainty about the etiology of
30–44 Monitor eGFR every 3 months kidney disease (absence of retinopathy,
Monitor electrolytes, bicarbonate, calcium, phosphorus, heavy proteinuria, active urine sediment,
parathyroid hormone, hemoglobin, albumin, and weight or rapid decline in GFR). Other triggers for
every 3–6 months
referral may include difficult management
Consider the need for dose adjustment of medications
issues (anemia, secondary hyperparathy-
,30 Referral to a nephrologist
roidism, metabolic bone disease, resistant
hypertension, or electrolyte disturbances)
lactic acidosis is low (1). GFR may be a ,130 mmHg to avoid diastolic blood or advanced kidney disease. The threshold
more appropriate measure to assess pressure levels below 60–70 mmHg. for referral may vary depending on the
continued metformin use than serum The UK Prospective Diabetes Study frequency with which a provider en-
Cr, considering that the serum Cr level (UKPDS) provided strong evidence that counters patients with diabetes and
can translate into widely varying blood pressure control can reduce the de- kidney disease. Consultation with a ne-
eGFR levels depending on age, ethnic- velopment of diabetic kidney disease (22). phrologist when stage 4 CKD develops
ity, and muscle mass (18). A review Interruption of the renin-angiotensin- (eGFR #30 mL/min/1.73 m2) has been
(19) proposed that metformin use aldosterone system with either ACE found to reduce cost, improve quality of
should be reevaluated at an eGFR inhibitors or ARBs contributes to reduc- care, and delay dialysis (27). However,
,45 mL/min/1.73 m2 with a reduction tions of kidney disease events in hy- other specialists and providers should
in maximum dose to 1,000 mg/day. pertensive patients with diabetes and also educate their patients about the pro-
Metformin should be discontinued eGFR ,60 mL/min/1.73 m 2 and UACR gressive nature of diabetic kidney disease,
when eGFR is ,30 mL/min/1.73 m2; in $300 mg/g Cr. the kidney preservation benefits of pro-
clinical situations in which there is an ACE inhibitors have been shown to re- active treatment of blood pressure and
increased risk of lactic acidosis, such duce major CVD events in patients with blood glucose, and the potential need for
as sepsis, hypotension, and hypoxia; or diabetes (23), thus further supporting the renal replacement therapy.
when there is a high risk of acute kidney use of these agents in patients with albu-
injury resulting in a worsening of GFR, such minuria, a CVD risk factor. In those with DIABETIC RETINOPATHY
as administration of radiocontrast dye in diabetic kidney disease, some evidence Recommendations
those with eGFR ,60 mL/min/1.73 m2. suggests that ARBs compared with ACE
c Optimize glycemic control to re-
Blood Pressure inhibitors are associated with a smaller
duce the risk or slow the progres-
increase in serum potassium levels (24).
There are no randomized controlled tri- sion of diabetic retinopathy. A
als of blood pressure levels in diabetes Combination Therapy c Optimize blood pressure and se-
that have examined CKD events as out- Two clinical trials studied the combina- rum lipid control to reduce the
comes. Blood pressure levels below tions of ACE inhibitors and ARBs and risk or slow the progression of di-
140/90 mmHg in diabetes are recom- found no benefits on CVD or diabetic abetic retinopathy. A
mended to reduce CVD mortality and kidney disease, and the drug combina-
Screening
slow CKD progression. In individuals tion had higher adverse event rates (hy-
c Adults with type 1 diabetes should
with albuminuria, consider lower blood perkalemia and/or acute kidney injury)
have an initial dilated and compre-
pressure targets of ,130/80 mmHg (25). Therefore, the combined use of ACE
hensive eye examination by an oph-
(20,21). Of note, there is an adverse inhibitors and ARBs should be avoided.
thalmologist or optometrist within
safety signal in clinical trials of diabetic Mineralocorticoid receptor blockers
5 years after the onset of diabetes. B
kidney disease when diastolic blood pres- (spironolactone) in combination with ACE
c Patients with type 2 diabetes should
sure is treated to below 70 mmHg and inhibitors or ARBs remain an area of great
have an initial dilated and compre-
especially below 60 mmHg in older pop- interest and have been explored in several
hensive eye examination by an oph-
ulations. As a result, clinical judgment short-term studies with a positive effect on
thalmologist or optometrist at the
should be used when attempting to albuminuria reduction in diabetic kidney
time of the diabetes diagnosis. B
achieve systolic blood pressure targets disease. There was, however, an increase
care.diabetesjournals.org Microvascular Complications and Foot Care S75

type 2 diabetes, with prevalence controlled type 2 diabetes, there was


c If there is no evidence of retinop-
strongly related to both the duration essentially no risk of development of
athy for one or more annual eye
of diabetes and the level of glycemic significant retinopathy with a 3-year in-
exams, then exams every 2 years
control. Diabetic retinopathy is the terval after a normal examination (35).
may be considered. If any level of
most frequent cause of new cases of Examinations will be required more fre-
diabetic retinopathy is present,
blindness among adults aged 20–74 quently by the ophthalmologist if reti-
subsequent dilated retinal exami-
years in developed countries. Glaucoma, nopathy is progressing.
nations for patients with type 1 or
cataracts, and other disorders of the eye Retinal photography, with remote
type 2 diabetes should be re-
occur earlier and more frequently in reading by experts, has great potential
peated at least annually by an
people with diabetes. to provide screening services in areas
ophthalmologist or optometrist.
In addition to diabetes duration, where qualified eye care professionals
If retinopathy is progressing or
factors that increase the risk of, or are are not readily available (36). High-quality
sight-threatening, then examina-
associated with, retinopathy include fundus photographs can detect most
tions will be required more fre-
chronic hyperglycemia (28), nephropa- clinically significant diabetic retinopathy.
quently. B
thy (29), hypertension (30), and dys- Interpretation of the images should be
c While retinal photography may
lipidemia (31). Intensive diabetes performed by a trained eye care pro-
serve as a screening tool for reti-
management with the goal of achieving vider. Retinal photography may also en-
nopathy, it is not a substitute for a
near-normoglycemia has been shown in hance efficiency and reduce costs when
comprehensive eye exam, which
large prospective randomized studies to the expertise of ophthalmologists can be
should be performed at least ini-
prevent and/or delay the onset and pro- used for more complex examinations and
tially and at intervals thereafter as
gression of diabetic retinopathy (15,32). for therapy (37). In-person exams are still
recommended by an eye care pro-
Lowering blood pressure has been necessary when the retinal photos are un-
fessional. E
shown to decrease retinopathy progres- acceptable and for follow-up if abnormal-
c Eye examinations should occur be-
sion, although tight targets (systolic ities are detected. Retinal photos are
fore pregnancy or in the first tri-
,120 mmHg) do not impart additional not a substitute for a comprehensive
mester, and then patients should
benefit (32). In patients with dyslipide- eye exam, which should be performed
be monitored every trimester and
mia, retinopathy progression may be at least initially and at intervals thereafter
for 1 year postpartum as indicated
slowed by the addition of fenofibrate, as recommended by an eye care profes-
by the degree of retinopathy. B
particularly with very mild nonprolifer- sional. Results of eye examinations should
Treatment ative diabetic retinopathy (NPDR) at be documented and transmitted to the
c Promptly refer patients with any baseline (31). Several case series and a referring health care professional.
level of macular edema, severe controlled prospective study suggest Type 1 Diabetes
nonproliferative diabetic retinop- that pregnancy in patients with type 1 Because retinopathy is estimated to
athy (a precursor of proliferative diabetes may aggravate retinopathy and take at least 5 years to develop after
diabetic retinopathy), or any pro- threaten vision, especially when glyce- the onset of hyperglycemia, patients
liferative diabetic retinopathy to mic control is poor at the time of con- with type 1 diabetes should have an ini-
an ophthalmologist who is knowl- ception (33,34). Laser photocoagulation tial dilated and comprehensive eye ex-
edgeable and experienced in the surgery can minimize the risk of vision amination within 5 years after the
management and treatment of di- loss (34). diagnosis of diabetes (38).
abetic retinopathy. A
c Laser photocoagulation therapy is Type 2 Diabetes
Screening
indicated to reduce the risk of vision The preventive effects of therapy and Patients with type 2 diabetes who may
loss in patients with high-risk pro- the fact that patients with proliferative have had years of undiagnosed diabetes
liferative diabetic retinopathy and, diabetic retinopathy (PDR) or macular and have a significant risk of prevalent
in some cases, severe nonprolifera- edema may be asymptomatic provide diabetic retinopathy at the time of di-
tive diabetic retinopathy. A strong support for screening to detect agnosis should have an initial dilated
c Intravitreal injections of antivas- diabetic retinopathy. and comprehensive eye examination at
cular endothelial growth factor An ophthalmologist or optometrist the time of diagnosis.
are indicated for center-involved who is knowledgeable and experienced Pregnancy
diabetic macular edema, which oc- in diagnosing diabetic retinopathy Pregnancy is associated with a rapid
curs beneath the foveal center and should perform the examinations. If di- progression of diabetic retinopathy
may threaten reading vision. A abetic retinopathy is present, prompt (39,40). Women with preexisting type
c The presence of retinopathy is referral to an ophthalmologist is recom- 1 or type 2 diabetes who are planning
not a contraindication to aspirin mended. Subsequent examinations for pregnancy or who have become preg-
therapy for cardioprotection, as patients with type 1 or type 2 diabetes nant should be counseled on the risk
aspirin does not increase the risk are generally repeated annually for pa- of development and/or progression of
of retinal hemorrhage. A tients with minimal to no retinopathy. diabetic retinopathy. In addition, rapid
Exams every 2 years may be cost- implementation of tight glycemic con-
Diabetic retinopathy is a highly specific effective after one or more normal eye trol in the setting of retinopathy is asso-
vascular complication of both type 1 and exams, and in a population with well- ciated with worsening of retinopathy
S76 Microvascular Complications and Foot Care Diabetes Care Volume 39, Supplement 1, January 2016

(34). Women who develop gestational di- replaced the need for laser photocoag- 3. Up to 50% of diabetic peripheral
abetes mellitus do not require an eye ulation in the vast majority of patients neuropathy (DPN) may be asymp-
examination during pregnancy and do with diabetic macular edema (47). tomatic. If not recognized and if pre-
not appear to be at increased risk of Most patients require near-monthly ventive foot care is not implemented,
developing diabetic retinopathy during administration of intravitreal therapy patients are at risk for injuries to their
pregnancy (41). with anti-VEGF agents during the first insensate feet.
12 months of treatment with fewer in- 4. Recognition and treatment of auto-
Treatment
jections needed in subsequent years to nomic neuropathy may improve
Two of the main motivations for screen-
maintain remission from center-involved symptoms, reduce sequelae, and im-
ing for diabetic retinopathy are to pre-
diabetic macular edema. Other emerging prove quality of life.
vent loss of vision and to intervene with
therapies for retinopathy that may use
treatment when vision loss can be pre-
sustained intravitreal delivery of phar- Specific treatment for the underlying
vented or reversed.
macological agents are currently under nerve damage, other than improved gly-
Photocoagulation Surgery investigation. cemic control, is currently not available.
Two large trials, the Diabetic Retinopathy Glycemic control can effectively prevent
Study (DRS) in patients with PDR and the NEUROPATHY DPN and cardiac autonomic neuropathy
Early Treatment Diabetic Retinopathy (CAN) in type 1 diabetes (48,49) and may
Study (ETDRS) in patients with macular Recommendations
modestly slow their progression in type 2
edema, provide the strongest support Screening diabetes (17) but does not reverse neuro-
for the therapeutic benefits of photoco- c All patients should be assessed for nal loss. Therapeutic strategies (pharma-
agulation surgery. The DRS (42) showed diabetic peripheral neuropathy cological and nonpharmacological) for
that panretinal photocoagulation surgery starting at diagnosis of type 2 di- the relief of symptoms related to painful
reduced the risk of severe vision loss from abetes and 5 years after the diag- DPN or autonomic neuropathy can poten-
PDR from 15.9% in untreated eyes to nosis of type 1 diabetes and at tially reduce pain (50) and improve qual-
6.4% in treated eyes, with the greatest least annually thereafter. B ity of life.
risk–benefit ratio in those with baseline c Assessment should include a care-
disease (disc neovascularization or vitre- ful history and 10-g monofilament Diagnosis
ous hemorrhage). The ETDRS also verified testing and at least one of the fol- Diabetic Peripheral Neuropathy
the benefits of panretinal photocoagula- lowing tests: pinprick, tempera- Patients with type 1 diabetes for 5
tion for high-risk PDR and in older-onset ture, or vibration sensation. B or more years and all patients with
patients with severe NPDR or less-than- c Symptoms and signs of autonomic type 2 diabetes should be assessed an-
high-risk PDR. Panretinal laser photoco- neuropathy should be assessed in nually for DPN using medical history
agulation is still commonly used to patients with microvascular and and simple clinical tests. Symptoms
manage complications of diabetic reti- neuropathic complications. E vary according to the class of sensory
nopathy that involve retinal neovasculari- Treatment fibers involved. The most common
zation and its complications. c Optimize glucose control to pre- early symptoms are induced by the in-
Antivascular Endothelial Growth Factor vent or delay the development of volvement of small fibers and include
Treatment neuropathy in patients with type 1 pain and dysesthesias (unpleasant
While the ETDRS (43) established the diabetes A and to slow the pro- sensations of burning and tingling).
benefit of focal laser photocoagulation gression of neuropathy in patients The involvement of large fibers may
surgery in eyes with clinically significant with type 2 diabetes. B cause numbness and loss of protective
macular edema (defined as retinal c Assess and treat patients to reduce sensation (LOPS). LOPS indicates the
edema located at or within 500 mm of pain related to diabetic peripheral presence of distal sensorimotor poly-
the center of the macula), current data neuropathy B and symptoms of au- neuropathy and is a risk factor for di-
from multiple well-designed clinical tri- tonomic neuropathy and to im- abetic foot ulceration. The following
als demonstrate that intravitreal anti- prove quality of life. E clinical tests may be used to assess
vascular endothelial growth factor small- and large-fiber function and
(anti-VEGF) agents provide a more ef- The diabetic neuropathies are a hetero- protective sensation:
fective treatment regimen for center- geneous group of disorders with diverse
involved diabetic macular edema than clinical manifestations. The early recog- 1. Small-fiber function: pinprick and
monotherapy or even combination ther- nition and appropriate management of temperature sensation
apy with laser (44–46). neuropathy in the patient with diabetes 2. Large-fiber function: vibration per-
Historically, laser photocoagulation is important. ception, 10-g monofilament, and an-
surgery in both trials was beneficial in kle reflexes
reducing the risk of further visual loss 1. Diabetic neuropathy is a diagnosis of 3. Protective sensation: 10-g monofilament
in affected patients but generally not exclusion. Nondiabetic neuropathies
beneficial in reversing already dimin- may be present in patients with di- These tests not only screen for the pres-
ished acuity. Now, intravitreal therapy abetes and may be treatable. ence of dysfunction but also predict future
with recombinant monoclonal neutralizing 2. Numerous treatment options exist for risk of complications. Electrophysiological
antibody to VEGF improves vision and has symptomatic diabetic neuropathy. testing or referral to a neurologist is rarely
care.diabetesjournals.org Microvascular Complications and Foot Care S77

needed, except in situations where the results are likely to be abnormal in the of painful DPN, may be effective and
clinical features are atypical or the diag- setting of recent uncontrolled hypergly- considered for the treatment of painful
nosis is unclear. cemia or diabetic ketoacidosis and often DPN. Comparative efficacy studies and
In all patients with diabetes and DPN, correlate poorly with symptoms. Con- trials that include quality-of-life out-
causes of neuropathy other than diabe- stipation is the most common lower- comes are rare, so treatment decisions
tes should be considered, including gastrointestinal symptom but can must consider each patient’s presenta-
toxins (alcohol), neurotoxic medications alternate with episodes of diarrhea. tion and comorbidities and often
(chemotherapy), vitamin B12 deficiency, follow a trial-and-error approach. Given
Genitourinary Disturbances
hypothyroidism, renal disease, malig- the range of partially effective treatment
Diabetic autonomic neuropathy may
nancies (multiple myeloma, broncho- options, a tailored and stepwise pharma-
also cause genitourinary disturbances.
genic carcinoma), infections (HIV), cological strategy with careful attention
In men, diabetic autonomic neuropathy
chronic inflammatory demyelinating to relative symptom improvement, med-
may cause erectile dysfunction and/or
neuropathy, inherited neuropathies, ication adherence, and medication side
retrograde ejaculation. Evaluation of
and vasculitis (51). effects is recommended to achieve pain
bladder function should be performed
reduction and improve quality of life
Diabetic Autonomic Neuropathy for individuals with diabetes who have
The symptoms and signs of autonomic (50,64,65).
recurrent urinary tract infections, pyelo-
dysfunction should be elicited carefully nephritis, incontinence, or a palpable Orthostatic Hypotension
during the history and physical exami- bladder. Treating orthostatic hypotension is chal-
nation. Major clinical manifestations of lenging. The therapeutic goal is to min-
diabetic autonomic neuropathy include Treatment imize postural symptoms rather than to
hypoglycemia unawareness, resting Glycemic Control restore normotension. Most patients
tachycardia, orthostatic hypotension, Near-normal glycemic control, imple- require both nonpharmacological mea-
gastroparesis, constipation, diarrhea, mented early in the course of diabetes, sures (e.g., ensuring adequate salt intake,
fecal incontinence, erectile dysfunction, has been shown to effectively delay or avoiding medications that aggravate hypo-
neurogenic bladder, and sudomotor prevent the development of DPN and tension, or using compressive garments
dysfunction with either increased or de- CAN in patients with type 1 diabetes over the legs and abdomen) and pharma-
creased sweating. (55–58). Although the evidence for the cological measures. Midodrine is the only
Cardiac Autonomic Neuropathy benefit of near-normal glycemic control drug approved by the FDA for the treat-
CAN is associated with mortality inde- is not as strong for type 2 diabetes, some ment of orthostatic hypotension.
pendent of other cardiovascular risk fac- studies have demonstrated a modest Gastroparesis
tors (52,53). In its early stages, CAN may slowing of progression (59,60) without Gastroparesis may improve with a low-
be completely asymptomatic and de- reversal of neuronal loss. Several obser- fat, low-fiber diet, optimized glycemic
tected only by decreased heart rate var- vational studies suggest that neuro- control, and prokinetic agents such as
iability with deep breathing. Advanced pathic symptoms improve not only metoclopramide or erythromycin. In
disease may be associated with resting with optimization of glycemic control 2009, the FDA added a boxed warning
tachycardia (.100 bpm) and orthostatic but also with the avoidance of extreme to the metoclopramide label highlighting
hypotension (a fall in systolic or diastolic blood glucose fluctuations. the risks of irreversible tardive dyskinesia
blood pressure by .20 mmHg or .10 Diabetic Peripheral Neuropathy after long-term use of metoclopramide.
mmHg, respectively, upon standing DPN symptoms, and especially neuro- The chronic use of metoclopramide
without an appropriate increase in heart pathic pain, can be severe and can im- should be avoided (66). Metoclopramide
rate). CAN treatment is generally fo- pact quality of life, limit mobility, and should be reserved for patients with the
cused on alleviating symptoms. contribute to depression and social dys- most severe symptoms that are unre-
Gastrointestinal Neuropathies function (61). Several medications have sponsive to other therapies. The medica-
Gastrointestinal neuropathies may in- been demonstrated to be effective for tion should be used at the lowest dose
volve any portion of the gastrointestinal the treatment of pain associated with and for the shortest duration possible,
tract with manifestations including DPN, but there is limited clinical evi- generally not to exceed 3 months, and
esophageal dysmotility, gastroparesis, dence regarding which medication is side effects should be closely monitored.
constipation, diarrhea, and fecal incon- most effective for an individual patient Erectile Dysfunction
tinence. Gastroparesis should be sus- (62,63). Treatments for erectile dysfunction may
pected in individuals with erratic The U.S. Food and Drug Administra- include phosphodiesterase type 5 inhib-
glucose control or with upper gastroin- tion (FDA) has approved three medi- itors, intracorporeal or intraurethral
testinal symptoms without another cations (pregabalin, duloxetine, and prostaglandins, vacuum devices, or pe-
identified cause. Evaluation of gastric tapentadol) for the treatment of pain as- nile prostheses. Interventions for other
emptying using the gastric emptying sociated with DPN, but none affords manifestations of autonomic neuropa-
breath test, a new noninvasive test complete relief, even when used in com- thy are described in the American Dia-
that does not use radiation-emitting bination. Tricyclic antidepressants, gaba- betes Association (ADA) statement on
compounds (54), or the double-isotope pentin, venlafaxine, carbamazepine, neuropathy (67). As with DPN treat-
scintigraphy may be performed if symp- tramadol, and topical capsaicin, al- ments, these interventions do not
toms suggest gastroparesis, but test though not approved for the treatment change the underlying pathology and
S78 Microvascular Complications and Foot Care Diabetes Care Volume 39, Supplement 1, January 2016

natural history of the disease process recognition and treatment of patients brachial index testing should be per-
but may improve the patient’s quality with diabetes and feet at risk for ulcers formed in patients with symptoms or
of life. and amputations can delay or prevent signs of PAD. Due to the high estimated
adverse outcomes. prevalence of PAD in patients with di-
FOOT CARE
The risk of ulcers or amputations is abetes and the fact that many patients
Recommendations increased in people who have the fol- with PAD are asymptomatic, an ADA
c Perform a comprehensive foot eval- lowing risk factors: consensus report on PAD (68) suggested
uation each year to identify risk fac- that ankle-brachial index screening be
tors for ulcers and amputations. B ○ History of foot ulcer performed in patients 50 years of age
c Obtain a prior history of ulceration, ○ Amputation and older and be considered in patients
amputation, Charcot foot, angio- ○ Foot deformities under 50 years of age who have other
plasty or vascular surgery, cigarette ○ Peripheral neuropathy with LOPS PAD risk factors (e.g., smoking, hyper-
smoking, retinopathy, and renal dis- ○ Preulcerative callus or corn tension, dyslipidemia, or duration of di-
ease and assess current symptoms ○ PAD abetes .10 years).
of neuropathy (pain, burning, ○ Poor glycemic control
numbness) and vascular disease ○ Visual impairment Patient Education
(leg fatigue, claudication). B ○ Diabetic nephropathy (especially pa- Patients with diabetes and high-risk foot
c The examination should include in- tients on dialysis) conditions (history of ulcer or amputa-
spection of the skin, assessment of ○ Cigarette smoking tion, deformity, LOPS, or PAD) should be
foot deformities, neurological assess- educated about their risk factors and
ment including 10-g monofilament Clinicians are encouraged to review ADA appropriate management. Patients at
testing and pinprick or vibration test- screening recommendations for further risk should understand the implications
ing or assessment of ankle reflexes, details and practical descriptions of how of foot deformities, LOPS, and PAD; the
and vascular assessment including to perform components of the compre- proper care of the foot, including nail
pulses in the legs and feet. B hensive foot examination (67). and skin care; and the importance of
c Patients with a history of ulcers or foot monitoring on a daily basis. Pa-
Evaluation for Loss of Protective
amputations, foot deformities, in- tients with LOPS should be educated
Sensation
sensate feet, and peripheral arte- on ways to substitute other sensory mo-
All adults with diabetes should un-
rial disease are at substantially dalities (palpation or visual inspection
dergo a comprehensive foot evaluation
increased risk for ulcers and ampu- using a nonbreakable mirror) for sur-
at least annually to identify high-risk
tations and should have their feet veillance of early foot problems.
conditions. Clinicians should ask about
examined at every visit. C history of foot ulcers or amputation,
The selection of appropriate foot-
c Patients with symptoms of claudi- wear and footwear behaviors at home
neuropathic and peripheral vascular
cation or decreased or absent should also be discussed. Patients’ un-
symptoms, impaired vision, renal dis-
pedal pulses should be referred derstanding of these issues and their
ease, tobacco use, and foot care prac-
for ankle-brachial index and for physical ability to conduct proper foot
tices. A general inspection of skin
further vascular assessment. C integrity and musculoskeletal defor-
surveillance and care should be as-
c A multidisciplinary approach is sessed. Patients with visual difficulties,
mities should be performed. Vascular
recommended for individuals physical constraints preventing move-
assessment should include inspection
with foot ulcers and high-risk feet ment, or cognitive problems that impair
and assessment of pedal pulses.
(e.g., dialysis patients and those their ability to assess the condition of
The neurological exam performed as
with Charcot foot, prior ulcers, or the foot and to institute appropriate re-
part of the foot examination is designed
amputation). B to identify LOPS rather than early neu-
sponses will need other people, such
c Refer patients who smoke or who as family members, to assist in their care.
ropathy. The 10-g monofilament is the
have histories of prior lower- most useful test to diagnose LOPS. Ide-
extremity complications, loss of ally, the 10-g monofilament test should Treatment
protective sensation, structural People with neuropathy or evidence of
be performed with at least one other
abnormalities, or peripheral arte- increased plantar pressures (e.g., ery-
assessment (pinprick, temperature or
rial disease to foot care specialists thema, warmth, or calluses) may be ade-
vibration sensation using a 128-Hz tun-
for ongoing preventive care and quately managed with well-fitted walking
ing fork, or ankle reflexes). Absent
lifelong surveillance. C monofilament sensation suggests LOPS,
shoes or athletic shoes that cushion the
c Provide general foot self-care educa- feet and redistribute pressure. People
while at least two normal tests (and no
tion to all patients with diabetes. B abnormal test) rule out LOPS.
with bony deformities (e.g., hammertoes,
prominent metatarsal heads, bunions)
Foot ulcers and amputation, which are Evaluation for Peripheral Arterial may need extra-wide or -deep shoes. Peo-
consequences of diabetic neuropathy Disease ple with bony deformities, including Char-
and/or peripheral arterial disease Initial screening for PAD should cot foot, who cannot be accommodated
(PAD), are common and represent include a history for decreased walking with commercial therapeutic footwear
major causes of morbidity and mor- speed, leg fatigue, claudication, and an will require custom-molded shoes. Spe-
tality in people with diabetes. Early assessment of the pedal pulses. Ankle- cial consideration and a thorough workup
care.diabetesjournals.org Microvascular Complications and Foot Care S79

should be performed when patients with function, hypertension, and diabetes. Circulation 21. Cushman WC, Evans GW, Byington RP,
neuropathy present with an acute onset 2004;110:32–35 et al.; ACCORD Study Group. Effects of intensive
9. de Boer IH, Rue TC, Cleary PA, et al.; Diabetes blood-pressure control in type 2 diabetes melli-
of a red, hot, swollen foot or ankle, and Control and Complications Trial/Epidemiology tus. N Engl J Med 2010;362:1575–1585
Charcot neuroarthropathy should be ex- of Diabetes Interventions and Complications 22. UK Prospective Diabetes Study Group. Tight
cluded. Early diagnosis and treatment of Study Research Group. Long-term renal out- blood pressure control and risk of macrovascu-
Charcot neuroarthropathy is the best way comes of patients with type 1 diabetes mellitus lar and microvascular complications in type 2
to prevent deformities that increase the and microalbuminuria: an analysis of the diabetes: UKPDS 38. BMJ 1998;317:703–713
Diabetes Control and Complications Trial/ 23. Heart Outcomes Prevention Evaluation
risk of ulceration and amputation. Epidemiology of Diabetes Interventions and Study Investigators. Effects of ramipril on car-
Most diabetic foot infections are poly- Complications cohort. Arch Intern Med 2011; diovascular and microvascular outcomes in peo-
microbial, with aerobic gram-positive 171:412–420 ple with diabetes mellitus: results of the HOPE
cocci. Staphylococci are the most com- 10. Molitch ME, Steffes M, Sun W, et al.; Epi- study and MICRO-HOPE substudy. Lancet 2000;
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infection do not require antibiotic ther- out albuminuria in adults with type 1 diabetes in tagonist vs a non-calcium antagonist hyperten-
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Kidney Foundation (NKF) and the National In- Group. Intensive blood-glucose control with sul- panics with NIDDM. Am J Kidney Dis 1998;31:
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practice guidelines for chronic kidney disease: ADVANCE Collaborative Group. Intensive blood thalmology 2005;112:799–805
evaluation, classification, and stratification. Ann glucose control and vascular outcomes in pa- 31. Chew EY, Davis MD, Danis RP, et al.; Action
Intern Med 2003;139:137–147 tients with type 2 diabetes. N Engl J Med to Control Cardiovascular Risk in Diabetes Eye
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Rogers N, Roth D; Modification of Diet in Renal 17. Ismail-Beigi F, Craven T, Banerji MA, et al.; management on the progression of diabetic ret-
Disease Study Group. A more accurate method ACCORD Trial Group. Effect of intensive treat- inopathy in persons with type 2 diabetes: the
to estimate glomerular filtration rate from se- ment of hyperglycaemia on microvascular out- Action to Control Cardiovascular Risk in Diabe-
rum creatinine: a new prediction equation. Ann comes in type 2 diabetes: an analysis of the tes (ACCORD) Eye Study. Ophthalmology 2014;
Intern Med 1999;130:461–470 ACCORD randomised trial. Lancet 2010;376: 121:2443–2451
5. National Kidney Foundation. KDOQI clinical 419–430 32. Chew EY, Ambrosius WT, Davis MD, et al.;
practice guideline for diabetes and CKD: 2012 18. Skupien J, Warram JH, Smiles A, Galecki A, ACCORD Study Group; ACCORD Eye Study
update. Am J Kidney Dis 2012;60:850–886 Stanton RC, Krolewski AS. Improved glycemic Group. Effects of medical therapies on retinop-
6. Krolewski AS, Niewczas MA, Skupien J, et al. control and risk of ESRD in patients with athy progression in type 2 diabetes. N Engl J
Early progressive renal decline precedes the onset type 1 diabetes and proteinuria. J Am Soc Neph- Med 2010;363:233–244
of microalbuminuria and its progression to macro- rol 2014;25:2916–2925 33. Fong DS, Aiello LP, Ferris FL 3rd, Klein R.
albuminuria. Diabetes Care 2014;37:226–234 19. Lipska KJ, Bailey CJ, Inzucchi SE. Use of met- Diabetic retinopathy. Diabetes Care 2004;27:
7. Garg JP, Bakris GL. Microalbuminuria: formin in the setting of mild-to-moderate renal 2540–2553
marker of vascular dysfunction, risk factor for insufficiency. Diabetes Care 2011;34:1431– 34. Diabetes Control and Complications Trial Re-
cardiovascular disease. Vasc Med 2002;7:35–43 1437 search Group. Effect of pregnancy on microvascular
8. Klausen K, Borch-Johnsen K, Feldt-Rasmussen 20. Emdin CA, Rahimi K, Neal B, Callender T, complications in the diabetes control and compli-
B, et al. Very low levels of microalbuminuria are Perkovic V, Patel A. Blood pressure lowering in cations trial. Diabetes Care 2000;23:1084–1091
associated with increased risk of coronary heart type 2 diabetes: a systematic review and meta- 35. Agardh E, Tababat-Khani P. Adopting 3-year
disease and death independently of renal analysis. JAMA 2015;313:603–615 screening intervals for sight-threatening retinal
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vascular lesions in type 2 diabetic subjects with- 49. Martin CL, Albers JW, Pop-Busui R; DCCT/ and Complications study (DCCT/EDIC). Circula-
out retinopathy. Diabetes Care 2011;34:1318– EDIC Research Group. Neuropathy and related tion 2009;119:2886–2893
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Taylor HR. Screening for presence or absence tions and Complications study. Diabetes Care and treating diabetic neuropathy. Cochrane Da-
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37. Ahmed J, Ward TP, Bursell S-E, Aiello LM, ican Academy of Neurology; American Associa- Action to Control Cardiovascular Risk in Diabe-
Cavallerano JD, Vigersky RA. The sensitivity and tion of Neuromuscular and Electrodiagnostic tes Investigators. Epidemiologic relationships
specificity of nonmydriatic digital stereoscopic Medicine; American Academy of Physical Med- between A1C and all-cause mortality during a
retinal imaging in detecting diabetic retinopa- icine and Rehabilitation. Evidence-based guide- median 3.4-year follow-up of glycemic treat-
thy. Diabetes Care 2006;29:2205–2209 line: treatment of painful diabetic neuropathy: ment in the ACCORD trial. Diabetes Care 2010;
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Canadian Ophthalmological Society evidence- the American Association of Neuromuscular 61. Sadosky A, Schaefer C, Mann R, et al.
based clinical practice guidelines for the and Electrodiagnostic Medicine, and the Amer- Burden of illness associated with painful di-
management of diabetic retinopathy. Can J ican Academy of Physical Medicine and Rehabil- abetic peripheral neuropathy among adults
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Diabetes Care Volume 39, Supplement 1, January 2016 S81

American Diabetes Association


10. Older Adults
Diabetes Care 2016;39(Suppl. 1):S81–S85 | DOI: 10.2337/dc16-S013

Recommendations
c Consider the assessment of medical, functional, mental, and social geriatric
domains for diabetes management in older adults to provide a framework to
determine targets and therapeutic approaches. E
c Screening for geriatric syndromes may be appropriate in older adults experi-
encing limitations in their basic and instrumental activities of daily living, as
they may affect diabetes self-management. E
c Older adults ($65 years of age) with diabetes should be considered a high-
priority population for depression screening and treatment. B
c Hypoglycemia should be avoided in older adults with diabetes. It should be
screened for and managed by adjusting glycemic targets and pharmacological
interventions. B

10. OLDER ADULTS


c Older adults who are functional and cognitively intact and have significant life
expectancy may receive diabetes care with goals similar to those developed for
younger adults. E
c Glycemic goals for some older adults might reasonably be relaxed, using indi-
vidual criteria, but hyperglycemia leading to symptoms or risk of acute hyper-
glycemic complications should be avoided in all patients. E
c Screening for diabetes complications should be individualized in older adults,
but particular attention should be paid to complications that would lead to
functional impairment. E
c Other cardiovascular risk factors should be treated in older adults with con-
sideration of the time frame of benefit and the individual patient. Treatment of
hypertension is indicated in virtually all older adults, and lipid-lowering and
aspirin therapy may benefit those with life expectancy at least equal to the
time frame of primary or secondary prevention trials. E
c When palliative care is needed in older adults with diabetes, strict blood
pressure control may not be necessary, and withdrawal of therapy may be
appropriate. Similarly, the intensity of lipid management can be relaxed, and
withdrawal of lipid-lowering therapy may be appropriate. E
c Consider diabetes education for the staff of long-term care facilities to improve
the management of older adults with diabetes. E
c Patients with diabetes residing in long-term care facilities need careful assess-
ment to establish a glycemic goal and to make appropriate choices of glucose-
lowering agents based on their clinical and functional status. E
c Overall comfort, prevention of distressing symptoms, and preservation of quality
of life and dignity are primary goals for diabetes management at the end of life. E

OVERVIEW
Diabetes is an important health condition for the aging population; ;26% of pa-
tients over the age of 65 years have diabetes (1), and this number is expected to
grow rapidly in the coming decades. Older individuals with diabetes have higher
rates of premature death, functional disability, and coexisting illnesses, such as
hypertension, coronary heart disease, and stroke, than those without diabetes. Older Suggested citation: American Diabetes Associa-
adults with diabetes also are at a greater risk than other older adults for several tion. Older adults. Sec. 10. In Standards of Med-
ical Care in Diabetesd2016. Diabetes Care
common geriatric syndromes, such as polypharmacy, cognitive impairment, urinary
2016;39(Suppl. 1):S81–S85
incontinence, injurious falls, and persistent pain. Screening for diabetes complications
© 2016 by the American Diabetes Association.
in older adults also should be individualized and periodically revisited, since the results Readers may use this article as long as the work
of screening tests may impact therapeutic approaches and targets. Older adults are at is properly cited, the use is educational and not
increased risk for depression and should therefore be screened and treated accordingly for profit, and the work is not altered.
S82 Older Adults Diabetes Care Volume 39, Supplement 1, January 2016

(2). Diabetes management may require maintain cognitive function in older no complications. Some older adults
assessment of medical, functional, mental, adults. However, studies examining the with diabetes are frail and have other
and social domains. This may provide a effects of intensive glycemic and blood underlying chronic conditions, substan-
framework to determine targets and pressure control to achieve specific tar- tial diabetes-related comorbidity, or
therapeutic approaches. Particular at- gets have not demonstrated a reduction limited physical or cognitive function-
tention should be paid to complications in brain function decline (12). ing. Other older individuals with diabe-
that can develop over short periods of Older adults with diabetes should be tes have little comorbidity and are
time and/or that would significantly carefully screened and monitored for cog- active. Life expectancies are highly vari-
impair functional status, such as visual nitive impairment (3). Several organiza- able for this population but are often
and lower-extremity complications. Please tions have released simple assessment longer than clinicians realize. Providers
refer to the American Diabetes Associa- tools, such as the Mini-Mental State Ex- caring for older adults with diabetes
tion (ADA) consensus report “Diabetes in amination (MMSE) and the Montreal must take this heterogeneity into con-
Older Adults” for details (3). Cognitive Assessment (MoCA), which sideration when setting and prioritizing
may help to identify patients requiring treatment goals (Table 10.1).
NEUROCOGNITIVE FUNCTION neuropsychological evaluation, particu-
Older adults with diabetes are at higher larly those in whom dementia is sus- Healthy Patients With Good
risk of cognitive decline and institution- pected (i.e., experiencing memory loss Functional Status
alization (4,5). The presentation of cog- and decline in their basic and instrumen- There are few long-term studies in
nitive impairment ranges from subtle tal activities of daily living). older adults demonstrating the bene-
executive dysfunction to memory loss fits of intensive glycemic, blood pres-
and overt dementia. Diabetes increases HYPOGLYCEMIA sure, and lipid control. Patients who
the incidence of all-cause dementia, It is important to prevent hypoglycemia can be expected to live long enough
Alzheimer disease, and vascular demen- to reduce the risk of cognitive decline to reap the benefits of long-term inten-
tia when compared with rates in people and to carefully assess and reassess pa- sive diabetes management, who have
with normal glucose tolerance (6). The tients’ risk for worsening of glycemic good cognitive and physical function,
effects of hyperglycemia and hyperinsu- control and functional decline. Older and who choose to do so via shared de-
linemia on the brain are areas of intense adults are at higher risk of hypoglycemia cision making may be treated using
research interest. Clinical trials of spe- for many reasons, including insulin de- therapeutic interventions and goals
cific interventionsdincluding cholines- ficiency and progressive renal insuffi- similar to those for younger adults
terase inhibitors and glutamatergic ciency. In addition, older adults tend to with diabetes. As with all patients
antagonistsdhave not shown positive have higher rates of unidentified cogni- with diabetes, diabetes self-management
therapeutic benefit in maintaining or tive deficits, causing difficulty in com- education and ongoing diabetes self-
significantly improving cognitive func- plex self-care activities (e.g., glucose management support are vital compo-
tion or in preventing cognitive decline monitoring, adjusting insulin doses, nents of diabetes care for older adults
(7). Recent pilot studies in patients etc.). These deficits have been associ- and their caregivers.
with mild cognitive impairment evaluat- ated with increased risk of hypoglyce- Patients With Complications and
ing the potential benefits of intranasal mia and with severe hypoglycemia Reduced Functionality
insulin therapy or metformin therapy linked to increased dementia. There- For patients with advanced diabetes com-
provide insights for future clinical trials fore, it is important to routinely screen plications, life-limiting comorbid illness, or
and mechanistic studies (8–10). older adults for cognitive dysfunction substantial cognitive or functional impair-
The presence of cognitive impairment and discuss findings with the caregivers. ment, it is reasonable to set less intensive
can make it challenging for clinicians to Hypoglycemic events should be dili- glycemic target goals. These patients are
help their patients to reach individual- gently monitored and avoided, whereas less likely to benefit from reducing the risk
ized glycemic, blood pressure, and lipid glycemic targets and pharmacological of microvascular complications and more
targets. Cognitive dysfunction makes it interventions may need to be adjusted likely to suffer serious adverse effects
difficult for patients to perform complex to accommodate for the changing needs from hypoglycemia. However, patients
self-care tasks, such as glucose monitor- of the older adult (3). with poorly controlled diabetes may be
ing and adjusting insulin doses. It also subject to acute complications of diabe-
hinders their ability to appropriately TREATMENT GOALS
tes, including dehydration, poor wound
maintain the timing and content of diet. Rationale healing, and hyperglycemic hyperosmolar
When clinicians are managing these The care of older adults with diabetes is coma. Glycemic goals at a minimum
types of patients, it is critical to simplify complicated by their clinical and func- should avoid these consequences.
drug regimens and to involve caregivers tional heterogeneity. Some older indi-
in all aspects of care. viduals may have developed diabetes Vulnerable Patients at the End of Life
Poor glycemic control is associated years earlier and have significant com- For patients receiving palliative care and
with a decline in cognitive function (11), plications, others are newly diagnosed end-of-life care, the focus should be to
and longer duration of diabetes worsens and may have had years of undiagnosed avoid symptoms and complications from
cognitive function. There are ongoing diabetes with resultant complications, glycemic management. Thus, when organ
studies evaluating whether preventing and still other older adults may have failure develops, several agents will have
or delaying diabetes onset may help to truly recent-onset disease with few or to be titrated or discontinued. For the
care.diabetesjournals.org Older Adults S83

Table 10.1—Framework for considering treatment goals for glycemia, blood pressure, and dyslipidemia in older adults with
diabetes
Patient Fasting or
characteristics/ Reasonable A1C preprandial
health status Rationale goal‡ glucose Bedtime glucose Blood pressure Lipids
Healthy (few coexisting Longer remaining ,7.5% 90–130 mg/dL 90–150 mg/dL ,140/90 mmHg Statin unless
chronic illnesses, intact life expectancy (58 mmol/mol) (5.0–7.2 mmol/L) (5.0–8.3 mmol/L) contraindicated
cognitive and functional or not tolerated
status)
Complex/intermediate Intermediate ,8.0% 90–150 mg/dL 100–180 mg/dL ,140/90 mmHg Statin unless
(multiple coexisting remaining life (64 mmol/mol) (5.0–8.3 mmol/L) (5.6–10.0 mmol/L) contraindicated
chronic illnesses* or expectancy, high or not tolerated
21 instrumental ADL treatment burden,
impairments or mild-to- hypoglycemia
moderate cognitive vulnerability,
impairment) fall risk
Very complex/poor health Limited remaining ,8.5%† 100–180 mg/dL 110–200 mg/dL ,150/90 mmHg Consider
(LTC or end-stage chronic life expectancy (69 mmol/mol) (5.6–10.0 mmol/L) (6.1–11.1 mmol/L) likelihood of
illnesses** or moderate- makes benefit benefit with
to-severe cognitive uncertain statin (secondary
impairment or 21 ADL prevention more
dependencies) so than primary)
This represents a consensus framework for considering treatment goals for glycemia, blood pressure, and dyslipidemia in older adults with diabetes. The patient
characteristic categories are general concepts. Not every patient will clearly fall into a particular category. Consideration of patient and caregiver preferences is an
important aspect of treatment individualization. Additionally, a patient’s health status and preferences may change over time. ADL, activities of daily living.
‡A lower A1C goal may be set for an individual if achievable without recurrent or severe hypoglycemia or undue treatment burden.
*Coexisting chronic illnesses are conditions serious enough to require medications or lifestyle management and may include arthritis, cancer,
congestive heart failure, depression, emphysema, falls, hypertension, incontinence, stage 3 or worse chronic kidney disease, myocardial infarction,
and stroke. By “multiple,” we mean at least three, but many patients may have five or more (27).
**The presence of a single end-stage chronic illness, such as stage 3–4 congestive heart failure or oxygen-dependent lung disease, chronic kidney disease requiring
dialysis, or uncontrolled metastatic cancer, may cause significant symptoms or impairment of functional status and significantly reduce life expectancy.
†A1C of 8.5% (69 mmol/mol) equates to an estimated average glucose of ;200 mg/dL (11.1 mmol/L). Looser A1C targets above 8.5% (69 mmol/mol)
are not recommended as they may expose patients to more frequent higher glucose values and the acute risks from glycosuria, dehydration,
hyperglycemic hyperosmolar syndrome, and poor wound healing.

dying patient most agents for type 2 di- Insulin Sensitizers hypoglycemia, and its use requires that
abetes may be removed. There is, how- Metformin is the first-line agent in older patients or caregivers have good visual
ever, no consensus for the management adults with type 2 diabetes. However, it and motor skills and cognitive ability.
of type 1 diabetes in this scenario (13,14). is contraindicated in patients with renal
insufficiency or significant heart failure. Incretin-Based Therapies
Beyond Glycemic Control Since serum creatinine levels do not ad- Glucagon-like peptide 1 receptor ago-
Although hyperglycemia control may be equately reflect renal function in older nists and dipeptidyl peptidase 4 inhibi-
important in older individuals with dia- people (muscle mass losses are associ- tors have few side effects, but their
betes, greater reductions in morbidity ated with chronic conditions and func- costs may be a barrier to some older
and mortality are likely to result from tional decline), a timed urine collection patients. A systematic review concluded
control of other cardiovascular risk fac- to assess creatinine clearance has been that incretin-based agents do not in-
tors rather than from tight glycemic con- recommended, particularly in those crease major adverse cardiovascular
trol alone. There is strong evidence from aged $80 years. Metformin may be events (19). Glucagon-like peptide 1
clinical trials of the value of treating hy- temporarily discontinued before proce- receptor agonists are injectable agents,
pertension in the elderly (15,16). There is dures, during hospitalizations, and which require visual, motor, and cogni-
less evidence for lipid-lowering and aspirin when acute illness may compromise re- tive skills.
therapy, although the benefits of these in- nal or liver function. Thiazolidinediones,
Sodium–Glucose Cotransporter 2
terventions for primary and secondary if used at all, should be used very cau-
Inhibitors
prevention are likely to apply to older tiously in those with, or at risk for, con-
Sodium–glucose cotransporter 2 inhibi-
adults whose life expectancies equal or ex- gestive heart failure and have been
tors offer an oral route, which may be
ceed the time frames seen in clinical trials. associated with fractures.
convenient for older adults with diabe-
tes; however, long-term experience is
PHARMACOLOGICAL THERAPY Insulin Secretagogues limited despite the initial efficacy and
Special care is required in prescribing Sulfonylureas and other insulin secre- safety data reported with these agents.
and monitoring pharmacological ther- tagogues are associated with hypo-
apy in older adults (17). Cost may be a glycemia and should be used with Other Factors to Consider
significant factor, especially as older caution. Glyburide is contraindicated The needs of older adults with diabetes
adults tend to be on many medications. in older adults (18). Insulin can also cause and their caregivers should be evaluated
S84 Older Adults Diabetes Care Volume 39, Supplement 1, January 2016

to construct a tailored care plan. Social intake and contribute to unintentional END-OF-LIFE CARE
difficulties may impair their quality of weight loss and undernutrition. Diets tai- The management of the older adult at
life and increase the risk of functional lored to a patient’s culture, preferences, the end of life receiving palliative medi-
dependency. The patient’s living situa- and personal goals might increase qual- cine or hospice is a unique situation.
tion must be considered, as it may affect ity of life, satisfaction with meals, and Overall, palliative medicine promotes
diabetes management and support. nutrition status (22). comfort, symptom control, and preven-
Older adults in assisted living facilities tion (pain, hypoglycemia and hyperglyce-
may not have support to administer Hypoglycemia mia, dehydration) and preservation of
their own medications, whereas those Older adults with diabetes in LTC are dignity and quality of life in patients
living in a nursing home (community liv- especially vulnerable to hypoglycemia. with limited life expectancy (21,24). A pa-
ing centers) may rely completely on the They have a disproportionately high tient has the right to refuse testing and
care plan and nursing support. Those re- number of clinical complications and co- treatment, whereas providers may con-
ceiving palliative care (with or without morbidities that can increase hypogly- sider withdrawing treatment and limiting
hospice) may require an approach that cemia risk: impaired renal function, diagnostic testing, including a reduction
emphasizes comfort and symptom man- slowed hormonal regulation and coun- in the frequency of finger-stick testing
agement, while deemphasizing strict terregulation, and suboptimal hydra- (25). Glucose targets should aim to pre-
metabolic and blood pressure control. tion, variable appetite and nutritional vent hypoglycemia and hyperglycemia.
intake, polypharmacy, and slowed intes- Treatment interventions need to be
TREATMENT IN SKILLED NURSING tinal absorption (23).
FACILITIES AND NURSING HOMES mindful of quality of life. Careful monitor-
Another consideration for the LTC set-
ing of oral intake is warranted. The de-
Management of diabetes in the long- ting is that unlike the hospital setting,
term care (LTC) setting (i.e., nursing cision process may need to involve the
medical providers are not required to
homes and skilled nursing facilities) is patient, family, and caregivers, leading
evaluate the patients daily. According
unique. Individualization of health care to a care plan that is both convenient
to federal guidelines, assessments
is important in all patients; however, and effective for the goals of care (26).
should be done at least every 30 days
The pharmacological therapy may in-
practical guidance is needed for medical for the first 90 days after admission
providers as well as the LTC staff and clude oral agents as first line, followed
and then at least once every 60 days.
caregivers. The American Medical Di- by a simplified insulin regimen. If needed,
Although in practice the patients may
rectors Association (AMDA) guidelines basal insulin can be implemented, ac-
actually be seen more frequently, the
offer a 12-step program for staff (20). concern is that patients may have uncon- companied by oral agents and without
This training includes diabetes detection trolled glucose levels or wide excursions rapid-acting insulin. Agents that can
and institutional quality assessment. It without the practitioner being notified. cause gastrointestinal symptoms such
is also recommended that LTC facilities Providers may make adjustments to as nausea or excess weight loss may not
develop their own policies and proce- treatment regimens by telephone, be good choices in this setting. As symp-
dures for prevention and management fax, or order directly at the LTC facili- toms progress, some agents may be
of hypoglycemia. ties provided they are given timely no- slowly tapered down and discontinued.
tification from a standardized alert Strata have been proposed for diabe-
Resources tes management in those with advanced
Staff of LTC facilities should receive ap- system.
The following alert strategy could be disease (14).
propriate diabetes education to improve
the management of older adults with di- considered:
1. A stable patient: continue with the
abetes. Major organizations such as the patient’s previous regimen, with a
1. Call provider immediately: in case
ADA, the American Geriatrics Society focus on the prevention of hypogly-
of hypoglycemia (,70 mg/dL
(AGS), the International Association of cemia and the management of hy-
[3.9 mmol/L]). Low finger-stick blood
Gerontology and Geriatrics (IAGG), and perglycemia, keeping levels below
glucose values should be confirmed
the European Diabetes Working Party the renal threshold of glucose. There
by laboratory glucose measurement.
for Older People (EDWPOP) concur with
2. Call as soon as possible: a) glucose is very little role for A1C monitoring
the AMDA on the need to individualize and lowering.
values between 70 and 100 mg/dL
treatments for each patient, the need to 2. A patient with organ failure: pre-
(between 3.9 and 5.6 mmol/L)
avoid both hypoglycemia and the meta- venting hypoglycemia is of greater
(regimen may need to be adjusted),
bolic complications of diabetes, and the significance. Dehydration must be pre-
b) glucose values greater than
need to provide adequate diabetes train-
250 mg/dL (13.9 mmol/L) within a vented and handled. In people with
ing to LTC staff (3,21).
24-h period, c) glucose values greater type 1 diabetes, insulin administration
Nutrition Considerations than 300 mg/dL (16.7 mmol/L) within may be reduced as the oral intake of
An older adult residing in an LTC facility 2 consecutive days, d) or when any food decreases. For those with type 2
may have irregular and unpredictable reading is too high, e) or the patient diabetes, agents that may cause hypo-
meal consumption, undernutrition, an- is sick, with vomiting or other malady glycemia should be titrated. The main
orexia, and impaired swallowing. Fur- that can reflect hyperglycemic crisis, goal is to avoid hypoglycemia, allow-
thermore, therapeutic diets may may lead to poor oral intake, and thus ing for glucose values in the upper
inadvertently lead to decreased food requires regimen adjustment. level of the desired target range.
care.diabetesjournals.org Older Adults S85

3. A dying patient: for patients with amnestic mild cognitive impairment: a pilot clin- 19. Rotz ME, Ganetsky VS, Sen S, Thomas TF.
type 2 diabetes, the discontinuation ical trial. Arch Neurol 2012;69:29–38 Implications of incretin-based therapies on cardio-
9. Freiherr J, Hallschmid M, Frey WH 2nd, et al. vascular disease. Int J Clin Pract 2015;69:531–549
of all medications may be a pertinent Intranasal insulin as a treatment for Alzheimer’s 20. American Medical Directors Association.
approach, as they are unlikely to have disease: a review of basic research and clinical Diabetes management in the long-term care
any oral intake. In patients with type 1 evidence. CNS Drugs 2013;27:505–514 setting [Internet]. Available from http://www
diabetes, there is no consensus, but a 10. Alagiakrishnan K, Sankaralingam S, Ghosh .amda.com/tools/guidelines.cfm#diabetes. Ac-
small amount of basal insulin may M, Mereu L, Senior P. Antidiabetic drugs and cessed 5 October 2015
their potential role in treating mild cognitive 21. Sinclair A, Morley JE, Rodriguez-Ma~ nas L,
maintain glucose levels and prevent impairment and Alzheimer’s disease. Discov et al. Diabetes mellitus in older people: position
acute hyperglycemic complications. Med 2013;16:277–286 statement on behalf of the International Asso-
11. Yaffe K, Falvey C, Hamilton N, et al. Diabe- ciation of Gerontology and Geriatrics (IAGG),
References tes, glucose control, and 9-year cognitive de- the European Diabetes Working Party for Older
1. Centers for Disease Control and Prevention. cline among older adults without dementia. People (EDWPOP), and the International Task
National diabetes statistics report: estimates of Arch Neurol 2012;69:1170–1175 Force of Experts in Diabetes. J Am Med Dir Assoc
diabetes and its burden in the United States, 12. Launer LJ, Miller ME, Williamson JD, et al.; 2012;13:497–502
2014 [Internet]. Available from http://www.cdc ACCORD MIND Investigators. Effects of inten- 22. Dorner B, Friedrich EK, Posthauer ME. Prac-
.gov/diabetes/data/statistics/2014statisticsreport sive glucose lowering on brain structure and tice paper of the American Dietetic Association:
.html. Accessed 1 October 2015 function in people with type 2 diabetes individualized nutrition approaches for older
2. Kimbro LB, Mangione CM, Steers WN, et al. (ACCORD MIND): a randomised open-label sub- adults in health care communities. J Am Diet
Depression and all-cause mortality in persons study. Lancet Neurol 2011;10:969–977 Assoc 2010;110:1554–1563
with diabetes mellitus: are older adults at 13. Sinclair A, Dunning T, Colagiuri S. Managing 23. Migdal A, Yarandi SS, Smiley D, Umpierrez
higher risk? Results from the Translating older people with type 2 diabetes: global guide- GE. Update on diabetes in the elderly and in
Research Into Action for Diabetes Study. J Am line. International Diabetes Federation, 2013 nursing home residents. J Am Med Dir Assoc
Geriatr Soc 2014;62:1017–1022 14. Angelo M, Ruchalski C, Sproge BJ. An ap- 2011;12:627–632.e2
3. Kirkman MS, Briscoe VJ, Clark N, et al. Diabe- proach to diabetes mellitus in hospice and pal- 24. Quinn K, Hudson P, Dunning T. Diabetes man-
tes in older adults. Diabetes Care 2012;35: liative medicine. J Palliat Med 2011;14:83–87 agement in patients receiving palliative care.
2650–2664 15. Beckett NS, Peters R, Fletcher AE, et al.; J Pain Symptom Manage 2006;32:275–286
4. Cukierman T, Gerstein HC, Williamson JD. HYVET Study Group. Treatment of hypertension 25. Ford-Dunn S, Smith A, Quin J. Management
Cognitive decline and dementia in diabetes: sys- in patients 80 years of age or older. N Engl J Med of diabetes during the last days of life: attitudes
tematic overview of prospective observational 2008;358:1887–1898 of consultant diabetologists and consultant pal-
studies. Diabetologia 2005;48:2460–2469 16. James PA, Oparil S, Carter BL, et al. 2014 liative care physicians in the UK. Palliat Med
5. Roberts RO, Knopman DS, Przybelski SA, evidence-based guideline for the management 2006;20:197–203
et al. Association of type 2 diabetes with brain of high blood pressure in adults: report from 26. Mallery LH, Ransom T, Steeves B, Cook B,
atrophy and cognitive impairment. Neurology the panel members appointed to the Eighth Dunbar P, Moorhouse P. Evidence-informed
2014;82:1132–1141 Joint National Committee (JNC 8). JAMA 2014; guidelines for treating frail older adults with
6. Xu WL, von Strauss E, Qiu CX, Winblad B, 311:507–520 type 2 diabetes: from the Diabetes Care Pro-
Fratiglioni L. Uncontrolled diabetes increases the 17. Valencia WM, Florez H. Pharmacological gram of Nova Scotia (DCPNS) and the Palliative
risk of Alzheimer’s disease: a population-based treatment of diabetes in older people. Diabetes and Therapeutic Harmonization (PATH) pro-
cohort study. Diabetologia 2009;52:1031–1039 Obes Metab 2014;16:1192–1203 gram. J Am Med Dir Assoc 2013;14:801–808
7. Ghezzi L, Scarpini E, Galimberti D. Disease- 18. Campanelli CM; American Geriatrics Society 27. Laiteerapong N, Iveniuk J, John PM,
modifying drugs in Alzheimer’s disease. Drug 2012 Beers Criteria Update Expert Panel. Ameri- Laumann EO, Huang ES. Classification of older
Des Devel Ther 2013;7:1471–1478 can Geriatrics Society updated Beers Criteria for adults who have diabetes by comorbid condi-
8. Craft S, Baker LD, Montine TJ, et al. Intranasal potentially inappropriate medication use in older tions, United States, 2005-2006. Prev Chronic
insulin therapy for Alzheimer disease and adults. J Am Geriatr Soc 2012;60:616–631 Dis 2012;9:E100
S86 Diabetes Care Volume 39, Supplement 1, January 2016

American Diabetes Association


11. Children and Adolescents
Diabetes Care 2016;39(Suppl. 1):S86–S93 | DOI: 10.2337/dc16-S014

TYPE 1 DIABETES
Three-quarters of all cases of type 1 diabetes are diagnosed in individuals ,18 years
of age. The provider must consider the unique aspects of care and management of
children and adolescents with type 1 diabetes, such as changes in insulin sensitivity
related to physical growth and sexual maturation, ability to provide self-care, su-
pervision in the child care and school environment, and neurological vulnerability to
hypoglycemia and hyperglycemia in young children, as well as possible adverse
neurocognitive effects of diabetic ketoacidosis (1,2). Attention to family dynamics,
developmental stages, and physiological differences related to sexual maturity are
11. CHILDREN AND ADOLESCENTS

all essential in developing and implementing an optimal diabetes regimen (3). Due
to the paucity of clinical research in children, the recommendations for children and
adolescents are less likely to be based on clinical trial evidence. However, expert
opinion and a review of available and relevant experimental data are summarized in
the American Diabetes Association (ADA) position statement “Care of Children and
Adolescents With Type 1 Diabetes” (4) and have been updated in the ADA position
statement “Type 1 Diabetes Through the Life Span” (5).
A multidisciplinary team of specialists trained in pediatric diabetes management
and sensitive to the challenges of children and adolescents with type 1 diabetes and
their families should provide care for this population. It is essential that diabetes
self-management education (DSME) and support (DSMS), medical nutrition ther-
apy, and psychosocial support be provided at diagnosis and regularly thereafter by
individuals experienced with the educational, nutritional, behavioral, and emotional
needs of the growing child and family. The appropriate balance between adult
supervision and independent self-care should be defined at the first interaction
and reevaluated at subsequent clinic visits. The balance between adult supervision
and independent self-care will evolve as the adolescent gradually becomes an
emerging young adult.
Diabetes Self-management Education and Support

Recommendation
c Youth with type 1 diabetes and parents/caregivers (for patients aged ,18
years) should receive culturally sensitive and developmentally appropriate
individualized diabetes self-management education and support according
to national standards at diagnosis and routinely thereafter. B

No matter how sound the medical regimen, it can only be effective if the family and/
or affected individuals are able to implement it. Family involvement is a vital com-
ponent of optimal diabetes management throughout childhood and adolescence.
Health care providers (the diabetes care team) who care for children and adoles-
cents must be capable of evaluating the educational, behavioral, emotional, and
psychosocial factors that impact implementation of a treatment plan and must work
with the individual and family to overcome barriers or redefine goals as appropriate.
DSME and DSMS require periodic reassessment, especially as the youth grows,
develops, and acquires the need for greater independent self-care skills. In addition,
Suggested citation: American Diabetes Associa-
it is necessary to assess the educational needs and skills of day care providers, school tion. Children and adolescents. Sec. 11. In Stan-
nurses, or other school personnel who participate in the care of the young child with dards of Medical Care in Diabetesd2016.
diabetes (6). Diabetes Care 2016;39(Suppl. 1):S86–S93
© 2016 by the American Diabetes Association.
School and Child Care Readers may use this article as long as the work
As a large portion of a child’s day is spent in school, close communication with and is properly cited, the use is educational and not
the cooperation of school or day care personnel are essential for optimal diabetes for profit, and the work is not altered.
care.diabetesjournals.org Children and Adolescents S87

management, safety, and maximal aca- Screening impairment after episodes of severe hypo-
demic opportunities. Refer to the ADA Screening for psychosocial distress and glycemia, current data have not confirmed
position statements “Diabetes Care in mental health problems is an important this notion (18–20). Furthermore, new
the School Setting” (7) and “Care of Young component of ongoing care. It is impor- therapeutic modalities, such as rapid-
Children With Diabetes in the Child Care tant to consider the impact of diabetes and long-acting insulin analogs, techno-
Setting” (8) for additional details. on quality of life as well as the develop- logical advances (e.g., continuous glucose
Psychosocial Issues
ment of mental health problems related monitors, low glucose suspend insulin
to diabetes distress, fear of hypoglyce- pumps), and education may mitigate the
Recommendations mia (and hyperglycemia), symptoms of incidence of severe hypoglycemia (21).
c At diagnosis and during routine anxiety, disordered eating behaviors as The Diabetes Control and Complica-
follow-up care, assess psychosocial well as eating disorders, and symptoms tions Trial (DCCT) demonstrated that
issues and family stresses that could of depression (15). Consider screening near-normalization of blood glucose levels
impact adherence to diabetes man- for depression and disordered eating was more difficult to achieve in adoles-
agement and provide appropriate behaviors using available screening cents than in adults. Nevertheless, the in-
referrals to trained mental health tools (9,16), and, with respect to disor- creased use of basal–bolus regimens,
professionals, preferably experi- dered eating, it is important to recognize insulin pumps, frequent blood glucose
enced in childhood diabetes. E the unique and dangerous disordered monitoring, goal setting, and improved
c Encourage developmentally appro- eating behavior of insulin omission for patient education in youth from infancy
priate family involvement in diabetes weight control in type 1 diabetes (17). through adolescence have been associ-
management tasks for children and The presence of a mental health profes- ated with more children reaching the
adolescents, recognizing that prema- sional on pediatric multidisciplinary blood glucose targets set by the ADA
ture transfer of diabetes care to the teams highlights the importance of at- (7,22–25) in those families in which both
child can result in nonadherence and tending to the psychosocial issues of di- the parents and the child with diabetes
deterioration in glycemic control. B abetes. These psychosocial factors are participate jointly to perform the required
c Consider mental health professionals significantly related to nonadherence, diabetes-related tasks. Furthermore,
as integral members of the pediatric suboptimal glycemic control, reduced studies documenting neurocognitive imag-
diabetes multidisciplinary team. E quality of life, and higher rates of acute ing differences related to hyperglycemia
and chronic diabetes complications. in children provide another compelling
Diabetes management throughout child- motivation for lowering glycemic targets (1).
Glycemic Control
hood and adolescence places substantial In selecting glycemic goals, the long-
burdens on the youth and family, neces- Recommendation term health benefits of achieving a lower
sitating ongoing assessment of psychoso- c An A1C goal of ,7.5% (58 mmol/mol) A1C should be balanced against the risks
cial issues and distress during routine is recommended across all pediatric of hypoglycemia and the developmental
diabetes visits (9–11). Further, the com- age-groups. E burdens of intensive regimens in children
plexities of diabetes management require and youth. In addition, achieving lower
ongoing parental involvement in care Current standards for diabetes manage- A1C levels is more likely to be related to
throughout childhood with developmen- ment reflect the need to lower glucose as setting lower A1C targets (26,27). A1C
tally appropriate family teamwork be- safely as possible. This should be done goals are presented in Table 11.1.
tween the growing child/teen and with stepwise goals. Special consideration
Autoimmune Conditions
parent in order to maintain adherence should be given to the risk of hypoglyce-
and to prevent deterioration in glycemic mia in young children (aged ,6 years) Recommendation
control (12,13). As diabetes-specific fam- who are often unable to recognize, artic- c Assess for the presence of additional
ily conflict is related to poorer adherence ulate, and/or manage their hypoglycemic autoimmune conditions soon after the
and glycemic control, it is appropriate to symptoms. This “hypoglycemia unaware- diagnosis and if symptoms develop. E
inquire about such conflict during visits ness” should be considered when estab-
and to either help to negotiate a plan lishing individualized glycemic targets. Because of the increased frequency of
for resolution or refer to an appropriate Although it was previously thought that other autoimmune diseases in type 1
mental health specialist (14). young children were at risk for cognitive diabetes, screening for thyroid dysfunction

Table 11.1—Blood glucose and A1C goals for type 1 diabetes across all pediatric age-groups
Blood glucose goal range
Before meals Bedtime/overnight A1C Rationale
90–130 mg/dL 90–150 mg/dL ,7.5% A lower goal (,7.0% [53 mmol/mol]) is reasonable if it can be
(5.0–7.2 mmol/L) (5.0–8.3 mmol/L) (58 mmol/mol) achieved without excessive hypoglycemia
Key concepts in setting glycemic goals:
c Goals should be individualized, and lower goals may be reasonable based on a benefit–risk assessment.
c Blood glucose goals should be modified in children with frequent hypoglycemia or hypoglycemia unawareness.
c Postprandial blood glucose values should be measured when there is a discrepancy between preprandial blood glucose values and A1C levels and
to assess preprandial insulin doses in those on basal–bolus regimens.
S88 Children and Adolescents Diabetes Care Volume 39, Supplement 1, January 2016

and celiac disease should be considered. Celiac Disease antibody positivity on a separate blood
Periodic screening in asymptomatic indi- Recommendations
sample). It is also advisable to check for
viduals has been recommended, but the c Consider screening children with HLA types in patients who are diagnosed
optimal frequency and benefit of screen- type 1 diabetes for celiac disease without a small intestinal biopsy. Asymp-
ing are unclear. by measuring either tissue transglu- tomatic at-risk children should have an in-
Although much less common than ce- taminase or deamidated gliadin an- testinal biopsy (37).
liac disease and thyroid dysfunction, tibodies, with documentation of In symptomatic children with type 1 di-
other autoimmune conditions, such as normal total serum IgA levels, soon abetes and confirmed celiac disease,
Addison disease (primary adrenal insuf- after the diagnosis of diabetes. E gluten-free diets reduce symptoms and
ficiency), autoimmune hepatitis, auto- c Consider screening in children who rates of hypoglycemia (38). The challeng-
immune gastritis, dermatomyositis, have a first-degree relative with celiac ing dietary restrictions associated with
and myasthenia gravis, occur more com- disease, growth failure, weight loss, having both type 1 diabetes and celiac dis-
monly in the population with type 1 dia- failure to gain weight, diarrhea, flatu- ease place a significant burden on individ-
betes than in the general pediatric lence, abdominal pain, or signs of uals. Therefore, we recommend a biopsy
population and should be assessed and malabsorption or in children with fre- to confirm the diagnosis of celiac disease,
monitored as clinically indicated. quent unexplained hypoglycemia or especially in asymptomatic children, be-
deterioration in glycemic control. E fore endorsing significant dietary changes.
Thyroid Disease
c Children with biopsy-confirmed celiac
Recommendations Management of Cardiovascular Risk
disease should be placed on a gluten-
c Consider testing children with Factors
free diet and have a consultation
type 1 diabetes for antithyroid per- Hypertension
with a dietitian experienced in manag-
oxidase and antithyroglobulin anti- ing both diabetes and celiac disease. B Recommendations
bodies soon after the diagnosis. E
c Measure thyroid-stimulating hor- Screening
Celiac disease is an immune-mediated dis- c Blood pressure should be measured
mone concentrations soon after the order that occurs with increased fre-
diagnosis of type 1 diabetes and after at each routine visit. Children found
quency in patients with type 1 diabetes to have high-normal blood pressure
glucose control has been estab- (1.6–16.4% of individuals compared with
lished. If normal, consider rechecking (systolic blood pressure or diastolic
0.3–1% in the general population) (33–35). blood pressure $90th percentile
every 1–2 years or sooner if the pa-
tient develops symptoms suggestive Testing. Testing for celiac disease in- for age, sex, and height) or hyper-
of thyroid dysfunction, thyromegaly, cludes measuring serum levels of IgA tension (systolic blood pressure or
an abnormal growth rate, or an un- and antitissue transglutaminase anti- diastolic blood pressure $95th per-
explained glycemic variation. E bodies, or, with IgA deficiency, screening centile for age, sex, and height)
can include measuring IgG tissue transglu- should have blood pressure con-
Autoimmune thyroid disease is the taminase antibodies or IgG deamidated firmed on 3 separate days. B
most common autoimmune disorder gliadin peptide antibodies. Because most
cases of celiac disease are diagnosed Treatment
associated with diabetes, occurring in
within the first 5 years after the diagnosis c Initial treatment of high-normal
17–30% of patients with type 1 diabe-
of type 1 diabetes, screening should be blood pressure (systolic blood pres-
tes (28). At the time of diagnosis, about
considered at the time of diagnosis and sure or diastolic blood pressure con-
25% of children with type 1 diabetes
repeated within 2 and 5 years thereafter. sistently $90th percentile for age,
have thyroid autoantibodies (29);
Although celiac disease can be diag- sex, and height) includes dietary
their presence is predictive of thyroid
nosed more than 10 years after diabe- modification and increased exercise,
dysfunctiondmost commonly hypothy-
tes diagnosis, there are insufficient data if appropriate, aimed at weight con-
roidism, although hyperthyroidism
trol. If target blood pressure is not
occurs in ;0.5% of cases (30,31). Thy- after 5 years to determine the optimal
screening frequency. Testing for antitis- reached with 3–6 months of initiating
roid function tests may be misleading
sue transglutaminase antibody should lifestyle intervention, pharmacologi-
(euthyroid sick syndrome) if performed
be considered at other times in patients cal treatment should be considered. E
at time of diagnosis owing to the effect
c In addition to lifestyle modification,
of previous hyperglycemia, ketosis or with symptoms suggestive of celiac disease
(35). A small-bowel biopsy in antibody- pharmacological treatment of hyper-
ketoacidosis, weight loss, etc. There-
positive children is recommended to tension (systolic blood pressure or
fore, thyroid function tests should be
confirm the diagnosis (36). European diastolic blood pressure consistently
performed soon after a period of meta-
guidelines on screening for celiac dis- $95th percentile for age, sex, and
bolic stability and good glycemic con-
height) should be considered as
trol. Subclinical hypothyroidism may ease in children (not specific to children
soon as hypertension is confirmed. E
be associated with increased risk of with type 1 diabetes) suggest that bi-
c ACE inhibitors or angiotensin recep-
symptomatic hypoglycemia (32) and re- opsy may not be necessary in symptom-
tor blockers should be considered
duced linear growth rate. Hyperthyroid- atic children with high antibody titers
for the initial pharmacological treat-
ism alters glucose metabolism and (i.e., greater than 10 times the upper limit
ment of hypertension, following re-
usually causes deterioration of meta- of normal) provided that further testing is
productive counseling due to the
bolic control. performed (verification of endomysial
care.diabetesjournals.org Children and Adolescents S89

potential teratogenic effects of have two or more cardiovascular disease however, studies have shown short-
both drug classes. E (CVD) risk factors (40–42), and the preva- term safety equivalent to that seen in
c The goal of treatment is blood lence of CVD risk factors increases with adults and efficacy in lowering LDL cho-
pressure consistently ,90th per- age (42), with girls having a higher risk lesterol levels in familial hypercholes-
centile for age, sex, and height. E burden than boys (41). terolemia or severe hyperlipidemia,
Pathophysiology. The atherosclerotic
improving endothelial function, and
Blood pressure measurements should process begins in childhood, and al- causing regression of carotid intimal
be determined using the appropriate thickening (54,55). Statins are not ap-
though CVD events are not expected
size cuff with the child seated and re-
to occur during childhood, observations proved for patients aged ,10 years,
laxed. Hypertension should be con- and statin treatment should generally
using a variety of methodologies show
firmed on at least 3 separate days. not be used in children with type 1
that youth with type 1 diabetes may have
Evaluation should proceed as clinically diabetes before this age. Statins are
subclinical CVD abnormalities within the
indicated. Treatment is generally initi- category X in pregnancy; therefore,
first decade of diagnosis (43–45). Studies
ated with an ACE inhibitor, but an angio- pregnancy prevention is of paramount
of carotid intima-media thickness have
tensin receptor blocker can be used if importance for postpubertal girls (see
yielded inconsistent results (39).
the ACE inhibitor is not tolerated (e.g., Section 12 “Management of Diabetes in
due to cough). Normal blood pressure Treatment. Pediatric lipid guidelines pro- Pregnancy” for more information).
levels for age, sex, and height and ap- vide some guidance relevant to children
Smoking
propriate methods for measurement with type 1 diabetes (46–48); however,
are available online at www.nhlbi.nih there are few studies on modifying lipid Recommendation
.gov/health/prof/heart/hbp/hbp_ped levels in children with type 1 diabetes. A c Elicit a smoking history at initial
.pdf (39). 6-month trial of dietary counseling and follow-up diabetes visits and
produced a significant improvement in discourage smoking in youth who
Dyslipidemia
lipid levels (49); likewise, a lifestyle do not smoke and encourage
Recommendations intervention trial with 6 months of ex- smoking cessation in those who
ercise in adolescents demonstrated im- do smoke. B
Testing
provement in lipid levels (50).
c Obtain a fasting lipid profile in chil-
Although intervention data are sparse, The adverse health effects of smoking
dren $10 years of age soon after
the American Heart Association (AHA) cat- are well recognized with respect to fu-
the diagnosis (after glucose con-
egorizes children with type 1 diabetes in ture cancer and CVD risk. In youth with
trol has been established). E
the highest tier for cardiovascular risk and diabetes, it is important to avoid addi-
c If lipids are abnormal, annual
recommends both lifestyle and pharmaco- tional CVD risk factors. Smoking increases
monitoring is reasonable. If LDL
logical treatment for those with elevated the risk of onset of albuminuria; there-
cholesterol values are within the
LDL cholesterol levels (48,51). Initial ther- fore, smoking avoidance is important
accepted risk level (,100 mg/dL
apy should be with a Step 2 AHA diet, to prevent both microvascular and mac-
[2.6 mmol/L]), a lipid profile re-
which restricts saturated fat to 7% of total rovascular complications (46,56). Dis-
peated every 3–5 years is rea-
calories and restricts dietary cholesterol to couraging cigarette smoking, including
sonable. E
200 mg/day. Data from randomized clini- e-cigarettes, is an important part of rou-
Treatment cal trials in children as young as 7 months tine diabetes care. In younger children, it
c Initial therapy should consist of of age indicate that this diet is safe and is important to assess exposure to ciga-
optimizing glucose control and does not interfere with normal growth rette smoke in the home due to the ad-
medical nutrition therapy using a and development (52). verse effects of secondhand smoke and
Step 2 American Heart Association For children with a significant family to discourage youth from ever smoking
diet to decrease the amount of history of CVD, the National Heart, Lung, if exposed to smokers in childhood.
saturated fat in the diet. B and Blood Institute recommends ob-
c After the age of 10 years, addition taining a fasting lipid panel beginning Microvascular Complications
at 2 years of age (46). Abnormal results Nephropathy
of a statin is suggested in patients
who, despite medical nutrition ther- from a random lipid panel should be Recommendations
apy and lifestyle changes, continue confirmed with a fasting lipid panel.
Screening
to have LDL cholesterol .160 mg/dL Data from the SEARCH for Diabetes in
c Annual screening for albuminuria
(4.1 mmol/L) or LDL cholesterol Youth (SEARCH) study show that im-
with a random spot urine sample
.130 mg/dL (3.4 mmol/L) and one proved glucose control over a 2-year pe-
for albumin–to–creatinine ra-
or more cardiovascular disease risk riod is associated with a more favorable
tio should be considered once
factors. E lipid profile; however, improved glyce-
the child has had diabetes for
c The goal of therapy is an LDL mic control alone will not normalize lip-
5 years. B
cholesterol value ,100 mg/dL ids in youth with type 1 diabetes and
c Estimate glomerular filtration rate
(2.6 mmol/L). E dyslipidemia (53).
at initial evaluation and then
Neither long-term safety nor cardio-
based on age, diabetes duration,
Population-based studies estimate that vascular outcome efficacy of statin ther-
and treatment. E
14–45% of children with type 1 diabetes apy has been established for children;
S90 Children and Adolescents Diabetes Care Volume 39, Supplement 1, January 2016

Treatment duration of only 1–2 years. Referrals team, including a physician, diabetes
c Treatment with an ACE inhibitor, should be made to eye care professionals nurse educator, registered dietitian,
titrated to normalization of albumin with expertise in diabetic retinopathy and behavioral specialist or social
excretion, should be considered and experience in counseling the pedi- worker, is essential. In addition to blood
when elevated urinary albumin– atric patient and family on the importance glucose control, treatment must in-
to–creatinine ratio (.30 mg/g) is of early prevention and intervention. clude management of comorbidities
documented with at least two of Neuropathy such as obesity, dyslipidemia, hyperten-
three urine samples. These should sion, and albumin levels from the outset.
Recommendation Presentation with ketosis or ketoacidosis
be obtained over a 6-month inter-
c Consider an annual comprehensive requires a period of insulin therapy un-
val following efforts to improve
foot exam for the child at the start til fasting and postprandial glycemia
glycemic control and normalize
of puberty or at age $10 years, have been restored to normal or near-
blood pressure. B
whichever is earlier, once the youth normal. Metformin therapy may be
has had type 1 diabetes for 5 years. E used as an adjunct after resolution of
Data from 7,549 participants ,20 years
of age in the T1D Exchange clinic registry ketosis/ketoacidosis. Initial treatment
Neuropathy rarely occurs in prepubertal should also be with insulin when the
emphasize the importance of good gly-
children or after only 1–2 years of diabe- distinction between type 1 diabetes
cemic and blood pressure control, par-
tes (60). A comprehensive foot exam, in- and type 2 diabetes is unclear and
ticularly as diabetes duration increases,
cluding inspection, palpation of dorsalis in patients who have random blood
in order to reduce the risk of nephropa-
thy. The data also underscore the impor-
pedis and posterior tibial pulses, assess- glucose concentrations $250 mg/dL
tance of routine screening to ensure
ment of the patellar and Achilles reflexes, (13.9 mmol/L) and/or A1C .9%
and determination of proprioception, vi- (75 mmol/mol) (65).
early diagnosis and timely treatment of bration, and monofilament sensation,
albuminuria (57). An estimation of glo- Patients and their families must prior-
should be performed annually along itize lifestyle modifications such as
merular filtration rate (GFR), calculated with assessment of symptoms of neuro- eating a balanced diet, maintaining a
using GFR estimating equations from pathic pain. Foot inspection can be per- healthy weight, and exercising regu-
the serum creatinine, height, age, and formed at each visit to educate youth larly. A family-centered approach to nu-
sex (58), should be determined at base- regarding the importance of foot care. trition and lifestyle modification is
line and repeated as indicated based on
essential in children with type 2 diabe-
clinical status, age, diabetes duration,
TYPE 2 DIABETES tes. Nutrition recommendations should
and therapies. Estimated GFR is calcu-
lated from a serum creatinine measure- For information on testing for type 2 be culturally appropriate and sensitive
ment using an estimating equation. This diabetes and prediabetes in children to family resources (see Section 3
and adolescents, please refer to Sec- “Foundations of Care and Comprehen-
is not a recommendation to perform a
measurement of creatinine clearance (in- tion 2 “Classification and Diagnosis of sive Medical Evaluation”).
Diabetes.” When insulin treatment is not re-
volves timed urine collection) every year.
The Centers for Disease Control and quired, initiation of metformin, currently
There are ongoing clinical trials assessing the only oral hypoglycemic agent specifi-
Prevention recently published projections
the efficacy of early treatment of persis- cally approved for use in children with
for type 2 diabetes prevalence using the
tent albuminuria with ACE inhibitors (59). type 2 diabetes, is recommended. How-
SEARCH database. Assuming a 2.3% an-
nual increase, the prevalence of type 2 ever, the Treatment Options for type 2 Di-
Retinopathy
diabetes in those under 20 years of age abetes in Adolescents and Youth (TODAY)
Recommendations will quadruple in 40 years (61,62). Given study found that metformin alone pro-
c An initial dilated and comprehen- the current obesity epidemic, distinguish- vided durable glycemic control (A1C
sive eye examination is recom- ing between type 1 and type 2 diabetes in #8% [64 mmol/mol] for 6 months) in ap-
mended at age $10 years or children can be difficult. For example, ex- proximately half of the subjects (66), sug-
after puberty has started, which- cessive weight is common in children with gesting that many youth with type 2
ever is earlier, once the youth type 1 diabetes (63). Furthermore, diabetes- diabetes are likely to require combination
has had diabetes for 3–5 years. B associated autoantibodies and ketosis treatment within a few years of diagnosis.
c After the initial examination, an- may be present in patients with features
nual routine follow-up is generally of type 2 diabetes (including obesity and Comorbidities
recommended. Less frequent ex- acanthosis nigricans) (64). Nevertheless, Comorbidities may already be present at
aminations, every 2 years, may accurate diagnosis is critical as treatment the time of diagnosis in youth with
be acceptable on the advice of an regimens, educational approaches, die- type 2 diabetes (67). Therefore, blood
eye care professional. E tary advice, and outcomes differ mark- pressure measurement, a fasting lipid
edly between the two diagnoses. panel, assessment for albumin excre-
Although retinopathy (like albuminuria) tion, and a dilated eye examination
most commonly occurs after the onset Treatment should be performed at diagnosis.
of puberty and after 5–10 years of dia- The general treatment goals for type 2 Thereafter, screening guidelines and
betes duration (60), it has been reported diabetes are the same as those for type treatment recommendations for hyper-
in prepubertal children and with diabetes 1 diabetes. A multidisciplinary diabetes tension, dyslipidemia, albumin excretion,
care.diabetesjournals.org Children and Adolescents S91

and retinopathy are similar to those for Although scientific evidence is limited, with type 1 diabetes. Pediatrics 2013;132:
youth with type 1 diabetes. Additional it is clear that comprehensive and coordi- e1395–e1402
10. Hood KK, Beavers DP, Yi-Frazier J, et al. Psy-
problems that may need to be addressed nated planning that begins in early ado- chosocial burden and glycemic control during
include polycystic ovary disease and lescence, or at least 1 year before the the first 6 years of diabetes: results from the
other comorbidities associated with pe- date of transition, is necessary to facilitate SEARCH for Diabetes in Youth study. J Adolesc
diatric obesity, such as sleep apnea, a seamless transition from pediatric to Health 2014;55:498–504
hepatic steatosis, orthopedic complica- adult health care (71,72). A comprehen- 11. Ducat L, Philipson LH, Anderson BJ. The
mental health comorbidities of diabetes. JAMA
tions, and psychosocial concerns. The sive discussion regarding the challenges 2014;312:691–692
ADA consensus report “Type 2 Diabetes faced during this period, including specific 12. Katz ML, Volkening LK, Butler DA, Anderson
in Children and Adolescents” (68) and a recommendations, is found in the ADA BJ, Laffel LM. Family-based psychoeducation
more recent American Academy of Pe- position statement “Diabetes Care for and care ambassador intervention to improve
diatrics clinical practice guideline (69) Emerging Adults: Recommendations for glycemic control in youth with type 1 diabetes: a
randomized trial. Pediatr Diabetes 2014;15:
provide guidance on the prevention, Transition From Pediatric to Adult Diabe- 142–150
screening, and treatment of type 2 di- tes Care Systems” (72). 13. Laffel LM, Vangsness L, Connell A, Goebel-
abetes and its comorbidities in children The National Diabetes Education Pro- Fabbri A, Butler D, Anderson BJ. Impact of
and adolescents. gram (NDEP) has materials available to ambulatory, family-focused teamwork inter-
facilitate the transition process (http:// vention on glycemic control in youth with
TRANSITION FROM PEDIATRIC TO ndep.nih.gov/transitions), and the En-
type 1 diabetes. J Pediatr 2003;142:409–416
ADULT CARE 14. Anderson BJ, Vangsness L, Connell A, Butler
docrine Society in collaboration with D, Goebel-Fabbri A, Laffel LM. Family conflict,
Recommendations the ADA and other organizations has de- adherence, and glycaemic control in youth with
c Health care providers and families veloped transition tools for clinicians short duration type 1 diabetes. Diabet Med
should begin to prepare youth in and youth and families (http://www 2002;19:635–642
15. Lawrence JM, Yi-Frazier JP, Black MH, et al.;
early to mid-adolescence and, at .endo-society.org/clinicalpractice/ SEARCH for Diabetes in Youth Study Group. De-
the latest, at least 1 year before transition_of_care.cfm). mographic and clinical correlates of diabetes-
the transition to adult health care. E related quality of life among youth with type 1
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