ADA Standards of Medical Care for Diabetes 2020

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J a The Journal of Clinical and Applied Research and Education Volume 43 | Supplement 1 nu a ry 2020

www.diabetes.org/diabetescare January 2020

ple m e p n U t S 1 American Diabetes Association Standards of Medical Care in diabetes—2020 Volume 43 |

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ISSN 0149-5992 Association

Diabetes

American

Diabetes

American

©2019 © 2019 by the American Diabetes Association. Readers may use this work as long as the work is properly cited, the use is educational and not for proﬁt, and the work is not altered. Readers may link to the version of record of this work on https://care.diabetesjournals.org, but ADA permission is required to post this work on any third-party website or platform. Requests to reuse or repurpose; adapt or modify; or post, display, or distribute this work may be sent to [email protected]. Association

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[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 Matthew C. Riddle, MD

ASSOCIATE EDITORS EDITORIAL BOARD George Bakris, MD Andrew J. Ahmann, MD M. Sue Kirkman, MD Lawrence Blonde, MD, FACP Linda A. Barbour, MD, MSPH John J.V. McMurray, MD, FRCP, FESC, Andrew J.M. Boulton, MD Ananda Basu, MD, FRCP FACC, FAHA, FRSE, FMedSci David D’Alessio, MD Roy W. Beck, MD, PhD MaureenAssociation Monaghan, PhD, CDE Linda A. DiMeglio, MA, MD, MPH Gianni Bellomo, MD Kristen J. Nadeau, MD, MS Linda Gonder-Frederick, PhD Geremia Bolli, MD Gregory A. Nichols, PhD, MBA Korey K. Hood, PhD Sonia Caprio, MD Bruce A. Perkins, MD, MPH Frank B. Hu, MD, MPH, PhD Jessica R. Castle, MD Ravi Retnakaran, MD, MSc, FRCPC Steven E. Kahn, MB, ChB J. Hans DeVries, MD, PhD Elizabeth Seaquist, MD Sanjay Kaul, MD, FACC, FAHA Kathleen M. Dungan, MD, MPH Jonathan Shaw, MD, FRCP, FRACP, Lawrence A. Leiter, MD, FRCPC, FACP, Thomas W. Gardner, MD, MS FAAHMS FACE, FACC, FAHA Jennifer Green, MD Jay M. Sosenko, MD, MS Robert G. Moses, MD Petr Heneberg, RNDr, PhD Kristina M. Utzschneider, MD Stephen Rich, PhD Norbert Hermanns,Diabetes PhD, MSc Daniel H. van Raalte, MD, PhD Julio Rosenstock, MD Reinhard W. Holl, MD, PhD Ram Weiss, MD, PhD Judith Wylie-Rosett, EdD, RD Philip Home, DM, DPhil Deborah Wexler, MD, MSc Byron J. Hoogwerf, MD, FACP, FACE Vincent C. Woo, MD, FRCPC George S. Jeha, MD Bernard Zinman, CM, MD, FRCPC, Lee M. Kaplan, MD, PhD FACP

AMERICAN DIABETES ASSOCIATION OFFICERS CHAIR OF THE BOARD PRESIDENT-ELECT, MEDICINE & SCIENCE David J. Herrick, MBA Robert H. Eckel, MD AmericanPRESIDENT, MEDICINE & SCIENCE Louis H. Philipson, MD, PhD, FACP PRESIDENT-ELECT, HEALTH CARE & EDUCATION PRESIDENT, HEALTH CARE & Mary de Groot, PhD EDUCATION Gretchen Youssef, MS, RD, CDE SECRETARY/TREASURER-ELECT SECRETARY/TREASURER Martha Parry Clark, MBA Brian Bertha, JD, MBA ©2019 CHAIR OF THE BOARD-ELECT CHIEF EXECUTIVE OFFICER Umesh Verma Tracey D. Brown, MBA, BChE

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 © 2019 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 [email protected]. The American Diabetes Association reserves the right toAssociation 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 [email protected], or visit the online journal for more information about submitting manuscripts, publication charges, ordering reprints, PRINT ISSN 0149-5992 subscribing to the journal, becoming an ADA member, advertising, permission to reuse ’ ONLINE ISSN 1935-5548 content, and the journalDiabetess publication policies. PRINTED IN THE USA Periodicals postage paid at Arlington, VA, and additional mailing ofﬁces.

AMERICAN DIABETES ASSOCIATION PERSONNEL AND CONTACTS

ASSOCIATE PUBLISHER, EDITORIAL MANAGER ADVERTISING REPRESENTATIVES SCHOLARLY JOURNALS Donna J. Reynolds Christian S. Kohler American Diabetes Association Paul Nalbandian TECHNICAL EDITOR Associate Publisher, Advertising & EDITORIAL OFFICE DIRECTOR AmericanTheresa M. Cooper Sponsorships Lyn Reynolds [email protected] (703) 549-1500, ext. 4806 PEER REVIEW MANAGER PRODUCTION COORDINATOR Shannon Potts Saleha Malik Tina Auletta Senior Account Executive ASSOCIATE MANAGER, PEER REVIEW DIRECTOR, MEMBERSHIP/SUBSCRIPTION [email protected] Larissa M. Pouch SERVICES (703) 549-1500, ext. 4809 Donald Crowl ©2019 PHARMACEUTICAL/DEVICE DIGITAL ADVERTISING DIRECTOR, SCHOLARLY JOURNALS eHealthcare Solutions Heather Norton Blackburn SENIOR ADVERTISING MANAGER Dan Mullen Julie DeVoss Graff VP, Professional Solutions ASSOCIATE DIRECTOR, SCHOLARLY JOURNALS [email protected] [email protected] Keang Hok (703) 299-5511 (609) 882-8887, ext. 112 January 2020 Volume 43, Supplement 1

Standards of Medical Care in Diabetes—2020

S1 Introduction S89 8. Obesity Management for the Treatment of Type 2 Diabetes S3 Professional Practice Committee Assessment S4 Summary of Revisions: Standards of Medical Care in Diabetes—2020 Diet, Physical Activity, and Behavioral Therapy Pharmacotherapy Medical Devices for Weight Loss S7 1. Improving Care and Promoting Health in Metabolic Surgery Populations S98 9. Pharmacologic Approaches to Glycemic Diabetes and Population Health Treatment Tailoring Treatment for Social Context Pharmacologic Therapy for Type 1 Diabetes Surgical Treatment for Type 1 Diabetes S14 2. Classiﬁcation and Diagnosis of Diabetes Pharmacologic Therapy for Type 2 Diabetes Classiﬁcation S111 10. Cardiovascular Disease and Risk Diagnostic Tests for Diabetes Management A1C Type 1 Diabetes The Risk Calculator Prediabetes and Type 2 Diabetes Hypertension/BloodAssociation Pressure Control Cystic Fibrosis–Related Diabetes Lipid Management Posttransplantation Diabetes Mellitus Statin Changes Monogenic Diabetes Syndromes Antiplatelet Agents Pancreatic Diabetes/Diabetes in the Cardiovascular Disease Context of the Exocrine Pancreas Cardiac Testing Gestational Diabetes Mellitus Screening Asymptomatic Patients Lifestyle and Pharmacologic Interventions Glucose-Lowering Therapies and Cardiovascular Outcomes S32 3. Prevention or Delay of Type 2 Diabetes 11. Microvascular Complications and Foot Care Lifestyle Interventions S135 Pharmacologic Interventions Chronic Kidney Disease Prevention of Cardiovascular Disease Diabetic Retinopathy Diabetes Self-management Education and Support DiabetesNeuropathy Foot Care

S37 4. Comprehensive Medical Evaluation and S152 12. Older Adults Assessment of Comorbidities Neurocognitive Function Patient-Centered Collaborative Care Hypoglycemia Comprehensive Medical Evaluation Treatment Goals Assessment of Comorbidities Lifestyle Management Pharmacologic Therapy S48 5. Facilitating Behavior Change and Well-being to Special Considerations for Type 1 Diabetes Improve Health Outcomes Treatment in Skilled Nursing Facilities and Nursing Homes Diabetes Self-management Education and Support End-of-Life Care Medical Nutrition Therapy Physical Activity S163 13. Children and Adolescents Smoking Cessation:American Tobacco and e-Cigarettes Type 1 Diabetes Psychosocial Issues Type 2 Diabetes Transition From Pediatric to Adult Care 6. Glycemic Targets S66 14. Management of Diabetes in Pregnancy Assessment of Glycemic Control S183 A1C Goals Diabetes in Pregnancy Hypoglycemia Preconception Counseling Intercurrent Illness Glycemic Targets Management of Gestational Diabetes Mellitus Management of Preexisting Type 1 Diabetes ©2019S77 7. Diabetes Technology and Type 2 Diabetes Self-monitoring of Blood Glucose Preeclampsia and Aspirin Continuous Glucose Monitors Pregnancy and Drug Considerations Insulin Delivery Postpartum Care This issue is freely accessible online at care.diabetesjournals.org/content/43/Supplement_1. Keep up with the latest information for Diabetes Care and other ADA titles via Facebook (/ADAJournals) and Twitter (@ADA_Journals).

S193 15. Diabetes Care in the Hospital Transition From the Hospital to the Ambulatory Setting Hospital Care Delivery Standards Preventing Admissions and Readmissions Glycemic Targets in Hospitalized Patients 16. Diabetes Advocacy Bedside Blood Glucose Monitoring S203 Glucose-Lowering Agents in Hospitalized Patients Advocacy Statements Hypoglycemia Disclosures Medical Nutrition Therapy in the Hospital S205 Self-management in the Hospital Standards for Special Situations S207 Index

Association

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Introduction: Standards of Medical Care in Diabetesd2020 Diabetes Care 2020;43(Suppl. 1):S1–S2 | https://doi.org/10.2337/dc20-SINT

Diabetes is a complex, chronic illness re- The ADA strives to improve and update immediateinclusion.Moreinformationon quiring continuous medical care with the Standards of Care to ensure that the “living Standards” canbefoundonthe multifactorial risk-reduction strategies clinicians, health plans, and policy mak- ADA’s professional website DiabetesPro at beyond glycemic control. Ongoing dia- ers can continue to rely on it as the professional.diabetes.org/content-page/ betes self-management education and most authoritative source for current living-standards.Association The Standards of Care support are critical to preventing acute guidelines for diabetes care. supersedes all previous ADA position statementsdand the recommendations complications and reducing the risk of long- INTRODUCTION ADA STANDARDS, STATEMENTS, term complications. Significant evidence thereindon clinical topics within the REPORTS, and REVIEWS exists that supports a range of interven- purview of the Standards of Care; ADA tions to improve diabetes outcomes. The ADA has been actively involved in position statements, while still contain- The American Diabetes Association the development and dissemination of ing valuable analysis, should not be con- ’ (ADA) “Standards of Medical Care in Di- diabetes care clinical practice recom- sidered the ADA s current position. The abetes,” referred to as the Standards of mendations and related documents for Standards of Care receives annual review 30 years. The ADA’s Standards of Medical Care, is intended to provide clinicians, and approval by the ADA Board of Directors. Care is viewed as an important resource patients, researchers, payers, and other Diabetes for health care professionals who care for ADA Statement interested individuals with the compo- people with diabetes. An ADA statement is an official nentsof diabetescare,general treatment ADA point of view or belief that goals, and tools to evaluate the quality of Standards of Care does not contain clinical practice care. The Standards of Care recommen- The annual Standards of Care recommendations and may be issued dations are not intended to preclude supplement to Diabetes Care contains on advocacy, policy, economic, or clinical judgment and must be applied official ADA position, is authored by medical issues related to diabetes. in the context of excellent clinical care, the ADA, and provides all of the ADA statements undergo a formal re- with adjustments for individual prefer- ADA’s current clinical practice view process, including a review by the ences, comorbidities, and other patient recommendations. appropriate ADA national committee, factors. For more detailed informationAmericanTo update the Standards of Care, the ADA science and medicine staff, and about the management of diabetes, please ADA’s Professional Practice Committee the ADA Board of Directors. refer to Medical Management of Type 1 (PPC) performs an extensive clinical di- Diabetes (1) and Medical Management of abetes literature search, supplemented Consensus Report Type 2 Diabetes (2). with input from ADA staff and the med- A consensus report of a particular The recommendations in the Stand- ical community at large. The PPC updates topic contains a comprehensive ards of Care include screening, diagnos- the Standards of Care annually. However, examination and is authored by an tic, and therapeutic actions that are known the Standards of Care is a “living” docu- expert panel (i.e., consensus panel) or believed©2019 to favorably affect health out- ment, where important updates are pub- and represents the panel’s collective comes of patients with diabetes. Many lished online should the PPC determine analysis, evaluation, and opinion. of these interventions have also been that new evidence or regulatory changes The need for a consensus report arises showntobecost-effective(3). (e.g., drug approvals, label changes) merit when clinicians, scientists, regulators,

The “Standards of Medical Care in Diabetes” was originally approved in 1988. Most recent review/revision: December 2019. © 2019 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for proﬁt, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license. S2 Introduction Diabetes Care Volume 43, Supplement 1, January 2020

Table 1—ADA evidence-grading system for “Standards of Medical Care in Diabetes” the evidence in support of the recom- E Level of mendation. Expert opinion is a separate evidence Description category for recommendations in which there is no evidence from clinical trials, A Clear evidence from well-conducted, generalizable randomized controlled trials that are adequately powered, including clinical trials may be impractical, or there fl c Evidence from a well-conducted multicenter trial is con icting evidence. Recommendations c Evidence from a meta-analysis that incorporated quality ratings in the analysis with A level evidence are based on large Compelling nonexperimental evidence, i.e., “all or none” rule developed by the Centre well-designed clinical trials or well-done for Evidence-Based Medicine at the University of Oxford meta-analyses. Generally, these recom- Supportive evidence from well-conducted randomized controlled trials that are mendations have the best chance of im- adequately powered, including proving outcomes when applied to the c Evidence from a well-conducted trial at one or more institutions c Evidence from a meta-analysis that incorporated quality ratings in the analysis population for which they are appropriate. B Supportive evidence from well-conducted cohort studies Recommendations with lower levels of c Evidence from a well-conducted prospective cohort study or registry evidence may be equally important c Evidence from a well-conducted meta-analysis of cohort studies but are not as well supported. Supportive evidence from a well-conducted case-control study Of course, evidence is only one com- C Supportive evidence from poorly controlled or uncontrolled studies ponent of clinical decision-making. Clini- c Evidence from randomized clinical trials with one or more major or three or more cians care for patients, not populations; minor methodological flaws that could invalidate the results guidelines must always be interpreted c Evidence from observational studies with high potential for bias (such as case with the individual patient in mind. In- series with comparison with historical controls) dividual circumstances, such as comorbid c Evidence from case series or case reports Association Conflicting evidence with the weight of evidence supporting the recommendation and coexisting diseases, age, education, ’ E Expert consensus or clinical experience disability, and, above all, patients values and preferences, must be considered and may lead to different treatment targets and/or policy makers desire guidance Standards of Care. The category may also and strategies. Furthermore, conven- and/or clarity on a medical or scientific include task force and expert committee tional evidence hierarchies, such as the issue related to diabetes for which the reports. one adapted by the ADA, may miss evidence is contradictory, emerging, or nuances important in diabetes care. incomplete. Consensus reports may also GRADING OF SCIENTIFIC EVIDENCE For example, although there is excellent highlight gaps in evidence and propose Since the ADA first began publishing evidence from clinical trials supporting areas of future research to address clinical practiceDiabetes guidelines, there has the importance of achieving multiple risk these gaps. A consensus report is not been considerable evolution in the eval- factor control, the optimal way to achieve an ADA position but represents expert uation of scientific evidence and in the this result is less clear. It is difficult to opinion only and is produced under the development of evidence-based guide- assess each component of such a complex auspices of the ADA by invited experts. lines. In 2002, the ADA developed a intervention. A consensus report may be developed af- classification system to grade the quality ter an ADA Clinical Conference or Re- of scientific evidence supporting ADA rec- References search Symposium. ommendations. A 2015 analysis of the 1. American Diabetes Association. Medical evidence cited in the Standards of Care Management of Type 1 Diabetes. 7th ed. Wang Scientific Review CC, Shah AC, Eds. Alexandria, VA, American Di- found steady improvement in quality abetes Association, 2017 A scientific review is a balanced review over the previous 10 years, with the 2. American Diabetes Association. Medical Man- and analysis of the literatureAmerican on a 2014 Standards of Care for the first time agement of Type 2 Diabetes. 7th ed. Burant CF, scientific or medical topic related having the majority of bulleted recom- Young LA, Eds. Alexandria, VA, American Diabetes to diabetes. mendations supported by A level or Association, 2012 3. Li R, ZhangP,BarkerLE,ChowdhuryFM,Zhang Ascientific review is not an ADA position B level evidence (4). A grading system X. Cost-effectiveness of interventions to prevent and does not contain clinical practice (Table 1) developed by the ADA and and control diabetes mellitus: a systematic recommendations but is produced un- modeled after existing methods was used to review. Diabetes Care 2010;33:1872–1894 der the auspices of the ADA by invited clarify and codify the evidence that forms 4. Grant RW, Kirkman MS. Trends in the evidence level for the American Diabetes Associa- experts. The scientificreviewmaypro- the basis for the recommendations. ADA ©2019 tion’s “Standards of Medical Care in Diabetes” vide a scientific rationale for clini- recommendations are assigned ratings of from 2005 to 2014. Diabetes Care 2015;38: cal practice recommendations in the A, B,orC, depending on the quality of 6–8 Diabetes Care Volume 43, Supplement 1, January 2020 S3

Professional Practice Committee: Standards of Medical Care in Diabetesd2020 Diabetes Care 2020;43(Suppl. 1):S3| https://doi.org/10.2337/dc20-SPPC

The Professional Practice Committee (PPC) and published since 15 October 2018. Hsu, MD; Sally C. Hughes, BA; Scott of the American Diabetes Association (ADA) Due to limitations associated with pro- Kahan, MD, MPH; Ka Hei Karen Lau, is responsible for the “Standards of Medical duction timelines, evidence published in MS,RD,LDN,CDE;JoseLeon,MD;Ingrid Care in Diabetes,” referred to as the Stand- late 2019 was not incorporated into the Libman, MD, PhD; Sarah K. Lyons, MD; MRVN AEADPOOIGHEALTH PROMOTING AND CARE IMPROVING ards of Care. The PPC is a multidisciplinary initial 2020 Standards of Care release (e.g., Medha Munshi, MD; Henry Rodriguez, expert committee comprised of physicians, Dapagliflozin in Patients with Heart Failure MD; AmyAssociation Shah, MD; Connor K. Smith, diabetes educators, and others who have and Reduced Ejection Fraction [DAPA-HF], BS; Andrea Steck, MD; William S. Yancy, expertise in a range of areas, including, but Cardiovascular Outcome Study of Linaglip- MD, MHS; and Ann Zmuda, DPM. not limited to, adult and pediatric endocri- tin Versus Glimepiride in Patients With Members of the PPC nology, epidemiology, public health, cardio- Type 2 Diabetes [CAROLINA], etc.), but Joshua J. Neumiller, PharmD, CDE, FASCP vascular risk management, microvascular salient new data will be incorporated in (Chair) complications, preconception and preg- a living Standards update in early 2020 George Bakris, MD nancy care, weight management and di- (professional.diabetes.org/content-page/ William T. Cefalu, MD abetes prevention, and use of technology in living-standards). Recommendations were Jill Crandall, MD diabetes management. Appointment to the revisedbasedonnewevidenceor,insome David D’Alessio, MD PPCisbasedonexcellenceinclinicalpractice cases,toclarifythe priorrecommendationDiabetesJennifer Green, MD and research. Although the primary role of or match the strength of the wording to the Elbert Huang, MD, MPH, FACP the PPC members is to review and update strength of the evidence. A table linking Kathryn Evans Kreider, DNP, APRN, FNP-BC, the Standards of Care, they may also be the changes in recommendations to new BC-ADM involved in ADA statements, reports, and evidence can be reviewed online at profes- Christine G. Lee, MD, MS reviews. sional.diabetes.org/SOC. The Standards Nisa Maruthur, MD, MHS ’ The ADA adheres to the National Acad- of Care is approved by the ADA s Board Anne Peters, MD emy of Medicine Standards for Developing of Directors, which includes health care Maria Jose Redondo, MD, PhD, MPH Trustworthy Clinical Practice Guidelines. All professionals, scientists, and lay people. Jane Reusch, MD members of the PPC arerequired to disclose Feedback from the larger clinical com- Emily Weatherup, MS, RDN, CDE fl potential con icts of interest with industry munity was invaluable for the annual Jennifer Wyckoff, MD and other relevant organizations. These 2019 revision of the Standards of Care. Deborah Young-Hyman, PhD, CDE disclosures are discussed at theAmerican onset of Readers who wish to comment on the each Standards of Care revision meeting. 2020 Standards of Care are invited to do so American College of Members of the committee, their employ- at professional.diabetes.org/SOC. CardiologydDesignated ers, and their disclosed conflicts of interest The PPC thanks the following indi- Representatives (Section 10) are listed in “Disclosures: Standards of viduals who provided their expertise Sandeep Das, MD, MPH, FACC Medical Care in Diabetesd2020” (https:// in reviewing and/or consulting with Mikhail Kosiborod, MD, FACC doi.org/10.2337/dc20-SPPC). The ADA funds the committee: Nidhi Bansal, MD; Linda ADA Staff development of the Standards of Care A. Barbour, MD, MSPH, FACP; Florence Mindy Saraco, MHA (corresponding author: out of©2019 its general revenues and does not Brown, MD; Thomas Buchanan, MD; Linda [email protected]) use industry support for this purpose. A. DiMeglio, MD; Alison B. Evert, MS, Malaika I. Hill, MA For the current revision, PPC members RD, CDE; Hermes Flores, MD, PhD; Matthew P. Petersen systematically searched MEDLINE for Thomas W. Gardner, MD, MS; Rose Shamera Robinson, MPH, RDN human studies related to each section Gubitosi-Klug, MD, PhD; William C. Kenneth P. Moritsugu, MD, MPH, FACPM

© 2019 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for proﬁt, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license. S4 Diabetes Care Volume 43, Supplement 1, January 2020

Summary of Revisions: Standards of Medical Care in Diabetesd2020 Diabetes Care 2020;43(Suppl. 1):S4–S6 | https://doi.org/10.2337/dc20-SREV

GENERAL CHANGES autoimmune diabetes in adults is now Centers for Disease Control (CDC) Diabetes The field of diabetes care is rapidly chang- acknowledged. Prevention Impact Tool Kit. More infor- ing as new research, technology, and A new recommendation (2.8) was added mation was added on the risk reduction treatments that can improve the health regarding testing for prediabetes and/or certain groups experienced with metformin and well-being of people with diabetes type 2 diabetes for women with overuse,basedon15-yearfollow-updata continue to emerge. With annual up- weight or obesity and/or who have one from the Diabetes Prevention Program dates since 1989, the American Diabetes or more additional risk factors for dia- Outcomes Study. Association (ADA) has long been a leader betes who are planning a pregnancy. Association in producing guidelines that capture the Additional considerations were added Section 4. Comprehensive Medical most current state of the field. to the section “Cystic Fibrosis–Related Evaluation and Assessment of Although levels of evidence for several Diabetes” (CFRD) regarding the use of Comorbidities (https://doi.org/10.2337/dc20-S004) recommendations have been updated, A1C tests to detect CFRD. The autoimmune diseases recommen- these changes are not outlined below The 2020 Standards of Care includes dation (4.12) was modified, and a new where the clinical recommendation has a new section on “Pancreatic Diabetes or recommendation was added (4.13) with remained the same. That is, changes in Diabetes in the Context of Disease of autoimmune thyroid disease and celiac evidence level from, for example, E to C the Exocrine Pancreas” to describe this SUMMARY OF REVISIONS disease screening guidance differenti- are not noted below. The 2020 Standards form of diabetes and its diverse set of ated, and more information on the prev- of Care contains, in addition to many etiologies. Diabetesalence of and screening for these diseases minor changes that clarify recommenda- The “Gestational Diabetes Mellitus” has been added to the text. tions or reflect new evidence, the follow- (GDM) section was revised, and the Because infection with hepatitis C virus ing more substantive revisions. two-step approach for screening and diagnosing GDM no longer includes Na- is associated with a higher prevalence of SECTION CHANGES tional Diabetes Data Group criteria. type 2 diabetes, discussion was added regarding glucose metabolism and erad- Section 1. Improving Care and Section 3. Prevention or Delay of ication of hepatitis C virus infection. Promoting Health in Populations The title of the hearing impairment (https://doi.org/10.2337/dc20-S001) Type 2 Diabetes (https://doi.org/10.2337/dc20-S003) section was changed to “Sensory Impair- Additional information was included on On the basis of a new consensus report, ment,” and new information was added, the rising cost of medications, particu- “Nutrition Therapy for Adults With Di- including content on impairment of smell. larly insulin. Americanabetes or Prediabetes: A Consensus Evidence was updated in the section A new section “Migrant and Seasonal Report” (https://doi.org/10.2337/dci19- “Periodontal Disease.” Agricultural Workers” was added to dis- 0014), published in April 2019, the sec- The section “Psychosocial/Emotional cuss the challenges of managing type 2 tion “Nutrition” was updated and a new Disorders,” including anxiety disorders, de- diabetes specific to this group. recommendation (3.3) was added to rec- pression, disordered eating behavior, and Section 2. Classification and Diagnosis ognize that a variety of eating patterns are serious mental illness, was moved to Sec- of Diabetes acceptable for people with prediabetes. tion 5 “Facilitating Behavior Change and (https://doi.org/10.2337/dc20-S002) Additional resources and information Well-being to Improve Health Outcomes” The©2019 debate as to whether slowly pro- were added regarding the National Di- (https://doi.org/10.2337/dc20-S005), in gressive autoimmune diabetes with an abetes Prevention Program, Medicare order to combine it with existing psycho- adult onset should be termed latent Diabetes Prevention Programs, and the social guidance found in that section.

Section 5. Facilitating Behavior 2 inhibitors or glucagon-like peptide 1 New evidence and a recommendation Change and Well-being to Improve (GLP-1) receptor agonists in patients with (9.6) were added on early combination Health Outcomes cardiovascular disease meeting A1C goals therapy for type 2 diabetes to extend the (https://doi.org/10.2337/dc20-S005) for cardiovascular benefit. time to treatment failure based on find- The title of this section was previously A new recommendation (6.11) on ings from the VERIFY trial. “Lifestyle Management” and was changed screening patients who are taking med- FDA approval of oral semaglutide has to more appropriately emphasize how ef- ication that can lead to hypoglycemia for been included in the discussion of com- fective behavior management and psycho- hypoglycemia unawareness was introduced. bination therapies. logical well-being are foundational to Intranasal glucagon and glucagon so- Figure 9.1 has been revised to include achieving treatment goals for people lution for subcutaneous injection were the latest trial findings on GLP-1 receptor with diabetes. included in the section “Hypoglycemia” agonists and SGLT2 inhibitors. It now The section “Nutrition Therapy” was due to their recent approval by the U.S. suggests that these drugs should be con- updated to include guidance and evi- Food and Drug Administration (FDA). sidered for patients when atherosclerotic dence presented in “Nutrition Therapy This section was modified to include a cardiovascular disease (ASCVD), heart for Adults With Diabetes or Prediabetes: new discussion on the use of continuous failure, or chronic kidney disease pre- A Consensus Report” (https://doi.org/ glucose monitoring technology in hypo- dominates independent of A1C. 10.2337/dci19-0014), published in May glycemia prevention. Figure 9.2 has been simplified to more 2019. easily guide providers through intensifi- Because of the emerging evidence from Section 7. Diabetes Technology cation to injectable therapies. the CDC on deaths related to e-cigarettes, (https://doi.org/10.2337/dc20-S007) more information was added discourag- Thissectionwasreorganizedintothree SectionAssociation 10. Cardiovascular Disease ing their use. broad categories titled “Self-Monitoring of and Risk Management Recommendations and supporting Blood Glucose,”“Continuous Glucose Mon- (https://doi.org/10.2337/dc20-S010) evidence on anxiety disorders, depres- itors,” and “Insulin Delivery.” Within these This section is endorsed for the second sion, disordered eating behavior, and revised sections, emphasis has been made consecutive year by the American Col- serious mental illness previously found on how there is no “one-size-fits-all” lege of Cardiology. at the end of Section 4 were moved to approach to technology use in people Blood pressure targets for pregnant Section 5 and are included under “Psy- with diabetes. Due tothe rapidly changing patients with pre-existing hypertension have chosocial Issues.” More information field of diabetes technology, the recom- been changed in the interest of reducing the on psychosocial screening for social mendations in each category have been risk for accelerated maternal hypertension determinants of health and significant revised, and more evidence has been and minimizing fetal growth impairment. changes in life circumstances was also added to support theDiabetes recommendations Recommendations for statin treat- added. throughout. ment (primary and secondary prevention, 10.19–10.28) have been revised to min- Section 6. Glycemic Targets Section 8. Obesity Management for imize ASCVD risk and to align with the (https://doi.org/10.2337/dc20-S006) the Treatment of Type 2 Diabetes “2018 AHA/ACC/AACVPR/AAPA/ABC/ Based on the publication “Clinical Tar- (https://doi.org/10.2337/dc20-S008) ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA gets for Continuous Glucose Monitoring The body mass index (BMI) calculation Guideline on the Management of Blood Data Interpretation: Recommendations recommendation (8.1) was modified to Cholesterol: Executive Summary: A Report From the International Consensus on Time recommend annual BMI calculations of the American College of Cardiology/ in Range” (https://doi.org/10.2337/dci19- rather than at every patient encounter. American Heart Association Task Force 0028) published in June 2019, new recom- More discussion was added on how on Clinical Practice Guidelines” (https:// mendations (6.4 and 6.5) wereAmerican added on providers measure and record patient doi.org/10.1016/j.jacc.2018.11.002), use of the ambulatory glucose profile (AGP) weight, including recommendations on published in June 2019. report and time in range (TIR) for assess- how to manage these encounters to Discussion of REDUCE-IT was added to ment of glycemic management. A discus- maximize patient comfort and engage- the section “Treatment of Other Lipo- sion of AGP reports, time in range, and ment. Other considerationsdlike access protein Fractions or Targets,” and a new glucose management indicators follow the to food and individual’smotivation recommendation (10.31) was included new recommendations. An example of an leveldwere added to the section “Lifestyle on considering icosapent ethyl for re- AGP report was also added (Fig. 6.1). Interventions.” ducing cardiovascular risk. Table©2019 6.1 was replaced with a simpli- Recommendations for treatment of fied estimated average glucose table. Section 9. Pharmacologic Approaches cardiovascular disease (10.43a, 10.43b, More discussion on the importance of to Glycemic Treatment 10.43c) are now individualized based on reducing therapeutic inertia in the manage- (https://doi.org/10.2337/dc20-S009) patients’ existing ASCVD, risk of ASCVD, ment of hyperglycemia and cardiovascular A discussion was added on access to diabetic kidney disease, or heart failure. disease was included in the section “A1C analog insulins and how there are mul- Discussion of the trials CANVAS, CANVAS- and Cardiovascular Disease Outcomes.” tiple approaches to insulin treatment, Renal, CREDENCE, DECLARE-TIMI 58, Also new to “A1C and Cardiovascular with the goal of keeping patients safe REWIND, and CARMELINA were added Disease Outcomes” is the strategy to and avoiding diabetic ketoacidosis and to the section “Glucose-Lowering Ther- introduce sodium–glucose cotransporter significant hypo- or hyperglycemia. apies and Cardiovascular Outcomes.” S6 Summary of Revisions Diabetes Care Volume 43, Supplement 1, January 2020

The cardiovascular outcomes trials of Section 12. Older Adults Section 14. Management of Diabetes available antihyperglycemic medications (https://doi.org/10.2337/dc20-S012) in Pregnancy completed after the issuance of FDA 2008 Within the section “Neurocognitive (https://doi.org/10.2337/dc20-S0014) guidelines table (Table 10.3) has been Function,” more information was added Greater emphasis has been placed divided into three tables by drug class on the importance of assessment for on preconception care for women (Table 10.3A on DPP-4 Inhibitors; Table cognitive decline and impairment. with diabetes, and a recommendation 10.3B on GLP-1 receptor agonists; and A new recommendation (12.14) urg- (14.5) focusing on nutrition, diabetes Table 10.3C on SGLT2 inhibitors). ing providers to consider cost of care education, and screening for diabetes and insurance coverage when prescrib- related complications was added. A Section 11. Microvascular Complications ing medications to older adults to reduce new table (Table 14.1) was also added and Foot Care the risk of cost-related nonadherence on preconception education, medical (https://doi.org/10.2337/dc20-S011) was added to the section “Pharmacologic assessment, and screening. The recommendation on screening for Therapy.” The GLP-1 receptor agonist Recommendations (14.9–14.12) on chronic kidney disease (11.1) has been and SGLT2 inhibitor discussions were use of continuous glucose monitors modifiedtoincludetwice-yearlyscreenings expanded in this section as well. and measuring glycemia in pregnancy for certain patients. A treatment recom- A new section titled “Special Con- were added to the section “Glycemic mendation (11.3) was modified to provide siderations for Older Adults With Targets in Pregnancy” to provide more more detail on use of SGLT2 inhibitors and Type 1 Diabetes” was added to ad- information on their utility. GLP-1 receptor agonists in patients with dress the treatment of this growing Further discussion has been added type 2 diabetes and diabetic kidney disease. population. regarding when insulin may not be A new recommendation (11.5) was added anAssociation option for some women with GDM, about avoiding discontinuation of RAS Section 13. Children and Adolescents and how oral agents may play a role in blockade in response to minor increases (https://doi.org/10.2337/dc20-S013) treatment in certain circumstances. in serum creatinine in the absence of To provide more detail for individual- The section “Postpartum Care” was volume depletion. izing targets, new A1C goal recommen- expanded to include recommenda- Additional information on acute kidney dations (13.21–13.24) were added to the tions (14.16–14.22) and supporting injury was added to the section “Chronic section “Glycemic Control.” evidence on postpartum insulin re- Kidney Disease,” with information on in- In the section “Management of Cardio- quirements, management of women creased serum creatinine levels. vascular Risk Factors,” the recommenda- with a history of GDM and risks of More findings were added from the tions for screening and treatment of type 2 diabetes, and psychosocial CREDENCE trial. hypertension (13.31–13.35) have been assessment. Screening for diabetic retinopathy rec- revised and includeDiabetes new criteria for ele- ommendations (11.16 and 11.17) and vated blood pressure. The dyslipidemia Section 15. Diabetes Care in the supportive text were revised to include testing recommendation (13.36) was Hospital consideration of retinal photograph with also modified, and more evidence was (https://doi.org/10.2337/dc20-S0015) remote reading or use of a validated as- added to the dyslipidemia screening Discussion of new studies supporting sessment tool as a way to improve screen- section. the use of closed-loop insulin delivery ing access. The retinopathy screening recommen- with linked pump/sensor devices to The section “Foot Care” was updated dation for type 1 diabetes (13.46) has been control blood glucose was added to with more evidence on therapeutic revised based on new evidence supporting thetype1diabetessection“Transi- footwear and evaluation for peripheral a lower frequency of eye examinations tioning Intravenous to Subcutaneous arterial disease. than previously recommended. Insulin.” Figure 11.1 was introducedAmerican (in place of A new recommendation (13.67) was New evidence was also added to 2019 Table 11.1dCKD Stages and Cor- addedtothesection“Pharmacologic Man- the section “Preventing Admissions and responding Focus of Kidney-Related agement” for type 2 diabetes due to new Readmissions.” Care) to show the risk of chronic kidney evidenceandFDAapproval ofliraglutidein disease progression, frequency of visits, children 10 years of age or older. Section 16. Diabetes Advocacy and referral to nephrology according to A new recommendation (13.76) on (https://doi.org/10.2337/dc20-S016) estimated glomerular filtration rate and pharmacologic treatment of hyperten- No changes have been made to this albuminuria.©2019 sion in type 2 diabetes was also added. section. Diabetes Care Volume 43, Supplement 1, January 2020 S7

1. Improving Care and Promoting American Diabetes Association Health in Populations: Standards of Medical Care in Diabetesd2020

Diabetes Care 2020;43(Suppl. 1):S7–S13 | https://doi.org/10.2337/dc20-S001

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes” includes the ADA’s current clinical practice recommendations and is intended to provide HEALTH PROMOTING AND CARE IMPROVING 1. the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Association Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc20- SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi .org/10.2337/dc20-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC. DIABETES AND POPULATION HEALTH Diabetes Recommendations 1.1 Ensure treatment decisions are timely, rely on evidence-based guidelines, and are made collaboratively with patients based on individual preferences, prognoses, and comorbidities. B 1.2 Align approaches to diabetes management with the Chronic Care Model. This model emphasizes person-centered team care, integrated long-term treatment approaches to diabetes and comorbidities, and ongoing collaborative communication and goal setting between all team members. A 1.3 Care systems should facilitate team-based care and utilization of patient registries, decision support tools, and community involvement to meet patient needs. B American 1.4 Assess diabetes health care maintenance (see Table 4.1) using reliable and relevant data metrics to improve processes of care and health outcomes, with simultaneous emphasis on care costs. B

Population health is defined as “the health outcomes of a group of individuals, including the distribution of health outcomes within the group”; these outcomes can bemeasured in termsof health outcomes(mortality, morbidity, health, and functional status),©2019 disease burden (incidence and prevalence), and behavioral and metabolic factors (exercise, diet, A1C, etc.) (1). Clinical practice recommendations for health care Suggested citation: American Diabetes Association. providers are tools that can ultimately improve health across populations; however, 1. Improving care and promoting health in pop- foroptimal outcomes, diabetes caremustalsobeindividualized foreach patient.Thus, ulations: Standards of Medical Care in Diabetesd efforts to improve population health will require a combination of system-level and 2020. Diabetes Care 2020;43(Suppl. 1):S7–S13 patient-level approaches. With such an integrated approach in mind, the American © 2019 by the American Diabetes Association. Diabetes Association (ADA) highlights the importance of patient-centered care, Readers may use this article as long as the work fi is properly cited, the use is educational and not de ned as care that considers individual patient comorbidities and prognoses; is for profit, and the work is not altered. More infor- respectful of and responsive to patient preferences, needs, and values; and ensures mation is available at http://www.diabetesjournals that patient values guide all clinical decisions (2). Clinical practice recommendations, .org/content/license. S8 Improving Care and Promoting Health Diabetes Care Volume 43, Supplement 1, January 2020

whether based on evidence or expert Chronic Care Model diabetes care delivery, including oppor- opinion, are intended to guide an overall Numerous interventions to improve ad- tunities and challenges (15). approach to care. The science and art of herence to the recommended standards Strategies for System-Level Improvement medicine come together when the clinician have been implemented. However, a Optimal diabetes management requires is faced with making treatment recommen- major barrier to optimal care is a delivery an organized, systematic approach and dations for a patient who may not meet the system that is often fragmented, lacks the involvement of a coordinated team eligibility criteria used in the studies on clinical information capabilities, dupli- of dedicated health care professionals which guidelines are based. Recognizing cates services, and is poorly designed working in an environment where that one size does not fit all, the standards for the coordinated delivery of chronic patient-centered high-quality care is a presented here provide guidance for when care. The Chronic Care Model (CCM) priority (6,16,17). While many diabetes and how to adapt recommendations for an takes these factors into consideration processes of care have improved nation- individual. and is an effective framework for improving the quality of diabetes care (8). ally in the past decade, the overall quality ofcare forpatients withdiabetes remains Care Delivery Systems Six Core Elements. The CCM includes six suboptimal (3). Efforts to increase the The proportion of patients with diabetes core elements to optimize the care of quality of diabetes care include provid- who achieve recommended A1C, blood patients with chronic disease: ing care that is concordant with evidence- pressure, and LDL cholesterol levels has based guidelines (18); expanding the remained stagnant in recent years (3). In 1. Delivery system design (moving from a role of teams to implement more in- 2013–2016, 64% of adults with diag- reactive to a proactive care delivery tensive disease management strategies nosed diabetes met individualized A1C system where planned visits are coordi- (6,19,20); tracking medication-taking be- target levels, 70% achieved recommen- nated through a team-based approach) haviorAssociation at a systems level (21); redesigning ded blood pressure control, 57% met the 2. Self-management support the organization of the care process LDL cholesterol target level, and 85% 3. Decision support (basing care on (22); implementing electronic health record were nonsmokers (3). Only 23% met evidence-based, effective care guide- tools (23,24); empowering and educating targets for glycemic, blood pressure, lines) patients (25,26); removing financial bar- and cholesterol measures while also 4. Clinical information systems (using reg- riers and reducing patient out-of-pocket avoiding smoking (3). The mean A1C fi istries that can provide patient-speci c costs for diabetes education, eye exams, nationally among people with diabetes and population-based support to the diabetes technology, and necessary med- increased slightly from 7.3% in 2005– care team) ications (6); assessing and addressing psy- 2008 to 7.5% in 2013–2016 based on the 5. Community resources and policies chosocial issues (27,28); and identifying, National Health and Nutrition Examina- (identifying or developing resources developing, and engaging community re- tion Survey (NHANES), with younger Diabetes to support healthy lifestyles) sources and public policies that support adults, women, and non-Hispanic black 6. Health systems (to create a quality- healthy lifestyles (29). The National Di- individuals less likely to meet treatment oriented culture) abetes Education Program maintains an targets (3). Certain segments of the pop- online resource (www.betterdiabetescare ulation, such as young adults and patients A 5-year effectiveness study of the CCM .nih.gov)tohelphealthcareprofessionals with complex comorbidities, financial or in 53,436 primary care patients with design and implement more effective other social hardships, and/or limited type 2 diabetes suggested that the use health care delivery systems for those English proficiency, face particular chal- of this model of care delivery reduced the with diabetes. lenges to goal-based care (4–6). Even cumulative incidence of diabetes-related after adjusting for these patient factors, complications and all-cause mortality (9). Care Teams the persistent variability in the quality of Patients who were enrolled in the CCM The care team, which centers around the diabetes care across providersAmerican and prac- experienced a reduction in cardiovascu- patient, should avoid therapeutic inertia tice settings indicates that substantial lar disease (CVD) risk by 56.6%, micro- and prioritize timely and appropriate system-level improvements are still vascular complications by 11.9%, and intensification of lifestyle and/or phar- needed. mortality by 66.1% (9). The same study macologic therapy for patients who have Diabetes poses a significant financial suggested that health care utilization was not achieved the recommended meta- burden to individuals and society. It is lower in the CCM group, resulting in bolictargets(30–32).Strategiesshownto estimated that the annual cost of diag- health care savings of $7,294 per indi- improve care team behavior and thereby nosed diabetes in 2017 was $327 billion, vidual over the study period (10). catalyze reductions in A1C, blood pres- including©2019 $237 billion in direct medical Redefining the roles of the health care sure, and/or LDL cholesterol include en- costs and $90 billion in reduced produc- delivery team and empowering patient gaging in explicit and collaborative goal tivity. After adjusting for inflation, eco- self-management are fundamental to the setting with patients (33,34); identifying nomic costs of diabetes increased by 26% successful implementation of the CCM (11). and addressing language, numeracy, or from 2012 to 2017 (7). This is attributed to Collaborative, multidisciplinary teams are cultural barriers to care (35–37); inte- the increased prevalence of diabetes and best suited to provide care for people with grating evidence-based guidelines and the increased cost per person with di- chronic conditions such as diabetes and clinical information tools into the process abetes. Ongoing population health strat- to facilitate patients’ self-management of care (18,38,39); soliciting performance egies are needed in order to reduce costs (12–14). There are references to guide feedback, setting reminders, and provid- and provide optimized care. the implementation of the CCM into ing structured care (e.g., guidelines, care.diabetesjournals.org Improving Care and Promoting Health S9

formal case management, and patient patients who are prescribed insulin report and the use of accurate, reliable data education resources) (6); and incorporat- cost-related insulin underuse (47). The cost metrics that include sociodemographic ing care management teams including of insulin has continued to increase in variables to examine health equity within nurses, dietitians, pharmacists, and other recent years for reasons that are not and across populations (59). providers (19,40). Initiatives such as the entirely clear. There are recommenda- In addition to quality improvement Patient-Centered Medical Home show tions from the ADA Insulin Access efforts, other strategies that simulta- promise for improving health outcomes and Affordability Working Group for ap- neously improve the quality of care and by fostering comprehensive primary care proaches to this issue from a systems potentially reduce costs are gaining mo- and offering new opportunities for team- level. Recommendations including concepts mentum and include reimbursement based chronic disease management (41). such as cost-sharing for insured people structures that, in contrast to visit-based with diabetes should be based on the billing, reward the provision of appropriate Telemedicine lowest priceavailable,list pricefor insulins and high-quality care to achieve metabolic fi Telemedicine is a growing eld that may that closely reflect net price, and health goals (60) and incentives that accommo- increase access to care for patients with plans that ensure that people with di- date personalized care goals (6,61). fi diabetes. Telemedicine is de ned as the abetes can access insulin without undue use of telecommunications to facilitate administrative burden or excessive cost remote delivery of health-related serv- (48). TAILORING TREATMENT FOR ices and clinical information (42). A grow- SOCIAL CONTEXT Access to Care and Quality Improvement ing body of evidence suggests that Recommendations The Affordable Care Act has resulted in various telemedicine modalities may 1.5 Providers should assess social con- increased access to care for many indi- be effective at reducing A1C in patients text, including potential food in- viduals with diabetes with an emphasis Association with type 2 diabetes compared with security, housing stability, and on the protection of people with preex- usual care or in addition to usual care financial barriers, and apply that isting conditions, health promotion, and (43). For rural populations or those with informationtotreatmentdeci- disease prevention (49). In fact, health limited physical access to health care, sions. A insurance coverage increased from 84.7% telemedicine has a growing body of 1.6 Refer patients to local commu- in 2009 to 90.1% in 2016 for adults with evidence for its effectiveness, particu- nity resources when available. B – larly with regard to glycemic control as diabetes aged 18 64 years. Coverage for 1.7 Provide patients with self- – $ measured by A1C (44 46). Interactive those 65 years remained near universal management support from lay strategies that facilitate communication (50). Patients who have either private or health coaches, navigators, or between providers and patients, includ- public insurance coverage are more likely community health workers when ing the use of web-based portals or text to meet quality indicatorsDiabetes for diabetes care available. A messaging and those that incorporate (51). As mandated by the Affordable Care medication adjustment, appear more Act, the Agency for Healthcare Research and Health inequities related to diabetes and effective. There is limited data avail- Quality developed a National Quality Strat- its complications are well documented able on the cost-effectiveness of these egy based on the triple aims that include and are heavily influenced by social de- strategies. improving the health of a population, terminants of health (62–66). Social de- overall quality and patient experience of Behaviors and Well-being terminants of health are defined as the care, and per capita cost (52,53). As health Successful diabetes care also requires economic, environmental, political, and care systems and practices adapt to the a systematic approach to supporting social conditions in which people live and changing landscape of health care, it will be patients’ behavior change efforts. High- are responsible for a major part of health important to integrate traditional disease- quality diabetes self-management ed- inequality worldwide (67). The ADA rec- specific metrics with measures of patient ucation and support (DSMES)American has ognizes the association between social experience, as well as cost, in assessing the been shown to improve patient self- and environmental factors and the pre- quality of diabetes care (54,55). Informa- management, satisfaction, and glucose vention and treatment of diabetes and tion and guidance specifictoqualityim- outcomes. National DSMES standards has issued a call for research that seeks to provement and practice transformation for call for an integrated approach that in- better understand how these social de- diabetes care is available from the National fl cludes clinical content and skills, behav- terminants in uence behaviors and how DiabetesEducationProgrampracticetrans- ioral strategies (goal setting, problem the relationships between these varia- fi solving), and engagement with psycho- formation website and the National In- bles might be modi ed for the preven- social©2019 concerns (28). For more informa- stitute of Diabetes and Digestive and tion and management of diabetes (68). tion on DSMES, see Section 5 “Facilitating Kidney Diseases report on diabetes care While a comprehensive strategy to re- Behavior Change and Well-being to Im- and quality (56,57). Using patient registries duce diabetes-related health inequities prove Health Outcomes” (https://doi and electronic health records, health sys- in populations has not been formally stud- .org/10.2337/dc20-S005). tems can evaluate the quality of diabetes ied, general recommendations from other care being delivered and perform inter- chronic disease models can be drawn upon Cost Considerations vention cycles as part of quality improve- to inform systems-level strategies in di- The cost of diabetes medications, partic- ment strategies (58). Critical to these abetes. For example, the National Academy ularly insulin, is an ongoing barrier to efforts is provider adherence to clinical of Medicine has published a framework for achieving glycemic goals. Up to 25% of practice recommendations (see Table 4.1) educating health care professionals on the S10 Improving Care and Promoting Health Diabetes Care Volume 43, Supplement 1, January 2020

importance of social determinants of health with low adherence to taking medica- are homeless need secure places to keep (69). Furthermore, there are resources tions appropriately and recommended their diabetes supplies, as well as re- available for the inclusion of standardized self-care behaviors, depression, diabetes frigerator access to properly store their sociodemographic variables in electronic distress, and worse glycemic control insulin and take it on a regular schedule. medical records to facilitate the measure- when compared with individuals who Risk for homelessness can be ascertained ment of health inequities as well as the are food secure (78,79). Older adults using a brief risk assessment tool de- impact of interventions designed to re- with food insecurity are more likely to veloped and validated for use among duce those inequities (70–72). have emergency department visits and veterans (85). Given the potential chal- Social determinants of health are not hospitalizations compared with older lenges, providers who care for homeless always recognized and often go undis- adults who do not report food insecurity individuals should be familiar with re- cussed in the clinical encounter (65). A (80). Risk for food insecurity can be sources or have access to social workers studyby Pietteet al.(73)found thatamong assessed with a validated two-item that can facilitate temporary housing for patients with chronic illnesses, two-thirds screening tool (81) that includes the their patients as a way to improve di- of those who reported not taking medi- statements:1)“Withinthepast12months abetes care. cations as prescribed due to cost never we worried whether our food would run shared this with their physician. In a study out before we got money to buy more” Migrant and Seasonal Agricultural using data from the National Health In- and 2) “Within the past 12 months the Workers terview Survey (NHIS), Patel et al. (65) food we bought just didn’tlastandwe Migrant and seasonal agricultural workers found that one-half of adults with diabetes didn’t have money to get more.” An may have a higher risk of type 2 diabetes reported financial stress and one-fifth affirmative response to either statement than the overall population. While mi- reported food insecurity. One population had a sensitivity of 97% and specificity of grantAssociation farmworker-specific data are lack- in which such issues must be considered is 83%. ing, most agricultural workers in the U.S. older adults, where social difficulties may are Latino, a population with a high rate of Treatment Considerations impair the quality of life and increase the type 2 diabetes. Living in severe poverty In those with diabetes and food insecu- risk of functional dependency (74) (see brings with it food insecurity, high chronic rity, the priority is mitigating the increased Section 12 “Older Adults,” https://doi.org/ stress, and increased risk of diabetes; risk for uncontrolled hyperglycemia and 10.2337/dc20-S012, for a detailed discus- there is also an association between severe hypoglycemia. Reasons for the sion of social considerations in older the use of certain pesticides and the increased risk of hyperglycemia include adults). Creating systems-level mecha- incidence of diabetes (85a). the steady consumption of inexpensive nisms to screen for social determinants Data from the Department of Labor carbohydrate-rich processed foods, binge of health may help overcome structural indicates that there are 2.5–3 million eating, financialDiabetes constraints to filling di- barriers and communication gaps be- agricultural workersintheU.S.,andthese abetes medication prescriptions, and tween patients and providers (65,75). agricultural workers travel throughout anxiety/depression leading to poor di- In addition, brief, validated screening the country serving as the backbone abetes self-care behaviors. Hypoglyce- tools for some social determinants of for a multibillion-dollar agricultural in- mia can occur as a result of inadequate health exist and could facilitate discussion dustry. According to 2018 health center or erratic carbohydrate consumption around factors that significantly impact data, 174 health centers across the U.S. following the administration of sulfony- treatment during the clinical encounter. reported that they provided health care lureas or insulin. See Table 9.1 for drug- Below is a discussion of assessment and services to 579,806 adult agricultural specific and patient factors, including treatment considerations in the context patients, and 78,332 had encounters of food insecurity, homelessness, and lim- cost and risk of hypoglycemia, for the for diabetes (13.5%) (86). ited English proficiency/low literacy. treatment options for adults with food Migrant farmworkers encounter nu- Americaninsecurityand type2 diabetes.Providers merous and overlapping barriers to re- Food Insecurity should consider these factors when mak- ceiving care. Migration, which may occur Food insecurity is the unreliable avail- ing treatment decisions in people with as frequently as every few weeks for ability of nutritious food and the inability food insecurity and seek local resources farmworkers, disrupts care. Cultural to consistently obtain food without re- that might help patients with diabetes and and linguistic barriers, lack of transpor- sorting to socially unacceptable practi- their family members to more regularly tation and money, lack of available work ces. Over 18% of the U.S. population obtain nutritious food (82). hours, unfamiliarity with new communi- reported food insecurity between 2005– ties,lackofaccess toresources, and other 2014©2019 (76). The rate is higher in some Homelessness barriers prevent migrant farmworkers racial/ethnic minority groups, including Homelessness often accompanies many from accessing health care. Without reg- African American and Latino popula- additional barriers to diabetes self- ular care, those with diabetes may suffer tions, low-income households, and homes management, including food insecurity, severe and often expensive complica- headed by a single mother. The rate of literacy and numeracy deficiencies, lack tions that affect quality of life. food insecurity in individuals with dia- of insurance, cognitive dysfunction, Health care providers should be attuned betes may be up to 20% (77). Addition- and mental health issues (83). The prev- to the working and living conditions of all ally, the risk for type 2 diabetes is alence of diabetes in the homeless pop- patients. If a migrant farmworker with increased twofold in those with food ulation is estimated to be around 8% (84). diabetes presents for care, appropriate insecurity (68) and has been associated Additionally, patients with diabetes who referrals should be initiated to social care.diabetesjournals.org Improving Care and Promoting Health S11

workers and community resources, as Intern Med. 12 August 2019 [Epub ahead of print] a large-scale hypertension program. JAMA 2013; available, to assist with removing barriers DOI: 10.1001/jamainternmed.2019.2396 310:699–705 to care. 4. Kerr EA, Heisler M, Krein SL, et al. Beyond 20. Peikes D, Chen A, Schore J, Brown R. Effects comorbidity counts: how do comorbidity type of care coordination on hospitalization, quality of and severity influence diabetes patients’ treat- care, and health care expenditures among Medi- Language Barriers ment priorities and self-management? J Gen care beneficiaries: 15 randomized trials. JAMA Providers who care for non-English speakers Intern Med 2007;22:1635–1640 2009;301:603–618 should develop or offer educational pro- 5. Fernandez A, Schillinger D, Warton EM, et al. 21. Raebel MA, Schmittdiel J, Karter AJ, grams and materials in multiple languages Language barriers, physician-patient language Konieczny JL, Steiner JF. Standardizing terminol- fi with the specific goals of preventing di- concordance, and glycemic control among in- ogy and de nitions of medication adherence and sured Latinos with diabetes: the Diabetes Study persistence in research employing electronic abetes and building diabetes awareness in of Northern California (DISTANCE). J Gen Intern databases. Med Care 2013;51(Suppl. 3):S11–S21 people who cannot easily read or write in Med 2011;26:170–176 22. Feifer C, Nemeth L, Nietert PJ, et al. Different English. The National Standards for Cultur- 6. TRIAD Study Group. Health systems, patients paths to high-quality care: three archetypes of ally and Linguistically Appropriate Services factors, and quality of care for diabetes: a syn- top-performing practice sites. Ann Fam Med in Health and Health Care (National CLAS thesis of findings from the TRIAD study. Diabetes 2007;5:233–241 – Standards) provide guidance on how health Care 2010;33:940 947 23. Reed M, Huang J, Graetz I, et al. Outpatient 7. American Diabetes Association. Economic electronic health recordsandthe clinicalcareand care providers can reduce language barriers costs of diabetes in the U.S. in 2017. Diabetes outcomes of patients with diabetes mellitus. Ann by improving their cultural competency, Care 2018;41:917–928 Intern Med 2012;157:482–489 addressing health literacy, and ensuring 8. Stellefson M, Dipnarine K, Stopka C. The 24. Cebul RD, Love TE, Jain AK, Hebert CJ. communication with language assistance chronic care model and diabetes management Electronic health records and quality of diabetes – (87). The National CLAS Standards website in US primary care settings: a systematic review. care. N Engl J Med 2011;365:825 833 Prev Chronic Dis 2013;10:E26 25. Battersby M, Von Korff M, Schaefer J, et al. offers a number of resources and ma- 9. Wan EYF, Fung CSC, Jiao FF, et al. Five-year Twelve evidence-basedAssociation principles for implement- terials that can be used to improve the effectiveness of the multidisciplinary Risk Assess- ing self-management support in primary care. Jt qualityofcaredeliverytonon-English- ment and Management Programme-Diabetes Comm J Qual Patient Saf 2010;36:561–570 speaking patients (87). Mellitus (RAMP-DM) on diabetes-related compli- 26. GrantRW,WaldJS, Schnipper JL, etal.Practice- cations and health service uses-a population-based linked online personal health records for type 2 Community Support and propensity-matched cohort study. Diabetes diabetes mellitus: a randomized controlled trial. – – Identification or development of com- Care 2018;41:49 59 Arch Intern Med 2008;168:1776 1782 10. Jiao FF, Fung CSC, Wan EYF, et al. Five-year 27. Young-Hyman D, de Groot M, Hill-Briggs F, munity resources to support healthy life- cost-effectiveness of the multidisciplinary Risk Gonzalez JS, Hood K, Peyrot M. Psychosocial care styles is a core element of the CCM (8). Assessment and Management Programme-Diabe- for people with diabetes: a position statement of Health care community linkages are tes Mellitus (RAMP-DM). Diabetes Care 2018;41: the American Diabetes Association. Diabetes receiving increasing attention from the 250–257 Care 2016;39:2126–2140 American Medical Association, the 11. Coleman K, AustinDiabetes BT, Brach C, Wagner EH. 28. Beck J, Greenwood DA, Blanton L, et al.; 2017 Evidence on the Chronic Care Model in the new Standards Revision Task Force. 2017 National Agency for Healthcare Research and millennium. Health Aff (Millwood) 2009;28:75–85 standards for diabetes self-management education Quality, and others as a means of pro- 12. Piatt GA, Anderson RM, Brooks MM, et al. 3- and support. Diabetes Care 2017;40:1409–1419 moting translation of clinical recommen- Year follow-up of clinical and behavioral im- 29. Pullen-Smith B, Carter-Edwards L, Leathers dations for lifestyle modification in provements following a multifaceted diabetes KH. Community health ambassadors: a model for real-world settings (88). Community health care intervention: results of a randomized con- engaging community leaders to promote better trolled trial. Diabetes Educ 2010;36:301–309 health in North Carolina. J Public Health Manag workers (CHWs) (89), peer supporters – – 13.KatonWJ,LinEHB,VonKorffM,etal.Col- Pract 2008;14(Suppl.):S73 S81 (90 92), and lay leaders (93) may assist laborative care for patients with depression and 30. Davidson MB. How our current medical care in the delivery of DSMES services (70,94), chronic illnesses. N Engl J Med 2010;363:2611– system fails people with diabetes: lack of timely, particularly in underserved communities. 2620 appropriate clinical decisions. Diabetes Care ACHWisdefined by the American Public 14. Parchman ML, Zeber JE, Romero RR, Pugh JA. 2009;32:370–372 Health Association as a “frontlineAmerican public Risk of coronary artery disease in type 2 diabetes 31. Selby JV, Uratsu CS, Fireman B, et al. Treat- and the delivery of care consistent with the ment intensification and risk factor control: to- health worker who is a trusted member of chronic care model in primary care settings: ward more clinically relevant quality measures. and/or has an unusually close understand- a STARNet study. Med Care 2007;45:1129–1134 Med Care 2009;47:395–402 ing of the community served” (95). CHWs 15. Del Valle KL, McDonnell ME. Chronic care 32. Raebel MA, Ellis JL, Schroeder EB, et al. can be part of a cost-effective, evidence- management services for complex diabetes man- Intensification of antihyperglycemic therapy basedstrategytoimprovethemanage- agement: a practical overview. Curr Diab Rep among patients with incident diabetes: a Surveil- lance Prevention and Management of Diabetes ment of diabetes and cardiovascular risk 2018;18:135 16.TriccoAC,IversNM,GrimshawJM,etal. Mellitus (SUPREME-DM) study. Pharmacoepide- factors in underserved communities and Effectiveness of quality improvement strategies miol Drug Saf 2014;23:699–710 health©2019 care systems (96). onthemanagementofdiabetes:asystematicreview 33. Grant RW, Pabon-Nau L, Ross KM, Youatt EJ, and meta-analysis. Lancet 2012;379:2252–2261 Pandiscio JC, Park ER. Diabetes oral medication References 17. Schmittdiel JA, Gopalan A, Lin MW, Banerjee initiation and intensification: patient views com- 1. Kindig D, Stoddart G. What is population S, Chau CV, Adams AS. Population health man- pared with current treatment guidelines. Diabe- health? Am J Public Health 2003;93:380–383 agement for diabetes: health care system-level tes Educ 2011;37:78–84 2. Institute of Medicine. Crossing the Quality approaches for improving quality and addressing 34. Tamhane S, Rodriguez-GutierrezR, Hargraves I, Chasm: A New Health System forthe 21st Century. disparities. Curr Diab Rep 2017;17:31 Montori VM. Shared decision-making in diabetes Washington, DC. The National Academies Press, 18. O’Connor PJ, Bodkin NL, Fradkin J, et al. Di- care. Curr Diab Rep 2015;15:112 2001 (https://doi.org/10.17226/10027) abetes performance measures: current status and 35. Schillinger D, Piette J, Grumbach K, et al. 3. Kazemian P, Shebl FM, McCann N, Walensky future directions. Diabetes Care 2011;34:1651–1659 Closing the loop: physician communication with RP, Wexler DJ. Evaluation of the cascade of di- 19. Jaffe MG, Lee GA, Young JD, Sidney S, Go AS. diabetic patients who have low health literacy. abetes care inthe UnitedStates,2005-2016. JAMA Improved blood pressure control associated with Arch Intern Med 2003;163:83–90 S12 Improving Care and Promoting Health Diabetes Care Volume 43, Supplement 1, January 2020

36. Rosal MC, Ockene IS, Restrepo A, et al. 52. Stiefel M, Nolan K. Measuring the triple 67. Commission on Social Determinants of Randomized trialof aliteracy-sensitive, culturally aim: a call for action. Popul Health Manag Health. Closing the gap in a generation: health tailored diabetes self-management intervention 2013;16:219–220 equity through action on the social determinants for low-income Latinos: Latinos en control. Di- 53. Agency for Healthcare Research & Quality. of health. Geneva, World Health Organiza- abetes Care 2011;34:838–844 About the National Quality Strategy, [Internet], tion. Available from: http://www.who.int/social_ 37. Osborn CY, Cavanaugh K, Wallston KA, et al. 2017. Available from: https://www.ahrq.gov/ determinants/final_report/csdh_finalreport_2008. Health literacy explains racial disparities in di- workingforquality/about/index.html. Accessed pdf. Accessed 25 October 2019 abetes medication adherence. J Health Commun 25 October 2019 68. Hill JO, Galloway JM, Goley A, et al. Socio- 2011;16(Suppl. 3):268–278 54. National Quality Forum. Homepage [Internet], ecological determinants of prediabetes and type 2 38. Garg AX, Adhikari NKJ, McDonald H, et al. 2017. Available from: http://www.qualityforum diabetes. Diabetes Care 2013;36:2430–2439 Effects of computerized clinical decision support .org/Home.aspx. Accessed 25 October 2019 69. National Academies of Sciences, Engineering, systemson practitionerperformance and patient 55. Burstin H, Johnson K. Getting to Better Care and Medicine. A Framework for Educating Health outcomes: a systematic review. JAMA 2005;293: and Outcomes forDiabetes Through Measurement. Professionals to Address the Social Determinants of 1223–1238 Evidence-Based Diabetes Management [Internet], Health. Washington, DC. The National Academies 39. Smith SA, Shah ND, Bryant SC, et al.; Evidens 2016. Available from: http://www.ajmc.com/ Press, 2016 (https://doi.org/10.17226/21923) Research Group. Chronic care model and shared journals/evidence-based-diabetes-management/ 70. National Academies of Sciences, Engineer- carein diabetes: randomized trial of an electronic 2016/march-2016/getting-to-better-care-and- ing, and Medicine. A Framework for Educating decision support system. Mayo Clin Proc 2008; outcomes-for-diabetes-through-measurement. Health Professionals to Address the Social De- 83:747–757 Accessed 25 October 2019 terminants of Health. Washington, DC. The Na- 40. Stone RA, Rao RH, Sevick MA, et al. Active 56. Practice Transformation [Internet], 2017. tional Academies Press, 2016 (https://doi.org/10 care management supported by home telemo- Available from: https://www.niddk.nih.gov/health- .17226/21923) nitoring in veterans with type 2 diabetes: the information/health-communication-programs/ndep/ 71. Chin MH, Clarke AR, Nocon RS, et al. A DiaTelrandomizedcontrolledtrial.DiabetesCare health-care-professionals/practice-transformation/ roadmap and best practices for organizations 2010;33:478–484 Pages/resourcedetail.aspx. Accessed 25 October to reduce racial and ethnic disparities in 41. Bojadzievski T, Gabbay RA. Patient-centered 2019 healthAssociation care. J Gen Intern Med 2012;27: medical home and diabetes. Diabetes Care 2011; 57. Diabetes Care and Quality: Past, Present, 992–1000 34:1047–1053 and Future [Internet], 2017. Available from: 72. National Quality Forum. National Voluntary 42. American Telemedicine Association. About https://www.niddk.nih.gov/health-information/ Consensus Standards for Ambulatory Cared Telehealth [Internet], 2018.. Available from: health-communication-programs/ndep/health- Measuring Healthcare Disparities [Internet], 2008. http://www.americantelemed.org/main/about/ care-professionals/practice-transformation/defining- Available from: https://www.qualityforum.org/ about-telemedicine/telemedicine-faqs. Accessed quality-care/diabetes-care-quality/Pages/default Publications/2008/03/National_Voluntary_Consensus_ 25 October 2019 .aspx. Accessed 25 October 2019 Standards_for_Ambulatory_Care%E2%80% 43. Lee SWH,Chan CKY, ChuaSS, Chaiyakunapruk 58. O’Connor PJ, Sperl-Hillen JM, Fazio CJ, Averbeck 94Measuring_Healthcare_Disparities.aspx. N. Comparative effectiveness of telemedicine BM, Rank BH, Margolis KL. Outpatient diabetes Accessed 25 October 2019 strategies on type 2 diabetes management: a sys- clinical decision support: current status and future 73. Piette JD, Heisler M, Wagner TH. Cost- tematicreviewandnetworkmeta-analysis.SciRep directions. Diabet Med 2016;33:734–741 related medication underuse among chronically 2017;7:12680 59. Centers for Medicare & Medicaid Services.. ill adults: the treatments people forgo, how 44. Faruque LI, Wiebe N, Ehteshami-Afshar A, CMS Equity Plan forDiabetes Medicare [Internet], 2017. often, and who is at risk. Am J Public Health et al.; Alberta Kidney Disease Network. Effect of Available from: https://www.cms.gov/About- 2004;94:1782–1787 telemedicine on glycated hemoglobin in diabetes: CMS/Agency-Information/OMH/equity-initiatives/ 74. Laiteerapong N, Karter AJ, Liu JY, et al. a systematic review and meta-analysis of ran- equity-plan.html. Accessed 25 October 2019 Correlates of quality of life in older adults domized trials. CMAJ 2017;189:E341–E364 60. Rosenthal MB, Cutler DM, Feder J. The ACO with diabetes: the Diabetes & Aging Study. Di- 45. Marcolino MS, Maia JX, Alkmim MBM, rules–striking the balance between participation abetes Care 2011;34:1749–1753 Boersma E, Ribeiro AL. Telemedicine applica- and transformative potential. N Engl J Med 2011; 75. O’GurekDT, HenkeC.A practicalapproachto tion in the care of diabetes patients: systematic 365:e6 screening for social determinants of health. Fam review and meta-analysis. PLoS One 2013;8: 61. Washington AE, Lipstein SH. The Patient- Pract Manag 2018;25:7–12 e79246 Centered Outcomes Research Institutedpromoting 76. Walker RJ, Grusnick J, Garacci E, Mendez C, 46. Heitkemper EM, Mamykina L, Travers J, better information, decisions, and health. N Engl J Egede LE. Trends in food insecurity in the USA for Smaldone A. Do health information technology Med 2011;365:e31 individuals with prediabetes, undiagnosed di- self-management interventions improve glycemic 62. Hutchinson RN, Shin S. Systematic review of abetes, and diagnosed diabetes. J Gen Intern control in medically underservedAmerican adults with di- health disparities for cardiovascular diseases and Med 2019;34:33–35 abetes? A systematic review and meta-analysis. J associated factors among American Indian and 77. Berkowitz SA, Karter AJ, Corbie-Smith G, et al. Am Med Inform Assoc 2017;24:1024–1035 Alaska Native populations. PLoS One 2014;9: Food insecurity, food “deserts,” and glycemic 47. Herkert D, Vijayakumar P, Luo J, et al. Cost- e80973 control in patients with diabetes: a longitudinal related insulin underuse among patients with di- 63. Borschuk AP, Everhart RS. Health disparities analysis. Diabetes Care 2018;41:1188–1195 abetes. JAMA Intern Med 2019;179:112–114 among youth with type 1 diabetes: a systematic 78. Heerman WJ, Wallston KA, Osborn CY, et al. 48.CefaluWT,DawesDE,GavlakG,etal.;Insulin review of the current literature. Fam Syst Health Food insecurity is associated with diabetes self- Access and Affordability Working Group. Insulin 2015;33:297–313 care behaviours and glycaemic control. Diabet Access and Affordability Working Group: Conclu- 64. Walker RJ, Strom Williams J, Egede LE. In- Med 2016;33:844–850 sions and recommendations. Diabetes Care 2018; fluence of race, ethnicity and social determinants 79. Silverman J, Krieger J, Kiefer M, Hebert P, 41:1299©2019–1311 of health on diabetes outcomes. Am J Med Sci Robinson J, Nelson K. The relationship between 49. Myerson R, Laiteerapong N. The Affordable 2016;351:366–373 food insecurity and depression, diabetes distress CareActanddiabetesdiagnosisandcare:exploring 65. Patel MR, Piette JD, Resnicow K, Kowalski- and medication adherence among low-income the potential impacts. Curr Diab Rep 2016;16:27 Dobson T, Heisler M. Social determinants of patients with poorly-controlled diabetes. J Gen 50. Casagrande SS, McEwen LN, Herman WH. health, cost-related nonadherence, and cost- Intern Med 2015;30:1476–1480 Changes in health insurance coverage under the reducing behaviors among adults with diabetes: 80. Schroeder EB, Zeng C, Sterrett AT, Kimpo TK, Affordable Care Act: a national sample of U.S. findings from the National Health Interview Paolino AR, Steiner JF. The longitudinal relation- adults with diabetes, 2009 and 2016. Diabetes Survey. Med Care 2016;54:796–803 ship between food insecurity in older adults with Care 2018;41:956–962 66. Steve SL, Tung EL, Schlichtman JJ, Peek ME. diabetes and emergency department visits, hos- 51. Insurance coverage and diabetes quality Social disorder in adults with type 2 diabetes: pitalizations, hemoglobin A1c, and medication indicators among patients in NHANES. Am J building on race, place, and poverty. Curr Diab adherence. J Diabetes Complications 2019;33: Manag Care 2016;22:484-90 Rep 2016;16:72 289–295 care.diabetesjournals.org Improving Care and Promoting Health S13

81. Hager ER, Quigg AM, Black MM, et al. De- q5tall&year52018&state5&fd5mh. Accessed 93. Foster G, Taylor SJC, Eldridge SE, Ramsay J, velopment and validity of a 2-item screen to 25 October 2019 Griffiths CJ. Self-management education pro- identify families at risk for food insecurity. Pe- 87. U.S. Department of Health & Human Serv- grammes by lay leaders for people with chronic diatrics 2010;126:e26–e32 ices. Think Cultural Health [Internet], 2017. Avail- conditions. Cochrane Database Syst Rev 2007 (4): 82. Seligman HK, Schillinger D. Hunger and able from: https://www.thinkculturalhealth.hhs CD005108 socioeconomic disparities in chronic disease. .gov/. Accessed 25 October 2019 94. Piatt GA, Rodgers EA, Xue L, Zgibor JC. N Engl J Med 2010;363:6–9 88. U.S. Department of Health & Human Serv- Integration and utilization of peer leaders for 83. White BM, Logan A, Magwood GS. Access to ices,Agencyfor Healthcare ResearchandQuality, diabetes self-management support: results diabetes care for populations experiencing Clinical-Community Linkages [Internet], 2016. homelessness: an integrated review. Curr Diab Available from: http://www.ahrq.gov/professionals/ from Project SEED (Support, Education, and Rep 2016;16:112 prevention-chronic-care/improve/community/index Evaluation in Diabetes). Diabetes Educ 2018; 84. Bernstein RS, Meurer LN, Plumb EJ, Jackson .html. Accessed 25 October 2019 44:373–382 JL. Diabetes and hypertension prevalence in 89. Egbujie BA, Delobelle PA, Levitt N, Puoane T, 95. Understanding Scope and Competencies: homeless adults in the United States: a system- Sanders D, van Wyk B. Role of community health A Contemporary Look at the United States atic review and meta-analysis. Am J Public Health workers in type2diabetes mellitus self-management: Community Health Worker Field: Progress Re- 2015;105:e46–e60 a scoping review. PLoSOne 2018;13:e0198424 port of the Community Health Worker (CHW) 85. Montgomery AE, Fargo JD, Kane V, Culhane 90. Heisler M, Vijan S, Makki F, Piette JD. Di- Core Consensus (C3) Project: Building National DP. Development and validation of an instru- abetes control with reciprocal peer support Consensus on CHW Core Roles, Skills, and Qual- ment to assess imminent risk of homelessness versus nurse care management: a randomized ities [Internet], 2016. Available from: http://files – among veterans. Public Health Rep 2014;129: trial. Ann Intern Med 2010;153:507 515 .ctctcdn.com/a907c850501/1c1289f0-88cc- 428–436 91. Long JA, Jahnle EC, Richardson DM, Loewenstein 49c3-a238-66def942c147.pdf. Accessed 25 Oc- 85a. Evangelou E, Ntritsos G, Chondrogiorgi M, G, Volpp KG. Peer mentoring and financial incentives tober 2019 Kavvoura FK, HernandezAF,´ Ntzani EE, Tzoulaki, I. to improve glucose control in African American 96. Community Health WorkersHelp PatientsMan- Exposureto pesticides and diabetes:a systematic veterans: a randomized trial. Ann Intern Med 2012; review and meta-analysis. Environment Interna- 156:416–424 age Diabetes [Internet], 2017. The Guide to Com- munity PreventiveAssociation Services (The Community Guide). tional 2016;91:60–68 92. Fisher EB, Boothroyd RI, Elstad EA, et al. Peer 86. U.S. Department of Health & Human Services, support of complex health behaviors in prevention Available from: https://www.thecommunityguide. Health Resources & Services Administration. and disease management with special reference to org/content/community-health-workers-help- 2018 Health Center Data [Internet], 2018. Available diabetes: systematic reviews. Clin Diabetes Endo- patients-manage-diabetes. Accessed 25 October from: https://bphc.hrsa.gov/uds/datacenter.aspx? crinol 2017;3:4 2019

Diabetes

American

2. Classiﬁcation and Diagnosis of American Diabetes Association Diabetes: Standards of Medical Care in Diabetesd2020

Diabetes Care 2020;43(Suppl. 1):S14–S31 | https://doi.org/10.2337/dc20-S002

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes” includesthe ADA’s current clinicalpractice recommendations and isintended to provide Association the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee (https://doi.org/10.2337/dc20-SPPC), a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc20-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.Diabetes CLASSIFICATION 2. CLASSIFICATION AND DIAGNOSIS OF DIABETES Diabetes can be classiﬁed into the following general categories:

1. Type 1 diabetes (due to autoimmune b-cell destruction, usually leading to absolute insulin deficiency) 2. Type 2 diabetes (due to a progressive loss of adequate b-cell insulin secretion frequently on the background of insulin resistance) 3. Gestational diabetes mellitus (diabetes diagnosed in the second or third trimester of pregnancy that was not clearly overt diabetes prior to gestation) 4. Specifictypesof diabetes due toothercauses, e.g.,monogenic diabetes syndromes (such as neonatal diabetesAmerican and maturity-onset diabetes of the young), diseases of the exocrine pancreas (such as cystic fibrosis and pancreatitis), 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 statement©2019“Diagnosis and Classiﬁcation of Diabetes Mellitus” (1).

Type 1 diabetes and type 2 diabetes are heterogeneous diseases in which clinical Suggested citation: American Diabetes Associa- presentation and disease progression may vary considerably. Classification is tion. 2. Classification and diagnosis of diabetes: important for determining therapy, but some individuals cannot be clearly classified Standards of Medical Care in Diabetesd2020. as having type 1 or type 2 diabetes at the time of diagnosis. The traditional paradigms Diabetes Care 2020;43(Suppl. 1):S14–S31 of type 2 diabetes occurring only in adults and type 1 diabetes only in children are no © 2019 by the American Diabetes Association. longer accurate, as both diseases occur in both age-groups. Children with type 1 Readers may use this article as long as the work is properly cited, the use is educational and not diabetes typically present with the hallmark symptoms of polyuria/polydipsia, and for profit, and the work is not altered. More infor- approximately one-third present with diabetic ketoacidosis (DKA) (2). The onset of mation is available at http://www.diabetesjournals type 1 diabetes may be more variable in adults; they may not present with the classic .org/content/license. care.diabetesjournals.org Classification and Diagnosis of Diabetes S15

Table 2.1—Staging of type 1 diabetes (8,9) Stage 1 Stage 2 Stage 3 Characteristics c Autoimmunity c Autoimmunity c New-onset hyperglycemia c Normoglycemia c Dysglycemia c Symptomatic c Presymptomatic c Presymptomatic Diagnostic criteria c Multiple autoantibodies c Multiple autoantibodies c Clinical symptoms c No IGT or IFG c Dysglycemia: IFG and/or IGT c Diabetes by standard criteria c FPG 100–125 mg/dL (5.6–6.9 mmol/L) c 2-h PG 140–199 mg/dL (7.8–11.0 mmol/L) c A1C 5.7–6.4% (39–47 mmol/mol) or $10% increase in A1C symptoms seen in children and may expe- serve as a framework for future research mainly been demonstrated among indi- rience temporary remission from the need and regulatory decision-making (8,9). There viduals who have impaired glucose tol- for insulin (3–5). Occasionally, patients is debate as to whether slowly progressive erance (IGT) with or without elevated with type 2 diabetes may present with autoimmune diabetes with an adult onset fasting glucose, not for individuals with DKA (6), particularly ethnic minorities (7). should be termed latent autoimmune di- isolated impaired fasting glucose (IFG) It is important for the provider to realize abetes in adults (LADA) or whether the or for those with prediabetes defined that classification of diabetes type is not clinical priority is awareness that slow auto- by A1C criteria. always straightforward at presentation and immune b-cell destruction means there may TheAssociation same tests may be used to screen that misdiagnosis is common (e.g., adults be long duration of marginal insulin secre- for and diagnose diabetes and to detect with type 1 diabetes misdiagnosed as hav- tory capacity. For the purpose of this clas- individuals with prediabetes (Table 2.2 ing type 2 diabetes; individuals with matu- sification, all forms of diabetes mediated by and Table 2.5). Diabetes may be identi- rity-onset diabetes of the young [MODY] autoimmune b-cell destruction are included fied anywhere along the spectrum of misdiagnosed as having type 1 diabetes, under the rubric of type 1 diabetes. clinical scenariosdin seemingly low- etc.). Although difficulties in distinguish- The paths to b-cell demise and dys- risk individuals who happen to have glu- ing diabetes type may occur in all age- function are less well defined in type 2 cosetesting,inindividualstestedbasedon groups at onset, the diagnosis becomes diabetes, but deficient b-cell insulin se- diabetes risk assessment, and in symp- more obvious over time. cretion, frequently in the setting of in- tomatic patients. In both type 1 and type 2 diabetes, sulin resistance,Diabetes appears to be the various genetic and environmental fac- common denominator. Characterization Fasting and 2-Hour Plasma Glucose tors can result in the progressive loss of of subtypes of this heterogeneous dis- The FPG and 2-h PG may be used to b-cell mass and/or function that mani- order have been developed and vali- diagnose diabetes (Table 2.2). The con- fests clinically as hyperglycemia. Once dated in Scandinavian and Northern cordance between the FPG and 2-h hyperglycemia occurs, patients with all European populations but have not PGtestsisimperfect,asistheconcor- forms of diabetes are at risk for devel- been confirmed in other ethnic and ra- dance between A1C and either glucose- oping the same chronic complications, cial groups. Type 2 diabetes is associated based test. Compared with FPG and although rates of progression may differ. with insulin secretory defects related A1C cut points, the 2-h PG value di- The identification of individualized ther- to inflammation and metabolic stress agnoses more people with prediabe- apies for diabetes in the future will re- among other contributors, including tes and diabetes (15). quire better characterization of the many genetic factors. Future classification paths to b-cell demise or dysfunctionAmerican (8). schemes for diabetes will likely focus A1C Characterization of the underlying path- on the pathophysiology of the underly- Recommendations ophysiology is more developed in type 1 ing b-cell dysfunction (8,10,11). 2.1 To avoid misdiagnosis or missed diabetes than in type 2 diabetes. It is now diagnosis, the A1C test should be clear from studies of first-degree relatives DIAGNOSTIC TESTS FOR DIABETES performed using a method that is of patients with type 1 diabetes that the Diabetes may be diagnosed based on certified by the NGSP and stan- persistent presence of two or more islet plasma glucose criteria, either the fast- dardized to the Diabetes Control autoantibodies is an almost certain pre- ing plasma glucose (FPG) value or the and Complications Trial (DCCT) dictor©2019 of clinical hyperglycemia and diabe- 2-h plasma glucose (2-h PG) value during assay. B tes. The rate of progression is dependent on a 75-g oral glucose tolerance test (OGTT), 2.2 Marked discordance between the age at first detection of autoantibody, or A1C criteria (12) (Table 2.2). measured A1C and plasma glu- numberofautoantibodies,autoantibody Generally, FPG, 2-h PG during 75-g cose levels should raise the pos- specificity, and autoantibody titer. Glu- OGTT, and A1C are equally appropriate sibility of A1C assay interference cose and A1C levels rise well before the for diagnostic screening. It should be due to hemoglobin variants (i.e., clinical onset of diabetes, making diag- noted that the tests do not necessarily hemoglobinopathies) and con- nosis feasible well before the onset of detect diabetes in the same individuals. sideration of using an assay with- DKA. Three distinct stages of type 1 di- The efficacy of interventions for primary out interference or plasma blood abetes can be identified (Table 2.1) and prevention of type 2 diabetes (13,14) has S16 Classification and Diagnosis of Diabetes Diabetes Care Volume 43, Supplement 1, January 2020

cut point, greater cost, limited availabil- between measured A1C and plasma glu- glucose criteria to diagnose di- ity of A1C testing in certain regions of cose levels should prompt consideration abetes. B the developing world, and the imperfect that the A1C assay may not be reliable for 2.3 In conditions associated with an correlation between A1C and average that individual. For patients with a hemo- altered relationship between A1C glucose in certain individuals. The A1C globin variant but normal red blood cell and glycemia, such as sickle cell test, with a diagnostic threshold of turnover, such as those with the sickle cell disease, pregnancy (second and $6.5% (48 mmol/mol), diagnoses only trait, an A1C assay without interference third trimesters and the postpar- 30% of the diabetes cases identified col- from hemoglobin variantsshould beused. tumperiod),glucose-6-phosphate lectively using A1C, FPG, or 2-h PG, ac- An updated list of A1C assays with inter- dehydrogenase deficiency, HIV, cording to National Health and Nutrition ferences is available at www.ngsp.org/ hemodialysis, recent blood loss Examination Survey (NHANES) data (16). interf.asp. or transfusion, or erythropoietin When using A1C to diagnose diabetes, African Americans heterozygous for therapy, only plasma blood glu- it is important to recognize that A1C is the common hemoglobin variant HbS cose criteria should be used to an indirect measure of average blood may have, for any given level of mean diagnose diabetes. B glucose levels and to take other factors glycemia, lower A1C by about 0.3% than into consideration that may impact he- those without the trait (20). Another ge- The A1C test should be performed using moglobin glycation independently of netic variant, X-linked glucose-6-phosphate a method that is certified by the NGSP glycemia, such as hemodialysis, preg- dehydrogenase G202A, carried by 11% of (www.ngsp.org) and standardized or nancy, HIV treatment (17,18), age, race/ African Americans, was associated with a traceable to the Diabetes Control and ethnicity, pregnancy status, genetic back- decrease in A1C of about 0.8% in homo- Complications Trial (DCCT) reference as- ground, and anemia/hemoglobinopathies. zygous men and 0.7% in homozygous say. Although point-of-care A1C assays Association (See OTHER CONDITIONS ALTERING THE RELATION- women compared with those without may be NGSP certified or U.S. Food and SHIP OF A1C AND GLYCEMIA below for more the variant (21). Drug Administration approved for diag- information.) Even in the absence of hemoglobin fi nosis, pro ciency testing is not always variants, A1C levels may vary with race/ Age mandated forperformingthe test. There- ethnicity independently of glycemia The epidemiological studies that formed fore, point-of-care assays approved for (22–24). For example, African Americans the basis for recommending A1C to diagnostic purposes should only be con- may have higher A1C levels than non- diagnose diabetes included only adult sidered in settings licensed to perform Hispanic whites with similar fasting and populations (16). However, recent ADA moderate-to-high complexity tests. As postglucose load glucose levels (25), and clinical guidance concluded that A1C, discussed in Section 6 “Glycemic Targets” A1C levels may be higher for a given mean FPG, or 2-h PG can be used to test for (https://doi.org/10.2337/dc20-S006), Diabetesglucose concentration when measured prediabetes or type 2 diabetes in children point-of-care A1C assays may be more with continuous glucose monitoring (26). and adolescents (see SCREENING AND TESTING generally applied for assessment of gly- Though conflicting data exists, African cemic control in the clinic. FOR PREDIABETES AND TYPE 2 DIABETES IN CHILDREN Americans may also have higher levels of AND ADOLESCENTS below for additional in- A1C has several advantages com- fructosamine and glycated albumin and formation) (19). pared with FPG and OGTT, including lower levels of 1,5-anhydroglucitol, sug- greater convenience (fasting not re- Race/Ethnicity/Hemoglobinopathies gesting that their glycemic burden (par- quired), greater preanalytical stability, Hemoglobin variants can interfere ticularly postprandially) may be higher and less day-to-day perturbations during with the measurement of A1C, al- (27,28). The association of A1C with risk stress, diet, or illness. However, these though most assays in use in the for complications appears to be similar advantages may be offset by the lower U.S. are unaffected by the most com- in African Americans and non-Hispanic sensitivity of A1C at theAmerican designated mon variants. Marked discrepancies whites (29,30).

Table 2.2—Criteria for the diagnosis of diabetes Other Conditions Altering the Relationship FPG $126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 h.* of A1C and Glycemia OR In conditions associated with increased 2-h PG $200 mg/dL (11.1 mmol/L) during OGTT. The test should be performed as described red blood cell turnover, such as sickle by the WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose cell disease, pregnancy (second and dissolved in water.* third trimesters), glucose-6-phosphate ©2019 fi OR dehydrogenase de ciency (31,32), he- A1C $6.5% (48 mmol/mol). The test should be performed in a laboratory using a method that modialysis, recent blood loss or trans- is NGSP certified and standardized to the DCCT assay.* fusion, or erythropoietin therapy, only OR plasma blood glucose criteria should be In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma used to diagnose diabetes (33). A1C is glucose $200 mg/dL (11.1 mmol/L). less reliable than blood glucose mea- DCCT, Diabetes Control and Complications Trial; FPG, fasting plasma glucose; OGTT, oral glucose surement in other conditions such as tolerance test; WHO, World Health Organization; 2-h PG, 2-h plasma glucose. *In the absence of the postpartum state (34–36), HIV unequivocal hyperglycemia, diagnosis requires two abnormal test results from the same sample or treated with certain drugs (17), and in two separate test samples. iron-deficient anemia (37). care.diabetesjournals.org Classification and Diagnosis of Diabetes S17

Confirming the Diagnosis knowing the plasma glucose level is modest fasting hyperglycemia that can Unless there is a clear clinical diagnosis critical because, in addition to confirm- rapidly change to severe hyperglycemia (e.g., patient in a hyperglycemic crisis or ing that symptoms are due to diabetes, and/or DKA with infection or other stress. with classic symptoms of hyperglycemia it will inform management decisions. Adults may retain sufficient b-cell func- and a random plasma glucose $200 Some providers may also want to know tion to prevent DKA for many years; such mg/dL [11.1 mmol/L]), diagnosis requires the A1C to determine how long a patient individuals may have remission or de- two abnormal test results from the same has had hyperglycemia. The criteria to creased insulin needs for months or years sample (38) or in two separate test diagnose diabetes are listed in Table 2.2. and eventually become dependent on samples. If using two separate test sam- insulin for survival and are at risk for DKA ples, it is recommended that the second TYPE 1 DIABETES (3–5,39,40). At this latter stage of the test, which may either be a repeat of the Recommendations disease, there is little or no insulin se- initial test or a different test, be per- cretion, as manifested by low orundetect- 2.4 Screening for type 1 diabetes risk formed without delay. For example, if the able levels of plasma C-peptide. Immune- with a panel of islet autoanti- A1C is 7.0% (53 mmol/mol) and a repeat mediated diabetes is the most common bodies is currently recommended result is 6.8% (51 mmol/mol), the di- form of diabetes in childhood and ado- in the setting of a research trial or agnosis of diabetes is confirmed. If two lescence, but it can occur at any age, even can be offered as an option for different tests (such as A1C and FPG) are in the 8th and 9th decades of life. first-degree family members of a both above the diagnostic threshold Autoimmune destruction of b-cells proband with type 1 diabetes. B when analyzed from the same sample has multiple genetic predispositions 2.5 Persistence of autoantibodies is or in two different test samples, this also and is also related to environmental a risk factor for clinical diabetes confirms the diagnosis. On the other factors that are still poorly defined. Al- and may serve as an indication for Association hand, if a patient has discordant results though patients are not typically obese intervention in the setting of from two different tests, then the test when they present with type 1 diabetes, a clinical trial. B result that is above the diagnostic cut obesity is increasingly common in the point should be repeated, with consid- general population and there is evidence eration of the possibility of A1C assay Immune-Mediated Diabetes that it may also be a risk factor for type 1 interference. The diagnosis is made on This form, previously called “insulin- diabetes. As such, obesity should not the basis of the confirmed test. For dependent diabetes” or “juvenile-onset preclude the diagnosis. People with example, if a patient meets the diabetes diabetes,” accounts for 5–10% of diabe- type 1 diabetes are also prone to other criterion of the A1C (two results $6.5% tes and is due to cellular-mediated au- autoimmune disorders such as Hashi- [48 mmol/mol]) but not FPG (,126 toimmune destruction of the pancreatic moto thyroiditis, Graves disease, celiac mg/dL [7.0 mmol/L]), that person should b-cells. AutoimmuneDiabetes markers include disease, Addison disease, vitiligo, auto- nevertheless be considered to have islet cell autoantibodies and autoanti- immune hepatitis, myasthenia gravis, diabetes. bodies to GAD (GAD65), insulin, the and pernicious anemia (see Section All the tests have preanalytic and tyrosine phosphatases IA-2 and IA-2b, 4 “Comprehensive Medical Evaluation analytic variability, so it is possible and zinc transporter 8 (ZnT8). Numer- and Assessment of Comorbidities,” that an abnormal result (i.e., above ous clinical studies are being conducted https://doi.org/10.2337/dc20-S004). the diagnostic threshold), when re- to test various methods of preventing peated, will produce a value below type 1 diabetes in those with evidence Idiopathic Type 1 Diabetes the diagnostic cut point. This scenario of islet autoimmunity (www.clinicaltrials Some forms of type 1 diabetes have no is likely for FPG and 2-h PG if the glucose .gov). Stage 1 of type 1 diabetes is defined known etiologies. These patients have per- samples remain at room temperature by the presence of two or more of these manent insulinopenia and are prone to DKA and are not centrifuged promptly.American Be- autoimmune markers. The disease has but have no evidence of b-cell autoimmu- cause of the potential for preanalytic strong HLA associations, with linkage to nity. However, only a minority of patients variability, it is critical that samples for the DQA and DQB genes. These HLA-DR/ with type 1 diabetes fall into this category. plasma glucose be spun and separated DQ alleles can be either predisposing or Individuals with autoantibody-negative immediately after they are drawn. If protective (Table 2.1). There are important type 1 diabetes of African or Asian ancestry patients have test results near the mar- genetic considerations, as most of the mu- may suffer from episodic DKA and exhibit gins of the diagnostic threshold, the tations that cause diabetes are dominantly varying degrees of insulin deficiency be- health care professional should discuss inherited. The importance of genetic testing tween episodes. This form of diabetes is signs©2019 and symptoms with the patient and is in the genetic counseling that follows. strongly inherited and is not HLA associated. repeat the test in 3–6 months. Some mutations are associated with other An absolute requirement for insulin re- conditions, which then may prompt addi- placement therapy in affected patients Diagnosis tional screenings. may be intermittent. Future research is In a patient with classic symptoms, The rate of b-cell destruction is quite needed to determine the cause of b-cell measurement of plasma glucose is suf- variable, being rapid in some individuals destruction in this rare clinical scenario. ficient to diagnose diabetes (symptoms (mainly infants and children) and slow in of hyperglycemia or hyperglycemic crisis others (mainly adults). Children and ado- Screening for Type 1 Diabetes Risk plus a random plasma glucose $200 lescents may present with DKA as the first The incidence and prevalence of type 1 mg/dL [11.1 mmol/L]). In these cases, manifestationof the disease.Others have diabetes is increasing (41). Patients with S18 Classification and Diagnosis of Diabetes Diabetes Care Volume 43, Supplement 1, January 2020

type 1 diabetes often present with acute PREDIABETES AND TYPE 2.13 Risk-based screening for predia- symptoms of diabetes and markedly 2 DIABETES betes and/or type 2 diabetes elevated blood glucose levels, and ap- Recommendations should be considered after the proximately one-third are diagnosed 2.6 Screening for prediabetes and onsetofpubertyorafter10years with life-threatening DKA (2). Multiple type 2 diabetes with an informal of age, whichever occurs earlier, studies indicate that measuring islet assessment of risk factors or val- in children and adolescents with autoantibodies in individuals genetically idated tools should be consid- overweight (BMI $85th percen- at risk for type 1 diabetes (e.g., relatives ered in asymptomatic adults. B tile) or obesity (BMI $95th per- of those with type 1 diabetes or indi- 2.7 Testing for prediabetes and/or centile) and who have one or viduals from the general population type 2 diabetes in asymptomatic more risk factor for diabetes. with type 1 diabetes–associated genetic people should be considered in (See Table 2.4 for evidence grad- factors) identifies individuals who may adults of any age with over- ing of risk factors.) develop type 1 diabetes (9). Such testing, weight or obesity (BMI $25 coupled with education about diabetes kg/m2 or $23 kg/m2 in Asian symptoms and close follow-up, may en- Prediabetes Americans) and who have one or “ ” able earlier identification of type 1 di- Prediabetes is the term used for indi- more additional risk factors for viduals whose glucose levels do not meet abetes onset. A study reported the risk of Table 2.3 B diabetes ( ). the criteria for diabetes but are too high progression to type 1 diabetes from the 2.8 Testing for prediabetes and/or time of seroconversion to autoantibody to be considered normal (29,30). Patients type 2 diabetes should be con- with prediabetes are defined by the positivity in three pediatric cohorts from sidered in women planning Finland, Germany, and the U.S. Of the presence of IFG and/or IGT and/or A1C pregnancy with overweight or 5.7Association–6.4% (39–47 mmol/mol) (Table 2.5). 585 children who developed more than obesity and/or who have one or two autoantibodies, nearly 70% devel- Prediabetes should not be viewed as a more additional risk factor for clinical entity in its own right but rather oped type 1 diabetes within 10 years and Table 2.3 C diabetes ( ). as an increased risk for diabetes and 84% within 15 years (42). These findings 2.9 For all people, testing should cardiovascular disease (CVD). Criteria arehighlysignificant because while the B begin at age 45 years. for testing for diabetes or prediabetes German group was recruited from off- 2.10 Iftests arenormal,repeattesting spring of parents with type 1 diabetes, in asymptomatic adults is outlined in carried out at a minimum of Table 2.3. Prediabetes is associated the Finnish and American groups were C 3-year intervals is reasonable. with obesity (especially abdominal or recruited from the general population. 2.11 To test for prediabetes and type fi visceral obesity), dyslipidemia with high Remarkably, the ndings in all three 2 diabetes, fasting plasma glu- groups were the same, suggesting that Diabetestriglycerides and/or low HDL choles- cose, 2-h plasma glucose during terol, and hypertension. thesamesequenceofeventsledtoclinical 75-g oral glucose tolerance test, “ ” Diagnosis disease in both sporadic and familial and A1C are equally appropriate fi cases of type 1 diabetes. Indeed, the risk (Table 2.2 and Table 2.5). B IFG is de ned as FPG levels between of type 1 diabetes increases as the number 2.12 In patients with prediabetes and 100 and 125 mg/dL (between 5.6 and of relevant autoantibodies detected intype 2 diabetes, identify and 6.9 mmol/L) (47,56) and IGT as 2-h PG – creases (43 45). In The Environmental De- treat other cardiovascular dis- during75-gOGTTlevelsbetween140 terminants of Diabetes in the Young ease risk factors. B and 199 mg/dL (between 7.8 and 11.0 (TEDDY) study, type 1 diabetes devel- mmol/L) (48). It should be noted that the oped in 21% of 363 subjects with at least one autoantibody at 3 years of age (46). Table 2.3—Criteria for testing for diabetes or prediabetes in asymptomatic adults Although there is currentlyAmerican a lack of 1. Testing should be considered in overweight or obese (BMI $25 kg/m2 or $23 kg/m2 in Asian accepted screening programs, one should Americans) adults who have one or more of the following risk factors: consider referring relatives of those with c First-degree relative with diabetes c type 1 diabetes for islet autoantibody High-risk race/ethnicity (e.g., African American, Latino, Native American, Asian American, Pacific Islander) testing for risk assessment in the set- c History of CVD ting of a clinical research study (see www c Hypertension ($140/90 mmHg or on therapy for hypertension) .diabetestrialnet.org). Widespread clini- c HDL cholesterol level ,35 mg/dL (0.90 mmol/L) and/or a triglyceride level .250 mg/dL cal testing of asymptomatic low-risk in- (2.82 mmol/L) dividuals©2019 is not currently recommended c Women with polycystic ovary syndrome due to lack of approved therapeutic inter- c Physical inactivity c Other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis ventions. Individuals who test positive nigricans) should be counseled about the risk of 2. Patients with prediabetes (A1C $5.7% [39 mmol/mol], IGT, or IFG) should be tested yearly. developing diabetes, diabetes symptoms, 3. Women who were diagnosed with GDM should have lifelong testing at least every 3 years. and DKA prevention. Numerous clinical 4. For all other patients, testing should begin at age 45 years. studies are being conducted to test various methods of preventing type 1 diabetes 5. If results are normal, testing should be repeated at a minimum of 3-year intervals, with consideration of more frequent testing depending on initial results and risk status. in those with evidence of autoimmunity (see www.clinicaltrials.gov). CVD, cardiovascular disease; GDM, gestational diabetes mellitus. care.diabetesjournals.org Classification and Diagnosis of Diabetes S19

Fig. 2.1 Table 2.4—Risk-based screening for type 2 diabetes or prediabetes in asymptomatic ( ) (diabetes.org/socrisktest). For children and adolescents in a clinical setting (163) additional background regarding risk factors and screening for prediabetes, see Testing should be considered in youth* who have overweight ($85th percentile) or obesity ($95th percentile) A and who have one or more additional risk factors based on the strength SCREENING AND TESTING FOR PREDIABETES AND of their association with diabetes: TYPE 2 DIABETES IN ASYMPTOMATIC ADULTS and c Maternal history of diabetes or GDM during the child’s gestation A also SCREENING AND TESTING FOR PREDIABETES AND TYPE 2 DIABETES IN CHILDREN AND ADOLESCENTS c Family history of type 2 diabetes in first- or second-degree relative A below. c Race/ethnicity (Native American, African American, Latino, Asian American, Pacific Islander) A Type 2 Diabetes c Signs of insulin resistance or conditions associated with insulin resistance (acanthosis Type 2 diabetes, previously referred to nigricans, hypertension, dyslipidemia, polycystic ovary syndrome, or small-for-gestational- “ ” age birth weight) B as noninsulin-dependent diabetes or “adult-onset diabetes,” accounts for 90– GDM, gestational diabetes mellitus. *After the onset of puberty or after 10 years of age, whichever occurs earlier. If tests are normal, repeat testing at a minimum of 3-year intervals, or more 95% of all diabetes. This form encom- frequently if BMI is increasing, is recommended. Reports of type 2 diabetes before age 10 years passes individuals who have relative exist, and this can be considered with numerous risk factors. (rather than absolute) insulin deficiency and have peripheral insulin resistance. At least initially, and often throughout their World Health Organization (WHO) and the high-risk participants in the Diabetes lifetime, these individuals may not need numerous other diabetes organizations Prevention Program (DPP) (51), and A1C insulin treatment to survive. define the IFG cutoff at 110 mg/dL at baseline was a strong predictor of There are various causes of type 2 (6.1 mmol/L). the development of glucose-defined di- Association diabetes. Although the specific etiologies As with the glucose measures, several abetes during the DPP and its follow-up are not known, autoimmune destruction prospective studies that used A1C to (52). Hence, it is reasonable to consider of b-cells does not occur and patients do predict the progression to diabetes as an A1C range of 5.7–6.4% (39–47 mmol/ not have any of the other known causes defined by A1C criteria demonstrated a mol) as identifying individuals with pre- of diabetes. Most but not all patients with strong, continuous association between diabetes. Similar tothose with IFGand/or type 2 diabetes have overweight or obe- A1C and subsequent diabetes. In a sys- IGT, individuals with A1C of 5.7–6.4% sity. Excess weight itself causes some tematic review of 44,203 individuals from (39–47 mmol/mol) should be informed degreeofinsulinresistance.Patientswho 16 cohort studies with a follow-up in- of their increased risk for diabetes and do not have obesity or overweight by terval averaging 5.6 years (range 2.8–12 CVD and counseled about effective strat- traditional weight criteria may have an years), those with A1C between 5.5% and egies to lower their risks (see Section Diabetesincreased percentage of body fat distrib- 6.0% (between 37 and 42 mmol/mol) 3 “Prevention or Delay of Type 2 Di- uted predominantly in the abdominal had a substantially increased risk of diabetes,” https://doi.org/10.2337/dc20- region. abetes (5-year incidence from 9% to S003). Similar to glucose measurements, DKA seldom occurs spontaneously in 25%). Those with an A1C range of 6.0– the continuum of risk is curvilinear, so as type 2 diabetes; when seen, it usually 6.5% (42–48 mmol/mol) had a 5-year A1C rises, the diabetes risk rises dispro- arises in association with the stress of risk of developing diabetes between 25% portionately (49). Aggressive interven- another illness such as infection or with and 50% and a relative risk 20 times tions and vigilant follow-up should be the use of certain drugs (e.g., cortico- higher compared with A1C of 5.0% pursued for those considered at very steroids, atypical antipsychotics, and (31 mmol/mol) (49). In a community- high risk (e.g., those with A1C .6.0% sodium–glucose cotransporter 2 in- based study of African American and [42 mmol/mol]). hibitors) (53,54). Type 2 diabetes fre- non-Hispanic white adults without dia- Table 2.5 summarizes the categories American quently goes undiagnosed for many betes, baseline A1C was a stronger pre- of prediabetes and Table 2.3 the cri- years because hyperglycemia develops dictor of subsequent diabetes and teria for prediabetes testing. The ADA gradually and, at earlier stages, is often cardiovascular events than fasting glucose diabetes risk test is an additional op- not severe enough for the patient to (50). Other analyses suggest that A1C of tion for assessment to determine the notice the classic diabetes symptoms. 5.7% (39 mmol/mol) or higher is associated appropriateness of testing for diabetes Nevertheless, even undiagnosed pa- with a diabetes risk similar to that of or prediabetesin asymptomatic adults. tients are at increased risk of developing macrovascular and microvascular — fi Table©2019 2.5 Criteria de ning prediabetes* complications. FPG 100 mg/dL (5.6 mmol/L) to 125 mg/dL (6.9 mmol/L) (IFG) Whereas patients with type 2 diabetes OR may have insulin levels that appear nor- 2-h PG during 75-g OGTT 140 mg/dL (7.8 mmol/L) to 199 mg/dL (11.0 mmol/L) (IGT) mal or elevated, the higher blood glucose OR levels inthese patientswould beexpected A1C 5.7–6.4% (39–47 mmol/mol) to result in even higher insulin values had b FPG, fasting plasma glucose; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; OGTT, their -cell function been normal. Thus, oral glucose tolerance test; 2-h PG, 2-h plasma glucose. *For all three tests, risk is continuous, insulin secretion is defective in these extending below the lower limit of the range and becoming disproportionately greater at the patients and insufficient to compensate higher end of the range. for insulin resistance. Insulin resistance S20 Classification and Diagnosis of Diabetes Diabetes Care Volume 43, Supplement 1, January 2020

may improve with weight reduction diabetes are undiagnosed (47,56). Al- BMI and Ethnicity and/or pharmacologic treatment of hy- though screening of asymptomatic indi- In general, BMI $25 kg/m2 is a risk factor perglycemia but is seldom restored to viduals to identify those with prediabetes for diabetes. However, data suggest that normal. or diabetes might seem reasonable, rig- the BMI cut point should be lower for the The risk of developing type 2 diabetes orous clinical trials to prove the effective- Asian American population (60,61). The increases with age, obesity, and lack of ness of such screening have not been BMI cut points fall consistently between physical activity. It occurs more fre- conducted and are unlikely to occur. 23 and 24 kg/m2 (sensitivity of 80%) for quently in women with prior gestational Based on a population estimate, diabe- nearly all Asian American subgroups diabetes mellitus (GDM), in those with tes in women of childbearing age is (with levels slightly lower for Japanese hypertension or dyslipidemia, and in underdiagnosed. Employing a probabi- Americans). This makes a rounded cut certain racial/ethnic subgroups (African listic model, Peterson et al. (57) dem- point of 23 kg/m2 practical. An argument American, American Indian, Hispanic/ onstratedcostandhealthbenefits of can be made to push the BMI cut point to Latino, and Asian American). It is often preconception screening. lower than 23 kg/m2 in favor of increased associated with a strong genetic predis- A large European randomized con- sensitivity; however, this would lead to position or family history in first-degree trolled trial compared the impact of an unacceptably low specificity (13.1%). relatives, more so than type 1 diabetes. screening for diabetes and intensive Data from the WHO also suggests that a However, the genetics of type 2 diabetes multifactorial intervention with that of BMI of $23 kg/m2 should be used to is poorly understood. In adults without screening and routine care (55). General define increased risk in Asian Americans traditional risk factors for type 2 diabetes practice patients between the ages of (62). The finding that one-third to one- and/or younger age, consider islet auto- 40 and 69 years were screened for di- half of diabetes in Asian Americans is antibody testing (e.g., GAD65 autoanti- abetes and randomly assigned by prac- undiagnosedAssociation suggests that testing is bodies) to exclude the diagnosis of tice to intensive treatment of multiple not occurring at lower BMI thresholds type 1 diabetes. risk factors or routine diabetes care. (63,64). After 5.3 years of follow-up, CVD risk Evidence also suggests that other pop- Screening and Testing for Prediabetes factorsweremodestlybutsignificantly ulations may benefit from lower BMI cut and Type 2 Diabetes in Asymptomatic improved with intensive treatment points. For example, in a large multieth- Adults compared with routine care, but the nic cohort study, for an equivalent in- Screening for prediabetes and type 2 incidence of first CVD events or mortal- cidencerateofdiabetes,aBMIof30 diabetes risk through an informal assess- ity was not significantly different be- kg/m2 in non-Hispanic whites was equiv- ment of risk factors (Table 2.3) or with tween the groups (48). The excellent alent to a BMI of 26 kg/m2 in African an assessment tool, such as the ADA risk care provided to patients in the routine Americans (65). test (Fig. 2.1) (online at diabetes.org/ care group andDiabetes the lack of an un- socrisktest), is recommended to guide screened control arm limited the au- Medications providers on whether performing a di- thors’ ability to determine whether Certain medications, such as glucocor- agnostic test (Table 2.2) is appropriate. screening and early treatment im- ticoids, thiazide diuretics, some HIV Prediabetes and type 2 diabetes meet proved outcomes compared with no medications, and atypical antipsy- criteria for conditions in which early screening and later treatment after chotics (66), are known to increase detection is appropriate. Both conditions clinical diagnoses. Computer simula- the risk of diabetes and should be are common and impose significant clin- tion modeling studies suggest that considered when deciding whether ical and public health burdens. There is major benefits are likely to accrue to screen. often a long presymptomatic phase be- from the early diagnosis and treat- Testing Interval fore the diagnosis of typeAmerican 2 diabetes. ment of hyperglycemia and cardiovas- The appropriate interval between Simple tests to detect preclinical disease cular risk factors in type 2 diabetes screening tests is not known (67). The are readily available. The duration of (58); moreover, screening, beginning at rationale for the 3-year interval is glycemic burden is a strong predictor age 30 or 45 years and independent of that with this interval, the number of of adverse outcomes. There are effec- risk factors, may be cost-effective false-positive tests that require confir- , tive interventions that prevent progres- ( $11,000 per quality-adjusted life- matory testing will be reduced and sion from prediabetes to diabetes (see year gained) (59). individuals with false-negative tests “ Section 3 Prevention or Delay of Type 2 Additional considerations regard- will be retested before substantial ” Diabetes,©2019https://doi.org/10.2337/dc20- ing testing for type 2 diabetes and time elapses and complications de- S003) and reduce the risk of diabetes prediabetes in asymptomatic patients velop (67). complications (see Section 10 “Cardiovas- include the following. cular Disease and Risk Management,” Community Screening https://doi.org/10.2337/dc20-S010, and Age Ideally, testing should be carried out Section 11 “Microvascular Complications Age is a major risk factor for diabetes. within a health care setting because of and Foot Care,” https://doi.org/10.2337/ Testing should begin at no later than the need for follow-up and treatment. dc20-S011). age 45 years for all patients. Screening Community screening outside a health Approximately one-quarter of people should be considered in adults of any care setting is generally not recom- with diabetes in the U.S. and nearly half age with overweight or obesity and one mended because people with positive of Asian and Hispanic Americans with or more risk factors for diabetes. tests may not seek, or have access to, care.diabetesjournals.org Classification and Diagnosis of Diabetes S21

Association

Diabetes

American

Figure 2.1—ADA risk test (diabetes.org/socrisktest). S22 Classiﬁcation and Diagnosis of Diabetes Diabetes Care Volume 43, Supplement 1, January 2020

appropriate follow-up testing and care. diabetes in children with cystic fibrosis or however, recent publications suggest However, in specific situations where symptoms suggestive of acute onset of that an A1C cut point lower than 5.4% an adequate referral system is estab- type 1 diabetes and only A1C assays (5.8% in a second study) would detect lished beforehand for positive tests, without interference are appropriate more than 90% of cases and reduce community screening may be consid- for children with hemoglobinopathies, patient screening burden (77,78). On- ered. Community testing may also be the ADA continues to recommend A1C going studies are underway to validate poorly targeted; i.e., it may fail to for diagnosis of type 2 diabetes in this this approach. Regardless of age, weight reach the groups most at risk and in- cohort (74,75). loss or failure of expected weight gain appropriately test those at very low risk is a risk for CFRD and should prompt or even those who have already been CYSTIC FIBROSIS–RELATED screening (77,78). Continuous glucose diagnosed (68). DIABETES monitoring or HOMA of b-cell function (79)maybemoresensitivethanOGTTto Screening in Dental Practices Recommendations detect risk for progression to CFRD; Because periodontal disease is associated 2.14 Annual screening for cystic however, evidence linking these results with diabetes, the utility of screening in a fibrosis–related diabetes (CFRD) to long-term outcomes is lacking, and dental setting and referral to primary care with an oral glucose tolerance these tests are not recommended for as a means to improve the diagnosis of test should begin by age 10 years screening (80). prediabetes and diabetes has been in all patients with cystic fibrosis CFRD mortality has significantly de- explored (69–71), with one study es- not previously diagnosed with creased over time, and the gap in mor- timating that 30% of patients $30 CFRD. B tality between cystic fibrosis patients years of age seen in general dental 2.15 A1C is not recommended as a with and without diabetes has consid- practices had dysglycemia (71). Further screening testforcysticfibrosis– Association erably narrowed (81). There are limited research is needed to demonstrate the related diabetes. B clinical trial data on therapy for CFRD. feasibility, effectiveness, and cost-effec- 2.16 Patients with cystic fibrosis– The largest study compared three regi- tiveness of screening in this setting. related diabetes should be mens: premeal insulin aspart, repagli- treated with insulin to attain Screening and Testing for Prediabetes nide, or oral placebo in cystic fibrosis individualized glycemic goals. A and Type 2 Diabetes in Children and patients with diabetes or abnormal glu- 2.17 Beginning 5 years after the di- Adolescents cose tolerance. Participants all had agnosis of cystic fibrosis–related In the last decade, the incidence and weight loss in the year preceding treatdiabetes, annual monitoring for prevalence of type 2 diabetes in chil- ment; however, in the insulin-treated complications of diabetes is rec- dren and adolescents has increased group, this pattern was reversed, and ommended. E dramatically, especially in racial and Diabetespatients gained 0.39 (60.21) BMI units ethnic minority populations (41). See (P 5 0.02). The repaglinide-treated Table 2.4 for recommendations on risk- Cystic fibrosis–related diabetes (CFRD) group had initial weight gain, but this based screening for type 2 diabetes or is the most common comorbidity in was not sustained by 6 months. The prediabetes in asymptomatic children people with cystic fibrosis, occurring in placebo group continued to lose weight and adolescents in a clinical setting about 20% of adolescents and 40–50% of (81). Insulin remains the most widely (19). See Table 2.2 and Table 2.5 for adults (76). Diabetes in this population, used therapy for CFRD (82). the criteriaforthe diagnosisof diabetes compared with individuals with type 1 or Additional resources for the clinical and prediabetes, respectively, which type 2 diabetes, is associated with worse management of CFRD can be found in apply to children, adolescents, and nutritional status, more severe inflam- the position statement “Clinical Care adults. See Section 13 “Children and matory lung disease, and greater mor- Guidelines for Cystic Fibrosis–Related Adolescents” (https://doi.org/10.2337/Americantality. Insulin insufficiency is the primary Diabetes: A Position Statement of the dc20-S013) for additional information defect in CFRD. Genetically determined American Diabetes Association and a on type 2 diabetes in children and b-cell function and insulin resistance Clinical Practice Guideline of the Cystic adolescents. associated with infection and inflamma- Fibrosis Foundation, Endorsed by the Some studies question the validity of tion may also contribute to the devel- Pediatric Endocrine Society” (83) and A1C in the pediatric population, espe- opment of CFRD. Milder abnormalities in the International Society for Pedi- cially among certain ethnicities, and sug- of glucose tolerance are even more com- atric and Adolescent Diabetes’s2014 gest OGTT or FPG as more suitable mon and occur at earlier ages than CFRD. clinical practice consensus guidelines diagnostic©2019 tests (72). However, many Whether individuals with IGT should be (84). of these studies do not recognize that treated with insulin replacement has not diabetes diagnostic criteria are based on currently been determined. Although POSTTRANSPLANTATION long-term health outcomes, and valida- screening for diabetes before the age DIABETES MELLITUS tions are not currently available in the of 10 years can identify risk for progres- Recommendations pediatric population (73). The ADA ac- sion to CFRD in those with abnormal 2.18 Patients should be screened af- fi knowledges the limited data supporting glucose tolerance, no bene t has been ter organ transplantation for A1C for diagnosing type 2 diabetes in established with respect to weight, hyperglycemia, with a formal children and adolescents. Although A1C height, BMI, or lung function. OGTT diagnosis of posttransplantation is not recommended for diagnosis of is the recommended screening test; care.diabetesjournals.org Classification and Diagnosis of Diabetes S23

acute infection (89–91). The OGTT is diabetes mellitus being best MONOGENIC DIABETES considered the gold standard test for SYNDROMES made once a patient is stable the diagnosis of PTDM (86,87,92,93). on an immunosuppressive reg- Recommendations However, screening patients using imen and in the absence of an 2.21 All children diagnosed with di- fasting glucose and/or A1C can identify acute infection. E abetes in the first 6 months of high-risk patients requiring further as- 2.19 The oral glucose tolerance test life should have immediate ge- sessment and may reduce the number is the preferred test to make netic testing for neonatal dia- of overall OGTTs required. a diagnosis of posttransplanta- betes. A Few randomized controlled studies tion diabetes mellitus. B 2.22 Children and those diagnosed have reported on the short- and long- 2.20 Immunosuppressive regimens in early adulthood who have term use of antihyperglycemic agents in shown to provide the best out- diabetes not characteristic of the setting of PTDM (91,94,95). Most comes for patient and graft type 1 or type 2 diabetes that studies have reported that transplant survival should be used, irre- occurs in successive generations patients with hyperglycemia and PTDM spective of posttransplantation (suggestive of an autosomal after transplantation have higher rates of diabetes mellitus risk. E dominant pattern of inheri- rejection, infection, and rehospitalization tance) should have genetic test- (89,91,96). ing for maturity-onset diabetes Several terms are used in the literature Insulin therapy is the agent of choice of the young. A to describe the presence of diabetes for the management of hyperglycemia, 2.23 In both instances, consultation following organ transplantation (85). PTDM, and preexisting diabetes and di- with a center specializing in di- “New-onset diabetes after transplanta- abetes in the hospital setting. After dis- Associationabetes genetics is recommen- tion” (NODAT) is one such designation charge,patientswithpreexistingdiabetes ded to understand the significance that describes individuals who develop could go back on their pretransplant reg- of these mutations and how best new-onset diabetes following trans- imen if they were in good control before to approach further evaluation, plant. NODAT excludes patients with transplantation. Those with previously poor treatment, and genetic counsel- pretransplant diabetes that was undi- control or with persistent hyperglycemia ing. E agnosed as well as posttransplant hy- should continue insulin with frequent perglycemia that resolves by the time home self-monitoring of blood glucose to of discharge (86). Another term, “post- determine when insulin dose reduc- Monogenic defects that cause b-cell transplantation diabetes mellitus” (PTDM) tions may be needed and when it dysfunction, such as neonatal diabetes (86,87), describes the presence of di- may be appropriateDiabetes to switch to non- and MODY, represent a small fraction abetes in the posttransplant setting insulin agents. of patients with diabetes (,5%). Ta- irrespective of the timing of diabetes No studies to date have established ble 2.6 describes the most common onset. which noninsulin agents are safest or causes of monogenic diabetes. For a com- Hyperglycemia is very common during most efficacious in PTDM. The choice prehensive list of causes, see Genetic the early posttransplant period, with of agent is usually made based on the side Diagnosis of Endocrine Disorders ;90% of kidney allograft recipients ex- effect profile of the medication and (102). hibiting hyperglycemia in the first few possible interactions with the patient’s weeks following transplant (86–89). In immunosuppression regimen (91). Drug Neonatal Diabetes most cases, such stress- or steroid- dose adjustments may be required be- Diabetes occurring under 6 months of induced hyperglycemia resolves by the cause of decreases in the glomerular age is termed “neonatal” or “congeni- time of discharge (89,90). Although filtration rate, a relatively common com- tal” diabetes, and about 80–85% of the use of immunosuppressiveAmerican therapies plication in transplant patients. A small casescanbefoundtohaveanunder- is a major contributor to the develop- short-term pilot study reported that lying monogenic cause (103). Neonatal ment of PTDM, the risks of transplant metformin was safe to use in renal trans- diabetes occurs much less often after rejection outweigh the risks of PTDM and plant recipients (97), but its safety has 6 months of age, whereas autoimmune the role of the diabetes care provider not been determined in other types of type 1 diabetes rarely occurs before is to treat hyperglycemia appropriately organ transplant. Thiazolidinediones 6 months of age. Neonatal diabetes regardless of the type of immunosup- have been used successfully in patients can either be transient or permanent. pression (86). Risk factors for PTDM in- withliver andkidney transplants, but side Transientdiabetesismostoftendueto clude©2019 both general diabetes risks (such as effects include fluid retention, heart fail- overexpression of genes on chromo- age, family history of diabetes, etc.) as ure, and osteopenia (98,99). Dipeptidyl some 6q24, is recurrent in about half well as transplant-specific factors, such peptidase 4 inhibitors do not interact of cases, and may be treatable with as use of immunosuppressant agents with immunosuppressant drugs and have medications other than insulin. Perma- (91). Whereas posttransplantation hy- demonstrated safety in small clinical trials nent neonatal diabetes is most commonly perglycemia is an important risk factor (100,101). Well-designed intervention due to autosomal dominant mutations in for subsequent PTDM, a formal diagnosis trials examining the efficacy and safety the genes encoding the Kir6.2 subunit of PTDM is optimally made once the of these and other antihyperglycemic (KCNJ11) and SUR1 subunit (ABCC8)of patient is stable on maintenance immu- agents in patients with PTDM are the b-cell KATP channel. Correct diagnosis nosuppression and in the absence of needed. has critical implications because most S24 Classification and Diagnosis of Diabetes Diabetes Care Volume 43, Supplement 1, January 2020

Table 2.6—Most common causes of monogenic diabetes (102) Gene Inheritance Clinical features MODY GCK AD GCK-MODY: stable, nonprogressive elevated fasting blood glucose; typically does not require treatment; microvascular complications are rare; small rise in 2-h PG level on OGTT (,54 mg/dL [3 mmol/L]) HNF1A AD HNF1A-MODY: progressive insulin secretory defect with presentation in adolescence or early adulthood; lowered renal threshold for glucosuria; large rise in 2-h PG level on OGTT (.90 mg/dL [5 mmol/L]); sensitive to sulfonylureas HNF4A AD HNF4A-MODY: progressive insulin secretory defect with presentation in adolescence or early adulthood; may have large birth weight and transient neonatal hypoglycemia; sensitive to sulfonylureas HNF1B AD HNF1B-MODY: developmental renal disease (typically cystic); genitourinary abnormalities; atrophy of the pancreas; hyperuricemia; gout Neonatal diabetes KCNJ11 AD Permanent or transient: IUGR; possible developmental delay and seizures; responsive to sulfonylureas INS AD Permanent: IUGR; insulin requiring ABCC8 AD Permanent or transient: IUGR; rarely developmental delay; responsive to sulfonylureas 6q24 (PLAGL1, AD for paternal Transient: IUGR; macroglossia; umbilical hernia; mechanisms include UPD6, paternal HYMA1) duplications duplication or maternal methylation defect; may beAssociation treatable with medications other than insulin GATA6 AD Permanent: pancreatic hypoplasia; cardiac malformations; pancreatic exocrine insufﬁciency; insulin requiring EIF2AK3 AR Permanent: Wolcott-Rallison syndrome: epiphyseal dysplasia; pancreatic exocrine insufﬁciency; insulin requiring FOXP3 X-linked Permanent: immunodysregulation, polyendocrinopathy, enteropathy X-linked (IPEX) syndrome: autoimmune diabetes; autoimmune thyroid disease; exfoliative dermatitis; insulin requiring AD, autosomal dominant; AR, autosomal recessive; IUGR, intrauterine growth restriction; OGTT, oral glucose tolerance test; 2-h PG, 2-h plasma glucose. Diabetes

patients with KATP-related neonatal di- MODY (MODY3), and HNF4A-MODY HNF4A-MODY). Additionally, diagnosis can abetes will exhibit improved glycemic (MODY1). lead to identification of other affected control when treated with high-dose For individuals with MODY, the treat- family members. Genetic screening is in- oral sulfonylureas instead of insulin. ment implications are considerable and creasingly available and cost-effective Insulin gene (INS) mutations are the warrant genetic testing (104,105). Clin- (104,105). second most common cause of perma- ically, patients with GCK-MODY exhibit A diagnosis of MODY should be con- nent neonatal diabetes, and, while mild, stable, fasting hyperglycemia and sidered in individuals who have atypical intensive insulin management is cur- do not require antihyperglycemic ther- diabetes and multiple family members rently the preferred treatment strategy, apy except sometimes during pregnancy. with diabetes not characteristic of type there are important geneticAmerican counseling Patients with HNF1A- or HNF4A-MODY 1 or type 2 diabetes, although admit- considerations, as most of the mutations usually respond well to low doses of tedly “atypical diabetes” is becoming that cause diabetes are dominantly in- sulfonylureas, which are considered increasingly difficult to precisely define fi herited. rst-line therapy. Mutations or deletions in the absence of a definitive set of tests in HNF1B are associated with renal cysts for either type of diabetes (104–110). In Maturity-Onset Diabetes of the Young and uterine malformations (renal cysts MODY is frequently characterized by most cases, the presence of autoantibodies and diabetes [RCAD] syndrome). Other for type 1 diabetes precludes further onset of hyperglycemia at an early age extremely rare forms of MODY have been testing for monogenic diabetes, but (classically before age 25 years, although reported to involve other transcription the presence of autoantibodies in pa- diagnosis©2019 may occur at older ages). factor genes including PDX1 (IPF1) and tients with monogenic diabetes has been MODY is characterized by impaired in- NEUROD1. sulin secretion with minimal or no de- reported (111). Individuals in whom fects in insulin action (in the absence of Diagnosis of Monogenic Diabetes monogenic diabetes is suspected should coexistent obesity). It is inherited in A diagnosis of one of the three most be referred to a specialist for further an autosomal dominant pattern with common forms of MODY, including GCK- evaluation if available, and consultation abnormalities in at least 13 genes on MODY, HNF1A-MODY, and HNF4A-MODY, is available from several centers. Readily different chromosomes identified to allows for more cost-effective therapy available commercial genetic testing fol- date. The most commonly reported (no therapy for GCK-MODY; sulfonylureas lowing the criteria listed below now forms are GCK-MODY (MODY2), HNF1A- as first-line therapy for HNF1A-MODY and enables a cost-effective (112), often care.diabetesjournals.org Classification and Diagnosis of Diabetes S25

cost-saving, genetic diagnosis that is in- pancreoprivic diabetes (1). The diverse Definition creasingly supported by health insur- set of etiologies includes pancreatitis For many years, GDM was defined as ance. A biomarker screening pathway (acute and chronic), trauma or pancre- any degree of glucose intolerance that fi such as the combination of urinary atectomy, neoplasia, cystic fibrosis (ad- was rst recognized during pregnancy (49), regardless of the degree C-peptide/creatinine ratio and antibody dressed elsewhere in this chapter), of hyperglycemia. This definition facili- screening may aid in determining who hemochromatosis, fibrocalculous pan- should get genetic testing for MODY tated a uniform strategy for detection creatopathy, rare genetic disorders (113). It is critical to correctly diagnose and classification of GDM, but this defi- (117), and idiopathic forms (1). A distin- one of the monogenic forms of diabetes nition has serious limitations (126). First, because these patients may be incor- guishing feature is concurrent pancreatic the best available evidence reveals that rectly diagnosed with type 1 or type 2 exocrine insufficiency (according to the many, perhaps most, cases of GDM rep- diabetes, leading to suboptimal, even monoclonal fecal elastase 1 test or direct resent preexisting hyperglycemia that is potentially harmful, treatment regimens function tests), pathological pancreatic detected by routine screening in preg- and delays in diagnosing other family imaging (endoscopic ultrasound, MRI, nancy, as routine screening is not widely members (114). The correct diagnosis is computed tomography) and absence of performed in nonpregnant women of especially critical for those with GCK- type 1 diabetes–associated autoimmu- reproductive age. It is the severity of MODY mutations where multiple studies nity (118–122). There is loss of both hyperglycemia that is clinically important have shown that no complications ensue insulin and glucagon secretion and often with regard to both short- and long-term maternal and fetal risks. Universal pre- in the absence of glucose-lowering ther- higher-than-expected insulin require- conception and/or first trimester screen- apy (115). Genetic counseling is recom- ments. Risk for microvascular complica- ing is hampered by lack of data and mended to ensure that affected tions is similar to other forms of diabetes. In Association consensus regarding both appropriate individuals understand the patterns of the context of pancreatectomy, islet auto- diagnostic thresholds and outcomes. A inheritance and the importance of a transplantation can be done to retain insulin compelling argument for further work in correct diagnosis. secretion (123,124). In some cases, this can this area is the fact that hyperglycemia The diagnosis of monogenic diabetes leadto insulin independence. In others, that would be diagnostic of diabetes should be considered in children and it may decrease insulin requirements outside of pregnancy and is present at adults diagnosed with diabetes in (125). early adulthood with the following the time of conception is associated with findings: an increased risk of congenital malfor- GESTATIONAL DIABETES MELLITUS mations that is not seen with lower c Diabetes diagnosed within the first glucose levels (127,128). Recommendations 6 months of life (with occasional cases DiabetesThe ongoing epidemic of obesity and 2.24 Test for undiagnosed predia- presenting later, mostly INS and diabetes has led to more type 2 diabetes betes and diabetes at the first ABCC8 mutations) (103,116) in women of reproductive age, with an prenatal visit in those with risk c Diabetes without typical features of increase in the number of pregnant factors using standard diagnos- type 1 or type 2 diabetes (negative women with undiagnosed type 2 diabetic criteria. B diabetes-associatedautoantibodies,non- tes in early pregnancy (129–132). Be- 2.25 Test for gestational diabetes obese, lacking other metabolic features cause of the number of pregnant women mellitus at 24–28 weeks of ges- especially with strong family history of with undiagnosed type 2 diabetes, it is tation in pregnant women not diabetes) reasonable to test women with risk fac- previously found to have diabe- c Stable, mild fasting hyperglycemia tors for type 2 diabetes (133) (Table 2.3) tes. A (100–150 mg/dL [5.5–8.5 mmol/L]), at their initial prenatal visit, using stan- 2.26 Test women with gestational stable A1C between 5.6American and 7.6% dard diagnostic criteria (Table 2.2). diabetes mellitus for prediabe- (between 38 and 60 mmol/mol), es- Women found to have diabetes by the tes or diabetes at 4–12 weeks pecially if nonobese standard diagnostic criteria used outside postpartum, using the 75-g oral of pregnancy should be classified as glucose tolerance test and clin- PANCREATIC DIABETES OR having diabetes complicating pregnancy ically appropriate nonpregnancy DIABETES IN THE CONTEXT (most often type 2 diabetes, rarely type 1 diagnostic criteria. B OF DISEASE OF THE diabetes or monogenic diabetes) and 2.27 Women with a history of ges- EXOCRINE PANCREAS managed accordingly. Women who tational diabetes mellitus should Pancreatic©2019 diabetes includes both struc- meet the lower glycemic criteria for have lifelong screening for the tural and functional loss of glucose- GDM should be diagnosed with that development of diabetes or pre- normalizing insulin secretion in the context condition and managed accordingly. diabetes at least every 3 years. B of exocrine pancreatic dysfunction and Other women should be rescreened 2.28 Women with a history of ges- is commonly misdiagnosed as type 2 for GDM between 24 and 28 weeks of tational diabetes mellitus found diabetes. Hyperglycemia due to general gestation (see Section 14 “Management to have prediabetes should re- pancreatic dysfunction has been called of Diabetes in Pregnancy,” https://doi ceive intensive lifestyle inter- “type 3c diabetes” and, more recently, .org/10.2337/dc20-S014). The Interna- ventions and/or metformin to diabetes in the context of disease of tional Association of the Diabetes and prevent diabetes. A the exocrine pancreas has been termed Pregnancy Study Groups (IADPSG) GDM S26 Classification and Diagnosis of Diabetes Diabetes Care Volume 43, Supplement 1, January 2020

diagnosticcriteria for the 75-g OGTT as well normal for pregnancy. For most compli- study population. This one-step strategy as the GDM screening and diagnostic cri- cations, there was no threshold for risk. was anticipated to significantly increase teria used in the two-step approach were These results have led to careful recon- the incidence of GDM (from 5–6% to 15– not derived from data in the first half of sideration of the diagnostic criteria for 20%), primarily because only one abnor- pregnancy, so the diagnosis of GDM in GDM. mal value, not two, became sufficient to early pregnancy by either FPG or OGTT GDM diagnosis (Table 2.7) can be ac- make the diagnosis (142). Many regional values is not evidence based (134) and complished with either of two strate- studies have investigated the impact of further work is needed. gies: adopting IADPSG criteria on prevalence GDM is often indicative of underly- and have seen a roughly one- to threefold ing b-cell dysfunction (135), which 1. The “one-step” 75-g OGTT derived increase (143). The anticipated increase confers marked increased risk for later from the IADPSG criteria or in the incidence of GDM could have a development of diabetes, generally but 2. The older “two-step” approach with a substantial impact on costs and medical not always type 2 diabetes, in the mother 50-g (nonfasting) screen followed by infrastructure needs and has the poten- after delivery (136,137). As effective pre- a 100-g OGTT for those who screen tial to “medicalize” pregnancies previ- vention interventions are available positive, based on the work of Car- ously categorized as normal. A recent (138,139), women diagnosed with GDM penter and Coustan’s interpretation follow-up study of women participating should receive lifelong screening for pre- of the older O’Sullivan (141a) criteria. in a blinded study of pregnancy OGTTs diabetes to allow interventions to reduce found that 11 years after their pregnan- diabetes risk and for type 2 diabetes to Different diagnostic criteria will iden- cies, women who would have been di- allow treatment at the earliest pos- tify different degrees of maternal hyper- agnosed with GDM by the one-step sible time (140). glycemia and maternal/fetal risk, leading approach,Association as compared with those some experts to debate, and disagree on, without, were at 3.4-fold higher risk Diagnosis optimal strategies for the diagnosis of of developing prediabetes and type 2 GDM carries risks for the mother, fetus, GDM. diabetes and had children with a higher and neonate. The Hyperglycemia and risk of obesity and increased body fat, One-Step Strategy Adverse Pregnancy Outcome (HAPO) suggesting that the larger group of The IADPSG defined diagnostic cut points study (141), a large-scale multinational women identified by the one-step ap- for GDM as the average fasting, 1-h, and 2-h cohort study completed by more than proach would benefit from increased 23,000 pregnant women, demonstrated PGvaluesduringa75-gOGTTinwomenat screening for diabetes and prediabetes – that risk of adverse maternal, fetal, and 24 28 weeks of gestation who participated that would accompany a history of GDM neonatal outcomes continuously in- in the HAPO study at which odds for ad- (144). The ADA recommends the IADPSG creased as a function of maternal glyce- verse outcomesDiabetes reached 1.75 times the diagnostic criteria with the intent of mia at 24–28 weeks of gestation, even estimated odds of these outcomes at the optimizing gestational outcomes be- within ranges previously considered meanfasting,1-h, and2-hPGlevels of the cause these criteria were the only ones based on pregnancy outcomes rather than end points such as prediction Table 2.7—Screening for and diagnosis of GDM One-step strategy of subsequent maternal diabetes. fi Perform a 75-g OGTT, with plasma glucose measurement when patient is fasting and at 1 The expected bene ts of using IADPSG to and 2 h, at 24–28 weeks of gestation in women not previously diagnosed with diabetes. the offspring are inferred from intervention The OGTT should be performed in the morning after an overnight fast of at least 8 h. trialsthatfocusedonwomenwithlower The diagnosis of GDM is made when any of the following plasma glucose values are met or levels of hyperglycemia than identified exceeded: using older GDM diagnostic criteria. Those c Fasting: 92 mg/dL (5.1American mmol/L) trials found modest benefits including re- c 1 h: 180 mg/dL (10.0 mmol/L) duced rates of large-for-gestational-age c 2 h: 153 mg/dL (8.5 mmol/L) births and preeclampsia (145,146). It is Two-step strategy important to note that 80–90% of women Step 1: Perform a 50-g GLT (nonfasting), with plasma glucose measurement at 1 h, at 24– being treated for mild GDM in these two 28 weeks of gestation in women not previously diagnosed with diabetes. randomized controlled trials could be man- If the plasma glucose level measured 1 h after the load is $130, 135, or 140 mg/dL (7.2, 7.5, or agedwithlifestyletherapyalone.The 7.8 mmol/L, respectively), proceed to a 100-g OGTT. OGTT glucose cutoffs in these two trials Step 2: The 100-g OGTT should be performed when the patient is fasting. ©2019 overlapped with the thresholds recom- The diagnosis of GDM is made when at least two* of the following four plasma glucose levels (measured fasting and at 1, 2, and 3 h during OGTT) are met or exceeded (Carpenter-Coustan mended by the IADPSG, and in one trial criteria [154]): (146), the 2-h PG threshold (140 mg/dL c Fasting: 95 mg/dL (5.3 mmol/L) [7.8 mmol/L]) was lower than the cutoff c 1 h: 180 mg/dL (10.0 mmol/L) recommended by the IADPSG (153 mg/ c 2 h: 155 mg/dL (8.6 mmol/L) dL [8.5 mmol/L]). No randomized con- c 3 h: 140 mg/dL (7.8 mmol/L) trolled trials of treating versus not GDM, gestational diabetes mellitus; GLT, glucose load test; OGTT, oral glucose tolerance test. treating GDM diagnosed by the IADPSG *American College of Obstetricians and Gynecologists notes that one elevated value can be used criteria but not the Carpenter-Coustan for diagnosis (150). criteria have been published to date. care.diabetesjournals.org Classification and Diagnosis of Diabetes S27

Data are also lacking on how the treat- of neonatal macrosomia, large-for- approaches have been inconsistent to ment of lower levels of hyperglycemia gestational-age births (153), and shoulder date (159,160). In addition, pregnancies affects a mother’s future risk for the dystocia, without increasing small-for- complicated by GDM per the IADPSG development of type 2 diabetes and her gestational-age births. ACOG currently criteria, but not recognized as such, offspring’s risk for obesity, diabetes, supports the two-step approach but have outcomes comparable to preg- and other metabolic disorders. Addi- notes that one elevated value, as op- nancies with diagnosed GDM by the tional well-designed clinical studies are posed to two, may be used for the di- more stringent two-stepcriteria(161,162). needed to determine the optimal in- agnosis of GDM (150). If this approach There remains strong consensus that tensity of monitoring and treatment of is implemented, the incidence of GDM establishing a uniform approach to di- womenwithGDMdiagnosedbythe by the two-step strategy will likely in- agnosing GDM will benefitpatients, one-step strategy (147,148). crease markedly. ACOG recommends caregivers, and policy makers. Longer- Two-Step Strategy either of two sets of diagnostic thresh- term outcome studies are currently underway. In 2013, the National Institutes of Health olds for the 3-h 100-g OGTTdCarpenter- (NIH) convened a consensus develop- Coustan or National Diabetes Data References ment conference to consider diagnostic Group (154,155). Each is based on dif- 1. American Diabetes Association. Diagnosis criteria for diagnosing GDM (149). The ferent mathematical conversions of the and classification of diabetes mellitus. Diabetes 15-member panel had representatives original recommended thresholds by Care 2014;37(Suppl. 1):S81–S90 from obstetrics and gynecology, maternal- O’Sullivan (141a), which used whole 2.DabeleaD,RewersA,StaffordJM,etal.; SEARCH for Diabetes in Youth Study Group. blood and nonenzymatic methods for fetal medicine, pediatrics, diabetes re- Trends in the prevalence of ketoacidosis at search, biostatistics, and other related glucose determination. A secondary diabetes diagnosis: the SEARCH for Diabetes fields. The panel recommended a two- analysis of data from a randomized in YouthAssociation Study. Pediatrics 2014;133:e938– step approach to screening that used a clinical trial of identification and treat- e945 1-h 50-g glucose load test (GLT) followed ment of mild GDM (156) demonstrated 3. HumphreysA,BravisV, KaurA,etal.Individual that treatment was similarly benefi- and diabetes presentation characteristics asso- by a 3-h 100-g OGTT for those who ciated with partial remission status in children screenedpositive.TheAmerican College cial in patients meeting only the lower and adults evaluated up to 12 months following of Obstetricians and Gynecologists thresholds per Carpenter-Coustan (154) diagnosisoftype1diabetes:anADDRESS-2(After (ACOG) recommends any of the com- and in those meeting only the higher Diagnosis Diabetes Research Support System-2) monly used thresholds of 130, 135, or thresholds per National Diabetes Data study analysis. Diabetes Res Clin Pract 2019;155: 140 mg/dL for the 1-h 50-g GLT (150). A Group (155). If the two-step approach is 107789 4. Thomas NJ, Lynam AL, Hill AV, et al. Type 1 di- systematic review for the U.S. Preventive used, it would appear advantageous to abetes defined by severe insulin deficiency occurs Services Task Force compared GLT cut- use the Carpenter-CoustanDiabetes lower diag- after 30 years of age and is commonly treated as offs of 130 mg/dL (7.2 mmol/L) and nostic thresholds as shown in step 2 in type 2 diabetes. Diabetologia 2019;62:1167–1172 140 mg/dL (7.8 mmol/L) (151). The Table 2.7. 5. Hope SV, Wienand-Barnett S, Shepherd M, et al. Practical classification guidelines for diabetes higher cutoff yielded sensitivity of 70– Future Considerations fi – in patients treated with insulin: a cross-sectional 88% and speci city of 69 89%, while the The conflicting recommendations from study of the accuracy of diabetes diagnosis. Br J – lower cutoff was 88 99% sensitive and expert groups underscore the fact that Gen Pract 2016;66:e315–e322 – fi 66 77% speci c. Data regarding a cutoff there are data to support each strategy. A 6. Zhong VW, Juhaeri J, Mayer-Davis EJ. Trends of 135 mg/dL are limited. As for other cost-benefit estimation comparing the in hospital admission for diabetic ketoacidosis screening tests, choiceof a cutoff isbased in adults with type 1 and type 2 diabetes in Eng- two strategies concluded that the one- – upon the trade-off between sensitivity land, 1998 2013: a retrospective cohort study. step approach is cost-effective only if Diabetes Care 2018;41:1870–1877 fi – and speci city. The use of A1C at 24 patients with GDM receive postdelivery 7. Newton CA, Raskin P. Diabetic ketoacidosis in 28 weeks of gestation as a screeningAmerican test counseling and care to prevent type 2 type 1 and type 2 diabetes mellitus: clinical and for GDM does not function as well as the diabetes (157). The decision of which biochemical differences. Arch Intern Med 2004; – GLT (152). strategy to implement must therefore be 164:1925 1931 KeyfactorscitedbytheNIHpanelin 8. Skyler JS, Bakris GL, Bonifacio E, et al. Dif- made based on the relative values placed ferentiation of diabetes by pathophysiology, their decision-making process were the on factors that have yet to be measured natural history, and prognosis. Diabetes 2017; lack of clinical trial data demonstrating (e.g., willingness to change practice 66:241–255 the benefits of the one-step strategy based on correlation studies rather 9. Insel RA, Dunne JL, Atkinson MA, et al. Staging and the potential negative consequen- than intervention trial results, available presymptomatic type 1 diabetes: a scientific ces©2019 of identifying a large group of infrastructure, and importance of cost statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes women with GDM, including medical- considerations). Care 2015;38:1964–1974 ization of pregnancy with increased As the IADPSG criteria (“one-step 10. Gale EA. Declassifying diabetes. Diabetolo- health care utilization and costs. More- strategy”) have been adopted interna- gia 2006;49:1989–1995 over, screening with a 50-g GLT does tionally, further evidence has emerged 11. Schwartz SS, Epstein S, Corkey BE, Grant SFA, not require fasting and is therefore to support improved pregnancy out- Gavin JR 3rd, Aguilar RB. The time is right for a fi easier to accomplish for many women. comes with cost savings (158) and new classi cation system for diabetes: rationale and implications of the b-cell-centric classifica- Treatment of higher-threshold mater- IADPSG may be the preferred approach. tion schema. Diabetes Care 2016;39:179–186 nal hyperglycemia, as identified by Data comparing population-wide out- 12. International Expert Committee. Interna- the two-step approach, reduces rates comeswithone-stepversustwo-step tional Expert Committee report on the role of S28 Classification and Diagnosis of Diabetes Diabetes Care Volume 43, Supplement 1, January 2020

the A1C assay in the diagnosis of diabetes. differencesinglycemicmarkers:across-sectional Prevention Trial-Type 1 Study Group. The pre- Diabetes Care 2009;32:1327–1334 analysis of community-based data. Ann Intern diction of type 1 diabetes by multiple autoan- 13. Knowler WC, Barrett-Connor E, Fowler SE, Med 2011;154:303–309 tibody levels and their incorporation into an et al.; Diabetes Prevention Program Research 28. Herman WH, Dungan KM, Wolffenbuttel autoantibody risk score in relatives of type 1 Group. Reduction in the incidence of type 2 BHR, et al. Racial and ethnic differences in diabetic patients. Diabetes Care 2013;36:2615– diabetes with lifestyle intervention or metfor- mean plasma glucose, hemoglobin A1c, and 2620 min. N Engl J Med 2002;346:393–403 1,5-anhydroglucitol in over 2000 patients with 44. Steck AK, Vehik K, Bonifacio E, et al.; TEDDY 14. Tuomilehto J, Lindstrom¨ J, Eriksson JG, type 2 diabetes. J Clin Endocrinol Metab 2009;94: Study Group. Predictors of progression from the et al.; Finnish Diabetes Prevention Study Group. 1689–1694 appearance of islet autoantibodies to early child- Prevention of type 2 diabetes mellitus by 29. Selvin E, Rawlings AM, Bergenstal RM, hood diabetes: The Environmental Determinants changes in lifestyle among subjects with im- Coresh J, Brancati FL. No racial differences in of Diabetes in the Young (TEDDY). Diabetes Care paired glucose tolerance. N Engl J Med 2001; the association of glycated hemoglobin with 2015;38:808–813 344:1343–1350 kidney disease and cardiovascular outcomes. 45. Orban T, Sosenko JM, Cuthbertson D, et al.; 15. Meijnikman AS, De Block CEM, Dirinck E, Diabetes Care 2013;36:2995–3001 Diabetes Prevention Trial-Type 1 Study Group. et al. Not performing an OGTT results in signif- 30. Selvin E. Are there clinical implications of Pancreatic islet autoantibodies as predictors of icant underdiagnosis of (pre)diabetes in a high racial differences in HbA1c? A difference, to be a type 1 diabetes in the Diabetes Prevention Trial- risk adult Caucasian population. Int J Obes 2017; difference, must make a difference. Diabetes Type 1. Diabetes Care 2009;32:2269–2274 41:1615–1620 Care 2016;39:1462–1467 46. Jacobsen LM, Larsson HE, Tamura RN, et al.; 16. Cowie CC, Rust KF, Byrd-Holt DD, et al. 31. Paterson AD. HbA1c for type 2 diabetes TEDDY Study Group. Predicting progression to Prevalence of diabetes and high risk for diabetes diagnosis in Africans and African Americans: type 1 diabetes from ages 3 to 6 in islet auto- using A1C criteria in the U.S. population in 1988– personalized medicine NOW! PLoS Med 2017; antibody positive TEDDY children. Pediatr Di- 2006. Diabetes Care 2010;33:562–568 14:e1002384 abetes 2019;20:263–270 17. Eckhardt BJ, Holzman RS, Kwan CK, Baghdadi 32. Cappellini MD, Fiorelli G. Glucose-6- 47. American Diabetes Association. Diagnosis fi J,AbergJA.Glycatedhemoglobin A asscreening phosphate dehydrogenase de ciency. Lan- and classification of diabetes mellitus. Diabetes 1c – for diabetes mellitus in HIV-infected individuals. cet 2008;371:64 74 CareAssociation 2011;34(Suppl. 1):S62–S69 ~ AIDS Patient Care STDS 2012;26:197–201 33. Picon´ MJ, Murri M, Munoz A, Fernandez-´ 48. Expert Committee on the Diagnosis and ı 18. Kim PS, Woods C, Georgoff P, et al. A1C Garcá JC, Gomez-Huelgas R, Tinahones FJ. He- Classification of Diabetes Mellitus. Report of underestimates glycemia in HIV infection. Di- moglobin A1c versus oral glucose tolerance test in the Expert Committee on the Diagnosis and abetes Care 2009;32:1591–1593 postpartum diabetes screening. Diabetes Care Classification of Diabetes Mellitus. Diabetes – 19. Arslanian S, Bacha F, Grey M, Marcus MD, 2012;35:1648 1653 Care 1997;20:1183–1197 White NH, Zeitler P. Evaluation and management 34. GoblCS,¨ BozkurtL, Yarragudi R, Tura A,Pacini 49. Zhang X, Gregg EW, Williamson DF, et al. A1C of youth-onset type 2 diabetes: a position state- G, Kautzky-Willer A. Is early postpartum HbA1c level and future risk of diabetes: a systematic ment by the American Diabetes Association. an appropriate risk predictor after pregnancy review. Diabetes Care 2010;33:1665–1673 with gestational diabetes mellitus? Acta Diabetol Diabetes Care 2018;41:2648–2668 50. Selvin E, Steffes MW, Zhu H, et al. Glycated 2014;51:715–722 20. LacyME,WelleniusGA,SumnerAE,CorreaA, hemoglobin, diabetes, and cardiovascular risk in 35. Megia A, Naf¨ S, Herranz L, et al. The use- Carnethon MR, Liem RI,et al. Association of sickle nondiabetic adults. N Engl J Med 2010;362:800– fulness of HbA1c in postpartum reclassification of cell trait with hemoglobin A1c in African Amer- 811 gestational diabetes.Diabetes BJOG 2012;119:891–894 icans. JAMA 2017;317:507–515 51. Ackermann RT, Cheng YJ, Williamson DF, 36. Welsh KJ, Kirkman MS, Sacks DB. Role of 21. Wheeler E, Leong A, Liu C-T, et al.; EPIC-CVD Gregg EW. Identifying adults at high risk for glycated proteins in the diagnosis and manage- Consortium; EPIC-InterAct Consortium; Lifelines diabetes and cardiovascular disease using he- ment of diabetes: research gaps and future Cohort Study. Impact of common genetic deter- moglobin A1c National Health and Nutrition directions. Diabetes Care 2016;39:1299–1306 minants of hemoglobin A1c on type 2 diabetes risk Examination Survey 2005-2006. Am J Prev 37. Kim C, Bullard KM, Herman WH, Beckles GL. and diagnosis in ancestrally diverse populations: Med 2011;40:11–17 Association between iron deficiency and A1C a transethnic genome-wide meta-analysis. PLoS 52. Diabetes Prevention Program Research Levels among adults without diabetes in the Med 2017;14:e1002383 Group. HbA1c as a predictor of diabetes and National Health and Nutrition Examination Sur- as an outcome in the diabetes prevention pro- 22. Ziemer DC, Kolm P, Weintraub WS, et al. vey, 1999–2006. Diabetes Care 2010;33:780– gram: a randomized clinical trial. Diabetes Care Glucose-independent, black-white differences in 785 2015;38:51–58 hemoglobin A1c levels: a cross-sectional analysis 38. Selvin E, Wang D, Matsushita K, Grams ME, – 53. Umpierrez G, Korytkowski M. Diabetic of 2 studies. Ann Intern Med 2010;152:770 777 Coresh J. Prognostic implications of single- emergencies - ketoacidosis, hyperglycaemic 23. Kumar PR, Bhansali A, Ravikiran M, et al. sample confirmatory testing for undiagnosed American hyperosmolar state and hypoglycaemia. Nat Utility of glycated hemoglobin in diagnosing diabetes: a prospective cohort study. Ann Rev Endocrinol 2016;12:222–232 type 2 diabetes mellitus: a community-based Intern Med 2018;169:156–164 – 54. Fadini GP, Bonora BM, Avogaro A. SGLT2 study. J Clin Endocrinol Metab 2010;95:2832 39. Mishra R, Hodge KM, Cousminer DL, Leslie inhibitors and diabetic ketoacidosis: data from 2835 RD, Grant SFA. A global perspective of latent the FDA Adverse Event Reporting System. Dia- 24. Herman WH. Are there clinical implications autoimmune diabetes in adults. Trends Endo- betologia 2017;60:1385–1389 of racial differences in HbA1c? Yes, to not con- crinol Metab 2018;29:638–650 fi sider can do great harm! Diabetes Care 2016;39: 40. Buzzetti R, Zampetti S, Maddaloni E. Adult- 55. Grif n SJ, Borch-Johnsen K, Davies MJ, 1458–1461 onset autoimmune diabetes: current knowledge et al. Effect of early intensive multifactorial 25. Herman WH, Ma Y, Uwaifo G, et al.; Diabetes and implications for management. Nat Rev En- therapy on 5-year cardiovascular outcomes Prevention©2019 Program Research Group. Differen- docrinol 2017;13:674–686 in individuals with type 2 diabetes detected ces in A1C by race and ethnicity among patients 41. Dabelea D, Mayer-Davis EJ, Saydah S, et al.; by screening (ADDITION-Europe): a cluster- with impaired glucose tolerance in the Diabetes SEARCH for Diabetes in Youth Study. Prevalence randomised trial. Lancet 2011;378:156– Prevention Program. Diabetes Care 2007;30: of type 1 and type 2 diabetes among children and 167 2453–2457 adolescents from 2001 to 2009. JAMA 2014;311: 56. Genuth S, Alberti KG, Bennett P, et al.; Expert 26. Bergenstal RM, Gal RL, Connor CG, et al.; T1D 1778–1786 Committee on the Diagnosis and Classification of Exchange Racial Differences Study Group. Racial 42. Ziegler AG, Rewers M, Simell O, et al. Se- Diabetes Mellitus. Follow-up report on the di- differences in the relationship of glucose con- roconversion to multiple islet autoantibodies agnosis of diabetes mellitus. Diabetes Care 2003; centrations and hemoglobin A1c levels. Ann and risk of progression to diabetes in children. 26:3160–3167 Intern Med 2017;167:95–102 JAMA 2013;309:2473–2479 57. Peterson C, Grosse SD, Li R, et al. Preventable 27. Selvin E, Steffes MW, Ballantyne CM, 43. Sosenko JM, Skyler JS, Palmer JP, et al.; Type health and cost burden of adverse birth out- Hoogeveen RC, Coresh J, Brancati FL. Racial 1 Diabetes TrialNet Study Group; Diabetes comes associated with pregestational diabetes in care.diabetesjournals.org Classification and Diagnosis of Diabetes S29

the United States. Am J Obstet Gynecol 2015; fasting plasma glucose in a multiethnic middle- 87. Hecking M, Werzowa J, Haidinger M, et al.; 212:74.e1–74.e9 school cohort. Diabetes Care 2013;36:429–435 European-New-Onset Diabetes After Transplan- 58. Herman WH, Ye W, Griffin SJ, et al. Early 73. Kapadia C, Zeitler P; Drugs and Therapeutics tationWorking Group.Novel viewson new-onset detection and treatment of type 2 diabetes Committee of the Pediatric Endocrine Society. diabetes after transplantation: development, reduce cardiovascular morbidity and mortality: Hemoglobin A1c measurement for the diagnosis prevention and treatment. Nephrol Dial Trans- a simulation of the results of the Anglo- of type 2 diabetes in children. Int J Pediatr plant 2013;28:550–566 Danish-Dutch Study of Intensive Treatment Endocrinol 2012;2012:31 88. Ramirez SC, Maaske J, Kim Y, et al. The in People With Screen-Detected Diabetes in 74. Kester LM, Hey H, Hannon TS. Using hemo- association betweenglycemiccontrolandclinical Primary Care (ADDITION-Europe). Diabetes globin A1c for prediabetes and diabetes diag- outcomes after kidney transplantation. Endocr Care 2015;38:1449–1455 nosis in adolescents: can adultrecommendations Pract 2014;20:894–900 59. Kahn R, Alperin P, Eddy D, et al. Age at be upheld for pediatric use? J Adolesc Health 89. Thomas MC, Moran J, Mathew TH, Russ GR, initiation and frequency of screening to detect 2012;50:321–323 Rao MM. Early peri-operative hyperglycaemia type 2 diabetes: a cost-effectiveness analysis. 75. Wu E-L, Kazzi NG, Lee JM. Cost-effectiveness and renal allograft rejection in patients without Lancet 2010;375:1365–1374 of screening strategies for identifying pediatric diabetes. BMC Nephrol 2000;1:1 60. Araneta MRG, Kanaya A, Fujimoto W, diabetes mellitus and dysglycemia. JAMA Pediatr 90. Chakkera HA, Weil EJ, Castro J, et al. Hy- et al. Optimum BMI cut-points to screen Asian 2013;167:32–39 perglycemia during the immediate period after Americans for type 2 diabetes: The UCSD 76. Moran A, Pillay K, Becker D, Granados A, kidney transplantation. Clin J Am Soc Nephrol Filipino Health Study and the North Kohala Hameed S, Acerini CL. ISPAD Clinical Practice Con- 2009;4:853–859 Study [Abstract]. Diabetes 2014;63(Suppl. 1): sensus Guidelines 2018: management of cystic 91. Wallia A, Illuri V, Molitch ME. Diabetes care A20 fibrosis-related diabetes in children and adolescents. after transplant: definitions, risk factors, and 61. Hsu WC, Araneta MRG, Kanaya AM, Chiang Pediatr Diabetes 2018;19(Suppl. 27):64–74 clinical management. Med Clin North Am JL, Fujimoto W. BMI cut points to identify at-risk 77. Gilmour JA, Sykes J, Etchells E, Tullis E. Cystic 2016;100:535–550 Asian Americans for type 2 diabetes screening. fibrosis-related diabetes screening in adults: 92. Sharif A, Moore RH, Baboolal K. The use of Diabetes Care 2015;38:150–158 a gap analysis and evaluation of accuracy of oral glucose tolerance tests to risk stratify for 62. WHO Expert Consultation. Appropriate body- glycated hemoglobin levels. Can J Diabetes 2019; new-onsetAssociation diabetes after transplantation: an mass index for Asian populations and its impli- 43:13–18 underdiagnosed phenomenon. Transplantation cations for policy and intervention strategies. 78. Gilmour JA. Response to the Letter to the 2006;82:1667–1672 Lancet 2004;363:157–163 Editor from Dr. Boudreau et al, “Validation of a 93. HeckingM, KainzA,WerzowaJ, etal.Glucose 63. Menke A, Casagrande S, Geiss L, Cowie CC. Stepwise Approach Using Glycated Hemoglobin metabolism after renal transplantation. Diabetes Prevalence of and trends in diabetes among Levels to Reduce the Number of Required Oral Care 2013;36:2763–2771 adults in the United States, 1988-2012. JAMA Glucose Tolerance Tests to Screen for Cystic 94. Galindo RJ, Fried M, Breen T, Tamler R. 2015;314:1021–1029 Fibrosis-Related Diabetes in Adults”. Can J Di- Hyperglycemia management in patients with 64. Centers for Disease Control and Preven- abetes 2019;43:163 posttransplantation diabetes. Endocr Pract tion. National diabetes statistics report: esti- 79. Mainguy C, Bellon G, Delaup V, et al. Sen- 2016;22:454–465 mates of diabetes and its burden in the United sitivity and specificity of different methods for 95. Jenssen T, Hartmann A. Emerging treat- States, 2017. Accessed 31 October 2019. Avail- cystic fibrosis-related diabetes screening: is the ments for post-transplantation diabetes melli- able from https://www.cdc.gov/diabetes/data/ oral glucose toleranceDiabetes test still the standard? tus. Nat Rev Nephrol 2015;11:465–477 statistics/statistics-report.html J Pediatr Endocrinol Metab 2017;30:27–35 96. Thomas MC, Mathew TH, Russ GR, Rao MM, 65. Chiu M, Austin PC, Manuel DG, Shah BR, Tu 80. Ode KL, Moran A. New insights into cystic Moran J. Early peri-operative glycaemic control JV. Deriving ethnic-specific BMI cutoff points for fibrosis-related diabetes in children. Lancet Di- and allograft rejection in patients with diabetes assessing diabetes risk. Diabetes Care 2011;34: abetes Endocrinol 2013;1:52–58 mellitus: a pilot study. Transplantation 2001;72: 1741–1748 81. Moran A, Dunitz J, Nathan B, Saeed A, Holme 1321–1324 66. Erickson SC, Le L, Zakharyan A, et al. New- B, Thomas W. Cystic fibrosis-related diabetes: 97. Kurian B, Joshi R, Helmuth A. Effectiveness onset treatment-dependent diabetes mellitus current trends in prevalence, incidence, and and long-term safety of thiazolidinediones and and hyperlipidemia associated with atypical an- mortality. Diabetes Care 2009;32:1626–1631 metformin in renal transplant recipients. Endocr tipsychotic use in older adults without schizo- 82. Onady GM, Stolfi A. Insulin and oral agents Pract 2008;14:979–984 phrenia or bipolar disorder. J Am Geriatr Soc for managing cystic fibrosis-related diabetes. 98. Budde K, Neumayer H-H, Fritsche L, 2012;60:474–479 Cochrane Database Syst Rev 2016;4:CD004730 Sulowicz W, Stomporˆ T, Eckland D. The phar- 67. Johnson SL, Tabaei BP, Herman WH. The 83. Moran A, Brunzell C, Cohen RC, et al.; CFRD macokinetics of pioglitazone in patients with efficacy and cost of alternativeAmerican strategies for Guidelines Committee. Clinical care guidelines impaired renal function. Br J Clin Pharmacol systematic screening for type 2 diabetes in the for cystic fibrosis-related diabetes: a position 2003;55:368–374 U.S. population 45-74 years of age. Diabetes Care statement of the American Diabetes Association 99. Luther P, Baldwin D Jr. Pioglitazone in the 2005;28:307–311 and a clinical practice guideline of the Cystic management of diabetes mellitus after trans- 68. Tabaei BP, Burke R, Constance A, et al. Fibrosis Foundation, endorsed by the Pediatric plantation. Am J Transplant 2004;4:2135– Community-based screening for diabetes in Endocrine Society. Diabetes Care 2010;33:2697– 2138 Michigan. Diabetes Care 2003;26:668–670 2708 100. Strøm Halden TA, Asberg˚ A, Vik K, 69. Lalla E, Kunzel C, Burkett S, Cheng B, Lamster 84. Moran A, Pillay K, Becker DJ, Acerini CL; Hartmann A, Jenssen T. Short-term efficacy IB. Identification of unrecognized diabetes and International Society for Pediatric and Adoles- and safety of sitagliptin treatment in long- pre-diabetes in a dental setting. J Dent Res 2011; cent Diabetes. ISPAD Clinical Practice Consensus term stable renal recipients with new-onset 90:855©2019–860 Guidelines 2014. Management of cystic fibrosis- diabetes after transplantation. Nephrol Dial 70. Lalla E, Cheng B, Kunzel C, Burkett S, Lamster related diabetes in children and adolescents. Transplant 2014;29:926–933 IB. Dental findings and identification of undiag- Pediatr Diabetes 2014;15(Suppl. 20):65–76 101. Lane JT, Odegaard DE, Haire CE, Collier DS, nosed hyperglycemia. J Dent Res 2013;92:888– 85. Shivaswamy V, Boerner B, Larsen J. Post- Wrenshall LE, Stevens RB. Sitagliptin therapy in 892 transplant diabetes mellitus: causes, treatment, kidney transplant recipients with new-onset di- 71. Herman WH, Taylor GW, Jacobson JJ, Burke and impact on outcomes. Endocr Rev 2016;37: abetes after transplantation. Transplantation R, Brown MB. Screening for prediabetes and 37–61 2011;92:e56–e57 type 2 diabetes in dental offices. J Public Health 86. Sharif A, Hecking M, de Vries APJ, et al. 102. Carmody D, Støy J, Greeley SA, Bell GI, Dent 2015;75:175–182 Proceedings from an international consensus Philipson LH. A clinical guide to monogenic di- 72. Buse JB, Kaufman FR, Linder B, Hirst K, El meeting on posttransplantation diabetes melli- abetes. In Genetic Diagnosis of Endocrine Dis- Ghormli L, Willi S; HEALTHY Study Group. Di- tus: recommendations and future directions. Am orders. 2nd ed. Weiss RE, Refetoff S, Eds. abetes screening with hemoglobin A1c versus J Transplant 2014;14:1992–2000 Philadelphia, PA, Elsevier, 2016 S30 Classification and Diagnosis of Diabetes Diabetes Care Volume 43, Supplement 1, January 2020

103. De Franco E, Flanagan SE, Houghton JAL, 117. Le Bodic L, Bignon JD, Raguen´ es` O, et al. 133. Mission JF, Catov J, Deihl TE, Feghali M, et al. The effect of early, comprehensive genomic The hereditary pancreatitis gene maps to long Scifres C. Early pregnancy diabetes screening and testing on clinical care in neonatal diabetes: an arm of chromosome 7. Hum Mol Genet 1996;5: diagnosis: prevalence, rates of abnormal test international cohort study. Lancet 2015;386: 549–554 results, and associated factors. Obstet Gynecol 957–963 118. Hardt PD, Brendel MD, Kloer HU, Bretzel 2017;130:1136–1142 104. Shields BM, Hicks S, Shepherd MH, RG. Is pancreatic diabetes (type 3c diabetes) 134. McIntyre HD, Sacks DA, Barbour LA, et al. Colclough K, Hattersley AT, Ellard S. Maturity- underdiagnosed and misdiagnosed? Diabetes Issues with the diagnosis and classification of onset diabetes of the young (MODY): how many Care 2008;31(Suppl. 2):S165–S169 hyperglycemia in early pregnancy. Diabetes Care cases are we missing? Diabetologia 2010;53: 119. Woodmansey C, McGovern AP, McCullough 2016;39:53–54 2504–2508 KA, et al. Incidence, demographics, and clinical 135. Buchanan TA, Xiang A, Kjos SL, Watanabe R. 105. Awa WL, Schober E, Wiegand S, et al. characteristics of diabetes of the exocrine pan- What is gestational diabetes? Diabetes Care Reclassification of diabetes type in pediatric creas (type 3c): a retrospective cohort study. 2007;30(Suppl. 2):S105–S111 patients initially classified as type 2 diabetes Diabetes Care 2017;40:1486–1493 136. Noctor E, Crowe C, Carmody LA, et al.; mellitus: 15 years follow-up using routine data 120. Duggan SN, Ewald N, Kelleher L, GriffinO, ATLANTIC-DIP investigators. Abnormal glucose from the German/Austrian DPV database. Di- Gibney J, Conlon KC. The nutritional manage- tolerance post-gestational diabetes mellitus as fi abetes Res Clin Pract 2011;94:463–467 ment of type 3c (pancreatogenic) diabetes in de ned by the International Association of Di- 106. Shepherd M, Shields B, Hammersley S, chronic pancreatitis. Eur J Clin Nutr 2017;71:3–8 abetes and Pregnancy Study Groups criteria. Eur J – et al.; UNITED Team. Systematic population 121. Makuc J. Management of pancreatogenic Endocrinol 2016;175:287 297 screening, using biomarkers and genetic testing, diabetes: challenges and solutions. Diabetes 137. Kim C, Newton KM, Knopp RH. Gestational – identifies 2.5% of the U.K. pediatric diabetes Metab Syndr Obes 2016;9:311 315 diabetes and the incidence of type 2 diabetes: population with monogenic diabetes. Diabetes 122. Andersen DK, Korc M, Petersen GM, et al. a systematic review. Diabetes Care 2002;25: – Care 2016;39:1879–1888 Diabetes, pancreatogenic diabetes, and pancre- 1862 1868 – 107. SEARCH Study Group. SEARCH for Diabetes atic cancer. Diabetes 2017;66:1103 1110 138. Ratner RE, Christophi CA, Metzger BE, et al.; Diabetes Prevention Program Research Group. in Youth: a multicenter study of the prevalence, 123. Bellin MD, Gelrud A, Arreaza-Rubin G, et al. Prevention of diabetes in women with a history of incidence and classification of diabetes mellitus Total pancreatectomy with islet autotransplan- Association gestational diabetes: effects of metformin and in youth. Control Clin Trials 2004;25:458–471 tation: summary of an NIDDK workshop. Ann – lifestyle interventions. J Clin Endocrinol Metab 108. Pihoker C, Gilliam LK, Ellard S, et al.; SEARCH Surg 2015;261:21 29 2008;93:4774–4779 for Diabetes in Youth Study Group. Prevalence, 124. Anazawa T, Okajima H, Masui T, Uemoto S. Current state and future evolution of pancreatic 139. Aroda VR, Christophi CA, Edelstein characteristics and clinical diagnosis of maturity islet transplantation. Ann Gastroenterol Surg SL, et al.; Diabetes Prevention Program Re- onset diabetes of the young due to mutations 2018;3:34–42 search Group. The effect of lifestyle interven- in HNF1A, HNF4A, and glucokinase: results from 125. Quartuccio M, Hall E, Singh V, et al. Gly- tion and metformin on preventing or delaying the SEARCH for Diabetes in Youth. J Clin Endo- cemic predictors of insulin independence after diabetes among women with and without crinol Metab 2013;98:4055–4062 total pancreatectomy with islet autotransplan- gestational diabetes: the Diabetes Preven- 109. Draznin B (Ed.). Atypical Diabetes: Patho- tation. J Clin Endocrinol Metab 2017;102:801– tion Program outcomes study 10-year follow- physiology, Clinical Presentations, and Treat- 809 up. J Clin Endocrinol Metab 2015;100: ment Options. Arlington, American Diabetes 126. Huvinen E, Koivusalo SB, Meinila¨ J, et al. 1646–1653 Association, 2018 Effects of a lifestyleDiabetes intervention during preg- 140. Wang C, Wei Y, Zhang X, et al. A randomized 110. DiabetesGenes. MODY Probability Calcula- nancy and first postpartum year: findings from clinical trial of exercise during pregnancy to tor. Accessed 26 September 2019. Available from the RADIEL study. J Clin Endocrinol Metab 2018; prevent gestational diabetes mellitus and im- https://www.diabetesgenes.org/mody-probability- 103:1669–1677 prove pregnancy outcome in overweight and calculator/ 127. Rosenn B, Miodovnik M, Combs CA, Khoury obese pregnant women. Am J Obstet Gynecol ´ ´ˇ ´ ´ ´ 111. Urbanova J, Rypackova B, ProchazkovaZ, J, Siddiqi TA. Glycemic thresholds for spontane- 2017;216:340–351 et al. Positivity for islet cell autoantibodies in ous abortion and congenital malformations in 141. Metzger BE, Lowe LP, Dyer AR, et al.; HAPO patients with monogenic diabetes is associated insulin-dependent diabetes mellitus. Obstet Study Cooperative Research Group. Hyperglyce- with later diabetes onset and higher HbA1c level. Gynecol 1994;84:515–520 mia and adverse pregnancy outcomes. N Engl J – Diabet Med 2014;31:466 471 128. Schaefer UM, Songster G, Xiang A, Med 2008;358:1991–2002 112. Naylor RN, John PM, Winn AN, et al. Cost- Berkowitz K, Buchanan TA, Kjos SL. Congenital 141a. O’Sullivan J, Mahan C. Criteria for the oral effectiveness of MODY genetic testing: trans- malformations in offspring of women with hy- glucose tolerance test in pregnancy. Diabetes lating genomic advances into practical health perglycemia first detected during pregnancy. Am 1964;13:278–285 – applications. Diabetes Care 2014;37:202American209 J Obstet Gynecol 1997;177:1165–1171 142. Sacks DA, Hadden DR, Maresh M, et al.; 113. Shields BM, Shepherd M, Hudson M, et al.; 129. Poltavskiy E, Kim DJ, Bang H. Comparison HAPO Study Cooperative Research Group. UNITED study team. Population-based assess- of screening scores for diabetes and predia- Frequency of gestational diabetes mellitus ment of a biomarker-based screening pathway betes. Diabetes Res Clin Pract 2016;118:146– at collaborating centers based on IADPSG to aid diagnosis of monogenic diabetes in young- 153 consensus panel-recommended criteria: the onset patients. Diabetes Care 2017;40:1017– 130. Feig DS, Hwee J, Shah BR, Booth GL, Hyperglycemia and Adverse Pregnancy Outcome 1025 Bierman AS, Lipscombe LL. Trends in incidence (HAPO) Study. Diabetes Care 2012;35:526–528 114. Hattersley A, Bruining J, Shield J, Njolstad P, of diabetes in pregnancy and serious perinatal 143. Brown FM, Wyckoff J. Application of one- Donaghue KC. The diagnosis and management of outcomes: a large, population-based study in step IADPSG versus two-step diagnostic criteria monogenic diabetes in children and adolescents. Ontario, Canada, 1996-2010. Diabetes Care for gestational diabetes in the real world: impact Pediatr©2019 Diabetes 2009;10(Suppl. 12):33–42 2014;37:1590–1596 on Health Services, clinical care, and outcomes. 115. Rubio-Cabezas O, Hattersley AT, Njølstad 131. Peng TY, Ehrlich SF, Crites Y, et al. Trends Curr Diab Rep 2017;17:85 PR, et al.; International Society for Pediatric and and racial and ethnic disparities in the preva- 144. Lowe WL Jr, Scholtens DM, Lowe LP, et al.; Adolescent Diabetes. ISPAD Clinical Practice lence of pregestational type 1 and type 2 dia- HAPO Follow-up Study Cooperative Research Consensus Guidelines 2014. The diagnosis and betes in Northern California: 1996-2014. Group. Association of gestational diabetes management of monogenic diabetes in children Am J Obstet Gynecol 2017;216:177.e1– with maternal disorders of glucose metabolism and adolescents. Pediatr Diabetes 2014;15(Suppl. 177.e8 and childhood adiposity. JAMA 2018;320:1005– 20):47–64 132. Jovanovicˇ L, Liang Y, Weng W, Hamilton M, 1016 116. Greeley SAW, Naylor RN, Philipson LH, Bell Chen L, Wintfeld N. Trends in the incidence of 145. Landon MB,Spong CY,Thom E,etal.;Eunice GI. Neonatal diabetes: an expanding list of genes diabetes, its clinical sequelae, and associated Kennedy Shriver National Institute of Child Health allows for improved diagnosis and treatment. costs in pregnancy. Diabetes Metab Res Rev and Human Development Maternal-Fetal Med- Curr Diab Rep 2011;11:519–532 2015;31:707–716 icine Units Network. A multicenter, randomized care.diabetesjournals.org Classification and Diagnosis of Diabetes S31

trial of treatment for mild gestational diabetes. N 152. Khalafallah A, Phuah E, Al-Barazan AM, results in improved pregnancy outcomes at a Engl J Med 2009;361:1339–1348 et al. Glycosylated haemoglobin for screening lower cost in a large cohort of pregnant women: 146. Crowther CA, Hiller JE, Moss JR, McPhee AJ, and diagnosis of gestational diabetes mellitus. the St. Carlos Gestational Diabetes Study. Di- Jeffries WS, Robinson JS; Australian Carbohy- BMJ Open 2016;6:e011059 abetes Care 2014;37:2442–2450 drate Intolerance Study in Pregnant Women 153. Horvath K, Koch K, Jeitler K, et al. Effects of 159. Wei Y, Yang H, Zhu W, et al. International (ACHOIS) Trial Group. Effect of treatment of treatment in women with gestational diabetes Association of Diabetes and Pregnancy Study gestational diabetes mellitus on pregnancy out- mellitus: systematic review and meta-analysis. Group criteria is suitable for gestational diabetes comes. N Engl J Med 2005;352:2477–2486 BMJ 2010;340:c1395 mellitus diagnosis: further evidence from China. 147. Tam WH, Ma RCW, Ozaki R, et al. In utero 154. Carpenter MW, Coustan DR. Criteria for Chin Med J (Engl) 2014;127:3553–3556 exposure to maternal hyperglycemia increases screening tests for gestational diabetes. Am J 160. Feldman RK, Tieu RS, Yasumura L. Gesta- – childhood cardiometabolic risk in offspring. Di- Obstet Gynecol 1982;144:768 773 tional diabetes screening: the International As- ﬁ abetes Care 2017;40:679–686 155. National Diabetes Data Group. Classi ca- sociation of the Diabetes and Pregnancy Study 148. Landon MB, Rice MM, Varner MW, et al.; tion and diagnosis of diabetes mellitus and other Groups compared with Carpenter-Coustan screen- categoriesof glucose intolerance. Diabetes 1979; Eunice Kennedy Shriver National Institute of Child ing. Obstet Gynecol 2016;127:10–17 – Health and Human Development Maternal-Fetal 28:1039 1057 161. Ethridge JK Jr, Catalano PM, Waters 156. Harper LM, Mele L, Landon MB, et al.; Medicine Units (MFMU) Network. Mild gesta- TP. Perinatal outcomes associated with the di- Eunice Kennedy Shriver National Institute of Child tional diabetes mellitus and long-term child agnosis of gestational diabetes made by the in- Health and Human Development (NICHD) health. Diabetes Care 2015;38:445–452 ternational association of the diabetes and Maternal-Fetal Medicine Units (MFMU) Network. 149. Vandorsten JP, Dodson WC, Espeland MA, pregnancy study groups criteria. Obstet Gynecol Carpenter-Coustan compared with National Di- – et al. NIH consensus development conference: abetes Data Group criteria for diagnosing 2014;124:571 578 diagnosing gestational diabetes mellitus. NIH gestational diabetes. Obstet Gynecol 2016; 162. Mayo K, Melamed N, Vandenberghe H, – Consens State Sci Statements 2013;29:1 31 127:893–898 Berger H. The impact of adoption of the 150. CommitteeonPracticeBulletinsdObstetrics. 157. Werner EF, Pettker CM, Zuckerwise L, et al. international association of diabetes in preg- Practice Bulletin No. 190: gestational diabetes Screening for gestational diabetes mellitus: are nancy studyAssociation group criteria for the screening and mellitus. Obstet Gynecol 2018;131:e49–e64 the criteria proposed by the International Association diagnosis of gestational diabetes. Am J Obstet 151. Donovan L, Hartling L, Muise M, Guthrie A, of the Diabetes and Pregnancy Study Groups cost- Gynecol 2015;212:224.e1–224.e9 Vandermeer B, Dryden DM. Screening tests for effective? Diabetes Care 2012;35:529–535 163. Hutchins J, Barajas RA, Hale D, Escaname E, gestational diabetes: a systematic review for the 158. Duran A, Saenz´ S, Torrejon´ MJ, et al. In- Lynch J. Type 2 diabetes in a 5-year-old and single U.S. Preventive Services Task Force. Ann Intern troduction of IADPSG criteria for the screening center experience of type 2 diabetes in youth Med 2013;159:115–122 and diagnosis of gestational diabetes mellitus under 10. Pediatr Diabetes 2017;18:674–677

Diabetes

American

3. Prevention or Delay of Type 2 American Diabetes Association Diabetes: Standards of Medical Care in Diabetesd2020

Diabetes Care 2020;43(Suppl. 1):S32–S36 | https://doi.org/10.2337/dc20-S003

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes” includes the ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools Association to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc20-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as wellastheevidence-gradingsystem for ADA’s clinical practicerecommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/ dc20-SINT). Readers who wish to comment on the StandardsofCare are invited to do so at professional.diabetes.org/SOC.

For guidelines related to screening for increased risk for typeDiabetes 2 diabetes (prediabetes), please refer to Section 2 “Classiﬁcation and Diagnosis of Diabetes” (https://doi.org/10 3. PREVENTION OR DELAY OF TYPE 2 DIABETES .2337/dc20-S002).

Recommendation 3.1 At least annual monitoring for the development of type 2 diabetes in those with prediabetes is suggested. E

Screening for prediabetes and type 2 diabetes risk through an informal assessment of risk factors (Table 2.3) or with an assessment tool, such as the American Diabetes Association risk test (Fig. 2.1), is recommended to guide providers on whether performing a diagnostic test for prediabetes (Table 2.5) and previously undiagnosed type 2 diabetes (Table 2.2American) is appropriate (see Section 2 “ Classification and Diagnosis of Diabetes,” https://doi.org/10.2337/dc20-S002). Those who are determined to be at high risk for type 2 diabetes, including people with A1C 5.7–6.4% (39–47 mmol/mol), impaired glucose tolerance, or impaired fasting glucose, are ideal candidates for diabetes prevention efforts. Using A1C to screen for prediabetes may be problematic in the presence of certain hemoglobinopathies or conditions that affect red blood cell turnover. See Section 2 “Classification and Diagnosis of Diabetes” (https://doi.org/10.2337/dc20-S002) and Section 6 “Glycemic Targets” (https://doi.org/10.2337/dc20-S006)©2019 for additional details on the appropriate use of the A1C test. Suggested citation: American Diabetes Associa- tion. 3. Prevention or delay of type 2 diabetes: LIFESTYLE INTERVENTIONS Standards of Medical Care in Diabetesd2020. Diabetes Care 2020;43(Suppl. 1):S32–S36 Recommendations © 2019 by the American Diabetes Association. 3.2 Refer patients with prediabetes to an intensive behavioral lifestyle inter- Readers may use this article as long as the work vention program modeled on the Diabetes Prevention Program (DPP) to is properly cited, the use is educational and not achieve and maintain 7% loss of initial body weight and increase moderate- for profit, and the work is not altered. More infor- intensity physical activity (such as brisk walking) to at least 150 min/week. A mation is available at http://www.diabetesjournals .org/content/license. care.diabetesjournals.org Prevention or Delay of Type 2 Diabetes S33

The 7% weight loss goal was selected Nutrition 3.3 A variety of eating patterns are because it was feasible to achieve and Structured behavioral weight loss ther- acceptable for persons with pre- maintain and likely to lessen the risk of apy, including a reduced calorie meal diabetes. B developing diabetes. Participants were plan and physical activity, is of para- 3.4 Based on patient preference, encouraged to achieve the 7% weight mount importance for those at high risk technology-assisted diabetes pre- loss during the first 6 months of the for developing type 2 diabetes who vention interventions may be effec- intervention. However, longer-term (4- have overweight or obesity (1,9). Be- tive in preventing type 2 diabetes year) data reveal maximal prevention cause weight loss through lifestyle and should be considered. B of diabetes observed at about 7–10% changes alone can be difficult to maintain 3.5 Given the cost-effectiveness of weight loss (9). The recommended pace long term (6), people being treated with diabetes prevention, such inter- of weight loss was 1–2 lb/week. Calorie weight loss therapy should have access vention programs should be cov- goals were calculated by estimating the to ongoing support and additional ther- ered by third-party payers. B daily calories needed to maintain the apeutic options (such as pharmacother- participant’s initial weight and subtracting apy) if needed. Based on intervention The Diabetes Prevention Program 500–1,000 calories/day (depending on trials, a variety of eating patterns may Several major randomized controlled initial body weight). The initial focus be appropriate for patients with pre- trials, including the Diabetes Prevention was on reducing total dietary fat. After diabetes (10), including Mediterranean Program (DPP) (1), the Finnish Diabetes several weeks, the concept of calorie (11–13) and low-calorie, low-fat eating PreventionStudy (DPS)(2),andthe Da Qing balance and the need to restrict calories patterns (8). An eating pattern repre- Diabetes Prevention Study (Da Qing study) as well as fat was introduced (8). sents the totality of all foods and (3), demonstrate that lifestyle/behavioral The goal for physical activity was se- beveragesAssociation consumed (14). In addition, therapy featuring an individualized re- lected to approximate at least 700 evidence suggests that the overall duced calorie meal plan is highly effective kcal/week expenditure from physical ac- quality of food consumed (as mea- in preventing type 2 diabetes and im- tivity. For ease of translation, this goal was sured by the Healthy Eating Index, proving other cardiometabolic markers described as at least 150 min of moderate- Alternative Healthy Eating Index, and (such as blood pressure, lipids, and in- intensity physical activity per week Dietary Approaches to Stop Hyperten- flammation) (4). The strongest evidence similar in intensity to brisk walking. Par- sion [DASH] score), with an emphasis for diabetes prevention in the U.S. comes ticipants were encouraged to distribute on whole grains, legumes, nuts, fruits from the DPP trial (1). The DPP demon- their activity throughout the week with a and vegetables and minimal refined strated that an intensive lifestyle inter- minimum frequency of three times per and processed foods, is also important vention could reduce the incidence of week and at least 10 min per session. A (15–18). type 2 diabetes by 58% over 3 years. maximum of 75 minDiabetes of strength training As is the case for those with di- Follow-up of three large studies of lifestyle could be applied toward the total abetes, individualized medical nutri- intervention for diabetes prevention has 150 min/week physical activity goal (8). tion therapy (see Section 5 “Facilitating shownsustainedreductionintherateof To implement the weight loss and Behavior Change and Well-being to conversion to type 2 diabetes: 39% re- physical activity goals, the DPP used Improve Health Outcomes,” https:// duction at 30 years in the Da Qing study (5), an individual model of treatment rather doi.org/10.2337/dc20-S005, for more 43% reduction at 7 years in the Finnish DPS than a group-based approach. This choice detailed information) is effective in (2), and 34% reduction at 10 years (6) and wasbasedonadesiretointervene lowering A1C in individuals diagnosed 27% reduction at 15 years (7) in the U.S. before participants had the possibility with prediabetes (19). Diabetes Prevention Program Outcomes of developing diabetes or losing inter- Study (DPPOS). Notably, in the 30-year est in the program. The individual ap- Physical Activity follow-up for the Da Qing study,American reduc- proach also allowed for tailoring of Just as 150 min/week of moderate- tions in all-cause mortality, cardiovascular interventions to reflect the diversity of intensity physical activity, such as brisk disease–related mortality, and microvascu- the population (8). walking, showed beneficial effects in lar complications were observed for the The DPP intervention was adminis- those with prediabetes (1), moderate- lifestyle intervention groups compared tered as a structured core curriculum intensity physical activity has been with the control group (5). followed by a more flexible mainte- shown to improve insulin sensitivity The two major goals of the DPP in- nance program of individual sessions, and reduce abdominal fat in children tensive, behavioral lifestyle intervention group classes, motivational campaigns, and young adults (20,21). On the basis were©2019 to achieve and maintain a minimum and restart opportunities. The 16-session of these findings, providers are encour- of 7% weight loss and 150 min of physical core curriculum was completed within aged to promote a DPP-style program, activity similar in intensity to brisk walk- the first 24 weeks of the program and including its focus on physical activity, to ing per week. The DPP lifestyle interven- included sections on lowering calories, all individuals who have been identified tion was a goal-based intervention: all increasing physical activity, self-monitor- to be at an increased risk of type 2 participants were given the same weight ing, maintaining healthy lifestyle bediabetes. In addition to aerobic activity, loss and physical activity goals, but in- haviors, and psychological, social, and an exercise regimen designed to prevent dividualization was permitted in the motivational challenges. For further de- diabetes may include resistance training specific methods used to achieve the tails on the core curriculum sessions, (8,22,23). Breaking up prolonged sed- goals (8). refer to ref. 8. entary time may also be encouraged, S34 Prevention or Delay of Type 2 Diabetes Diabetes Care Volume 43, Supplement 1, January 2020

as it is associated with moderately producing weight loss and diabetes risk PHARMACOLOGIC lower postprandial glucose levels reduction (39–42). The use of community INTERVENTIONS (24,25). The preventive effects of health workers to support DPP efforts Recommendations exercise appear to extend to the pre- has been shown to be effective with 3.6 Metformin therapy for preven- “ vention of gestational diabetes mellitus cost savings (43,44) (see Section 1 Im- tion of type 2 diabetes should be (GDM) (26). proving Care and Promoting Health considered in those with predia- ” in Populations, https://doi.org/10 betes, especially for those with Tobacco Use .2337/dc20-S001, for more informa- BMI $35 kg/m2, those aged ,60 Smoking may increase the risk of type 2 tion). Given the cost-effectiveness of years, and women with prior diabetes (27); therefore, evaluation for diabetes prevention, such intervention gestational diabetes mellitus. A tobacco use and referral for tobacco programs should be covered by third- 3.7 Long-term use of metformin may cessation, if indicated, should be part party payers. be associated with biochemical of routine care for those at risk for The CDC coordinates the National Di- vitamin B12 deficiency, and pe- diabetes. Of note, the years immedi- abetes Prevention Program (National DPP), riodic measurement of vitamin ately following smoking cessation may a resource designed to bring evidence- B12 levels should be considered represent a time of increased risk for based lifestyle change programs for pre- in metformin-treated patients, – diabetes (27 29) and patients should venting type 2 diabetes to communities especially in those with anemia be monitored for diabetes develop- (www.cdc.gov/diabetes/prevention/index or peripheral neuropathy. B ment and receive evidence-based inter- .htm). This online resource includes loca- ventions for diabetes prevention as tions of CDC-recognized diabetes preven- describedinthissection.SeeSection tion lifestyle change programs (available PharmacologicAssociation agents including met- 5 “Facilitating Behavior Change and atnccd.cdc.gov/DDT_DPRP/Programs formin, a-glucosidase inhibitors, glu- Well-being to Improve Health Outcomes” .aspx). To be eligible for this program, cagon-like peptide 1 receptor agonists, (https://doi.org/10.2337/dc20-S005) for patients must have a BMI in the over- thiazolidinediones, and several agents more detailed information. weight range and be at risk for diabetes approved for weight loss have been based on laboratory testing or a posi- shown in research studies to decrease Technology-Assisted Interventions to tive risk test (available at www.cdc.gov/ the incidence of diabetes to various Deliver Lifestyle Interventions prediabetes/takethetest/). Results from degrees in those with prediabetes Technology-assisted interventions may the CDC’s National DPP during the first (1,47–53), though none are approved effectively deliver the DPP lifestyle 4 years of implementation are promis- by the U.S. Food and Drug Administra- intervention, reducing weight and, ing (45). The CDC has also developed tion specifically for diabetes preven- therefore, diabetes risk (30–35). Such the Diabetes PreventionDiabetes Impact Tool tion. The risk versus benefitofeach technology-assisted interventions may Kit (available at nccd.cdc.gov/toolkit/ medication must be weighed. Metfor- deliver content through smartphone diabetesimpact) to help organizations min has the strongest evidence base and web-based applications and tele- assess the economics of providing or (54) and demonstrated long-term health (30). The Centers for Disease covering the National DPP lifestyle safety as pharmacologic therapy for Control and Prevention (CDC) Diabetes change program (46). diabetes prevention (52). For other Prevention Recognition Program (DPRP) drugs, cost, side effects, and durable (www.cdc.gov/diabetes/prevention/ National Policy efficacy require consideration. requirements-recognition.htm) certifies In an effort to expand preventive services Metformin was overall less effective technology-assisted modalities as ef- using a cost-effective model that began than lifestyle modification in the DPP, fective vehicles for DPP-based inter- in April 2018, the Centers for Medicare though group differences declined over ventions; such programsAmerican must use an & Medicaid Services expanded Medi- time in the DPPOS (7), and metformin approved curriculum, include interac- care reimbursement coverage for the may be cost-saving over a 10-year tion with a coach, and attain the DPRP National DPP lifestyle intervention to period (38). During initial follow up outcomes of participation, physical organizations recognized by the CDC in the DPP, metformin was as effective activity reporting, and weight loss. that become Medicare suppliers for this as lifestyle modification in participants The selection of an in-person or virtual service (online at innovation.cms.gov/ with BMI $35 kg/m2 but not signifi- program should be based on patient initiatives/medicare-diabetes-prevention- cantly better than placebo in those over preference. program/). The locations of Medicare 60 years of age (1). In the DPP, for ©2019 DPPs are available online at innovation women with a history of GDM, met- Cost-effectiveness .cms.gov/initiatives/medicare-diabetes- formin and intensive lifestyle modifi- A cost-effectiveness model suggested prevention-program/mdpp-map.html. cationledtoanequivalent50% that the lifestyle intervention used in To qualify for Medicare coverage, patients reduction in diabetes risk (55), and the DPP was cost-effective (36,37). Ac- must have a BMI in the overweight both interventions remained highly ef- tual cost data from the DPP and DPPOS range and laboratory testing consistent fective during a 10-year follow-up pe- confirmed this (38). Group delivery of with prediabetes in the last year. Med- riod (56). By the time of the 15-year DPP content in community or primary icaid coverage of the DPP lifestyle follow-up (DPPOS), exploratory analy- care settings has the potential to reintervention is also expanding on a ses demonstrated that participants duce overall program costs while still state-by-state basis. with a higher baseline fasting glucose care.diabetesjournals.org Prevention or Delay of Type 2 Diabetes S35

($110 mg/dL vs. 95–109 mg/dL) and Change and Well-being to Improve 9. Hamman RF, Wing RR, Edelstein SL, et al. women with a history of GDM (vs. Health Outcomes,” https://doi.org/10 Effect of weight loss with lifestyle intervention – women without a history of GDM) ex- .2337/dc20-S005) can also apply to people on risk of diabetes. Diabetes Care 2006;29:2102 2107 perienced higher risk reductions with with prediabetes. Currently, there are sig- 10. Evert AB, Dennison M, Gardner CD, et al. metformin (compared with the placebo nificant barriers to the provision of educa- Nutrition therapy for adults with diabetes or arm) (57). In the Indian Diabetes Pre- tion and support to those with prediabetes. prediabetes: a consensus report. Diabetes Care vention Program (IDPP-1), metformin and However, the strategies for supporting 2019;42:731–754 the lifestyle intervention reduced diabetes successful behavior change and the 11. Salas-Salvado´ J, Guasch-Ferre´ M, Lee C-H, Estruch R, Clish CB, Ros E. Protective effects of risk similarly at 30 months; of note, the healthy behaviors recommended for the Mediterranean diet on type 2 diabetes and lifestyle intervention in IDPP-1 was less people with prediabetes are compara- metabolic syndrome. J Nutr 2016;146:920S– intensive than that in the DPP (58). Based ble to those for people with diabetes. 927S on findings from the DPP, metformin should Although reimbursement remains a bar- 12. Bloomfield HE, Koeller E, Greer N, MacDonald be recommended as an option for high-risk rier, studies show that providers of di- R, Kane R, Wilt TJ. Effects on health outcomes of a Mediterranean diet with no restriction on fat individuals (e.g., those with a history of abetes self-management education and intake: a systematic review and meta-analysis. 2 GDM or those with BMI $35 kg/m ). support are particularly well equipped to Ann Intern Med 2016;165:491–500 Consider monitoring vitamin B12 levels assist people with prediabetes in develop- 13. Estruch R, Ros E, Salas-Salvado´ J, et al.; in those taking metformin chronically to ing and maintaining behaviors that can PREDIMED Study Investigators. Primary pre- check for possible deficiency (56) (see Sec- prevent or delay the development of di- vention of cardiovascular disease with a Med- iterranean diet supplemented with extra-virgin tion 9 “Pharmacologic Approaches to Gly- abetes (19,63). olive oil or nuts. N Engl J Med 2018;378:e34 cemic Treatment,” https://doi.org/10 14. Department of Health and Human Services .2337/dc20-S009, for more details). and DepartmentAssociation of Agriculture. Dietary Guide- References lines for Americans 2015–2020, Eighth Edition. 1. Knowler WC, Barrett-Connor E, Fowler SE, Accessed 31 October 2019. Available from https:// PREVENTION OF et al.; Diabetes Prevention Program Research health.gov/dietaryguidelines/2015/guidelines/ CARDIOVASCULAR DISEASE Group. Reduction in the incidence of type 2 15. Ley SH, Hamdy O, Mohan V, Hu FB. Pre- diabetes with lifestyle intervention or metfor- vention and management of type 2 diabetes: Recommendation min. N Engl J Med 2002;346:393–403 dietary components and nutritional strategies. 3.8 Prediabetesisassociatedwith 2. Lindstrom¨ J, Ilanne-Parikka P, Peltonen M, Lancet 2014;383:1999–2007 heightened cardiovascular risk; et al.; Finnish Diabetes Prevention Study Group. 16. Jacobs S, Harmon BE, Boushey CJ, et al. A priori-defined diet quality indexes and risk of therefore, screening for and Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of type 2 diabetes: the Multiethnic Cohort. Diabe- treatment of modifiable risk fac- the Finnish Diabetes Prevention Study. Lancet tologia 2015;58:98–112 tors for cardiovascular disease 2006;368:1673–1679 17. Chiuve SE, Fung TT, Rimm EB, et al. Alter- are suggested. B 3. Li G, Zhang P, WangDiabetes J, et al. Cardiovascular native dietary indices both strongly predict mortality, all-cause mortality, and diabetes in- risk of chronic disease. J Nutr 2012;142:1009– 1018 People with prediabetes often have other cidence after lifestyle intervention for people with impaired glucose tolerance in the Da Qing 18. Schwingshackl L, Bogensberger B, Hoffmann cardiovascular risk factors, including hyper- Diabetes Prevention Study: a 23-year follow-up G. Diet quality as assessed by the Healthy Eating tension and dyslipidemia (59), and are at study. Lancet Diabetes Endocrinol 2014;2:474– Index, Alternate Healthy Eating Index, Dietary increased risk for cardiovascular disease 480 Approaches to Stop Hypertension score, and (60,61). Although treatment goals for peo- 4. Nathan DM, Bennett PH, Crandall JP, et al.; health outcomes: an updated systematic review DPP Research Group. Does diabetes prevention and meta-analysis of cohort studies. J Acad Nutr ple with prediabetes are the same as for the translate into reduced long-term vascular com- Diet 2018;118:74–100.e11 general population (62), increased vigilance plications of diabetes? Diabetologia 2019;62: 19. Parker AR, Byham-Gray L, Denmark R, is warranted to identify and treat these 1319–1328 Winkle PJ. The effect of medical nutrition therapy and other cardiovascular risk factors (e.g., 5. Gong Q, Zhang P, Wang J, et al.; Da Qing by a registered dietitian nutritionist in patients smoking). AmericanDiabetes Prevention Study Group. Morbidity and with prediabetes participating in a randomized mortality after lifestyle intervention for people controlled clinical research trial. J Acad Nutr Diet 2014;114:1739–1748 DIABETES SELF-MANAGEMENT with impaired glucose tolerance: 30-year results of the Da Qing Diabetes Prevention Outcome 20. Fedewa MV, Gist NH, Evans EM, DishmanRK. EDUCATION AND SUPPORT Study. Lancet Diabetes Endocrinol 2019;7:452– Exercise and insulin resistance in youth: a meta- – Recommendation 461 analysis. Pediatrics 2014;133:e163 e174 3.9 6. Knowler WC, Fowler SE, Hamman RF, et al.; 21. Davis CL, Pollock NK, Waller JL, et al. Exercise Diabetes self-management edu- Diabetes Prevention Program Research Group. dose and diabetes risk in overweight and obese cationandsupportprogramsmay 10-year follow-up of diabetes incidence and children: a randomized controlled trial. JAMA be appropriate venues for people weight loss in the Diabetes Prevention Program 2012;308:1103–1112 ©2019with prediabetes to receive ed- Outcomes Study. Lancet 2009;374:1677–1686 22. Sigal RJ, Alberga AS, Goldfield GS, et al. ucation and support to develop 7. Nathan DM, Barrett-Connor E, Crandall JP, Effects of aerobic training, resistance training, et al.; Diabetes Prevention Program Research or both on percentage body fat and cardiomet- and maintain behaviors that can Group. Long-term effects of lifestyle interven- abolic risk markers in obese adolescents: the prevent or delay the develop- tion or metformin on diabetes development HealthyEating Aerobic and ResistanceTraining in ment of type 2 diabetes. B and microvascular complications: the DPP Out- Youth randomized clinical trial. JAMA Pediatr comes Study. Lancet Diabetes Endocrinol 2015; 2014;168:1006–1014 – As for those with established diabe- 3:866 875 23. Dai X, Zhai L, Chen Q, et al. Two-year- 8. Diabetes Prevention Program (DPP) Research supervised resistance training prevented diabetes tes, the standards for diabetes self- Group. The Diabetes Prevention Program (DPP): incidence in people with prediabetes: a random- management education and support description of lifestyle intervention. Diabetes ised control trial. Diabetes Metab Res Rev 2019; (see Section 5 “Facilitating Behavior Care 2002;25:2165–2171 35:e3143 S36 Prevention or Delay of Type 2 Diabetes Diabetes Care Volume 43, Supplement 1, January 2020

24. Thorp AA, Kingwell BA, Sethi P, Hammond L, Care 2013;36:4172–4175]. Diabetes Care 2012; 51. DeFronzo RA, Tripathy D, Schwenke DC, Owen N, Dunstan DW. Alternating bouts of sitting 35:723–730 et al.; ACT NOW Study. Pioglitazone for diabetes and standing attenuate postprandial glucose re- 39. AckermannRT,FinchEA,BrizendineE,ZhouH, prevention in impaired glucose tolerance. N Engl sponses. Med Sci Sports Exerc 2014;46:2053–2061 Marrero DG. Translating the Diabetes Preven- J Med 2011;364:1104–1115 25. HealyGN, Dunstan DW,Salmon J,etal.Breaks tion Program into the community. The DEPLOY 52. Diabetes Prevention Program Research in sedentary time: beneficial associations with pilot study. Am J Prev Med 2008;35:357–363 Group. Long-term safety, tolerability, and weight metabolic risk. Diabetes Care 2008;31:661–666 40. Balk EM, Earley A, Raman G, Avendano EA, loss associated with metformin in the Diabetes 26. Russo LM, Nobles C, Ertel KA, Chasan-Taber Pittas AG, Remington PL. Combined diet and Prevention Program Outcomes Study. Diabetes L, Whitcomb BW. Physical activity interventions physical activity promotion programs to prevent Care 2012;35:731–737 in pregnancy and risk of gestational diabetes type 2 diabetes among persons at increased risk: 53. Garvey WT, Ryan DH, Henry R, et al. Pre- mellitus: a systematic review and meta-analysis. a systematic review for the Community Preven- vention of type 2 diabetes in subjects with Obstet Gynecol 2015;125:576–582 tive Services Task Force. Ann Intern Med 2015; prediabetes and metabolic syndrome treated 27. Yeh H-C, Duncan BB, Schmidt MI, Wang N-Y, 163:437–451 with phentermine and topiramate extended re- Brancati FL. Smoking, smoking cessation, and risk 41. Li R, Qu S, Zhang P, et al. Economic evaluation lease. Diabetes Care 2014;37:912–921 for type 2 diabetes mellitus: a cohort study. Ann of combined diet and physical activity promotion 54. Moin T, Schmittdiel JA, Flory JH, et al. Review Intern Med 2010;152:10–17 programs to prevent type 2 diabetes among of metformin use for type 2 diabetes prevention. 28. Oba S, Noda M, Waki K, et al.; Japan Public persons at increased risk: a systematic review Am J Prev Med 2018;55:565–574 Health Center-based Prospective Study Group. for the Community Preventive Services Task 55. Ratner RE, Christophi CA, Metzger BE, et al.; Smoking cessation increases short-term risk of Force. Ann Intern Med 2015;163:452–460 Diabetes Prevention Program Research Group. type 2 diabetes irrespective of weight gain: the 42. Gilmer T, O’Connor PJ, Schiff JS, et al. Cost- Preventionofdiabetesinwomenwithahistoryof Japan Public Health Center-based Prospective effectiveness of a community-based Diabetes gestational diabetes: effects of metformin and Study [published correction appears in PLoS One Prevention Program with participation incen- lifestyle interventions. J Clin Endocrinol Metab 2013;8:10.1371/annotation/23aa7c42-9a4d- tives for Medicaid beneficiaries. Health Serv 2008;93:4774–4779 42a7-8f50-9d0ac4b85396]. PLoS One 2012;7: Res 2018;53:4704–4724 56. Aroda VR, Christophi CA, Edelstein SL, et al.; e17061 43. The Community Guide. Diabetesprevention: DiabetesAssociation Prevention Program Research Group. 29. Hu Y, Zong G, Liu G, et al. Smoking cessation, interventions engaging community health The effect of lifestyle intervention and metfor- weight change, type 2 diabetes, and mortality. workers, 2016. Accessed 31 October 2019. Avail- min on preventing or delaying diabetes among N Engl J Med 2018;379:623–632 able from https://www.thecommunityguide.org/ women with and without gestational diabetes: 30. Grock S, Ku J-H, Kim J, Moin T. A review of findings/diabetes-prevention-interventions- the Diabetes Prevention Program outcomes technology-assisted interventions for diabetes engaging-community-health-workers study 10-year follow-up. J Clin Endocrinol Metab prevention. Curr Diab Rep 2017;17:107 44. Jacob V, Chattopadhyay SK, Hopkins DP, 2015;100:1646–1653 31. Sepah SC, Jiang L, Peters AL. Translating the et al. Economics of community health workers 57. Diabetes Prevention Program Research Diabetes Prevention Program into an online so- for chronic disease: findings from Community Group. Long-term effects of metformin on di- cial network: validation against CDC standards. Guide systematic reviews. Am J Prev Med 2019; abetes prevention: identification of subgroups Diabetes Educ 2014;40:435–443 56:e95–e106 that benefited most in the Diabetes Preven- 32. Bian RR, Piatt GA, Sen A, et al. The effect of 45. Ely EK, Gruss SM, Luman ET, et al. A national tion Program and Diabetes Prevention Program technology-mediated diabetes prevention in- effort to prevent type 2 diabetes: participant- Outcomes Study. Diabetes Care 2019;42:601–608 terventions on weight: a meta-analysis. J Med level evaluationDiabetes of CDC’s National Diabetes 58. Ramachandran A, Snehalatha C, Mary S, Internet Res 2017;19:e76 Prevention Program. Diabetes Care 2017;40: Mukesh B, Bhaskar AD, Vijay V; Indian Diabetes 33. Sepah SC, Jiang L, Peters AL. Long-term 1331–1341 Prevention Programme (IDPP). The Indian Di- outcomes of a Web-based diabetes prevention 46. Lanza A, Soler R, Smith B, Hoerger T, abetes Prevention Programme shows that life- program: 2-year results of a single-arm longitu- Neuwahl S, Zhang P. The Diabetes Prevention style modification and metformin prevent type 2 dinal study. J Med Internet Res 2015;17:e92 Impact Tool Kit: an online tool kit to assess the diabetes in Asian Indian subjects with impaired 34. Moin T, Damschroder LJ, AuYoung M, et al. cost-effectiveness of preventing type 2 diabetes. glucose tolerance (IDPP-1). Diabetologia 2006; Results from a trial of an online diabetes pre- J Public Health Manag Pract 2019;25:E1–E5 49:289–297 vention program intervention. Am J Prev Med 47. Chiasson J-L, Josse RG, Gomis R, Hanefeld M, 59. Ali MK, Bullard KM, Saydah S, Imperatore G, 2018;55:583–591 Karasik A, Laakso M; STOP-NIDDM Trail Research Gregg EW. Cardiovascular and renal burdens of 35. Michaelides A, Major J, Pienkosz E Jr, Wood Group. Acarbose for prevention of type 2 di- prediabetes in the USA: analysis of data from M, Kim Y, Toro-Ramos T. Usefulness of a novel abetes mellitus: the STOP-NIDDM randomised serial cross-sectional surveys, 1988-2014. Lancet mobile Diabetes Prevention Program delivery trial. Lancet 2002;359:2072–2077 Diabetes Endocrinol 2018;6:392–403 platform with human coaching: 65-week obser- 48. Torgerson JS, Hauptman J, Boldrin MN, 60. Pan Y, Chen W, Wang Y. Prediabetes and vational follow-up. JMIR MhealthAmerican Uhealth 2018; Sjostr¨ om¨ L. XENical in the prevention of diabetes outcome of ischemic stroke or transient ischemic 6:e93 in obese subjects (XENDOS) study: a randomized attack: a systematic review and meta-analysis. 36. Herman WH, Hoerger TJ, Brandle M, et al.; study of orlistat as an adjunct to lifestyle changes J Stroke Cerebrovasc Dis 2019;28:683–692 Diabetes Prevention Program Research Group. for the prevention of type 2 diabetes in obese 61. Huang Y, Cai X, Mai W, Li M, Hu Y. Association The cost-effectiveness of lifestyle modification patients. Diabetes Care 2004;27:155–161 between prediabetes and risk of cardiovascular or metformin in preventing type 2 diabetes in 49. le Roux CW, Astrup A, Fujioka K, et al.; SCALE disease and all cause mortality: systematic re- adults with impaired glucose tolerance. Ann Obesity Prediabetes NN8022-1839 Study view and meta-analysis. BMJ 2016;355:i5953 Intern Med 2005;142:323–332 Group. 3 years of liraglutide versus placebo 62. Bress AP, King JB, Kreider KE, et al.; SPRINT 37. Chen F, Su W, Becker SH, et al. Clinical and for type 2 diabetes risk reduction and weight Research Group. Effect of intensive versus stan- economic©2019 impact of a digital, remotely-delivered management in individuals with prediabetes: dard blood pressure treatment according to intensive behavioral counseling program on a randomised, double-blind trial. Lancet 2017; baseline prediabetes status: a post hoc analysis Medicare beneficiaries at risk for diabetes and 389:1399–1409 of a randomized trial. Diabetes Care 2017;40: cardiovascular disease. PLoS One 2016;11: 50. Gerstein HC, Yusuf S, Bosch J, et al.; DREAM 1401–1408 e0163627 (DiabetesREductionAssessmentwithramipril and 63. Butcher MK, Vanderwood KK, Hall TO, 38. Diabetes Prevention Program Research rosiglitazone Medication) Trial Investigators. Ef- Gohdes D, Helgerson SD, Harwell TS. Capacity Group. The 10-year cost-effectiveness of lifestyle fect of rosiglitazone on the frequency of diabetes of diabetes education programs to provide both intervention or metformin for diabetes preven- in patients with impaired glucose tolerance or diabetes self-management education and to tion: an intent-to-treat analysis of the DPP/ impaired fasting glucose: a randomised controlled implement diabetes prevention services. J Public DPPOS [published correction appears in Diabetes trial. Lancet 2006;368:1096–1105 Health Manag Pract 2011;17:242–247 Diabetes Care Volume 43, Supplement 1, January 2020 S37

4. Comprehensive Medical American Diabetes Association Evaluation and Assessment of Comorbidities: Standards of Medical Care in Diabetesd2020

Diabetes Care 2020;43(Suppl. 1):S37–S47 | https://doi.org/10.2337/dc20-S004 .MDCLEAUTO N COMORBIDITIES AND EVALUATION MEDICAL 4. The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes” Association includes the ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc20-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence- grading system for ADA’s clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc20-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.Diabetes

PATIENT-CENTERED COLLABORATIVE CARE

Recommendations 4.1 A patient-centered communication style that uses person-centered and strength-based language and active listening; elicits patient preferences and beliefs; and assesses literacy, numeracy, and potential barriers to care should be used to optimize patient health outcomes and health-related quality of life. B 4.2 Diabetes care should be managed by a multidisciplinary team that may draw from primary care physicians,American subspecialty physicians, nurse practitioners, physician assistants, nurses, dietitians, exercise specialists, pharmacists, dentists, podiatrists, and mental health professionals. E

A successful medical evaluation depends on beneﬁcial interactions between the patient and the care team. The Chronic Care Model (1–3) (see Section 1 “Improving Care and Promoting Health in Populations,” https://doi.org/10.2337/dc20-S001) is a patient-centered approach to care that requires a close working relationship between©2019 the patient and clinicians involved in treatment planning. People with Suggested citation: American Diabetes Associa- diabetes should receive health care from an interdisciplinary team that may include tion. 4. Comprehensive medical evaluation and physicians, nurse practitioners, physician assistants, nurses, dietitians, exercise special- assessment of comorbidities: Standards of Med- ists, pharmacists, dentists, podiatrists, and mental health professionals. Individuals with ical Care in Diabetesd2020. Diabetes Care diabetes must assume an active role in their care. The patient, family or support people, 2020;43(Suppl. 1):S37–S47 physicians, and health care team should together formulate the management plan, © 2020 by the American Diabetes Association. which includes lifestyle management (see Section 5 “Facilitating Behavior Change and Readers may use this article as long as the work is ” properly cited, the use is educational and not for Well-being to Improve Health Outcomes, https://doi.org/10.2337/dc20-S005). proﬁt, and the work is not altered. More infor- The goals of treatment for diabetes are to prevent or delay complications and optimize mation is available at http://www.diabetesjournals quality of life (Fig. 4.1). Treatment goals and plans should be created with patients based .org/content/license. S38 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 43, Supplement 1, January 2020

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Figure 4.1—Decision cycle for patient-centered glycemic management in type 2 diabetes. Reprinted from Davies et al. (99).

on their individual preferences, values, and “nonadherenceDiabetes” when the outcomes language in diabetes care and education goals. The management plan should take of self-management are not optimal (8). can help to inform and motivate people, into account the patient’sage,cognitive The familiar terms “noncompliance” and yet language that shames and judges may abilities, school/work schedule and con- “nonadherence” denote a passive, obe- undermine this effort. The American Diabe- ditions, health beliefs, support systems, dient role for a person with diabetes in tes Association (ADA) and the American eating patterns, physical activity, social “following doctor’sorders” that is at odds Association of Diabetes Educators consen- situation, financial concerns, cultural fac- with the active role people with diabetes sus report, “The Use of Language in Diabetes tors,literacyandnumeracy(mathematical take in directing the day-to-day decision- Care and Education,” provides the authors’ literacy), diabetes complications and du- making, planning, monitoring, evaluation, expert opinion regarding the use of language ration of disease, comorbidities, health and problem-solving involved in diabetes by health care professionals when speaking priorities, other medical conditions, pref- self-management.Using anonjudgmental or writing about diabetes for people with erences for care, and life expectancy.American Var- approach that normalizes periodic lapses diabetes or for professional audiences (14). ious strategies and techniques should be in self-management may help minimize Although further research is needed to ad- used to support patients’ self-management patients’ resistance toreporting problems dress the impact of language on diabetes efforts, including providing education with self-management. Empathizing and outcomes, the report includes five key on problem-solving skills for all aspects using active listening techniques, such as consensus recommendations for lan- of diabetes management. open-ended questions, reflective state- guage use: Provider communication with patients ments, and summarizing what the patient and families should acknowledge that said, can help facilitate communication. c Use language that is neutral, nonjudg- multiple©2019 factors impact glycemic manage- Patients’ perceptions about their own mental, and based on facts, actions, or ment but also emphasize that collabo- ability, or self-efficacy, to self-manage physiology/biology. ratively developed treatment plans and diabetes are one important psychosocial c Use language free from stigma. a healthy lifestyle can significantly im- factor related to improved diabetes self- c Use language that is strength based, respect- prove disease outcomes and well-being management and treatment outcomes in ful, and inclusive and that imparts hope. (4–7). Thus, the goal of provider-patient diabetes (9–13) and should be a target of c Use language that fosters collabora- communication is to establish a collaborative ongoing assessment, patient education, tion between patients and providers. relationship and to assess and address and treatment planning. c Use language that is person centered self-management barriers without blam- Language has a strong impact on percep- (e.g., “person with diabetes” is pre- ing patients for “noncompliance” or tions and behavior. The use of empowering ferred over “diabetic”). care.diabetesjournals.org Comprehensive Medical Evaluation and Assessment of Comorbidities S39

COMPREHENSIVE MEDICAL support a patient. In addition to the Immunizations EVALUATION medical history, physical examination, Recommendations and laboratory tests, providers should Recommendations 4.7 Provide routinely recommen- assess diabetes self-management behav- 4.3 A complete medical evaluation ded vaccinations for children iors, nutrition, and psychosocial health (see should be performed at the initial and adults with diabetes as in- Section 5 “Facilitating Behavior Change and visit to: dicated by age. C Well-beingtoImprove Health Outcomes,” c Confirm the diagnosis and classify 4.8 Annual vaccination against in- https://doi.org/10.2337/dc20-S005) and diabetes. B fluenza is recommended for all give guidance on routine immunizations. c Evaluate for diabetes complica- people $6 months of age, es- The assessment of sleep pattern and tions and potential comorbid pecially those with diabetes. C duration should be considered; a recent conditions. B 4.9 Vaccination against pneumo- meta-analysis found that poor sleep c Review previous treatment and coccal disease, including pneu- quality, short sleep, and long sleep risk factor control in patients with mococcal pneumonia, with were associated with higher A1C in established diabetes. B 13-valent pneumococcal conju- people with type 2 diabetes (15). In- c Begin patient engagement in the gate vaccine (PCV13) is recom- terval follow-up visits should occur at formulation of a care manage- mended for children before age least every 3–6 months, individualized ment plan. B 2 years. People with diabetes to the patient, and then annually. c Develop a plan for continuing care. B ages 2 through 64 years should Lifestyle management and psychoso- 4.4 A follow-up visit should include also receive 23-valent pneumo- cial care are the cornerstones of diabetes most components of the initial coccal polysaccharide vaccine management. Patients should be re- comprehensive medical evalua- Association(PPSV23). At age $65 years, ferred for diabetes self-management ed- tion, including interval medical his- regardless of vaccination his- ucation and support, medical nutrition tory, assessment of medication- tory, additional PPSV23 vacci- therapy, and assessment of psychosocial/ taking behavior and intolerance/ nation is necessary. C emotional health concerns if indicated. side effects, physical examination, 4.10 Administer a 2- or 3-dose series Patients should receive recommended laboratory evaluation as appro- of hepatitis B vaccine, depend- preventive care services (e.g., immuniza- priate to assess attainment of ing on the vaccine, to unvacci- tions, cancer screening, etc.); smoking A1C and metabolic targets, and nated adults with diabetes ages cessation counseling; and ophthalmolog- assessment of risk for complica- 18 through 59 years. C ical, dental, and podiatric referrals. tions, diabetes self-management 4.11 Consider administering a 3-dose The assessment of risk of acute and behaviors, nutrition, psychosocial series of hepatitis B vaccine to chronic diabetes complicationsDiabetes and treat- health, and the need for referrals, unvaccinated adults with ment planning are key components of immunizations, or other routine diabetes $60 years of age. C initialandfollow-upvisits(Table4.2).The health maintenance screening. B risk of atherosclerotic cardiovascular 4.5 Ongoing management should Children and adults with diabetes should disease and heart failure (Section 10 be guided by the assessment receive vaccinations according to age- “Cardiovascular Disease and Risk Man- of diabetes complications and agement,”https://doi.org/10.2337/dc20- appropriate recommendations (16,17). The shared decision-making to set S010), chronic kidney disease staging Centers for Disease Control and Prevention therapeutic goals. B (Section 11 “Microvascular Complica- (CDC) provides vaccination schedules 4.6 The 10-year risk of a first atheroscle- tions and Foot Care,” https://doi.org/10 specifically for children, adolescents, and rotic cardiovascular disease event .2337/dc20-S011), and risk of treatment- adults with diabetes at cdc.gov/vaccines/ should be assessed using the race- Americanassociated hypoglycemia (Table 4.3) schedules/. and sex-specific Pooled Cohort Equa- should be used to individualize targets People with diabetes are at higher risk tions to better stratify atherosclerotic forglycemia(Section6“GlycemicTargets,” for hepatitis B infection and are more cardiovascular disease risk. B https://doi.org/10.2337/dc20-S006), blood likely to develop complications from in- pressure, and lipids and to select specific fluenza and pneumococcal disease. The The comprehensive medical evalua- glucose-lowering medication (Section CDC Advisory Committee on Immunization tion includes the initial and follow-up 9 “Pharmacologic ApproachestoGlycemic Practices (ACIP) recommends influenza, evaluations, assessment of complica- Treatment,” https://doi.org/10.2337/dc20- pneumococcal, and hepatitis B vaccinations, psychosocial assessment, manage- ©2019 S009), antihypertension medication, and tions specifically for people with diabetes. ment of comorbid conditions, and statin treatment intensity. Vaccinations against tetanus-diphtheria- engagement of the patient throughout Additional referrals should be arranged pertussis, measles-mumps-rubella, human theprocess. Whilea comprehensive list is as necessary (Table 4.4). Clinicians should papillomavirus, and shingles are also im- Table 4.1 provided in , in clinical practice ensure that individuals with diabetes are portantforadultswithdiabetes, as they are the provider may need to prioritize the appropriately screened for complications for the general population. components of the medical evaluation and comorbidities. Discussing and imple- given the available resources and time. mentinganapproachtoglycemiccontrol Influenza The goal is to provide the health care with the patientisa part,not the sole goal, Influenza is a common, preventable in- team information so it can optimally of the patient encounter. fectious disease associated with high S40 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 43, Supplement 1, January 2020

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Diabetes

American

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Diabetes

American

mortality and morbidity in vulnerable with a mortality rate as high as 50% (19). be due to contact with infected blood or populations, including youth, older The ADA endorses recommendations from through improper equipment use (glucose adults, and people with chronic dis- the CDC ACIP that adults age $65 years, monitoring devices or infected needles). eases. Influenza vaccination in people who are at higher risk for pneumococcal Because of the higher likelihood of trans- withdiabeteshasbeenfoundtosig-©2019 disease, receive an additional 23-valent mission, hepatitis B vaccine is recommen- nificantly reduce influenza and diabe- pneumococcal polysaccharide vaccine ded for adults with diabetes age ,60 years. tes-related hospital admissions (18). (PPSV23),regardless of priorpneumococcal Foradultsage$60years, hepatitisB vaccine may be administered at the discretion of the Pneumococcal Pneumonia vaccination history. See detailed recom- treating clinician based on the patient’s Like influenza, pneumococcal pneumo- mendations at www.cdc.gov/vaccines/hcp/ fi likelihood of acquiring hepatitis B infection. nia is a common, preventable disease. acip-recs/vacc-speci c/pneumo.html. People with diabetes are at increased risk Hepatitis B for the bacteremic form of pneumococ- Compared with the general population, ASSESSMENT OF COMORBIDITIES cal infection and have been reported to people with type 1 or type 2 diabetes Besides assessing diabetes-related com- haveahighriskofnosocomialbacteremia, have higher rates of hepatitis B. This may plications, clinicians and their patients S42 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 43, Supplement 1, January 2020

Table 4.2—Assessment and treatment plan* endometrium, colon/rectum, breast, and bladder (33). The association may Assessing risk of diabetes complications result from shared risk factors between c ASCVD and heart failure history type 2 diabetes and cancer (older age, c ASCVD risk factors and 10-year ASCVD risk assessment c Staging of chronic kidney disease (see Table 11.1) obesity, and physical inactivity) but may c Hypoglycemia risk (Table 4.3) also be due to diabetes-related factors Goal setting (34), such as underlying disease physiol- c Set A1C/blood glucose target ogy or diabetes treatments, although c If hypertension is present, establish blood pressure target evidencefortheselinks isscarce.Patients c Diabetes self-management goals with diabetes should be encouraged to Therapeutic treatment plans undergo recommended age- and sex- c Lifestyle management appropriate cancer screenings and to c Pharmacologic therapy: glucose lowering reduce their modifiable cancer risk fac- c Pharmacologic therapy: cardiovascular disease risk factors and renal c Use of glucose monitoring and insulin delivery devices tors (obesity, physical inactivity, and c Referral to diabetes education and medical specialists (as needed) smoking). New onset of atypical diabetes (lean body habitus, negative family his- ASCVD, atherosclerotic cardiovascular disease. *Assessment and treatment planning are essential components of initial and all follow-up visits. tory) in a middle-aged or older patient may precede the diagnosis of pancreatic adenocarcinoma (35). However, in the need to be aware of common comorbid- diseases, with thyroid disease, celiac dis- absence of other symptoms (e.g., weight ities that affect people with diabetes and ease, and pernicious anemia (vitamin B12 loss,Association abdominal pain), routine screen- may complicate management (20–24). deficiency) being among the most common ing of all such patients is not currently Diabetes comorbidities are conditions (25). Other associated conditions include recommended. that affect people with diabetes more autoimmune hepatitis, primary adrenal in- often than age-matched people without sufficiency (Addison disease), dermatomyo- Cognitive Impairment/Dementia – diabetes. This section discusses many of sitis, and myasthenia gravis (26 29). Type 1 Recommendation the common comorbidities observed in diabetes may also occur with other auto- 4.14 In the presence of cognitive im- fi patients with diabetes but is not neces- immune diseases in the context of speci c pairment, diabetes treatment regi- sarily inclusive of all the conditions that genetic disorders or polyglandular autoim- mens should be simplified as much have been reported. mune syndromes (30). Given the high prev- as possible and tailored to min- fi alence, nonspeci c symptoms, and imize the risk of hypoglycemia. B Autoimmune Diseases insidious onset ofDiabetes primary hypothyroidism, Recommendations routine screening for thyroid dysfunction is fi 4.12 Patients with type 1 diabetes recommended for all patients with type 1 Diabetes is associated with a signi - should be screened for autoim- diabetes. Screening for celiac disease should cantly increased risk and rate of cogni- mune thyroid disease soon af- be considered in adult patients with sug- tive decline and an increased risk of ter diagnosis and periodically gestive symptoms (e.g., diarrhea, malab- dementia (36,37). A recent meta-analysis thereafter. B sorption, abdominal pain) or signs (e.g., of prospective observational studies in 4.13 Adult patients with type 1 di- osteoporosis, vitamin deficiencies, iron de- people with diabetes showed 73% in- abetes should be screened for ficiency anemia) (31,32). Measurement of creased risk of all types of dementia, celiac disease in the presence of vitamin B12 levels should be considered for 56% increased risk of Alzheimer demen- gastrointestinal symptoms, signs, patients with type 1 diabetes and peripheral tia, and 127% increased risk of vascular or laboratory manifestationsAmerican sug- neuropathy or unexplained anemia. dementia compared with individuals gestive of celiac disease. B without diabetes (38). The reverse is Cancer also true: people with Alzheimer de- People with type 1 diabetes are at in- Diabetes is associated with increased mentia are more likely to develop di- creased risk for other autoimmune risk of cancers of the liver, pancreas, abetes than people without Alzheimer dementia. In a 15-year prospective — study of community-dwelling people Table 4.3 Assessment of hypoglycemia risk . ©2019Factors that increase risk of treatment-associated hypoglycemia 60 years of age, the presence of di- c Use of insulin or insulin secretagogues (i.e., sulfonylureas, meglitinides) abetes at baseline significantly increased c Impaired kidney or hepatic function the age- and sex-adjusted incidence of c Longer duration of diabetes all-cause dementia, Alzheimer dementia, c Frailty and older age and vascular dementia compared with c Cognitive impairment rates in those with normal glucose tol- c Impaired counterregulatory response, hypoglycemia unawareness c Physical or intellectual disability that may impair behavioral response to hypoglycemia erance (39). c Alcohol use c Polypharmacy (especially ACE inhibitors, angiotensin receptor blockers, nonselective b-blockers) Hyperglycemia In those with type 2 diabetes, the de- See references 100–104. gree and duration of hyperglycemia are care.diabetesjournals.org Comprehensive Medical Evaluation and Assessment of Comorbidities S43

Table 4.4—Referrals for initial care management mediated, at least in part, by weight loss c Eye care professional for annual dilated eye exam (53–55). c Family planning for women of reproductive age c Registered dietitian nutritionist for medical nutrition therapy Hepatitis C Infection c Diabetes self-management education and support Infection with hepatitis C virus (HCV) is c Dentist for comprehensive dental and periodontal examination associated with a higher prevalence of c Mental health professional, if indicated type 2 diabetes, which is present in up to one-third of individuals with chronic HCV infection. HCV may impair glucose me- related to dementia. More rapid cog- low reporting rate for cognitive-related tabolism by several mechanisms, in- nitive decline is associated with both adverse events, including cognitive dys- cluding directly via viral proteins and increased A1C and longer duration of function or dementia, with statin ther- indirectly by altering proinflammatory diabetes (38). The Action to Control apy, similar to rates seen with other cytokine levels (56). The use of newer Cardiovascular Risk in Diabetes (ACCORD) commonly prescribed cardiovascular direct-acting antiviral drugs produces a study found that each 1% higher A1C medications (46). Therefore, fear of sustained virological response (cure) in level was associated with lower cog- cognitive decline should not be a bar- nearly all cases and has been reported nitive function in individuals with rier to statin use in individuals with to improve glucose metabolism in intype 2 diabetes (40). However, the diabetes and a high risk for cardiovas- dividuals with diabetes (57). A meta- ACCORD study found no difference cular disease. analysis of mostly observational stud- in cognitive outcomes in participants ies found a mean reduction in A1C 2 randomly assigned to intensive and Nonalcoholic Fatty Liver Disease levelsAssociation of 0.45% (95% CI 0.60 to 2 standard glycemic control, supporting 0.30) and reduced requirement for Recommendation glucose-lowering medication use fol- the recommendation that intensive 4.15 Patients with type 2 diabetes or glucose control should not be advised lowing successful eradication of HCV prediabetes and elevated liver infection (58). for the improvement of cognitive func- enzymes (ALT) or fatty liver on tion in individuals with type 2 diabetes ultrasound should be evaluated Pancreatitis (41). for presence of nonalcoholic steatohepatitis and liver fibrosis. C Recommendation Hypoglycemia 4.16 Islet autotransplantation should In type 2 diabetes, severe hypoglycemia Diabetes is associated with the develop- be considered for patients re- is associated with reduced cognitive ment of nonalcoholicDiabetes fatty liver disease, quiring total pancreatectomy function, and those with poor cognitive including its more severe manifesta- for medically refractory chronic function have more severe hypoglyce- tions of nonalcoholic steatohepatitis, pancreatitis to prevent postsur- mia. In a long-term study of older pa- liver fibrosis, cirrhosis, and hepatocel- gical diabetes. C tients with type 2 diabetes, individuals lular carcinoma (47). Elevations of he- with one or more recorded episodes of patic transaminase concentrations are Diabetes is linked to diseases of the severe hypoglycemia had a stepwise in- associated with higher BMI, waist cir- exocrine pancreas such as pancreatitis, crease in risk of dementia (42). Likewise, cumference, and triglyceride levels and which may disrupt the global architec- the ACCORD trial found that as cognitive lower HDL cholesterol levels. Noninva- ture or physiology of the pancreas, often function decreased, the risk of severe sive tests, such as elastography or fibrosis resulting in both exocrine and endocrine hypoglycemia increased (43). Tailoring biomarkers, may be used to assess risk of dysfunction. Up to half of patients with glycemic therapy may helpAmerican to prevent fibrosis, but referral to a liver specialist diabetes may have some degree of im- hypoglycemia in individuals with cogni- and liver biopsy may be required for paired exocrine pancreas function (59). tive dysfunction. definitive diagnosis (48). Interventions People with diabetes are at an approx- Nutrition that improve metabolic abnormalities imately twofold higher risk of developing In one study, adherence to the Mediter- in patients with diabetes (weight loss, acute pancreatitis (60). ranean diet correlated with improved glycemic control, and treatment with Conversely, prediabetes and/or diabe- cognitive function (44). However, a re- specific drugs for hyperglycemia or dyslip- tes has been found to develop in approx- cent Cochrane review found insufficient idemia) are also beneficial for fatty liver imately one-third of patients after an evidence©2019 to recommend any dietary disease(49,50).PioglitazoneandvitaminE episode of acute pancreatitis (61); thus, change for the prevention or treatment treatment of biopsy-proven nonalcoholic the relationship is likely bidirectional. of cognitive dysfunction (45). steatohepatitis have been shown to im- Postpancreatitis diabetes may include prove liver histology, but effects on longer- either new-onset disease or previously Statins term clinical outcomes are not known unrecognized diabetes (62). Studies of A systematic review has reported that data (51,52). Treatment with liraglutide and patients treated with incretin-based ther- do not support an adverse effect of statins with sodium–glucose cotransporter 2 in- apies for diabetes have also reported that on cognition (46). The U.S. Food and Drug hibitors (dapagliflozin and empagliflozin) pancreatitis may occur more frequently Administration postmarketing surveil- has also shown some promise in prelim- with these medications, but results have lance databases have also revealed a inary studies, although benefits may be been mixed (63,64). S44 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 43, Supplement 1, January 2020

Islet autotransplantation should be twice as prevalent in people with diabetes diabetes. Among patients with HIV considered for patients requiring total compared with those without, after and diabetes, preventive health care pancreatectomy for medically refractory adjusting for age and other risk factors using an approach similar to that used chronic pancreatitis to prevent postsur- for hearing impairment (75). Low HDL, in patients without HIV is critical to gical diabetes. Approximately one-third coronary heart disease, peripheral neu- reduce the risks of microvascular and of patients undergoing total pancreatec- ropathy, and general poor health have macrovascular complications. tomy with islet autotransplantation are been reported as risk factors for hearing ForpatientswithHIVandARV-associated insulin free 1 year postoperatively, and impairment for people with diabetes, hyperglycemia, it may be appropriate to observational studies from different cen- but an association of hearing loss with consider discontinuing the problematic ters have demonstrated islet graft func- blood glucose levels has not been ARV agents if safe and effective alter- tion up to a decade after the surgery in consistently observed (76). In the Di- natives areavailable(82).Beforemaking some patients (65–69). Both patient and abetes Control and Complications Trial/ ARV substitutions, carefully consider disease factors should be carefully con- Epidemiology of Diabetes Interventions the possible effect on HIV virological sidered when deciding the indications and Complications (DCCT/EDIC) cohort, control and the potential adverse ef- and timing of this surgery. Surgeries time-weighted mean A1C was associated fects of new ARV agents. In some cases, should be performed in skilled facilities with increased risk of hearing impairment antihyperglycemic agents may still be that have demonstrated expertise in islet when tested after long-term (.20 years) necessary. autotransplantation. follow-up (77). Impairment in smell, but not taste, has also been reported in in- Low Testosterone in Men dividuals with diabetes (78). Fractures RecommendationAssociation Age-specific hip fracture risk is signifi- 4.18 In men with diabetes who have cantly increased in both people with HIV symptoms or signs of hypogo- type 1 diabetes (relative risk 6.3) and Recommendation nadism, such as decreased sex- those with type 2 diabetes (relative risk 4.17 Patients with HIV should be ual desire (libido) or activity, or 1.7) in both sexes (70). Type 1 diabetes is screened for diabetes and pre- erectile dysfunction, consider associated with osteoporosis, but in type 2 diabetes with a fasting glucose screening with a morning se- diabetes, an increased risk of hip fracture testbeforestartingantiretroviral rum testosterone level. B is seen despite higher bone mineral den- therapy, at the time of switching sity (BMD) (71). In three large observa- antiretroviral therapy, and 3–6 Mean levels of testosterone are lower tional studies of older adults, femoral neck months after starting or switch- in men with diabetes compared with age- BMD T score and the World Health ing antiretroviralDiabetes therapy. If ini- matched men without diabetes, but Organization Fracture Risk Assessment tial screening results are normal, obesity is a major confounder (83,84). Tool (FRAX) score were associated with fasting glucose should be checked Treatment in asymptomatic men is con- hip and nonspine fractures. Fracture annually. E troversial. Testosterone replacement in risk was higher in participants with men with symptomatic hypogonadism diabetes compared with those without Diabetes risk is increased with certain may have benefits including improved diabetes for a given T score and age or protease inhibitors (PIs) and nucleoside sexual function, well-being, muscle mass for a given FRAX score (72). Providers reverse transcriptase inhibitors (NRTIs). and strength, and bone density (85). In should assess fracture history and risk New-onset diabetes is estimated to men with diabetes who have symp- factors in older patients with diabetes occur in more than 5% of patients toms or signs of low testosterone and recommend measurement of BMD infected with HIV on PIs, whereas (hypogonadism), a morning total testos- if appropriate for the patient’s age and Americanmore than 15% may have prediabetes terone level should be measured using sex. Fracture prevention strategies for (79). PIs are associated with insulin an accurate and reliable assay. In men people with diabetes are the same resistance and may also lead to apo- who have total testosterone levels close as for the general population and in- ptosis of pancreatic b-cells. NRTIs also to the lower limit, it is reasonable to check clude vitamin D supplementation. For affect fat distribution (both lipohyper- sex hormone–binding globulin, as it is patients with type 2 diabetes with fracture trophy and lipoatrophy), which is asso- often low in diabetes and associated with risk factors, thiazolidinediones (73) and ciated with insulin resistance. lower testosterone levels. Further test- sodium–glucose cotransporter 2 inhibi- Individuals with HIV are at higher risk ing (such as luteinizing hormone and tors (74) should be used with caution. ©2019 for developing prediabetes and diabetes follicle-stimulating hormone levels) may on antiretroviral (ARV) therapies, so a be needed to determine if the patient Sensory Impairment screening protocol is recommended (80). has hypogonadism. Testosterone re- Hearing impairment, both in high-frequency The A1C test may underestimate glyce- placement in older men with hypogonad- and low- to mid-frequency ranges, is more mia in people with HIV; it is not recom- ism has been associated with increased common in people with diabetes than in mended for diagnosis and may present coronary artery plaque volume and, in those without, perhaps due to neuropathy challenges for monitoring (81). In those some studies, an increase in cardiovas- and/or vascular disease. In a National Health with prediabetes, weight loss through cular events, which should be considered and Nutrition Examination Survey (NHANES) healthy nutrition and physical activity when assessing the risks and benefits of analysis, hearing impairment was about may reduce the progression toward treatment (86,87). care.diabetesjournals.org Comprehensive Medical Evaluation and Assessment of Comorbidities S45

Obstructive Sleep Apnea treatment and risk of complications in patients 18. Goeijenbier M, van Sloten TT, Slobbe L, et al. Age-adjusted rates of obstructive sleep with type 2 diabetes (UKPDS 33). Lancet 1998; Benefits of flu vaccination for persons with di- apnea, a risk factor for cardiovascular 352:837–853 abetes mellitus: a review. Vaccine 2017;35: fi 5. NathanDM,GenuthS,LachinJ,etal.;Diabetes 5095–5101 disease, are signi cantly higher (4- to Control and Complications Trial Research Group. 19. Smith SA, Poland GA. Use of influenza and 10-fold) with obesity, especially with The effect of intensive treatment of diabetes on pneumococcal vaccines in people with diabetes. central obesity (88). The prevalence of the development and progression of long-term Diabetes Care 2000;23:95–108 obstructive sleep apnea in the popula- complications in insulin-dependent diabetes 20. Selvin E, Coresh J, Brancati FL. The burden tion with type 2 diabetes may be as high mellitus. N Engl J Med 1993;329:977–986 and treatment of diabetes in elderly individuals 6. Lachin JM, Genuth S, Nathan DM, Zinman B, in the U.S. Diabetes Care 2006;29:2415–2419 as 23%, and the prevalence of any sleep- Rutledge BN; DCCT/EDIC Research Group. Effect 21. Grant RW, Ashburner JM, Hong CS, Chang Y, disordered breathing may be as high as of glycemic exposure on the risk of microvascular Barry MJ, Atlas SJ. Defining patient complexity 58% (89,90). In obese participants en- complications in the Diabetes Control and Com- from the primary care physician’s perspective: rolled in the Action for Health in Diabetes plications Trialdrevisited. Diabetes 2008;57: a cohort study [published correction appears in (Look AHEAD) trial, it exceeded 80% (91). 995–1001 Ann Intern Med 2012;157:152]. Ann Intern Med 7. White NH, Cleary PA, Dahms W, Goldstein D, 2011;155:797–804 Patients with symptoms suggestive of Malone J, Tamborlane WV; Diabetes Control and 22. Tinetti ME, Fried TR, Boyd CM. Designing obstructive sleep apnea (e.g., excessive Complications Trial (DCCT)/Epidemiology of Di- health care for the most common chronic con- daytime sleepiness, snoring, witnessed abetes Interventions and Complications (EDIC) ditiondmultimorbidity. JAMA 2012;307:2493– apnea) should be considered for screen- Research Group. Beneficial effects of intensive 2494 ing (92). Sleep apnea treatment (lifestyle therapy of diabetes during adolescence: out- 23. Sudore RL, Karter AJ, Huang ES, et al. Symp- fi comes after the conclusion of the Diabetes tom burden of adults with type 2 diabetes across modi cation, continuous positive airway Control and Complications Trial (DCCT). J Pediatr the disease course: diabetes & aging study. pressure, oral appliances, and surgery) 2001;139:804–812 J Gen Intern Med 2012;27:1674–1681 significantly improves quality of life and 8. Anderson RM, Funnell MM. Compliance and 24. BorgnakkeAssociation WS, Ylostalo¨ PV, Taylor GW, blood pressure control. The evidence adherence are dysfunctional concepts in diabe- Genco RJ. Effect of periodontal disease on di- for a treatment effect on glycemic con- tes care. Diabetes Educ 2000;26:597–604 abetes: systematic review of epidemiologic 9. Sarkar U, Fisher L, Schillinger D. Is self-efficacy observational evidence. J Periodontol 2013; trol is mixed (93). associated with diabetes self-management 84(Suppl.):S135–S152 across race/ethnicity and health literacy? Dia- 25. Nederstigt C, Uitbeijerse BS, Janssen LGM, Periodontal Disease betes Care 2006;29:823–829 Corssmit EPM, de Koning EJP, Dekkers OM. Periodontal disease is more severe, and 10. King DK, Glasgow RE, Toobert DJ, et al. Self- Associated auto-immune disease in type 1 di- may be more prevalent, in patients with efficacy, problem solving, and social-environmental abetes patients: a systematic review and meta- – diabetes than in those without and has support are associated with diabetes self- analysis. Eur J Endocrinol 2019;180:135 144 management behaviors. Diabetes Care 2010;33: 26. De Block CE, De Leeuw IH, Van Gaal LF. High been associated with higher A1C levels 751–753 prevalence of manifestations of gastric autoim- (94–96). Longitudinal studies suggest 11. Nouwen A, Urquhart Law G, Hussain S, munity in parietal cell antibody-positive type 1 that people with periodontal disease McGovern S, NapierDiabetes H. Comparison of the (insulin-dependent) diabetic patients. The Bel- have higher rates of incident diabetes. role of self-efficacy and illness representations gian Diabetes Registry. J Clin Endocrinol Metab in relation to dietary self-care and diabetes – Current evidence suggests that peri- 1999;84:4062 4067 distress in adolescents with type 1 diabetes. 27. Triolo TM, Armstrong TK, McFann K, et al. odontal disease adversely affects diabe- Psychol Health 2009;24:1071–1084 Additional autoimmune disease found in 33% of tes outcomes, although evidence for 12. Beckerle CM, Lavin MA. Association of self- patients at type 1 diabetes onset. Diabetes Care treatmentbenefitsremainscontroversial efficacy and self-care with glycemic control in 2011;34:1211–1213 (24,97). In a randomized clinical trial, diabetes. Diabetes Spectr 2013;26:172–178 28. Hughes JW, Riddlesworth TD, DiMeglio LA, 13. IannottiRJ, SchneiderS, NanselTR,et al.Self- Miller KM, Rickels MR, McGill JB; T1D Exchange intensive periodontal treatment was efficacy, outcome expectations, and diabetes Clinic Network. Autoimmune diseases in children associated with better glycemic control self-management in adolescents with type 1 and adults with type 1 diabetes from the T1D (A1C 8.3% vs. 7.8% in control subjects diabetes. J Dev Behav Pediatr 2006;27:98–105 Exchange Clinic Registry. J Clin Endocrinol Metab and the intensive-treatment group, re- 14. Dickinson JK, GuzmanSJ, Maryniuk MD, et al. 2016;101:4931–4937 spectively) and reductionAmerican in inflam- The use of language in diabetes care and edu- 29. Kahaly GJ, Hansen MP. Type 1 diabetes cation. Diabetes Care 2017;40:1790–1799 associated autoimmunity. Autoimmun Rev 2016; matory markers after 12 months of 15. Lee SWH, Ng KY, Chin WK. The impact of 15:644–648 follow-up (98). sleep amount and sleep quality on glycemic 30. Eisenbarth GS, Gottlieb PA. Autoimmune control in type 2 diabetes: a systematic review polyendocrine syndromes. N Engl J Med 2004; References and meta-analysis. Sleep Med Rev 2017;31:91– 350:2068–2079 1. Stellefson M, Dipnarine K, Stopka C. The 101 31. Rubio-Tapia A, Hill ID, Kelly CP, Calderwood chronic care model and diabetes management 16. Robinson CL, Romero JR, Kempe A, Pellegrini AH, Murray JA; American College of Gastroen- in US primary care settings: a systematic review. C; Advisory Committee on Immunization Prac- terology. ACG clinical guidelines: diagnosis and Prev Chronic Dis 2013;10:E26 tices (ACIP) Child/Adolescent Immunization management of celiac disease. Am J Gastro- 2. Coleman©2019 K, Austin BT, Brach C, Wagner EH. Work Group. Advisory Committee on Immuni- enterol 2013;108:656–676; quiz 677 Evidence on the Chronic Care Model in the new zation Practices recommended immunization 32. Husby S, Murray JA, Katzka DA. AGA clinical millennium. Health Aff (Millwood) 2009;28:75– schedule for children and adolescents aged practice update on diagnosis and monitoring of 85 18 years or younger – United States, 2017. celiac diseasedchanging utility of serology and 3. GabbayRA,Bailit MH,Mauger DT,WagnerEH, MMWR Morb Mortal Wkly Rep 2017;66:134– histologic measures: expert review. Gastroen- Siminerio L. Multipayer patient-centered med- 135 terology 2019;156:885–889 ical home implementation guided by the chronic 17. Kim DK, Riley LE, Harriman KH, Hunter P, 33. Suh S, Kim K-W. Diabetes and cancer: is care model. Jt Comm J Qual Patient Saf 2011;37: Bridges CB. Advisory Committee on Immuniza- diabetes causally related to cancer? Diabetes 265–273 tion Practices recommended immunization Metab J 2011;35:193–198 4. UK Prospective DiabetesStudy (UKPDS) Group. schedule for adults aged 19 years or older – 34. Giovannucci E, Harlan DM, Archer MC, et al. Intensive blood-glucose control with sulphonylur- United States, 2017. MMWR Morb Mortal Wkly Diabetes and cancer: a consensus report. CA eas or insulin compared with conventional Rep 2017;66:136–138 Cancer J Clin 2010;60:207–221 S46 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 43, Supplement 1, January 2020

35. Aggarwal G, Kamada P, Chari ST. Prevalence steatohepatitis and prediabetes or type 2 diabetes summary of an NIDDK workshop. Ann Surg of diabetes mellitus in pancreatic cancer com- mellitus: a randomized trial. Ann Intern Med 2016; 2015;261:21–29 pared to common cancers. Pancreas 2013;42: 165:305–315 66. Sutherland DER, Radosevich DM, Bellin MD, 198–201 51. Belfort R, Harrison SA, Brown K, et al. A et al. Total pancreatectomy and islet autotrans- 36. Cukierman T, Gerstein HC, Williamson JD. placebo-controlled trial of pioglitazone in sub- plantation for chronic pancreatitis. J Am Coll Surg Cognitive decline and dementia in diabetesd jects with nonalcoholic steatohepatitis. N Engl J 2012;214:409–424; discussion 424–426 systematic overview of prospective observa- Med 2006;355:2297–2307 67. Quartuccio M, Hall E, Singh V, et al. Glycemic tional studies. Diabetologia 2005;48:2460–2469 52. Sanyal AJ, Chalasani N, Kowdley KV, et al.; predictors of insulin independence after total 37. BiesselsGJ,StaekenborgS,BrunnerE,BrayneC, NASH CRN. Pioglitazone, vitamin E, or placebo for pancreatectomy with islet autotransplantation. Scheltens P. Risk of dementia in diabetes mellitus: nonalcoholic steatohepatitis. N Engl J Med 2010; J Clin Endocrinol Metab 2017;102:801–809 a systematic review. Lancet Neurol 2006;5:64–74 362:1675–1685 68. Webb MA, Illouz SC, Pollard CA, et al. Islet 38. Gudala K, Bansal D, Schifano F, Bhansali A. 53. Armstrong MJ, Gaunt P, Aithal GP, et al.; auto transplantation following total pancreatec- Diabetes mellitus and risk of dementia: a meta- LEAN trial team. Liraglutide safety and efficacy in tomy: a long-term assessment of graft function. analysis of prospective observational studies. J patients with non-alcoholic steatohepatitis Pancreas 2008;37:282–287 Diabetes Investig 2013;4:640–650 (LEAN):amulticentre,double-blind, randomised, 69. Wu Q, Zhang M, Qin Y, et al. Systematic 39. Ohara T, Doi Y, Ninomiya T, et al. Glucose placebo-controlled phase 2 study. Lancet 2016; review and meta-analysis of islet autotransplan- tolerance status and risk of dementia in the 387:679–690 tation after total pancreatectomy in chronic community: the Hisayama study. Neurology 54. Shimizu M, Suzuki K, Kato K, et al. Evaluation pancreatitis patients. Endocr J 2015;62:227–234 2011;77:1126–1134 of the effects of dapagliflozin, a sodium-glucose 70. Janghorbani M, Van Dam RM, Willett WC, Hu 40. Cukierman-Yaffe T, Gerstein HC, Williamson co-transporter-2 inhibitor, on hepatic steatosis FB. Systematic review of type 1 and type 2 JD, et al.; Action to Control Cardiovascular Risk in and fibrosis using transient elastography in pa- diabetes mellitus and risk of fracture. Am J Diabetes-Memory in Diabetes (ACCORD-MIND) tients with type 2 diabetes and non-alcoholic Epidemiol 2007;166:495–505 Investigators. Relationship between baseline fatty liver disease. Diabetes Obes Metab 2019; 71. Vestergaard P. Discrepancies in bone min- glycemic control and cognitive function in indi- 21:285–292 eral density and fracture risk in patients with viduals with type 2 diabetes and other cardio- 55. Sattar N, Fitchett D, Hantel S, George JT, typeAssociation 1 and type 2 diabetesda meta-analysis. vascular risk factors: the Action to Control Zinman B. Empagliflozin is associated with improve- Osteoporos Int 2007;18:427–444 Cardiovascular Risk in Diabetes-Memory in Di- ments in liver enzymes potentially consistent with 72. Schwartz AV, Vittinghoff E, Bauer DC, et al.; abetes (ACCORD-MIND) trial. Diabetes Care reductions in liver fat: results from randomised Study of Osteoporotic Fractures (SOF) Research 2009;32:221–226 trials including the EMPA-REG OUTCOMEÒ trial. Group; Osteoporotic Fractures in Men (MrOS) 41. Launer LJ, Miller ME, Williamson JD, et al.; Diabetologia 2018;61:2155–2163 Research Group; Health, Aging, and Body Com- ACCORD MIND investigators. Effects of intensive 56. Lecube A, Hernandez´ C, Genesca` J, SimoR.´ position (Health ABC) Research Group. Associ- glucose lowering on brain structure and function Proinflammatory cytokines, insulin resistance, ation of BMD and FRAX score with risk of fracture in people with type 2 diabetes (ACCORD MIND): and insulin secretion in chronic hepatitis C in older adults with type 2 diabetes. JAMA 2011; a randomised open-label substudy. Lancet Neu- patients: a case-control study. Diabetes Care 305:2184–2192 rol 2011;10:969–977 2006;29:1096–1101 73. Kahn SE,ZinmanB, LachinJM, etal.; Diabetes 42. Whitmer RA, Karter AJ, Yaffe K, Quesenberry 57. Hum J, Jou JH, Green PK, et al. Improvement OutcomeProgression Trial (ADOPT)Study Group. CP Jr, Selby JV. Hypoglycemic episodes and risk of in glycemic control of type 2 diabetes after Rosiglitazone-associated fractures in type 2 di- dementia in older patients with type 2 diabetes successful treatmentDiabetes of hepatitis C virus. Di- abetes: an analysis from A Diabetes Outcome mellitus. JAMA 2009;301:1565–1572 abetes Care 2017;40:1173–1180 Progression Trial (ADOPT). Diabetes Care 2008;31: 43. Punthakee Z, Miller ME, Launer LJ, et al.; 58. Carnovale C, Pozzi M, Dassano A, et al. The 845–851 ACCORD Group of Investigators; ACCORD-MIND impact of a successful treatment of hepatitis C 74. Taylor SI, Blau JE, Rother KI. Possible adverse Investigators. Poor cognitive function and risk of virus on glyco-metabolic control in diabetic effects of SGLT2 inhibitors on bone. Lancet Di- severe hypoglycemia in type 2 diabetes: post hoc patients: a systematic review and meta-analysis. abetes Endocrinol 2015;3:8–10 epidemiologic analysis of the ACCORD trial. Di- Acta Diabetol 2019;56:341–354 75. Bainbridge KE, Hoffman HJ, Cowie CC. Di- abetes Care 2012;35:787–793 59. Piciucchi M, Capurso G, Archibugi L, Delle abetes and hearing impairment in the United 44. Scarmeas N, Stern Y, Mayeux R, Manly JJ, Fave MM, Capasso M, Delle Fave G. Exocrine States: audiometric evidence from the National Schupf N, Luchsinger JA. Mediterranean diet and pancreatic insufficiency in diabetic patients: Health and Nutrition Examination Survey, mild cognitive impairment. Arch Neurol 2009;66: prevalence, mechanisms, and treatment. Int J 1999 to 2004. Ann Intern Med 2008;149:1–10 216–225 Endocrinol 2015;2015:595649 76. Bainbridge KE, Hoffman HJ, Cowie CC. Risk 45. Ooi CP, Loke SC, Yassin Z, Hamid T-A. Car- 60.LeeY-K,HuangM-Y,HsuC-Y,SuY-C.Bidirec- factorsfor hearingimpairmentamongU.S.adults bohydrates for improving theAmerican cognitive perfor- tional relationship between diabetes and acute with diabetes: National Health and Nutrition mance of independent-living older adults with pancreatitis: a population-based cohort study in Examination Survey 1999-2004. Diabetes Care normal cognition or mild cognitive impairment. Taiwan. Medicine (Baltimore) 2016;95:e2448 2011;34:1540–1545 Cochrane Database Syst Rev 2011;4:CD007220 61. Das SLM, Singh PP, Phillips ARJ, Murphy R, 77. Schade DS, Lorenzi GM, Braffett BH, et al.; 46. Richardson K, Schoen M, French B, et al. Windsor JA, PetrovMS. Newlydiagnoseddiabetes DCCT/EDIC Research Group. Hearing impairment Statins and cognitive function: a systematic re- mellitus after acute pancreatitis: a systematic and type 1 diabetes in the Diabetes Control and view. Ann Intern Med 2013;159:688–697 review and meta-analysis. Gut 2014;63:818–831 Complications Trial/Epidemiology of Diabetes 47. El-Serag HB, Tran T, Everhart JE. Diabetes 62. Petrov MS. Diabetes of the exocrine pan- Interventions and Complications (DCCT/EDIC) increases the risk of chronic liver disease and creas: American Diabetes Association-compliant cohort. Diabetes Care 2018;41:2495–2501 hepatocellular carcinoma. Gastroenterology 2004; lexicon. Pancreatology 2017;17:523–526 78. Rasmussen VF, Vestergaard ET, Hejlesen O, 126:460©2019–468 63. Thomsen RW, Pedersen L, Møller N, Kahlert Andersson CUN, Cichosz SL. Prevalence of taste 48. Chalasani N, Younossi Z, Lavine JE, et al. The J, Beck-Nielsen H, Sørensen HT. Incretin-based and smell impairment in adults with diabetes: diagnosis and management of nonalcoholic fatty therapy and risk of acute pancreatitis: a nation- a cross-sectional analysis of data from the Na- liver disease: practice guidance from the Amer- wide population-based case-control study. Di- tional Health and Nutrition Examination Survey ican Association for the Study of Liver Diseases. abetes Care 2015;38:1089–1098 (NHANES). Prim Care Diabetes 2018;12:453–459 Hepatology 2018;67:328–357 64. Tkaćˇ I, Raz I. Combined analysis of three 79. Monroe AK, Glesby MJ, Brown TT. Diagnos- 49. American Gastroenterological Association. large interventional trials with gliptins indicates ing and managing diabetes in HIV-infected pa- American Gastroenterological Association medical increased incidence of acute pancreatitis in tients: current concepts. Clin Infect Dis 2015; position statement: nonalcoholic fatty liver disease. patients with type 2 diabetes. Diabetes Care 60:453–462 Gastroenterology 2002;123:1702–1704 2017;40:284–286 80. Schambelan M, Benson CA, Carr A, et al.; 50. Cusi K, Orsak B, Bril F, et al. Long-term pio- 65. Bellin MD, Gelrud A, Arreaza-Rubin G, et al. Total International AIDS Society-USA. Management glitazone treatment for patients with nonalcoholic pancreatectomy with islet autotransplantation: of metabolic complications associated with care.diabetesjournals.org Comprehensive Medical Evaluation and Assessment of Comorbidities S47

antiretroviral therapy for HIV-1 infection: rec- Nutrition Examination Survey, 2005-2006. Prev 97. Simpson TC, Weldon JC, Worthington HV, ommendations of an International AIDS Society- Med 2010;51:18–23 et al. Treatment of periodontal disease for USA panel. J Acquir Immune Defic Syndr 2002;31: 89. West SD, Nicoll DJ, Stradling JR. Prevalence glycaemic control in people with diabetes melli- 257–275 of obstructive sleep apnoea in men with type 2 tus. Cochrane Database Syst Rev 2015 11: 81. Kim PS, Woods C, Georgoff P, et al. A1C diabetes. Thorax 2006;61:945–950 CD004714 underestimates glycemia in HIV infection. Di- 90. Resnick HE, Redline S, Shahar E, et al.; Sleep 98. D’Aiuto F, Gkranias N, Bhowruth D, et al.; abetes Care 2009;32:1591–1593 Heart Health Study. Diabetes and sleep distur- TASTE Group. Systemic effects of periodontitis treat- 82. Wohl DA, McComsey G, Tebas P, et al. bances: findings from the Sleep Heart Health ment in patients with type 2 diabetes: a 12 month, Current concepts in the diagnosis and manage- Study. Diabetes Care 2003;26:702–709 single-centre, investigator-masked, randomised trial. ment of metabolic complications of HIV infec- 91. Foster GD, Sanders MH, Millman R, et al.; Lancet Diabetes Endocrinol 2018;6:954–965 tion and its therapy. Clin Infect Dis 2006;43: Sleep AHEAD Research Group. Obstructive sleep 99. Davies MJ, D’Alessio DA, Fradkin J, et al. 645–653 apnea among obese patients with type 2 di- Management of hyperglycemia in type 2 diabe- 83. Dhindsa S, Miller MG, McWhirter CL, et al. abetes. Diabetes Care 2009;32:1017–1019 tes, 2018. A consensus report by the American Testosterone concentrationsin diabeticandnon- 92. Bibbins-Domingo K, Grossman DC, Curry SJ, Diabetes Association (ADA) and the European diabetic obese men. Diabetes Care 2010;33: etal.;USPreventiveServicesTaskForce.Screening Association for the Study of Diabetes (EASD). 1186–1192 for obstructive sleep apnea in adults: US Pre- Diabetes Care 2018;41:2669–2701 84. Grossmann M. Low testosterone in men ventive Services Task Force recommendation 100. Lipska KJ, Ross JS, Wang Y, et al. National with type 2 diabetes: significance and treatment. statement. JAMA 2017;317:407–414 trends in US hospital admissions for hypergly- J Clin Endocrinol Metab 2011;96:2341–2353 93. Shaw JE, Punjabi NM, Wilding JP, Alberti cemia and hypoglycemia among Medicare ben- 85. Bhasin S, Cunningham GR, Hayes FJ, et al.; KGMM, Zimmet PZ; International Diabetes Fed- eficiaries, 1999 to 2011. JAMA Intern Med 2014; Task Force, Endocrine Society. Testosterone eration Taskforce on Epidemiology and Preven- 174:1116–1124 therapy in men with androgen deficiency syn- tion. Sleep-disordered breathing and type 2 101. Shorr RI, Ray WA, Daugherty JR, GriffinMR. dromes: an Endocrine Society clinical practice diabetes: a report from the International Diabetes Incidence and risk factors for serious hypoglyce- guideline. J Clin Endocrinol Metab 2010;95: Federation Taskforce on Epidemiology and Pre- mia in older persons using insulin or sulfonylureas. 2536–2559 vention. Diabetes Res Clin Pract 2008;81:2–12 Arch InternAssociation Med 1997;157:1681–1686 86. Budoff MJ, Ellenberg SS, Lewis CE, et al. 94. Khader YS, Dauod AS, El-Qaderi SS, Alkafajei 102. Abdelhafiz AH, Rodr´ıguez-Manas~ L, Morley Testosterone treatment and coronary artery A, Batayha WQ. Periodontal status of diabetics JE, Sinclair AJ. Hypoglycemia in older people - a plaque volume in older men with low testoster- compared with nondiabetics: a meta-analysis. J less well recognized risk factor for frailty. Aging one. JAMA 2017;317:708–716 Diabetes Complications 2006;20:59–68 Dis 2015;6:156–167 87. Kloner RA, Carson C III, Dobs A, Kopecky S, 95. Casanova L, Hughes FJ, Preshaw PM. Di- 103. Yun J-S, Ko S-H, Ko S-H, et al. Presence of Mohler ER III. Testosterone and cardiovascular abetes and periodontal disease: a two-way re- macroalbuminuria predicts severe hypoglycemia disease. J Am Coll Cardiol 2016;67:545–557 lationship. Br Dent J 2014;217:433–437 in patients with type 2 diabetes: a 10-year follow-up 88. Li C, Ford ES, Zhao G, Croft JB, Balluz LS, 96. Eke PI, Thornton-Evans GO, Wei L, Borgnakke study. Diabetes Care 2013;36:1283–1289 Mokdad AH. Prevalence of self-reported clini- WS, Dye BA, Genco RJ. Periodontitis in US adults: 104. ChelliahA,BurgeMR.Hypoglycaemiainelderly cally diagnosed sleep apnea according to obesity National Health and Nutrition Examination Survey patients with diabetes mellitus: causes and strategies status in men and women: National Health and 2009-2014. J Am Dent AssocDiabetes 2018;149:576–588.e6 for prevention. Drugs Aging 2004;21:511–530

American

5. Facilitating Behavior Change American Diabetes Association and Well-being to Improve Health Outcomes: Standards of Medical Care in Diabetesd2020

Diabetes Care 2020;43(Suppl. 1):S48–S65 | https://doi.org/10.2337/dc20-S005

Association The American Diabetes Association (ADA) “Standards of Medical Care in Diabe- tes” includes the ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10 .2337/dc20-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations, please refer to theDiabetes Standards of Care In- troduction (https://doi.org/10.2337/dc20-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes

5. FACILITATING BEHAVIOR CHANGE AND WELL-BEING .org/SOC.

Effective behavior management and psychological well-being are foundational to achieving treatment goals for people with diabetes (1,2). Essential to achieving these goals are diabetes self-management education and support (DSMES), medical nutrition therapy (MNT), routine physical activity, smoking cessation counseling when needed, and psychosocial care. Following an initial comprehensive medical evaluation (see Section 4, “Comprehensive Medical Evaluation and Assessment of Comorbidities,” https://doi.org/10.2337/dc20-S004),American patients and providers are encouraged to engage in person-centered collaborative care (3–6), which is guided by shared decision-making in treatment regimen selection, facilitation of obtaining needed medical and psychosocial resources, and shared monitoring of agreed-upon regimen and lifestyle (7). Re-evaluation during routine care should include not only assessment of medical health but also behavioral and mental health outcomes, especially during times of deterioration in health and well-being.

DIABETES©2019 SELF-MANAGEMENT EDUCATION AND SUPPORT Suggested citation: American Diabetes Associa- Recommendations tion. 5. Facilitating behavior change and well- 5.1 In accordance with the national standards for diabetes self-management being to improve health outcomes: Standards of Medical Care in Diabetesd2020. Diabetes Care education and support, all people with diabetes should participate in diabetes 2020;43(Suppl. 1):S48–S65 self-management education and receive the support needed to facilitate the © 2019 by the American Diabetes Association. knowledge, decision-making, and skills mastery necessary for diabetes self- Readers may use this article as long as the work care. A is properly cited, the use is educational and not 5.2 There are four critical times to evaluate the need for diabetes self- for proﬁt, and the work is not altered. More infor- management education to promote skills acquisition in support of regimen mation is available at http://www.diabetesjournals .org/content/license. care.diabetesjournals.org Facilitating Behavior Change and Well-being to Improve Health Outcomes S49

judgmental words with increased feelings lower A1C (14,16–18), lower self-reported implementation, medical nutri- of shame and guilt, providers are encour- weight (19,20), improved quality of life tion therapy, and well-being: at aged to consider the impact that language (17,21), reduced all-cause mortality risk diagnosis, annually, when com- has on building therapeutic relationships (22), healthy coping (5,23), and reduced plicating factors arise, and when and to choose positive, strength-based health care costs (24–26). Better out- transitions in care occur. E words and phrases that put people first comes were reported for DSMES inter- 5.3 Clinical outcomes, health status, (4,10). Patient performance of self-man- ventions that were over 10 h in total and well-being are key goals of agement behaviors, as well as psychosocial duration (18), included ongoing support diabetes self-management edu- factors with the potential to impact the (12,27), were culturally (28,29) and age cation and support that should person’s self-management, should be appropriate (30,31), were tailored to be measured as part of routine monitored. Please see Section 4 “Compre- individual needs and preferences, and care. C hensive Medical Evaluation and Assess- addressed psychosocial issues and incor- 5.4 Diabetes self-management edu- ment of Comorbidities”(https://doi.org/ porated behavioral strategies (13,23,32,33). cation and support should be pa- 10.2337/dc20-S004) for more on use of Individual and group approaches are tient centered, may be given in language. effective (20,34,35), with a slight ben- group or individual settings and/ DSMES and the current national stan- efit realized by those who engage in or use technology, and should be dards guiding it (2,11) are based on evi- both (18). communicated with the entire dence of benefit. Specifically, DSMES Emerging evidence demonstrates the diabetes care team. A helps people with diabetes to identify benefitof internet-based DSMES services 5.5 Because diabetes self-management and implement effective self-management for diabetes prevention and the man- educationandsupportcanimprove strategies and cope with diabetes at four agement of type 2 diabetes (36–38). outcomes and reduce costs B, Association critical time points (see below) (2). On- Technology-enabled diabetes self-man- reimbursement by third-party going DSMES helps people with diabetes agement solutions improve A1C most payers is recommended. C to maintain effective self-management effectively when there is two-way com- throughout a lifetime of diabetes as they munication between the patient and the Diabetes self-management education face new challenges and as advances in health care team, individualized feed- and support (DSMES) services facilitate treatment become available (12). back, use of patient-generated health the knowledge, decision-making, and Four critical time points have been data, and education (38). Current re- skills mastery necessary for optimal dia- defined when the need for DSMES is to search supports nurses, dietitians, and betes self-care and incorporate the be evaluated by the medical care pro- pharmacists as providers of DSMES who needs, goals, and life experiences of vider and/or multidisciplinary team, may also tailor curriculum to the person’s the person with diabetes. The overall with referrals madeDiabetes as needed (2): needs (39–41). Members of the DSMES objectives of DSMES are to support in- team should have specialized clinical formed decision-making, self-care be- 1. At diagnosis knowledge in diabetes and behavior havior, problem-solving, and active 2. Annually for assessment of education, change principles. Certification as a diabetes collaboration with the health care nutrition, and emotional needs educator (see www.ncbde.org) and/or team to improve clinical outcomes, 3. When new complicating factors (health board certification in advanced diabetes health status, and well-being in a cost- conditions, physical limitations, emo- management (see www.diabeteseducator effective manner (2). Providers are en- tional factors, or basic living needs) .org/education/certification/bc_adm) dem- couraged to consider the burden of arise that influence self-management onstrates an individual’s specialized training treatment and the patient’s level of 4. When transitions in care occur in and understanding of diabetes manage- confidence/self-efficacy for management ment and support. (11). Additionally, there behaviors as well as the level ofAmerican social and DSMES focuses on supporting patient is growing evidence for the role of com- family support when providing DSMES. empowerment by providing people munity health workers (42,43), as well as Patient performance of self-manage- with diabetesthetoolstomakeinformed peer (42–46) and lay leaders (47), in pro- ment behaviors, including its effect on self-management decisions (13). Diabe- viding ongoing support. clinical outcomes, health status, and tes care has shifted to an approach that DSMES is associated with an increased quality of life, as well as the psychosocial places the person with diabetes and his use of primary care and preventive ser- factors impacting the person’s ability or her family/support system at the center vices (24,48,49) and less frequent use of to self-manage should be monitored as of the care model, working in collaboration acute care and inpatient hospital services part of©2019 routine clinical care. A randomized with health care professionals. Patient- (19). Patients who participate in DSMES controlled trial testing a decision-making centered care is respectful of and respon- are more likely to follow best practice education and skill-building program (8) sive to individual patient preferences, treatment recommendations, particu- showed that addressing these targets needs, and values. It ensures that patient larly among the Medicare population, improved health outcomes in a popu- values guide all decision-making (14). and have lower Medicare and insurance lation in need of health care resources. claim costs (25,48). Despite these bene- Furthermore, following a DSMES cur- Evidence for the Benefits fits, reports indicate that only 5–7% riculum improves quality of care (9). Studies have found that DSMES is of individuals eligible for DSMES through In addition, in response to the grow- associated with improved diabetes Medicare or a private insurance plan ing literature that associates potentially knowledgeandself-carebehaviors(14,15), actually receive it (50,51). This low S50 Facilitating Behavior Change and Well-being to Improve Health Outcomes Diabetes Care Volume 43, Supplement 1, January 2020

participation may be due to lack of with A1C decreases of 1.0–1.9% for peo- team be knowledgeable about nutrition referral or other identified barriers ple with type 1 diabetes (57) and 0.3– therapy principles for people with all such as logistical issues (accessibility, 2.0% for people with type 2 diabetes (57). types of diabetes and be supportive of timing, costs) and thelackofaperceived See Table 5.1 for specific nutrition rec- their implementation. Members of the benefit (52). Thus, in addition to educat- ommendations. Because of the progres- health care team should complement ing referring providers about the benefits sive nature of type 2 diabetes, behavior MNT by providing evidence-based guid- of DSMES and the critical times to refer modification alone may not be adequate ance that helps people with diabetes (2), alternative and innovative models to maintain euglycemia over time. How- make healthy food choices that meet of DSMES delivery need to be explored ever, after medication is initiated, nu- their individualized needs and improve and evaluated. trition therapy continues to be an overall health. A variety of eating pat- important component and should be ternsareacceptable forthemanagement Reimbursement integrated with the overall treatment of diabetes (41,58,60). Until the evidence Medicare reimburses DSMES when that plan (55). surrounding comparative benefits of dif- service meets the national standards ferent eating patterns in specific individ- (2,11) and is recognized by the Ameri- Goals of Nutrition Therapy for Adults uals strengthens, health care providers can Diabetes Association (ADA) or other With Diabetes should focus on the key factors that are approval bodies. DSMES is also covered 1. To promote and support healthful common among the patterns: 1) empha- by most health insurance plans. Ongoing eating patterns, emphasizing a variety size nonstarchy vegetables, 2) minimize support has been shown to be instru- of nutrient-dense foods in appropri- added sugars and refined grains, and 3) mental for improving outcomes when ate portion sizes, to improve overall choose whole foods over highly pro- it is implemented after the completion health and: cessedAssociation foods to the extent possible of education services. DSMES is fre- c achieve and maintain body weight (41). An individualized eating pattern quently reimbursed when performed goals also considers the individual’s health in person. However, although DSMES c attain individualized glycemic, blood status, skills, resources, food preferen- can also be provided via phone calls pressure, and lipid goals ces, and health goals. Referral to an RD/ and telehealth, these remote versions c delay or prevent the complications RDN is essential to assess the overall may not always be reimbursed. Changes of diabetes nutrition status of, and to work collab- in reimbursement policies that increase 2. To address individual nutrition needs oratively with, the patient to create DSMES access and utilization will result based on personal and cultural pref- a personalized meal plan that coordi- in a positive impact to beneficiaries’ erences, health literacy and numeracy, nates and aligns with the overall treat- clinical outcomes, quality of life, health access to healthful foods, willingness ment plan, including physical activity care utilization, and costs (53,54). and ability toDiabetes make behavioral changes, and medication use. The Mediterranean- andexistingbarrierstochange style (61,62), low-carbohydrate (63– MEDICAL NUTRITION THERAPY 3. To maintain the pleasure of eating by 65), and vegetarian or plant-based Please refer to the ADA consensus report providing nonjudgmental messages (66,67) eating patterns are all examples “Nutrition Therapy for Adults With Di- about food choices while limiting of healthful eating patterns that have abetes or Prediabetes: A Consensus Re- food choices only when indicated shown positive results in research, but port” for more information on nutrition by scientific evidence individualized meal planning should fo- therapy (41). For many individuals with 4. To provide an individual with diabe- cus on personal preferences, needs, and diabetes, the most challenging part of tes the practical tools for developing goals. Reducing overall carbohydrate in- the treatment plan is determining what healthy eating patterns rather than take for individuals with diabetes has to eat. There is not a “one-size-fits-all” focusing on individual macronutrients, demonstrated the most evidence for eating pattern for individualsAmerican with diabe- micronutrients, or single foods improving glycemia and may be applied tes, and meal planning should be individ- in a variety of eating patterns that meet ualized. Nutrition therapy plays an Eating Patterns, Macronutrient individual needs and preferences. For integral role in overall diabetes manage- Distribution, and Meal Planning individuals with type 2 diabetes not ment, and each person with diabetes Evidence suggests that there is not an meeting glycemic targets or for whom should be actively engaged in education, ideal percentage of calories from carbo- reducing glucose-lowering drugs is a self-management, and treatment plan- hydrate, protein, and fat for people with priority, reducing overall carbohydrate ning with his or her health care team, diabetes. Therefore, macronutrient dis- intake with a low- or very-low-carbohy- including©2019 the collaborative development tribution should be based on an individ- drate eating pattern is a viable option of an individualized eating plan (41,55). ualized assessment of current eating (63–65). As research studies on some All individuals with diabetes should be patterns, preferences, and metabolic low-carbohydrate eating plans generally referred for individualized MNT provided goals. Consider personal preferences indicate challenges with long-term sus- by a registered dietitian nutritionist (RD/ (e.g., tradition, culture, religion, health tainability, it is important to reassess and RDN) who is knowledgeable and skilled beliefs and goals, economics) as well as individualize meal plan guidance regu- in providing diabetes-specific MNT (56) metabolic goals when working with in- larly for those interested in this ap- at diagnosis and as needed throughout dividuals to determine the best eating proach. This eating pattern is not the life span, similar to DSMES. MNT pattern for them (41,58,59). It is impor- recommended at this time for women delivered by an RD/RDN is associated tant that each member of the health care who are pregnant or lactating, people care.diabetesjournals.org Facilitating Behavior Change and Well-being to Improve Health Outcomes S51

Table 5.1—Medical nutrition therapy recommendations Topic Recommendation Evidence rating Effectiveness of 5.6 An individualized medical nutrition therapy program as needed to achieve treatment goals, A nutrition therapy provided by a registered dietitian nutritionist (RD/RDN), preferably one who has comprehensive knowledge and experience in diabetes care, is recommended for all people with type 1 or type 2 diabetes, prediabetes, and gestational diabetes mellitus. 5.7 Because diabetes medical nutrition therapy can result in cost savings B and improved B, A, E outcomes (e.g., A1C reduction, reduced weight, decrease in cholesterol) A, medical nutrition therapy should be adequately reimbursed by insurance and other payers. E Energy balance 5.8 For all patients with overweight or obesity, lifestyle modification to achieve and maintain A a minimum weight loss of 5% is recommended for all patients with diabetes and prediabetes. Eating patterns and 5.9 There is no single ideal dietary distribution of calories among carbohydrates, fats, and proteins E macronutrient for people with diabetes; therefore, meal plans should be individualized while keeping total distribution calorie and metabolic goals in mind. 5.10 A variety of eating patterns are acceptable for the management of type 2 diabetes and B prediabetes. Carbohydrates 5.11 Carbohydrate intake should emphasize nutrient-dense carbohydrate sources that are B high in fiber and minimally processed. Eating plans should emphasize nonstarchy vegetables, minimal added sugars, fruits, whole grains, as well as dairy products. 5.12 Reducing overall carbohydrate intake for individuals with diabetes has demonstrated the B most evidence for improving glycemia and may be applied in a variety of eating patterns that meet individual needs and preferences. 5.13 For people with diabetes who are prescribed a flexible insulin therapy program,Association education A, B on how to use carbohydrate counting A and on dosing for fat and protein content B should be used to determine mealtime insulin dosing. 5.14 For adults using fixed insulin doses, consistent pattern of carbohydrate intake with respect to B time and amount, while considering the insulin action time, can result in improved glycemia and reduce the risk for hypoglycemia. 5.15 People with diabetes and those at risk are advised to replace sugar-sweetened beverages B, A (including fruit juices) with water as much as possible in order to control glycemia and weight and reduce their risk for cardiovascular disease and fatty liver B and should minimize the consumption of foods with added sugar that have the capacity to displace healthier, more nutrient-dense food choices. A Protein 5.16 In individuals with type 2 diabetes, ingestedDiabetes protein appears to increase insulin response B without increasing plasma glucose concentrations. Therefore, carbohydrate sources high in protein should be avoided when trying to treat or prevent hypoglycemia. Dietary fat 5.17 An eating plan emphasizing elements of a Mediterranean-style eating pattern rich in B monounsaturated and polyunsaturated fats may be considered to improve glucose metabolism and lower cardiovascular disease risk. 5.18 Eating foods rich in long-chain n-3 fatty acids, such as fatty fish (EPA and DHA) and nuts and B, A seeds (ALA), is recommended to prevent or treat cardiovascular disease B; however, evidence does not support a beneficial role for the routine use of n-3 dietary supplements. A Micronutrients and 5.19 There is no clear evidence that dietary supplementation with vitamins, minerals (such as C herbal supplements chromium and vitamin D), herbs, or spices (such as cinnamon or aloe vera) can improve outcomes in people with diabetes who do not have underlying deficiencies, and they are Americannot generally recommended for glycemic control. Alcohol 5.20 Adults with diabetes who drink alcohol should do so in moderation (no more than one drink C per day for adult women and no more than two drinks per day for adult men). 5.21 Educating people with diabetes about the signs, symptoms, and self-management of delayed B hypoglycemia after drinking alcohol, especially when using insulin or insulin secretagogues, is recommended. The importance of glucose monitoring after drinking alcoholic beverages to reduce hypoglycemia risk should be emphasized. Sodium 5.22 As for the general population, people with diabetes and prediabetes should limit sodium B consumption to ,2,300 mg/day. Nonnutritive©20195.23 The use of nonnutritive sweeteners may have the potential to reduce overall calorie and B sweeteners carbohydrateintakeif substitutedfor caloric (sugar)sweetenersandwithoutcompensationby intake of additional calories from other food sources. For those who consume sugar- sweetened beverages regularly, a low-calorie or nonnutritive-sweetened beverage may serve as a short-term replacement strategy, but overall, people are encouraged to decrease both sweetened and nonnutritive-sweetened beverages and use other alternatives, with an emphasis on water intake. S52 Facilitating Behavior Change and Well-being to Improve Health Outcomes Diabetes Care Volume 43, Supplement 1, January 2020

with or at risk for disordered eating, or involving both aerobic and resistance importance of providing guidance on people who have renal disease, and it exercise (73,76,77) and a healthy eating an individualized meal plan containing should be used with caution in patients plan, such as a Mediterranean-style eating nutrient-dense foods, such as vegeta- taking sodium–glucose cotransporter pattern (78). bles, fruits, legumes, dairy, lean sources 2 inhibitors due to the potential risk For many individuals with overweight of protein (including plant-based sources of ketoacidosis (68,69). There is inade- and obesity with type 2 diabetes, 5% as well as lean meats, fish, and poultry), quate research in type 1 diabetes to weight loss is needed to achieve bene- nuts, seeds, and whole grains, cannot be support one eating pattern over another ficial outcomes in glycemic control, lipids, overemphasized (92), as well as guidance at this time. and blood pressure (79). It should be on achieving the desired energy deficit The diabetes plate method is com- noted, however, that the clinical benefits (93–96). Any approach to meal planning monly used for providing basic meal of weight loss are progressive, and more should be individualized considering the planning guidance (70) and provides a intensive weight loss goals (i.e., 15%) may health status, personal preferences, and visual guide showing how to portion be appropriate to maximize benefitde- ability of the person with diabetes to calories (featuring a 9-inch plate) and pending on need, feasibility, and safety sustain the recommendations in the plan. carbohydrates (by limiting them to what (80,81). In select individuals with type 2 fits in one-quarter of the plate) and places diabetes, an overall healthy eating plan Carbohydrates an emphasis on low-carbohydrate (or non- that results in energy deficit in conjunc- Studies examining the ideal amount starchy) vegetables. Providing a visual/ tion with weight loss medications and/or of carbohydrate intake for people with small graphic of the diabetes plate method metabolic surgery should be considered diabetes are inconclusive, although mon- is preferred, as descriptions of the concept to help achieve weight loss and mainte- itoring carbohydrate intake and con- can be confusing when unfamiliar. nance goals, lower A1C, and reduce CVD sideringAssociation the blood glucose response to risk (82–84). Overweight and obesity dietary carbohydrate are key for improv- Weight Management are also increasingly prevalent in people ing postprandial glucose management Management and reduction of weight with type 1 diabetes and present clinical (97,98). The literature concerning gly- is important for people with type 1 di- challenges regarding diabetes treatment cemic index and glycemic load in in- abetes, type 2 diabetes, or prediabetes and CVD risk factors (85,86). Sustaining dividuals with diabetes is complex, often and overweight or obesity. To support weightlosscanbechallenging(79,87)but yielding mixed results, though in some weight loss and improve A1C, cardio- has long-term benefits; maintaining studies lowering the glycemic load of vascular disease (CVD) risk factors, and weightlossfor5yearsisassociated consumed carbohydrates has demon- well-being in adults with overweight/ with sustained improvements in A1C and strated A1C reductions of 0.2% to 0.5% obesity and prediabetes or diabetes, lipid levels (88). MNT guidance from an (99,100). Studies longer than 12 weeks MNT and DSMES services should include RD/RDN with expertiseDiabetes in diabetes and report no significant influence of glycemic an individualized eating plan in a format weight management, throughout the index or glycemic load independent of that results in an energy deficit in com- course of a structured weight loss plan, weight loss on A1C; however, mixed bination with enhanced physical activ- is strongly recommended. results have been reported for fasting ity (41). Lifestyle intervention programs People with diabetes and prediabetes glucose levels and endogenous insulin should be intensive and have frequent should be screened and evaluated during levels. follow-up to achieve significant reduc- DSMES and MNT encounters for disor- Reducing overall carbohydrate intake tions in excess body weight and improve dered eating, and nutrition therapy for individuals with diabetes has dem- clinical indicators. There is strong and should be individualized to accommo- onstrated evidence for improving gly- consistent evidence that modest persis- date disorders (41). Disordered eating cemia and may be applied in a variety tent weight loss can delay the progres- can make following an eating plan chal- of eating patterns that meet individ- sion from prediabetes toAmerican type 2 diabetes lenging, and individuals should be re- ual needs and preferences (41). For (58,71,72) (see Section 3 “Prevention or ferred to a mental health professional as people with type 2 diabetes or predia- Delay of Type 2 Diabetes,” https://doi needed. Studies have demonstrated that betes, low-carbohydrate eating plans .org/10.2337/dc20-S003) and is benefi- a variety of eating plans, varying in mac- show potential to improve glycemia cial to the management of type 2 diabe- ronutrient composition, can be used and lipid outcomes for up to 1 year tes (see Section 8“ObesityManagement effectively and safely in the short term (63,65,90,101–104). Part of the chal- for the Treatment of Type 2 Diabetes,” (1–2 years) to achieve weight loss in lenge in interpreting low-carbohydrate https://doi.org/10.2337/dc20-S008). people with diabetes. This includes struc- research has been due to the wide range ©2019In prediabetes, the weight loss goal tured low-calorie meal plans with meal of definitions for a low-carbohydrate is 7–10% for preventing progression to replacements (80,88,89) and the Medit- eating plan (65,100). As research stud- type 2 diabetes (73). In conjunction erranean-style eating pattern (78), as well ies on low-carbohydrate eating plans with lifestyle therapy, medication-assisted as low-carbohydrate meal plans (90). generally indicate challenges with long- weight loss can be considered for peo- However, no single approach has been term sustainability, it is important to ple at risk for type 2 diabetes when proven to be consistently superior reassess and individualize meal plan needed to achieve and sustain 7–10% (41,91,92), and more data are needed guidance regularly for those interested weight loss (74,75). People with predia- to identify and validate those meal plans in this approach. Providers should main- betes at a healthy weight should also that are optimal with respect to long-term tain consistent medical oversight and be considered for lifestyle intervention outcomes and patient acceptability. The recognize that certain groups are not care.diabetesjournals.org Facilitating Behavior Change and Well-being to Improve Health Outcomes S53

appropriate for low-carbohydrate eating and/or high-protein mixed meals is is not an ideal percentage of calories plans, including women who are preg- recommended to address delayed hy- from fat for people with or at risk for nant or lactating, children, and people perglycemia that may occur 3 h or more diabetes and that macronutrient distri- who have renal disease or disordered after eating (41). Checking glucose 3 h bution should be individualized accord- eating behavior, and these plans should after eating may help to determine if ing to the patient’s eating patterns, be used with caution in those taking additional insulin adjustments are required preferences, and metabolic goals (41). sodium–glucose cotransporter 2 inhibitors (112,113). Continuous glucose monitoring The type of fats consumed is more im- because of the potential risk of ketoacidosis or self-monitoring of blood glucose portant than total amount of fat when (68,69). There is inadequate research should guide decision making for admin- looking at metabolic goals and CVD about dietary patterns for type 1 diabe- istration of additional insulin. For indi- risk, and it is recommended that the tes to support one eating plan over viduals on a fixed daily insulin schedule, percentage of total calories from satu- another at this time. meal planning should emphasize a rel- rated fats should be limited (78,105, Most individuals with diabetes re- atively fixed carbohydrate consump- 119–121). Multiple randomized con- port a moderate intake of carbohydrate tion pattern with respect to both time trolled trials including patients with (44–46% of total calories) (58). Efforts and amount, while considering insulin type 2 diabetes have reported that a to modify habitual eating patterns are action time (41). Mediterranean-style eating pattern (78, often unsuccessful in the long term; 122–127), rich in polyunsaturated and people generally go back to their usual Protein monounsaturated fats, can improve both macronutrient distribution (58). Thus, There is no evidence that adjusting the glycemic management and blood lipids. the recommended approach is to indi- daily level of protein intake (typically 1– However, supplements do not seem to vidualize meal plans to meet caloric goals 1.5 g/kg body wt/day or 15–20% total have theAssociation same effects as their whole- with a macronutrient distribution that is calories) will improve health in individ- food counterparts. A systematic review more consistent with the individual’s uals without diabetic kidney disease, and concluded that dietary supplements usual intake to increase the likelihood research is inconclusive regarding the with n-3 fatty acids did not improve for long-term maintenance. ideal amount of dietary protein to opti- glycemic management in individuals As for all individuals in developed mize either glycemic management or with type 2 diabetes (99). Randomized countries, both children and adults CVD risk (99,114). Therefore, protein controlled trials also do not support with diabetes are encouraged to mini- intake goals should be individualized recommending n-3 supplements for pri- mize intake of refined carbohydrates and based on current eating patterns. mary or secondary prevention of CVD added sugars and instead focus on carbo- Some research has found successful (128–132). People with diabetes should hydrates from vegetables, legumes, fruits, management of type 2 diabetes with be advised to follow the guidelines for dairy (milk and yogurt), and whole grains. meal plans includingDiabetes slightly higher levels the general population for the recom- The consumption of sugar-sweetened of protein (20–30%), which may contrib- mended intakes of saturated fat, die- beverages (including fruit juices) and pro- ute to increased satiety (115). tary cholesterol, and trans fat (105). In cessed food products with high amounts Those with diabetic kidney disease general, trans fats should be avoided. of refined grains and added sugars is (with albuminuria and/or reduced esti- In addition, as saturated fats are progres- strongly discouraged (105–107). mated glomerular filtration rate) should sively decreased in the diet, they should Individuals with type 1 or type 2 di- aim to maintain dietary protein at the be replaced with unsaturated fats and not abetes taking insulin at mealtime should recommended daily allowance of 0.8 g/kg with refined carbohydrates (126). be offered intensive and ongoing edu- body wt/day. Reducing the amount of cation on the need to couple insulin dietary protein below the recommended Sodium administration with carbohydrate intake. daily allowance is not recommended be- As for the general population, people For people whose meal scheduleAmerican or car- cause it does not alter glycemic meas- with diabetes are advised to limit their bohydrate consumption is variable, reg- ures, cardiovascular risk measures, or the sodium consumption to ,2,300 mg/day ularcounselingtohelpthemunderstand rate at which glomerular filtration rate (41). Restriction below 1,500 mg, even the complex relationship between car- declines (116,117). for those with hypertension, is generally bohydrate intake and insulin needs In individuals with type 2 diabetes, not recommended (133–135). Sodium is important. In addition, education on protein intake may enhance or increase intake recommendations should take using the insulin-to-carbohydrate ratios the insulin response to dietary carbohy- into account palatability, availability, af- for meal planning can assist them with drates (118). Therefore, use of carbohy- fordability, and the difficulty of achiev- effectively©2019 modifying insulin dosing from drate sources high in protein (such as ing low-sodium recommendations in a meal to meal and improving glycemic milk and nuts) to treat or prevent hypo- nutritionally adequate diet (136). management (58,97,108–111). Results glycemia should be avoided due to the from recent high-fat and/or high-protein potential concurrent rise in endogenous Micronutrients and Supplements mixed meals studies continue to support insulin. There continues to be no clear evidence previous findings that glucose response of benefit from herbal or nonherbal to mixed meals high in protein and/or fat Fats (i.e., vitamin or mineral) supplemen- along with carbohydrate differ among The ideal amount of dietary fat for in- tation for people with diabetes without individuals; therefore, a cautious approach dividuals with diabetes is controver- underlying deficiencies (41). Metformin to increasing insulin doses for high-fat sial. New evidence suggests that there is associated with vitamin B12 deficiency S54 Facilitating Behavior Change and Well-being to Improve Health Outcomes Diabetes Care Volume 43, Supplement 1, January 2020

per a report from the Diabetes Preven- reduce overall calorie and carbohydrate be interrupted every 30 min for tion Program Outcomes Study (DPPOS), intake (58). Most systematic reviews and blood glucose benefits. C suggesting that periodic testing of vita- meta-analyses show benefits for nonnu- 5.28 Flexibility training and balance min B12 levels should be considered tritive sweetener use in weight loss training are recommended 2–3 in patients taking metformin, particularly (142,143); however, some research sug- times/week for older adults with in those with anemia or peripheral gests an association with weight gain diabetes. Yoga and tai chi may neuropathy (137). Routine supplemen- (144). When use of sugar substitutes be included based on individual tation with antioxidants, such as vita- is meant to reduce overall caloric and preferences to increase flexibil- mins E and C and carotene, is not advised carbohydrate intake, people should be ity, muscular strength, and bal- due to lack of evidence of efficacy and counseled to avoid compensating with ance. C concern related to long-term safety. In intake of additional calories from other addition, there is insufficient evidence to food sources (41). Regulatory agencies support the routine use of herbal supple- set acceptable daily intake levels for each Physical activity is a general term that ments and micronutrients, such as cin- nonnutritive sweetener, defined as the includes all movement that increases namon (138), curcumin, vitamin D (139), amount that can be safely consumed energy use and is an important part of aloe vera, or chromium, to improve gly- over a person’s lifetime (41,145). For the diabetes management plan. Exercise cemia in people with diabetes (41,140). those who consume sugar-sweetened is a more specific form of physical activ- However, for special populations, in- beverages regularly, a low-calorie or ity that is structured and designed to cluding pregnant or lactating women, nonnutritive-sweetened beverage may improve physical fitness. Both physical older adults, vegetarians, and people serve as a short-term replacement strat- activity and exercise are important. Ex- following very low-calorie or low-carbo- egy, but overall, people are encour- erciseAssociation has been shown to improve blood hydrate diets, a multivitamin may be aged to decrease both sweetened and glucose control, reduce cardiovascu- necessary. nonnutritive-sweetened beverages and lar risk factors, contribute to weight use other alternatives, with an emphasis loss, and improve well-being (147). Phys- Alcohol on water intake (146). ical activity is as important for those with Moderate alcohol intake does not have type 1 diabetes as it is for the general major detrimental effects on long-term population, but its specific role in the blood glucose management in people PHYSICAL ACTIVITY prevention of diabetes complications with diabetes. Risks associated with al- Recommendations and the management of blood glucose cohol consumption include hypogly- 5.24 Children and adolescents with is not as clear as it is for those with type 2 cemia and/or delayed hypoglycemia type 1Diabetes or type 2 diabetes or diabetes. A recent study suggested that (particularly for those using insulin or prediabetes should engage in the percentage of people with diabetes insulin secretagogue therapies), weight 60 min/day or more of moder- who achieved the recommended exer- gain, and hyperglycemia (for those con- ate- or vigorous-intensity aerobic cise level per week (150 min) varied by suming excessive amounts) (41,140). activity, with vigorous muscle- race. Objective measurement by accel- People with diabetes should be educated strengthening and bone-strength- erometer showed that 44.2%, 42.6%, and about these risks and encouraged to ening activities at least 3 days/ 65.1% of whites, African Americans, and monitor blood glucose frequently after week. C Hispanics, respectively, met the thresh- drinking alcohol to minimize such risks. 5.25 Most adults with type 1 C and old (148). It is important for diabetes care People with diabetes can follow the same type 2 B diabetes should engage management teams to understand the fi guidelines as those without diabetes if in 150 min or more of moderate- dif culty that many patients have reach- they choose to drink. ForAmerican women, no to vigorous-intensity aerobic ac- ing recommended treatment targets and more than one drink per day, and for tivity per week, spread over at to identify individualized approaches to men, no more than two drinks per day is least 3 days/week, with no more improve goal achievement. recommended (one drink is equal to a than 2 consecutive days without Moderate to high volumes of aerobic 12-oz beer, a 5-oz glass of wine, or 1.5 oz activity. Shorter durations (min- activity are associated with substantially of distilled spirits). imum 75 min/week) of vigorous- lower cardiovascular and overall mortal- intensity or interval training may ity risks in both type 1 and type 2 diabetes Nonnutritive Sweeteners be sufficient for younger and (149).A recentprospective observational For©2019 some people with diabetes who more physically fit individuals. study of adults with type 1 diabetes are accustomed to sugar-sweetened 5.26 Adults with type 1 C and type 2 B suggested that higher amounts of phys- products, nonnutritive sweeteners (con- diabetes should engage in 2–3 ical activity led to reduced cardiovascular taining few or no calories) may be an sessions/week of resistance ex- mortality after a mean follow-up time of acceptable substitute for nutritive sweet- ercise on nonconsecutive days. 11.4 years for patients with and without eners (those containing calories, such 5.27 All adults, and particularly those chronic kidney disease (150). Addition- as sugar, honey, and agave syrup) when with type 2 diabetes, should ally, structured exercise interventions of ’ consumed in moderation. While use decrease the amount of time at least 8 weeks duration have been of nonnutritive sweeteners does not spent in daily sedentary behav- shown to lower A1C by an average of fi appear to have a signi cant effect on ior. B Prolonged sitting should 0.66% in people with type 2 diabetes, glycemic management (141), they can even without a significant change in BMI care.diabetesjournals.org Facilitating Behavior Change and Well-being to Improve Health Outcomes S55

(151). There are also considerable data more than 2 days to elapse between resistance training in older adults with for the health benefits (e.g., increased exercise sessions, is recommended to type 2 diabetes (169) and for an additive cardiovascular fitness, greater muscle decrease insulin resistance, regardless benefit of combined aerobic and resis- strength, improved insulin sensitivity, of diabetes type (161,162). Over time, tance exercise in adults with type 2 di- etc.) of regular exercise for those with activities should progress in intensity, abetes (170). If not contraindicated, type 1 diabetes (152). A recent study frequency, and/or duration to at least patients with type 2 diabetes should suggested that exercise training in type 1 150 min/week of moderate-intensity ex- be encouraged to do at least two weekly diabetes may also improve several im- ercise. Adults able to run at 6 miles/h sessions of resistance exercise (exercise portant markers such as triglyceride (9.7 km/h) for at least 25 min can benefit with free weights or weight machines), level, LDL, waist circumference, and sufficiently from shorter-intensity activ- with each session consisting of at least body mass (153). Higher levels of exercise ity (75 min/week) (156). Many adults, one set (group of consecutive repetitive intensity are associated with greater including most with type 2 diabetes, exercise motions) of five or more differ- improvements in A1C and in fitness would be unable or unwilling to partic- ent resistance exercises involving the (154). Other benefits include slowing ipate in such intense exercise and should large muscle groups (169). the decline in mobility among over- engage in moderate exercise for the For type 1 diabetes, although exercise weight patients with diabetes (155). recommended duration. Adults with di- in general is associated with improve- The ADA position statement “Physical abetes should engage in 2–3 sessions/ ment in disease status, care needs to be Activity/Exercise and Diabetes” reviews week of resistance exercise on noncon- taken in titrating exercise with respect the evidence for the benefits of exercise secutive days (163). Although heavier to glycemic management. Each individ- in people with type 1 and type 2 diabetes resistance training with free weights ual with type 1 diabetes has a variable and offers specific recommendation (156). and weight machines may improve glycemicAssociation response to exercise. This var- Physical activity and exercise should be glycemic control and strength (164), iability should be taken into consider- recommended and prescribed to all indi- resistance training of any intensity is ation when recommending the type viduals with diabetes as part of manage- recommended to improve strength, and duration of exercise for a given in- ment of glycemia and overall health. balance, and the ability to engage in dividual (171). Specific recommendations and precau- activities of daily living throughout the Women with preexisting diabetes, tions will vary by the type of diabetes, life span. Providers and staff should help particularly type 2 diabetes, and those age, activity done, and presence of di- patients set stepwise goals toward meet- at risk for or presenting with gestational abetes-related health complications. ing the recommended exercise targets. diabetes mellitus should be advised to Recommendations should be tailored As persons intensify their exercise pro- engage in regular moderate physical to meet the specific needs of each in- gram, medical monitoring may be indi- activity prior to and during their preg- dividual (156). cated to ensure safetyDiabetes and evaluate the nancies as tolerated (156). effects on glucose management. (See Exercise and Children the section PHYSICAL ACTIVITY AND GLYCEMIC Pre-exercise Evaluation All children, including children with di- CONTROL below) As discussed more fully in Section 10 abetes or prediabetes, should be en- Recent evidence supports that all in- “Cardiovascular Disease and Risk Man- couraged to engage in regular physical dividuals, including those with diabetes, agement” (https://doi.org/10.2337/ activity. Children should engage in at should be encouraged to reduce the dc20-S010), the best protocol for as- least 60 min of moderate to vigorous amount of time spent being sedentary sessing asymptomatic patients with aerobic activity every day with muscle- (e.g., working at a computer, watching diabetes for coronary artery disease re- and bone-strengthening activities at television) by breaking up bouts of sed- mainsunclear.TheADAconsensus report least 3 days per week (157). In general, entary activity (.30 min) by briefly “Screening for Coronary Artery Disease in youth with type 1 diabetes beneAmericanfit from standing, walking, or performing other Patients With Diabetes” (172) concluded being physically active, and an active light physical activities (165,166). Avoid- that routine testing is not recommended. lifestyle should be recommended to ing extended sedentary periods may help However, providers should perform a all (158). Youth with type 1 diabetes prevent type 2 diabetes for those at risk careful history, assess cardiovascular who engage in more physical activity and may also aid in glycemic control for risk factors, and be aware of the atypical may have better health outcomes those with diabetes. presentation of coronary artery disease and health-related quality of life (159, A wide range of activities, including in patients with diabetes. Certainly, high- 160). yoga, tai chi, and other types, can have risk patients should be encouraged to ©2019 significant impacts on A1C, flexibility, start with short periods of low-intensity Frequency and Type of Physical muscle strength, and balance (147, exercise and slowly increase the inten- Activity 167,168). Flexibility and balance exercises sity and duration as tolerated. Providers People with diabetes should perform may be particularly important in older should assess patients for conditions aerobic and resistance exercise regularly adults with diabetes to maintain range that might contraindicate certain types (156). Aerobic activity bouts should ide- of motion, strength, and balance (156). of exercise or predispose to injury, such as ally last at least 10 min, with the goal of uncontrolledhypertension,untreated ;30 min/day or more, most days of the Physical Activity and Glycemic Control proliferative retinopathy, autonomic week for adults with type 2 diabetes. Clinical trials have provided strong evi- neuropathy, peripheral neuropathy, and Daily exercise, or at least not allowing dence for the A1C-lowering value of ahistoryoffootulcersorCharcotfoot.The S56 Facilitating Behavior Change and Well-being to Improve Health Outcomes Diabetes Care Volume 43, Supplement 1, January 2020

patient’s age and previous physical activity an ophthalmologist prior to engaging SMOKING CESSATION: TOBACCO level should be considered. The provider in an intense exercise regimen may be AND E-CIGARETTES should customize the exercise regimen appropriate. Recommendations to the individual’sneeds.Thosewith Peripheral Neuropathy 5.29 Advise all patients not to use complications may require a more thorough Decreased pain sensation and a higher cigarettes and other tobacco evaluation prior to beginning an exer- pain threshold in the extremities can products A or e-cigarettes. A cise program (171). result in an increased risk of skin break- 5.30 After identification of tobacco or down, infection, and Charcot joint de- e-cigarette use, include smoking Hypoglycemia struction with some forms of exercise. cessation counseling and other In individuals taking insulin and/or insulin Therefore, a thorough assessment forms of treatment as a routine secretagogues, physical activity may component of diabetes care. A should be done to ensure that neurop- cause hypoglycemia if the medication athy does not alter kinesthetic or pro- dose or carbohydrate consumption is Results from epidemiological, case- not altered. Individuals on these thera- prioceptive sensation during physical control, and cohort studies provide con- pies may need to ingest some added activity, particularly in those with more vincing evidence to support the causal carbohydrate if pre-exercise glucose lev- severe neuropathy. Studies have shown link between cigarette smoking and els are ,90 mg/dL (5.0 mmol/L), depend- that moderate-intensity walking may health risks (178). Recent data show ing on whether they are able to lower not lead to an increased risk of foot tobacco use is higher among adults insulin doses during the workout (such ulcers or reulceration in those with with chronic conditions(179)aswell as as with an insulin pump or reduced pre- peripheral neuropathy who use proper in adolescents and young adults with exercise insulin dosage), the time of day footwear(174).Inaddition,150min/week diabetesAssociation (180). Smokers with diabetes exercise is done, and the intensity and of moderate exercise was reported to (and people with diabetes exposed to duration of the activity (156,171). In improve outcomes in patients with pre- second-hand smoke) have a height- some patients, hypoglycemia after diabetic neuropathy (175). All individuals ened risk of CVD, premature death, exercise may occur and last for several with peripheral neuropathy should wear microvascular complications, and worse hours due to increased insulin sensitivity. proper footwear and examine their feet glycemic control when compared with Hypoglycemia is less common in patients – daily to detect lesions early. Anyone nonsmokers (181 183). Smoking may with diabetes who are not treated with with a foot injury or open sore should have a role in the development of type 2 insulin or insulin secretagogues, and no – be restricted to non–weight-bearing diabetes (184 187). routine preventive measures for hypo- The routine and thorough assessment activities. glycemia are usually advised in these Diabetesof tobacco use is essential to prevent cases. Intense activities may actually Autonomic Neuropathy smoking or encourage cessation. Numer- raise blood glucose levels instead of Autonomic neuropathy can increase the ous large randomized clinical trials have lowering them, especially if pre-exercise risk of exercise-induced injury or ad- demonstrated the efficacy and cost- glucose levels are elevated (152). Be- verse events through decreased cardiac effectiveness of brief counseling in cause of the variation in glycemic re- responsiveness to exercise, postural hy- smoking cessation, including the use of sponse to exercise bouts, patients need potension, impaired thermoregulation, telephone quit lines, in reducing tobacco to be educated to check blood glucose impaired night vision due to impaired use. Pharmacologic therapy to assist with levels before and after periods of ex- papillary reaction, and greater suscepti- smoking cessation in people with diabe- ercise and about the potential pro- bility to hypoglycemia (176). Cardiovas- tes has been shown to be effective (188), longed effects (depending on intensity cular autonomic neuropathy is also an and for the patient motivated to quit, the and duration) (see the section DIABETES Americanindependent risk factor for cardiovascu- addition of pharmacologic therapy to SELF-MANAGEMENT EDUCATION AND SUPPORT lar death and silent myocardial ischemia counseling is more effective than either above). (177). Therefore, individuals with diabetic treatment alone (189). Special consider- autonomic neuropathy should undergo ations should include assessment of level Exercise in the Presence of cardiac investigation before beginning of nicotine dependence, which is asso- Microvascular Complications ciated with difficulty in quitting and re- “ physical activity more intense than See Section 11 Microvascular Compli- lapse (190). Although some patients may ” that to which they are accustomed. cations and Foot Care (https://doi.org/ gain weight in the period shortly after 10.2337/dc20-S011)©2019 for more informa- Diabetic Kidney Disease smoking cessation (191), recent research tion on these long-term complications. Physical activity can acutely increase has demonstrated that this weight gain urinary albumin excretion. However, Retinopathy does not diminish the substantial CVD If proliferative diabetic retinopathy or there is no evidence that vigorous- benefit realized from smoking cessation severe nonproliferative diabetic retinop- intensity exercise accelerates the rate (192). One study in smokers with newly athy is present, then vigorous-intensity of progression of diabetic kidney disease, diagnosed type 2 diabetes found that aerobic or resistance exercise may be and there appears to be no need for smoking cessation was associated with contraindicated because of the risk of specific exercise restrictions for people amelioration of metabolic parameters triggering vitreous hemorrhage or ret- with diabetic kidney disease in general and reduced blood pressure and albu- inal detachment (173). Consultation with (173). minuria at 1 year (193). care.diabetesjournals.org Facilitating Behavior Change and Well-being to Improve Health Outcomes S57

In recent years e-cigarettes have multifaceted issues when integrating as feeling overwhelmed or stressed by gained public awareness and popularity diabetes care into daily life (11). having diabetes (see the section DIABETES because of perceptions that e-cigarette Emotional well-being is an important DISTRESS below), changes in finances, or use is less harmful than regular cigarette part of diabetes care and self-management. competing medical demands (e.g., the smoking (194,195). However, in light of Psychological and social problems can diagnosis of a comorbid condition). In recent Centers for Disease Control and impair the individual’s(11,197–201) or circumstances where persons other Prevention evidence (196) of deaths re- family’s (200) ability to carry out di- than the patient are significantly in- lated to e-cigarette use, no persons abetes care tasks and therefore poten- volved in diabetes management, these should be advised to use e-cigarettes, tially compromise health status. There issues should be explored with non- either as a way to stop smoking tobacco are opportunities for the clinician to medical care providers (205). Standard- or as a recreational drug. routinely assess psychosocial status ized and validated tools for psychosocial in a timely and efficient manner for monitoring and assessment can also be PSYCHOSOCIAL ISSUES referral to appropriate services (202, used by providers (1), with positive Recommendations 203). A systematic review and meta- findings leading to referral to a mental 5.31 Psychosocial care should be in- analysis showed that psychosocial in- health provider specializing in diabetes tegrated with a collaborative, terventions modestly but significantly for comprehensive evaluation, diagno- patient-centered approach and improved A1C (standardized mean dif- sis, and treatment. provided to all people with di- ference –0.29%) and mental health out- Diabetes Distress abetes, with the goals of opti- comes (204). However, there was a mizing health outcomes and limited association between the effects Recommendation health-related quality of life. A on A1C and mental health, and no in- 5.35 AssociationRoutinely monitor people with 5.32 Psychosocial screening and tervention characteristics predicted ben- diabetes for diabetes distress, follow-up may include, but are efit on both outcomes. particularly when treatment not limited to, attitudes about targets are not met and/or at diabetes, expectations for med- Screening the onset of diabetes complica- ical management and outcomes, Key opportunities for psychosocial screen- tions. B affect or mood, general and ing occur at diabetes diagnosis, during diabetes-related quality of life, regularly scheduled management visits, Diabetes distress is very common and is available resources (financial, during hospitalizations, with new onset distinct from other psychological disor- social, and emotional), and psy- of complications, during significant tran- ders (207–209). Diabetes distress refers chiatric history. E sitions in care such as from pediatric to to significant negative psychological re- 5.33 Providers should consider assess- adult care teams (205),Diabetes or when prob- actions related to emotional burdens and ment for symptoms of diabetes lems with achieving A1C goals, quality of worries specific to an individual’s expe- distress, depression, anxiety, dis- life, or self-management are identified rience in having to manage a severe, ordered eating, and cognitive (2). Patients are likely to exhibit psycho- complicated, and demanding chronic capacities using appropriate logical vulnerability at diagnosis, when disease such as diabetes (208–210). standardized and validated tools their medical status changes (e.g., end The constant behavioral demands (med- at the initial visit, at periodic of the honeymoon period), when the ication dosing, frequency, and titration; intervals, and when there is a need for intensified treatment is ev- monitoring blood glucose, food intake, change in disease, treatment, or ident, and when complications are dis- eating patterns, and physical activity) of life circumstance. Including care- covered. Significant changes in life diabetes self-management and the po- givers and family members in this circumstances, often called social deter- tential or actuality of disease progression assessment is recommended.AmericanB minants of health, are known to con- are directly associated with reports of 5.34 Consider screening older adults siderably affect a person’s ability to diabetes distress (208). The prevalence (aged $65 years) with diabetes self-manage their illness. Thus, screen- of diabetes distress is reported to be 18– for cognitive impairment and ing for social determinants of health 45% with an incidence of 38–48% over depression. B (e.g., loss of employment, birth of a child, 18 months in persons with type 2 di- or other family-based stresses) should abetes (210). In the second Diabetes Please refer to the ADA position state- also be incorporated into routine care Attitudes, Wishes and Needs (DAWN2) ment “Psychosocial Care for People With (206). study, significant diabetes distress was Diabetes©2019” for a list of assessment tools Providers can start with informal ver- reported by 45% of the participants, but and additional details (1). bal inquires, for example, by asking only 24% reported that their health care Complex environmental, social, be- whether there have been persistent teams asked them how diabetes affected havioral, and emotional factors, known changes in mood during the past 2 weeks their lives (207). High levels of diabetes as psychosocial factors, influence living or since the patient’s last visit and distress significantly impact medication- with diabetes, both type 1 and type 2, whether the person can identify a trig- taking behaviors and are linked to higher and achieving satisfactory medical out- gering event or change in circumstan- A1C, lower self-efficacy, and poorer comes and psychological well-being. ces. Providers should also ask whether dietary and exercise behaviors (5,208,210). Thus, individuals with diabetes and their there are new or different barriers to DSMES has been shown to reduce diabe- families are challenged with complex, treatment and self-management, such tes distress (5). It may be helpful to S58 Facilitating Behavior Change and Well-being to Improve Health Outcomes Diabetes Care Volume 43, Supplement 1, January 2020

provide counseling regarding expected ADA Mental Health Provider Directory measures is provided in the ADA position diabetes-related versus generalized psy- (professional.diabetes.org/mhp_listing). statement “Psychosocial Care for People chological distress, at diagnosis and when Ideally, psychosocial care providers with Diabetes” (1). disease state or treatment changes (211). should be embedded in diabetes care Diabetes distress should be routinely settings. Although the clinician may not Anxiety Disorders monitored (212) using person-based feel qualified to treat psychological prob- Recommendations diabetes-specific validated measures (1). lems (214), optimizing the patient-pro- 5.36 Consider screening for anxiety If diabetes distress is identified, the person vider relationship as a foundation may in people exhibiting anxiety should be referred for specificdiabetes increase the likelihood of the patient or worries regarding diabetes education to address areas of diabetes accepting referral for other services. complications, insulin admin- self-care causing the patient distress Collaborative care interventions and a istration, and taking medications, and impacting clinical management. team approach have demonstrated ef- as well as fear of hypoglyce- Peoplewhoseself-careremainsim- ficacy in diabetes self-management, out- mia and/or hypoglycemia un- paired after tailored diabetes education comes of depression, and psychosocial awareness that interferes with should be referred by their care team to a functioning (5,6). self-managementbehaviors,and behavioral health provider for evaluation in those who express fear, and treatment. Psychosocial/Emotional Distress dread, or irrational thoughts Other psychosocial issues known to Clinically significant psychopathologic di- and/or show anxiety symp- affect self-management and health out- agnoses are considerably more preva- toms such as avoidance becomes include attitudes about the illness, lent in people with diabetes than in haviors, excessive repetitive expectations for medical management those without (215,216). Symptoms, Associationbehaviors, or social withdrawal. and outcomes, available resources (fi- both clinical and subclinical, that inter- Refer for treatment if anxiety is nancial, social, and emotional) (213), and fere with the person’s ability to carry out present. B psychiatric history. daily diabetes self-management tasks 5.37 People with hypoglycemia un- must be addressed. In addition to im- awareness, which can co-occur Referral to a Mental Health Specialist pacting a person’s ability to carry out with fear of hypoglycemia, should Indications for referral to a mental health self-management, and the association of be treated using blood glucose specialist familiar with diabetes manage- mental health diagnosis and poorer awareness training (or other ev- ment may include positive screening for short-term glycemic stability, symptoms idence-based intervention) to overall stress related to work-life bal- of emotional distress are associated with help re-establish awareness of ance, diabetes distress, diabetes man- mortality risk (215). Providers should symptoms of hypoglycemia and agement difficulties, depression, anxiety, consider an assessmentDiabetes of symptoms reduce fear of hypoglycemia. A disordered eating,and cognitive dysfunc- of depression, anxiety, disordered eat- tion (see Table 5.2 for a complete list). It ing, and cognitive capacities using ap- Anxiety symptoms and diagnosable dis- is preferable to incorporate psychosocial propriate standardized/validated tools at orders (e.g., generalized anxiety disorder, assessment and treatment into routine the initial visit, at periodic intervals when body dysmorphic disorder, obsessive- care rather than waiting for a specific patient distress is suspected, and when compulsive disorder, specific phobias, problem or deterioration in metabolic or there is a change in health, treatment, or and posttraumatic stress disorder) are psychological status to occur (32,207). life circumstance. Inclusion of caregivers common in people with diabetes (217). Providers should identify behavioral and and family members in this assessment The Behavioral Risk Factor Surveillance mental health providers, ideally those is recommended. Diabetes distress is ad- System (BRFSS) estimated the lifetime who are knowledgeableAmerican about diabetes dressed as an independent condition (see prevalence of generalized anxiety disorder treatment and the psychosocial aspects the section DIABETES DISTRESS above), as this to be 19.5% in people with either type 1 or of diabetes, to whom they can refer pa- state is very common and expected and type 2 diabetes (218). Common diabetes- tients. The ADA provides a list of mental is distinct from the psychological dis- specific concerns include fears related to health providers who have received orders discussed below (1). A list of age- hypoglycemia (219,220), not meeting additional education in diabetes at the appropriate screening and evaluation blood glucose targets (217), and insulin

Table 5.2—Situations that warrant referral of a person with diabetes to a mental health provider for evaluation and treatment c If self-care remains impaired in a person with diabetes distress after tailored diabetes education ©2019c If a person has a positive screen on a validated screening tool for depressive symptoms c In the presence of symptoms or suspicions of disordered eating behavior, an eating disorder, or disrupted patterns of eating c If intentional omission of insulin or oral medication to cause weight loss is identified c If a person has a positive screen for anxiety or fear of hypoglycemia c If a serious mental illness is suspected c In youth and families with behavioral self-care difficulties, repeated hospitalizations for diabetic ketoacidosis, or significant distress c If a person screens positive for cognitive impairment c Declining or impaired ability to perform diabetes self-care behaviors c Before undergoing bariatric or metabolic surgery and after surgery if assessment reveals an ongoing need for adjustment support care.diabetesjournals.org Facilitating Behavior Change and Well-being to Improve Health Outcomes S59

injections or infusion (221). Onset of treatment approaches in con- with symptoms of disordered eat- complications presents another critical junction with collaborative care ing behavior, an eating disorder, or point in the disease course when anxiety with the patient’sdiabetestreat- disrupted patterns of eating. B can occur (1). People with diabetes who ment team. A 5.42 Consider screening for disor- exhibit excessive diabetes self-manage- dered or disrupted eating using ment behaviors well beyond what is History of depression, current depres- validated screening measures prescribed or needed to achieve glyce- sion, and antidepressant medication use when hyperglycemia and weight mic targets may be experiencing symp- are risk factors for the development loss are unexplained based on toms of obsessive compulsive disorder of type 2 diabetes, especially if the in- self-reported behaviors related (222). dividual has other risk factors such as to medication dosing, meal plan, General anxiety is a predictor of in- obesity and family history of type 2 di- and physical activity. In addi- jection-related anxiety and associated abetes (228–230). Elevated depressive tion, a review of the medical with fear of hypoglycemia (220,223). symptoms and depressive disorders af- regimen is recommended to iden- Fear of hypoglycemia and hypoglyce- fect one in four patients with type 1 or tify potential treatment-related mia unawareness often co-occur. In- type 2 diabetes (199). Thus, routine effects on hunger/caloric intake. B terventions aimed at treating one often screening for depressive symptoms is fi bene t both (224). Fear of hypoglycemia indicated in this high-risk population in- Estimated prevalence of disordered may explain avoidance of behaviors as- cluding people with type 1 or type 2 eating behavior and diagnosable eat- sociated with lowering glucose such as diabetes, gestational diabetes mellitus, ing disorders in people with diabetes increasing insulin doses or frequency of and postpartum diabetes. Regardless varies (234–236). For people with monitoring. If fear of hypoglycemia is of diabetes type, women have signifi- type 1Association diabetes, insulin omission causing fi identi ed and a person does not have cantly higher rates of depression than glycosuria in order to lose weight is the symptoms of hypoglycemia, a structured men (231). most commonly reported disordered eat- program of blood glucose awareness Routine monitoring with appropriate ing behavior (237,238); in people with training delivered in routine clinical prac- validatedmeasures(1)canhelptoidentify type 2 diabetes, bingeing (excessive food tice can improve A1C, reduce the rate if referral is warranted. Adult patients intake with an accompanying sense ofloss of severe hypoglycemia, and restore with a history of depressive symptoms of control) is most commonly reported. hypoglycemia awareness (225,226). If or disorder need ongoing monitoring of For people with type 2 diabetes treated not available within the practice setting, depression recurrence within the context with insulin, intentional omission is also a structured program targeting both of routine care (228). Integrating mental frequently reported (239). People with fear of hypoglycemia and unawareness and physical healthDiabetes care can improve diabetesand diagnosable eatingdisorders should be sought out and implemented outcomes. When a patient is in psycho- have high rates of comorbid psychiatric fi by a quali ed behavioral practitioner logical therapy (talk therapy), the mental disorders (240). People with type 1 di- (224,227). health provider should be incorporated abetes and eating disorders have high into the diabetes treatment team (232). rates of diabetes distress and fear of Depression As with DSMES, person-centered collab- hypoglycemia (241). Recommendations orative care approaches have been 5.38 Providers should consider an- shown to improve both depression When evaluating symptoms of disor- nual screening of all patients and medical outcomes (233). dered or disrupted eating (when the with diabetes, especially those Various randomized controlled trials individual exhibits eating behavior that with a self-reported history of have shown improvements in diabetes is nonvolitional and maladaptive) in depression, fordepressivesymp-Americanand depression health outcomes when people with diabetes, etiology and toms with age-appropriate de- depression is treated (233). It is impor- motivation for the behavior should be pression screening measures, tant to note that medical regimen should considered (236,242). Adjunctive med- recognizing that further evalu- also be monitored in response to re- ication such as glucagon-like peptide 1 ation will be necessary for induction in depressive symptoms. People receptor agonists (243) may help indi- dividuals who have a positive may agree to or adopt previously refused viduals not only to meet glycemic tar- screen. B treatment strategies (improving ability gets but also to regulate hunger and 5.39 Beginning at diagnosis of com- to follow recommended treatment be- food intake, thus having the potential to ©2019plications or when there are haviors), which may include increased reduce uncontrollable hunger and bu- significant changes in medical physical activity and intensification of limic symptoms. status, consider assessment for regimenbehaviorsandmonitoring,result- depression. B ing in changed glucose profiles. Serious Mental Illness 5.40 Referrals for treatment of de- Recommendations Disordered Eating Behavior pression should be made to 5.43 Incorporate active monitoring mental health providers with Recommendations of diabetes self-care activities experience using cognitive be- 5.41 Providers should consider reeval- into treatment goals for people havioral therapy, interpersonal uating the treatment regimen of with diabetes and serious men- therapy, or other evidence-based people with diabetes who present tal illness. B S60 Facilitating Behavior Change and Well-being to Improve Health Outcomes Diabetes Care Volume 43, Supplement 1, January 2020

5.44 American Association of Diabetes Educators, of the effect on glycemic control. Patient Educ Annually screen people who are and the Academy of Nutrition and Dietetics. Couns 2016;99:926–943 prescribed atypical antipsychotic Diabetes Care 2015;38:1372–1382 19. Steinsbekk A, Rygg LØ, Lisulo M, Rise MB, medications for prediabetes or 3. Rutten GEHM,AlzaidA. Person-centredtype 2 Fretheim A. Group based diabetes self-management diabetes. B diabetes care: time for a paradigm shift. Lancet education compared to routine treatment for – 5.45 If a second-generation antipsy- Diabetes Endocrinol 2018;6:264 266 people with type 2 diabetes mellitus. A system- 4. Dickinson JK, Guzman SJ, Maryniuk MD, et al. atic review with meta-analysis. BMC Health Serv chotic medication is prescribed The use of language in diabetes care and edu- Res 2012;12:213 for adolescents or adults with cation. Diabetes Care 2017;40:1790–1799 20. Deakin T, McShane CE, Cade JE, Williams diabetes, changes in weight, 5. FisherL,HesslerD,GlasgowRE,etal.REDEEM: RDRR. Group based training for self-manage- glycemic control, and choles- a pragmatic trial to reduce diabetes distress. ment strategies in people with type 2 diabetes terol levels should be carefully Diabetes Care 2013;36:2551–2558 mellitus. Cochrane Database Syst Rev 2005;2: 6. Huang Y, Wei X, Wu T, Chen R, Guo A. CD003417 monitored and the treatment Collaborative care for patients with depression 21. Cochran J, Conn VS. Meta-analysis of qual- C regimen should be reassessed. and diabetes mellitus: a systematic review and ity of life outcomes following diabetes self- meta-analysis. BMC Psychiatry 2013;13:260 management training. Diabetes Educ 2008;34: Studies of individuals with serious men- 7. Hill-Briggs F. Problem solving in diabetes self- 815–823 tal illness, particularly schizophrenia management: a model of chronic illness self- 22. He X, Li J, Wang B, et al. Diabetes self- and other thought disorders, show sig- management behavior. Ann Behav Med 2003;25: management education reduces risk of all-cause 182–193 mortality in type 2 diabetes patients: a systematic nificantly increased rates of type 2 di- 8. Fitzpatrick SL, Golden SH, Stewart K, et al. review and meta-analysis. Endocrine 2017;55: abetes (244). People with schizophrenia Effect of DECIDE (Decision-making Education for 712–731 should be monitored for type 2 diabetes Choices In Diabetes Everyday) program delivery 23. Thorpe CT, Fahey LE, Johnson H, Deshpande because of the known comorbidity. modalities on clinical and behavioral outcomes in M, Thorpe JM, Fisher EB. Facilitating healthy Disordered thinking and judgment can urban African Americans with type 2 diabetes: copingAssociation in patients with diabetes: a systematic a randomized trial. Diabetes Care 2016;39:2149– – be expected to make it difficult to review. Diabetes Educ 2013;39:33 52 2157 24. Robbins JM, Thatcher GE, Webb DA, engage in behavior that reduces risk 9. Brunisholz KD, Briot P, Hamilton S, et al. Valdmanis VG. Nutritionist visits, diabetes clas- factors for type 2 diabetes, such as Diabetes self-management education improves ses, and hospitalization rates and charges: the restrained eating for weight manage- quality of care and clinical outcomes determined Urban Diabetes Study. Diabetes Care 2008;31: ment. Coordinated management of di- by a diabetes bundle measure. J Multidiscip 655–660 – abetes or prediabetes and serious Healthc 2014;7:533 542 25. Duncan I, Ahmed T, Li QE, et al. Assessing the 10. Dickinson JK, Maryniuk MD. Building ther- mental illness is recommended to value of the diabetes educator. Diabetes Educ apeutic relationships: choosing words that put 2011;37:638–657 achieve diabetes treatment targets. people first. Clin Diabetes 2017;35:51–54 26. Strawbridge LM, Lloyd JT, Meadow A, Riley In addition, those taking second-gener- 11. Beck J, Greenwood DA, Blanton L, et al.; 2017 GF, Howell BL. One-year outcomes of diabetes ation (atypical) antipsychotics, such as Standards RevisionDiabetes Task Force. 2017 National self-management training among Medicare ben- olanzapine, require greater monitoring Standards for Diabetes Self-Management Edu- eficiaries newly diagnosed with diabetes. Med cation and Support. Diabetes Care 2017;40: – because of an increase in risk of type 2 Care 2017;55:391 397 1409–1419 27. Piatt GA, Anderson RM, Brooks MM, et al. 3- diabetes associated with this medica- 12. Tang TS, Funnell MM, Brown MB, Kurlander year follow-up of clinical and behavioral im- tion (245,246). Serious mental illness is JE. Self-management support in “real-world” provements following a multifaceted diabetes often associated with the inability to settings: an empowerment-based intervention. care intervention: results of a randomized evaluate and utilizeinformationto make Patient Educ Couns 2010;79:178–184 controlled trial. Diabetes Educ 2010;36:301– judgments about treatment options. 13. Marrero DG, Ard J, Delamater AM, et al. 309 Twenty-first century behavioral medicine: a con- 28. Glazier RH, Bajcar J, Kennie NR, Willson K. A When a person has an established di- text for empowering clinicians and patients with systematic review of interventions to improve agnosis of a mental illness that impacts diabetes: a consensus report. Diabetes Care diabetes care in socially disadvantaged popula- judgment, activities of daily living, and 2013;36:463–470 tions. Diabetes Care 2006;29:1675–1688 ability to establish a collaborativeAmerican re- 14. Norris SL, Lau J, Smith SJ, Schmid CH, 29. Hawthorne K, Robles Y, Cannings-John R, lationship with care providers, it is Engelgau MM. Self-management education for Edwards AGK. Culturally appropriate health ed- adults with type 2 diabetes: a meta-analysis of wise to include a nonmedical caretaker ucation for type 2 diabetes mellitus in ethnic the effect on glycemic control. Diabetes Care minority groups. Cochrane Database Syst Rev in decision-making regarding the med- 2002;25:1159–1171 2008;3:CD006424 ical regimen. This person can help im- 15. Haas L, Maryniuk M, Beck J, et al.; 2012 30. Chodosh J, MortonSC, MojicaW, et al. Meta- prove the patient’s ability to follow the Standards Revision Task Force. National Standards analysis: chronic disease self-management pro- agreed-upon regimen through both for Diabetes Self-Management Education and Sup- gramsforolder adults.Ann InternMed2005;143: port. Diabetes Care 2013;37(Suppl. 1):S144–S153 – monitoring and caretaking functions 427 438 16. Frosch DL, Uy V, Ochoa S, Mangione CM. 31. Sarkisian CA, Brown AF, Norris KC, Wintz RL, (247).©2019 Evaluation of a behavior support intervention for Mangione CM. A systematic review of diabetes patients with poorly controlled diabetes. Arch self-care interventions for older, African Amer- References Intern Med 2011;171:2011–2017 ican, or Latino adults. Diabetes Educ 2003;29: 1. Young-Hyman D, de Groot M, Hill-Briggs F, 17. Cooke D, Bond R, Lawton J, et al.; U.K. NIHR 467–479 Gonzalez JS, Hood K, Peyrot M. Psychosocial care DAFNE Study Group. Structured type 1 diabe- 32. Peyrot M, Rubin RR. Behavioral and psy- for people with diabetes: a position statement of tes education delivered within routine care: chosocial interventions in diabetes: a concep- the American Diabetes Association. Diabetes impact on glycemic control and diabetes-specific tual review. Diabetes Care 2007;30:2433– Care 2016;39:2126–2140 quality of life. Diabetes Care 2013;36:270– 2440 2. Powers MA, Bardsley J, Cypress M, et al. 272 33. Naik AD, Palmer N, Petersen NJ, et al. Com- Diabetes self-management education and sup- 18. Chrvala CA, Sherr D, Lipman RD. Diabetes parative effectiveness of goal setting in diabetes port in type 2 diabetes: a joint position statement self-management education for adults with mellitus group clinics: randomized clinical trial. of the American Diabetes Association, the type 2 diabetes mellitus: a systematic review Arch Intern Med 2011;171:453–459 care.diabetesjournals.org Facilitating Behavior Change and Well-being to Improve Health Outcomes S61

34. Duke S-AS, Colagiuri S, Colagiuri R. Individual comprehensive diabetes clinical care. Diabetes 62. Boucher JL. Mediterranean eating pattern. patienteducationfor peoplewithtype 2 diabetes Spectr 2010;23:41–46 Diabetes Spectr 2017;30:72–76 mellitus. Cochrane Database Syst Rev 2009;1: 50. Strawbridge LM, Lloyd JT, Meadow A, Riley 63. Sainsbury E, Kizirian NV, Partridge SR, Gill T, CD005268 GF, Howell BL. Use of Medicare’s diabetes self- Colagiuri S, Gibson AA. Effect of dietary carbohy- 35. Odgers-Jewell K, Ball LE, Kelly JT, Isenring EA, managementtrainingbenefit.HealthEducBehav drate restriction on glycemic control in adults with Reidlinger DP, Thomas R. Effectiveness of group- 2015;42:530–538 diabetes: a systematic review and meta-analysis. based self-management education for individu- 51. Li R, Shrestha SS, Lipman R, Burrows NR, Kolb Diabetes Res Clin Pract 2018;139:239–252 als with type 2 diabetes: a systematic review with LE, Rutledge S; Centers for Disease Control and 64. van Zuuren EJ, Fedorowicz Z, Kuijpers T, Pijl meta-analyses and meta-regression. Diabet Med Prevention (CDC). Diabetes self-management H. Effects of low-carbohydrate- compared with 2017;34:1027–1039 education and training among privately insured low-fat-diet interventions on metabolic control 36. PereiraK, PhillipsB,JohnsonC, Vorderstrasse A. persons with newly diagnosed diabetesdUnited in people with type 2 diabetes: a systematic Internet delivered diabetes self-management ed- States, 2011–2012. MMWR Morb Mortal Wkly review including GRADE assessments. Am J Clin ucation: a review. Diabetes Technol Ther 2015;17: Rep 2014;63:1045–1049 Nutr 2018;108:300–331 55–63 52. Horigan G, Davies M, Findlay-White F, 65. Snorgaard O, Poulsen GM, Andersen HK, 37. Sepah SC, Jiang L, Peters AL. Long-term Chaney D, Coates V. Reasons why patients re- Astrup A. Systematic review and meta-analysis outcomes of a web-based diabetes prevention ferred to diabetes education programmes of dietary carbohydrate restriction in patients program: 2-year results of a single-arm longitu- choosenot toattend:asystematicreview. Diabet with type 2 diabetes. BMJ Open Diabetes Res – dinal study. J Med Internet Res 2015;17:e92 Med 2017;34:14 26 Care 2017;5:e000354 38. Greenwood DA, Gee PM, Fatkin KJ, Peeples 53. Center For Health Law and Policy Innova- 66. Rinaldi S, Campbell EE, Fournier J, O’Connor M. A systematic review of reviews evaluating tion. Reconsidering cost-sharing for diabetes C, Madill J. A comprehensive review of the self-management education: recommenda- technology-enabled diabetes self-management literature supporting recommendations from tions for policy reform. Accessed 1 November education and support. J Diabetes Sci Technol the Canadian Diabetes Association for the use 2019. Available from http://www.chlpi.org/ 2017;11:1015–1027 of a plant-based diet for management of type health_library/reconsidering-cost-sharing-diabetes- 39. vanEikenhorstL,TaxisK,van DijkL,deGierH. 2 diabetes. Can J Diabetes 2016;40:471–477 self-management-education-recommendations- Pharmacist-led self-management interventions 67. PawlakAssociation R. Vegetarian diets in the prevention policy-reform/ to improve diabetes outcomes. A systematic and management of diabetes and its complica- 54. Turner RM, Ma Q, Lorig K, Greenberg J, literature review and meta-analysis. Front Phar- tions. Diabetes Spectr 2017;30:82–88 DeVries AR. Evaluation of a diabetes self- macol 2017;8:891 68. U.S. Food and Drug Administration. FDA management program: claims analysis on co- 40. Tshiananga JKT, Kocher S, Weber C, Erny- Drug Safety Communication: FDA revises labels morbid illnesses, health care utilization, and cost. of SGLT2 inhibitors for diabetes to include warn- Albrecht K, Berndt K, Neeser K. The effect of J Med Internet Res 2018;20:e207 ings about too much acid in the blood and serious nurse-led diabetes self-management education 55. Davies MJ, D’Alessio DA, Fradkin J, et al. urinary tract infections. Accessed 1 November on glycosylated hemoglobin and cardiovascular Management of hyperglycemia in type 2 diabe- 2019. Available from http://www.fda.gov/Drugs/ risk factors: a meta-analysis. Diabetes Educ 2012; tes, 2018. A consensus report by the American – DrugSafety/ucm475463.htm 38:108 123 Diabetes Association (ADA) and the European 69. Blau JE, Tella SH, Taylor SI, Rother KI. Ke- 41. Evert AB, Dennison M, Gardner CD, et al. Association for the Study of Diabetes (EASD). toacidosis associated with SGLT2 inhibitor treat- Nutrition therapy for adults with diabetes or Diabetes Care 2018;41:2669–2701 ment: analysis of FAERS data. Diabetes Metab prediabetes: a consensus report. Diabetes Care 56. Briggs Early K, StanleyDiabetes K. Position of the – Res Rev 2017;33:e2924 2019;42:731 754 Academy of Nutrition and Dietetics: the role of 70. Bowen ME, Cavanaugh KL, Wolff K, et al. The 42. Shah M, Kaselitz E, Heisler M. The role of medical nutrition therapy and registered dieti- diabetes nutrition education study randomized community health workers in diabetes: update tiannutritionistsinthepreventionandtreatment controlled trial: a comparative effectiveness on current literature. Curr Diab Rep 2013;13: of prediabetes and type 2 diabetes. J Acad Nutr study of approaches to nutrition in diabetes 163–171 Diet 2018;118:343–353 43. Spencer MS, Kieffer EC, Sinco B, et al. Out- 57. Franz MJ, MacLeod J, Evert A, et al. Academy self-management education. Patient Educ Couns – comes at 18 months from a community health of Nutrition and Dietetics nutrition practice 2016;99:1368 1376 workerandpeerleaderdiabetesself-management guideline for type 1 and type 2 diabetes in adults: 71. Mudaliar U, Zabetian A, Goodman M, et al. program for Latino adults. Diabetes Care 2018;41: systematic review of evidence for medical nu- Cardiometabolic risk factor changes observed in 1414–1422 trition therapy effectiveness and recommenda- Diabetes Prevention Programs in US settings: 44. Heisler M, Vijan S, Makki F, Piette JD. Di- tions for integration into the nutrition care asystematicreviewandmeta-analysis. PLoS Med abetes control with reciprocal peer support process. J Acad Nutr Diet 2017;117:1659–1679 2016;13:e1002095 versus nurse care management: aAmerican randomized 58. MacLeod J, Franz MJ, Handu D, et al. Acad- 72. Balk EM, Earley A, Raman G, Avendano EA, trial. Ann Intern Med 2010;153:507–515 emy of Nutrition and Dietetics nutrition practice Pittas AG, Remington PL. Combined diet and 45. Long JA, Jahnle EC, Richardson DM, guideline for type 1 and type 2 diabetes in adults: physical activity promotion programs to pre- Loewenstein G, Volpp KG. Peer mentoring and nutrition intervention evidence reviews and vent type 2 diabetes among persons at increased financial incentives to improve glucose control recommendations. J Acad Nutr Diet 2017;117: risk: a systematic review for the Community in African American veterans: a randomized 1637–1658 Preventive Services Task Force. Ann Intern trial. Ann Intern Med 2012;156:416–424 59. Schwingshackl L, Chaimani A, Hoffmann G, Med 2015;163:437–451 46. Fisher EB, Boothroyd RI, Elstad EA, et al. Peer Schwedhelm C, Boeing H. A network meta-anal- 73. Hamman RF, Wing RR, Edelstein SL, et al. support of complex health behaviors in preven- ysis on the comparative efficacy of different Effect of weight loss with lifestyle intervention and disease management with special ref- dietary approaches on glycaemic control in pa- tion on risk of diabetes. Diabetes Care 2006; erence©2019 to diabetes: systematic reviews. Clin tients with type 2 diabetes mellitus. Eur J Epi- 29:2102–2107 Diabetes Endocrinol 2017;3:4 demiol 2018;33:157–170 74. Garvey WT, Ryan DH, Bohannon NJV, et al. 47. Foster G, Taylor SJC, Eldridge SE, Ramsay J, 60. Schwingshackl L, Schwedhelm C, Hoffmann Weight-loss therapy in type 2 diabetes: effects of Griffiths CJ. Self-management education pro- G, et al. Food groups and risk of all-cause phentermine and topiramate extended release. grammes by lay leaders for people with chronic mortality: a systematic review and meta-analysis Diabetes Care 2014;37:3309–3316 conditions. Cochrane Database Syst Rev 2007;4: of prospective studies. Am J Clin Nutr 2017;105: 75. Kahan S, Fujioka K. Obesity pharmacother- CD005108 1462–1473 apy in patients with type 2 diabetes. Diabetes 48. Duncan I, Birkmeyer C, Coughlin S, Li QE, 61. Esposito K, Maiorino MI, Ciotola M, et al. Spectrum 2017;30:250–257 Sherr D, Boren S. Assessing the value of diabetes Effects of a Mediterranean-style diet on the need 76. Jeon CY, Lokken RP, Hu FB, van Dam RM. education. Diabetes Educ 2009;35:752–760 for antihyperglycemic drug therapy in patients Physical activity of moderate intensity and risk of 49. Johnson TM, Murray MR, Huang Y. Associ- with newly diagnosed type 2 diabetes: a random- type 2 diabetes: a systematic review. Diabetes ations between self-management education and ized trial. Ann Intern Med 2009;151:306–314 Care 2007;30:744–752 S62 Facilitating Behavior Change and Well-being to Improve Health Outcomes Diabetes Care Volume 43, Supplement 1, January 2020

77. DuncanGE, PerriMG, Theriaque DW, Hutson trial of a moderate-carbohydrate versus very an open-label, non-randomized, controlled AD, Eckel RH, Stacpoole PW. Exercise training, low-carbohydrate diet in overweight adults study. Diabetes Ther 2018;9:583–612 without weight loss, increases insulin sensitivity with type 2 diabetes mellitus or prediabetes. 102. van Wyk HJ, Davis RE, Davies JS. A critical and postheparin plasma lipase activity in pre- Nutr Diabetes 2017;7:304 review of low-carbohydrate diets in people viously sedentary adults. Diabetes Care 2003;26: 91. EmadianA,AndrewsRC,EnglandCY,Wallace with type 2 diabetes. Diabet Med 2016;33: 557–562 V, Thompson JL. The effect of macronutrients 148–157 78. Estruch R, Ros E, Salas-Salvado´ J, et al.; on glycaemic control: a systematic review of 103. Meng Y, Bai H, Wang S, Li Z, Wang Q, Chen L. PREDIMED Study Investigators. Primary preven- dietary randomised controlled trials in over- Efficacy of low carbohydrate diet for type 2 tion of cardiovascular disease with a Mediter- weight and obese adults with type 2 diabetes diabetes mellitus management: a systematic ranean diet supplemented with extra-virgin olive in which there was no difference in weight loss review and meta-analysis of randomized con- oil or nuts. N Engl J Med 2018;378:e34 between treatment groups. Br J Nutr 2015;114: trolled trials. Diabetes Res Clin Pract 2017;131: 79. Franz MJ, Boucher JL, Rutten-Ramos S, 1656–1666 124–131 VanWormer JJ. Lifestyle weight-loss interven- 92. Gardner CD, Trepanowski JF, Del Gobbo LC, 104. Tay J, Luscombe-Marsh ND, Thompson CH, tion outcomes in overweight and obese adults Hauser ME, Rigdon J, Ioannidis JPA, et al. Effect of et al. Comparison of low- and high-carbohydrate with type 2 diabetes: a systematic review and low-fat vs low-carbohydrate diet on 12-month diets for type 2 diabetes management: a ran- meta-analysis of randomized clinical trials. J Acad weight loss in overweight adults and the asso- domized trial. Am J Clin Nutr 2015;102:780– Nutr Diet 2015;115:1447–1463 ciation with genotype pattern or insulin secre- 790 80. Lean ME, Leslie WS, Barnes AC, et al. Primary tion: the DIETFITS randomized clinical trial. JAMA 105. U.S. Department of Agriculture and U.S. care-led weight management for remission of 2018;319:667–679 Department of Health and Human Services. Di- type 2 diabetes (DiRECT): an open-label, cluster- 93. Sacks FM, Bray GA, Carey VJ, et al. Com- etaryguidelinesfor Americans2015-2020,Eighth – randomised trial. Lancet 2018;391:541 551 parison of weight-loss diets with different com- Edition, 2015. Accessed 1 November 2019. Avail- 81. Wing RR, Lang W, Wadden TA, et al.; Look positions of fat, protein, and carbohydrates. N able from https://health.gov/dietaryguidelines/ fi AHEAD Research Group. Bene ts of modest Engl J Med 2009;360:859–873 2015/guidelines/ weight loss in improving cardiovascular risk 94. de Souza RJ, Bray GA, Carey VJ, et al. Effects 106. Nansel TR, Lipsky LM, Liu A. Greater diet factors in overweight and obese individuals of 4 weight-loss diets differing in fat, protein, and qualityAssociation is associated with more optimal glyce- with type 2 diabetes. Diabetes Care 2011;34: carbohydrate on fat mass, lean mass, visceral mic control in a longitudinal study of youth – 1481 1486 adipose tissue, and hepatic fat: results from the with type 1 diabetes. Am J Clin Nutr 2016; 82. Sjostr¨ om¨ L, Peltonen M, Jacobson P, et al. POUNDS LOST trial. Am J Clin Nutr 2012;95:614– 104:81–87 Association of bariatric surgery with long-term 625 107. Katz ML, Mehta S, Nansel T, Quinn H, Lipsky remission of type 2 diabetes and with microvas- 95. Johnston BC, Kanters S, Bandayrel K, et al. LM, Laffel LMB. Associations of nutrient intake cular and macrovascular complications. JAMA Comparison of weight loss among named diet with glycemic control in youth with type 1 di- 2014;311:2297–2304 programs in overweight and obese adults: abetes: differences by insulin regimen. Diabetes 83. Garvey WT, Ryan DH, Bohannon NJV, et al. a meta-analysis. JAMA 2014;312:923–933 Technol Ther 2014;16:512–518 Weight-loss therapy in type 2 diabetes: effects of 96. Fox CS, Golden SH, Anderson C, et al.; 108. Rossi MCE, Nicolucci A, Di Bartolo P, et al. phentermine and topiramate extended release. American Heart Association Diabetes Commit- Diabetes Interactive Diary: a new telemedicine Diabetes Care 2014;37:3309–3316 tee of the Council on Lifestyle and Cardiometa- system enabling flexible diet and insulin ther- 84. Cefalu WT, Leiter LA, de Bruin TWA, Gause- bolic Health; Council on Clinical Cardiology, apy while improving quality of life: an open- Nilsson I, Sugg J, Parikh SJ. Dapagliflozin’sef- Diabetes Council on Cardiovascular and Stroke Nursing, label, international, multicenter, randomized fects on glycemia and cardiovascular risk fac- Council on Cardiovascular Surgery and Anesthe- study. Diabetes Care 2010;33:109–115 tors in high-risk patients with type 2 diabetes: sia, Council on Quality of Care and Outcomes 109. Laurenzi A, Bolla AM, Panigoni G, et al. a 24-week, multicenter, randomized, double- Research; American Diabetes Association. Up- Effects of carbohydrate counting on glucose blind, placebo-controlled study with a 28- date on prevention of cardiovascular disease in control and quality of life over 24 weeks in adult week extension. Diabetes Care 2015;38: patients with type 1 diabetes on continuous 1218–1227 adults with type 2 diabetes mellitus in light of fi subcutaneous insulin infusion: a randomized, 85. Prinz N, Schwandt A, Becker M, et al. Tra- recent evidence: a scienti c statement from the jectories of body mass index from childhood to American Heart Association and the American prospective clinical trial (GIOCAR). Diabetes – young adulthood among patients with type 1 Diabetes Association. Diabetes Care 2015;38: Care 2011;34:823 827 – ¨ ¨ diabetesda longitudinal group-based modeling 1777 1803 110. Samann A, Muhlhauser I, Bender R, Kloos fl approach based on the DPV Registry. J Pediatr 97. DAFNE Study Group. Training in exible, Ch, Muller¨ UA. Glycaemic control and severe fl 2018;201:78–85.e4 intensive insulin management to enable dietary hypoglycaemia following training in exible, in- 86. Lipman TH, Levitt Katz LE,American Ratcliffe SJ, et al. freedom in people with type 1 diabetes: dose tensiveinsulintherapytoenable dietaryfreedom Increasing incidence of type 1 diabetes in youth: adjustment for normal eating (DAFNE) rando- in people with type 1 diabetes: a prospective twenty years of the Philadelphia Pediatric Di- mised controlled trial. BMJ 2002;325:746 implementation study. Diabetologia 2005;48: – abetes Registry. Diabetes Care 2013;36:1597– 98. Delahanty LM, Nathan DM, Lachin JM, et al.; 1965 1970 1603 Diabetes Control and Complications Trial/ 111. Bell KJ, Barclay AW, Petocz P, Colagiuri S, fi 87. Sumithran P, Prendergast LA, Delbridge E, Epidemiology of Diabetes Interventions and Brand-Miller JC. Ef cacy of carbohydrate count- et al. Long-term persistence of hormonal adap- Complications. Association of diet with glycated ing in type 1 diabetes: a systematic review and tations to weight loss. N Engl J Med 2011;365: hemoglobin during intensive treatment of meta-analysis. Lancet Diabetes Endocrinol 2014; 1597–1604 type 1 diabetes in the Diabetes Control and 2:133–140 88. Hamdy O, Mottalib A, Morsi A, et al. Long- Complications Trial. Am J Clin Nutr 2009;89: 112. Bell KJ, Toschi E, Steil GM, Wolpert HA. term©2019 effect of intensive lifestyle intervention on 518–524 Optimized mealtime insulin dosing for fat and cardiovascular risk factors in patients with di- 99. Wheeler ML, Dunbar SA, Jaacks LM, et al. proteinintype1diabetes:applicationofamodel- abetes in real-world clinical practice: a 5-year Macronutrients, food groups, and eating pat- based approach to derive insulin doses for open- longitudinal study. BMJ Open Diabetes Res Care terns in the management of diabetes: a system- loop diabetes management. Diabetes Care 2016; 2017;5:e000259[ atic review of the literature, 2010. Diabetes Care 39:1631–1634 89. Mottalib A, Salsberg V, Mohd-Yusof B-N, 2012;35:434–445 113. Campbell MD, Walker M, King D, et al. et al. Effects of nutrition therapy on HbA1c 100. Thomas D, Elliott EJ. Low glycaemic index, Carbohydrate counting at meal time followed and cardiovascular disease risk factors in over- or low glycaemic load, diets for diabetes mellitus. by a small secondary postprandial bolus injection weight and obese patients with type 2 diabetes. Cochrane Database Syst Rev 2009;1:CD006296 at 3 hours prevents late hyperglycemia, with- Nutr J 2018;17:42 101. Hallberg SJ, McKenzie AL, Williams PT, et al. out hypoglycemia, after a high-carbohydrate, 90. Saslow LR, Daubenmier JJ, Moskowitz JT, Effectiveness and safety of a novel care model high-fat meal in type 1 diabetes. Diabetes Care et al. Twelve-month outcomes of a randomized for the management of type 2 diabetes at 1 year: 2016;39:e141–e142 care.diabetesjournals.org Facilitating Behavior Change and Well-being to Improve Health Outcomes S63

114. Tuttle KR, Bakris GL, Bilous RW, et al. Di- 129. Crochemore ICC, Souza AFP, de Souza ACF, from human and animal studies. Int J Obes 2016; abetic kidney disease: a report from an ADA Rosado EL. v-3 polyunsaturated fatty acid sup- 40:381–394 Consensus Conference. Diabetes Care 2014;37: plementation does not influence body compo- 144. Azad MB, Abou-Setta AM, Chauhan BF, 2864–2883 sition, insulin resistance, and lipemia in women et al. Nonnutritive sweeteners and cardiometa- 115. Ley SH, Hamdy O, Mohan V, Hu FB. Pre- with type 2 diabetes and obesity. Nutr Clin Pract bolic health: a systematic review and meta- vention and management of type 2 diabetes: 2012;27:553–560 analysis of randomized controlled trials and dietary components and nutritional strategies. 130. Holman RR, Paul S, Farmer A, Tucker L, prospective cohort studies. CMAJ 2017;189: Lancet 2014;383:1999–2007 Stratton IM, Neil HA; Atorvastatin in Factorial E929–E939 116. Pan Y, Guo LL, Jin HM. Low-protein diet for with Omega-3 EE90 Risk Reduction in Diabetes 145. EckelRH,JakicicJM,Ard JD,etal.2013AHA/ diabetic nephropathy: a meta-analysis of ran- Study Group. AtorvastatininFactorialwithOmega- ACC guidelineon lifestylemanagementto reduce domizedcontrolledtrials. Am J ClinNutr 2008;88: 3 EE90 Risk Reduction in Diabetes (AFORRD): cardiovascular risk: a report of the American 660–666 a randomised controlled trial. Diabetologia 2009; College of Cardiology/American Heart Associa- 117. Robertson L, Waugh N, Robertson A. Pro- 52:50–59 tion Task Force on Practice Guidelines. Circula- tein restriction for diabetic renal disease. Co- 131. KromhoutD, GeleijnseJM, deGoede J, et al. tion 2013;129(Suppl.):S76–S99 chrane Database Syst Rev 2007;4:CD002181 n-3 fatty acids, ventricular arrhythmia-related 146. Johnson RK, Lichtenstein AH, Anderson 118. Layman DK, Clifton P, Gannon MC, Krauss events, and fatal myocardial infarction in post- CAM,etal.;AmericanHeartAssociationNutrition RM, Nuttall FQ. Protein in optimal health: heart myocardial infarction patients with diabetes. Committee of the Council on Lifestyle and Car- disease and type 2 diabetes. Am J Clin Nutr 2008; Diabetes Care 2011;34:2515–2520 diometabolic Health; Council on Cardiovascular – 87:1571S 1575S 132. Bosch J, Gerstein HC, Dagenais GR, et al.; and Stroke Nursing; Council on Clinical Cardiol- 119. Ros E. Dietary cis-monounsaturated fatty ORIGIN Trial Investigators. n-3 fatty acids and ogy; Council on Quality of Care and Outcomes acids and metabolic control in type 2 diabe- cardiovascular outcomes in patients with dysgly- Research;StrokeCouncil.Low-caloriesweetened – tes. Am J Clin Nutr 2003;78(Suppl.):617S cemia. N Engl J Med 2012;367:309–318 beverages and cardiometabolic health: a science 625S 133. Thomas MC, Moran J, Forsblom C, et al.; advisory from the American Heart Association. 120. Forouhi NG, Imamura F, Sharp SJ, et al. FinnDianeStudy Group. Theassociationbetween Circulation 2018;138:e126–e140 Association of plasma phospholipid n-3 and n-6 dietary sodium intake, ESRD, and all-cause mor- 147. 2018Association Physical Activity Guidelines Advisory polyunsaturated fatty acids with type 2 diabetes: tality in patients with type 1 diabetes. Diabetes Committee. 2018 Physical Activity Guidelines the EPIC-InterAct case-cohort study. PLoS Med Care 2011;34:861–866 Advisory Committee Scientific Report. Washing- 2016;13:e1002094 134. Ekinci EI,Clarke S,Thomas MC,et al. Dietary ton, DC, U.S. Department of Health and Human 121. Wang DD, Li Y, Chiuve SE, et al. Association salt intake and mortality in patients with type 2 Services, 2018 of specific dietary fats with total and cause- diabetes. Diabetes Care 2011;34:703–709 148. Bazargan-Hejazi S, Arroyo JS, Hsia S, Brojeni specific mortality. JAMA Intern Med 2016;176: 135. Lennon SL, DellaValle DM, Rodder SG, et al. NR, Pan D. A racial comparison of differences 1134–1145 2015 Evidence Analysis Library evidence-based between self-reported and objectively measured 122. Brehm BJ, Lattin BL, Summer SS, et al. One- nutrition practice guideline for the management physical activity among US adults with diabetes. year comparison of a high-monounsaturated fat of hypertension in adults. J Acad Nutr Diet 2017; Ethn Dis 2017;27:403–410 diet with a high-carbohydrate diet in type 2 117:1445–1458.e17 149. Sluik D, Buijsse B, Muckelbauer R, et al. diabetes. Diabetes Care 2009;32:215–220 136. Maillot M, Drewnowski A. A conflict be- Physical activity and mortality in individuals with 123. Shai I, Schwarzfuchs D, Henkin Y, et al.; tween nutritionally adequate diets and meeting diabetes mellitus: a prospective study and Dietary Intervention Randomized Controlled Tri- Diabetes the 2010 dietary guidelines for sodium. Am J meta-analysis. Arch Intern Med 2012;172: al (DIRECT) Group. Weight loss with a low- Prev Med 2012;42:174–179 1285–1295 carbohydrate, Mediterranean, or low-fat diet. 137. Aroda VR, Edelstein SL, Goldberg RB, et al.; 150. Tikkanen-Dolenc H, Waden´ J, Forsblom C, N Engl J Med 2008;359:229–241 Diabetes Prevention Program Research Group. et al.; FinnDiane Study Group. Physical activ- 124. Brunerova L, Smejkalova V, Potockova J, Andel M. A comparison of the influence of a high- Long-term metformin use and vitamin B12 de- ity reduces risk of premature mortality in pa- fi fat diet enriched in monounsaturated fatty acids ciency in the Diabetes Prevention Program tients with type 1 diabetes with and without – and conventional diet on weight loss and met- Outcomes Study. J Clin Endocrinol Metab kidney disease. Diabetes Care 2017;40:1727 – abolic parameters in obese non-diabetic and 2016;101:1754 1761 1732 type 2 diabetic patients. Diabet Med 2007;24: 138. Allen RW, Schwartzman E, Baker WL, 151. Boule´ NG, Haddad E, Kenny GP, Wells GA, 533–540 Coleman CI, Phung OJ. Cinnamon use in type Sigal RJ. Effects of exercise on glycemic control 125. Bloomfield HE, Koeller E, Greer N, 2 diabetes: an updated systematic review and and body mass in type 2 diabetes mellitus: – MacDonald R, Kane R, Wilt TJ. Effects on health meta-analysis. Ann Fam Med 2013;11:452 a meta-analysis of controlled clinical trials. – outcomes of a Mediterranean dietAmerican with no re- 459 JAMA 2001;286:1218 1227 striction on fat intake: a systematic review and 139. Mitri J, Pittas AG. Vitamin D and diabetes. 152. Peters AL, Laffel L (Eds). American Diabetes – meta-analysis. Ann Intern Med 2016;165:491– Endocrinol Metab Clin North Am 2014;43:205 Association/JDRF Type 1 Diabetes Sourcebook.Alex- 500 232 andria, VA, American Diabetes Association, 2013 126. Sacks FM, Lichtenstein AH, Wu JHY, et al.; 140. Mozaffarian D. Dietary and policy priorities 153. Ostman C, Jewiss D, King N, Smart NA. American Heart Association. Dietary fats and for cardiovascular disease, diabetes, and obesity: Clinical outcomes to exercise training in type 1 cardiovascular disease: a presidential advisory a comprehensive review. Circulation 2016;133: diabetes: a systematic review and meta-analysis. from the American Heart Association. Circulation 187–225 Diabetes Res Clin Pract 2018;139:380–391 2017;136:e1–e23 141. Grotz VL, Pi-Sunyer X, Porte D Jr, Roberts A, 154. Boule´ NG, Kenny GP, Haddad E, Wells GA, 127. Jacobson TA, Maki KC, Orringer CE, et al.; Richard Trout J. A 12-week randomized clinical Sigal RJ. Meta-analysis of the effect of structured NLA Expert©2019 Panel. National Lipid Association trial investigating the potential for sucralose to exercise training on cardiorespiratory fitness in recommendations for patient-centered manage- affect glucose homeostasis. Regul Toxicol Phar- type 2 diabetes mellitus. Diabetologia 2003;46: ment of dyslipidemia: part 2. J Clin Lipidol 2015; macol 2017;88:22–33 1071–1081 9(Suppl.):S1–S122.e1 142. Miller PE, Perez V. Low-calorie sweeteners 155. Rejeski WJ, Ip EH, Bertoni AG, et al.; Look 128. Harris WS, Mozaffarian D, Rimm E, et al. and body weight and composition: a meta- AHEAD Research Group. Lifestyle change and Omega-6 fatty acids and risk for cardiovascular analysis of randomized controlled trials and mobility in obese adults with type 2 diabetes. N disease: a science advisory from the American prospective cohort studies. Am J Clin Nutr Engl J Med 2012;366:1209–1217 Heart Association Nutrition Subcommittee of 2014;100:765–777 156. Colberg SR, Sigal RJ, Yardley JE, et al. the Council on Nutrition, Physical Activity, 143. Rogers PJ, Hogenkamp PS, de Graaf C, et al. Physical activity/exercise and diabetes: and Metabolism; Council on Cardiovascular Does low-energy sweetener consumption affect a position statement of the American Di- Nursing; and Council on Epidemiology and energy intake and body weight? A systematic abetes Association. Diabetes Care 2016;39: Prevention. Circulation 2009;119:902–907 review, including meta-analyses, of the evidence 2065–2079 S64 Facilitating Behavior Change and Well-being to Improve Health Outcomes Diabetes Care Volume 43, Supplement 1, January 2020

157. Janssen I, Leblanc AG. Systematic review 172. Bax JJ, Young LH, Frye RL, Bonow RO, for type 2 diabetes mellitus: a cohort study. Ann of the health benefits of physical activity and Steinberg HO, Barrett EJ; ADA. Screening for Intern Med 2010;152:10–17 fitness in school-aged children and youth. Int J coronaryartery disease in patients with diabetes. 188. Tonstad S, Lawrence D. Varenicline in Behav Nutr Phys Act 2010;7:40 Diabetes Care 2007;30:2729–2736 smokers with diabetes: a pooled analysis of 158. Riddell MC, Gallen IW, Smart CE, et al. 173. Colberg SR. Exercise and Diabetes: A Clini- 15 randomized, placebo-controlled studies Exercise management in type 1 diabetes: a con- cian’s Guide to Prescribing Physical Activity. 1st of varenicline. J Diabetes Investig 2017;8: sensus statement. Lancet Diabetes Endocrinol ed. Alexandria, VA, American Diabetes Associa- 93–100 2017;5:377–390 tion, 2013 189. West R. Tobacco smoking: health impact, 159. Anderson BJ, Laffel LM, Domenger C, et al. 174. Lemaster JW, Reiber GE, Smith DG, prevalence, correlates and interventions. Psy- Factors associated with diabetes-specific health- Heagerty PJ, Wallace C. Daily weight-bearing chol Health 2017;32:1018–1036 related quality of life in youth with type 1 di- activity does not increase the risk of diabetic 190. Ranney L, Melvin C, Lux L, McClain E, Lohr abetes: the global TEENs study. Diabetes Care foot ulcers. Med Sci Sports Exerc 2003;35:1093– KN. Systematic review: smoking cessation in- 2017;40:1002–1009 1099 tervention strategies for adults and adults in 160. Adolfsson P, Riddell MC, Taplin CE, et al. 175. Smith AG, Russell J, Feldman EL, et al. special populations. Ann Intern Med 2006;145: ISPAD clinical practice consensus guidelines Lifestyle intervention for pre-diabetic neuropa- 845–856 2018: exercise in children and adolescents thy. Diabetes Care 2006;29:1294–1299 191. Tian J, Venn A, Otahal P, Gall S. The with diabetes. Pediatr Diabetes 2018;19(Suppl. 176. Spallone V, Ziegler D, Freeman R, et al.; association between quitting smoking and 27):205–226 Toronto Consensus Panel on Diabetic Neuropa- weight gain: a systematic review and meta- 161. Jelleyman C, Yates T, O’Donovan G, et al. thy. Cardiovascular autonomic neuropathy in analysis of prospective cohort studies. Obes The effects of high-intensity interval training on diabetes: clinical impact, assessment, diagnosis, Rev 2015;16:883–901 glucose regulationand insulin resistance:a meta- and management. Diabetes Metab Res Rev 192. Clair C, Rigotti NA, Porneala B, et al. As- analysis. Obes Rev 2015;16:942–961 2011;27:639–653 sociation of smoking cessation and weight 162. Little JP, Gillen JB, Percival ME, et al. Low- 177. Pop-Busui R, Evans GW, Gerstein HC, et al.; changewith cardiovasculardiseaseamongadults volume high-intensity interval training re- Action to Control Cardiovascular Risk in Diabetes with and without diabetes. JAMA 2013;309: duces hyperglycemia and increases muscle Study Group. Effects of cardiac autonomic dys- 1014Association–1021 mitochondrial capacity in patients with function on mortality risk in the Action to Control 193. Voulgari C, Katsilambros N, Tentolouris N. type 2 diabetes. J Appl Physiol (1985) 2011; Cardiovascular Risk in Diabetes (ACCORD) trial. Smoking cessation predicts amelioration of mi- 111:1554–1560 Diabetes Care 2010;33:1578–1584 croalbuminuria in newly diagnosed type 2 di- 163. U.S. Department of Health and Human 178. Suarez L, Barrett-Connor E. Interaction abetes mellitus: a 1-year prospective study. Services. 2008 Physical activity guidelines for between cigarette smoking and diabetes mellitus Metabolism 2011;60:1456–1464 americans: index. Accessed 1 November 2019. in the prediction of death attributed to cardiovas- 194. Huerta TR, Walker DM, Mullen D, Johnson Available from http://www.health.gov/paguidelines/ cular disease. Am J Epidemiol 1984;120:670–675 TJ, Ford EW. Trends in e-cigarette awareness and guidelines/default.aspx 179. Stanton CA, Keith DR, Gaalema DE, et al. perceived harmfulness in the U.S. Am J Prev Med 164. Willey KA, Singh MAF. Battling insulin re- Trends in tobacco use among US adults with 2017;52:339–346 sistance in elderly obese people with type 2 chronic health conditions: National Survey on 195. Pericot-Valverde I, Gaalema DE, Priest JS, diabetes: bring on the heavy weights. Diabetes Drug Use and Health 2005-2013. Prev Med 2016; Higgins ST. E-cigarette awareness, perceived Care 2003;26:1580–1588 92:160–168 harmfulness, and ever use among U.S. adults. 165. Katzmarzyk PT, Church TS, Craig CL, 180. BaeJ.DifferencesincigaretteusebehaviorsDiabetesPrev Med 2017;104:92–99 Bouchard C. Sitting time and mortality from byageat the timeofdiagnosis withdiabetesfrom 196. Centers for Disease Control and Preven- all causes, cardiovascular disease, and cancer. young adulthood to adulthood: results from the tion. Outbreak of lung injury associated with Med Sci Sports Exerc 2009;41:998–1005 National Longitudinal Study of Adolescent e-cigaretteuse,orvaping,2019.Accessed27Sep- 166. Dempsey PC, Larsen RN, Sethi P, et al. Health. J Prev Med Public Health 2013;46: tember 2019. Available from https://www.cdc Benefits for type 2 diabetes of interrupting 249–260 .gov/tobacco/basic_information/e-cigarettes/ prolonged sitting with brief bouts of light walking 181. Sliwi´ nska-Mosso´ n´ M, Milnerowicz H. The severe-lung-disease.html or simple resistance activities. Diabetes Care impact of smoking on the development of di- 197. Anderson RJ, Grigsby AB, Freedland KE, 2016;39:964–972 abetes and its complications. Diab Vasc Dis Res et al. Anxiety and poor glycemic control: 167. Cui J, Yan J-H, Yan L-M, Pan L, Le J-J, Guo Y-Z. 2017;14:265–276 a meta-analytic review of the literature. Int J Effects of yoga in adults with type 2 diabetes 182. KarD,GilliesC,ZaccardiF,etal.Relationship Psychiatry Med 2002;32:235–247 mellitus: a meta-analysis. J Diabetes Investig of cardiometabolic parameters in non-smokers, 198. Delahanty LM, Grant RW, Wittenberg E, 2017;8:201–209 current smokers, and quitters in diabetes: a sys- et al. Association of diabetes-related emo- 168. Lee MS, Jun JH, Lim H-J,American Lim H-S. A systematic review and meta-analysis. Cardiovasc tional distress with diabetes treatment in pri- tematic review and meta-analysis of tai chi for Diabetol 2016;15:158 mary care patients with type 2 diabetes. Diabet treating type 2 diabetes. Maturitas 2015;80:14– 183. Pan A, Wang Y, Talaei M, Hu FB. Relation of Med 2007;24:48–54 23 smoking with total mortality and cardiovascular 199. Anderson RJ, Freedland KE, Clouse RE, 169. Colberg SR, Sigal RJ, Fernhall B, et al.; events among patients with diabetes mellitus: Lustman PJ. The prevalence of comorbid de- American College of Sports Medicine; American a meta-analysis and systematic review. Circula- pression in adults with diabetes: a meta-analysis. Diabetes Association. Exercise and type 2 dition 2015;132:1795–1804 Diabetes Care 2001;24:1069–1078 abetes: the American College of Sports Medicine 184. Jankowich M, Choudhary G, Taveira TH, Wu 200. Kovacs Burns K, Nicolucci A, Holt RIG, and the American Diabetes Association: joint W-C. Age-, race-, and gender-specific prevalence et al.; DAWN2 Study Group. Diabetes Atti- positionstatementexecutive summary. Diabetes of diabetes among smokers. Diabetes Res Clin tudes, Wishes and Needs second study Care©2019 2010;33:2692–2696 Pract 2011;93:e101–e105 (DAWN2Ô): cross-national benchmarking 170. Church TS, Blair SN, Cocreham S, et al. 185. Akter S, Goto A, Mizoue T. Smoking and the indicators for family members living with peo- Effects of aerobic and resistance training on riskoftype2diabetesinJapan:asystematicreview ple with diabetes. Diabet Med 2013;30:778– hemoglobin A1c levels in patients with type 2 and meta-analysis. J Epidemiol 2017;27:553–561 788 diabetes: a randomized controlled trial. JAMA 186. Liu X, Bragg F, Yang L, et al.; China Kadoorie 201. Ducat L, Philipson LH, Anderson BJ. The 2010;304:2253–2262 Biobank Collaborative Group. Smoking and mental health comorbidities of diabetes. JAMA 171. Peters A, Laffel L, Colberg SR, Riddell MC. smoking cessation in relation to risk of diabetes 2014;312:691–692 Physical activity: regulation of glucose metabo- in Chinese men and women: a 9-year prospective 202. Gonzalvo JD, Hamm J, Eaves S, et al. A lism, clinical management strategies, and weight study of 0z5 million people. Lancet Public Health practical approach to mental health for the control. In American Diabetes Association/JDRF 2018;3:e167–e176 diabetes educator. AADE Pract 2019;7:29–44 Type 1 Diabetes Sourcebook. Alexandria, VA, 187. YehH-C,DuncanBB,SchmidtMI,WangN-Y, 203. Robinson DJ, Coons M, Haensel H, Vallis M, American Diabetes Association, 2013 Brancati FL. Smoking, smoking cessation, and risk Yale J-F; Diabetes Canada Clinical Practice care.diabetesjournals.org Facilitating Behavior Change and Well-being to Improve Health Outcomes S65

Guidelines Expert Committee. Diabetes and 218. Li C, Barker L, Ford ES, Zhang X, Strine TW, collaborative care in patients with diabetes mental health. Can J Diabetes 2018;42(Suppl. 1): Mokdad AH. Diabetes and anxiety in US adults: and depression. Arch Gen Psychiatry 2004;61: S130–S141 findings from the 2006 Behavioral Risk Factor 1042–1049 204. Harkness E, Macdonald W, Valderas J, Surveillance System. Diabet Med 2008;25:878– 234. Pinhas-Hamiel O, Hamiel U, Levy-Shraga Y. Coventry P, Gask L, Bower P. Identifying psycho- 881 Eating disorders in adolescents with type 1 di- social interventions that improve both physical 219. Cox DJ, Irvine A, Gonder-Frederick L, abetes: challenges in diagnosis and treatment. and mental health in patients with diabetes: Nowacek G, Butterfield J. Fear of hypoglycemia: World J Diabetes 2015;6:517–526 a systematic review and meta-analysis. Diabetes quantification, validation, and utilization. Diabe- 235. Papelbaum M, Appolinario´ JC, Moreira Care 2010;33:926–930 tes Care 1987;10:617–621 R de O, Ellinger VCM, Kupfer R, Coutinho WF. 205. Weissberg-Benchell J, Shapiro JB. A review 220. Wild D, von Maltzahn R, Brohan E, Prevalence of eating disorders and psychiatric of interventions aimed at facilitating successful Christensen T, Clauson P, Gonder-Frederick L. comorbidityinaclinical sampleof type2diabetes transition planning and transfer to adult care A critical review of the literature on fear of mellitus patients. Br J Psychiatry 2005;27:135– among youth with chronic illness. Pediatr Ann hypoglycemia in diabetes: implications for di- 138 2017;46:e182–e187 abetes management and patient education. Pa- 236. Young-Hyman DL, Davis CL. Disordered 206. O’Gurek DT, Henke C. A practical approach tient Educ Couns 2007;68:10–15 eating behavior in individuals with diabetes: to screening for social determinants of health. 221. Zambanini A, Newson RB, Maisey M, Feher importance of context, evaluation, and classifi- Fam Pract Manag 2018;25:7–12 MD. Injection related anxiety in insulin-treated cation. Diabetes Care 2010;33:683–689 207. Nicolucci A, Kovacs Burns K, Holt RIG, et al.; diabetes. Diabetes Res Clin Pract 1999;46:239– 237. Pinhas-Hamiel O, Hamiel U, Greenfield Y, DAWN2StudyGroup. Diabetes Attitudes,Wishes 246 et al. Detecting intentional insulin omission for and Needs second study (DAWN2Ô): cross- 222. American Psychiatric Association. Diagnos- weight loss in girls with type 1 diabetes mellitus. – national benchmarking of diabetes-related psy- tic and Statistical Manual of Mental Disorders. Int J Eat Disord 2013;46:819 825 chosocial outcomes for people with diabetes. Fifth Edition, 2013. Accessed 1 November 2019. 238. Goebel-Fabbri AE, Fikkan J, Franko DL, Diabet Med 2013;30:767–777 Available from http://psychiatryonline.org/doi/ Pearson K, Anderson BJ, Weinger K. Insulin re- 208. Fisher L, Hessler DM, Polonsky WH, Mullan book/10.1176/appi.books.9780890425596 striction and associated morbidity and mortality J. When is diabetes distress clinically meaningful? 223. Mitsonis C, Dimopoulos N, Psarra V. P01- in women with type 1 diabetes. Diabetes Care Association– Establishing cut points for the Diabetes Distress 138 Clinical implications of anxiety in diabetes: 2008;31:415 419 Scale. Diabetes Care 2012;35:259–264 a critical review of the evidence base. Eur 239. WeingerK, Beverly EA.Barrierstoachieving 209. Fisher L, Glasgow RE, Strycker LA. The Psychiatry 2009;24:S526 glycemic targets: who omits insulin and why? – relationship between diabetes distress and clin- 224. Yeoh E, Choudhary P, Nwokolo M, Ayis S, Diabetes Care 2010;33:450 452 Amiel SA. Interventions that restore awareness ical depression with glycemic control among 240. Hudson JI, Hiripi E, Pope HG Jr, Kessler RC. of hypoglycemia in adults with type 1 diabetes: Theprevalenceandcorrelatesof eating disorders patients with type 2 diabetes. Diabetes Care a systematic review and meta-analysis. Diabetes in the National Comorbidity Survey Replication. 2010;33:1034–1036 Care 2015;38:1592–1609 Biol Psychiatry 2007;61:348–358 210. Aikens JE. Prospective associations be- 225. Cox DJ, Gonder-Frederick L, Polonsky W, 241. Martyn-Nemeth P, Quinn L, Hacker E, tween emotional distress and poor outcomes Schlundt D, Kovatchev B, Clarke W. Blood glucose Park H, Kujath AS. Diabetes distress may in type 2 diabetes. Diabetes Care 2012;35:2472– awarenesstraining(BGAT-2):long-term benefits. adversely affect the eating styles of women 2478 Diabetes Care 2001;24:637–642 with type 1 diabetes. Acta Diabetol 2014;51: 211. Fisher L, Skaff MM, Mullan JT, et al. Clin- 226. Gonder-Frederick LA, Schmidt KM, Vajda 683–686 ical depression versus distress among patients Diabetes KA, et al. Psychometric properties of the Hypo- 242. Peterson CM, Fischer S, Young-Hyman D. with type 2 diabetes: not just a question of glycemia Fear Survey-II for adults with type 1 Topical review: a comprehensive risk model for semantics. Diabetes Care 2007;30:542–548 diabetes. Diabetes Care 2011;34:801–806 disordered eating in youth with type 1 diabetes. J 212. Snoek FJ, Bremmer MA, Hermanns N. 227. Cox DJ, Kovatchev B, Koev D, et al. Hypo- Pediatr Psychol 2015;40:385–390 Constructs of depression and distress in diabe- glycemia anticipation, awareness and treat- 243. Garber AJ. Novel GLP-1 receptor agonists tes: time for an appraisal. Lancet Diabetes En- ment training (HAATT) reduces occurrence of for diabetes. Expert Opin Investig Drugs 2012;21: – docrinol 2015;3:450 460 severe hypoglycemia among adults with type 1 45–57 213. Gary TL, Safford MM, Gerzoff RB, et al. diabetes mellitus. Int J Behav Med 2004;11:212– 244. Suvisaari J, Peral¨ a¨ J, Saarni SI, et al. Type Perception of neighborhood problems, health 218 2 diabetes among persons with schizophrenia behaviors, and diabetes outcomes among 228. Lustman PJ, Griffith LS, Clouse RE. Depres- and other psychotic disorders in a general pop- adults with diabetes in managed care: the sion in adults with diabetes. Results of 5-yr ulation survey. Eur Arch Psychiatry Clin Neurosci Translating Research Into Action for Diabe- follow-up study. Diabetes Care 1988;11:605–612 2008;258:129–136 – tes (TRIAD) study. Diabetes Care 2008;31:273 229. de Groot M, Crick KA, Long M, Saha C, 245. Koro CE, Fedder DO, L’Italien GJ, et al. 278 AmericanShubrook JH. lifetime duration of depressive Assessment of independent effect of olanza- 214. BeverlyEA,HultgrenBA,BrooksKM,Ritholz disorders in patients with type 2 diabetes. Di- pine and risperidone on risk of diabetes MD, Abrahamson MJ, Weinger K. Understand- abetes Care 2016;39:2174–2181 among patients with schizophrenia: population ing physicians’ challenges when treating type 2 230. Rubin RR, Ma Y, Marrero DG, et al.; Di- based nested case-control study. BMJ 2002; diabetic patients’ social and emotional difficul- abetes Prevention Program Research Group. 325:243 ties: a qualitative study. Diabetes Care 2011;34: Elevated depression symptoms, antidepressant 246. American Diabetes Association; American 1086–1088 medicine use, and risk of developing diabetes Psychiatric Association; American Association of 215. Naicker K, Johnson JA, Skogen JC, et al. Type during the diabetes prevention program. Diabe- Clinical Endocrinologists; North American Asso- 2 diabetes and comorbid symptoms of depres- tes Care 2008;31:420–426 ciation for the Study of Obesity. Consensus sion©2019 and anxiety: longitudinal associations 231. Clouse RE, Lustman PJ, Freedland KE, development conference on antipsychotic drugs with mortality risk. Diabetes Care 2017;40: Griffith LS, McGill JB, Carney RM. Depression andobesityand diabetes. DiabetesCare2004;27: 352–358 and coronary heart disease in women with di- 596–601 216. de Groot M, Golden SH, Wagner J. Psycho- abetes. Psychosom Med 2003;65:376–383 247. Kruse J, Schmitz N, Thefeld W; German logical conditions in adults with diabetes. Am 232. Katon WJ, Lin EHB, Von Korff M, et al. National Health Interview and Examination Sur- Psychol 2016;71:552–562 Collaborative care for patients with depression vey. On the association between diabetes and 217. Smith KJ, Beland´ M, Clyde M, et al. Asso- and chronic illnesses. N Engl J Med 2010;363: mental disorders in a community sample: results ciation of diabetes with anxiety: a systematic 2611–2620 from the German National Health Interview and reviewand meta-analysis. J Psychosom Res 2013; 233. Katon WJ, Von Korff M, Lin EHB, et al. Examination Survey. Diabetes Care 2003;26: 74:89–99 The Pathways Study: a randomized trial of 1841–1846 S66 Diabetes Care Volume 43, Supplement 1, January 2020

6. Glycemic Targets: Standards of American Diabetes Association Medical Care in Diabetesd2020

Diabetes Care 2020;43(Suppl. 1):S66–S76 | https://doi.org/10.2337/dc20-S006

The American Diabetes Association (ADA) “Standards of Medical Care in Diabe- tes”includestheADA’scurrentclinicalpracticerecommendationsandisintendedto provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Association Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc20- SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi .org/10.2337/dc20-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC. 6. GLYCEMIC TARGETS Diabetes ASSESSMENT OF GLYCEMIC CONTROL Glycemic management is primarily assessed with the A1C test, which was the measure studied in clinical trials demonstrating the benefits of improved glycemic control. Patient self-monitoring of blood glucose (SMBG) may help with self- management and medication adjustment, particularly in individuals taking insulin. Continuous glucose monitoring (CGM) also has an important role in assessing the effectiveness and safety of treatment in many patients with type 1 diabetes, and limited data suggest it may also be helpful in selected patients with type 2 diabetes, such as those on intensive insulin regimens (1). A1C Testing American Recommendations 6.1 Perform the A1C test at least two times a year in patients who are meeting treatment goals (and who have stable glycemic control). E 6.2 Perform the A1C test quarterly in patients whose therapy has changed or who are not meeting glycemic goals. E 6.3 Point-of-care testing for A1C provides the opportunity for more timely ©2019treatment changes. E fl A1C re ects average glycemia over approximately 3 months. The performance of Suggested citation: American Diabetes Associa- the test is generally excellent for National Glycohemoglobin Standardization tion. 6. Glycemic targets: Standards of Medical Program (NGSP)-certified assays (see www.ngsp.org). The test is the major tool Care in Diabetesd2020. Diabetes Care 2020; for assessing glycemic control and has strong predictive value for diabetes 43(Suppl. 1):S66–S76 complications (1–3). Thus, A1C testing should be performed routinely in all patients © 2019 by the American Diabetes Association. with diabetesdat initial assessment and as part of continuing care. Measurement Readers may use this article as long as the work approximately every 3 months determines whether patients’ glycemic targets have is properly cited, the use is educational and not for profit, and the work is not altered. More infor- been reached and maintained. The frequency of A1C testing should depend on mation is available at http://www.diabetesjournals the clinical situation, the treatment regimen, and the clinician’s judgment. The .org/content/license. care.diabetesjournals.org Glycemic Targets S67

use of point-of-care A1C testing may also inform the accuracy of the patient’s ethnic groups in the regression lines provide an opportunity for more timely meter (or the patient’s reported SMBG between A1C and mean glucose, al- treatment changes during encounters results) and the adequacy of the SMBG though the study was underpowered between patients and providers. Pa- testing schedule. to detect a difference and there was a tients with type 2 diabetes with stable trend toward a difference between the glycemia well within target may do well Correlation Between SMBG and A1C African/African American and non-Hispanic with A1C testing only twice per year. Table 6.1 shows the correlation between white cohorts, with higher A1C values Unstable or intensively managed pa- A1C levels and mean glucose levels based observed in Africans/African Americans tients or people not at goal with treat- on the international A1C-Derived Average compared with non-Hispanic whites ment adjustments may require testing Glucose (ADAG)study,which assessedthe for a given mean glucose. Other studies more frequently (every 3 months) (4). correlation between A1C and frequent have also demonstrated higher A1C levels SMBG and CGM in 507 adults (83% non- in African Americans than in whites A1C Limitations Hispanic whites) with type 1, type 2, and at a given mean glucose concentration The A1C test is an indirect measure of no diabetes (6), and an empirical study of (8,9). average glycemia and, as such, is sub- the average blood glucose levels at pre- A1C assays are available that do not ject to limitations. As with any labo- meal, postmeal, and bedtime associated demonstrate a statistically significant ratory test, there is variability in the with specified A1C levels using data from difference in individuals with hemoglo- measurement of A1C. Although such the ADAG trial (7). The American Diabe- bin variants. Other assays have statisti- variability is less on an intraindividual tes Association (ADA) and the American cally significant interference, but the basis than that of blood glucose measure- Association for Clinical Chemistry have difference is not clinically significant. ments, clinicians should exercise judg- determined that the correlation (r 5 Use ofAssociation an assay with such statistically ment when using A1C as the sole basis 0.92) in the ADAG trial is strong enough significant interference may explain a for assessing glycemic control, particu- to justify reporting both the A1C result report that for any level of mean glyce- larly if the result is close to the threshold and the estimated average glucose (eAG) mia, African Americans heterozygous for that might prompt a change in medica- result when a clinician orders the A1C the common hemoglobin variant HbS tion therapy. Conditions that affect red test. Clinicians should note that the had lower A1C by about 0.3 percentage blood cell turnover (hemolytic and other mean plasma glucose numbers in Table points when compared with those with- anemias, glucose-6-phosphate dehydro- 6.1 are based on ;2,700 readings per A1C out the trait (10,11). Another genetic genase deficiency, recent blood trans- in the ADAG trial. In a recent report, mean variant, X-linked glucose-6-phosphate fusion, use of drugs that stimulate glucose measured with CGM versus cen- dehydrogenase G202A, carried by 11% erythropoesis, end-stage kidney disease, tral laboratory–measured A1C in 387 of African Americans, was associated and pregnancy) may result in discrep- participants in threeDiabetes randomized trials with a decrease in A1C of about 0.8% ancies between the A1C result and the demonstrated that A1C may underesti- in hemizygous men and 0.7% in homo- patient’s true mean glycemia. Hemoglo- mate or overestimate mean glucose (5). zygous women compared with those bin variants must be considered, partic- Thus, as suggested, a patient’s CGM pro- without the trait (12). ularly when the A1C result does not file has considerable potential for opti- A small study comparing A1C to CGM correlate with the patient’s SMBG levels. mizing his or her glycemic management data in children with type 1 diabetes However, most assays in use in the U.S. (5). found a highly statistically significant are accurate in individuals heterozy- correlation between A1C and mean gous for the most common variants A1C Differences in Ethnic Populations blood glucose, although the correlation (see www.ngsp.org/interf.asp). Other and Children (r 5 0.7) was significantly lower than in measures of average glycemia such as In the ADAG study, there were no sig- the ADAG trial (13). Whether there are fructosamine and 1,5-anhydroglucitolAmericannificant differences among racial and clinically meaningful differences in how are available, but their translation into average glucose levels and their prog- Table 6.1—Estimated average glucose (eAG) nostic significance are not as clear as for A1C (%) mg/dL* mmol/L A1C. Though some variability in the relationship between average glucose lev- 5 97 (76–120) 5.4 (4.2–6.7) els and A1C exists among different 6 126 (100–152) 7.0 (5.5–8.5) individuals, generally the association be- 7 154 (123–185) 8.6 (6.8–10.3) tween©2019 mean glucose and A1C within an 8 183 (147–217) 10.2 (8.1–12.1) individual correlates over time (5). 9 212 (170–249) 11.8 (9.4–13.9) A1C does not provide a measure of 10 240 (193–282) 13.4 (10.7–15.7) glycemic variability or hypoglycemia. For 11 269 (217–314) 14.9 (12.0–17.5) patients prone to glycemic variability, 12 298 (240–347) 16.5 (13.3–19.3) especially patients with type 1 diabetes Data in parentheses are 95% CI. A calculator for converting A1C results into eAG, in either mg/dL or or type 2 diabetes with severe insulin mmol/L, is available at professional.diabetes.org/eAG. *These estimates are based on ADAG data deficiency, glycemic control is best of ;2,700 glucose measurements over 3 months per A1C measurement in 507 adults with type 1, evaluated by the combination of results type 2, or no diabetes. The correlation between A1C and average glucose was 0.92 (6,7). Adapted from Nathan et al. (6). from SMBG or CGM and A1C. A1C may S68 Glycemic Targets Diabetes Care Volume 43, Supplement 1, January 2020

A1C relates to average glucose in children response to therapy and assess whether providers. Reports can be generated or in different ethnicities is an area for glycemic targets are being safely achieved. from CGM that will allow the provider further study (8,14,15). Until further The international consensus on time in to determine time in range (TIR) and to evidence is available, it seems prudent range provides guidance on standardized assess hypoglycemia, hyperglycemia, and to establish A1C goals in these popula- CGM metrics (see Table 6.2) and consid- glycemic variability. As discussed in a re- tions with consideration of both individ- erations for clinical interpretation and cent consensus document, a report for- ualized SMBG and A1C results. care (17). To make these metrics more matted as shown in Fig. 6.1 can be actionable, standardized reports with generated (17). Published data sug- Glucose Assessment visual cues such as the Ambulatory Glu- gest a strong correlation between TIR cose Profile (see Fig. 6.1) are recommended and A1C, with a goal of 70% TIR aligning Recommendations (17) and may help the patient and the with an A1C of ;7% in two prospective 6.4 Standardized, single-page glu- provider interpret the data and use it to studies (18,19). cose reports with visual cues guide treatment decisions. Integrating such as the Ambulatory Glucose SMBG and CGM results into diabetes A1C GOALS Profile (AGP) should be consid- management can be useful for guiding ered as a standard printout for For glycemic goals in older adults, please medical nutrition therapy and physical “ ” all CGM devices. E refer to Section 12 Older Adults (https:// activity, preventing hypoglycemia, and doi.org/10.2337/dc20-S012).Forglycemic 6.5 Time in range (TIR) is associated adjusting medications. As recently re- goals in children, please refer to Section with the risk of microvascular viewed, while A1C is currently the primary 13 “Children and Adolescents” (https:// complications and should be an measure guiding glucose management doi.org/10.2337/dc20-S013).Forglycemic acceptable end point for clinical and a valuable marker of the risk of trials and can be used for assess- goalsAssociation in pregnant women, please refer to developing diabetes complications, the “ ment of glycemic control. Addi- Section 14 Management of Diabetes in Glucose Management Indicator (GMI) along ” tionally, time below target (,70 Pregnancy (https://doi.org/10.2337/dc20- with the other CGM metricsare suggested and ,54 mg/dL [3.9 and 3.0 S014). to provide for a much more personalized mmol/L]) and time above target diabetes management plan. The incorpo- (.180 mg/dL [10.0 mmol/L]) are Recommendations ration of these metrics into clinical prac- useful parameters for reevaluation 6.6 An A1C goal for many nonpreg- tice is in evolution, and optimization of of the treatment regimen. E nant adults of ,7% (53 mmol/mol) CGM terminology will evolve to suit pa- is appropriate. A ’ tient and provider needs. The patient s 6.7 On the basis of provider judge- fi For many people with diabetes, glucose speci c needsDiabetes and goals should dictate ment and patient preference, monitoring is key for the achievement of SMBG frequency and timing or the con- achievement of lower A1C levels glycemic targets. Major clinical trials of sideration of CGM use. Please refer to (such as ,6.5%) may be accept- “ ” insulin-treated patients have included Section 7 Diabetes Technology (https:// able if this can be achieved safely SMBG as part of multifactorial interven- doi.org/10.2337/dc20-S007) for a fuller without significant hypoglyce- fi tions to demonstrate the bene t of in- discussion of the use of SMBG and CGM. mia or other adverse effects of tensive glycemic control on diabetes treatment. C complications (16). SMBG is thus an in- Glucose Assessment Using 6.8 Less stringent A1C goals (such as tegral component of effective therapy of Continuous Glucose Monitoring ,8% [64 mmol/mol]) may be patients taking insulin. In recent years, With the advent of new technology, CGM appropriate for patients with a CGM has emerged as a complementary has evolved rapidly in both accuracy and history of severe hypoglycemia, method for the assessmentAmerican of glucose affordability. As such, many patients have limited life expectancy, advanced levels. Glucose monitoring allows pa- these data available to assist with both microvascular or macrovascular tients to evaluate their individual self-management and assessment by

Table 6.2—Standardized continuous glucose monitoring (CGM) metrics for clinical care 1. Number of days CGM device is worn (recommend 14 days) 2. Percentage of time CGM device is active (recommend 70% of data from 14 days) ©20193. Mean glucose 4. Glucose management indicator (GMI) 5. Glycemic variability (%CV) target #36%* 6. Time above range (TAR): % of readings and time .250 mg/dL (.13.9 mmol/L) Level 2 7. Time above range (TAR): % of readings and time 181–250 mg/dL (10.1–13.9 mmol/L) Level 1 8. Time in range (TIR): % of readings and time 70–180 mg/dL (3.9–10.0 mmol/L) In range 9. Time below range (TBR): % of readings and time 54–69 mg/dL (3.0–3.8 mmol/L) Level 1 10. Time below range (TBR): % of readings and time ,54 mg/dL (,3.0 mmol/L) Level 2 CGM, continuous glucose monitoring; CV, coefﬁcient of variation. *Some studies suggest that lower %CV targets (,33%) provide additional protection against hypoglycemia for those receiving insulin or sulfonylureas. Adapted from Battelino et al. (17). care.diabetesjournals.org Glycemic Targets S69

Association Figure 6.1—Sample Ambulatory Glucose Proﬁle (AGP) report. Adapted from Battelino et al. (17).

glycemic separation between the treat- low hypoglycemia risk with a long life complications, extensive comorbid ment groups diminished and disappeared expectancy. conditions, or long-standing dia- during follow-up. Given the substantially increased risk betes in whom the goal is difficult The Kumamoto Study (22) and UK of hypoglycemia in type 1 diabetes and to achieve despite diabetes self- Prospective Diabetes Study (UKPDS) with polypharmacy in type 2 diabetes, management education, appropri- (23,24) confirmed that intensive glyce- the risks of lower glycemic targets may ate glucose monitoring, and effi fi fective doses of multiple glucose- mic control signi cantlyDiabetes decreased rates outweigh the potential bene ts on lowering agents including insulin. of microvascular complications in pa- microvascular complications. Three land- B tients with short-duration type 2 diabe- mark trials (Action to Control Cardiovas- 6.9 Reassess glycemic targets over tes. Long-term follow-up of the UKPDS cular Risk in Diabetes [ACCORD], Action time based on the criteria in cohorts showed enduring effects of early in Diabetes and Vascular Disease: Pre- Fig. 6.2 or, in older adults, glycemic control on most microvascular terax and Diamicron MR Controlled Eval- Table 12.1. E complications (25). uation [ADVANCE], and Veterans Affairs Therefore, achieving A1C targets Diabetes Trial [VADT]) were conducted of ,7% (53 mmol/mol) has been shown to test the effects of near normalization A1C and Microvascular Complications to reduce microvascular complications of blood glucose on cardiovascular out- Hyperglycemia defines diabetes, and gly- of type 1 and type 2 diabetes when comes in individuals with long-standing cemic control is fundamentalAmerican to diabetes instituted early in the course of disease type 2 diabetes and either known car- management. The Diabetes Control and (26). Epidemiologic analyses of the DCCT diovascular disease (CVD) or high cardio- Complications Trial (DCCT) (16), a pro- (16) and UKPDS (27) demonstrate a cur- vascular risk. These trials showed that spective randomized controlled trial of lower A1C levels were associated with vilinear relationship between A1C and intensive (mean A1C about 7% [53 reduced onset or progression of some microvascular complications. Such anal- mmol/mol]) versus standard (mean A1C microvascular complications (28–30). yses suggest that, on a population level, about 9% [75 mmol/mol]) glycemic control The concerning mortality findings in the greatest number of complications in patients with type 1 diabetes, showed the ACCORD trial (31), discussed below, will be averted by taking patients from definitively that better glycemic control and the relatively intense efforts re- is associated©2019 with 50–76% reductions very poor control to fair/good control. quired to achieve near euglycemia should in rates of development and progres- These analyses also suggest that further also be considered when setting glycemic sion of microvascular (retinopathy, neu- lowering of A1C from 7% to 6% [53 mmol/mol targets for individuals with long-standing ropathy, and diabetic kidney disease) to 42 mmol/mol] is associated with fur- diabetes such as those studied in ACCORD, complications. Follow-up of the DCCT ther reduction in the risk of microvascular ADVANCE, and VADT. Findings from these cohorts in the Epidemiology of Diabetes complications, although the absolute risk studies suggest caution is needed in Interventions and Complications (EDIC) reductions become much smaller. The im- treating diabetes aggressively to near- study (20,21) demonstrated persistence plication of these findings is that there is no normal A1C goals in people with long- of these microvascular benefits over need to deintensify therapy for an individ- standing type 2 diabetes with or at two decades despite the fact that the ualwithanA1Cbetween6%and7%and significantriskofCVD.However, onthe S70 Glycemic Targets Diabetes Care Volume 43, Supplement 1, January 2020

basis of physician judgment and patient years of observational follow-up, those targets, therapeutic approaches, and preferences, select patients, especially originally randomized to intensive glyce- population characteristics (41). those with little comorbidity and long mic control had significant long-term Mortality findings in ACCORD (31) and life expectancy, may benefit from adopt- reductions in MI (15% with sulfonylurea subgroup analyses of VADT (42) suggest ing more intensive glycemic targets if or insulin as initial pharmacotherapy, that the potential risks of intensive gly- they can achieve it safely without hy- 33% with metformin as initial pharma- cemic control may outweigh its benefits poglycemia or significant therapeutic cotherapy) and in all-cause mortality in higher-risk patients. In all three trials, burden. (13% and 27%, respectively) (25). severe hypoglycemia was significantly ACCORD, ADVANCE, and VADT sug- more likely in participants who were A1C and Cardiovascular Disease gested no significant reduction in CVD randomly assigned to the intensive gly- Outcomes outcomes with intensive glycemic con- cemic control arm. Those patients with Cardiovascular Disease and Type 1 Diabetes trol in participants followed for shorter long duration of diabetes, a known history CVD is a more common cause of death durations (3.5–5.6 years) and who had of hypoglycemia, advanced atherosclero- than microvascular complications in pop- more advanced type 2 diabetes than sis, or advanced age/frailty may benefit ulations with diabetes. There is evidence UKPDS participants. All three trials from less aggressive targets (43,44). fi for a cardiovascular bene t of intensive were conducted in relatively older par- As discussed further below, severe glycemic control after long-term follow-up ticipants with longer known duration of hypoglycemia is a potent marker of of cohorts treated early in the course of diabetes (mean duration 8–11 years) and high absolute risk of cardiovascular type 1 diabetes. In the DCCT, there was a either CVD or multiple cardiovascular risk events and mortality (45). Providers trend toward lower risk of CVD events factors. The target A1C among intensive- should be vigilant in preventing hypo- with intensive control. In the 9-year control subjects was ,6% (42 mmol/mol) glycemiaAssociation and should not aggressively post-DCCT follow-up of the EDIC cohort, in ACCORD, ,6.5% (48 mmol/mol) in attempt to achieve near-normal A1C participants previously randomized to ADVANCE, and a 1.5% reduction in A1C levels in patients in whom such tar- fi the intensive arm had a signi cant 57% compared with control subjects in VADT, gets cannot be safely and reasonably reduction in the risk of nonfatal myo- with achieved A1C of 6.4% vs. 7.5% achieved. As discussed in Section 9 “Phar- cardial infarction (MI), stroke, or car- (46 mmol/mol vs. 58 mmol/mol) in macologic Approaches to Glycemic Treat- diovascular death compared with those ACCORD, 6.5% vs. 7.3% (48 mmol/mol ment”(https://doi.org/10.2337/dc20-S009), previously randomized to the standard vs. 56 mmol/mol) in ADVANCE, and 6.9% addition of specificsodium–glucose co- fi arm (32). The bene t of intensive gly- vs. 8.4% (52 mmol/mol vs. 68 mmol/mol) transporter 2 inhibitors (SGLT2i) or gluca- cemic control in this cohort with type 1 in VADT. Details of these studies are gon-like peptide 1 receptor agonists (GLP-1 diabetes has been shown to persist for reviewed extensively in “Intensive Gly- RA) that have demonstrated CVD benefit several decades (33) and to be associ- cemic ControlDiabetes and the Prevention of are recommended for use in patients with ated with a modest reduction in all- Cardiovascular Events: Implications of established CVD or indicators of high risk. cause mortality (34). the ACCORD, ADVANCE, and VA Diabetes As outlined in more detail in Section 9 Cardiovascular Disease and Type 2 Diabetes Trials” (38). “Pharmacologic Approaches to Glycemic In type 2 diabetes, there is evidence The glycemic control comparison in Treatment” (https://doi.org/10.2337/dc20- that more intensive treatment of glyce- ACCORD was halted early due to an S009) and Section 10 “Cardiovascular Dis- mia in newly diagnosed patients may increased mortality rate in the intensive ease and Risk Management” (https://doi reduce long-term CVD rates. In addi- compared with the standard treatment .org/10.2337/dc20-S010), the cardiovas- tion, data from the Swedish National arm (1.41% vs. 1.14% per year; hazard cular benefits of SGLT2i or GLP-1 RA are Diabetes Registry and Joint Asia Diabetes ratio 1.22 [95% CI 1.01–1.46]), with a not dependent upon A1C lowering, so Evaluation (JADE) demonstrate greater similar increase in cardiovascular deaths. initiationcanbeconsideredinpeoplewith proportions of people withAmerican diabetes be- Analysis of the ACCORD data did not type 2 diabetes and CVD independent of ing diagnosed at ,40 years of age and a identify a clear explanation for the ex- the current A1C or A1C goal. Based on demonstrably increased burden of heart cess mortality in the intensive treat- these considerations, the following two disease and years of life lost in people ment arm (31). strategies are offered (46): diagnosed at a younger age (35–37). Longer-term follow-up has shown no Thus, for prevention of both microvas- evidence of cardiovascular benefitor 1. If already on dual therapy or multiple cular and macrovascular complications harm in the ADVANCE trial (39). The glucose-lowering therapies and not of diabetes, there is a major call to end-stage renal disease rate was lower on an SGLT2i or GLP-1 RA, consider overcome©2019 therapeutic inertia and treat in the intensive treatment group over switching to one of these agents with fi to target for an individual patient (37). follow-up. However, 10-year follow-up of proven cardiovascular bene t. During the UKPDS, there was a 16% the VADT cohort (40) showed a reduction 2. Introduce SGLT2i or GLP-1 RA in pa- reduction in CVD events (combined fa- in the risk of cardiovascular events (52.7 tients with CVD at A1C goal for car- fi tal or nonfatal MI and sudden death) [control group] vs. 44.1 [intervention diovascular bene t. in the intensive glycemic control arm group] events per 1,000 person-years) Setting and Modifying A1C Goals that did not reach statistical signifi- with no benefit in cardiovascular or over- Numerous factors must be considered cance (P 5 0.052), and there was no all mortality. Heterogeneity of mortal- when setting glycemic targets. The ADA suggestion of benefit on other CVD out- ity effects across studies was noted, proposes general targets appropriate comes (e.g., stroke). However, after 10 which may reflect differences in glycemic for many patients but emphasizes the care.diabetesjournals.org Glycemic Targets S71

in Table 6.3. The recommendations include blood glucose levels that appear to correlate with achievement of an A1C of ,7% (53 mmol/mol). Pregnancy recommendations are discussed in more detail in Section 14 “Management of Diabetes in Pregnancy” (https://doi .org/10.2337/dc20-S014). The issue of preprandial versus postprandial SMBG targets is complex (48). Elevated postchallenge (2-h oral glucose tolerance test) glucose values have been associated with increased cardiovascular risk independent of fasting plasma glucose in some epidemiologic studies, but intervention trials have not shown postprandial glucose to be a cardiovascular risk factor independent of A1C. In subjects with diabetes, surrogate measures of vascular pathology, such as endothelialAssociation dysfunction, are negatively affectedbypostprandialhyperglycemia. It is clear that postprandial hyperglycemia, like preprandial hyperglycemia, contributes to elevated A1C levels, with Figure 6.2—Depicted are patient and disease factors used to determine optimal A1C targets. its relative contribution being greater at Characteristics and predicaments toward the left justify more stringent efforts to lower A1C; A1C levels that are closer to 7% (53 mmol/ 5 those toward the right suggest less stringent efforts. A1C 7% 53 mmol/mol. Adapted with mol). However, outcome studies have permission from Inzucchi et al. (47). clearly shown A1C to be the primary predictor of complications, and landmark importance of individualization based on Diabetes is a chronic disease that trials of glycemic control such as the DCCT key patient characteristics. Glycemic tar- progresses over decades.Diabetes Thus, a goal and UKPDS relied overwhelmingly on pre- gets must be individualized in the context that might be appropriate for an indi- prandial SMBG. Additionally, a random- of shared decision-making to address the vidual early in the course of the disease ized controlled trial in patients with needs and preferences of each patient may change over time. Newly diag- known CVD found no CVD benefitof and the individual characteristics that nosed patients and/or those without insulin regimens targeting postprandial influence risks and benefits of therapy comorbidities that limit life expectancy glucose compared with those targeting for each patient. may benefitfromintensivecontrolproven preprandial glucose (49). Therefore, it is The factors to consider in individual- to prevent microvascular complications. reasonable for postprandial testing to be izing goals are depicted in Fig. 6.2. Figure Both DCCT/EDIC and UKPDS demon- recommended for individuals who have 6.2 is not designed to be applied rigidly strated metabolic memory, or a legacy premeal glucose values within target but but to be used as a broad construct to effect, in which a finite period of intensive have A1C values above target. Measuring guide clinical decision-makingAmerican (47) and control yielded bene fits that extended for postprandial plasma glucose 1–2 h after engagein shared decision-making inboth decades after that control ended. Thus, the start of a meal and using treatments type 1 and type 2 diabetes. More strin- a finite period of intensive control to near- aimed at reducing postprandial plasma fi gent targets may be recommended if normal A1C may yield enduring bene ts glucose values to ,180mg/dL(10.0mmol/L) they can be achieved safely and with even if control is subsequently deintensi- may help to lower A1C. fi acceptable burden of therapy and if life ed as patient characteristics change. An analysis of data from 470 partici- Over time, comorbidities may emerge, pants in the ADAG study (237 with type 1 expectancy is sufficient to reap benefits decreasing life expectancy and thereby diabetes and 147 with type 2 diabetes) of stringent targets. Less stringent tar- ©2019 potential to reap benefits from intensive found that the glucose ranges high- gets (A1C up to 8% [64 mmol/mol]) may control. Also, with longer duration of lighted in Table 6.1 are adequate to be recommended if the life expectancy of disease, diabetes may become more meet targets and decrease hypoglycemia fi the patient is such that the bene ts of an difficult to control, with increasing risks (7,50). These findings support that pre- intensive goal may not be realized, or if and burdens of therapy. Thus, A1C tar- meal glucose targets may be relaxed the risks and burdens outweigh the po- gets should be reevaluated over time to without undermining overall glycemic tential benefits. Severe or frequent hy- balance the risks and benefits as patient control as measured by A1C. These poglycemia is an absolute indication for factors change. data prompted the revision in the the modification of treatment regimens, Recommended glycemic targets for ADA-recommended premeal glucose tar- including setting higher glycemic goals. many nonpregnant adults are shown get to 80–130 mg/dL (4.4–7.2 mmol/L) S72 Glycemic Targets Diabetes Care Volume 43, Supplement 1, January 2020

fi but did not affect the de nition of hy- Table 6.3—Summary of glycemic recommendations for many nonpregnant adults poglycemia. with diabetes A1C ,7.0% (53 mmol/mol)* HYPOGLYCEMIA Preprandial capillary plasma glucose 80–130 mg/dL* (4.4–7.2 mmol/L) Recommendations Peak postprandial capillary plasma glucose† ,180 mg/dL* (10.0 mmol/L) 6.10 Individuals at risk for hypogly- *More or less stringent glycemic goals may be appropriate for individual patients. Goals should be cemia should be asked about individualized based on duration of diabetes, age/life expectancy, comorbid conditions, known CVD or advanced microvascular complications, hypoglycemia unawareness, and individual patient symptomatic and asymptom- considerations. †Postprandial glucose may be targeted if A1C goals are not met despite reaching atic hypoglycemia at each en- preprandial glucose goals. Postprandial glucose measurements should be made 1–2 h after the counter. C beginning of the meal, generally peak levels in patients with diabetes. 6.11 In patients taking medication thatcanleadtohypoglycemia, investigate, screen, and assess If a patient has level 2 hypoglycemia at least several weeks in order to risk for or occurrence of un- without adrenergic or neuroglycopenic partially reverse hypoglycemia recognized hypoglycemia, con- symptoms, they likely have hypoglycemia unawareness and reduce risk of sidering that patients may unawareness (discussed further below). future episodes. A have hypoglycemia unaware- This clinical scenario warrants investiga- 6.16 Ongoing assessment of cogni- ness. C tion and review of the medical regimen. tive function is suggested with 6.12 Glucose (15–20 g) is the preferred Lastly, level 3 hypoglycemia is defined as a increased vigilance for hypogly- treatment for the conscious in- severe event characterized by altered cemia by the clinician, patient, dividual with blood glucose ,70 mentalAssociation and/or physical functioning and caregivers if low cognition mg/dL [3.9 mmol/L]), although that requires assistance from another or declining cognition is found. B any form of carbohydrate that person for recovery. contains glucose may be used. Symptoms of hypoglycemia include, Fifteen minutes after treatment, Hypoglycemia is the major limiting but are not limited to, shakiness, irrita- if SMBG shows continued hypo- factor in the glycemic management of bility, confusion, tachycardia, and hun- glycemia,thetreatmentshouldbe type 1 and type 2 diabetes. Recommen- ger. Hypoglycemia may be inconvenient repeated. Once SMBG returns to dations regarding the classification of or frightening to patients with diabetes. normal, the individual should con- hypoglycemia are outlined in Table 6.4 Level 3 hypoglycemia may be recognized sume a meal or snack to prevent (51–56). Level 1 hypoglycemia is defined or unrecognized and can progress to recurrence of hypoglycemia. B as a measurableDiabetes glucose concentration loss of consciousness, seizure, coma, 6.13 Glucagon should be prescribed ,70 mg/dL (3.9 mmol/L) but $54 mg/dL or death. It is reversed by administration for all individuals at increased risk (3.0 mmol/L). A blood glucose concen- of rapid-acting glucose or glucagon. Hy- of level 2 hypoglycemia, defined tration of 70 mg/dL (3.9 mmol/L) has poglycemia can cause acute harm to the as blood glucose ,54 mg/dL been recognized as a threshold for neu- person with diabetes or others, espe- (3.0 mmol/L), so it is available roendocrine responses to falling glucose cially if it causes falls, motor vehicle should it be needed. Caregivers, in people without diabetes. Because accidents, or other injury. Recurrent schoolpersonnel,orfamilymem- many people with diabetes demonstrate level 2 hypoglycemia and/or level 3 hy- bers of these individuals should impaired counterregulatory responses poglycemia is an urgent medical issue know where it is and when and to hypoglycemia and/or experience hy- andrequiresinterventionwithmedical how to administer it. Glucagon poglycemia unawareness, a measured regimen adjustment, behavioral inter- administration is notAmerican limited to glucose level ,70 mg/dL (3.9 mmol/L) is vention, and, in some cases, use of health care professionals, partic- considered clinically important, inde- technology to assist with hypoglycemia ularly with the availability of intra- pendent of the severity of acute hypo- prevention and identification (52,57–60). nasal and stable soluble glucagon glycemic symptoms. Level 2 hypoglycemia A large cohort study suggested that available in autoinjector pens. E (defined as a blood glucose concentration among older adults with type 2 diabetes, 6.14 Hypoglycemia unawareness or ,54 mg/dL [3.0 mmol/L]) is the thresh- a history of level 3 hypoglycemia was one or more episodes of level old at which neuroglycopenic symp- associated with greater risk of dementia 3 hypoglycemia should trigger toms begin to occur and requires immediate (61). Conversely, in a substudy of the ©2019hypoglycemia avoidance edu- action to resolve the hypoglycemic event. ACCORD trial, cognitive impairment at cation and reevaluation of the treatment regimen. E Table 6.4—Classification of hypoglycemia 6.15 Insulin-treated patients with hy- Glycemic criteria/description poglycemia unawareness, one level 3 hypoglycemic event, or Level 1 Glucose ,70 mg/dL (3.9 mmol/L) and $54 mg/dL (3.0 mmol/L) a pattern of unexplained level 2 Level 2 Glucose ,54 mg/dL (3.0 mmol/L) hypoglycemiashouldbeadvised Level 3 A severe event characterized by altered mental and/or physical status requiring to raise their glycemic targets to assistance for treatment of hypoglycemia strictly avoid hypoglycemia for Reprinted from Agiostratidou et al. (51). care.diabetesjournals.org Glycemic Targets S73

baseline or decline in cognitive function and hypoglycemia unawareness that per- use of glucagon, including where during the trial was significantly associ- sists despite medical treatment, human the glucagon product is kept and ated with subsequent episodes of level islet transplantation may be an option, when and how to administer. An in- 3 hypoglycemia (62). Evidence from but the approach remains experimental dividual does not need to be a health DCCT/EDIC, which involved adolescents (72,73). care professional to safely administer and younger adults with type 1 diabetes, In 2015, the ADA changed its prepran- glucagon. In addition to traditional glu- foundnoassociationbetweenfre- dial glycemic target from 70–130 mg/dL cagon injection powder that requires quency of level 3 hypoglycemia and (3.9–7.2 mmol/L) to 80–130 mg/dL (4.4– reconstitution prior to injection, intra- cognitive decline (63), as discussed in 7.2 mmol/L). This change reflects the nasal glucagon and glucagon solution Section 13 “Children and Adolescents” results of the ADAG study, which dem- for subcutaneous injection recently re- (https://doi.org/10.2337/dc20-S013). onstrated that higher glycemic targets ceived U.S. Food and Drug Administra- Studiesofratesoflevel3hypoglycemia corresponded to A1C goals (7). An addition approval. Care should be taken to that rely on claims data for hospitaliza- tional goal of raising the lower range of ensure that glucagon products are not tion, emergency department visits, and the glycemic target was to limit over- expired. ambulance use substantially underesti- treatment and provide a safety margin mate rates of level 3 hypoglycemia (64) in patients titrating glucose-lowering Hypoglycemia Prevention yet find high burden of hypoglycemia in drugs such as insulin to glycemic targets. Hypoglycemia prevention is a critical adults over 60 years of age in the com- component of diabetes management. munity (65). African Americans are at Hypoglycemia Treatment SMBG and, for some patients, CGM substantially increased risk of level 3 hy- Providers should continue to counsel are essential tools to assess therapy poglycemia (65,66). In addition to age patients to treat hypoglycemia with and detectAssociation incipient hypoglycemia. Pa- and race, other important risk factors fast-acting carbohydrates at the hypo- tients should understand situations that found in a community-based epidemi- glycemia alert value of 70 mg/dL increase their risk of hypoglycemia, such ologic cohort of older black and white (3.9 mmol/L) or less. This should be as when fasting for tests or procedures, adultswithtype 2 diabetes include insulin reviewed at each patient visit. Hypogly- when meals are delayed, during and after use, poor or moderate versus good glycemia treatment requires ingestion of the consumption of alcohol, during and cemic control, albuminuria, and poor glucose- or carbohydrate-containing foods after intense exercise, and during sleep. cognitive function (65). Level 3 hypo- (74–76). The acute glycemic response Hypoglycemia may increase the risk of glycemia was associated with mortal- correlates better with the glucose con- harm to self or others, such as with ity in participants in both the standard tent of food than with the carbohy- driving. Teaching people with diabetes and the intensive glycemia arms of the drate content of food. Pure glucose is the to balance insulin use and carbohydrate ACCORD trial, but the relationships be- preferred treatment,Diabetes but any form of intake and exercise are necessary, but tween hypoglycemia, achieved A1C, and carbohydrate that contains glucose will these strategies are not always sufficient treatment intensity were not straightfor- raise blood glucose. Added fat may retard for prevention. ward. An association of level 3 hypo- and then prolong the acute glycemic In type 1 diabetes and severely insulin glycemia with mortality was also found response. In type 2 diabetes, ingested deficient type 2 diabetes, hypoglycemia in the ADVANCE trial (67). An association protein may increase insulin response unawareness (or hypoglycemia-associated between self-reported level 3 hypoglyce- without increasing plasma glucose con- autonomic failure) can severely com- mia and 5-year mortality has also been centrations (77). Therefore, carbohy- promise stringent diabetes control and reported in clinical practice (68) drate sourceshigh in protein should not quality of life. This syndrome is char- Young children with type 1 diabetes be used to treat or prevent hypogly- acterized by deficient counterregu- and the elderly, including those with cemia. Ongoing insulin activity or latory hormone release, especially in type 1 and type 2 diabetesAmerican (61,69), insulin secretagogues may lead to older adults, and a diminished auto- are noted as particularly vulnerable to recurrent hypoglycemia unless more nomic response, which are both risk hypoglycemia because of their reduced food is ingested after recovery. Once factors for, and caused by, hypoglyce- ability to recognize hypoglycemic symp- the glucose returns to normal, the in- mia. A corollary to this “vicious cycle” is toms and effectively communicate their dividual should be counseled to eat a that several weeks of avoidance of needs. Individualized glucose targets, meal or snack to prevent recurrent hypoglycemia has been demonstrated patient education, dietary intervention hypoglycemia. to improve counterregulation and hy- (e.g., bedtime snack to prevent overnight Glucagon poglycemiaawarenessin manypatients hypoglycemia©2019 when specifi cally needed The use of glucagon is indicated for (78). Hence, patients with one or more to treat low blood glucose), exercise the treatment of hypoglycemia in peo- episodes of clinically significant hypo- management, medication adjustment, ple unable or unwilling to consume glycemia may benefitfromatleast glucose monitoring, and routine clinical carbohydrates by mouth. Those in close short-term relaxation of glycemic tar- surveillance may improve patient out- contact with, or having custodial care gets and availability of glucagon (79). comes (70). CGM with automated low of, people with hypoglycemia-prone di- glucose suspend has been shown to be abetes (family members, roommates, Use of CGM Technology in effective in reducing hypoglycemia in school personnel, childcare providers, Hypoglycemia Prevention type 1 diabetes (71). For patients with correctional institution staff, or cow- With the advent of CGM and CGM- type1diabetes withlevel 3hypoglycemia orkers) should be instructed on the assisted pump therapy, there has been a S74 Glycemic Targets Diabetes Care Volume 43, Supplement 1, January 2020

promise of alarm-based prevention of hyperglycemia requires temporary ad- 11. Rohlfing C, Hanson S, Little RR. Measure- hypoglycemia (80,81). To date, there justment of the treatment regimen ment of hemoglobin A1c in patients with sickle have been six randomized controlled and immediate interaction with the di- cell trait. JAMA 2017;317:2237 12. Wheeler E, Leong A, Liu C-T, et al.; EPIC-CVD trials in adults with type 1 diabetes abetes care team. The patient treated Consortium; EPIC-InterAct Consortium; Lifelines and seven in adults and children with with noninsulin therapies or medical Cohort Study. Impact of common genetic deter- type 1 diabetes using real-time CGM. nutrition therapy alone may require in- minants of Hemoglobin A1c on type 2 diabetes These studies had differing A1C at entry sulin. Adequate fluid and caloric intake risk and diagnosis in ancestrally diverse popu- and differing primary end points and thus must be ensured. Infection or dehydra- lations: A transethnic genome-wide meta- analysis. PLoS Med 2017;14:e1002383 must be interpreted carefully. Real-time tion is more likely to necessitate hospi- 13. Wilson DM, Kollman; Diabetes Research in CGM studies can be divided into studies talization of the person with diabetes Children Network (DirecNet) Study Group. Re- with elevated A1C with the primary end than the person without diabetes. lationship of A1C to glucose concentrations in point of A1C reduction and studies with A physician with expertise in diabe- children with type 1 diabetes: assessments by A1C near target with the primary end tes management should treat the hos- high-frequency glucose determinations by sensors. Diabetes Care 2008;31:381–385 point of reduction in hypoglycemia pitalized patient. For further information 14. Buse JB, Kaufman FR, Linder B, Hirst K, El (81–97). In people with type 1 and on the management of diabetic keto- Ghormli L, Willi S; HEALTHY Study Group. Di- type 2 diabetes with A1C above target, acidosis and the nonketotic hyperglyce- abetes screening with hemoglobin A1c versus CGM improved A1C between 0.3% and mic hyperosmolar state, please refer to fasting plasma glucose in a multiethnic middle- – 0.6%. For studies targeting hypoglyce- the ADA consensus report “Hyperglyce- school cohort. Diabetes Care 2013;36:429 435 15. Kamps JL, Hempe JM, Chalew SA. Racial mia, most studies demonstrated a sig- mic Crises in Adult Patients With Diabe- disparity in A1C independent of mean blood nificant reduction in time spent between tes” (105). glucose in childrenwith type 1 diabetes. Diabetes 54 and 70 mg/dL. No study to date has CareAssociation 2010;33:1025–1027 reported a decrease in level 3 hypogly- References 16. Diabetes Control and Complications Trial Research Group. The effect of intensive treat- cemia. In a single study using intermit- 1. Laiteerapong N, Ham SA, Gao Y, et al. The ment of diabetes on the development and tently scanned CGM, adults with type 1 legacy effect in type 2 diabetes: impact of early glycemic control on future complications (the progression of long-term complications in diabetes with A1C near goal and im- Diabetes & Aging Study). Diabetes Care 2019;42: insulin-dependent diabetes mellitus. N Engl J paired awareness of hypoglycemia demon- 416–426 Med 1993;329:977–986 stratednochangeinA1Canddecreased 2. Stratton IM, Adler AI, Neil HAW, et al. Asso- 17. Battelino T, Danne T, Bergenstal RM, et al. Clinical targets for continuous glucose monitor- level 2 hypoglycemia (88). For people ciation of glycaemia with macrovascular and ing data interpretation: recommendations from with type 2 diabetes, studies examining microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. the international consensus on time in range. the impact of CGM on hypoglycemic BMJ 2000;321:405–412 Diabetes Care 2019;42:1593–1603 events are limited; a recent meta- 3. Little RR, Rohlfing CL, Sacks DB; National 18. Beck RW, Bergenstal RM, Cheng P, et al. The analysis does not reflect a significant GlycohemoglobinDiabetes Standardization Program relationships between time in range, hypergly- (NGSP) Steering Committee. Status of hemoglo- cemia metrics, and HbA1c. J Diabetes Sci Technol impact on hypoglycemic events in type 2 2019;13:614–626 bin A1c measurement and goals for improve- diabetes (98), whereas improvements in ment:fromchaostoorderforimprovingdiabetes 19. Vigersky RA, McMahon C. The relationship A1C were observed in most studies care. Clin Chem 2011;57:205–214 of hemoglobin A1C to time-in-range in patients (98–104). Overall, real-time CGM ap- 4. Jovanovicˇ L, Savas H, Mehta M, Trujillo A, with diabetes. Diabetes Technol Ther 2019;21: pears to be a useful tool for decreasing Pettitt DJ. Frequent monitoring of A1C during 81–85 20. Diabetes Control and Complications Trial time spent in hypoglycemia range in pregnancy as a treatment tool to guide therapy. Diabetes Care 2011;34:53–54 (DCCT)/Epidemiology of Diabetes Interventions people with impaired awareness. 5. Beck RW, ConnorCG, Mullen DM,WesleyDM, and Complications (EDIC) Research Group. Effect Bergenstal RM. The fallacy of average: how using of intensive diabetes therapy on the progression INTERCURRENT ILLNESS HbA1c alone to assess glycemic control can be of diabetic retinopathy in patients with type 1 For further information on management misleading. Diabetes Care 2017;40:994–999 diabetes: 18 years of follow-up in the DCCT/EDIC. Diabetes 2015;64:631–642 of patients with hyperglycemiaAmerican in the 6. Nathan DM, Kuenen J, Borg R, Zheng H, Schoenfeld D, Heine RJ; A1c-Derived Average 21. Lachin JM, Genuth S, Cleary P, Davis MD, hospital, please refer to Section 15 Glucose Study Group. Translating the A1C assay Nathan DM; Diabetes Control and Complications “Diabetes Care in the Hospital” (https:// into estimated average glucose values [published Trial/Epidemiology of Diabetes Interventions doi.org/10.2337/dc20-S015). correction appears in Diabetes Care 2009;32: and Complications Research Group. Retinopathy Stressful events (e.g., illness, trauma, 207]. Diabetes Care 2008;31:1473–1478 and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy surgery, etc.) may worsen glycemic con- 7. Wei N, Zheng H, Nathan DM. Empirically establishing blood glucose targets to achieve [published correction appears in N Engl J Med trol and precipitate diabetic ketoacidosis HbA1c goals. Diabetes Care 2014;37:1048–1051 2000;342:1376]. N Engl J Med 2000;342:381–389 or nonketotic hyperglycemic hyperos- 8. Selvin E. Are there clinical implications of 22. Ohkubo Y, Kishikawa H, Araki E, et al. In- ©2019 racial differences in HbA ? A difference, to be tensive insulin therapy prevents the progression molar state, life-threatening conditions 1c that require immediate medical care to a difference, must make a difference. Diabetes of diabetic microvascular complications in Jap- – anese patients with non-insulin-dependent di- prevent complications and death. Any Care 2016;39:1462 1467 9. Bergenstal RM, Gal RL, Connor CG, et al.; T1D abetes mellitus: a randomized prospective 6-year condition leading to deterioration in Exchange Racial Differences Study Group. Ra- study. Diabetes Res Clin Pract 1995;28:103–117 glycemic control necessitates more fre- cial differences in the relationship of glucose 23. UK Prospective Diabetes Study (UKPDS) quent monitoring of blood glucose; concentrations and hemoglobin A1c levels. Ann Group. Effect of intensive blood-glucose control ketosis-prone patients also require urine Intern Med 2017;167:95–102 with metformin on complications in overweight 10. Lacy ME, Wellenius GA, Sumner AE, et al. patients with type 2 diabetes (UKPDS 34). Lancet or blood ketone monitoring. If accom- Association of sickle cell trait with hemoglobin 1998;352:854–865 panied by ketosis, vomiting, or alteration A1c in African Americans. JAMA 2017;317:507– 24. UK Prospective Diabetes Study (UKPDS) in the level of consciousness, marked 515 Group. Intensive blood-glucose control with care.diabetesjournals.org Glycemic Targets S75

sulphonylureas or insulin compared with con- its relation to glycaemic control: a nationwide Control and Complications Trial (DCCT) on pe- ventional treatment and risk of complications in observational study. Diabetes Obes Metab. 1 ripheral neuropathy in type 1 diabetes during patients with type 2 diabetes (UKPDS 33). Lancet October 2019 [Epub ahead of print]. DOI: the Epidemiology of Diabetes Interventions 1998;352:837–853 10.1111/dom.13885 and Complications (EDIC) study. Diabetes Care 25. Holman RR, Paul SK, Bethel MA, Matthews 38. Skyler JS, Bergenstal R, Bonow RO, et al.; 2010;33:1090–1096 DR, Neil HAW. 10-year follow-up of intensive American Diabetes Association; American Col- 51. Agiostratidou G, Anhalt H, Ball D, et al. glucose control in type 2 diabetes. N Engl J Med lege of Cardiology Foundation; American Heart Standardizing clinically meaningful outcome 2008;359:1577–1589 Association. Intensive glycemic control and the measures beyond HbA1c for type 1 diabetes: 26. Lind M, Pivodic A, Svensson A-M, Olafsd´ ottir´ prevention of cardiovascular events: implica- a consensus report of the American Association AF, Wedel H, Ludvigsson J. HbA1c level as a risk tions of the ACCORD, ADVANCE, and VA diabetes of Clinical Endocrinologists, the American Asso- factor for retinopathy and nephropathy in children trials: a position statement of the American ciation of Diabetes Educators, the American and adults with type 1 diabetes: Swedish pop- Diabetes Association and a scientific statement Diabetes Association, the Endocrine Society, ulation based cohort study. BMJ 2019;366:l4894 of the American College of Cardiology Founda- JDRF International, The Leona M. and Harry B. 27. Adler AI, Stratton IM, Neil HAW, et al. tion and the American Heart Association. Di- Helmsley Charitable Trust, the Pediatric Endo- Association of systolic blood pressure with mac- abetes Care 2009;32:187–192 crine Society, and the T1D Exchange. Diabetes rovascular and microvascular complications of 39. Zoungas S, Chalmers J, Neal B, et al.; ADVANCE- Care 2017;40:1622–1630 type 2 diabetes (UKPDS 36): prospective obser- ON Collaborative Group. Follow-up of blood- 52. Lamounier RN, Geloneze B, Leite SO, et al.; vational study. BMJ 2000;321:412–419 pressure lowering and glucose control in type 2 HAT Brazil study group. Hypoglycemia incidence 28. Duckworth W, Abraira C, Moritz T, et al.; diabetes. N Engl J Med 2014;371:1392–1406 and awareness among insulin-treated patients VADT Investigators. Glucose control and vascular 40. Hayward RA, Reaven PD, Wiitala WL, et al.; with diabetes: the HAT study in Brazil. Diabetol complications in veterans with type 2 diabetes. VADT Investigators. Follow-up of glycemic con- Metab Syndr 2018;10:83 N Engl J Med 2009;360:129–139 trol and cardiovascular outcomes in type 2 di- 53. Li P, Geng Z,Ladage VP,Wu J, Lorincz I,Doshi JA. 29. Patel A, MacMahon S, Chalmers J, et al.; abetes. N Engl J Med 2015;372:2197–2206 Early hypoglycaemia and adherence after basal ADVANCE Collaborative Group. Intensive blood 41. Turnbull FM, Abraira C, Anderson RJ, et al.; insulin initiation in a nationally representative sam- glucose control and vascular outcomes in pa- Control Group. Intensive glucose control and ple of MedicareAssociation beneficiaries with type 2 diabetes. tients with type 2 diabetes. N Engl J Med 2008; macrovascular outcomes in type 2 diabetes Diabetes Obes Metab. 12 July 2019 [Epub ahead of 358:2560–2572 [published correction appears in Diabetologia print]. DOI: 10.1111/dom.13832 30. Ismail-Beigi F, Craven T, Banerji MA, et al.; 2009;52:2470]. Diabetologia 2009;52:2288– 54. Shivaprasad C, Aiswarya Y, Kejal S, et al. ACCORD trial group. Effect of intensive treat- 2298 Comparison of CGM-derived measures of glyce- ment of hyperglycaemia on microvascular out- 42. Duckworth WC, Abraira C, Moritz TE, et al.; mic variability between pancreatogenic diabetes comes in type 2 diabetes: an analysis of the Investigators of the VADT. The duration of di- and type 2 diabetes mellitus. J Diabetes Sci ACCORDrandomised trial. Lancet 2010;376:419– abetes affects the response to intensive glu- Technol. 7 July 2019 [Epub ahead of print]. 430 cose control in type 2 subjects: the VA Diabetes DOI: 10.1177/1932296819860133 31. Gerstein HC, Miller ME, Byington RP, et al.; Trial. J Diabetes Complications 2011;25:355–361 55. Hendrieckx C, Ivory N, Singh H, Frier BM, Action to Control Cardiovascular Risk in Diabetes 43. Lipska KJ, Ross JS, Miao Y, Shah ND, Lee SJ, Speight J. Impact of severe hypoglycaemia on Study Group. Effects of intensive glucose low- Steinman MA. Potential overtreatment of di- psychological outcomes in adults with type 2 ering in type 2 diabetes. N Engl J Med 2008;358: abetes mellitus in older adults with tight glycemic diabetes: a systematic review. Diabet Med 2019; 2545–2559 control. JAMA InternDiabetes Med 2015;175:356–362 36:1082 –1091 32. Nathan DM, Cleary PA, Backlund J-YC, et al.; 44. Vijan S, Sussman JB, Yudkin JS, Hayward RA. 56. Yang W, Ma J, Yuan G, et al. Determining the Diabetes Control and Complications Trial/ Effectof patients’ risks andpreferences on health optimal fasting glucose target for patients with Epidemiology of Diabetes Interventions and gains with plasma glucose level lowering in type 2 type 2 diabetes: results of the multicentre, open- Complications (DCCT/EDIC) Study Research Group. diabetes mellitus. JAMA Intern Med 2014;174: label, randomized-controlled FPG GOAL trial. Intensive diabetes treatment and cardiovascular 1227–1234 Diabetes Obes Metab 2019;21:1973–1977 disease in patients with type 1 diabetes. N Engl J 45. LeeAK, WarrenB,LeeCJ, etal.The association 57. Amiel SA, Choudhary P, Jacob P, et al. Hypo- Med 2005;353:2643–2653 of severe hypoglycemia with incident cardiovas- glycaemia Awareness Restoration Programme for 33. Nathan DM, Zinman B, Cleary PA, et al.; cular events and mortality in adults with type 2 People with Type 1 Diabetes and Problematic Diabetes Control and Complications Trial/ diabetes. Diabetes Care 2018;41:104–111 HypoglycaemiaPersistingDespiteOptimisedSelf- Epidemiology of Diabetes Interventions and 46. Davies MJ, D’Alessio DA, Fradkin J, et al. care (HARPdoc): protocol for a group randomised Complications (DCCT/EDIC) Research Group. Management of hyperglycemia in type 2 diabe- controlled trial of a novel intervention addressing Modern-day clinical course of type 1 diabetes tes, 2018. A consensus report by the American cognitions. BMJ Open 2019;9:e030356 mellitus after 30 years’ duration:American the diabetes Diabetes Association (ADA) and the European 58. Harris SM, Joyce H, Miller A, Connor C, Amiel control and complications trial/epidemiology of Association for the Study of Diabetes (EASD). SA, Mulnier H. The attitude of healthcare pro- diabetes interventions and complications and Diabetes Care 2018;41:2669–2701 fessionalsplaysanimportantroleintheuptakeof Pittsburgh epidemiology of diabetes complica- 47. Inzucchi SE, Bergenstal RM, Buse JB, et al. diabetes self-management education: analysis of tions experience (1983-2005). Arch Intern Med Management of hyperglycemia in type 2 diabe- the Barriers to Uptake of Type 1 Diabetes Ed- 2009;169:1307–1316 tes, 2015: a patient-centered approach: update ucation (BUD1E) study survey. Diabet Med 2018; 34. Orchard TJ, Nathan DM, Zinman B, et al.; to a position statement of the American Diabetes 61:1189–1196 Writing Group for the DCCT/EDIC Research Association and the European Association for 59. Choudhary P, Amiel SA. Hypoglycaemia in Group. Association between 7 years of intensive the Study of Diabetes. Diabetes Care 2015;38: type 1 diabetes: technological treatments, their treatment of type 1 diabetes and long-term 140–149 limitations and the place of psychology. Diabe- mortality.©2019 JAMA 2015;313:45–53 48. American Diabetes Association. Postpran- tologia 2018;61:761–769 35. Yeung RO, Zhang Y, Luk A, et al. Metabolic dial blood glucose. Diabetes Care 2001;24: 60. Hopkins D, Lawrence I, Mansell P, et al. Improved profiles and treatment gaps in young-onset 775–778 biomedical and psychological outcomes 1 year after type 2 diabetes in Asia (the JADE programme): 49. Raz I, Wilson PWF, Strojek K, et al. Effects of structured education in flexible insulin therapy for a cross-sectional study of a prospective cohort. prandial versus fasting glycemia on cardiovas- people with type 1 diabetes: the U.K. DAFNE expe- Lancet Diabetes Endocrinol 2014;2:935–943 cular outcomes in type 2 diabetes: the HEART2D rience. Diabetes Care 2012;35:1638–1642 36. Sattar N, Rawshani A, Franzen´ S, et al. Age at trial. Diabetes Care 2009;32:381–386 61. Whitmer RA, Karter AJ, Yaffe K, Quesenberry diagnosis of type 2 diabetes mellitus and asso- 50. Albers JW, Herman WH, Pop-Busui R, et al.; CP Jr, Selby JV. Hypoglycemic episodes and risk ciations with cardiovascular and mortality risks. Diabetes Control and Complications Trial/ of dementia in older patients with type 2 dia- Circulation 2019;139:2228–2237 Epidemiology of Diabetes Interventions and betes mellitus. JAMA 2009;301:1565–1572 37. Zabala A, Darsalia V, Holzmann MJ, et al. Risk Complications Research Group. Effect of prior 62. Punthakee Z, Miller ME, Launer LJ, et al.; of first stroke in people with type 2 diabetes and intensive insulin treatment during the Diabetes ACCORD Group of Investigators; ACCORD-MIND S76 Glycemic Targets Diabetes Care Volume 43, Supplement 1, January 2020

Investigators. Poor cognitive function and risk of 78. Cryer PE. Diverse causes of hypoglycemia- with insulin pump therapy: a randomised con- severe hypoglycemia in type 2 diabetes: post associated autonomic failure in diabetes. N Engl J trolled trial. Diabetologia 2012;55:3155–3162 hoc epidemiologic analysis of the ACCORD trial. Med 2004;350:2272–2279 92. Deiss D, Bolinder J, Riveline J-P, et al. Im- Diabetes Care 2012;35:787–793 79. Mitchell BD, He X, Sturdy IM, Cagle AP, Settles proved glycemic control in poorly controlled 63. Jacobson AM, Musen G, Ryan CM, et al.; JA. Glucagon prescription patternsinpatientswith patients with type 1 diabetes using real-time Diabetes Control and Complications Trial/ either type 1 or 2 diabetes with newly prescribed continuous glucose monitoring. Diabetes Care Epidemiology of Diabetes Interventions and Com- insulin. Endocr Pract 2016;22:123–135 2006;29:2730–2732 plications Study Research Group. Long-term effect 80. Hermanns N, Heinemann L, Freckmann G, 93. Tamborlane WV, Beck RW, Bode BW, et al.; of diabetes and its treatment on cognitive func- Waldenmaier D, Ehrmann D. Impact of CGM on Juvenile Diabetes Research Foundation Continu- tion. N Engl J Med 2007;356:1842–1852 the management of hypoglycemia problems: ous Glucose Monitoring Study Group. Continuous 64. Karter AJ, Moffet HH, Liu JY, Lipska KJ. overview and secondary analysis of the HypoDE glucose monitoring and intensive treatment of Surveillance of hypoglycemiadlimitations of study. J Diabetes Sci Technol 2019;13:636–644 type 1 diabetes. N Engl J Med 2008;359:1464–1476 emergency department and hospital utilization 81. Heinemann L, Freckmann G, Ehrmann D, 94. O’Connell MA, Donath S, O’Neal DN, et al. data. JAMA Intern Med 2018;178:987–988 et al. Real-time continuous glucose monitoring Glycaemic impact of patient-led use of sensor-guided 65. Lee AK, Lee CJ, Huang ES, Sharrett AR, Coresh in adults with type 1 diabetes and impaired pump therapy in type 1 diabetes: a randomised J, Selvin E. Risk factors for severe hypoglycemia in hypoglycaemia awareness or severe hypoglycae- controlled trial. Diabetologia 2009;52:1250–1257 black and white adults with diabetes: the Ath- mia treated with multiple daily insulin injections 95. Beck RW, Hirsch IB, Laffel L, et al.; Juvenile erosclerosis Risk in Communities (ARIC) study. (HypoDE): a multicentre, randomised controlled Diabetes Research Foundation Continuous Glu- Diabetes Care 2017;40:1661–1667 trial. Lancet 2018;391:1367–1377 cose Monitoring Study Group. The effect of con- 66. Karter AJ, Lipska KJ, O’Connor PJ, et al.; 82. Beck RW, Riddlesworth T, Ruedy K, et al. tinuous glucose monitoring in well-controlled SUPREME-DM Study Group. High rates of severe Effect of Continuous glucose monitoring on type 1 diabetes. Diabetes Care 2009;32: hypoglycemia among African American patients glycemic control in adults with type 1 diabetes 1378–1383 with diabetes: the surveillance, prevention, and using insulin injections: the DIAMOND random- 96. Battelino T, Phillip M, Bratina N, Nimri R, Management of Diabetes Mellitus (SUPREME- ized clinical trial. JAMA 2017;317:371–378 Oskarsson P, Bolinder J. Effect of continuous DM) network. J Diabetes Complications 2017;31: 83. Lind M, Polonsky W, Hirsch IB, et al. Con- glucoseAssociation monitoring on hypoglycemia in type 1 869–873 tinuous glucose monitoring vs conventional diabetes. Diabetes Care 2011;34:795–800 67. Zoungas S, Patel A, Chalmers J, et al.; AD- therapy for glycemic control in adults with 97. Ludvigsson J, Hanas R. Continuous subcuta- VANCE Collaborative Group. Severe hypoglyce- type1 diabetes treatedwith multipledailyinsulin neous glucose monitoring improved metabolic mia and risks of vascular events and death. N Engl injections: the GOLD randomized clinical trial. control in pediatric patients with type 1 diabetes: J Med 2010;363:1410–1418 JAMA 2017;317:379–387 a controlled crossover study. Pediatrics 2003; 68. McCoy RG, Van Houten HK, Ziegenfuss JY, Shah 84. Sequeira PA, Montoya L, Ruelas V, et al. 111:933–938 ND,WermersRA,SmithSA.Increasedmortalityof Continuous glucose monitoring pilot in low- 98. Dicembrini I, Mannucci E, Monami M, Pala L. patients with diabetes reporting severe hypogly- income type 1 diabetes patients. Diabetes Technol Impact of technology on glycemic control in cemia. Diabetes Care 2012;35:1897–1901 Ther 2013;15:855–858 type 2 diabetes: a meta-analysis of randomized 69. DuBose SN, Weinstock RS, Beck RW, et al. 85. Tumminia A, Crimi S, Sciacca L, et al. Efficacy trials on continuous glucose monitoring and Hypoglycemia in older adults with type 1 di- of real-time continuous glucose monitoring on continuous subcutaneous insulin infusion. Di- abetes. Diabetes Technol Ther 2016;18:765–771 glycaemic control and glucose variability in type 1 abetes Obes Metab. 1 August 2019 [Epub ahead 70. Seaquist ER, Anderson J, Childs B, et al. diabetic patientsDiabetes treated with either insulin of print]. DOI: 10.1111/dom.13845 Hypoglycemia and diabetes: a report of a work- pumps or multiple insulin injection therapy: 99. Beck RW, Riddlesworth TD, Ruedy K, et al.; group of the American Diabetes Association and arandomized controlled crossovertrial. Diabetes DIAMOND Study Group. Continuous glucose the Endocrine Society. Diabetes Care 2013;36: Metab Res Rev 2015;31:61–68 monitoring versus usual care in patients with 1384–1395 86. Bolinder J, Antuna R, Geelhoed-Duijvestijn P, type 2 diabetes receiving multiple daily insulin 71. Bergenstal RM, Klonoff DC, Garg SK, et al.; Kroger¨ J, Weitgasser R. Novel glucose-sensing injections: a randomized trial. Ann Intern Med ASPIRE In-Home Study Group. Threshold-based technology and hypoglycaemia in type 1 diabe- 2017;167:365–374 insulin-pump interruption for reduction of hy- tes: a multicentre, non-masked, randomised 100. Ehrhardt NM, Chellappa M, Walker MS, poglycemia. N Engl J Med 2013;369:224–232 controlled trial. Lancet 2016;388:2254–2263 Fonda SJ, Vigersky RA. The effect of real-time 72. Hering BJ, Clarke WR, Bridges ND, et al.; 87. Hermanns N, Schumann B, Kulzer B, Haak T. continuous glucose monitoring on glycemic con- Clinical Islet Transplantation Consortium. Phase The impact of continuous glucose monitoring on trol in patients with type 2 diabetes mellitus. 3 trial of transplantation of human islets in type 1 low interstitial glucose values and low blood J Diabetes Sci Technol 2011;5:668–675 diabetes complicated by severe hypoglycemia. glucose values assessed by point-of-care blood 101. Haak T, Hanaire H, Ajjan R, Hermanns N, Diabetes Care 2016;39:1230–1240 glucose meters: results of a crossover trial. J Riveline J-P, Rayman G. Flash glucose-sensing tech- 73. Harlan DM. Islet transplantationAmerican for hypo- Diabetes Sci Technol 2014;8:516–522 nology as a replacement for blood glucose mon- glycemia unawareness/severe hypoglycemia: ca- 88. Reddy M, Jugnee N, El Laboudi A, Spanudakis itoring for the management of insulin-treated veat emptor. Diabetes Care 2016;39:1072–1074 E, Anantharaja S, Oliver N. A randomized con- type 2 diabetes: a multicenter, open-label random- 74. McTavish L, Wiltshire E. Effective treatment trolled pilot study of continuous glucose moni- ized controlled trial. Diabetes Ther 2017;8:55–73 of hypoglycemia in children with type 1 diabetes: toring and flash glucosemonitoring inpeople with 102. Yoo HJ, An HG, Park SY, et al. Use of a real a randomized controlled clinical trial. Pediatr type 1 diabetes and impaired awareness of time continuous glucose monitoring system as a Diabetes 2011;12(4pt2):381–387 hypoglycaemia. Diabet Med 2018;35:483–490 motivational device for poorly controlled type 2 75. McTavish L, Corley B, Weatherall M, 89. Riddlesworth T, Price D, Cohen N, Beck RW. diabetes. Diabetes Res Clin Pract 2008;82:73–79 Wiltshire E, Krebs JD. Weight-based carbohy- Hypoglycemic event frequency and the effect of 103. Garg S, Zisser H, Schwartz S, et al. Improve- drate©2019 treatment of hypoglycaemia in people with continuous glucose monitoring in adults with ment in glycemic excursions with a transcuta- type 1 diabetes using insulin pump therapy: type 1 diabetes using multiple daily insulin neous, real-time continuous glucose sensor: a randomized crossover clinical trial. Diabet injections. Diabetes Ther 2017;8:947–951 a randomized controlled trial. Diabetes Care Med 2018;35:339–346 90. van Beers CAJ, DeVries JH, Kleijer SJ, et al. 2006;29:44–50 76. Georgakopoulos K, Katsilambros N, Fragaki Continuous glucose monitoring for patients 104. New JP, Ajjan R, Pfeiffer AFH, Freckmann G. M, et al. Recovery from insulin-induced hypo- with type 1 diabetes and impaired awareness Continuous glucose monitoring in people with glycemia after saccharose or glucose adminis- of hypoglycaemia (IN CONTROL): a randomised, diabetes: the randomized controlled Glucose tration. Clin Physiol Biochem 1990;8:267–272 open-label, crossover trial. Lancet Diabetes En- Level Awareness in Diabetes Study (GLADIS). 77. Layman DK, Clifton P, Gannon MC, Krauss docrinol 2016;4:893–902 Diabet Med 2015;32:609–617 RM, Nuttall FQ. Protein in optimal health: heart 91. Battelino T, Conget I, Olsen B, et al.; SWITCH 105. Kitabchi AE, Umpierrez GE, Miles JM, Fisher disease and type 2 diabetes. Am J Clin Nutr 2008; Study Group. The use and efficacy of continuous JN. Hyperglycemic crises in adult patients with 87:1571S–1575S glucose monitoring in type 1 diabetes treated diabetes. Diabetes Care 2009;32:1335–1343 Diabetes Care Volume 43, Supplement 1, January 2020 S77

7. Diabetes Technology: Standards American Diabetes Association of Medical Care in Diabetesd2020

Diabetes Care 2020;43(Suppl. 1):S77–S88 | https://doi.org/10.2337/dc20-S007

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes” includes the ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, Association and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc20-SPPC), TECHNOLOGY DIABETES 7. are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc20-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes .org/SOC.

Diabetes technology is the term used to describe the hardware, devices, and software that people with diabetes use to help manage their condition, fromDiabetes lifestyle to blood glucose levels. Historically, diabetes technology has been divided into two main categories: insulin administered by syringe, pen, or pump, and blood glucose monitoring as assessed by meter or continuous glucose monitor. More recently, diabetes technology has expanded to include hybrid devices that both monitor glucose and deliver insulin, some automatically, as well as software that serves as a medical device, providing diabetes self-management support. Diabetes technology, when coupled with education and follow-up, can improve the lives and health of people with diabetes; however, the complexity and rapid change of the diabetes technology landscape can also be a barrier to patient and provider implementation. OVERALL STATEMENT American Recommendation 7.1 Use of technology should be individualized based on a patient’s needs, desires, skilllevel,andavailabilityofdevices.Nonproﬁtwebsitescanofferadvice for providers and patients to determine the suitability of various options. E

Technologyisrapidlychanging,butthereisno“one-size-fits-all”approachtotechnology use in people with diabetes. Insurance coverage can lag behind device availability, patient©2019 interest in devices and willingness to change can vary, and providers may have trouble keeping up with newly released technology. Not-for-profit websites such as DiabetesWise.org (1) and others can help providers and patients make decisions as Suggested citation: American Diabetes Associa- tion. 7. Diabetes Technology: Standards of Med- to the initial choice of devices. Other sources, including health care providers and d fi ical Care in Diabetes 2020. Diabetes Care device manufacturers, can help people troubleshoot when dif culties arise. 2020;43(Suppl. 1):S77–S88 SELF-MONITORING OF BLOOD GLUCOSE © 2019 by the American Diabetes Association. Readers may use this article as long as the work is Recommendations properly cited, the use is educational and not fi 7.2 Most patients using intensive insulin regimens (multiple daily injections or for pro t, and the work is not altered. More information is available at http://www.diabetesjournals insulin pump therapy) should be encouraged to assess glucose levels using .org/content/license. S78 Diabetes Technology Diabetes Care Volume 43, Supplement 1, January 2020

glucose monitoring (CGM) has emerged almost 27,000 children and adolescents self-monitoring of blood glucose as a method for the assessment of glu- with type 1 diabetes showed that, after (and/or continuous glucose mon- cose levels (discussed below). Glucose adjustment for multiple confounders, itoring) prior to meals and monitoring allows patients to evaluate increased daily frequency of SMBG was snacks, at bedtime, prior to ex- their individual response to therapy and significantly associated with lower A1C ercise, when they suspect low assess whether glycemic targets are (–0.2% per additional test per day) and blood glucose, after treating being safely achieved. Integrating with fewer acute complications (7). low blood glucose until they results into diabetes management can are normoglycemic, and prior be a useful tool for guiding medical Patients Using Basal Insulin and/or to and while performing critical nutrition therapy and physical activity, Oral Agents tasks such as driving. B preventing hypoglycemia, and adjusting The evidence is insufficient regarding 7.3 When prescribed as part of a medications (particularly prandial insulin when to prescribe SMBG and how often diabetes self-management edu- doses). The patient’s specific needs and testing is needed for insulin-treated pa- cation and support program, self- goals should dictate SMBG frequency tients who do not use intensive insulin monitoring of blood glucose may and timing or the consideration of regimens, such as those with type 2 help to guide treatment decisions CGM use. diabetes using basal insulin with or with- and/or self-management for pa- out oral agents. However, for patients tients taking less-frequent insulin Optimizing SMBG Monitor Use using basal insulin, assessing fasting glu- injections. B SMBG accuracy is dependent on the cose with SMBG to inform dose adjust- 7.4 Although self-monitoring of blood instrument and user, so it is important ments to achieve blood glucose targets glucose in patients on noninsulin ’ to evaluate each patient s monitoring results in lower A1C (8,9). therapies has not shown clinically Association technique, both initially and at regular In people with type 2 diabetes not significant reductions in A1C, it intervals thereafter. Optimal use of using insulin, routine glucose monitoring may be helpful when altering SMBG requires proper review and in- may be of limited additional clinical diet, physical activity, and/or terpretation of the data, by both the benefit. By itself, even when combined medications (particularly medica- patient and the provider, to ensure that with education, it has showed limited tions that can cause hypoglyce- data are used in an effective and timely improvement in outcomes(10–13). How- mia) in conjunction with a treatment manner. In patients with type 1 diabetes, ever, for some individuals, glucose mon- adjustment program. E there is a correlation between greater itoring can provide insight into the 7.5 When prescribing self-monitoring SMBG frequency and lower A1C (3). impact of diet, physical activity, and of blood glucose, ensure that pa- Among patients who check their blood medication management on glucose lev- tients receive ongoing instruction glucose at leastDiabetes once daily, many report els. Glucose monitoring may also be and regular evaluation of techni- taking no action when results are high or useful in assessing hypoglycemia, glu- que, results, and their ability to use low (4). Patients should be taught how cose levels during intercurrent illness, data from self-monitoring of blood to use SMBG data to adjust food or discrepancies between measured glucose to adjust therapy. E intake, exercise, or pharmacologic ther- A1C and glucose levels when there is con- 7.6 Health care providers should be fi apy to achieve speci c goals. The ongoing cern an A1C result may not be reliable aware of medications and other need for and frequency of SMBG should in specific individuals. It may be useful factors, such as high-dose vita- be reevaluated at each routine visit to when coupled with a treatment adjust- min C and hypoxemia, that can avoid overuse, particularly if SMBG is not ment program. In a year-long study of interfere with glucose meter being used effectively for self-management insulin-naive patients with suboptimal accuracy and provide clinical – (4 6). initial glycemic stability, a group trained management as indicated. E AmericanPatients on Intensive Insulin Regimens in structured SMBG (a paper tool was 7.7 Providers should be aware of the SMBG is especially important for insulin- used at least quarterly to collect and differences in accuracy among treated patients to monitor for and pre- interpret seven-point SMBG profiles glucose metersdonly U.S. Food vent hypoglycemia and hyperglycemia. taken on 3 consecutive days) reduced and Drug Administration–approved Most patients using intensive insulin regi- their A1C by 0.3% more than the control meters should be used with un- mens (multiple daily injections or insulin group (14). A trial of once-daily SMBG expired strips, purchased from a pump therapy) should be encouraged to that included enhanced patient pharmacy or licensed distributor. E assess glucose levels using SMBG (and/ feedback through messaging found no ©2019 or CGM) prior to meals and snacks, at clinically or statistically significant Major clinical trials of insulin-treated bedtime, occasionally postprandially, change in A1C at 1 year (13). Meta- patients have included self-monitoring prior to exercise, when they suspect low analyses have suggested that SMBG can of blood glucose (SMBG) as part of blood glucose, after treating low blood reduce A1C by 0.25–0.3% at 6 months multifactorial interventions to demon- glucose until they are normoglycemic, (15–17), but the effect was attenuated at strate the benefit of intensive glycemic and prior to and while performing critical 12 months in one analysis (15). Reduc- control on diabetes complications (2). tasks such as driving. For many patients tions in A1C were greater (20.3%) in SMBG is thus an integral component using SMBG, this will require testing up trials where structured SMBG data were of effective therapy of patients tak- to 6–10 times daily, although individual used to adjust medications, but A1C was ing insulin. In recent years, continuous needs may vary. A database study of not changed significantly without such care.diabetesjournals.org Diabetes Technology S79

structured diabetes therapy adjustment Meter Standards 7.9 When used properly, real-time (17). A key consideration is that performing Glucose meters meeting U.S. Food and continuous glucose monitors in SMBG alone does not lower blood glucose Drug Administration (FDA) guidance for conjunction with insulintherapy levels. To be useful, the information must meter accuracy provide the most reliable are a useful tool to lower A1C be integrated into clinical and self-man- data for diabetes management. There are levels and/or reduce hypoglyce- agement plans. several current standards for accuracy of mia in adults with type 1 diabetes Glucose Meter Accuracy blood glucose monitors, but the two most used are those of the International Or- who are not meeting glycemic Although many meters function well ganization for Standardization (ISO) (ISO targets, have hypoglycemia un- under a variety of circumstances, pro- 15197:2013) and the FDA. The current awareness, and/or have episodes viders and people with diabetes need to A ISO and FDA standards are compared in of hypoglycemia. be aware of factors that can impair meter 7.10 Table 7.2. In Europe, currently marketed When used properly, intermit- accuracy. A meter reading that seems monitors must meet current ISO stand- tently scanned continuous glucose discordant with clinical reality needs to ards. In the U.S., currently marketed monitors in conjunction with in- be retested or tested in a laboratory. monitors must meet the standard under sulin therapy are useful tools to Providers in intensive care unit settings which they were approved, which may lower A1C levels and/or reduce need to be particularly aware of the not be the current standard. Moreover, hypoglycemia in adults with type potential for abnormal meter readings, the monitoring of current accuracy is 1 diabetes who are not meeting and laboratory-based values should be left to the manufacturer and not rou- glycemic targets, have hypogly- used if there is any doubt. Some meters tinely checked by an independent cemia unawareness, and/or have give error messages if meter readings C source. episodes of hypoglycemia. are likely to be false (18). 7.11 Association Patients assume their glucose monitor When used properly, real-time Oxygen. Currently available glucose mon- and intermittently scanned con- itors utilize an enzymatic reaction linked to is accurate because it is FDA cleared, but often that is not the case. There is sub- tinuous glucose monitors in con- an electrochemical reaction, either glucose junction with insulin therapy are oxidase or glucose dehydrogenase (19). stantial variation in the accuracy of widely used blood glucose monitoring useful tools to lower A1C and/or Glucose oxidase monitors are sensitive reduce hypoglycemia in adults to the oxygen available and should only systems (20). The Diabetes Technology Society Blood Glucose Monitoring Sys- with type 2 diabetes who are be used with capillary blood in patients B tem Surveillance Program provides in- not meeting glycemic targets. with normal oxygen saturation. Higher 7.12 formation on the performance of devices Continuous glucose monitoring oxygen tensions (i.e., arterial blood or (CGM) should be considered in all oxygen therapy) may result in false low used for SMBG (diabetestechnology.org/ surveillance). In aDiabetes recent analysis, the children and adolescents with type glucose readings, and low oxygen tensions 1 diabetes, whether using injec- (i.e.,highaltitude,hypoxia,orvenousblood program found that only 6 of the top 18 glucose meters met the accuracy tions or continuous subcutaneous readings) may lead to false high glucose insulin infusion, as an additional readings. Glucose dehydrogenase moni- standard (21). Counterfeit Strips. Patients should be ad- tool to help improve glucose con- tors are not sensitive to oxygen. trol. Benefits of CGM correlate Temperature. Because the reaction is sen- vised against purchasing or reselling pre- owned or second-hand test strips, as with adherence to ongoing use sitive to temperature, all monitors have B these may give incorrect results. Only of the device. an acceptable temperature range (19). 7.13 Real-time continuous glucose Most will show an error if the temper- unopened vials of glucose test strips should be used to ensure SMBG accuracy. monitoring (CGM) devices should ature is unacceptable, but a few will be used as close to daily as pos- provide a reading and a message indi- sible for maximal benefit. Inter- AmericanCONTINUOUS GLUCOSE cating that the value may be incorrect. mittently scanned CGM devices MONITORING DEVICES Interfering Substances. There are a few should be scanned frequently, at Table 7.3 fi physiologic and pharmacologic factors See for de nitions of types of a minimum once every 8 h. A that interfere with glucose readings. CGM devices. 7.14 Real-time continuous glucose mon- Most interfere only with glucose oxidase Recommendations itors may be used effectively to Table 7.1 systems (19). They are listed in . 7.8 When prescribing continuous glu- improve A1C levels, time in range, cose monitoring (CGM) devices, and neonatal outcomes in pregnant Table©2019 7.1—Interfering substances for robust diabetes education, train- women with type 1 diabetes. B glucose readings ing, and support are required for 7.15 Blinded continuous glucose Glucose oxidase monitors optimal CGM device implementa- monitor data, when coupled Uric acid Galactose tion and ongoing use. People with diabetes self-management Xylose using CGM devices need to education and medication dose Acetaminophen have the ability to perform self- adjustment, can be helpful in L-dopa monitoring of blood glucose in identifying and correcting pat- Ascorbic acid order to calibrate their monitor terns of hyper- and hypoglyce- Glucose dehydrogenase monitors and/or verify readings if discor- mia in people with type 1 Icodextrin (used in peritoneal dialysis) dant from their symptoms. E diabetes and type 2 diabetes. E S80 Diabetes Technology Diabetes Care Volume 43, Supplement 1, January 2020

Table 7.2—Comparison of ISO 15197:2013 and FDA blood glucose meter accuracy standards Setting FDA (154,155) ISO 15197:2013 (156) Home use 95% within 15% for all BG in the usable BG range† 95% within 15% for BG $100 mg/dL 99% within 20% for all BG in the usable BG range† 95% within 15 mg/dL for BG ,100 mg/dL 99% in A or B region of consensus error grid‡ Hospital use 95% within 12% for BG $75 mg/dL 95% within 12 mg/dL for BG ,75 mg/dL 98% within 15% for BG $75 mg/dL 98% within 15 mg/dL for BG ,75 mg/dL BG, blood glucose; FDA, U.S. Food and Drug Administration; ISO, International Organization for Standardization. To convert mg/dL to mmol/L, see endmemo.com/medical/unitconvert/Glucose.php. †The range of blood glucose values for which the meter has been proven accurate and will provide readings (other than low, high, or error). ‡Values outside of the “clinically acceptable” A and B regions are considered “outlier” readings and may be dangerous to use for therapeutic decisions (157).

Somereal-timesystemsrequirecalibra- Real-time CGM Device Use in Adults 7.16 People who have been using tion by the user, which varies in frequency With Type 1 Diabetes continuous glucose monitors depending on the device. Additionally, for Data exist to support the use of real-time should have continued access some CGM systems, the FDA suggests CGM in adults, both those on multiple across third-party payers. E SMBG for making treatment decisions. daily injections (MDI) and continuous fi subcutaneons insulin infusion (CSII). In CGM measures interstitial glucose Devices that require SMBG con rmation “ ” termsAssociation of RCTs in people with type 1 (which correlates well with plasma glu- are called adjunctive, while those that “ ” diabetes, there are four studies in adults cose). There are two basic types of CGM do not are called nonadjunctive. An RCT with A1C as the primary outcome devices: those that provide unblinded data of 226 adults suggested that a CGM device (28–32), three studies in adults with to the user and those that are blinded with could be used safely and effectively without regular confirmatory SMBG in patients hypoglycemia as the primary outcome data available to the patient and their (33–35), four studies in adults and chil- health care provider for retrospective anal- with well-controlled type 1 diabetes at low risk of severe hypoglycemia (23). Two dren with A1C as the primary outcome ysis. Table 7.3 provides the definitions (36–39), and three studies in adults and CGM devices are approved by the FDA for the types of CGM devices. For devices children with hypoglycemia as a primary for making treatment decisions without that provide patients unblinded data, outcome (40–42). SMBG calibration or confirmation (24,25). most of the published randomized con- The abundanceDiabetes of data provided by Primary Outcome: A1C Reduction trolled trials (RCTs) have been performed CGM offers opportunities to analyze pa- In general, A1C reduction was shown in using real-time CGM devices that have tient data more granularly than was pre- studies where the baseline A1C was higher. alarms and alerts. It is difficult to deter- viously possible, providing additional In two larger studies in adults with type 1 mine how much impact having these information to aid in achieving glycemic diabetes that assessed the benefitofreal- notices makes in terms of reacting to targets. A variety of metrics have been pro- timeCGMinpatientsonMDI,therewere glucose levels. There is one small study posed (26) and are discussed in Section significant reductions in A1C: –0.6% in one in patients at risk for hypoglycemia that 6, “Glycemic Targets” (https://doi.org/10 (28,29) and –0.43% in the other (30). No compares real-time CGM with intermit- .21337/dc20-S006). CGM is essential for reductioninA1Cwasseeninasmallstudy tently scanned CGM (isCGM) (22). The creating the ambulatory glucose profile performed in underserved, less well- study showed improvement in time spent (AGP) and providing data on time in educated adults with type 1 diabetes in hypoglycemia with real-timeAmerican CGM com- range, percentage of time spent above (31). In the adult subset of the JDRF CGM paredwithisCGM. and below range, and variability (27). study, there was a significant reduction in A1C of –0.53% (43) in patients who were primarily treated with insulin pump ther- — Table 7.3 Continuous glucose monitoring (CGM) devices apy. Better adherence in wearing the Real-time CGM CGM systems that measure glucose levels continuously and real-time CGM device resulted in a provide the user automated alarms and alerts at specific greater likelihood of an improvement in glucose levels and/or for changing glucose levels. glycemic control (32,36). Intermittently scanned CGM CGM systems that measure glucose levels continuously but ©2019 only display glucose values when swiped by a reader or Primary Outcome: Hypoglycemia a smart phone that reveals the glucose levels. In studies in adults where reduction in Blinded (professional) CGM CGM devices that measure glucose levels that are not episodes of hypoglycemia was the pri- displayed to the patient in real time. These devices are mary end point, significant reductions generally initiated in a clinic, using a reader that is were seen in individuals with type 1 owned by the clinic. They are removed after a period of diabetes on MDI or CSII (33–35). In time (generally 10–14 days) and analyzed by the patient and provider to assess glycemic patterns and trends. one study in patients who were at higher Unblinded CGM CGM devices that measure glucose levels that are displayed risk for episodes of hypoglycemia (35), to the patient. there was a reduction in rates of all levels of hypoglycemia (see Section 6 “Glycemic care.diabetesjournals.org Diabetes Technology S81

Targets,” https://doi.org/10.2337/dc20-S006, (50); and in another, participants were on glycemiccontrol(58).Onecriticalcomponent for hypoglycemia definitions). Real-time CSII or MDI (42). The findings in studies to success with CGM is near-daily wearing of CGM may be particularly useful in in- with MDI alone (50) and in two studies in thedevice(37,59–61). sulin-treated patients with hypogly- people using oral agents with or with- Though data from small observational cemia unawareness and/or frequent out insulin (48,49) showed significant studies demonstrate that real-time CGM hypoglycemic episodes, although studies reductions in A1C levels. The Multiple can be worn by patients ,8 years old and have not been powered to show con- Daily Injections and Continuous Glucose theuseofreal-timeCGMprovidesinsight sistent reductions in severe (level 3) Monitoring in Diabetes (DIAMOND) study to glycemic patterns (54,55), an RCT in hypoglycemia (36–38). in people with type 2 diabetes on MDI did children aged 4–9 years did not demon- not show a reduction in hypoglycemia strate improvements in glycemic control Intermittently Scanned CGM Device (50), although it did show a reduction in following 6 months of real-time CGM use Use in Adults With Type 1 Diabetes A1C. Studies in individuals with type 2 (53). However, observational feasibility isCGM does not currently provide alarms diabetes on oral agents with or without studies of toddlers demonstrated a high and alerts but is an option used by many insulin did not show reductions in rates of degree of parental satisfaction and sus- patients. There is relatively little RCT data hypoglycemia (48,49). tained use of the devices despite the in- proving benefit in people with type 1 In one study of isCGM in people with ability to change the degree of glycemic diabetes. One study, designed to show a type 2 diabetes on a variety of insulin control attained (56). reduction in episodes of hypoglycemia in regimens and an initial A1C of ;8.8%, no Registry data has also shown an asso- patients at higher risk for hypoglycemia, reduction in A1C was seen; however, the ciation between real-time CGM use and showed a significant benefit in terms of time spent in a hypoglycemic range was lower A1C levels (43,57), even when lim- time spent in a hypoglycemic range (P , reduced by 43% (51). In a study of isCGM iting assessmentAssociation of real-time CGM use to 0.0001) (33). Additional observational in individuals with type 2 diabetes on participants on injection therapy (57). studies have shown benefit in terms MDI, the A1C was reduced by 0.82% in Impact on Hypoglycemia of A1C reduction (44). the intervention group and 0.33% in the There are no studies solely including pedi- 5 There are several published reviews control group (P 0.005) with no change atric patients that assess rates of hypogly- – of data available on isCGM (45 47). The in rates of hypoglycemia (52). cemia as the primary outcome. Some of the Norwegian Institute of Public Health con- studies where pediatric and adult patients ducted an assessment of isCGM clini- Real-time CGM Device Use in Children were combined together did show potential cal effectiveness, cost-effectiveness, and and Adolescents With Type 1 Diabetes reductions in hypoglycemia (10,62,63). safety for individuals with type 1 and Dataregardinguseofreal-time CGMin youth type 2 diabetes, based on data available consist of findingsDiabetes from RCTs and small Intermittently Scanned CGM Device until January 2017 (45). The authors con- observational studies as well as analysis Use in Children and Adolescents With cluded that, although there were few of data collected by registries. Seven RCTs Type 1 Diabetes quality data available at the time of the have included both adult and pediatric par- Data on use of isCGM in children come from report, isCGM may increase treatment ticipants (36–42), while others have only observational studies. In these reports, satisfaction, increase time in range, and included pediatric participants (53) or limited isCGM is favorably adopted and is associated reduce frequency of nocturnal hypoglyce- the analysis of larger studies to just the with improvements in outcomes (64–67). mia, without differences in A1C or quality pediatric participants (36). Given the feasi- of life or serious adverse events. The bility problems of performing RCTs in very Impact of Frequency of CGM Device Canadian Agency for Drugs and Technol- young children, small observational Use (All Age-groups) ogies in Health reviewed existing data on studies have also provided data on For patients with type 1 diabetes using isCGM performance and accuracy, hypo- real-time CGM use in the youngest real-time CGM, an important predictor of glycemia, effect on A1C, andAmerican patient sat- age-groups (54–56). Finally, while limited A1C lowering for all age-groups was fre- isfaction and quality of life and concluded by the observational nature, registry data quency of sensor use (36). In this study, that the system could replace SMBG, provide some evidence of real-world use overall use was highest in those aged particularly in patients who require of the technologies (43,57). $25 years (who had the most improvement frequent testing (46). A final review (47) in A1C) and lower in younger age-groups. also supported the use of isCGM as a more Impact on Glycemic Control affordable alternative to real-time CGM When data from adult and pediatric par- Real-time CGM Device Use in systems for individuals with diabetes who ticipants are analyzed together, real-time Pregnancy are on©2019 intensive insulin therapy. CGM use in RCTs has been associated with One well-designed RCT showed a reduc- reduction in A1C levels (37–39). Yet in the tion in A1C levels in adult women with Real-time and Intermittently Scanned JDRF CGM trial, when youth were ana- type 1 diabetes on MDI or CSII who were CGM Device Use in Adults With Type 2 lyzed by age-group (8- to 14-year-olds and pregnant (68). Neonatal outcomes were Diabetes 15-to24-year-olds), nochange in A1C was better when the mother used CGM dur- Studies in people with type 2 diabetes are seen, likely due to poor real-time CGM ing pregnancy (28). Two studies employ- heterogeneous in designdin two, par- adherence (36). Indeed, in a secondary ing intermittent use of real-time CGM ticipants were using basal insulin with analysis of that RCT’sdatainbothpediatric showed no difference in neonatal out- oral agents or oral agents alone (48,49); cohorts, those who used the sensor $6 comes in women with type 1 diabetes in one, individuals were on MDI alone days/week had an improvement in their (69) or gestational diabetes mellitus (70). S82 Diabetes Technology Diabetes Care Volume 43, Supplement 1, January 2020

Use of Blinded (Professional) CGM pens with prefilled cartridges or reusable 7.21 U.S. Food and Drug Administration– Devices insulin pens with replaceable insulin car- approvedinsulindosecalculators/ Blinded CGM devices, which provide tridges. Some reusable pens include a mem- decision support systems may retrospective data for analysis, can be ory function, which can recall dose amounts be helpful for titrating insulin used to identify patterns of hypo- and and timing. “Smart” pens that can be pro- doses. E hyperglycemia. While minimal RCT data grammed to calculate insulin doses and 7.22 Competent patients using dia- exist to support their use, in some set- provide downloadable data reports are betes devices should be allowed tings, blinded CGM can be helpful to also available. Pens also vary with respect to use them in an inpatient evaluate patients when either real- to dosing increment and minimal dose, setting when proper supervi- time or isCGM is not available to the which can range from half-unit doses to sion is available. E patient or the patient prefers a blinded 2-unit dose increments. analysis. It can be particularly useful to Needle thickness (gauge) and length evaluate periods of hypoglycemia in Injecting insulin with a syringe or pen is is another consideration. Needle gauges patients on agents that can cause hy- the insulin delivery method used by most range from 22 to 33, with higher gauge poglycemia for making medication dose people with diabetes (76,77), although indicating a thinner needle. A thicker adjustments. It can also be useful to inhaled insulin is also available. Others needle can give a dose of insulin more evaluate for periods of hyperglycemia. Use use insulin pumps or automated insulin quickly, while a thinner needle may cause of blinded CGM should always be cou- delivery devices (see sections on those less pain. Needle length ranges from 4 to pled with analysis and interpretation for topics below). For patients with diabetes 12.7 mm, with some evidence suggesting the patient, along with education as who use insulin, insulin syringes and pens shorter needles may lower the risk of needed to adjust medication and change are both able to deliver insulin safely and intramuscularinjection.Whenreused,nee-Association lifestyle behaviors. effectively for the achievement of glyce- dles may be duller and thus injection more mic targets. When choosing among de- painful. Proper insulin technique is a req- Side Effects of CGM Devices livery systems, patient preferences, cost, uisite to obtain the full benefits of insulin Contact dermatitis has been reported with insulin type and dosing regimen, and self- injection therapy, and concerns with tech- all devices that attach to the skin (71). In management capabilities should be con- nique and using the proper technique are somecasesthishasbeenlinkedtothe sidered. It is important to note that while outlined in Section 9 “Pharmacologic Ap- presence of isobornyl acrylate, which is a many insulin types are available for pur- proaches to Glycemic Treatment” (https:// skin sensitizer and can cause an additional chase as either pens or vials, others may doi.org/10.2337/dc20-S009). spreading allergic reaction (72–74). Patch only be available in one form or the other Another insulin delivery option is a testing can be done to identify the cause and there may be significant cost differ- disposable patch-like device, which proof the contact dermatitis (75). ences betweenDiabetes pens and vials (see Table vides a continuous, subcutaneous infu- 9.3 for a list of insulin product costs with sion of rapid-acting insulin (basal), as INSULIN DELIVERY dosage forms). Insulin pens may allow well as 2 unit increments of bolus insulin Insulin Syringes and Pens people with vision impairment or dex- at the press of a button (82). terity issues to dose insulin accurately Bolus calculators have been developed Recommendations (78–80), while insulin injection aids are to aid in dosing decisions (83–87). These 7.17 For people with diabetes who also available to help with these issues. are subject to FDA approval to ensure require insulin, insulin syringes (For a helpful list of injection aids, see safety in terms of dosing recommenda- or insulin pens may be used for main.diabetes.org/dforg/pdfs/2018/ tions. People who are interested in using insulin delivery with consideration 2018-cg-injection-aids.pdf.) Inhaled insu- these systems should be encouraged to of patient preference, insulin type lin can be useful in people who have an use those that are FDA approved. Pro- and dosing regimen, cost, and Americanaversion to giving injections. vider input and education can be helpful self-management capabilities. B The most common syringe sizes are for setting the initial dosing calculations 7.18 Insulin pens or insulin injection 1 mL, 0.5 mL, and 0.3 mL, allowing doses with ongoing follow-up for adjustments aids may be considered for pa- of up to 100 units, 50 units, and 30 units as needed. tients with dexterity issues or of U-100 insulin, respectively. In a few vision impairment to facilitate parts of the world, insulin syringes still Insulin Pumps the administration of accurate have U-80 and U-40 markings for older insulin doses. C Recommendations insulin concentrations and veterinary in- 7.19 Patients using insulin should 7.23 Insulin pump therapy may be ©2019 sulin, and U-500 syringes are available have an examination of insulin considered as an option for all for the use of U-500 insulin. Syringes injection/infusion sites on a rou- adults, children, and adolescents are generally used once but may be tine basisdatleastannuallyand with type 1 diabetes who are able reused by the same individual in resource- if there are clinical issues related to safely manage the device. A limited settings with appropriate storage to insulin delivery. E 7.24 Individuals with diabetes who and cleansing (81). 7.20 Smart pens may be useful for have been successfully using Insulin pens offer added convenience some patients to help with dose continuous subcutaneous insulin by combining the vial and syringe into capture and dosing recommen- infusion should have continued a single device. Insulin pens, allowing dations. E access across third-party payers. E pushbutton injections, come as disposable care.diabetesjournals.org Diabetes Technology S83

CSII or insulin pumps have been available must be recognized and managed early diabetes, there is insufficient evidence to in the U.S. for 40 years. These devices (97); lipohypertrophy or, less frequently, make recommendations. deliver rapid-acting insulin throughout the lipoatrophy (98,99); and pump site in- Commonbarrierstopumptherapyadop- day to help manage blood glucose levels. fection (100). Discontinuation of pump tion in children and adolescents are con- Most insulin pumps use tubing to deliver therapy is relatively uncommon today; cerns regarding the physical interference of insulin through a cannula, while a few the frequency has decreased over the the device, discomfort with idea of having a attach directly to the skin, without tubing. past few decades, and its causes have device on the body, therapeutic effective- Most studies comparing MDI with CSII changed (100,101). Current reasons for ness, and financial burden (107,117). have been relatively small and of short attrition are problems with cost, wear- duration. However, a recent systematic ability, disliking the pump, suboptimal Insulin Pumps in Patients With Type 2 review and meta-analysis concluded that glycemic control, or mood disorders and Other Types of Diabetes pump therapy has modest advantages (e.g., anxiety or depression) (102). Certain patients with insulin deficiency, for lowering A1C (20.30% [95% CI 20.58 for instance those with long standing to 20.02]) and for reducing severe hypo- Insulin Pumps in Pediatric Patients type 2 diabetes, those who have had a glycemia rates in children and adults (88). The safety of insulin pumps in youth has pancreatectomy, and/or individuals with There is no consensus to guide choosing been established for over 15 years (103). cystic fibrosis may benefit from insulin which form of insulin administration is best Studying the effectiveness of CSII in pump therapy. This is an individual de- for a given patient, and research to guide lowering A1C has been challenging be- cision and must be tailored to fit patient this decision-making is needed (89). Thus, cause of the potential selection bias of needs and preferences. thechoiceofMDIoraninsulinpumpis observational studies. Participants on often based upon the individual character- CSII may have a higher socioeconomic InsulinAssociation Pumps in Older Adults istics of the patient and which is most likely status that may facilitate better glycemic Older individuals with type 1 diabetes to benefit him or her. Newer systems, such control (104) versus MDI. In addition, the benefit from ongoing insulin pump ther- as sensor-augmented pumps and auto- fast pace of development of new insulins apy. There is no data to suggest that matic insulin delivery systems, are dis- and technologies quickly renders com- measurement of C-peptide levels or cussed elsewhere in this section. parisons obsolete. However, RCTs com- antibodies predicts success with insulin Adoption of pump therapy in the U.S. paring CSII and MDI with insulin analogs pump therapy (118,119). Additionally, shows geographical variations, which demonstrate a modest improvement in frequency of follow-up does not influ- may be related to provider preference A1C in participants on CSII (105,106). ence outcomes. Access to insulin pump or center characteristics (90,91) and so- Observational studies, registry data, therapy should be allowed/continued in cioeconomic status, as pump therapy is and meta-analysis have also suggested older adults as it is for younger people. more common in individuals of higher an improvement ofDiabetes glycemic control in socioeconomic status as reflected by participants on CSII (107–109). Although Combined Insulin Pump and Sensor race/ethnicity, private health insurance, hypoglycemia was a major adverse effect Systems family income, and education (91,92). of intensified insulin regimen in the Di- Recommendations Given the additional barriers to optimal abetes Control and Complications Trial 7.25 Sensor-augmented pump ther- diabetes care observed in disadvantaged (DCCT) (110), data suggest that CSII may apy with automatic low glucose groups (93), addressing the differences reduce the rates of severe hypoglycemia suspend may be considered for in access to insulin pumps and other compared with MDI (109,111–113). adults and children with type 1 diabetes technology may contribute to There is also evidence that CSII may diabetes to prevent/mitigate fewer health disparities. reduce DKA risk (109,114) and diabetes episodes of hypoglycemia. B Pump therapy can be successfully complications, in particular, retinopathy 7.26 Automated insulin delivery systems started at the time of diagnosisAmerican (94,95). and peripheral neuropathy in youth, may be considered in children B Practical aspects of pump therapy initia- compared with MDI (62). Finally, treat- and adults with type 1 diabetes tion include assessment of patient and ment satisfaction and quality-of-life to improve glycemic control. A family readiness (although there is no measures improved on CSII compared 7.27 Individual patients may be using consensus on which factors to consider with MDI (115,116). Therefore, CSII can systems not approved by the U.S. in adults [96] or pediatric patients), se- be used safely and effectively in youth Food and Drug Administration lection of pump type and initial pump with type 1 diabetes to assist with achiev- such as do-it-yourself closed settings, patient/family education of po- ing targeted glycemic control while re- loop systems and others; providers tential©2019 pump complications (e.g., diabetic ducing the risk of hypoglycemia and DKA, cannot prescribe these systems ketoacidosis [DKA] with infusion set fail- improving quality of life and preventing but can provide safety informa- ure), transition from MDI, and introduction long-term complications. Based on pa- tion/troubleshooting/backup of advanced pump settings (e.g., tem- tient–provider shared decision-making, advice for the individual devices porary basal rates, extended/square/ insulin pumps may be considered in all to enhance patient safety. E dual wave bolus). pediatric patients. In particular, pump Complications of the pump can be therapy may be the preferred mode of caused by issues with infusion sets (dis- insulin delivery for children under 7 years Sensor-Augmented Pumps lodgement, occlusion), which place pa- of age (63). Because of a paucity of data Sensor-augmented pumps that suspend tients at risk for ketosis and DKA and thus in adolescents and youth with type 2 insulin when glucose is low or predicted S84 Diabetes Technology Diabetes Care Volume 43, Supplement 1, January 2020

to go low within the next 30 min have delivery (139–141). These systems are or less information, such as being part of been approved by the FDA. The Auto- not approved by the FDA, although there a registry or data repository or not). mation to Simulate Pancreatic Insulin are efforts underway to obtain regula- There are many online programs that Response (ASPIRE) trial of 247 patients tory approval for them. The information offer lifestyle counseling to aid with with type 1 diabetes and documented on how to set up and manage these weight loss and increase physical activity nocturnal hypoglycemia showed that systems is freely available on the inter- (144). Many of these include a health sensor-augmented insulin pump therapy net, and there are internet groups where coach and can create small groups of with a low glucose suspend function people inform each other as to how to set similar patients in social networks. There significantly reduced nocturnal hypogly- up and use them. Although not pre- are programs that aim to treat predia- cemia over 3 months without increasing scribed by providers, it is important to betes and prevent progression to diabe- A1C levels (39). In a different sensor- keep patients who are using these meth- tes, often following the model of the augmented pump, predictive low glu- ods for automated insulin delivery safe. Diabetes Prevention Program (145,146). cose suspend reduced time spent with Part of this entails making sure people Others assist in improving diabetes out- glucose ,70 mg/dL from 3.6% at baseline have a “backup plan” in case of pump comes by remotely monitoring patient to 2.6% (3.2% with sensor-augmented failure. Additionally, in most DIY systems, clinical data (for instance, wireless mon- pump therapy without predictive low insulin doses are adjusted based on the itoring of glucose levels, weight, or blood glucose suspend) without rebound hyper- pump settings for basal rates, carbohy- pressure) and providing feedback and glycemia during a 6-week randomized drate ratios, correction doses, and insulin coaching (147–149). There are text mes- crossover trial (120). These devices may activity. Therefore, these settings can be saging approaches that tie into a variety offer the opportunity to reduce hypogly- evaluated and changed based on the of different types of lifestyle and treat- cemia for those with a history ofnocturnal patient’s insulin requirements. mentAssociation programs, which vary in terms of hypoglycemia. Additional studies have their effectiveness (150,151). For many of been performed, in adults and children, Digital Health Technology these interventions, there are limited RCT showing the benefits of this technology Increasingly, people are turning to the data and long-term follow-up is lacking. (121,122). internet for advice, coaching, connec- But for an individual patient, opting into Automated insulin delivery systems tion, and health care. Diabetes, in part one of these programs can be helpful and, increase and decrease insulin delivery because it is both common and numeric, for many, is an attractive option. based on sensor derived glucose level to lends itself to the development of apps begin to approximate physiologic insulin and online programs. The FDA approves Inpatient Care delivery. These systems consist of three and monitors clinically validated, digital, Patients who are comfortable using their components: an insulin pump, a contin- usually online, health technologies diabetes devices, such as insulin pumps uous glucose sensor, and an algorithm intended to treatDiabetes a medical or psycho- and sensors, should be given the chance that determines insulin delivery. With logical conditiondthese are known as to use them in an inpatient setting if they these systems, insulin delivery can not digital therapeutics or “digiceuticals” are competent to do so (152,153). Pa- only be suspended but also increased or (142). Other applications, such as those tients who are familiar with treating their decreased based on sensor glucose val- that assist in displaying or storing data, own glucose levels can often adjust in- ues. Emerging evidence suggests such encourage a healthy lifestyle or provide sulin doses more knowledgably than in- systems may lower the risk of exercise- limited clinical data support. Therefore, it patient staff who do not personally know related hypoglycemia (123) and may is possible to find apps that have been the patient or their management style. have psychosocial benefits (124–127). fully reviewed and approved and others However, this should occur based on the While eventually insulin delivery in designed and promoted by people with hospital’s policies for diabetes manage- closed-loop systems may be truly auto- relatively little skill or knowledge in the ment, and there should be supervision to mated, currently mealsAmerican must be an- clinical treatment of diabetes. be sure that the individual can adjust their nounced. A so-called hybrid approach, Anareaofparticular importanceisthat insulin doses in a hospitalized setting hybrid closed-loop, has been adopted in of online privacy and security. There are where factors such as infection, certain first-generation closed-loop systems and established cloud-based data collection medications, immobility, changes in diet, requires users to bolus for meals and programs, such as Tidepool, Glooko, and and other factors can impact insulin sen- snacks. Multiple studies, utilizing a vari- others, that have been developed with sitivity and the response to insulin. ety of systems with varying algorithms, appropriate data security features and pump, and sensors have been performed are HIPAA (U.S. Health Insurance Porta- The Future in©2019 adults and children (128 –138). Use of bility and Accountability Act of 1996) The pace of development in diabetes these systems depends on patient pref- compliant. These programs can be useful technology is extremely rapid. New ap- erence and selection of patients (and/or for monitoring patients, both by the proaches and tools are available each caregivers) who are capable of safely and patients themselves as well as their year. It is hard for research to keep up effectively using the devices. healthcareteam(143).Consumersshould with these advances because by the Some people with type 1 diabetes read the policy regarding data privacy time a study is completed, newer ver- have been using “do-it-yourself” (DIY) and sharing before providing data into sions of the devices are already on the systems that combine a pump and a real- an application and learn how they can market. The most important component time CGM with a controller and an control how their data will be used (some in all of these systems is the patient. algorithm designed to automate insulin programs offer the ability to share more Technology selection must be appropriate care.diabetesjournals.org Diabetes Technology S85

for the individual. Simply having a device 12. Simon J, Gray A, Clarke P, Wade A, Neil A, 1 November 2019. Availablefrom https://www.fda or application does not change outcomes Farmer A; Diabetes Glycaemic Education and .gov/NewsEvents/Newsroom/PressAnnouncements/ unless the human being engages with it Monitoring Trial Group. Cost effectiveness of self ucm577890.htm monitoring of blood glucose in patients with non- 26. Danne T, Nimri R, Battelino T, et al. In- to create positive health benefits. This insulin treated type 2 diabetes: economic eval- ternational consensus on use of continuous underscores the need for the health care uation of data from the DiGEM trial. BMJ 2008; glucose monitoring. Diabetes Care 2017;40: provider to assist the patient in device/ 336:1177–1180 1631–1640 program selection and to support its use 13. Young LA, Buse JB, Weaver MA, et al.; 27. Battelino T, Danne T, Bergenstal RM, et al. Monitor Trial Group. Glucose self-monitoring Clinical targets for continuous glucose monitor- through ongoing education and training. in non-insulin-treated patients with type 2 di- ing data interpretation: recommendations from Expectations must be tempered by realityd abetes in primary care settings: a randomized the international consensus on time in range. we do not yet have technology that com- trial. JAMA Intern Med 2017;177:920–929 Diabetes Care 2019;42:1593–1603 pletely eliminates the self-care tasks neces- 14. Polonsky WH, Fisher L, Schikman CH, et al. 28. Beck RW, Riddlesworth T, Ruedy K, et al.; sary for treating diabetes, but the tools Structured self-monitoring of blood glucose sig- DIAMOND Study Group. Effect of continuous nificantly reduces A1C levels in poorly controlled, glucose monitoring on glycemic control in adults described in this section can make it easier noninsulin-treated type 2 diabetes: results from with type 1 diabetes using insulin injections: the to manage. the Structured Testing Program study. Diabetes DIAMOND randomized clinical trial. JAMA 2017; Care 2011;34:262–267 317:371–378 References 15. Malanda UL, Welschen LMC, Riphagen II, 29. Riddlesworth T, Price D, Cohen N, Beck RW. 1. DiabetesWise.org. Accessed 24 September Dekker JM, Nijpels G, Bot SDM. Self-monitoring Hypoglycemic event frequency and the effect of 2019. Available from https://www.diabeteswise of blood glucose in patients with type 2 diabetes continuous glucose monitoring in adults with .org mellitus who are not using insulin. Cochrane type 1 diabetes using multiple daily insulin 2. NathanDM,GenuthS,LachinJ,etal.;Diabetes Database Syst Rev 2012;1:CD005060 injections. Diabetes Ther 2017;8:947–951 Control and Complications Trial Research Group. 16. Willett LR. ACP Journal Club. Meta-analysis: 30. Lind M, Polonsky W, Hirsch IB, et al. Con- The effect of intensive treatment of diabetes on self-monitoring in non-insulin-treated type 2 di- tinuousAssociation glucose monitoring vs conventional ther- the development and progression of long-term abetes improved HbA1c by 0.25%. Ann Intern apy for glycemic control in adults with type 1 complications in insulin-dependent diabetes Med 2012;156:JC6–JC12 diabetes treated with multiple daily insulin in- mellitus. N Engl J Med 1993;329:977–986 17. Mannucci E, Antenore A, Giorgino F, Scavini jections: the GOLD randomized clinical trial 3. Miller KM, Beck RW, Bergenstal RM, et al.; M. Effects of structured versus unstructured self- [published correction appears in JAMA 2017; T1D Exchange Clinic Network. Evidence of a monitoring of blood glucose on glucose control in 317:1912]. JAMA 2017;317:379–387 strong association between frequency of self- patients with non-insulin-treated type 2 diabe- 31. Sequeira PA, Montoya L, Ruelas V, et al. Con- monitoring of blood glucose and hemoglobin A1c tes: a meta-analysis of randomized controlled tinuous glucose monitoring pilot in low-income levels in T1D Exchange clinic registry participants. trials. J Diabetes Sci Technol 2018;12:183–189 type 1 diabetes patients. Diabetes Technol Ther Diabetes Care 2013;36:2009–2014 18. Sai S, Urata M, Ogawa I. Evaluation of 2013;15:855–858 4. Grant RW, Huang ES, Wexler DJ, et al. Patients linearity and interference effect on SMBG and 32. Tumminia A, Crimi S, Sciacca L, et al. Efficacy who self-monitor blood glucose and their unused POCT devices, showing drastic high values, low of real-time continuous glucose monitoring on testing results. Am J Manag Care 2015;21:e119–e129 values, or error messages. J Diabetes Sci Technol glycaemic control and glucose variability in 5. Gellad WF, Zhao X, Thorpe CT, Mor MK, Good 2019;13:734–743 Diabetestype 1 diabetic patients treated with either CB, Fine MJ. Dual use of Department of Veterans 19. Ginsberg BH. Factors affecting blood glucose insulin pumps or multiple insulin injection ther- Affairs and Medicare benefits and use of test monitoring: sources of errors in measurement. J apy: a randomized controlled crossover trial. strips in veterans with type 2 diabetes mellitus. Diabetes Sci Technol 2009;3:903–913 Diabetes Metab Res Rev 2015;31:61–68 JAMA Intern Med 2015;175:26–34 20. King F, Ahn D, Hsiao V, Porco T, Klonoff DC. A 33. Bolinder J, Antuna R, Geelhoed-Duijvestijn P, 6. Endocrine Society and Choosing Wisely. review of blood glucose monitor accuracy. Di- Kroger¨ J, Weitgasser R. Novel glucose-sensing Five things physicians and patients should abetes Technol Ther 2018;20:843–856 technology and hypoglycaemia in type 1 diabe- question.Accessed1November2019.Available 21. Klonoff DC, Parkes JL, Kovatchev BP, et al. tes: a multicentre, non-masked, randomised from http://www.choosingwisely.org/societies/ Investigation of the accuracy of 18 marketed controlled trial. Lancet 2016;388:2254–2263 endocrine-society/ blood glucose monitors. Diabetes Care 2018;41: 34. Hermanns N, Schumann B, Kulzer B, Haak T. 7. Ziegler R, Heidtmann B, Hilgard D, Hofer S, 1681–1688 The impact of continuous glucose monitoring on Rosenbauer J, Holl R; DPV-Wiss-Initiative. Fre- 22. Reddy M, Jugnee N, El Laboudi A, Spanudakis low interstitial glucose values and low blood quencyofSMBGcorrelateswithHbA1candacute E, Anantharaja S, Oliver N. A randomized con- glucose values assessed by point-of-care blood complications in children and adolescents with trolled pilot study of continuous glucose mon- glucose meters: results of a crossover trial. J type 1 diabetes. Pediatr Diabetes 2011;12:11American–17 itoring and flash glucose monitoring in people Diabetes Sci Technol 2014;8:516–522 8. Rosenstock J, Davies M, Home PD, Larsen J, with type 1 diabetes and impaired awareness of 35. van Beers CAJ, DeVries JH, Kleijer SJ, et al. Koenen C, Schernthaner G. A randomised, hypoglycaemia. Diabet Med 2018;35:483–490 Continuous glucose monitoring for patients with 52-week, treat-to-target trial comparing insulin 23. Aleppo G, Ruedy KJ, Riddlesworth TD, et al.; type 1 diabetes and impaired awareness of detemir with insulin glargine when administered REPLACE-BG Study Group. REPLACE-BG: a ran- hypoglycaemia (IN CONTROL): a randomised, as add-on to glucose-lowering drugs in insulin- domized trial comparing continuous glucose open-label, crossover trial. Lancet Diabetes En- naive people with type 2 diabetes. Diabetologia monitoring with and without routine blood docrinol 2016;4:893–902 2008;51:408–416 glucose monitoring in adults with well-controlled 36. Tamborlane WV, Beck RW, Bode BW, et al.; 9. Garber AJ. Treat-to-target trials: uses, inter- type 1 diabetes. Diabetes Care 2017;40:538–545 Juvenile Diabetes Research Foundation Contin- pretation©2019 and review of concepts. Diabetes Obes 24. U.S. Food and Drug Administration. FDA uous Glucose Monitoring Study Group. Contin- Metab 2014;16:193–205 news release: FDA expands indication for continuous glucose monitoring and intensive treatment 10. Farmer A, Wade A, Goyder E, et al. Impact of uous glucose monitoring system, first to replace of type 1 diabetes. N Engl J Med 2008;359:1464– self monitoring of blood glucose in the manage- fingerstick testing for diabetes treatment deci- 1476 ment of patients with non-insulin treated di- sions, 2016. Accessed 1 November 2019. Avail- 37. Battelino T, Conget I, Olsen B, et al.; SWITCH abetes: open parallel group randomised trial. able from https://www.fda.gov/newsevents/ Study Group. The use and efficacy of continuous BMJ 2007;335:132 newsroom/pressannouncements/ucm534056 glucose monitoring in type 1 diabetes treated 11. O’KaneMJ,BuntingB,CopelandM,CoatesVE; .htm with insulin pump therapy: a randomised con- ESMON study group. Efficacy of self monitoring of 25. U.S. Food and Drug Administration. FDA trolled trial. Diabetologia 2012;55:3155–3162 blood glucose in patients with newly diagnosed news release: FDA approves first continuous 38. Deiss D, Bolinder J, Riveline J-P, et al. Im- type 2 diabetes (ESMON study): randomised glucose monitoring system for adults not re- proved glycemic control in poorly controlled controlled trial. BMJ 2008;336:1174–1177 quiring blood sample calibration, 2017. Accessed patients with type 1 diabetes using real-time S86 Diabetes Technology Diabetes Care Volume 43, Supplement 1, January 2020

continuous glucose monitoring. Diabetes Care type 2 diabetes: a multicenter, open-label ran- and support by healthcare professionals. Diabe- 2006;29:2730–2732 domized controlled trial. Diabetes Ther 2017;8: tes Metab Syndr 2019;13:2923–2926 39. O’Connell MA, Donath S, O’Neal DN, et al. 55–73 65. Vergier J, Samper M, Dalla-Vale F, et al. Glycaemic impact of patient-led use of sensor- 52. Yaron M, Roitman E, Aharon-Hananel G, Evaluation of flash glucose monitoring after guided pump therapy in type 1 diabetes: et al. Effect of flash glucose monitoring technol- long-term use: a pediatric survey. Prim Care Di- a randomised controlled trial. Diabetologia ogy on glycemic control and treatment satisfac- abetes 2019;13:63–70 2009;52:1250–1257 tion in patients with type 2 diabetes. Diabetes 66. Landau Z, Abiri S, Gruber N, et al. Use of flash 40. Battelino T, Phillip M, Bratina N, Nimri R, Care 2019;42:1178–1184 glucose-sensing technology (FreeStyle Libre) in Oskarsson P, Bolinder J. Effect of continuous 53. Mauras N, Beck R, Xing D, et al.; Diabetes youth with type 1 diabetes: AWeSoMe study glucose monitoring on hypoglycemia in type 1 Research in Children Network (DirecNet) Study group real-life observational experience. Acta diabetes. Diabetes Care 2011;34:795–800 Group. A randomized clinical trial to assess the Diabetol 2018;55:1303–1310 41. Heinemann L, Freckmann G, Ehrmann D, efficacy and safety of real-time continuous glu- 67. Deja G, Kłeczek M, Chumie˛cki M, Strzała- et al. Real-time continuous glucose monitoring cose monitoring in the management of type 1 Kłeczek A, Deja R, Jarosz-Chobot P. The useful- in adults with type 1 diabetes and impaired diabetes in young children aged 4 to ,10 years. ness of the FlashStyle Libre system in glycemic hypoglycaemia awareness or severe hypoglycae- Diabetes Care 2012;35:204–210 control in children with type 1 diabetes during mia treated with multiple daily insulin injections 54. Jeha GS, Karaviti LP, Anderson B, et al. summer camp. Pediatr Endocrinol Diabetes (HypoDE): a multicentre, randomised controlled Continuous glucose monitoring and the reality Metab 2018;24:11–19 trial. Lancet 2018;391:1367–1377 of metabolic control in preschool children with 68. Feig DS, Donovan LE, Corcoy R, et al.; 42. Beck RW, Hirsch IB, Laffel L, et al.; Juvenile type 1 diabetes. Diabetes Care 2004;27:2881– CONCEPTT Collaborative Group. Continuous glu- Diabetes Research Foundation Continuous Glu- 2886 cose monitoring in pregnant women with type 1 cose Monitoring Study Group. The effect of con- 55. Gandrud LM, Xing D, Kollman C, et al. The diabetes (CONCEPTT): a multicentre inter- tinuous glucose monitoring in well-controlled Medtronic Minimed Gold continuous glucose national randomised controlled trial. Lancet type 1 diabetes. Diabetes Care 2009;32: monitoring system: an effective means to dis- 2017;390:2347–2359 1378–1383 cover hypo- and hyperglycemia in children under 69. Secher AL, Ringholm L, Andersen HU, Damm 43. Wong JC, Foster NC, Maahs DM, et al.; T1D 7 years of age. Diabetes Technol Ther 2007;9: P, MathiesenAssociation ER. The effect of real-time contin- Exchange Clinic Network. Real-time continuous 307–316 uous glucose monitoring in pregnant women glucose monitoring among participants in the 56. Tsalikian E, Fox L, Weinzimer S, et al.; Di- with diabetes: a randomized controlled trial. T1D Exchange clinic registry. Diabetes Care 2014; abetes Research in Children Network Study Diabetes Care 2013;36:1877–1883 37:2702–2709 Group. Feasibility of prolonged continuous glu- 70. Wei Q, Sun Z, Yang Y, Yu H, Ding H, Wang S. 44. Paris I, Henry C, Pirard F, Gerard´ A-C, Colin cose monitoring in toddlers with type 1 diabetes. Effect of a CGMS and SMBG on maternal and IM. The new FreeStyle libre flash glucose mon- Pediatr Diabetes 2012;13:301–307 neonatal outcomes in gestational diabetes mel- itoring system improves the glycaemic control 57. Foster NC, Miller KM, Tamborlane WV, litus: a randomized controlled trial. Sci Rep 2016; in a cohort of people with type 1 diabetes Bergenstal RM, Beck RW; T1D Exchange Clinic 6:19920 followed in real-life conditions over a period Network. Continuous glucose monitoring in pa- 71. Pleus S, Ulbrich S, Zschornack E, Kamann S, of one year. Endocrinol Diabetes Metab 2018;1: tients with type 1 diabetes using insulin injec- Haug C, Freckmann G. Documentation of skin- e00023 tions. Diabetes Care 2016;39:e81–e82 related issues associated with continuous glu- 45. Norwegian Institute of Public Health. Free- 58. Beck RW, Buckingham B, Miller K, et al.; cose monitoring use in the scientific literature. Style Libre flash glucose self-monitoring sys- Juvenile DiabetesDiabetes Research Foundation Contin- Diabetes Technol Ther 2019;21:538–545 tem: a single-technology assessment, 2017. uous Glucose Monitoring Study Group. Factors 72. Kamann S, Aerts O, Heinemann L. Further Accessed 1 November 2019. Available from predictive of use and of benefit from continuous evidence of severe allergic contact dermatitis http://www.fhi.no/en/publ/2017/freestyle- glucose monitoring in type 1 diabetes. Diabetes from isobornyl acrylate while using a continuous libre-systemet-for-egenmaling-av-blodsukker- Care 2009;32:1947–1953 glucose monitoring system. J Diabetes Sci Tech- en-hurtigmetodevurder/ 59. Juvenile Diabetes Research Foundation Con- nol 2018;12:630–633 46. Palylyk-Colwell E, Ford C. Flash glucose tinuous Glucose Monitoring Study Group. Effec- 73. Aerts O, Herman A, Bruze M, Goossens A, monitoring system for diabetes. In CADTH Issues tiveness of continuous glucose monitoring in a Mowitz M. FreeStyle Libre: contact irritation in Emerging Health Technologies. Ottawa, ON, clinical care environment: evidence from the versus contact allergy. Lancet 2017;390:1644 Canadian Agency for Drugs and Technologies in Juvenile Diabetes Research Foundation contin- 74. Herman A, Aerts O, Baeck M, et al. Allergic Health, 2016. Accessed 1 November 2019. Avail- uous glucose monitoring (JDRF-CGM) trial. Di- contact dermatitis caused by isobornyl acrylate able from http://www.ncbi.nlm.nih.gov/books/ abetes Care 2010;33:17–22 in FreestyleÒ Libre, a newly introduced glucose NBK476439/ 60. Chase HP, Beck RW, Xing D, et al. Continuous sensor. Contact Dermat 2017;77:367–373 47. Leelarathna L, Wilmot EG. Flash forward: glucosemonitoringin youthwithtype 1diabetes: 75. Hyry HSI, Liippo JP, Virtanen HM. Allergic a review of flash glucose monitoring.American Diabet Med 12-month follow-up of the Juvenile Diabetes contact dermatitis caused by glucose sensors in 2018;35:472–482 Research Foundation continuous glucose mon- type 1 diabetes patients. Contact Dermat 2019; 48. Yoo HJ, An HG, Park SY, et al. Use of a real itoring randomized trial. Diabetes Technol Ther 81:161–166 time continuous glucose monitoring system as a 2010;12:507–515 76. Lasalvia P, Barahona-Correa JE, Romero- motivational device for poorly controlled type 2 61. Pickup JC, Freeman SC, Sutton AJ. Glycaemic Alvernia DM, et al. Pen devices for insulin self- diabetes. Diabetes Res Clin Pract 2008;82:73–79 control in type 1 diabetes during real time administration compared with needle and vial: 49. Ehrhardt NM, Chellappa M, Walker MS, continuous glucose monitoring compared with systematic review of the literature and meta- Fonda SJ, Vigersky RA. The effect of real-time self monitoring of blood glucose: meta-analysis analysis. J Diabetes Sci Technol 2016;10:959–966 continuous glucose monitoring on glycemic con- of randomised controlled trials using individual 77. Hanas R, de Beaufort C, Hoey H, Anderson B. trol©2019 in patients with type 2 diabetes mellitus. patient data. BMJ 2011;343:d3805 Insulin delivery by injection in children and J Diabetes Sci Technol 2011;5:668–675 62. Zabeen B, Craig ME, Virk SA, et al. Insulin adolescents with diabetes. Pediatr Diabetes 50. Beck RW, Riddlesworth TD, Ruedy K, et al.; pump therapy is associated with lower rates of 2011;12:518–526 DIAMOND Study Group. Continuous glucose retinopathy and peripheral nerve abnormality. 78. Pfutzner¨ A, Schipper C, Niemeyer M, et al. monitoring versus usual care in patients with PLoS One 2016;11:e0153033 Comparison of patient preference for two insulin type 2 diabetes receiving multiple daily insulin 63. Sundberg F, Barnard K, Cato A, et al. ISPAD injection pen devices in relation to patient injections: a randomized trial. Ann Intern Med Guidelines. Managing diabetes in preschool chil- dexterity skills. J Diabetes Sci Technol 2012;6: 2017;167:365–374 dren. Pediatr Diabetes 2017;18:499–517 910–916 51. Haak T, Hanaire H, Ajjan R, Hermanns N, 64. PintusD,NgSM.FreeStyleLibreflashglucose 79. Williams AS, Schnarrenberger PA. A com- Riveline J-P, Rayman G. Flash glucose-sensing monitoring improves patient quality of life mea- parison of dosing accuracy: visually impaired and technology as a replacement for blood glucose sures in children with type 1 diabetes mellitus sighted people using insulin pens. J Diabetes Sci monitoring for the management of insulin-treated (T1DM) with appropriate provision of education Technol 2010;4:514–521 care.diabetesjournals.org Diabetes Technology S87

80. Reinauer KM, Joksch G, Renn W, Eggstein M. infusion in toddlers starting at diagnosis of 109. Karges B, Schwandt A, Heidtmann B, et al. Insulin pens in elderly diabetic patients. Diabetes type 1 diabetes mellitus. A multicenter analysis Association of insulin pump therapy vs insulin Care 1990;13:1136–1137 of 104 patients from 63 centres in Germany and injection therapy with severe hypoglycemia, 81. Thomas DR, Fischer RG, Nicholas WC, Beghe Austria. Pediatr Diabetes 2008;9:590–595 ketoacidosis, and glycemic control among chil- C, Hatten KW, Thomas JN. Disposable insulin 96. Peters AL, Ahmann AJ, Battelino T, et al. dren, adolescents, and young adults with type 1 syringe reuse and aseptic practices in diabetic Diabetes technology-continuous subcutaneous diabetes. JAMA 2017;318:1358–1366 patients. J Gen Intern Med 1989;4:97–100 insulin infusion therapy and continuous glucose 110. The DCCT Research Group. Epidemiology of 82. Winter A, Lintner M, Knezevich E. V-Go monitoring in adults: an Endocrine Society clin- severe hypoglycemia in the Diabetes Control and insulin delivery system versus multiple daily ical practice guideline. J Clin Endocrinol Metab Complications Trial. Am J Med 1991;90:450–459 insulin injections for patients with uncontrolled 2016;101:3922–3937 111. Haynes A, Hermann JM, Miller KM, et al. type 2 diabetes mellitus. J Diabetes Sci Technol 97. Wheeler BJ, Heels K, Donaghue KC, Reith DM, Severe hypoglycemia rates are not associated 2015;9:1111–1116 Ambler GR. Insulin pump-associated adverse with HbA1c: a cross-sectional analysis of 3 con- 83. Bailey TS, Stone JY. A novel pen-based Blue- events in children and adolescents–a prospective temporary pediatric diabetes registry databases. tooth-enabled insulin delivery system with in- study. Diabetes Technol Ther 2014;16:558–562 Pediatr Diabetes 2017;18:643–650 sulin dose tracking and advice. Expert Opin Drug 98. Kordonouri O, Lauterborn R, Deiss D. 112. Pickup JC, Sutton AJ. Severe hypoglycaemia Deliv 2017;14:697–703 Lipohypertrophy in young patients with type 1 and glycaemic control in type 1 diabetes: meta- 84. Eiland L, McLarney M, Thangavelu T, Drincic diabetes. Diabetes Care 2002;25:634–634 analysis of multiple daily insulin injections com- A. App-based insulin calculators: current and 99. Kordonouri O, Hartmann R, Remus K, Blasig¨ pared with continuous subcutaneous insulin future state. Curr Diab Rep 2018;18:123 S, Sadeghian E, Danne T. Benefit of supplemen- infusion. Diabet Med 2008; 25:765–774 85. Huckvale K, Adomaviciute S, Prieto JT, Leow tary fat plus protein counting as compared with 113. Birkebaek NH, Drivvoll AK, Aakeson K, et al. MK-S, Car J. Smartphone apps for calculating conventional carbohydrate counting for insulin Incidence of severe hypoglycemia in children insulin dose: a systematic assessment. BMC Med bolus calculation in children with pump therapy. withtype1 diabetesinthe Nordiccountriesin the 2015;13:106 Pediatr Diabetes 2012;13:540–544 period 2008-2012: association with hemoglobin 86. Breton MD, Patek SD, Lv D, et al. Continuous 100. Guinn TS, Bailey GJ, Mecklenburg RS. Fac- A 1c and treatment modality. BMJ Open Diabetes glucose monitoring and insulin informed advi- tors related to discontinuation of continuous Res CareAssociation 2017;5:e000377 sory system with automated titration and dosing subcutaneous insulin-infusion therapy. Diabetes 114. Maahs DM, Hermann JM, Holman N, et al.; of insulin reduces glucose variability in type 1 Care 1988;11:46–51 National Paediatric Diabetes Audit and the Royal diabetes mellitus. Diabetes Technol Ther 2018; 101. Wong JC, Boyle C, DiMeglio LA, et al.; T1D College of Paediatrics and Child Health, the DPV 20:531–540 Exchange Clinic Network. Evaluation of pump Initiative, and the T1D Exchange Clinic Network. 87. Bergenstal RM, Johnson M, Passi R, et al. discontinuation and associated factors in the T1D Rates of diabetic ketoacidosis: international Automated insulin dosing guidance to optimise Exchange clinic registry. J Diabetes Sci Technol comparison with 49,859 pediatric patients insulin management in patients with type 2 2017;11:224–232 with type 1 diabetes from England, Wales, the diabetes: a multicentre, randomised controlled 102. Wong JC, Dolan LM, Yang TT, Hood KK. U.S., Austria, and Germany. Diabetes Care 2015; trial. Lancet 2019;393:1138–1148 Insulin pump use and glycemic control in ado- 38:1876–1882 88. Yeh H-C, Brown TT, Maruthur N, et al. Com- lescents with type 1 diabetes: predictors of 115. Weintrob N, Benzaquen H, Galatzer A, et al. parative effectiveness and safety of methods change in method of insulin delivery across Comparison of continuous subcutaneous insulin of insulin delivery and glucose monitoring for two years. Pediatr Diabetes 2015;16:592–599 infusion and multiple daily injection regimens in diabetes mellitus: a systematic review and meta- 103. PlotnickLP,ClarkLM,BrancatiFL,ErlingerT.Diabeteschildren with type 1 diabetes: a randomized open analysis. Ann Intern Med 2012;157:336–347 Safety and effectiveness of insulin pump therapy crossover trial. Pediatrics 2003;112:559–564 89. Pickup JC. The evidence base for diabetes in children and adolescents with type 1 diabetes. 116. Opipari-Arrigan L, Fredericks EM, Burkhart technology: appropriate and inappropriate Diabetes Care 2003;26:1142–1146 N, Dale L, Hodge M, Foster C. Continuous submeta-analysis. J Diabetes Sci Technol 2013;7: 104. Redondo MJ, Connor CG, Ruedy KJ, et al.; cutaneous insulin infusion benefits quality of life 1567–1574 Pediatric Diabetes Consortium. Pediatric Diabe- in preschool-age children with type 1 diabetes 90. Blackman SM, Raghinaru D, Adi S, et al. tes Consortium Type 1 Diabetes New Onset mellitus. Pediatr Diabetes 2007;8:377–383 Insulin pump use in young children in the T1D (NeOn) study: factors associated with HbA1c 117. Commissariat PV, Boyle CT, Miller KM, et al. Exchange clinic registry is associated with lower levels one year after diagnosis. Pediatr Diabetes Insulin pump use in young children with type 1 hemoglobin A1c levels than injection therapy. 2014;15:294–302 diabetes: sociodemographic factors and parent- Pediatr Diabetes 2014;15:564–572 105. Doyle EA, Weinzimer SA, Steffen AT, Ahern reported barriers. Diabetes Technol Ther 2017; 91. Lin MH, Connor CG, Ruedy KJ, et al.; Pediatric JAH, Vincent M, Tamborlane WVA. A random- 19:363–369 Diabetes Consortium. Race, socioeconomic sta- ized, prospective trial comparing the efficacy of 118. Gill M, Chhabra H, Shah M, Zhu C, tus, and treatment center are associated with continuous subcutaneous insulin infusion with Grunberger G. C-peptide and beta-cell autoan- insulin pump therapy in youth inAmerican the first year multiple daily injections using insulin glargine. tibody testing prior to initiating continuous sub- following diagnosis of type 1 diabetes. Diabetes Diabetes Care 2004;27:1554–1558 cutaneous insulin infusion pump therapy did not Technol Ther 2013;15:929–934 106. Alemzadeh R, Ellis JN, Holzum MK, Parton improve utilization or medical costs among older 92. Willi SM, Miller KM, DiMeglio LA, et al.; T1D EA, Wyatt DT. Beneficial effects of continuous adults with diabetes mellitus. Endocr Pract 2018; Exchange Clinic Network. Racial-ethnic dispar- subcutaneous insulin infusion and flexible mul- 24:634–645 ities in management and outcomes among chil- tiple daily insulin regimen using insulin glargine 119. Vigersky RA, Huang S, Cordero TL, et al.; dren with type 1 diabetes. Pediatrics 2015;135: in type 1 diabetes. Pediatrics 2004;114:e91–e95 OpT2mise Study Group. Improved HbA1c, total 424–434 107. Sherr JL, Hermann JM, Campbell F, et al.; daily insulin dose, and treatment satisfaction 93. Redondo MJ, Libman I, Cheng P, et al.; T1D Exchange Clinic Network, the DPV Initiative, with insulin pump therapy compared to multiple Pediatric©2019 Diabetes Consortium. Racial/ethnic mi- and the National Paediatric Diabetes Audit and daily insulin injections in patients with type 2 nority youth with recent-onset type 1 diabetes the Royal College of Paediatrics and Child Health diabetes irrespective of baseline C-peptide lev- have poor prognostic factors. Diabetes Care registries.Useof insulinpumptherapyinchildren els. Endocr Pract 2018;24:446–452 2018;41:1017–1024 and adolescents with type 1 diabetes and its 120. Forlenza GP, Li Z, Buckingham BA, et al. 94. Ramchandani N, Ten S, Anhalt H, et al. Insulin impact on metabolic control: comparison of Predictive low-glucose suspend reduces hypo- pump therapy from the time of diagnosis of results from three large, transatlantic paediatric glycemiainadults,adolescents,andchildrenwith type 1 diabetes. Diabetes Technol Ther 2006;8: registries. Diabetologia 2016;59:87–91 type 1 diabetes in an at-home randomized 663–670 108. Jeitler K, Horvath K, Berghold A, et al. crossover study: results of the PROLOG trial. 95. Berghaeuser MA, Kapellen T, Heidtmann B, Continuous subcutaneous insulin infusion versus Diabetes Care 2018;41:2155–2161 Haberland H, Klinkert C, Holl RW; German work- multiple daily insulin injections in patients with 121. Wood MA, Shulman DI, Forlenza GP, et al. ing group for insulin pump treatment in paedi- diabetes mellitus: systematic review and meta- In-clinic evaluation of the MiniMed 670G system atric patients. Continuous subcutaneous insulin analysis. Diabetologia 2008;51:941–951 “suspend before low” feature in children with S88 Diabetes Technology Diabetes Care Volume 43, Supplement 1, January 2020

type 1 diabetes. Diabetes Technol Ther 2018;20: patients with type 1 diabetes in a supervised 147. Oberg¨ U, Isaksson U, Jutterstrom¨ L, Orre CJ, 731–737 hotel setting. Diabetes Obes Metab 2019;21: Hornsten¨ A.˚ Perceptions of persons with type 2 122. Beato-V´ıbora PI, Quiros-L´ opez´ C, Lazaro-´ 183–187 diabetes treated in Swedish primary health care: Mart´ın L, et al. Impact of sensor-augmented 134. Forlenza GP, Ekhlaspour L, Breton M, et al. qualitative study on using eHealth Services for pump therapy with predictive low-glucose sus- Successful at-home use of the Tandem Contro- self-management support. JMIR Diabetes 2018; pend function on glycemic control and patient l-IQ artificial pancreas system in young children 3:e7 satisfaction in adults and children with type 1 during a randomized controlled trial. Diabetes 148. Bollyky JB, Bravata D, Yang J, Williamson M, diabetes. Diabetes Technol Ther 2018;20:738– Technol Ther 2019;21:159–169 Schneider J. Remote lifestyle coaching plus a 743 135. Anderson SM, Buckingham BA, Breton MD, connected glucose meter with certified diabetes 123. Sherr JL, Cengiz E, Palerm CC, et al. Re- et al. Hybrid closed-loop control is safe and educator support improves glucose and weight duced hypoglycemia and increased time in effective for people with type 1 diabetes who loss for people with type 2 diabetes. J Diabetes target using closed-loop insulin delivery during are at moderate to high risk for hypoglycemia. Res 2018;2018:3961730 nights with or without antecedent afternoon Diabetes Technol Ther 2019;21:356–363 149. Wilhide Iii CC, Peeples MM, Anthony exercise in type 1 diabetes. Diabetes Care 2013; 136. Forlenza GP, Pinhas-Hamiel O, Liljenquist Kouyate´ RC. Evidence-based mHealth chronic 36:2909–2914 DR, et al. Safety evaluation of the MiniMed 670G disease mobile app intervention design: devel- 124. Troncone A, Bonfanti R, Iafusco D, et al. system in children 7-13 years of age with type 1 opment of a framework. JMIR Res Protoc 2016; Evaluating the experience of children with type 1 diabetes. Diabetes Technol Ther 2019;21:11–19 5:e25 diabetes and their parents taking part in an 137. Karageorgiou V, Papaioannou TG, Bellos I, 150. McGill DE, Volkening LK, Butler DA, artificial pancreas clinical trial over multiple et al. Effectiveness of artificial pancreas in the Wasserman RM, Anderson BJ, Laffel LM. Text- days in a diabetes camp setting. Diabetes non-adult population: a systematic review and message responsiveness to blood glucose Care 2016;39:2158–2164 network meta-analysis. Metabolism 2019;90: monitoring reminders is associated with HbA1c 125. Barnard KD, Wysocki T, Allen JM, et al. 20–30 benefit in teenagers with type 1 diabetes. Diabet Closing the loop overnight at home setting: 138. Brown S, Raghinaru D, Emory E, Kovatchev Med 2019;36:600–605 psychosocial impact for adolescents with type B. First look at Control-IQ: a new-generation 151. Shen Y, WangF, ZhangX, et al. Effectiveness 1 diabetes and their parents. BMJ Open Diabetes automated insulin delivery system. Diabetes of internet-basedAssociation interventions on glycemic con- Res Care 2014;2:e000025 Care 2018;41:2634–2636 trol in patients with type 2 diabetes: meta- 126. Barnard KD, Wysocki T, Thabit H, et al.; 139. Lewis D. History and perspective on DIY analysis of randomized controlled trials. J Med Angela Consortium. Psychosocial aspects of closed looping. J Diabetes Sci Technol 2019;13: Internet Res 2018;20:e172 closed- and open-loop insulin delivery: closing 790–793 152. Stone MP, Agrawal P, Chen X, et al. Ret- the loop in adults with type 1 diabetes in the 140. Hng T-M, Burren D. Appearance of do-it- rospective analysis of 3-month real-world glu- home setting. Diabet Med 2015;32:601–608 yourself closed-loop systems to manage type 1 cose data after the MiniMed 670G system 127. Weissberg-Benchell J, Hessler D, Polonsky diabetes. Intern Med J 2018;48:1400–1404 commercial launch. Diabetes Technol Ther WH, Fisher L. Psychosocial impact of the bionic 141. Petruzelkova L, Soupal J, Plasova V, et al. 2018;20:689–692 pancreas during summer camp. J Diabetes Sci Excellent glycemic control maintained by open- 153. Umpierrez GE, Klonoff DC. Diabetes tech- Technol 2016;10:840–844 source hybrid closed-loop AndroidAPS during nology update: use of insulin pumps and con- 128. Bergenstal RM, Garg S, Weinzimer SA, et al. and after sustained physical activity. Diabetes tinuous glucose monitoring in the hospital. Safety of a hybrid closed-loop insulin delivery Technol Ther 2018;20:744–750 Diabetes Care 2018;41:1579–1589 system in patients with type 1 diabetes. JAMA 142. Fleming GA,Diabetes Petrie JR, Bergenstal RM, Holl 154. U.S. Food and Drug Administration. Self- 2016;316:1407–1408 RW, Peters AL, Heinemann L. Diabetes digital app Monitoring Blood Glucose Test Systems for Over- 129. Garg SK, Weinzimer SA, Tamborlane WV, technology: benefits, challenges, and recom- the-Counter Use [Internet], 2016. Accessed 1 etal.Glucoseoutcomeswith thein-homeuseof a mendations. A consensusreport by the European November2019.Availablefrom: http://www.fda hybrid closed-loop insulin delivery system in Association for the Study of Diabetes (EASD) and .gov/regulatory-information/searchfda-guidance- adolescents and adults with type 1 diabetes. the American Diabetes Association (ADA) Dia- documents/self-monitoring-bloodglucose-test- Diabetes Technol Ther 2017;19:155–163 betes Technology Working Group. Diabetes Care systems-over-counter-use-0 130. Tauschmann M, Thabit H, Bally L, et al.; 5 December 2019 [Epub ahead of print]. DOI: 155. U.S. Food and Drug Administration. Blood APCam11 Consortium. Closed-loop insulin de- 10.2337/dci19-0062 Glucose Monitoring Test Systems for Prescrip- livery in suboptimally controlled type 1 diabetes: 143. Wong JC, Izadi Z, Schroeder S, et al. A pilot tionPoint-of-CareUse:Guidancefor Industryand a multicentre, 12-week randomised trial. Lancet study of use of a software platform for the Food and Drug Administration Staff [Internet], 2018;392:1321–1329 collection, integration, and visualization of di- 2016. Accessed 1 November 2019. Available from 131. Ekhlaspour L, Forlenza GP, Chernavvsky D, abetes device data by health care providers in a http://www.fda.gov/downloads/medicaldevices/ et al. Closed loop control in adolescents and multidisciplinary pediatric setting. Diabetes deviceregulationandguidance/guidancedocuments/ children during winter sports:American use of the Tandem Technol Ther 2018;20:806 –816 ucm380325.pdf Control-IQ AP system. Pediatr Diabetes 2019;20: 144. Chao DY, Lin TM, Ma W-Y. Enhanced self- 156. International Standards Organization. ISO 759–768 efficacy and behavioral changes among patients 15197:2013. In vitro diagnostic test systems – 132. Buckingham BA, Christiansen MP, Forlenza with diabetes: cloud-based mobile health plat- requirements for blood glucose monitoring GP, et al. Performance of the Omnipod person- form and mobile app service. JMIR Diabetes systems for self-testing in managing diabetes alized model predictive control algorithm with 2019;4:e11017 mellitus. Accessed 24 September 2019. Avail- meal bolus challenges in adults with type 1 145. Sepah SC, Jiang L, Peters AL. Translating the able from http://www.iso.org/cms/render/live/en/ diabetes. Diabetes Technol Ther 2018;20:585– Diabetes Prevention Program into an online sites/isoorg/contents/data/standard/05/49/54976 595 social network: validation against CDC standards. .html 133.©2019 Renard E, Tubiana-Ru fi N, Bonnemaison- Diabetes Educ 2014;40:435–443 157. Parkes JL, Slatin SL, Pardo S, Ginsberg BH. A Gilbert E, et al. Closed-loop driven by control-to- 146. Kaufman N, Ferrin C, Sugrue D. Using new consensus error grid to evaluate the clinical range algorithm outperforms threshold-low-glucose- digital health technology to prevent and treat significance of inaccuracies in the measurement suspend insulin delivery on glucose control albeit diabetes. Diabetes Technol Ther 2019;21(S1): of blood glucose. Diabetes Care 2000;23:1143– not on nocturnal hypoglycaemia in prepubertal S79–S94 1148 Diabetes Care Volume 43, Supplement 1, January 2020 S89

8. Obesity Management for the American Diabetes Association Treatment of Type 2 Diabetes: Standards of Medical Care in Diabetesd2020

Diabetes Care 2020;43(Suppl. 1):S89–S97 | https://doi.org/10.2337/dc20-S008 .OEIYMNGMN O H RAMN FTP DIABETES 2 TYPE OF TREATMENT THE FOR MANAGEMENT OBESITY 8. Association The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes” includes the ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc20-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence- grading system for ADA’s clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc20-SINT). ReadersDiabetes who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

There is strong and consistent evidence that obesity management can delay the progression from prediabetes to type 2 diabetes (1–5) and is beneﬁcial in the treatment of type 2 diabetes (6–17). In patients with type 2 diabetes who also have overweight or obesity, modest and sustained weight loss has been shown to improve glycemiccontrolandtoreducethe needforglucose-lowering medications (6–8).Small studies have demonstrated that in patients with type 2 diabetes and obesity, more extreme dietary energy restriction with very low-calorie diets can reduce A1C to ,6.5% (48 mmol/mol) and fasting glucose to ,126 mg/dL (7.0 mmol/L) in the absence of pharmacologicAmerican therapy or ongoing procedures (10,18,19). The goal of this section is to provide evidence-based recommendations for weight-loss therapy, including diet, behavioral, pharmacologic, and surgical interventions, for obesity management as treatment for hyperglycemia in type 2 diabetes.

ASSESSMENT

Recommendations 8.1©2019Measure height and weight and calculate BMI at annual visits or more frequently. E Suggested citation: American Diabetes Associa- 8.2 Based on clinical considerations, such as the presence of comorbid heart tion. 8. Obesity management for the treatment failure or significant unexplained weight gain or loss, weight may need to be of type 2 diabetes: Standards of Medical Care in d monitored and evaluated more frequently. B If deterioration of medical status Diabetes 2020. Diabetes Care 2020;43(Suppl. 1): S89–S97 (https://doi.org/10.2337/dc20-s008) is associated with significant weight gain or loss, inpatient evaluation should fi © 2019 by the American Diabetes Association. be considered, speci cally focused on the association between medication Readers may use this article as long as the work use, food intake, and glycemic status. E is properly cited, the use is educational and not 8.3 For patients with a high level of weight-related distress, special accommo- for profit, and the work is not altered. More infor- dations should be made to ensure privacy during weighing. E mation is available at http://www.diabetesjournals .org/content/license. S90 Obesity Management for the Treatment of Type 2 Diabetes Diabetes Care Volume 43, Supplement 1, January 2020

Height and weight should be mea- DIET, PHYSICAL ACTIVITY, AND 8.10 To achieve weight loss of .5%, sured and used to calculate BMI at an- BEHAVIORAL THERAPY short-term (3-month) interven- nual visits or more frequently when Recommendations tions that use very low-calorie appropriate (20). BMI can be calcu- 8.4 Diet, physical activity, and be- diets (#800 kcal/day) and meal lated manually as weight divided by havioral therapy designed to replacements may be prescribed the square of height in meters (kg/m2) achieve and maintain $5% for carefully selected patients by or electronically using the electronic weight loss is recommended trained practitioners in medical medical record or other resources (20). for patients with type 2 diabetes care settings with close medical Clinical considerations, such as the who have overweight or obesity monitoring. To maintain weight presence of comorbid heart failure and are ready to achieve weight loss, such programs must incor- or unexplained weight change, may fi porate long-term comprehensive warrant more frequent weight mea- loss. Greater bene ts in control weight-maintenance counseling. B surement and evaluation (21,22). of diabetes and cardiovascular When weighing is questioned or re- risk factors may be gained from B Among patients with both type 2 diabe- fused, the practitioner should query even greater weight loss. 8.5 tes and overweight or obesity who also for concerns, and the need for weight Such interventions should be $ have inadequate glycemic, blood pres- monitoring should be explained as a high intensity ( 16 sessions in 6 sure, and lipid control and/or other part of the medical evaluation process months) and focus on dietary obesity-related medical conditions, life- that helps to inform treatment deci- changes, physical activity, and be- style changes that result in modest and sions (23,24). If patients report or havioral strategies to achieve a sustained weight loss produce clinically exhibit a high level of weight-related 500–750 kcal/day energy deficit. A meaningfulAssociation reductions in blood glucose, distress, special accommodations should 8.6 Individual’smotivation,lifecircum- A1C, and triglycerides (6–8). Greater be made to ensure privacy during weigh- stances, and willingness to make weight loss produces even greater ben- ing. Once calculated, BMI should be clas- lifestyle changes to achieve weight efits, including reductions in blood pres- sified to determine the presence of loss should be assessed along with sure, improvements in LDL and HDL overweight or obesity, discussed with medical status when weight loss cholesterol, and reductions in the need the patient, and documented in the interventions are undertaken. C for medications to control blood glucose, patient record. In Asian Americans, the 8.7 As all energy-deficit food intake blood pressure, and lipids (6–8,28), and BMI cut points to define overweight and will result in weight loss, eating may result in achievement of glycemic obesity are lower than in other popu- plans should be individualized to goals in the absence of glucose-lowering lations (Table 8.1) (25,26). Providers meet the patient’sprotein,fat, agent use in some patients (29,30). For should advise patients with over- Diabetes and carbohydrate needs while a more detailed discussion of lifestyle weight or obesity that, in general, A still promoting weight loss. management approaches and recom- higher BMIs increase the risk of car- 8.8 Food availability should be que- mendations see Section 5 “Facilitating diovascular disease and all-cause mor- ried, as well as other cultural Behavior Change and Well-being to Im- tality, as well as other adverse health circumstances that could affect prove Health Outcomes” (https://doi and quality of life outcomes. Providers C dietary patterns. .org/10.2337/dc20-S005). For a detailed should assess each patient’sreadi- 8.9 For patients who achieve short- discussion of nutrition interventions ness to engage in behavioral changes term weight-loss goals, long-term please also refer to “Nutrition Therapy for weight loss and jointly deter- ($1 year) weight maintenance for Adults with Diabetes or Prediabe- mine weight-loss goals and patient- programs are recommended when tes: A Consensus Report” (https://doi appropriate intervention strategies (27). available. Such programs should .org/10.2337/dci19-0014). Strategies may include dietaryAmerican changes, at minimum provide monthly con- physical activity, behavioral therapy, tact, as well as encourage ongo- Look AHEAD Trial pharmacologic therapy, and metabolic ing monitoring of body weight Although the Action for Health in Di- Table 8.1 surgery ( ). The latter two (weeklyormorefrequently)and abetes (Look AHEAD) trial did not show that an intensive lifestyle interven- strategies may be prescribed for care- other self-monitoring strategies, fully selected patients as adjuncts to tion reduced cardiovascular events including high levels of physical diet, physical activity, and behavioral in adults with type 2 diabetes and over- activity (200–300 min/week). A therapy.©2019 weight or obesity (31), it did show the

Table 8.1—Treatment options for overweight and obesity in type 2 diabetes BMI category (kg/m2) Treatment 25.0–26.9 (or 23.0–24.9*) 27.0–29.9 (or 25.0–27.4*) $30.0 (or $27.5*) Diet, physical activity, and behavioral therapy ††† Pharmacotherapy †† Metabolic surgery † *Recommended cut points for Asian American individuals (expert opinion). †Treatment may be indicated for select motivated patients. care.diabetesjournals.org S91

feasibility of achieving and maintaining practitioners, with close patient moni- PHARMACOTHERAPY fi long-term weight loss in patients with toring, can be bene cial. Within the in- Recommendations type 2 diabetes. In the Look AHEAD tensive lifestyle intervention group of the 8.11 When choosing glucose-lowering intensive lifestyle intervention group, Look AHEAD trial, for example, use of a medications for patients with mean weight loss was 4.7% at 8 years partial meal replacement plan was as- type 2 diabetes and overweight (32). Approximately 50% of intensive sociated with improvements in diet or obesity, consider a medica- lifestyle intervention participants lost quality (38). The diet choice should be tion’s effect on weight. B and maintained $5% of their initial based on the patient’s health status and 8.12 Whenever possible, minimize body weight, and 27% lost and main- preferences, including a determination medications for comorbid con- tained $10% of their initial body weight of food availability and other cultural ditions that are associated with at 8 years (32). Participants randomly circumstances that could affect dietary weight gain. E assigned to the intensive lifestyle group patterns (39). 8.13 Weight-loss medications are ef- achieved equivalent risk factor con- Intensive behavioral lifestyle interven- fective as adjuncts to diet, phys- trol but required fewer glucose-, blood tions should include $16 sessions in ical activity, and behavioral pressure–, and lipid-lowering medica- 6 months and focus on dietary changes, counseling for selected patients tions than those randomly assigned physical activity, and behavioral strate- with type 2 diabetes and to standard care. Secondary analyses gies to achieve an ;500–750 kcal/day BMI $27 kg/m2. Potential ben- of the Look AHEAD trial and other large energy deficit. Interventions should be efits must be weighed against cardiovascular outcome studies docu- provided by trained interventionists in potential risks of medications. A ment other benefits of weight loss in either individual or group sessions (34). 8.14 If a patient’s response to weight- patients with type 2 diabetes, includ- Assessing an individual’s motivation level, Associationloss medications is ,5% weight ing improvements in mobility, physical life circumstances, and willingness to im- loss after 3 months or if there and sexual function, and health-related plement lifestyle changes to achieve weight are significant safety or tolera- quality of life (23). A post hoc analysis loss should be considered along with med- bility issues at any time, the of the Look AHEAD study suggests ical status when weight-loss interventions medication should be discon- that heterogeneous treatment effects are recommended and initiated (27). tinued and alternative medica- may have been present. Participants Patients with type 2 diabetes and tions or treatment approaches who had moderately or poorly controlled overweight or obesity who have lost should be considered. A diabetes (A1C $6.8% [51 mmol/mol]) weight during a 6-month intensive be- as well as those with well-controlled havioral lifestyle intervention should be diabetes (A1C ,6.8% [51 mmol/mol]) enrolled in long-term ($1 year) compre- Glucose-Lowering Therapy and good self-reported health were hensive weight-lossDiabetes maintenance pro- Agents associated with varying degrees foundtohavesignificantly reduced grams that provide at least monthly of weight loss include metformin, cardiovascular events with inten- contact with a trained interventionist a-glucosidase inhibitors, sodium–glucose sive lifestyle intervention during and focus on ongoing monitoring of cotransporter 2 inhibitors, glucagon-like follow-up (33). body weight (weekly or more frequently) peptide 1 receptor agonists, and amylin and/or other self-monitoring strategies mimetics. Dipeptidyl peptidase 4 inhibi- Lifestyle Interventions such as tracking intake, steps, etc.; con- tors are weight neutral. Unlike these Significant weight loss can be attained tinued consumption of a reduced-calorie agents, insulin secretagogues, thiazolidi- with lifestyle programs that achieve a diet; and participation in high levels of nediones, and insulin often cause weight 500–750 kcal/day energy deficit, which in physical activity (200–300 min/week) gain (see Section 9 “Pharmacologic Ap- most cases is approximately 1,200–1,500 (40). Some commercial and proprietary proaches to Glycemic Treatment,” https:// kcal/day for women and 1,500American–1,800 weight-loss programs have shown doi.org/10.2337/dc20-s009). kcal/day for men, adjusted for the indi- promising weight-loss results (41). A meta-analysis of 227 randomized vidual’s baseline body weight. Weight When provided by trained practi- controlled trials of glucose-lowering loss of 3–5% is the minimum necessary tioners in medical care settings with treatments in type 2 diabetes found for clinical benefit (20,34). However, close medical monitoring, short-term that A1C changes were not associated weight-loss benefits are progressive; (3-month) interventions that use very with baseline BMI, indicating that pa- more intensive weight-loss goals (.5%, low-calorie diets (defined as #800 tients with obesity can benefit from the .7%, .15%, etc.) may be pursued if kcal/day) and total meal replacements same types of treatments for diabetes as needed©2019 to achieve a healthy weight may achieve greater short-term weight normal-weight patients (44). and/or if the patient is more motivated loss (10–15%) than intensive behav- and more intensive goals can be feasibly ioral lifestyle interventions that typically Concomitant Medications and safely attained. achieve 5% weight loss. However, weight Providers should carefully review the Dietary interventions may differ in the regain following the cessation of very patient’s concomitant medications types of foods they restrict (such as high- low-calorie diets is greater than regain and, whenever possible, minimize or fat or high-carbohydrate foods) but are following intensive behavioral lifestyle provide alternatives for medications effective if they create the necessary interventions unless a long-term com- that promote weight gain. Examples of energy deficit (20,35–37). Use of meal prehensive weight-loss maintenance medications associated with weight gain replacement plans prescribed by trained program is provided (42,43). include antipsychotics (e.g., clozapine, S92 Obesity Management for the Treatment of Type 2 Diabetes Diabetes Care Volume 43, Supplement 1, January 2020

olanzapine, risperidone, etc.) and anti- MEDICAL DEVICES FOR WEIGHT conditions and social and situa- depressants (e.g., tricyclic antidepres- LOSS tional circumstances that have sants, selective serotonin reuptake Several minimally invasive medical de- the potential to interfere with inhibitors, and monoamine oxidase vices have been approved by the FDA for surgery outcomes. B inhibitors), glucocorticoids, injectable short-term weight loss (48,49). It remains 8.20 People who undergo metabolic progestins, anticonvulsants includ- to be seen how these are used for obesity surgery should routinely be ing gabapentin, and possibly sedating treatment. Given the high cost, limited evaluated to assess the need antihistamines and anticholinergics (45). insurance coverage, and paucity of data for ongoing mental health serv- in people with diabetes at this time, ices to help with the adjustment Approved Weight-Loss Medications medical devices for weight loss are cur- to medical and psychosocial The U.S. Food and Drug Administration rently not considered to be the standard changes after surgery. C (FDA) has approved medications for both of care for obesity management in peo- short-term and long-term weight man- ple with type 2 diabetes. Several gastrointestinal (GI) operations agement as adjuncts to diet, exercise, including partial gastrectomies and bari- and behavioral therapy. Nearly all FDA- METABOLIC SURGERY atric procedures (40) promote dramatic approved medications for weight loss and durable weight loss and improvement have been shown to improve glycemic Recommendations of type 2 diabetes in many patients. Given 8.15 control in patients with type 2 diabetes Metabolic surgery should be the magnitude and rapidity of the effect of and delay progression to type 2 diabetes recommended as an option to GI surgery on hyperglycemia and exper- in patients at risk (46). Phentermine and treat type 2 diabetes in imental evidence that rearrangements of other older adrenergic agents are indi- screened surgical candidates GIAssociation anatomy similar to those in some $ 2 cated as short-term (#12 weeks) treat- with BMI 40 kg/m (BMI metabolic procedures directly affect glu- $ 2 ment (47). Five weight-loss medications 37.5 kg/m in Asian Americans) cose homeostasis (41), GI interventions – are FDA approved for long-term use andinadultswithBMI35.0 have been suggested as treatments for 2 – 2 (more than a few weeks) by patients 39.9 kg/m (32.5 37.4 kg/m in type 2 diabetes, and in that context they 2 with BMI $27 kg/m with one or more Asian Americans) who do not are termed “metabolic surgery.” achieve durable weight loss obesity-associated comorbid condition A substantial body of evidence has now and improvement in comorbid- (e.g., type 2 diabetes, hypertension, been accumulated, including data from ities (including hyperglycemia) and/or dyslipidemia) who are motivated numerous randomized controlled (non- with nonsurgical methods. A to lose weight (46). Medications approved blinded) clinical trials, demonstrating that 8.16 Metabolic surgery may be con- by the FDA for the treatment of obesity Diabetesmetabolic surgery achieves superior gly- sidered as an option for adults and their key advantages and disadvan- cemic control and reduction of cardiovas- with type 2 diabetes and BMI tages are summarized in Table 8.2. The cular risk factors in patients with type 2 30.0–34.9 kg/m2 (27.5–32.4 rationale for weight-loss medication use diabetes and obesity compared with var- kg/m2 in Asian Americans) who is to help patients to more consistently ious lifestyle/medical interventions (17). do not achieve durable weight adhere to low-calorie diets and to rein- Improvements in microvascular compli- loss and improvement in co- force lifestyle changes. Providers should cations of diabetes, cardiovascular dis- morbidities (including hypergly- be knowledgeable about the product ease, and cancer have been observed cemia) with tested efficacious label and should balance the potential only in nonrandomized observational nonsurgical methods. A benefits of successful weight loss against studies (50–61). Cohort studies attempt- 8.17 Metabolic surgery should be the potential risks of the medication for ing to match surgical and nonsurgical sub- performed in high-volume cen- each patient. These medications are con- jects suggest that the procedure may Americanters with multidisciplinary teams traindicated in women who are pregnant reduce longer-term mortality (51). knowledgeable about and expe- or actively trying to conceive. Women On the basis of this mounting evi- rienced in the management of of reproductive potential must receive dence, several organizations and gov- diabetes and gastrointestinal counseling regarding the use of reliable ernment agencies have recommended surgery. E methods of contraception. expanding the indications for metabolic 8.18 Long-term lifestyle support and surgery to include patients with type 2 routine monitoring of micronu- fi diabetes who do not achieve durable Assessing Ef cacy and Safety trient and nutritional status Ef©2019ficacy and safety should be assessed weight loss and improvement in comor- must be provided to patients at least monthly for the first 3 months bidities (including hyperglycemia) with after surgery, according to of treatment. If a patient’s response is reasonable nonsurgical methods at BMIs guidelines for postoperative deemed insufficient (weight loss ,5%) as low as 30 kg/m2 (27.5 kg/m2 for Asian management of metabolic sur- after3monthsoriftherearesignificant Americans) (62–69). Randomized con- gery by national and interna- safety or tolerability issues at any trolled trials have documented diabetes tional professional societies. C time, the medication should be dis- 8.19 People being considered for met- remission during postoperative follow- – continued and alternative medica- abolic surgery should be evalu- up ranging from 1 to 5 years in 30 63% tions or treatment approaches should ated for comorbid psychological of patients with Roux-en-Y gastric bypass be considered. (RYGB), which generally leads to greater care.diabetesjournals.org Table 8.2—Medications approved by the FDA for the treatment of obesity ©2019 1-Year (52- or 56-week) mean weight loss (% loss from baseline) National Average Typical adult Average wholesale Drug Acquisition Weight loss maintenance price (30-day Cost (30-day (% loss from Common side effects Possible safety concerns/considerations Medication name dose supply) (108) supply) (109) Treatment arm baseline) (110–115) (110–115) Short-term treatment (£12 weeks) Phentermine (116) 8–37.5 mg q.d.* $5–$56 (37.5 mg $3 (37.5 mg dose) 15 mg q.d.† 6.1 Dry mouth, insomnia, dizziness, c Contraindicated for use in combination with dose) 7.5 mg q.d.† 5.5 irritability, increased BP monoamine oxidase inhibitors AmericanPBO 1.2 Long-term treatment (>12 weeks) Lipase inhibitor Orlistat (3) 60 mg t.i.d. (OTC) $41–$82 $43 120 mg t.i.d.‡ 9.6 Abdominal pain, flatulence, fecal c Potential malabsorption of fat-soluble vitamins 120 mg t.i.d. (Rx) $823 $556 PBO 5.6 urgency, back pain, headache (A, D, E, K) and of certain medications (e.g., cyclosporine, thyroid hormone, anticonvulsants, etc.) c Rare cases of severe liver injury reported c Cholelithiasis c Nephrolithiasis

Selective serotonin (5-HT) 5-HT2C receptor agonist Lorcaserin (14)** 10 mg b.i.d. $360 $288 10 mg b.i.d. 4.5 Headache, nausea, dizziness, fatigue, c Serotonin syndrome–like and neuroleptic Lorcaserin XR 20 mg q.d. $360 $287 PBO 1.5 nasopharyngitis, increased BP malignant syndrome–like reactions theoretically possible when coadministered with other serotonergic or antidopaminergic agents Diabetes c Monitor for depression or suicidal thoughts c Avoid in liver and renal failure Sympathomimetic amine anorectic/antiepileptic combination Phentermine/topiramate 7.5 mg/46 mg $223 (7.5 mg/ $178 (7.5 mg/ 15 mg/92 mg q.d.| 9.8 Constipation, paresthesia, insomnia, c Birth defects ER (117) q.d.§ 46 mg dose) 46 mg dose) 7.5 mg/46 mg q.d.| 7.8 nasopharyngitis, xerostomia, c Cognitive impairment PBO 1.2 increased BP c Acute angle-closure glaucoma Opioid antagonist/antidepressant combination Naltrexone/bupropion 8 mg/90 mg, $334 $268 16 mg/180 mg b.i.d. 5.0 Constipation, nausea, headache, c Contraindicated in patients with uncontrolled ER (15) 2 tablets b.i.d. xerostomia, insomnia hypertension and/or seizure disorders PBO 1.8 c Contraindicated for use with chronic opioid therapy c Acute angle-closure glaucoma Black box warning: Associationc Risk of suicidal behavior/ideation Glucagon-like peptide 1 receptor agonist Liraglutide (16)** 3 mg q.d. $1,497 $1,199 3.0 mg q.d. 6.0 Gastrointestinal side effects common c ?Acute pancreatitis 1.8 mg q.d. 4.7 (nausea, vomiting, diarrhea), c Caution when initiating or increasing dose due to injection site reactions potential risk of acute kidney injury PBO 2.0 Black box warning: c Risk of thyroid C-cell tumors All medications are contraindicated in women who are or may become pregnant. Women of reproductive potential must be counseled regarding the use of reliable methods of contraception. Select safety and side effect information is provided; for a comprehensive discussion of safety considerations, please refer to the prescribing information for each agent. b.i.d., twice daily; BP, blood pressure; ER, extended release; MEN 2, multiple endocrine neoplasia syndrome type 2; MTC, medullary thyroid carcinoma; OTC, over the counter; PBO, placebo; q.d., daily; Rx, prescription; t.i.d., three times daily; XR, extended release. *Use lowest effective dose; maximum appropriate dose is 37.5 mg. †Duration of treatment was 28 weeks in a general obese adult population. **Agent has demonstrated cardiovascular safety in a dedicated cardiovascular outcome trial (118,119). ‡Enrolled participants had normal (79%) or impaired (21%) glucose tolerance. §Maximum dose, depending on response, is 15 mg/92 mg q.d. |Approximately 68% of enrolled participants had type 2 diabetes or impaired glucose tolerance. S93 S94 Obesity Management for the Treatment of Type 2 Diabetes Diabetes Care Volume 43, Supplement 1, January 2020

degrees and lengths of remission compared of minimally invasive approaches (lapa- or other mental health conditions should with other bariatric surgeries (17,70). Avail- roscopic surgery), enhanced training and therefore first be assessed by a mental able data suggest an erosion of diabetes credentialing, and involvement of multi- health professional with expertise in remission over time (71): 35–50% or disciplinary teams. Mortality rates with obesity management prior to consider- more of patients who initially achieve metabolic operations are typically 0.1– ation for surgery (107). Surgery should remission of diabetes eventually experi- 0.5%, similar to cholecystectomy or hys- be postponed in patients with alcohol ence recurrence. However, the median terectomy (87–91). Morbidity has also or substance abuse disorders, significant disease-free period among such individ- dramatically declined with laparoscopic depression, suicidal ideation, or other men- uals following RYGB is 8.3 years (72,73). approaches. Major complications rates tal health conditions until these condi- With or without diabetes relapse, the (e.g., venous thromboembolism, need tions have been fully addressed. Individuals majority of patients who undergo sur- for operative reintervention) are 2–6%, with preoperative psychopathology should gery maintain substantial improvement with other minor complications in up to be assessed regularly following metabolic of glycemic control from baseline for 15% (87–96), rates which compare favor- surgery to optimize mental health man- at least 5 years (74,75) to 15 years ably with those for other commonly per- agement and to ensure that psychiatric (51,52,73,76–78). formed elective operations (91). Empirical symptomsdo not interferewith weightloss Exceedingly few presurgical predic- data suggest that proficiency of the and lifestyle changes. tors of success have been identified, operating surgeon is an important but younger age, shorter duration of factor for determining mortality, com- diabetes (e.g., ,8 years) (79), nonuse plications,reoperations,andreadmissions References 1. Knowler WC, Barrett-Connor E, Fowler SE, of insulin, maintenance of weight loss, (97). Accordingly, metabolic surgery should et al.; Diabetes Prevention Program Research and better glycemic control are consis- be performed in high-volume centers with Group.Association Reduction in the incidence of type 2 tently associated with higher rates of multidisciplinary teams knowledge- diabetes with lifestyle intervention or metfor- diabetes remission and/or lower risk able about and experienced in the man- min. N Engl J Med 2002;346:393–403 of weight regain (51,77,79,80). Greater agement of diabetes and GI surgery. 2. Garvey WT, Ryan DH, Henry R, et al. Pre- vention of type 2 diabetes in subjects with baseline visceral fat area may also help to Longer-term concerns include dump- prediabetes and metabolic syndrome treated predict better postoperative outcomes, ing syndrome (nausea, colic, and diar- with phentermine and topiramate extended especially among Asian American pa- rhea), vitamin and mineral deficiencies, release. Diabetes Care 2014;37:912–921 tients with type 2 diabetes, who typically anemia, osteoporosis, and, rarely, severe 3. Torgerson JS, Hauptman J, Boldrin MN, have more visceral fat compared with hypoglycemia (98). Long-term nutritional Sjostr¨ om¨ L. XENical in the prevention of Diabetes fi in Obese Subjects (XENDOS) study: a randomized Caucasians with diabetes of the same and micronutrient de ciencies and re- study of orlistat as an adjunct to lifestyle changes BMI (81). Beyond improving glycemia, lated complications occur with variable for the prevention of type 2 diabetes in obese metabolic surgery has been shown to frequency dependingDiabetes on the type of patients. Diabetes Care 2004;27:155–161 confer additional health benefits in ran- procedure and require lifelong vitamin/ 4. le Roux CW, Astrup A, Fujioka K, et al.; SCALE domized controlled trials, including nutritional supplementation, thus long- Obesity Prediabetes NN8022-1839 Study Group. 3 years of liraglutide versus placebo substantial reductions in cardiovascular term lifestyle support and routine mon- for type 2 diabetes risk reduction and weight disease risk factors (17), reductions in itoring of micronutrient and nutritional management in individuals with prediabetes: incidence of microvascular disease (82), status should be provided to patients a randomised, double-blind trial. Lancet 2017; and enhancements in quality of life after surgery (99,100). Postprandial hy- 389:1399–1409 5. Booth H, Khan O, Prevost T, et al. Incidence of (74,79,83). poglycemia is most likely to occur with type 2 diabetes after bariatric surgery: popula- Although metabolic surgery has been RYGB (100,101). The exact prevalence of tion-based matched cohort study. Lancet Dia- shown to improve the metabolic profiles symptomatic hypoglycemia is unknown. betes Endocrinol 2014;2:963–968 of patients with type 1 diabetes and mor- In one study, it affected 11% of 450 pa- 6. UKPDS Group. UK Prospective Diabetes Study bid obesity, establishing theAmerican role of met- tients who had undergone RYGB or ver- 7: response of fasting plasma glucose to diet therapy in newly presenting type II diabetic pa- abolic surgery in such patients will require tical sleeve gastrectomy (98). Patients tients. Metabolism 1990;39:905–912 larger and longer studies (84). who undergo metabolic surgery may be 7. Goldstein DJ. Beneficial health effects of Metabolic surgery is more expensive at increased risk for substance use, in- modest weight loss. Int J Obes Relat Metab than nonsurgical management strate- cluding drug and alcohol use and ciga- Disord 1992;16:397–415 gies, but retrospective analyses and mod- rette smoking. Additional potential risks 8. Pastors JG, Warshaw H, Daly A, Franz M, Kulkarni K. The evidence for the effectiveness eling studies suggest that metabolic of metabolic surgery that have been of medical nutrition therapy in diabetes man- surgery may be cost-effective or even described include worsening or new- agement. Diabetes Care 2002;25:608–613 cost-saving©2019 for patients with type 2 di- onset depression and/or anxiety, need 9. Lim EL, Hollingsworth KG, Aribisala BS, Chen abetes. However, results are largely de- for additional GI surgery, and suicidal MJ, Mathers JC, Taylor R. Reversal of type 2 pendent on assumptions about the ideation (102–105). diabetes: normalisation of beta cell function in association with decreased pancreas and liver tri- long-term effectiveness and safety of People with diabetes presenting for acylglycerol. Diabetologia 2011;54:2506–2514 the procedures (85,86). metabolic surgery also have increased 10. Jackness C, Karmally W, Febres G, et al. Very rates of depression and other major low-calorie diet mimics the early beneficial effect Adverse Effects psychiatric disorders (106). Candidates of Roux-en-Y gastric bypass on insulin sensitivity and b-cell function in type 2 diabetic patients. The safety of metabolic surgery has for metabolic surgery with histories of Diabetes 2013;62:3027–3032 improved significantly over the past alcohol, tobacco, or substance abuse; 11. Rothberg AE, McEwen LN, Kraftson AT, several decades, with continued refinement significant depression; suicidal ideation; Fowler CE, Herman WH. Very-low-energy diet care.diabetesjournals.org S95

for type 2 diabetes: an underutilized therapy? implications for policy and intervention strate- intervention strategies for weight loss and pre- J Diabetes Complications 2014;28:506–510 gies. Lancet 2004;363:157–163 vention of weight regain for adults. Med Sci 12. Hollander PA, Elbein SC, Hirsch IB, et al. Role 26. Araneta MRG, Kanaya AM, Hsu WC, et al. Sports Exerc 2009;41:459–471 of orlistat in the treatment of obese patients with Optimum BMI cut points to screen Asian Amer- 41. Gudzune KA, Doshi RS, Mehta AK, et al. type 2 diabetes. A 1-year randomized double- icans for type 2 diabetes. Diabetes Care 2015;38: Efficacy of commercial weight-loss programs: an blind study. Diabetes Care 1998;21:1288–1294 814–820 updated systematic review. Ann Intern Med 13. Garvey WT, Ryan DH, Bohannon NJV, et al. 27. Warren J, Smalley B, Barefoot N. Higher 2015;162:501–512 Weight-loss therapy in type 2 diabetes: effects of motivation for weight loss in African American 42. Tsai AG, Wadden TA. The evolution of very- phentermine and topiramate extended release. than Caucasian rural patients with hypertension low-calorie diets: an update and meta-analysis. Diabetes Care 2014;37:3309–3316 and/or diabetes. Ethn Dis 2016;26:77–84 Obesity (Silver Spring) 2006;14:1283–1293 14. O’Neil PM, Smith SR, Weissman NJ, et al. 28. Rothberg AE, McEwen LN, Kraftson AT, et al. 43. Johansson K, Neovius M, Hemmingsson E. Randomized placebo-controlled clinical trial of Impact of weight loss on waist circumference Effectsofanti-obesitydrugs,diet,andexerciseon lorcaserin for weight loss in type 2 diabetes and the components of the metabolic syn- weight-loss maintenance after a very-low-calorie mellitus: the BLOOM-DM study. Obesity (Silver drome. BMJ Open Diabetes Res Care 2017;5: diet or low-calorie diet: a systematic review and Spring) 2012;20:1426–1436 e000341 meta-analysis of randomized controlled trials. 15. Hollander P, Gupta AK, Plodkowski R, et al.; 29. Lean ME, Leslie WS, Barnes AC, et al. Primary Am J Clin Nutr 2014;99:14–23 COR-Diabetes Study Group. Effects of naltrexone care-led weight management for remission of 44. Cai X, Yang W, Gao X, Zhou L, Han X, Ji L. sustained-release/bupropion sustained-release type 2 diabetes (DiRECT): an open-label, cluster- Baseline body mass index and the efficacy of combination therapy on body weight and gly- randomised trial. Lancet 2018;391:541–551 hypoglycemic treatment in type 2 diabetes: cemic parameters in overweight and obese 30. Lean MEJ, Leslie WS, Barnes AC, et al. Dura- a meta-analysis. PLoS One 2016;11:e0166625 patients with type 2 diabetes. Diabetes Care bility of a primary care-led weight-management 45. Domecq JP, Prutsky G, Leppin A, et al. Clin- 2013;36:4022–4029 intervention for remission of type 2 diabetes: ical review: drugs commonly associated with 16. Davies MJ, Bergenstal R, Bode B, et al.; 2-year results of the DiRECT open-label, cluster- weight change: a systematic review and meta- NN8022-1922 Study Group. Efficacy of liraglutide randomised trial. Lancet Diabetes Endocrinol analysis. J Clin Endocrinol Metab 2015;100:363– for weight loss among patients with type 2 2019;7:344–355 370 Association diabetes: the SCALE diabetes randomized clinical 31. Wing RR, Bolin P, Brancati FL, et al.; Look 46. Kahan S, Fujioka K. Obesity pharmacother- trial. JAMA 2015;314:687–699 AHEAD Research Group. Cardiovascular effects apy in patients with type 2 diabetes. Diabetes 17. Rubino F, Nathan DM, Eckel RH, et al.; of intensive lifestyle intervention in type 2 di- Spectr 2017;30:250–257 Delegates of the 2nd Diabetes Surgery Summit. abetes. N Engl J Med 2013;369:145–154 47. Drugs.com. Phentermine [FDA prescribing Metabolic surgery in the treatment algorithm 32. Look AHEAD Research Group. Eight-year information]. Accessed 22 October 2019. Available for type 2 diabetes: a joint statement by in- weight losses with an intensive lifestyle inter- from https://www.drugs.com/pro/phentermine ternational diabetes organizations. Diabetes vention: the Look AHEAD study. Obesity (Silver .html Care 2016;39:861–877 Spring) 2014;22:5–13 48. Sullivan S. Endoscopic medical devices for 18. Day JW, Ottaway N, Patterson JT, et al. A new 33. Baum A, Scarpa J, Bruzelius E, Tamler R, Basu primary obesity treatment in patients with di- glucagon and GLP-1 co-agonist eliminates obe- S, Faghmous J. Targeting weight loss interven- abetes. Diabetes Spectr 2017;30:258–264 sity in rodents. Nat Chem Biol 2009;5:749–757 tions to reduce cardiovascular complications of 49. Greenway FL, Aronne LJ, Raben A, et al. A 19. Steven S, Hollingsworth KG, Al-Mrabeh A, type 2 diabetes: a machine learning-based post- randomized, double-blind, placebo-controlled et al. Very low-calorie diet and 6 months of hoc analysis of heterogeneousDiabetes treatment ef- study of gelesis100: a novel nonsystemic oral weight stability in type 2 diabetes: pathophys- fects in the Look AHEAD trial. Lancet Diabetes hydrogel for weight loss. Obesity (Silver Spring) iological changes in responders and nonre- Endocrinol 2017;5:808–815 2019;27:205–216 sponders. Diabetes Care 2016;39:808–815 34. Franz MJ, Boucher JL, Rutten-Ramos S, 50. Sjostr¨ om¨ L, Lindroos A-K, Peltonen M, et al.; 20. Jensen MD, Ryan DH, Apovian CM, et al.; VanWormer JJ. Lifestyle weight-loss intervention Swedish Obese Subjects Study Scientific Group. American College of Cardiology/American Heart outcomes in overweight and obese adults with Lifestyle, diabetes, and cardiovascular risk fac- Association Task Force on Practice Guidelines; type 2 diabetes: a systematic review and meta- tors 10 years after bariatric surgery. N Engl Obesity Society. 2013 AHA/ACC/TOS guideline analysis of randomized clinical trials. J Acad Nutr J Med 2004;351:2683–2693 for the management of overweight and obesity Diet 2015;115:1447–1463 51. Sjostr¨ om¨ L, Peltonen M, Jacobson P, et al. in adults: a report of the American College of 35. Sacks FM, Bray GA, Carey VJ, et al. Com- Association of bariatric surgery with long-term Cardiology/AmericanHeartAssociationTaskForce parison of weight-loss diets with different com- remission of type 2 diabetes and with microvas- on Practice Guidelines and The Obesity Society. positions of fat, protein, and carbohydrates. cular and macrovascular complications. JAMA J Am Coll Cardiol 2014;63(25 Pt B):2985–3023 N Engl J Med 2009;360:859–873 2014;311:2297–2304 21. Yancy CW, Jessup M, Bozkurt B, et al.; 36. de Souza RJ, Bray GA, Carey VJ, et al. Effects 52. Adams TD, Davidson LE, Litwin SE, et al. American College of CardiologyAmerican Foundation; of 4 weight-loss diets differing in fat, protein, and Health benefits of gastric bypass surgery after American Heart Association Task Force on Prac- carbohydrate on fat mass, lean mass, visceral 6 years. JAMA 2012;308:1122–1131 tice Guidelines. 2013 ACCF/AHA guideline for the adipose tissue, and hepatic fat: results from 53. Sjostr¨ om¨ L, Narbro K, Sjostr¨ om¨ CD, et al.; management of heart failure: a report of the the POUNDS LOST trial. Am J Clin Nutr 2012; Swedish Obese Subjects Study. Effects of bari- American College of Cardiology Foundation/ 95:614–625 atric surgery on mortality in Swedish obese American Heart Association Task Force on Prac- 37. Johnston BC, Kanters S, Bandayrel K, et al. subjects. N Engl J Med 2007;357:741–752 tice Guidelines. J Am Coll Cardiol 2013;62:e147– Comparison of weight loss among named diet 54. Sjostr¨ om¨ L, Gummesson A, Sjostr¨ om¨ CD, e239 programs in overweight and obese adults: a et al.; Swedish Obese Subjects Study. Effects 22. Bosch X, Monclus´ E, Escoda O, et al. Un- meta-analysis. JAMA 2014;312:923–933 of bariatric surgery on cancer incidence in obese intentional©2019 weight loss: clinical characteristics 38. Raynor HA, Anderson AM, Miller GD, et al.; patients in Sweden (Swedish Obese Subjects and outcomes in a prospective cohort of 2677 pa- Look AHEAD Research Group. Partial meal re- Study): a prospective, controlled intervention tients. PLoS One 2017;12:e0175125 placement plan and quality of the diet at 1 year: trial. Lancet Oncol 2009;10:653–662 23. Wilding JPH. The importance of weight Action for Health in Diabetes (Look AHEAD) trial. 55. Sjostr¨ om¨ L, Peltonen M, Jacobson P, et al. management in type 2 diabetes mellitus. Int J J Acad Nutr Diet 2015;115:731–742 Bariatric surgery and long-term cardiovascular Clin Pract 2014;68:682–691 39. Leung CW, Epel ES, Ritchie LD, Crawford PB, events. JAMA 2012;307:56–65 24. Van Gaal L, Scheen A. Weight management Laraia BA. Food insecurity is inversely associated 56. Adams TD, Gress RE, Smith SC, et al. Long- in type 2 diabetes: current and emerging ap- with diet quality of lower-income adults. J Acad term mortality after gastric bypass surgery. N proaches to treatment. Diabetes Care 2015;38: Nutr Diet 2014;114:1943–1953.e2 Engl J Med 2007;357:753–761 1161–1172 40. Donnelly JE, Blair SN, Jakicic JM, Manore 57. Arterburn DE, Olsen MK, Smith VA, et al. 25. WHO Expert Consultation. Appropriate MM, Rankin JW, Smith BK; American College of Association between bariatric surgery and long- body-mass index for Asian populations and its Sports Medicine. Appropriate physical activity term survival. JAMA 2015;313:62–70 S96 Obesity Management for the Treatment of Type 2 Diabetes Diabetes Care Volume 43, Supplement 1, January 2020

58. Adams TD, Arterburn DE, Nathan DM, Eckel Subjects (SOS) study. Diabetologia 2015;58: 87. Flum DR, Belle SH, King WC, et al.; Longi- RH. Clinical outcomes of metabolic surgery: 1448–1453 tudinal Assessment of Bariatric Surgery (LABS) microvascular and macrovascular complications. 73. Arterburn DE, Bogart A, Sherwood NE, Consortium. Perioperative safety in the longitu- Diabetes Care 2016;39:912–923 et al. A multisite study of long-term remission dinal assessment of bariatric surgery. N Engl J 59. Sheng B, Truong K, Spitler H, Zhang L, Tong X, and relapse of type 2 diabetes mellitus fol- Med 2009;361:445–454 Chen L. The long-term effects of bariatric sur- lowing gastric bypass. Obes Surg 2013;23:93– 88. Courcoulas AP, Christian NJ, Belle SH, et al.; gery on type 2 diabetes remission, micro- 102 Longitudinal Assessment of Bariatric Surgery vascular and macrovascular complications, and 74. Mingrone G, Panunzi S, De Gaetano A, et al. (LABS) Consortium. Weight change and health mortality: a systematic review and meta-analysis. Bariatric-metabolic surgery versus conventional outcomes at 3 years after bariatric surgery Obes Surg 2017;27:2724–2732 medical treatment in obese patients with type 2 among individuals with severe obesity. JAMA 60. Fisher DP, Johnson E, Haneuse S, et al. diabetes: 5 year follow-up of an open-label, 2013;310:2416–2425 Association between bariatric surgery and mac- single-centre, randomised controlled trial. Lan- 89. Arterburn DE, Courcoulas AP. Bariatric sur- rovascular disease outcomes in patients with cet 2015;386:964–973 gery for obesity and metabolic conditions in type 2 diabetes and severe obesity. JAMA 2018; 75. Schauer PR, Bhatt DL, Kirwan JP, et al.; adults. BMJ 2014;349:g3961 320:1570–1582 STAMPEDE Investigators. Bariatric surgery ver- 90. Young MT, Gebhart A, Phelan MJ, Nguyen 61. Billeter AT, Scheurlen KM, Probst P, et al. sus intensive medical therapy for diabetesd5- NT. Use and outcomes of laparoscopic sleeve Meta-analysis of metabolic surgery versus med- year outcomes. N Engl J Med 2017;376:641–651 gastrectomy vs laparoscopic gastric bypass: anal- ical treatment for microvascular complications 76. Cohen RV, Pinheiro JC, Schiavon CA, Salles JE, ysis of the American College of Surgeons NSQIP. in patients with type 2 diabetes mellitus. Br J Surg Wajchenberg BL, Cummings DE. Effects of gastric J Am Coll Surg 2015;220:880–885 2018;105:168–181 bypass surgery in patients with type 2 diabetes 91. Aminian A, Brethauer SA, Kirwan JP, Kashyap 62. Rubino F, Kaplan LM, Schauer PR, Cummings and only mild obesity. Diabetes Care 2012;35: SR, Burguera B, Schauer PR. How safe is meta- DE; Diabetes Surgery Summit Delegates. The 1420–1428 bolic/diabetes surgery? Diabetes Obes Metab Diabetes Surgery Summit consensus conference: 77. Brethauer SA, Aminian A, Romero-Talamas´ 2015;17:198–201 recommendations for the evaluation and use of H, et al. Can diabetes be surgically cured? Long- 92. Birkmeyer NJO, Dimick JB, Share D, et al.; gastrointestinal surgery to treat type 2 diabetes term metabolic effects of bariatric surgery in MichiganAssociation Bariatric Surgery Collaborative. Hospi- mellitus. Ann Surg 2010;251:399–405 obese patients with type 2 diabetes mellitus. Ann tal complication rates with bariatric surgery in 63. Cummings DE, Cohen RV. Beyond BMI: the Surg 2013;258:628–636; discussion 636–637 Michigan. JAMA 2010;304:435–442 need for new guidelines governing the use of 78. Hsu C-C, Almulaiﬁ A, Chen J-C, et al. Effect of 93. Altieri MS, Yang J, Telem DA, et al. Lap band bariatric and metabolic surgery. Lancet Diabetes bariatric surgery vs medical treatment on type 2 outcomes from 19,221 patients across centers Endocrinol 2014;2:175–181 diabetes in patients with body mass index lower and over a decade within the state of New York. 64. Zimmet P,Alberti KGMM,Rubino F, Dixon JB. than 35: ﬁve-year outcomes. JAMA Surg 2015; Surg Endosc 2016;30:1725–1732 IDF’s view of bariatric surgery in type 2 diabetes. 150:1117–1124 94. Hutter MM, Schirmer BD, Jones DB, et al. Lancet 2011;378:108–110 79. Schauer PR, Bhatt DL, Kirwan JP, et al.; First report from the American College of Sur- 65. Kasama K, Mui W, Lee WJ, et al. IFSO-APC STAMPEDE Investigators. Bariatric surgery ver- geons Bariatric Surgery Center Network: lapa- consensus statements 2011. Obes Surg 2012;22: sus intensive medical therapy for diabetesd roscopic sleeve gastrectomy has morbidity and 677–684 3-year outcomes. N Engl J Med 2014;370:2002– effectiveness positioned between the band and 66. Wentworth JM, Burton P, Laurie C, Brown 2013 the bypass. Ann Surg 2011;254:410–420; discus- WA, O’Brien PE. Five-year outcomes of a ran- 80. Hariri K, GuevaraDiabetes D, Jayaram A, Kini SU, sion 420–422 domized trial of gastric band surgery in over- Herron DM, Fernandez-Ranvier G. Preoperative 95. NguyenNT,SloneJA,NguyenX-MT,Hartman weight but not obese people with type 2 insulin therapy as a marker for type 2 diabetes JS, Hoyt DB. A prospective randomized trial of diabetes. Diabetes Care 2017;40:e44–e45 remission in obese patients after bariatric sur- laparoscopic gastric bypass versus laparoscopic 67. Cummings DE, Arterburn DE, Westbrook EO, gery. Surg Obes Relat Dis 2018;14:332–337 adjustable gastric banding for the treatment of et al. Gastric bypass surgery vs intensive life- 81. Yu H, Di J, Bao Y, et al. Visceral fat area as a morbid obesity: outcomes, quality of life, and style and medical intervention for type 2 di- new predictor of short-term diabetes remission costs. Ann Surg 2009;250:631–641 abetes: the CROSSROADS randomised controlled after Roux-en-Y gastric bypass surgery in Chinese 96. Courcoulas AP, King WC, Belle SH, et al. trial. Diabetologia 2016;59:945–953 patients with a body mass index less than 35 Seven-year weight trajectories and health out- 68. Liang Z, Wu Q, Chen B, Yu P, Zhao H, Ouyang kg/m2. Surg Obes Relat Dis 2015;11:6–11 comes in the Longitudinal Assessment of Bari- X. Effect of laparoscopic Roux-en-Y gastric by- 82. O’Brien R, Johnson E, Haneuse S, et al. atric Surgery (LABS) Study. JAMA Surg 2018;153: pass surgery on type 2 diabetes mellitus with Microvascular outcomes in patients with diabe- 427–434 hypertension: a randomized controlled trial. Di- tes after bariatric surgery versus usual care: 97. Birkmeyer JD, Finks JF, O’Reilly A, et al.; abetes Res Clin Pract 2013;101:50–56 a matched cohort study. Ann Intern Med Michigan Bariatric Surgery Collaborative. Surgi- 69. Aminian A, Chang J, BrethauerAmerican SA, Kim JJ; 2018;169:300–310 cal skill and complication rates after bariatric American Society for Metabolic and Bariatric 83. Halperin F, Ding S-A, Simonson DC, et al. surgery. N Engl J Med 2013;369:1434–1442 Surgery Clinical Issues Committee. ASMBS up- Roux-en-Y gastric bypass surgery or lifestyle with 98. Service GJ, Thompson GB, Service FJ, dated position statement on bariatric surgery in intensive medical management in patients with Andrews JC, Collazo-Clavell ML, Lloyd RV. Hyper- class I obesity (BMI 30–35 kg/m2). Surg Obes type 2 diabetes: feasibility and 1-year results of insulinemic hypoglycemia with nesidioblastosis Relat Dis 2018;14:1071–1087 a randomized clinical trial. JAMA Surg 2014; after gastric-bypass surgery. N Engl J Med 2005; 70. Isaman DJM, Rothberg AE, Herman WH. 149:716–726 353:249–254 Reconciliation of type 2 diabetes remission rates 84. Kirwan JP, Aminian A, Kashyap SR, Burguera 99. Mechanick JI, Kushner RF, Sugerman HJ, in studies of Roux-en-Y gastric bypass. Diabetes B, Brethauer SA, Schauer PR. Bariatric surgery in et al.; American Association of Clinical Endocri- Care©2019 2016;39:2247–2253 obese patients with type 1 diabetes. Diabetes nologists; Obesity Society; American Society for 71. Ikramuddin S, Korner J, Lee W-J, et al. Du- Care 2016;39:941–948 Metabolic & Bariatric Surgery. American Asso- rability of addition of Roux-en-Y gastric bypass to 85. Rubin JK, Hinrichs-Krapels S, Hesketh R, ciation of Clinical Endocrinologists, The Obesity lifestyle intervention and medical management Martin A, Herman WH, Rubino F. Identifying Society, and American Society for Metabolic & in achieving primary treatment goals for un- barriers to appropriate use of metabolic/ Bariatric Surgery medical guidelines for clinical controlled type 2 diabetes in mild to moderate bariatric surgery for type 2 diabetes treatment: practice for the perioperative nutritional, met- obesity:arandomizedcontroltrial.DiabetesCare policy lab results. Diabetes Care 2016;39:954– abolic, and nonsurgical support of the bariatric 2016;39:1510–1518 963 surgery patient. Obesity (Silver Spring) 2009; 72. Sjoholm¨ K, Pajunen P, Jacobson P, et al. 86. Fouse T, Schauer P. The socioeconomic 17(Suppl. 1):S1–S70 Incidence and remission of type 2 diabetes in impact of morbid obesity and factors affecting 100. Mechanick JI, Youdim A, Jones DB, et al.; relation to degree of obesity at baseline and access to obesity surgery. Surg Clin North Am American Association of Clinical Endocrinolo- 2 year weight change: the Swedish Obese 2016;96:669–679 gists; Obesity Society; American Society for care.diabetesjournals.org S97

Metabolic & Bariatric Surgery. Clinical prac- 107. Greenberg I, Sogg S, M Perna F. Behavioral Accessed 22 October 2019. Available from tice guidelines for the perioperative nutritional, and psychological care in weight loss surgery: https://www.belviq.com metabolic, and nonsurgical support of the bari- best practice update. Obesity (Silver Spring) 114. VIVUS, Inc. Qsymia (phentermine and top- atric surgery patientd2013 update: cospon- 2009;17:880–884 iramate extended-release) capsules [prescribing sored by American Association of Clinical 108. TruvenHealthAnalytics.IntroductiontoRED information]. Accessed 22 October 2019. Avail- Endocrinologists, The Obesity Society, and Amer- BOOK Online. Accessed 2 October 2019. Avail- able from https://qsymia.com ican Society for Metabolic & Bariatric Surgery. able from https://www.micromedexsolutions 115. Novo Nordisk. Saxenda (liraglutide) injec- Obesity (Silver Spring) 2013;21(Suppl. 1):S1–S27 .com/micromedex2/4.34.0/WebHelp/RED_ tion [prescribing information]. Accessed 22 Oc- 101. Lee CJ, Clark JM, Schweitzer M, et al. Prev- BOOK/Introduction_to_REDB_BOOK_Online tober 2019. Available from https://www alence of and risk factors for hypoglycemic symp- .htm .saxenda.com toms after gastric bypass and sleeve gastrectomy. 109. Data.Medicaid.gov. NADAC (National Av- 116. Aronne LJ, Wadden TA, Peterson C, Winslow Obesity (Silver Spring) 2015;23:1079–1084 erage Drug Acquisition Cost), 2019. Accessed D, Odeh S, Gadde KM. Evaluation of phentermine 102. Conason A, Teixeira J, Hsu C-H, Puma L, Knafo 2 October 2019. Available from https://data and topiramate versus phentermine/topiramate D, Geliebter A. Substance use following bariatric .medicaid.gov/Drug-Pricing-and-Payment/NADAC- extended-release in obese adults. Obesity weight loss surgery. JAMA Surg 2013;148:145–150 National-Average-Drug-Acquisition-Cost-/a4y5- (Silver Spring) 2013;21:2163–2171 103. Bhatti JA, Nathens AB, Thiruchelvam D, 998d 117. Gadde KM, Allison DB, Ryan DH, et al. Grantcharov T, Goldstein BI, Redelmeier DA. 110. U.S.NationalLibraryofMedicine.Phentermine Effects of low-dose, controlled-release, phenter- Self-harm emergencies after bariatric surgery: –phentermine hydrochloride capsule.Accessed22 mine plus topiramate combination on weight a population-based cohort study. JAMA Surg October 2019. Available from https://dailymed and associated comorbidities in overweight and 2016;151:226–232 .nlm.nih.gov/dailymed/drugInfo.cfm?setid5 obese adults (CONQUER): a randomised, pla- 104. Peterhansel¨ C, Petroff D, Klinitzke G, 737eef3b-9a6b-4ab3-a25c-49d84d2a0197 cebo-controlled, phase 3 trial. Lancet 2011;377: Kersting A, Wagner B. Risk of completed suicide 111. Nalpropion Pharmaceuticals. Contrave 1341–1352 after bariatric surgery: a systematic review. Obes (naltrexone HCl/bupropion HCl) Extended- 118. Bohula EA, Wiviott SD, McGuire DK, et al.; Rev 2013;14:369–382 Release Tablets [prescribing information]. Ac- CAMELLIA–TIMI 61 Steering Committee and In- 105. Jakobsen GS, SmastuenMC,SandbuR,etal.˚ cessed 22 October 2019. Available from: https:// vestigators.Association Cardiovascular safety of lorcaserin Association of bariatric surgery vs medical obe- contrave.com in overweight or obese patients. N Engl J Med sity treatment with long-term medical com- 112. CHEPLAPHARM and H2-Pharma. Xenical 2018;379:1107–1117 plications and obesity-related comorbidities. (orlistat) [prescribing information]. Accessed 119. Marso SP, Daniels GH, Brown-Frandsen K, JAMA 2018;319:291–301 22 October 2019. Available from https:// et al.; LEADER Steering Committee; LEADER 106. Young-Hyman D, Peyrot M. Psychosocial xenical.com Trial Investigators. Liraglutide and cardiovascu- Care for People with Diabetes. Alexandria,VA, 113. Eisai Inc. Belviq (lorcaserin HCl) and Belviq lar outcomes in type 2 diabetes. N Engl J Med American Diabetes Association, 2012 XR (lorcaserin HCl) [prescribing information]. 2016;375:311–322

Diabetes

American

9. Pharmacologic Approaches to American Diabetes Association Glycemic Treatment: Standards of Medical Care in Diabetesd2020

Diabetes Care 2020;43(Suppl. 1):S98–S110 | https://doi.org/10.2337/dc20-S009

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes” Association includes the ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc20-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence- grading system for ADA’s clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc20-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.Diabetes

PHARMACOLOGIC THERAPY FOR TYPE 1 DIABETES

Recommendations

9. PHARMACOLOGIC APPROACHES TO GLYCEMIC TREATMENT 9.1 Mostpeoplewithtype1diabetesshouldbetreatedwithmultipledailyinjections of prandial and basal insulin, or continuous subcutaneous insulin infusion. A 9.2 Most individuals with type 1 diabetes should use rapid-acting insulin analogs to reduce hypoglycemia risk. A 9.3 Patients with type 1 diabetes should be trained to match prandial insulin doses to carbohydrate intake,American premeal blood glucose, and anticipated physical activity. C Insulin Therapy Because the hallmark of type 1 diabetes is absent or near-absent b-cell function, insulin treatment is essential for individuals with type 1 diabetes. In addition to hyperglycemia, insulinopenia can contribute to other metabolic disturbances like hypertriglyceridemia and ketoacidosis as well as tissue catabolism that can be life threatening. Severe metabolic decompensation can be, and was, mostly prevented with once or twice daily injections for the six or seven decades after the discovery©2019 of insulin. However, over the past three decades, evidence has accumulated supporting more intensive insulin replacement, using multiple daily injections of Suggested citation: American Diabetes Associa- insulin or continuous subcutaneous administration through an insulin pump, as tion. 2. Pharmacologic approaches to glycemic providing the best combination of effectiveness and safety for people with type 1 treatment: StandardsofMedicalCareinDiabetesd diabetes. The Diabetes Control and Complications Trial (DCCT) demonstrated that 2020. Diabetes Care 2020;43(Suppl. 1):S98–S110 intensive therapy with multiple daily injections or continuous subcutaneous insulin © 2019 by the American Diabetes Association. infusion (CSII) reduced A1C and was associated with improved long-term outcomes Readers may use this article as long as the work – is properly cited, the use is educational and not (1 3). The study was carried out with short-acting (regular) and intermediate-acting for proﬁt, and the work is not altered. More infor- (NPH) human insulins. In this landmark trial, lower A1C with intensive control (7%) mation is available at http://www.diabetesjournals led to ;50% reductions in microvascular complications over 6 years of treatment. .org/content/license. care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S99

However, intensive therapy was associ- meta-analysis concluded that pump ther- Typical multidose regimens for pa- ated with a higher rate of severe hypo- apy has modest advantages for lowering tients with type 1 diabetes combine glycemiathanconventional treatment (62 A1C (–0.30% [95% CI –0.58 to –0.02]) and premeal use of shorter-acting insulins compared with 19 episodes per 100 pa- for reducing severe hypoglycemia rates with a longer-acting formulation, usually tient-years of therapy). Follow-up of sub- in children and adults (11). However, there at night. The long-acting basal dose is jects from the DCCT more than 10 years is no consensus to guide the choice of titrated to regulate overnight, fasting after the active treatment component of injection or pump therapy in a given glucose. Postprandial glucose excur- the study demonstrated less macrovas- patient, and research to guide this sions are best controlled by a well-timed cular as well as less microvascular com- decision-making is needed (12). The arrival injection of prandial insulin. The opti- plications in the group that received of continuous glucose monitors to clinical mal time to administer prandial insulin intensive treatment. practice has proven beneficial in specific varies, based on the pharmacokinetics Over the last 25 years, rapid-acting and circumstances. Reduction of nocturnal of the formulation (regular, RAA, in- long-acting insulin analogs have been hypoglycemia in people with type 1 di- haled), the premeal blood glucose level, developed that have distinct pharmaco- abetes using insulin pumps with glucose and carbohydrate consumption. Recom- kinetics compared with recombinant hu- sensors is improved by automatic sus- mendations for prandial insulin dose man insulins: basal insulin analogs have pension of insulin delivery at a preset administration should therefore be indi- longer duration of action with flatter, glucose level (12–14). The U.S. Food and vidualized. Physiologic insulin secretion more constant plasma concentrations Drug Administration (FDA) has also ap- varies with glycemia, meal size, and tissue and activity profiles than NPH insulin; proved the first hybrid closed-loop pump demands for glucose. To approach this rapid-acting analogs (RAA) have a quicker system. The safety and efficacy of hybrid variability in people using insulin treat- onset and peak and shorter duration of closed-loop systems has been supported ment,Association strategies have evolved to adjust action than regular human insulin. In in the literature in adolescents and adults prandial doses based on predicted needs. people with type 1 diabetes, treatment with type 1 diabetes (15,16), and recent Thus, education of patients on how to with analog insulins is associated with less evidence suggests that a closed-loop adjust prandial insulin to account for hypoglycemia and weight gain as well as system is superior to sensor-augmented carbohydrate intake, premeal glucose lower A1C compared with human insu- pump therapy for glycemic control levels, and anticipated activity can be lins (4–6). More recently, two new insulin and reduction of hypoglycemia over 3 effective and should be offered to most formulations with enhanced rapid action months of comparison in children and patients (20,21). For individuals in whom profiles have been introduced. Inhaled adults with type 1 diabetes (17). Intensive carbohydrate counting is effective, esti- human insulin has a rapid peak and insulinmanagementusingaversionofCSII mates of the fat and protein content of shortened duration of action compared and continuous glucose monitoring should meals can be incorporated into their with RAA and may cause less hypogly- be considered in mostDiabetes patients. See Sec- prandial dosing for added benefit (22). cemia and weight gain (7), and faster- tion 7 “Diabetes Technology” (https://doi acting insulin aspart may reduce prandial .org/10.2337/dc20-S007) for a full discus- Insulin Injection Technique excursions better than RAA (8); further sion of insulin delivery devices. Ensuring that patients and/or caregivers investigationisneededtoestablishaclear In general, patients with type 1 di- understand correct insulin injection tech- place for these agents in diabetes man- abetes require 50% of their daily insulin nique is important to optimize glucose agement. In addition, new longer-acting as basal and 50% as prandial. Total daily control and insulin use safety. Thus, it is basal analogs (U-300 glargine or degludec) insulin requirements can be estimated important that insulin be delivered into may confer a lower hypoglycemia risk based on weight, with typical doses the proper tissue in the right way. Rec- compared with U-100 glargine in patients ranging from 0.4 to 1.0 units/kg/day. ommendations have been published else- with type 1 diabetes (9,10). Despite the Higher amounts are required during pu- where outlining best practices for insulin advantages of insulin analogsAmerican in patients berty, pregnancy, and medical illness. injection (23). Proper insulin injection tech- with type 1 diabetes, for some patients the The American Diabetes Association/ nique includes injecting into appropriate expense and/or intensity of treatment JDRF Type 1 Diabetes Sourcebook notes body areas, injection site rotation, ap- required for their use is prohibitive. There 0.5 units/kg/day as a typical starting dose propriate care of injection sites to avoid are multiple approaches to insulin treat- in patients with type 1 diabetes who are infection or other complications, and avoid- ment, and the central precept in the metabolically stable, with half adminis- ance of intramuscular (IM) insulin delivery. management of type 1 diabetes is tered as prandial insulin given to control Exogenous-delivered insulin should be that some form of insulin be given in blood glucose after meals and the other injected into subcutaneous tissue, not a planned©2019 regimen tailored to the in- half as basal insulin to control glycemia intramuscularly. Recommended sites for dividual patient to keep them safe, out of in the periods between meal absorption insulin injection include the abdomen, diabetic ketoacidosis, and avoid signifi- (18); this guideline provides detailed in- thigh, buttock, and upper arm. Because cant hypoglycemia, with every effort formation on intensification of therapy insulin absorption from IM sites differs made to reach the patient’s glycemic to meet individualized needs. In addi- according to the activity of the muscle, targets. tion, the American Diabetes Association inadvertent IM injection can lead to un- Most studies comparing multiple daily position statement “Type 1 Diabetes predictable insulin absorption and vari- injections with CSII have been rela- Management Through the Life Span” able effects on glucose, with IM injection tively small and of short duration. How- provides a thorough overview of type 1 being associated with frequent and unex- ever, a recent systematic review and diabetes treatment (19). plained hypoglycemia in several reports. S100 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 43, Supplement 1, January 2020

Risk for IM insulin delivery is increased in exenatide to insulin therapy caused at treatment initiation to extend younger, leaner patients when injecting small (0.2%) reductions in A1C compared thetimetotreatmentfailure.A into the limbs rather than truncal sites with insulin alone in people with type 1 9.7 The early introduction of insulin (abdomen and buttocks) and when using diabetes and also reduced body weight should be considered if there is longer needles. Recent evidence supports by ;3 kg (29). Similarly, the addition evidence of ongoing catabolism the use of short needles (e.g., 4-mm pen of a sodium–glucose cotransporter 2 (weight loss), if symptoms of needles) as effective and well tolerated (SGLT2) inhibitor to insulin therapy has hyperglycemia are present, or when compared with longer needles, been associated with improvements in when A1C levels (.10% [86 including a study performed in obese A1C and body weight when compared mmol/mol]) or blood glucose lev- adults (24). with insulin alone (30,31); however, SGLT2 els ($300 mg/dL [16.7 mmol/L]) Injection site rotation is additionally inhibitor use in type 1 diabetes is associ- are very high. E necessary to avoid lipohypertrophy, an ated with a two- to fourfold increase 9.8 A patient-centered approach accumulation of subcutaneous fat in rein ketoacidosis. The risks and benefits should be used to guide the sponse tothe adipogenicactions ofinsulin of adjunctive agents continue to be eval- choice of pharmacologic agents. at a site of multiple injections. Lipohyper- uated, but only pramlintide is approved Considerations include cardiovas- trophy appears as soft, smooth raised for treatment of type 1 diabetes. cular comorbidities, hypoglycemia areas several centimeters in breadth risk,impactonweight,cost, riskfor and can contribute to erratic insulin ab- SURGICAL TREATMENT FOR TYPE 1 side effects, and patient preferen- sorption, increased glycemic variability, DIABETES ces (Table 9.2 and Figure 9.1). E and unexplained hypoglycemic episodes. Pancreas and Islet Transplantation 9.9 Among patients with type 2 di- Patients and/or caregivers should receive Successful pancreas and islet transplan- Associationabetes who have established education about proper injection site rotation can normalize glucose levels and atherosclerotic cardiovascular tation and to recognize and avoid areas mitigate microvascular complications of disease or indicators of high risk, of lipohypertrophy. As noted in Table 4.1, type 1 diabetes. However, patients re- established kidney disease, or heart examination of insulin injection sites for ceiving these treatments require life- failure, a sodium–glucose cotrans- the presence of lipohypertrophy, as well long immunosuppression to prevent porter 2 inhibitor or glucagon-like as assessment of injection device use graft rejection and/or recurrence of peptide 1 receptor agonist with and injection technique, are key compo- autoimmune islet destruction. Given the demonstrated cardiovascular dis- nents of a comprehensive diabetes med- potential adverse effects of immunosup- ease benefit(Table 9.1, Table 10 ical evaluation and treatment plan. As pressive therapy, pancreas transplan- .3B,Table10.3C)isrecommended referenced above, there are now numer- tation should be reserved for patients as part of the glucose-lowering ous evidence-based insulin delivery rec- with type 1 diabetesDiabetes undergoing si- regimen independent of A1C and ommendations that have been published. multaneous renal transplantation, fol- in consideration of patient-specific Proper insulin injection technique may lowing renal transplantation, or for those factors (Figure 9.1). A lead to more effective use of this therapy with recurrent ketoacidosis or severe 9.10 In patients with type 2 diabetes and, as such, holds the potential for im- hypoglycemia despite intensive glycemic who need greater glucose low- proved clinical outcomes. management (32). With the advent of ering than can be obtained with improved continuous glucose monitors, oral agents, glucagon-like pep- closed-loop pump-sensor systems, and Noninsulin Treatments for Type 1 tide 1 receptor agonists are pre- devices that offer alternative approaches Diabetes ferredtoinsulinwhenpossible.B Injectable and oral glucose-lowering for patients with hypoglycemia unaware- 9.11 Intensification of treatment for drugs have been studied for their efficacy ness, the role of pancreas transplantation patients with type 2 diabetes as adjuncts to insulin treatmentAmerican of type 1 alone, as well as islet transplant, will need not meeting treatment goals diabetes. Pramlintide is based on the to be reconsidered. should not be delayed. B naturally occurring b-cell peptide amylin 9.12 The medication regimen and and is approved for use in adults with PHARMACOLOGIC THERAPY FOR medication-taking behavior type 1 diabetes. Results from random- TYPE 2 DIABETES should be reevaluated at regular ized controlled studies show variable Recommendations intervals (every 3–6 months) and reductions of A1C (0–0.3%) and body 9.4 Metformin is the preferred ini- adjusted as needed to incorpo- weight (1–2 kg) with addition of pram- tial pharmacologic agent for rate specificfactorsthatimpact lintide©2019 to insulin (25,26). Similarly, re- the treatment of type 2 diabetes. choice of treatment (Fig. 4.1 and sults have been reported for several A Table 9.1). E agents currently approved only for 9.5 Once initiated, metformin should the treatment of type 2 diabetes. The be continued as long as it is tol- addition of metformin to adults with The American Diabetes Association/ erated and not contraindicated; type 1 diabetes caused small reductions European Association for the Study of other agents, including insulin, in body weight and lipid levels but did Diabetes consensus report “Manage- should be added to metformin. A not improve A1C (27,28). The addition ment of Hyperglycemia in Type 2 Di- 9.6 Early combination therapy can of the glucagon-like peptide 1 (GLP-1) abetes, 2018” and the 2019 update be considered in some patients receptor agonists (RAs) liraglutide and (33,34) recommend a patient-centered care.diabetesjournals.org Table 9.1—Drug-specific and©2019 patient factors to consider when selecting antihyperglycemic treatment in adults with type 2 diabetes

American

Diabetes hraooi prahst lcmcTetetS101 Treatment Glycemic to Approaches Pharmacologic Association

*For agent-speciﬁc dosing recommendations, please refer to the manufacturers’ prescribing information. †FDA approved for CVD beneﬁt. ‡FDA-approved for heart failure indication; §FDA-approved for CKD indication. CV, cardiovascular; DPP-4, dipeptidyl peptidase 4; DKA, diabetic ketoacidosis; DKD, diabetic kidney disease; GLP-1 RAs, glucagon-like peptide 1 receptor agonists; HF, heart failure; NASH, nonalcoholic steatohepatitis; SGLT2, sodium–glucose cotransporter 2; SQ, subcutaneous; T2DM, type 2 diabetes. S102 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 43, Supplement 1, January 2020

approach to choosing appropriate phar- very high circulating levels (e.g., as a re- positive and negative effects of new drugs macologic treatment of blood glucose sult of overdose or acute renal failure) and reduces patient risk and expense (42); (Fig. 9.1). This includes consideration of have been associated with lactic acidosis. based on these factors, sequential addi- efficacy and key patient factors: 1)im- However, the occurrence of this compli- tion of oral agents to metformin has been portant comorbidities such as atheroscle- cation is now known to be very rare, and the standard of care. However, there is rotic cardiovascular disease (ASCVD) and metformin may be safely used in patients data to support initial combination ther- indicators of high ASCVD risk, chronic with reduced estimated glomerular filtra- apyfor morerapidattainment of glycemic kidney disease (CKD), and heart failure tion rates (eGFR); the FDA has revised the goals (43,44), and a recent clinical trial (HF) (see Section 10 “Cardiovascular Dis- label for metformin to reflect its safety in has demonstrated that this approach is ease and Risk Management,” https://doi patients with eGFR $30 mL/min/1.73 m2 superior to sequential addition of medica- .org/10.2337/dc20-S010, and Section 11 (37). A recent randomized trial confirmed tionsforextendingprimary andsecondary “Microvascular Complications and Foot previousobservations that metforminuse failure (45). In the VERIFY trial, partic- Care,” https://doi.org/10.2337/dc20-S011), is associated with vitamin B12 deficiency ipants receiving the initial combination of 2) hypoglycemia risk, 3) effects on body and worsening of symptoms of neurop- metformin and the dipeptidyl peptidase 4 weight, 4) side effects, 5) cost, and 6) athy (38). This is compatible with a recent (DPP-4) inhibitor vildagliptin had a slower patient preferences. Lifestyle modifica- report from the Diabetes Prevention Pro- decline of glycemic control compared tions that improve health (see Section gramOutcomesStudy(DPPOS)suggesting with metformin alone and to vildagliptin 5 “Facilitating Behavior Change and periodic testing of vitamin B12 (39). added sequentially to metformin. These Well-being to Improve Health Outcomes,” In patients with contraindications or results have not been generalized to oral https://doi.org/10.2337/dc20-S005) should intolerance to metformin, initial therapy agents other than vildagliptin, but they be emphasized along with any pharma- should be based on patient factors; suggestAssociation that more intensive early treat- cologic therapy. Section 12 “Older Adults” consider a drug from another class de- ment has some benefits and should be (https://doi.org/10.2337/dc20-S012)andSec- picted in Fig. 9.1. When A1C is $1.5% considered through a shared decision- tion 13 “Children and Adolescents” (12.5 mmol/mol) above the glycemic making process with patients, as appropriate. (https://doi.org/10.2337/dc20-S013) target (see Section 6 “Glycemic Targets,” Moreover, since the absolute effectiveness have recommendations specific for older https://doi.org/10.2337/dc20-S006, for of most oral medications rarely exceeds adults and for children and adolescents selecting appropriate targets), many pa- 1%, initial combination therapy should be with type 2 diabetes, respectively; Sec- tients will require dual combination ther- considered in patients presenting with tion 10 “Cardiovascular Disease and Risk apy to achieve their target A1C level (40). A1C levels 1.5–2.0% above target. Management” (https://doi.org/10.2337/ Insulin has the advantage of being effec- The choice of medication added to dc20-S010) and Section 11 “Microvascular tive where other agents are not and should metformin is based on the clinical char- Complications and Foot Care” (https://doi be considered asDiabetes part of any combination acteristics of the patient and their pref- .org/10.2337/dc20-S011)haverecommen- regimen when hyperglycemia is severe, erences. Important clinical characteristics dations for the use of glucose-lowering especially if catabolic features (weight include the presence of established drugs in the management of cardiovascular loss, hypertriglyceridemia, ketosis) are ASCVD or indicators of high ASCVD risk, and renal disease, respectively. present. It is common practice to initiate other comorbidities, and risk for specific insulin therapy for patients who present adverse drug effects, as well as safety, Initial Therapy with blood glucose levels $300 mg/dL tolerability, and cost. Although there are Metformin should be started at the time (16.7 mmol/L) or A1C .10% (86 mmol/mol) numerous trials comparing dual therapy type 2 diabetes is diagnosed unless there or if the patient has symptoms of hy- with metformin alone, there is little ev- are contraindications; for many patients perglycemia (i.e., polyuria or polydipsia) idence to support one combination over this will be monotherapy in combination or evidence of catabolism (weight loss) another. A comparative effectiveness with lifestyle modifications.American Metformin (Fig. 9.2). As glucose toxicity resolves, meta-analysis suggests that each new is effective and safe, is inexpensive, and simplifying the regimen and/or changing class of noninsulin agents added to initial may reduce risk of cardiovascular events to oral agents is often possible. However, therapy with metformin generally lowers and death (35). Metformin is available in there is evidence that patients with un- A1C approximately 0.7–1.0% (46,47). If the an immediate-release form for twice- controlled hyperglycemia associated with A1C target is not achieved after approxi- daily dosing or as an extended-release type 2 diabetes can also be effectively mately 3 months, metformin can be com- form that can be given once daily. Com- treated with a sulfonylurea (41). bined with any one of the preferred six pared with sulfonylureas, metformin as treatment options: sulfonylurea, thiazolidine- fi©2019rst-line therapy has bene ficial effects on Combination Therapy dione, DPP-4 inhibitor, SGLT2 inhibitor, GLP-1 A1C, weight, and cardiovascular mortal- Because type 2 diabetes is a progressive RA, or basal insulin; the choice of which agent ity (36); there is little systematic data disease in many patients, maintenance of to add is based on drug-specificeffectsand available for other oral agents as initial glycemic targets with monotherapy is patient factors (Fig. 9.1 and Table 9.1). therapy of type 2 diabetes. The principal often possible for only a few years, after Forpatients withestablished ASCVD or side effects of metformin are gastroin- which combination therapy is necessary. indicators of high ASCVD risk (such as testinal intolerance due to bloating, ab- Current recommendations have been to patients $55 years of age with coronary, dominal discomfort, and diarrhea; these use stepwise addition of medications carotid, or lower-extremity artery steno- canbemitigated bygradualdosetitration. tometformintomaintainA1Cattarget. sis .50% or left ventricular hypertro- The drug is cleared by renal filtration, and This allows a clearer assessment of the phy), established kidney disease, or heart ©2019 care.diabetesjournals.org

American

Diabetes hraooi prahst lcmcTetetS103 Treatment Glycemic to Approaches Pharmacologic Association

Figure 9.1—Glucose-lowering medication in type 2 diabetes: overall approach. For appropriate context, see Fig. 4.1. ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease; CVOTs, cardiovascular outcomes trials; DPP-4i, dipeptidyl peptidase 4 inhibitor; eGFR, estimated glomerular ﬁltration rate; GLP-1 RA, glucagon-like peptide 1 receptor agonist; HF, heart failure; SGLT2i, sodium–glucose cotransporter 2 inhibitor; SU, sulfonylurea; TZD, thiazolidinedione. Adapted from Davies and colleagues (33,34). S104 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 43, Supplement 1, January 2020

Association

Diabetes

American

Figure9.2—Intensifyingtoinjectabletherapies.DSMES,diabetesself-managementeducationandsupport;FPG,fastingplasmaglucose;FRC,ﬁxed-ratio combination; GLP-1 RA, glucagon-like peptide 1 receptor agonist; max, maximum; PPG, postprandial glucose. Adapted from Davies et al. (33). care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S105

failure, an SGLT-2 inhibitor or GLP-1 RA with preferred option for patients requiring Insulin Therapy demonstrated CVD benefit(Table 9.1, the potency of an injectable therapy for Many patients with type 2 diabetes even- Table 10.3B, Table 10.3C) is recommended glucose control (Fig. 9.2). However, high tually require and benefit from insulin as part of the glucose-lowering regimen costs and tolerability issues are impor- therapy (Fig. 9.2). See the section INSULIN independent ofA1C and in consideration of tant barriers to the use of GLP-1 RAs. INJECTION TECHNIQUE above, for guidance on patient-specificfactors(Figure 9.1). For Cost for diabetes medicine has in- how to administer insulin safely and patients without established ASCVD, indi- creased dramatically over the past two effectively. The progressive nature of catorsofhighASCVDrisk,HF,orCKD,the decades, and an increasing proportion is type 2 diabetes should be regularly choice of a second agent to add to met- now passed on to patients and their families and objectively explained to patients, formin is not yet guided by empiric evi- (53). Table 9.2 provides cost information for and providers should avoid using insulin dence. Rather, drug choice is based on currently approved noninsulin therapies. Of as a threat or describing it as a sign of avoidance of side effects, particularly hy- note, prices listed are average wholesale personal failure or punishment. Rather, poglycemia and weight gain, cost, and prices (AWP) (54) and National Average the utility and importance of insulin to patient preferences (48). Similar consider- Drug Acquisition Costs (NADAC) (55), sep- maintain glycemic control once progres- ations are applied in patients who require a arate measures to allow for a comparison of sion of the disease overcomes the effect of third agent to achieve glycemic goals; there drug prices but do notaccountfor discounts, other agents should be emphasized. Ed- is very little trial-based evidence to guide rebates, or other price adjustments often ucating and involving patients in insulin this choice. In all cases, treatment regimens involved in prescription sales that affect the management is beneficial. For example, need to be continuously reviewed for actual cost incurred by the patient. Med- instruction of patients in self-titration of efficacy, side effects, and patient burden ication costs can be a major source of stress insulin doses based on self-monitoring of (Table 9.1). In some instances, patients will for patients with diabetes and contribute to blood glucoseAssociation improves glycemic control require medication reduction or discontin- worse adherence with medications (56); in patients with type 2 diabetes initiating uation. Common reasons for this include cost-reducing strategies may improve ad- insulin (58). Comprehensive education re- ineffectiveness, intolerable side effects, ex- herence in some cases (57). garding self-monitoring of blood glucose, pense, or a change in glycemic goals (e.g., in diet, and the avoidance and appropriate response to development of comorbidities Cardiovascular Outcomes Trials treatment of hypoglycemia are critically or changes in treatment goals). Section There are now multiple large randomized important in any patient using insulin. 12 “Older Adults”(https://doi.org/10.2337/ controlled trials reporting statistically dc20-S012) has a full discussion of treat- significant reductions in cardiovascular Basal Insulin ment considerations in older adults, a events in patients with type 2 diabetes Basal insulinalone isthe most convenient settingwhere changes of glycemic goals treated with an SGLT2 inhibitor (em- initial insulin regimen and can be added and de-escalation of therapy is common. pagliflozin, canagliDiabetesflozin, dapagliflozin) to metformin and other oral agents. Although most patients prefer oral or GLP-1 RA (liraglutide, semaglutide, Starting doses can be estimated based medications to drugs that need to be dulaglutide); see Section 10 “Cardiovas- on body weight (0.1–0.2 units/kg/day) injected, the eventual need for the cular Disease and Risk Management” and the degree of hyperglycemia, with greater potency of injectable medica- (https://doi.org/10.2337/dc20-S010) for individualized titration over days to weeks tions is common, particularly in people details. The subjects enrolled in the cardio- as needed. The principal action of basal with a longer duration of diabetes. The vascular outcome trials using empagliflozin, insulinistorestrainhepaticglucosepro- addition of basal insulin, either human canagliflozin, liraglutide, and semaglutide duction and limit hyperglycemia overnight NPH or one of the long-acting insulin had A1C $7%, and more than 70% were and between meals (59,60). Control of analogs, to oral agent regimens is a well- taking metformin at baseline. Thus, a prac- fasting glucose can be achieved with established approach that is effective for tical extension of these results to clinical human NPH insulin or a long-acting insulin many patients. In addition,American recent evi- practice is to use these drugs preferen- analog. In clinical trials, long-acting basal dence supports the utility of GLP-1 RAs in tially in patients with type 2 diabetes and analogs (U-100 glargine or detemir) have patients not reaching glycemic targets established ASCVD or indicators of high been demonstrated to reduce the risk of with use of non-GLP-1 RA oral agent ASCVD risk. For these patients, incorpo- symptomaticandnocturnalhypoglycemia regimens. While most GLP-1 RA products rating one of the SGLT2 inhibitors or compared with NPH insulin (61–66), al- are injectable, an oral formulation of GLP-1 RAs that have been demonstrated though these advantages are modest and semaglutide is now commercially avail- to have cardiovascular disease benefitis may not persist (67). Longer-acting basal able (49). In trials comparing the ad- recommended (Table 9.1). In cardiovascular analogs (U-300 glargine or degludec) may dition©2019 of an injectable GLP-1 RAs or outcomes trials, empagliflozin, canagliflozin, convey a lower hypoglycemia risk com- insulin in patients needing further glu- dapagliflozin, liraglutide, semaglutide, and pared with U-100 glargine when used in cose lowering, the efficacy of the two dulaglutide all had beneficial effects on combination with oral agents (68–74). treatments was similar (50–52). How- indices of CKD. See Section 11 “Microvas- Despite evidence for reduced hypoglyce- ever, GLP-1 RAs in these trials had a cular Complications and Foot Care”(https:// mia with newer, longer-acting basal in- lower risk of hypoglycemia and beneficial doi.org/10.2337/dc20-S011) for a detailed sulin analogs in clinical trial settings, in effects on body weight compared with discussion on how CKD may impact treat- practice these effects may be modest insulin, albeit with greater gastroin- ment choices. Additional large randomized compared with NPH insulin (75). testinal side effects. Thus, trial results trials of other agents in these classes are The cost of insulin has been rising support injectable GLP-1 RAs as the ongoing. steadily over the past two decades, at S106 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 43, Supplement 1, January 2020

Table 9.2—Median monthly (30-day) cost of maximum approved daily dose of noninsulin glucose-lowering agents in the U.S. Dosage strength/product Median AWP Median NADAC Maximum approved Class Compound(s) (if applicable) (min, max)† (min, max)† daily dose* Biguanides c Metformin 500 mg (IR) $84 ($4, $85) $2 2,000 mg 850 mg (IR) $108 ($6, $109) $3 2,550 mg 1,000 mg (IR) $87 ($4, $88) $2 2,000 mg 500 mg (ER) $89 ($87, $7,412) $5 ($5, $988) 2,000 mg 750 mg (ER) $74 ($65, $74) $4 1,500 mg 1,000 mg (ER) $242 ($242, $7,214) $224 ($224, $910) 2,000 mg Sulfonylureas (2nd c Glimepiride 4 mg $74 ($71, $198) $4 8 mg generation) c Glipizide 10 mg (IR) $75 ($67, $97) $5 40 mg (IR) 10 mg (XL) $48 $15 20 mg (XL) c Glyburide 6 mg (micronized) $50 ($48, $71) $4 12 mg (micronized) 5 mg $93 ($63, $103) $11 20 mg Thiazolidinediones c Pioglitazone 45 mg $348 ($283, $349) $4 45 mg c Rosiglitazone 4 mg $407 $330 8 mg a-Glucosidase c Acarbose 100 mg $106 ($104, $106) $23 300 mg inhibitors c Miglitol 100 mg $241 $311 300 mg Meglitinides (glinides) c Nateglinide 120 mg $155 $39 360 mg c Repaglinide 2 mg $878 ($162, $897) $39 16 mg DPP-4 inhibitors c Alogliptin 25 mg $234 $168 25 mg c Saxagliptin 5 mg $505 $403Association5 mg c Linagliptin 5 mg $523 $419 5 mg c Sitagliptin 100 mg $541 $433 100 mg SGLT2 inhibitors c Ertugliflozin 15 mg $338 $271 15 mg c Dapagliflozin 10 mg $591 $473 10 mg c Empagliflozin 25 mg $591 $473 25 mg c Canagliflozin 300 mg $593 $475 300 mg GLP-1 RAs c Exenatide (extended release) 2 mg powder for $840 $672 2 mg** suspension or pen c Exenatide 10 mg pen $876 $730 20 mg c Dulaglutide 1.5/0.5 mL pen $911 $730 1.5 mg** c Semaglutide 1 mg pen $927 $745 1 mg** 14 mg (tablet)Diabetes $927 N/A 14 mg c Liraglutide 18 mg/3 mL pen $1,106 $886 1.8 mg c Lixisenatide 300 mg/3 mL pen $744 N/A 20 mg Bile acid sequestrant c Colesevelam 625 mg tabs $712 ($674, $712) $177 3.75 g 3.75 g suspension $675 $415 3.75 g Dopamine-2 agonist c Bromocriptine 0.8 mg $906 $729 4.8 mg Amylin mimetic c Pramlintide 120 mg pen $2,623 $2,097 120 mg/injection††† AWP, average wholesale price; DPP-4, dipeptidyl peptidase 4; ER and XL, extended release; GLP-1 RA, glucagon-like peptide 1 receptor agonist; IR, immediate release; N/A, data not available; NADAC, National Average Drug Acquisition Cost; SGLT2, sodium–glucose cotransporter 2. †Calculated for30-day supply (AWP[54]orNADAC[55]unitprice3 numberof dosesrequiredtoprovidemaximumapproveddailydose3 30 days); median AWP or NADAC listed alone when only one product and/or price. *Utilized to calculate median AWP and NADAC (min, max); generic prices used, if available commercially. **AAmericandministered once weekly. †††AWP and NADAC calculated based on 120 mg three times daily.

a pace several fold that of other medical familiar with its use (75). Human regular patient needs (see Figure 9.2). People expenditures (76). This expense contrib- insulin, NPH, and 70/30 NPH/regular prod- with type 2 diabetes are generally more utes significant burden to patients as ucts can be purchased for considerably insulin resistant than those with type 1 insulin has become a growing “out-of- less than the AWP and NADAC prices listed diabetes, require higher daily doses (;1 pocket” cost for people with diabetes, in Table 9.3 at select pharmacies. unit/kg), and have lower rates of hypo- and direct patient costs contribute to glycemia (77). Titration can be based treatment©2019 nonadherence (76). Therefore, Prandial Insulin on home glucose monitoring or A1C. consideration of cost is an important com- Many individuals with type 2 diabetes With significant additions to the prandial ponent of effective management. For require doses of insulin before meals, in insulin dose, particularly with the evening many patients with type 2 diabetes addition to basal insulin, to reach glyce- meal, consideration should be given to (e.g., individuals with relaxed A1C goals, mic targets. A dose of 4 units or 10% of decreasing basal insulin. Meta-analyses low rates of hypoglycemia, and prominent the amount of basal insulin at the largest of trials comparing rapid-acting insulin insulin resistance, as well as those with meal or the meal with the greatest post- analogs with human regular insulin in cost concerns), human insulin (NPH and prandial excursion is a safe estimate for patients with type 2 diabetes have not regular) may be the appropriate choice initiating therapy. The prandial insulin reported important differences in A1C of therapy, and clinicians should be regimen can then be intensified based on or hypoglycemia (78,79). care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S107

Table 9.3—Median cost of insulin products in the U.S. calculated as AWP (54) and NADAC (55) per 1,000 units of specified dosage form/product Insulins Compounds Dosage form/product Median AWP (min, max)* MedianNADAC(min, max)* Rapid-acting c Lispro follow-on U-100 vial $157 $126 product U-100 prefilled pen $202 $162 c Lispro U-100 vial $330 $264 U-100 3 mL cartridges $408 $327 U-100 prefilled pen; U-200 $424 $340 prefilled pen c Glulisine U-100 vial $341 $273 U-100 prefilled pen $439 $353 c Aspart U-100 vial $347† $278† U-100 3 mL cartridges $430 $345 U-100 prefilled pen $447† $358† c Inhaled insulin Inhalation cartridges $924 $606 Short-acting c human regular U-100 vial $165 ($165, $178)†† $134 ($134, $146)†† Intermediate-acting c human NPH U-100 vial $165 ($165, $178)†† $135 ($135, $146)†† U-100 prefilled pen $377 $304 Concentrated human c U-500 human regular U-500 vial $178 $144 regular insulin insulin U-500 prefilled pen $230 $184 Long-acting c Glargine follow-on U-100 prefilled pen $261 $210 product Association c Glargine U-100 vial; U-100 prefilled pen $340 $272 U-300 prefilled pen $346 $280 c Detemir U-100 vial; U-100 prefilled pen $370 $295 c Degludec U-100 vial; U-100 prefilled pen; $407 $326 U-200 prefilled pen Premixed insulin products c NPH/regular 70/30 U-100 vial $165 ($165, $178) $134 ($134, $145) U-100 prefilled pen $377 $303 c Lispro 50/50 U-100 vial $342 $274 U-100 prefilled pen $424 $338 c Lispro 75/25 U-100 vial $342 $274 U-100 prefilled pen $424 $340 c Aspart 70/30 U-100 vial Diabetes$360 $289 U-100 prefilled pen $447 $358 Premixed insulin/GLP-1 RA c Glargine/Lixisenatide 100/33 prefilled pen $565 $454 products c Degludec/Liraglutide 100/3.6 prefilled pen $832 $668 AWP, average wholesale price; GLP-1, glucagon-like peptide 1; NADAC, National Average Drug Acquisition Cost. *AWP or NADAC calculated as in Table 9.2. †Inclusive of both the original and “faster-acting” products. ††AWP and NADAC data presented do not include vials of regular human insulin and NPH available at Walmart for approximately $25/vial; median listed alone when only one product and/or price.

Concentrated Insulins units/mL).Theseconcentrated preparations hypoglycemia or weight gain (83), al- Several concentrated insulin prepara- maybemoreconvenientandcomfortable though results from a larger study are tions are currently available. U-500 reg- for patients to inject and may improve needed for confirmation. Inhaled insulin ular insulin is, by definition,Americanfive times adherence in those with insulin resistance is contraindicated in patients with chronic more concentrated than U-100 regular who require large doses of insulin. While lung disease, such as asthma and chronic insulin. Regular U-500 has distinct phar- U-500 regular insulin is available in both obstructive pulmonary disease, and is not macokinetics with delayed onset and prefilled pens and vials (a dedicated syringe recommended in patients who smoke or longer duration of action, has character- was approved in July 2016), other concen- who recently stopped smoking. All pa- istics more like an intermediate-acting trated insulins are available only in prefilled tients require spirometry (FEV1) testing to (NPH) insulin, and can be used as two or pens to minimize the risk of dosing errors. identify potential lung diseaseprior to and three daily injections (80). U-300 glargine after starting inhaled insulin therapy. and©2019 U-200 degludec are three and two Inhaled Insulin times as concentrated as their U-100 Inhaled insulin is available for prandial Combination Injectable Therapy formulations, and allow higher doses use with a limited dosing range; studies in If basal insulin has been titrated to an of basal insulin administration per vol- people with type 1diabetes suggest rapid acceptable fasting blood glucose level (or ume used. U-300 glargine has a longer pharmacokinetics (7). A pilot study found if the dose is .0.5 units/kg/day) and A1C duration of action than U-100 glargine evidence that compared with injectable remains above target, consider advancing but modestly lower efficacy per unit rapid-acting insulin, supplemental doses to combination injectable therapy (Fig. administered (81,82). The FDA has also of inhaled insulin taken based on post- 9.2). This approach can use a GLP-1 RA approved a concentrated formulation of prandial glucose levels may improve blood added to basal insulin or multiple doses of rapid-acting insulin lispro, U-200 (200 glucose management without additional insulin. The combination of basal insulin S108 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 43, Supplement 1, January 2020

and GLP-1 RA has potent glucose-lower- in type 1 diabetic participants of the Diabetes 15. Bergenstal RM, Garg S, Weinzimer SA, et al. ing actions and less weight gain and hypo- Control and Complications Trial/Epidemiology of Safety of a hybrid closed-loop insulin delivery fi Diabetes Interventions and Complications (DCCT/ system in patients with type 1 diabetes. JAMA glycemia compared with intensi ed insulin – – – EDIC) study. Diabetes 2006;55:3556 3565 2016;316:1407 1408 regimens (84 86). Two different once-daily 2. Nathan DM, Cleary PA, Backlund J-YC, et al.; 16. Garg SK, Weinzimer SA, Tamborlane WV, fixed-dual combination products contain- Diabetes Control and Complications Trial/ et al. Glucose outcomes with the in-home use of a ing basal insulin plus a GLP-1 RA are Epidemiology of Diabetes Interventions and hybrid closed-loop insulin delivery system in ado- available: insulin glargine plus lixisenatide Complications (DCCT/EDIC) Study Research Group. lescents and adults with type 1 diabetes. Diabetes – and insulin degludec plus liraglutide. Intensive diabetes treatment and cardiovascular Technol Ther 2017;19:155 163 disease in patients with type 1 diabetes. N Engl J fi 17. Tauschmann M, Thabit H, Bally L, et al.; Intensi cation of insulin treatment can Med 2005;353:2643–2653 APCam11 Consortium. Closed-loop insulin de- be done by adding doses of prandial to 3. Diabetes Control and Complications Trial livery in suboptimally controlled type 1 diabetes: basal insulin. Starting with a single pran- (DCCT)/Epidemiology of Diabetes Interventions a multicentre, 12-week randomised trial. Lancet dial dose with the largest meal of the day and Complications (EDIC) Study Research Group. 2018;392:1321–1329 Mortality in type 1 diabetes in the DCCT/EDIC is simple and effective, and it can be 18. Peters A, Laffel L (Eds.). American Diabetes versus the general population. Diabetes Care Association/JDRF Type 1 Diabetes Sourcebook. advanced to a regimen with multiple 2016;39:1378–1383 Alexandria, VA, American Diabetes Association, prandial doses if necessary (87). Alter- 4. Tricco AC, Ashoor HM, Antony J, et al. Safety, 2013 natively, in a patient on basal insulin in effectiveness, and cost effectiveness of long 19. Chiang JL,KirkmanMS,LaffelLMB,PetersAL; whom additional prandial coverage is acting versus intermediate acting insulin for pa- Type 1 Diabetes Sourcebook Authors. Type 1 di- tients with type 1 diabetes: systematic review desired, the regimen can be converted abetes through the life span: a position state- and network meta-analysis. BMJ 2014;349:g5459 ment of the American Diabetes Association. to two doses of a premixed insulin. Each 5. Bartley PC, Bogoev M, Larsen J, Philotheou A. Diabetes Care 2014;37:2034–2054 approach has advantages and disadvan- Long-term efficacy and safety of insulin detemir 20. Bell KJ, Barclay AW, Petocz P, Colagiuri S, tages. For example, basal/prandial regi- compared to Neutral Protamine Hagedorn in- Brand-MillerAssociation JC. Efficacy of carbohydrate count- mens offer greater flexibility for patients sulin in patients with type 1 diabetes using a ing in type 1 diabetes: a systematic review and treat-to-target basal-bolus regimen with insulin who eat on irregular schedules. On the meta-analysis. Lancet Diabetes Endocrinol 2014; aspart at meals: a 2-year, randomized, controlled 2:133–140 other hand, two doses of premixed in- trial. Diabet Med 2008;25:442–449 21. Vaz EC, Porf´ırio GJM, Nunes HRC, Nunes- sulin is a simple, convenient means of 6. DeWitt DE, Hirsch IB. Outpatient insulin ther- Nogueira VDS. Effectiveness and safety of car- spreading insulin across the day. More- apy in type 1 and type 2 diabetes mellitus: bohydrate counting in the management of adult over, humaninsulins,separately,self-mixed, scientific review. JAMA 2003;289:2254–2264 patients with type 1 diabetes mellitus: a system- 7. BodeBW,McGillJB,LorberDL,GrossJL,Chang or as premixed NPH/regular (70/30) atic review and meta-analysis. Arch Endocrinol PC, Bregman DB; Affinity 1 Study Group. Inhaled Metab 2018;62:337–345 formulations, are less costly alternatives technosphere insulin compared with injected 22. Bell KJ, Smart CE, Steil GM, Brand-Miller JC, to insulin analogs. Figure 9.2 outlines prandial insulin in type 1 diabetes: a randomized King B, Wolpert HA. Impact of fat, protein, and these options, as well as recommendations 24-week trial. Diabetes Care 2015;38:2266–2273 glycemic index on postprandial glucose control in for further intensification, if needed, to 8. Russell-Jones D,Diabetes Bode BW, De Block C, et al. type 1 diabetes: implications for intensive diabetes Fast-acting insulin aspart improves glycemic con- achieve glycemic goals. When initiating management in the continuous glucose monitor- trol in basal-bolus treatment for type 1 diabetes: ing era. Diabetes Care 2015;38:1008–1015 combination injectable therapy, metformin results of a 26-week multicenter, active-controlled, 23. Frid AH, Kreugel G, Grassi G, et al. New insulin therapy should be maintained while sulfo- treat-to-target, randomized, parallel-group trial delivery recommendations. Mayo Clin Proc nylureas and DPP-4 inhibitors are typically (onset 1). Diabetes Care 2017;40:943–950 2016;91:1231–1255 discontinued. In patients with suboptimal 9. Lane W, Bailey TS, Gerety G, et al.; Group 24. Bergenstal RM, Strock ES, Peremislov D, Information; SWITCH 1. Effect of insulin degludec blood glucose control, especially those re- Gibney MA, Parvu V, Hirsch LJ. Safety and ef- vs insulin glargine U100 on hypoglycemia in ficacy of insulin therapy delivered via a 4mm pen quiring large insulin doses, adjunctive use patients with type 1 diabetes: the SWITCH 1 needle in obese patients with diabetes. Mayo of a thiazolidinedione or an SGLT2 inhibitor randomized clinical trial. JAMA 2017;318:33–44 Clin Proc 2015;90:329–338 mayhelptoimprovecontrol and reduce the 10. Home PD, Bergenstal RM, Bolli GB, et al. New 25. Ratner RE,DickeyR, FinemanM,et al.Amylin amountofinsulin needed, though potential insulin glargine 300 units/mL versus glargine replacement with pramlintide as an adjunct to 100 units/mL in people with type 1 diabetes: side effects should be considered.American Once a insulin therapy improves long-term glycaemic a randomized, phase 3a, open-label clinical and weight control in type 1 diabetes mellitus: basal/bolus insulin regimen is initiated, trial (EDITION 4). Diabetes Care 2015;38:2217– a1-year,randomizedcontrolledtrial.DiabetMed dose titration is important, with adjust- 2225 2004;21:1204–1212 ments made in both mealtime and basal 11. Yeh H-C, Brown TT, Maruthur N, et al. 26. Edelman S, Garg S, Frias J, et al. A double-blind, insulins based on the blood glucose levels Comparative effectiveness and safety of meth- placebo-controlled trial assessing pramlintide treat- ods of insulin delivery and glucose monitoring for and an understanding of the pharma- ment in the setting of intensive insulin therapy in diabetes mellitus: a systematic review and meta- type 1 diabetes. Diabetes Care 2006;29:2189–2195 codynamic profile of each formulation analysis. Ann Intern Med 2012;157:336–347 27. Meng H,ZhangA, LiangY,Hao J,Zhang X,Lu J. (pattern control). As people with type 2 12. Pickup JC. The evidence base for diabetes Effect of metformin on glycaemic control in diabetes©2019 get older, it may become necessary technology: appropriate and inappropriate meta- patients with type 1 diabetes: a meta-analysis – to simplify complex insulin regimens be- analysis. J Diabetes Sci Technol 2013;7:1567 1574 of randomized controlled trials. Diabetes Metab 13. Bergenstal RM, Klonoff DC, Garg SK, et al.; Res Rev 2018;34:e2983 cause of a decline in self-management ASPIRE In-Home Study Group. Threshold-based 28. Petrie JR, Chaturvedi N, Ford I, et al.; RE- ability (see Section 12 “Older Adults,” insulin-pump interruption for reduction of hy- MOVAL Study Group. Cardiovascular and met- https://doi.org/10.2337/dc20-S012). poglycemia. N Engl J Med 2013;369:224–232 abolic effects of metformin in patients with 14. Buckingham BA, Raghinaru D, Cameron F, type 1 diabetes (REMOVAL): a double-blind, et al.; In Home Closed Loop Study Group. Predictive randomised, placebo-controlled trial. Lancet Di- References low-glucose insulin suspension reduces duration of abetes Endocrinol 2017;5:597–609 1. Cleary PA, Orchard TJ, Genuth S, et al.; DCCT/ nocturnal hypoglycemia in children without in- 29. Wang W, Liu H, Xiao S, Liu S, Li X, Yu P. Effects EDIC Research Group. The effect of intensive creasing ketosis. Diabetes Care 2015;38:1197– of insulin plus glucagon-like peptide-1 receptor glycemic treatment on coronary artery calcification 1204 agonists (GLP-1RAs) in treating type 1 diabetes care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S109

mellitus: a systematic review and meta-analysis. than sequential add-on therapy in subjects adults with diabetes. Diabetes Res Clin Pract Diabetes Ther 2017;8:727–738 with new-onset diabetes. Results from the Effi- 2018;143:24–33 30. Dandona P, Mathieu C, Phillip M, et al.; cacy and Durability of Initial Combination Ther- 57. Patel MR, Piette JD, Resnicow K, Kowalski- DEPICT-1 Investigators. Efficacy and safety of apy for Type 2 Diabetes (EDICT): a randomized Dobson T, Heisler M. Social determinants of dapagliflozin in patients with inadequately con- trial. Diabetes Obes Metab 2015;17:268–275 health, cost-related nonadherence, and cost- trolled type 1 diabetes (DEPICT-1): 24 week 44. Phung OJ, Sobieraj DM, Engel SS, Rajpathak reducing behaviors among adults with diabetes: results from a multicentre, double-blind, phase SN. Early combination therapy for the treatment findings from the National Health Interview 3, randomised controlled trial. Lancet Diabetes of type 2 diabetes mellitus: systematic review Survey. Med Care 2016;54:796–803 Endocrinol 2017;5:864–876 and meta-analysis. Diabetes Obes Metab 2014; 58. Blonde L, Merilainen M, Karwe V, Raskin P; 31. Rosenstock J, Marquard J, Laffel LM, et al. 16:410–417 TITRATE Study Group. Patient-directed titration for Empagliflozin as adjunctive to insulin therapy in 45. Matthews DR, Paldanius´ PM, Proot P, Chiang achieving glycaemic goals using a once-daily basal type 1 diabetes: the EASE trials. Diabetes Care Y, Stumvoll M, Prato SD; VERIFY study group. insulin analogue: an assessment of two different 2018;41:2560–2569 Glycaemic durability of an early combination fasting plasma glucose targets - the TITRATE study. 32. Dean PG, Kukla A, Stegall MD, Kudva Y. therapy with vildagliptin and metformin versus Diabetes Obes Metab 2009;11:623–631 Pancreas transplantation. BMJ 2017;357:j1321 sequential metformin monotherapy in newly 59. Porcellati F, Lucidi P, Cioli P, et al. Pharma- 33. Davies MJ, D’Alessio DA, Fradkin J, et al. diagnosed type 2 diabetes (VERIFY): a 5-year, cokinetics and pharmacodynamics of insulin Management of hyperglycemia in type 2 diabe- multicentre, randomised, double-blind trial. Lan- glargine given in the evening as compared tes, 2018. A consensus report by the American cet 2019;394:1519–1529 with in the morning in type 2 diabetes. Diabetes Diabetes Association (ADA) and the European 46. Bennett WL, Maruthur NM, Singh S, et al. Care 2015;38:503–512 Association for the Study of Diabetes (EASD). Comparative effectiveness and safety of medi- 60. Wang Z, Hedrington MS, Gogitidze Joy N, et al. Diabetes Care 2018;41:2669–2701 cations for type 2 diabetes: an update including Dose-response effects of insulin glargine in type 34. Buse JB, Wexler DJ, Tsapas A, Rossing P, new drugs and 2-drug combinations. Ann Intern 2 diabetes. Diabetes Care 2010;33:1555–1560 Mingrone G, Mathieu C, et al. 2019 update to: Med 2011;154:602–613 61. Singh SR, Ahmad F, Lal A, Yu C, Bai Z, Bennett management of hyperglycemia in type 2 diabe- 47. Maloney A, Rosenstock J, Fonseca V. A H. Efficacy and safety of insulin analogues for tes, 2018: a consensus report by the American model-based meta-analysis of 24 antihypergly- the managementAssociation of diabetes mellitus: a meta- Diabetes Association (ADA) and the European cemic drugs for type 2 diabetes: comparison of analysis. CMAJ 2009;180:385–397 Association for the Study of Diabetes (EASD). treatment effects at therapeutic doses. Clin 62. Horvath K, Jeitler K, Berghold A, et al. Long- Diabetes Care 19 December 2019 [Epub ahead of Pharmacol Ther 2019;105:1213–1223 acting insulin analogues versus NPH insulin (hu- print].DOI: 10.2337/dci19-0066 48. Vijan S, Sussman JB, Yudkin JS, Hayward RA. manisophane insulin) for type 2 diabetesmellitus. 35. Holman RR, Paul SK, Bethel MA, Matthews Effect of patients’ risks and preferences on Cochrane Database Syst Rev 2007 (2):CD005613 DR, Neil HAW. 10-year follow-up of intensive health gains with plasma glucose level lowering 63. Monami M, Marchionni N, Mannucci E. glucose control in type 2 diabetes. N Engl J Med in type 2 diabetes mellitus. JAMA Intern Med Long-acting insulin analogues versus NPH human 2008;359:1577–1589 2014;174:1227–1234 insulin in type 2 diabetes: a meta-analysis. Di- 36. Maruthur NM, Tseng E, Hutfless S, et al. 49. Pratley R, Amod A, Hoff ST, et al.; PIONEER abetes Res Clin Pract 2008;81:184–189 Diabetes medications as monotherapy or metfor- 4 investigators. Oral semaglutide versus sub- 64. Owens DR, Traylor L, Mullins P, Landgraf W. min-based combination therapy for type 2 diabe- cutaneous liraglutide and placebo in type 2 di- Patient-level meta-analysis of efficacy and hypo- tes: a systematic review and meta-analysis. Ann abetes (PIONEER 4): a randomised, double-blind, glycaemia in people with type 2 diabetes ini- Intern Med 2016;164:740–751 phase 3a trial. LancetDiabetes 2019;394:39–50 tiating insulin glargine 100U/mL or neutral 37. U.S. Food and Drug Administration. FDA 50. Singh S, Wright EE Jr, Kwan AYM, et al. protamine Hagedorn insulin analysed according Drug Safety Communication: FDA revises warn- Glucagon-like peptide-1 receptor agonists com- to concomitant oral antidiabetes therapy. Di- ings regarding use of the diabetes medicine pared with basal insulins for the treatment of abetes Res Clin Pract 2017;124(Supplement C): metformin in certain patients with reduced kid- type 2 diabetes mellitus: a systematic review and 57–65 ney function. Accessed 1 November 2019. Avail- meta-analysis. Diabetes Obes Metab 2017;19: 65. Riddle MC, Rosenstock J, Gerich J; Insulin able from http://www.fda.gov/Drugs/DrugSafety/ 228–238 Glargine 4002 Study Investigators. The treat-to- ucm493244.htm 51. Levin PA, Nguyen H, Wittbrodt ET, Kim SC. target trial: randomized addition of glargine or 38. Out M, Kooy A, Lehert P, Schalkwijk CA, Glucagon-like peptide-1 receptor agonists: human NPH insulin to oral therapy of type 2 Stehouwer CDA. Long-term treatment with met- a systematic review of comparative effectiveness diabetic patients. Diabetes Care 2003;26:3080– formin in type 2 diabetes and methylmalonic acid: research. Diabetes Metab Syndr Obes 2017;10: 3086 post hoc analysis of a randomized controlled 4.3year 123–139 66. Hermansen K, Davies M, Derezinski T, trial. J Diabetes Complications 2018;32:171–178 52. Abd El Aziz MS, Kahle M, Meier JJ, Nauck MA. Martinez Ravn G, Clauson P, Home P. A 39. Aroda VR, Edelstein SL, GoldbergAmerican RB, et al.; A meta-analysis comparing clinical effects of 26-week, randomized, parallel, treat-to-target Diabetes Prevention Program Research Group. short- or long-acting GLP-1 receptor agonists trial comparing insulin detemir with NPH insulin Long-term metformin use and vitamin B12 de- versus insulin treatment from head-to-head as add-on therapy to oral glucose-lowering drugs ficiency in the Diabetes Prevention Program studies in type 2 diabetic patients. Diabetes in insulin-naive people with type 2 diabetes. Outcomes Study. J Clin Endocrinol Metab Obes Metab 2017;19:216–227 Diabetes Care 2006;29:1269–1274 2016;101:1754–1761 53. Riddle MC, Herman WH. The cost of diabetes 67. Yki-Jarvinen¨ H, Kauppinen-Makelin¨ R, 40. Henry RR, Murray AV, Marmolejo MH, care-an elephant in the room. Diabetes Care Tiikkainen M, et al. Insulin glargine or NPH Hennicken D, Ptaszynska A, List JF. Dapagliflozin, 2018;41:929–932 combined with metformin in type 2 diabetes: metformin XR, or both: initial pharmacotherapy 54. Truven Health Analytics. Micromedex 2.0 the LANMET study. Diabetologia 2006;49:442– for type 2 diabetes, a randomised controlled Introduction to RED BOOK Online, 2018. Accessed 451 trial.©2019 Int J Clin Pract 2012;66:446 –456 1 November 2019. Available from http://www 68. Bolli GB, Riddle MC, Bergenstal RM, et al.; on 41. Babu A, Mehta A, Guerrero P, et al. Safe and .micromedexsolutions.com/micromedex2/ behalf of the EDITION 3 study investigators. New simple emergency department discharge therapy 4.34.0/WebHelp/RED_BOOK/Introduction_to_ insulinglargine 300 U/mlcompared with glargine for patients with type 2 diabetes mellitus and severe REDB_BOOK_Online.htm 100 U/ml in insulin-na¨ıve people with type 2 hyperglycemia. Endocr Pract 2009;15:696–704 55. Centers for Medicare & Medicaid Services. diabetes on oral glucose-lowering drugs: a ran- 42. Cahn A, Cefalu WT. Clinical considerations NADAC (national average drug acquisition cost), domized controlled trial (EDITION 3). Diabetes for use of initial combination therapy in type 2 drug pricing and payment. Accessed 1 November Obes Metab 2015;17:386–394 diabetes. Diabetes Care 2016;39(Suppl. 2):S137– 2019. Available from https://data.medicaid.gov/ 69. Terauchi Y, Koyama M, Cheng X, et al. New S145 Drug-Pricing-and-Payment/NADAC-National-Average- insulin glargine 300 U/ml versus glargine 100 43. Abdul-Ghani MA, Puckett C, Triplitt C, et al. Drug-Acquisition-Cost-/a4y5-998d. U/ml in Japanese people with type 2 diabetes Initial combination therapy with metformin, 56. Kang H, Lobo JM, Kim S, Sohn M-W. Cost- using basal insulin and oral antihyperglycaemic pioglitazone and exenatide is more effective related medication non-adherence among U.S. drugs: glucose control and hypoglycaemia in a S110 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 43, Supplement 1, January 2020

randomized controlled trial (EDITION JP 2). department visits or hospital admissions and units/mL in people with type 2 diabetes Diabetes Obes Metab 2016;18:366–374 with glycemic control in patients with type 2 using oral agents and basal insulin: glucose 70. Yki-Jarvinen¨ H, Bergenstal RM, Bolli GB, et al. diabetes. JAMA 2018;320:53–62 control and hypoglycemia in a 6-month ran- Glycaemic control and hypoglycaemia with new 76. Cefalu WT, Dawes DE, Gavlak G, et al.; Insulin domized controlled trial (EDITION 2). Diabetes insulin glargine 300 U/ml versus insulin glargine Access and Affordability Working Group. Con- Care 2014;37:3235–3243 100U/mlinpeoplewithtype 2 diabetes using basal clusions and recommendations. Diabetes Care 83. Akturk HK, Snell-Bergeon JK, Rewers A, et al. insulin and oral antihyperglycaemic drugs: the 2018;41:1299–1311 Improved postprandial glucose with inhaled EDITION 2 randomized 12-month trial including 77. McCall AL. Insulin therapy and hypoglycemia. technosphere insulin compared with insulin as- 6-month extension. Diabetes Obes Metab 2015;17: Endocrinol Metab Clin North Am 2012;41:57–87 part in patients with type 1 diabetes on multiple 1142–1149 78. Mannucci E, Monami M, Marchionni N. daily injections: the STAT study. Diabetes Technol 71. Marso SP, McGuire DK, Zinman B, et al.; Short-acting insulin analogues vs. regular human Ther 2018;20:639–647 DEVOTE Study Group. Efficacy and safety of insulin in type 2 diabetes: a meta-analysis. Di- 84. Diamant M, Nauck MA, Shaginian R, et al.; 4B degludec versus glargine in type 2 diabetes. N abetes Obes Metab 2009;11:53–59 Study Group. Glucagon-like peptide 1 receptor Engl J Med 2017;377:723–732 79. Heller S, Bode B, Kozlovski P, Svendsen AL. agonist or bolus insulin with optimized basal 72. Rodbard HW, Cariou B, Zinman B, et al.; Meta-analysis of insulin aspart versus regular insulin in type 2 diabetes. Diabetes Care 2014; BEGIN Once Long trial investigators. Compar- human insulin used in a basal-bolus regimen for 37:2763–2773 ison of insulin degludec with insulin glargine in the treatment of diabetes mellitus. J Diabetes 85. Eng C, Kramer CK, Zinman B, Retnakaran R. insulin-naive subjects with type 2 diabetes: a 2013;5:482–491 Glucagon-like peptide-1 receptor agonist and 2-year randomized, treat-to-target trial. Diabet 80. Wysham C, Hood RC, Warren ML, Wang T, basal insulin combination treatment for the Med 2013;30:1298–1304 Morwick TM, Jackson JA. Effect of total daily management of type 2 diabetes: a systematic 73. Wysham C, Bhargava A, Chaykin L, et al. dose on efficacy, dosing, and safety of 2 dose review and meta-analysis. Lancet 2014;384: Effect of insulin degludec vs insulin glargine U100 titration regimens of human regular U500 insu- 2228–2234 on hypoglycemia in patients with type 2 diabetes: lin in severely insulin-resistant patients with 86. Maiorino MI, Chiodini P, Bellastella G, the SWITCH 2 randomized clinical trial. JAMA 2017; type 2 diabetes. Endocr Pract 2016;22:653–665 Capuano A, Esposito K, Giugliano D. Insulin and 318:45–56 81. Riddle MC, Yki-Jarvinen¨ H, Bolli GB, et al. glucagon-likeAssociation peptide 1 receptor agonist combi- 74. Zinman B, Philis-Tsimikas A, Cariou B, et al.; One-year sustained glycaemic control and less nation therapy in type 2 diabetes: a systematic NN1250-3579 (BEGIN Once Long) Trial Investi- hypoglycaemia with new insulin glargine 300 review and meta-analysis of randomized con- gators. Insulin degludec versus insulin glargine U/ml compared with 100 U/ml in people with trolled trials. Diabetes Care 2017;40:614–624 in insulin-naive patients with type 2 diabetes: type 2 diabetes using basal plus meal-time in- 87. Rodbard HW, Visco VE, Andersen H, Hiort a 1-year, randomized, treat-to-target trial (BEGIN sulin: the EDITION 1 12-month randomized trial, LC, Shu DHW. Treatment intensification with Once Long). Diabetes Care 2012;35:2464–2471 including 6-month extension. Diabetes Obes stepwise addition of prandial insulin aspart 75. Lipska KJ, Parker MM, Moffet HH, Huang ES, Metab 2015;17:835–842 boluses compared with full basal-bolus therapy Karter AJ. Association of initiation of basal in- 82. Yki-Jarvinen¨ H, Bergenstal R, Ziemen M, (FullSTEP Study): a randomised, treat-to-target sulin analogs vs neutral protamine Hagedorn et al.; EDITION 2 Study Investigators. New in- clinical trial. Lancet Diabetes Endocrinol 2014;2: insulin with hypoglycemia-related emergency sulin glargine 300 units/mL versus glargine 100 30–37 Diabetes

American

10. Cardiovascular Disease and American Diabetes Association Risk Management: Standards of Medical Care in Diabetesd2020

Diabetes Care 2020;43(Suppl. 1):S111–S134 | https://doi.org/10.2337/dc20-s010 0 ADOACLRDSAEADRS MANAGEMENT RISK AND DISEASE CARDIOVASCULAR 10.

The American Diabetes Association (ADA) “Standards of Medical Care in Diabe- tes”includestheADA’scurrentclinicalpracticerecommendationsandisintendedto Association provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc20- SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi .org/10.2337/dc20-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC. Diabetes

For prevention and management of diabetes complications in children and adolescents, please refer to Section 13 “Children and Adolescents” (https://doi.org/10.2337/ dc20-S013). Atherosclerotic cardiovascular disease (ASCVD)ddefined as coronary heart disease (CHD), cerebrovascular disease, or peripheral arterial disease presumed to be of atherosclerotic origindis the leading cause of morbidity and mortality for individuals with diabetes and results in an estimated $37.3 billion in cardiovascular-related spending per year associated with diabetes (1). Common conditions coexisting with type 2 diabetes (e.g., hypertension and dyslipidemia) are clearriskfactorsforASCVD,anddiabetesitself confers independent risk. NumAmericanerous studies have shown the efficacy of controlling individual cardiovascular risk factors in preventing or slowing ASCVD in people with diabetes. Furthermore,large benefitsare seenwhenmultiple cardiovascularriskfactorsare addressed simultaneously. Under the current paradigm of aggressive risk factor modification in patients with diabetes, there is evidence that measures of 10-year coronary heart disease (CHD) risk among U.S. adults with diabetes have improved significantly over the past decade (2) and that ASCVD morbidityandmortalityhavedecreased(3,4). Heart failure is another major cause of morbidity and mortality from cardiovascu- This section has received endorsement from the American College of Cardiology. lar disease.©2019 Recent studies have found that rates of incident heart failure hospitalization Suggested citation: American Diabetes Asso- (adjusted forageandsex)weretwofold higherinpatientswith diabetescompared with those ciation. 10. Cardiovascular disease and risk without (5,6). People with diabetes may have heart failure with preserved ejection fraction management: Standards of Medical Care in (HFpEF) or with reduced ejection fraction (HFrEF). Hypertension is often a precursor of heart Diabetesd2020. Diabetes Care 2020;43(Suppl.1): failure of either type, and ASCVD can coexist with either type (7), whereas prior myocardial S111–S134 infarction (MI) is often a major factor in HFrEF. Rates of heart failure hospitalization have © 2019 by the American Diabetes Association. been improved in recent trials including patients with type 2 diabetes, most of whom also Readers may use this article as long as the work – – is properly cited, the use is educational and not had ASCVD, with sodium glucose cotransporter 2 (SGLT2) inhibitors (8 10). for profit, and the work is not altered. More infor- For prevention and management of both ASCVD and heart failure, cardio- mation is available at http://www.diabetesjournals vascular risk factors should be systematically assessed at least annually in all patients .org/content/license. S112 Cardiovascular Disease and Risk Management Diabetes Care Volume 43, Supplement 1, January 2020

with diabetes. These risk factors in- epidemiology, diagnosis, and treatment making process that addresses clude obesity/overweight, hyperten- of hypertension (17). cardiovascular risk, potential sion, dyslipidemia, smoking, a family adverse effects of antihyper- history of premature coronary disease, Screening and Diagnosis tensive medications, and pa- chronic kidney disease, and the pres- Recommendations tient preferences. C ence of albuminuria. Modifiable abnor- 10.1 Blood pressure should be mea- 10.4 For individuals with diabetes mal risk factors should be treated as sured at every routine clinical and hypertension at higher car- described in these guidelines. visit. Patients found to have el- diovascular risk(existingathero- $ evatedbloodpressure( 140/90 sclerotic cardiovascular disease THE RISK CALCULATOR mmHg) should have blood pres- [ASCVD] or 10-year ASCVD risk fi The American College of Cardiology/ sure con rmed using multiple $15%),a blood pressure target American Heart Association ASCVD risk readings, including measure- of ,130/80 mmHg may be ap- calculator (Risk Estimator Plus) is generally ments on a separate day, to propriate, if it can be safely B a useful tool to estimate 10-year ASCVD diagnose hypertension. attained. C 10.2 risk (available online at tools.acc.org/ All hypertensive patients with 10.5 For individuals with diabetes ASCVD-Risk-Estimator-Plus). The calcu- diabetes should monitor their and hypertension at lower risk B lator includes diabetes as a risk factor, blood pressure at home. for cardiovascular disease (10- since diabetes itself confers increased risk year atherosclerotic cardio- for ASCVD, although it should be acknowl- Blood pressure should be measured at vascular disease risk ,15%), edged that these risk calculators do not every routine clinical visit by a trained treat to a blood pressure target accountforthedurationofdiabetesorthe individual and should follow the Associationof ,140/90 mmHg. A presence of diabetes complications, such guidelines established for the general pop- 10.6 In pregnant patients with dia- as albuminuria. Although some variability ulation: measurement in the seated posi- betes and preexisting hyperten- fl in calibration exists in various subgroups, tion,withfeetonthe oor and arm sion, a blood pressure target including by sex, race, and diabetes, the supported at heart level, after 5 min of of #135/85 mmHg is suggested overall risk prediction does not differ in rest. Cuff size should be appropriate for the in the interest of reducing the those with or without diabetes (11–14), upper-arm circumference. Elevated values risk for accelerated maternal fi validating the use of risk calculators in should be con rmed on a separate day. hypertension A and minimizing people with diabetes. The 10-year risk of a Postural changes in blood pressure and impaired fetal growth. E first ASCVD event should be assessed to pulse may be evidence of autonomic neu- better stratify ASCVD risk and help guide ropathy and thereforeDiabetes require adjustment therapy, as described below. of blood pressure targets.Orthostatic blood Randomized clinical trials have demon- Recently, risk scores and other car- pressure measurements should be checked strated unequivocally that treatment of , diovascular biomarkers have been devel- on initial visit and as indicated. hypertension to blood pressure 140/90 oped for risk stratification of secondary Home blood pressure self-monitoring mmHg reduces cardiovascular events prevention patients (i.e., those who are and 24-h ambulatory blood pressure as well as microvascular complications – already high risk because they have monitoring may provide evidence of (21 27). Therefore, patients with type 1 ASCVD) but are not yet in widespread white coat hypertension, masked hyper- or type 2 diabetes who have hyperten- use (15,16). With newer, more expensive tension, or other discrepancies between sion should, at a minimum, be treated fi “ ” , lipid-lowering therapies now available, of ce and true blood pressure (17). In to blood pressure targets of 140/90 fi fi use of these risk assessments may help addition to con rming or refuting a di- mmHg. The bene ts and risks of inten- target these new therapies to “higher agnosis of hypertension, home blood sifying antihypertensive therapy to tar- American , risk” ASCVD patients in the future. pressure assessment may be useful to get blood pressures lower than 140/90 monitor antihypertensive treatment. mmHg (e.g., ,130/80 or ,120/80 Studies of individuals without diabetes mmHg) have been evaluated in large HYPERTENSION/BLOOD PRESSURE found that home measurements may randomized clinical trials and meta- CONTROL better correlate with ASCVD risk than analyses of clinical trials. Notably, there Hypertension, defined as a sustained office measurements (18,19). Moreover, is an absence of high-quality data avail- blood pressure $140/90 mmHg, is com- home blood pressure monitoring may able to guide blood pressure targets in mon among patients with either type 1 improve patient medication adherence type 1 diabetes. or©2019 type 2 diabetes. Hypertension is a and thus help reduce cardiovascular major risk factor for both ASCVD and risk (20). Randomized Controlled Trials of Intensive microvascular complications. Moreover, Versus Standard Blood Pressure Control numerous studies have shown that anti- Treatment Goals The Action to Control Cardiovascular Risk hypertensive therapy reduces ASCVD Recommendations in Diabetes Blood Pressure (ACCORD BP) events, heart failure, and microvascular trial provides the strongest direct assess- 10.3 For patients with diabetes and complications. Please refer to the Amer- ment of the benefits and risks of intensive hypertension, blood pressure ican Diabetes Association (ADA) position blood pressure control among people targets should be individual- statement “Diabetes and Hyperten- with type 2 diabetes (28). In ACCORD ized through a shared decision- sion” for a detailed review of the BP, compared with standard blood care.diabetesjournals.org Cardiovascular Disease and Risk Management S113

pressure control (target systolic blood relevance of their results to people A number of post hoc analyses have pressure ,140 mmHg), intensive blood with diabetes is less clear. The Action attempted to explain the apparently pressure control (target systolic blood in Diabetes and Vascular Disease: Pre- divergent results of ACCORD BP and pressure ,120 mmHg) did not reduce terax and Diamicron MR Controlled SPRINT. Some investigators have argued total major atherosclerotic cardiovascu- Evaluation–Blood Pressure (ADVANCE that the divergent results are not due to lar events but did reduce the risk of BP) trial did not explicitly test blood differences between people with and with- stroke, at the expense of increased ad- pressure targets (29); the achieved out diabetes but rather are due to differ- verse events (Table 10.1). The ACCORD blood pressure in the intervention ences in study design or to characteristics BP results suggest that blood pressure group was higher than that achieved other than diabetes (31–33). Others have targets more intensive than ,140/90 in the ACCORD BP intensive arm and opined that the divergent results are most mmHg are not likely to improve car- would be consistent with a target readily explained by the lack of benefitof diovascular outcomes among most blood pressure of ,140/ 90 mmHg. intensive blood pressure control on cardio- people with type 2 diabetes but may Notably, ACCORD BP and SPRINT mea- vascular mortality in ACCORD BP, which be reasonable for patients who may sured blood pressure using automated may be due to differential mechanisms derive the most benefit and have office blood pressure measurement, underlying cardiovascular disease in type been educated about added treatment which yields values that are generally 2 diabetes, to chance, or both (34). burden, side effects, and costs, as dis- lower than typical office blood pres- cussed below. sure readings by approximately 5–10 Meta-analyses of Trials Additional studies, such as the Sys- mmHg (30), suggesting that im- To clarify optimal blood pressure targets tolic Blood Pressure Intervention Trial plementing the ACCORD BP or SPRINT in patients with diabetes, meta-analyses (SPRINT) and the Hypertension Optimal protocols in an outpatient clinic might have stratiAssociationfied clinical trials by mean Treatment (HOT) trial, also examined require a systolic blood pressure tar- baseline blood pressure or mean blood effects of intensive versus standard get higher than ,120 mmHg, such as pressure attained in the intervention (or control (Table 10.1), though the ,130 mmHg. intensive treatment) arm. Based on these

Table 10.1—Randomized controlled trials of intensive versus standard hypertension treatment strategies Clinical trial Population Intensive Standard Outcomes ACCORD BP (28) 4,733 participants with SBP target: SBP target: c No benefit in primary end point: composite T2D aged 40–79 years ,120 mmHg 130–140 mmHg of nonfatal MI, nonfatal stroke, and CVD with prior evidence Achieved (mean) Achieved (mean) death of CVD or multiple SBP/DBP: DiabetesSBP/DBP: c Stroke risk reduced 41% with intensive cardiovascular risk 119.3/64.4 mmHg 13.5/70.5 mmHg control, not sustained through follow-up factors beyond the period of active treatment c Adverse events more common in intensive group, particularly elevated serum creatinine and electrolyte abnormalities ADVANCE BP (29) 11,140 participants Intervention: a single-pill, Control: placebo c Intervention reduced risk of primary with T2D aged fixed-dose combination Achieved (mean) composite end point of major 55 years and older of perindopril and SBP/DBP: macrovascular and microvascular events with prior evidence indapamide 141.6/75.2 mmHg (9%), death from any cause (14%), and of CVD or multiple Achieved (mean) death from CVD (18%) cardiovascular risk SBP/DBP: c 6-year observational follow-up found factors American136/73 mmHg reduction in risk of death in intervention group attenuated but still significant (174) HOT (185) 18,790 participants, DBP target: DBP target: c In the overall trial, there was no including 1,501 #80 mmHg #90 mmHg cardiovascular benefit with more intensive with diabetes targets c In the subpopulation with diabetes, an intensive DBP target was associated with a significantly reduced risk (51%) of CVD events SPRINT©2019 (39) 9,361 participants SBP target: SBP target: c Intensive SBP target lowered risk of the without diabetes ,120 mmHg ,140 mmHg primary composite outcome 25% (MI, ACS, Achieved (mean): Achieved (mean): stroke, heart failure, and death due to CVD) 121.4 mmHg 136.2 mmHg c Intensive target reduced risk of death 27% c Intensive therapy increased risks of electrolyte abnormalities and AKI ACCORD BP, Action to Control Cardiovascular Risk in Diabetes Blood Pressure trial; ACS, acute coronary syndrome; ADVANCE BP, Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation–Blood Pressure trial; AKI, acute kidney injury; CVD, cardiovascular disease; DBP, diastolic blood pressure; HOT, Hypertension Optimal Treatment trial; MI, myocardial infarction; SBP, systolic blood pressure; SPRINT, Systolic Blood Pressure Intervention Trial; T2D, type 2 diabetes. Data from this table can also be found in the ADA position statement “Diabetes and Hypertension” (17). S114 Cardiovascular Disease and Risk Management Diabetes Care Volume 43, Supplement 1, January 2020

analyses, antihypertensive treatment ap- syncope, falls, acute kidney injury, and recommends use of antihypertensive pears to be beneficial when mean base- electrolyte abnormalities) should also be therapy to maintain systolic blood pres- line blood pressure is $140/90 mmHg or taken into account (28,39–41). Patients sure between 110 and 140 mmHg and mean attained intensive blood pressure with older age, chronic kidney disease, diastolic blood pressure between 80 and is $130/80 mmHg (17,21,22,24–26). and frailty have been shown to be at 85 mmHg (44). Among trials with lower baseline or higher risk of adverse effects of intensive During pregnancy, treatment with ACE attained blood pressure, antihyperten- blood pressure control (41). In addition, inhibitors, angiotensin receptor blockers sive treatment reduced the risk of stroke, patients with orthostatic hypotension, (ARBs), and spironolactone are contra- retinopathy, and albuminuria, but effects substantial comorbidity, functional lim- indicated as they may cause fetal dam- on other ASCVD outcomes and heart itations, or polypharmacy may be at high age. Antihypertensive drugs known to be failure were not evident. Taken together, risk of adverse effects, and some patients effective and safe in pregnancy include these meta-analyses consistently show may prefer higher blood pressure targets methyldopa, labetalol, and long-acting that treating patients with baseline blood to enhance quality of life. Patients with nifedipine, while hydralzine may be con- pressure $140 mmHg to targets ,140 low absolute cardiovascular risk (10-year sidered in the acute management of mmHg is beneficial, while more-intensive ASCVD risk ,15%) or with a history of hypertension in pregnancy or severe targets may offer additional (though adverse effects of intensive blood pres- preeclampsia (45). Diuretics are not rec- probably less robust) benefits. sure control or at high risk of such ommended for blood pressure control in adverse effects should have a higher pregnancy but may be used during late- Individualization of Treatment Targets blood pressure target. In such patients, stage pregnancy if needed for volume Patients and clinicians should engage in a blood pressure target of ,140/90 control (45,46). The American College of a shared decision-making process to de- mmHg is recommended, if it can be safely ObstetriciansAssociation and Gynecologists also rec- termine individual blood pressure tar- attained. ommends that postpartum patients with gets (17). This approach acknowledges gestational hypertension, preeclampsia, that the benefits and risks of intensive Pregnancy and Antihypertensive and superimposed preeclampsia have blood pressure targets are uncertain and Medications their blood pressures observed for may vary across patients and is consis- There are few randomized controlled 72 h in the hospital and for 7–10 days tent with a patient-focused approach to trials of antihypertensive therapy in preg- postpartum. Long-term follow-up is rec- care that values patient priorities and nant women with diabetes. A 2014 ommended for these women as they provider judgment (35). Secondary anal- Cochrane systematic review of antihy- have increased lifetime cardiovascular yses of ACCORD BP and SPRINT suggest pertensive therapy for mild to moder- risk (47). See Section 14 “Management that clinical factors can help determine ate chronic hypertension that included of Diabetes in Pregnancy” (https://doi individuals more likely to benefit and 49 trials and overDiabetes 4,700 women did not .org/10.2337/dc20-S014) for additional less likely to be harmed by intensive find any conclusive evidence for or information. blood pressure control (36). against blood pressure treatment to fi Absolute bene t from blood pres- reduce the risk of preeclampsia for Treatment Strategies sure reduction correlated with absolute the mother or effects on perinatal out- Lifestyle Intervention baseline cardiovascular risk in SPRINT comes such as preterm birth, small-for- Recommendation and in earlier clinical trials conducted gestational-age infants, or fetal death 10.7 at higher baseline blood pressure levels (42). The more recent Control of Hyper- Forpatients withbloodpressure . (11,37). Extrapolation of these studies tension in Pregnancy Study (CHIPS) (43) 120/80 mmHg, lifestyle inter- suggests that patients with diabetes enrolled mostly women with chronic vention consists of weight loss if may also be more likely to benefit hypertension. In CHIPS, targeting a di- overweight or obese, a Dietary from intensive blood pressureAmerican control astolic blood pressure of 85 mmHg dur- Approaches to Stop Hyperten- when they have high absolute cardio- ing pregnancy was associated with sion (DASH)-style eating pattern vascular risk. Therefore, it may be rea- reduced likelihood of developing accel- including reducing sodium and sonable to target blood pressure erated maternal hypertension and no increasing potassium intake, ,130/80 mmHg among patients with demonstrable adverse outcome for in- moderation of alcohol intake, A diabetes and either clinically diag- fants compared with targeting a higher and increased physical activity. nosed cardiovascular disease (particu- diastolic blood pressure. The mean sys- larly stroke, which was significantly tolic blood pressure achieved in the Lifestyle management is an important reduced©2019 in ACCORD BP) or 10-year more intensively treated group was component of hypertension treatment ASCVD risk $15%, if it can be attained 133.1 6 0.5 mmHg, and the mean di- because it lowers blood pressure, enhan- safely. This approach is consistent with astolic blood pressure achieved in that ces the effectiveness of some antihyper- guidelines from the American College of group was 85.3 6 0.3 mmHg. Therefore, tensive medications, promotes other Cardiology/American Heart Association, current evidence supports controlling aspects of metabolic and vascular health, which advocate a blood pressure target blood pressure to these levels, with a andgenerally leadstofewadverseeffects. ,130/80 mmHg for all patients, with or target of #135/85 mmHg. A similar Lifestyle therapy consists of reducing ex- without diabetes (38). approach is supported by the Interna- cess body weight through caloric restric- Potential adverse effects of antihyper- tional Society for the Study of Hyperten- tion, restricting sodium intake (,2,300 tensive therapy (e.g., hypotension, sion in Pregnancy, which specifically mg/day), increasing consumption of fruits care.diabetesjournals.org Cardiovascular Disease and Risk Management S115

and vegetables (8–10 servings per day) the combination of an ACE inhibitor or patients with diabetes and uri- and low-fat dairy products (2–3 servings ARB and a direct renin inhibitor, is not nary albumin-to-creatinine ra- per day), avoiding excessive alcohol con- recommended given the lack of added tio $300 mg/g creatinine A or sumption (no more than 2 servings per ASCVD benefit and increased rate of 30–299 mg/g creatinine. B If day in menandnomore than 1 servingper adverse eventsdnamely, hyperkalemia, one class is not tolerated, the day in women) (48), and increasing ac- syncope, and acute kidney injury (AKI) other should be substituted. B tivity levels (49). (60–62). Titration of and/or addition of 10.13 ForpatientstreatedwithanACE These lifestyle interventions are rea- further blood pressure medications inhibitor, angiotensin receptor sonable for individuals with diabetes and should be made in a timely fashion to blocker, or diuretic, serum cre- mildly elevated blood pressure (systolic overcome clinical inertia in achieving atinine/estimated glomerular fil- .120 mmHg or diastolic .80 mmHg) blood pressure targets. tration rate and serum potassium and should be initiated along with phar- Bedtime Dosing. Growing evidence sug- levels should be monitored at macologic therapy when hypertension is gests that there is an association be- least annually. B diagnosed (Fig. 10.1) (49). A lifestyle tween the absence of nocturnal blood therapy plan should be developed in Initial Number of Antihypertensive pressure dipping and the incidence of collaboration with the patient and dis- Medications. Initial treatment for people ASCVD. A meta-analysis of randomized cussed as part of diabetes management. with diabetes depends on the severity clinical trials found a small benefitof of hypertension (Fig. 10.1). Those with evening versus morning dosing of anti- Pharmacologic Interventions blood pressure between 140/90 mmHg hypertensive medications with regard to blood pressure control but had no data Recommendations and 159/99 mmHg may begin with a on clinical effects (63). In two subgroup 10.8 Patients with confirmed office- single drug. For patients with blood Association $ analyses of a single subsequent random- based blood pressure $140/ pressure 160/100 mmHg, initial phar- ized controlled trial, moving at least one 90 mmHg should, in addition macologic treatment with two antihy- antihypertensive medication to bedtime to lifestyle therapy, have prompt pertensive medications is recommended significantly reduced cardiovascular events, initiation and timely titration of in order to more effectively achieve – but results were based on a small num- pharmacologic therapy to achieve adequate blood pressure control (50 52). A Single-pill antihypertensive combinations berofevents(64). blood pressure goals. Hyperkalemia and Acute Kidney Injury. 10.9 Patients with confirmed office- may improve medication adherence in Treatment with ACE inhibitors or ARBs based blood pressure $160/ some patients (53). Classes of Antihypertensive Medications. can cause AKI and hyperkalemia, while 100 mmHg should, in addition Initial treatment for hypertension should diuretics can cause AKI and either hypo- tolifestyletherapy,haveprompt include any of theDiabetes drug classes demon- kalemia or hyperkalemia (depending on initiation and timely titration of strated to reduce cardiovascular events mechanism of action) (65,66). Detection two drugs or a single-pill combi- in patients with diabetes: ACE inhibitors and management of these abnormalities nation of drugs demonstrated to (54,55), ARBs (54,55), thiazide-like di- is important because AKI and hyperkale- reduce cardiovascular events in uretics (56), or dihydropyridine calcium mia each increase the risks of cardiovas- patients with diabetes. A channel blockers (57). For patients cular events and death (67). Therefore, 10.10 Treatment for hypertension with albuminuria (urine albumin-to- serum creatinine and potassium should should include drug classes creatinine ratio [UACR] $30 mg/g), initial be monitored during treatment with an demonstrated to reduce cardio- treatment should include an ACE inhib- ACE inhibitor, ARB, or diuretic, particularly vascular events in patients with itor or ARB in order to reduce the risk among patients with reduced glomerular diabetes (ACE inhibitors, angioten- of progressive kidney disease (17) (Fig. filtration who are at increased risk of sin receptor blockers, thiazide-like American10.1). In the absence of albuminuria, hyperkalemia and AKI (65,66,68). diuretics, or dihydropyridine cal- risk of progressive kidney disease is cium channel blockers). A low, and ACE inhibitors and ARBs have Resistant Hypertension 10.11 Multiple-drug therapy is gener- not been found to afford superior ally required to achieve blood Recommendation cardioprotection when compared with 10.14 pressure targets. However, com- Patients with hypertension who thiazide-like diuretics or dihydropyridine binations of ACE inhibitors and are not meeting blood pres- calcium channel blockers (58). b-Blockers angiotensin receptor blockers sure targets on three classes may be used for the treatment of prior and combinations of ACE inhib- of antihypertensive medica- ©2019 MI, active angina, or heart failure but itors or angiotensin receptor tions (including a diuretic) have not been shown to reduce mortality blockers with direct renin inhib- should be considered for min- as blood pressure–lowering agents in the itors should not be used. A eralocorticoid receptor antag- absence of these conditions (23,59). B 10.12 An ACE inhibitor or angiotensin onist therapy. Multiple-Drug Therapy. Multiple-drug receptor blocker, at the maxi- therapy is often required to achieve Resistant hypertension is defined as mum tolerated dose indicated blood pressure targets (Fig. 10.1), par- blood pressure $140/90 mmHg despite for blood pressure treatment, ticularly in the setting of diabetic kidney a therapeutic strategy that includes ap- is the recommended first-line disease. However, the use of both ACE propriate lifestyle management plus a treatment for hypertension in inhibitors and ARBs in combination, or diuretic and two other antihypertensive S116 Cardiovascular Disease and Risk Management Diabetes Care Volume 43, Supplement 1, January 2020

Association

Diabetes

American

©2019Figure 10.1—Recommendations for the treatment of conﬁrmed hypertension in people with diabetes. *An ACE inhibitor (ACEi) or angiotensin receptor blocker (ARB) is suggested to treat hypertension for patients with urine albumin-to-creatinine ratio 30–299 mg/g creatinine and strongly recommended for patients with urine albumin-to-creatinine ratio $300 mg/g creatinine. **Thiazide-like diuretic; long-acting agents shown to reduce cardiovascular events, such as chlorthalidone and indapamide, are preferred. ***Dihydropyridine calcium channel blocker (CCB). BP, blood pressure. Adapted from de Boer et al. (17).

drugs belonging to different classes at medication nonadherence, white coat should be identiﬁed and addressed (Fig. adequate doses. Prior to diagnosing re- hypertension, and secondary hyperten- 10.1). Mineralocorticoid receptor antag- sistant hypertension, a number of other sion. In general, barriers to medication onists are effective for management of conditions should be excluded, including adherence (such as cost and side effects) resistant hypertension in patients with care.diabetesjournals.org Cardiovascular Disease and Risk Management S117

type 2 diabetes when added to existing increasing plant stanols/sterols, n-3 fatty effects occur. There is evidence for ben- treatment with an ACE inhibitor or ARB, acids, and viscous fiber (such as in oats, efit from even extremely low, less than thiazide-like diuretic, and dihydropyri- legumes, and citrus) intake (76). Glyce- daily statin doses (78). dine calcium channel blocker (69). mic control may also beneficially modify Mineralocorticoid receptor antagonists plasma lipid levels, particularly in pa- STATIN TREATMENT also reduce albuminuria and have addi- tients with very high triglycerides and Primary Prevention tional cardiovascular benefits (70–73). poor glycemic control. See Section 5 Recommendations However, adding a mineralocorticoid re- “Facilitating Behavior Change and Well- 10.19 For patients with diabetes aged ceptor antagonist to a regimen including being to Improve Health Outcomes” 40–75 years without atheroscle- an ACE inhibitor or ARB may increase the (https://doi.org/10.2337/dc20-S010) for ad- rotic cardiovascular disease, use risk for hyperkalemia, emphasizing the ditional nutrition information. moderate-intensity statin ther- importance of regular monitoring for apy in addition to lifestyle ther- Ongoing Therapy and Monitoring serum creatinine and potassium in these apy. A With Lipid Panel patients, and long-term outcome studies 10.20 For patients with diabetes are needed to better evaluate the role of Recommendations aged 20–39 years with addi- mineralocorticoid receptor antagonists 10.17 In adults not taking statins or tional atherosclerotic cardiovas- in blood pressure management. other lipid-lowering therapy, it cular disease risk factors, it may be is reasonable to obtain a lipid reasonable to initiate statin ther- LIPID MANAGEMENT profile at the time of diabetes apy in addition to lifestyle Lifestyle Intervention diagnosis, at an initial medical therapy. C evaluation, and every 5 years 10.21AssociationIn patients with diabetes at Recommendations thereafter if under the age of higher risk, especially those 10.15 Lifestyle modification focusing 40 years, or more frequently if with multiple atherosclerotic on weight loss (if indicated); indicated. E cardiovascular disease risk fac- applicationofaMediterranean 10.18 Obtain a lipid profile at initia- tors or aged 50–70 years, it is style or Dietary Approaches tion of statins or other lipid- reasonable to use high-inten- to Stop Hypertension (DASH) lowering therapy, 4–12 weeks sity statin therapy. B eating pattern; reduction of after initiation or a change 10.22 In adults with diabetes and saturated fat and trans fat; in dose, and annually thereaf- 10-year atherosclerotic cardio- increase of dietary n-3 fatty ter as it may help to monitor vascular disease risk of 20% or acids, viscous fiber, and plant the response to therapy and in- higher, it may be reasonable to stanols/sterols intake; and inform medicationDiabetes adherence. E add ezetimibe to maximally creased physical activity should tolerated statin therapy to re- be recommended to improve In adults with diabetes, it is reasonable duce LDL cholesterol levels by the lipid profile and reduce the to obtain a lipid profile (total cholesterol, 50% or more. C risk of developing atheroscle- LDL cholesterol, HDL cholesterol, and tri- rotic cardiovascular disease in glycerides) at the time of diagnosis, at the patients with diabetes. A initial medical evaluation, and at least every Secondary Prevention 10.16 Intensify lifestyle therapy and 5 years thereafter in patients under the age Recommendations optimize glycemic control for of 40 years. In younger patients with longer 10.23 For patients of all ages with patients with elevated triglyc- duration of disease (such as those with $ diabetes and atherosclerotic eride levels ( 150 mg/dL [1.7 youth-onset type 1 diabetes), more fre- cardiovascular disease, high-in- mmol/L]) and/or lowAmerican HDL cho- quent lipid profiles may be reasonable. A , tensity statin therapy should be lesterol ( 40 mg/dL [1.0 lipid panel should also be obtained imme- , addedtolifestyletherapy.A mmol/L] for men, 50 mg/dL diately before initiating statin therapy. C 10.24 For patients with diabetes and [1.3 mmol/L] for women). Once a patient is taking a statin, LDL atherosclerotic cardiovascular cholesterol levels should be assessed 4– disease considered very high Lifestyle intervention, including weight 12 weeks after initiation of statin therapy, risk using specificcriteria,if loss (74), increased physical activity, and after any change in dose, and on an in- LDL cholesterol is $70 mg/dL medical nutrition therapy, allows some dividual basis (e.g., to monitor for medica- on maximally tolerated statin patients©2019 to reduce ASCVD risk factors. tion adherence and efficacy). If LDL dose, consider adding additional Nutrition intervention should be tailored cholesterol levels are not responding in LDL-lowering therapy (such as according to each patient’s age, diabetes spite of medication adherence, clinical ezetimibe or PCSK9 inhibitor). type, pharmacologic treatment, lipid judgment is recommended to determine A Ezetimibe may be preferred levels, and medical conditions. the need for and timing of lipid panels. In due to lower cost. Recommendations should focus on individual patients, the highly variable LDL 10.25 For patients who do not toler- application of a Mediterranean style cholesterol–lowering response seen with ate the intended intensity, the diet (75) or Dietary Approaches to Stop statins is poorly understood (77). Clini- maximally tolerated statin dose Hypertension (DASH) eating pattern, re- cians should attempt to find a dose or should be used. E ducing saturated and trans fat intake and alternative statin that is tolerable if side S118 Cardiovascular Disease and Risk Management Diabetes Care Volume 43, Supplement 1, January 2020

the only dose of statin that a patient can it may also be reasonable to add ezeti- 10.26 In adults with diabetes aged tolerate. For patients who do not tolerate mibe to maximally tolerated statin ther- .75 years already on statin the intended intensity of statin, the apy if needed to reduce LDL cholesterol therapy, it is reasonable to maximally tolerated statin dose should levels by 50% or more (12). The evidence continue statin treatment. B be used. is lower for patients aged .75 years; 10.27 In adults with diabetes aged .75 As in those without diabetes, absolute relatively few older patients with diabe- years, it may be reasonable to reductions in ASCVD outcomes (CHD tes have been enrolled in primary pre- initiate statin therapy after dis- death and nonfatal MI) are greatest in vention trials. However, heterogeneity cussion of potential benefits and people with high baseline ASCVD risk by age has not been seen in the relative risks. C (known ASCVD and/or very high LDL benefit of lipid-lowering therapy in tri- 10.28 Statin therapy is contraindi- cholesterollevels),buttheoverallbenefits als that included older participants cated in pregnancy. B of statin therapy in people with diabetes (80,87,88), and because older age con- Initiating Statin Therapy Based on Risk at moderate or even low risk for ASCVD fershigherrisk,theabsolutebenefitsare Patients with type 2 diabetes have an are convincing (89,90). The relative ben- actually greater (80,92). Moderate-in- fi increased prevalence of lipid abnormalities, e t of lipid-lowering therapy has been tensity statin therapy is recommended contributing to their high risk of ASCVD. uniform across most subgroups tested in patients with diabetes who are 75 fi Multiple clinical trials have demonstrated (80,88), including subgroups that varied years or older. However, the risk-bene t fi the beneficial effects of statin therapy on with respect to age and other risk factors. pro le should be routinely evaluated in this population, with downward titra- ASCVD outcomes in subjects with and Primary Prevention (Patients Without tion of dose performed as needed. See without CHD (79,80). Subgroup analyses ASCVD) Section 12 “Older Adults” (https://doi of patients with diabetes in larger trials For primary prevention, moderate-dose sta- Association .org/10.2337/dc20-S012) for more de- (81–85) and trials in patients with diabetes tin therapy is recommended for those tails on clinical considerations for this (86,87) showed significant primary and 40 years and older (82,89,90), though population. secondary prevention of ASCVD events high-intensity therapy may be consid- Age <40 Years and/or Type 1 Diabetes. Very ered on an individual basis in the context andCHDdeathinpatientswithdiabetes. little clinical trial evidence exists for of additional ASCVD risk factors. The Meta-analyses, including data from over patients with type 2 diabetes under evidence is strong for patients with di- 18,000 patients with diabetes from 14 ran- the age of 40 years or for patients abetes aged 40–75 years, an age-group domized trials of statin therapy (mean with type 1 diabetes of any age. For follow-up 4.3 years), demonstrate a 9% well represented in statin trials showing pediatric recommendations, see Section fi proportional reduction in all-cause mortal- bene t. Since risk is enhanced in patients 13 “Children and Adolescents” (https:// ity and 13% reduction in vascular mortality with diabetes,Diabetes as noted above, patients doi.org/10.2337/dc20-S013). In the for each mmol/L (39 mg/dL) reduction in who also have multiple other coronary Heart Protection Study (lower age limit LDL cholesterol (88). risk factors have increased risk, equiva- 40 years), the subgroup of ;600 patients Accordingly, statins are the drugs of lent to that of those with ASCVD. As such, with type 1 diabetes had a proportion- choice for LDL cholesterol lowering and recent guidelines recommend that in ately similar, although not statistically cardioprotection. Table 10.2 shows the patients with diabetes who are at higher significant, reduction in risk as patients two statin dosing intensities that are risk, especially those with multiple with type 2 diabetes (82). Even though recommended for use in clinical practice: ASCVD risk factors or aged 50–70 years, the data are not definitive, similar statin high-intensity statin therapy will achieve it is reasonable to prescribe high-intensity treatment approaches should be consid- approximately a $50% reduction in LDL statin therapy (12,91). Furthermore, for ered for patients with type 1 or type 2 cholesterol, and moderate-intensity sta- patients with diabetes whose ASCVD risk diabetes, particularly in the presence tin regimens achieve 30–49%American reductions is $20%, i.e., an ASCVD risk equivalent, of other cardiovascular risk factors. Pa- in LDL cholesterol. Low-dose statin ther- the same high-intensity statin therapy is tients below the age of 40 have lower apy is generally not recommended in recommended as for those with docu- risk of developing a cardiovascular event patients with diabetes but is sometimes mented ASCVD (12). In those individuals, over a 10-year horizon; however, their lifetime risk of developing cardiovascular disease and suffering an MI, stroke, Table 10.2—High-intensity and moderate-intensity statin therapy* or cardiovascular death is high. For ©2019High-intensity statin therapy Moderate-intensity statin therapy patients who are younger than 40 years (lowers LDL cholesterol by $50%) (lowers LDL cholesterol by 30–49%) of age and/or have type 1 diabetes with other ASCVD risk factors, it is rec- Atorvastatin 40–80 mg Atorvastatin 10–20 mg Rosuvastatin 20–40 mg Rosuvastatin 5–10 mg ommended that the patient and health Simvastatin 20–40 mg care provider discuss the relative benefi Pravastatin 40–80 mg ts and risks and consider the use Lovastatin 40 mg of moderate-intensity statin therapy. Fluvastatin XL 80 mg Please refer to “Type 1 Diabetes Pitavastatin 1–4mg Mellitus and Cardiovascular Dis- ease: A Scientific Statement From *Once-daily dosing. XL, extended release. theAmericanHeartAssociationand care.diabetesjournals.org Cardiovascular Disease and Risk Management S119

American Diabetes Association” (93) Guidelines (12) for recommendations for feature who were receiving their maxi- for additional discussion. primary and secondary prevention and for mally tolerated statin therapy (two- statinandcombinationtreatmentinadults thirds were on high-intensity statin) Secondary Prevention (Patients With with diabetes (97). but who still had LDL cholesterol $70 mg/dL ASCVD) or non-HDL cholesterol $100 mg/dL (95). Because risk is high in patients with Combination Therapy for LDL Patients were randomized to receive sub- ASCVD, intensive therapy is indicated Cholesterol Lowering cutaneous injections of evolocumab (either and has been shown to be of benefit Statins and Ezetimibe 140 mg every 2 weeks or 420 mg every in multiple large randomized cardiovas- The IMProved Reduction of Outcomes: month based on patient preference) cular outcomes trials (88,92,94,95). High- Vytorin Efficacy International Trial versus placebo. Evolocumab reduced intensity statin therapy is recommended (IMPROVE-IT) was a randomized controlled LDL cholesterol by 59% from a me- for all patients with diabetes and ASCVD. trial in 18,144 patients comparing the dian of 92 to 30 mg/dL in the treatment This recommendation is based on the addition of ezetimibe to simvastatin arm. Cholesterol Treatment Trialists’ Collab- therapy versus simvastatin alone. Indi- During the median follow-up of 2.2 oration involving 26 statin trials, of viduals were $50 years of age, had years, the composite outcome of cardio- which 5 compared high-intensity versus experienced a recent acute coronary vascular death, MI, stroke, hospitaliza- moderate-intensity statins. Together, syndrome (ACS), and were treated for tion for angina, or revascularization they found reductions in nonfatal car- an average of 6 years. Overall, the ad- occurred in 11.3% vs. 9.8% of the placebo diovascular events with more intensive dition of ezetimibe led to a 6.4% relative and evolocumab groups, respectively, therapy, in patients with and without benefit and a 2% absolute reduction in representing a 15% relative risk reduc- diabetes (80,84,94). major adverse cardiovascular events, tion (PAssociation, 0.001). The combined end Over the past few years, there have with the degree of benefit being directly point of cardiovascular death, MI, or been multiple large randomized trials proportional to the change in LDL cho- stroke was reduced by 20%, from investigating the benefits of adding lesterol, which was 70 mg/dL in the statin 7.4% to 5.9% (P , 0.001). Importantly, nonstatin agents to statin therapy, in- group on average and 54 mg/dL in the similar benefits were seen in a prespe- cluding those that evaluated further combination group (92). In those with cified subgroup of patients with diabe- lowering of LDL cholesterol with eze- diabetes (27% of participants), the com- tes, comprising 11,031 patients (40% of timibe (92,96) and proprotein conver- bination of moderate-intensity simvas- the trial) (100). tase subtilisin/kexin type 9 (PCSK9) tatin (40 mg) and ezetimibe (10 mg) inhibitors (95). Each trial found a sig- showed a significant reduction of major Treatment of Other Lipoprotein nificant benefitinthereductionof adverse cardiovascularDiabetes events with an Fractions or Targets ASCVD events that was directly related absolute risk reduction of 5% (40% vs. Recommendations to the degree of further LDL cholesterol 45% cumulative incidence at 7 years) and 10.29 For patients with fasting tri- lowering. These large trials included a a relative risk reduction of 14% (hazard glyceride levels $500 mg/dL, fi – signi cant number of participants with ratio [HR] 0.86 [95% CI 0.78 0.94]) over evaluate for secondary causes diabetes. For very high-risk patients moderate-intensity simvastatin (40 mg) of hypertriglyceridemia and con- with ASCVD who are on high-intensity alone (96). sider medical therapy to reduce (and maximally tolerated) statin the risk of pancreatitis. C therapy and have an LDL chole- Statins and PCSK9 Inhibitors 10.30 In adults with moderate hyper- $ sterol 70 mg/dL, the addition of Placebo-controlled trials evaluating the triglyceridemia (fasting or non- nonstatin LDL-lowering therapy can addition of the PCSK9 inhibitors evolo- fasting triglycerides 175–499 be considered following aAmerican clinician- cumab and alirocumab to maximally mg/dL), clinicians should ad- patient discussion about the net ben- tolerated doses of statin therapy in dress and treat lifestyle factors fi fi e t, safety, and cost. De nition of very participants who were at high risk for (obesity and metabolic syn- high-risk patients with ASCVD includes ASCVD demonstrated an average reduc- drome), secondary factors fi the use of speci ccriteria(major tion in LDL cholesterol ranging from (diabetes, chronic liver or kid- ASCVD events and high-risk condi- 36% to 59%. These agents have been ney disease and/or nephrotic tions); refer to the 2018 American Col- approved as adjunctive therapy for syndrome, hypothyroidism), lege of Cardiology/American Heart patients with ASCVD or familial hyper- and medications that raise tri- Association multisociety guideline on cholesterolemia who are receiving max- glycerides. C the management©2019 of blood cholesterol imally tolerated statin therapy but 10.31 In patients with atherosclerotic for further details regarding this def- require additional lowering of LDL cho- cardiovascular disease or other inition of risk (12). lesterol (98,99). cardiovascular risk factors on a Please see 2018 AHA/ACC/AACVPR/ The effects of PCSK9 inhibition on statin with controlled LDL cho- AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/ ASCVD outcomes was investigated in lesterol but elevated trigly- NLA/PCNA Guideline on the Manage- the Further Cardiovascular Outcomes cerides (135–499 mg/dL), the ment of Blood Cholesterol: Executive Research With PCSK9 Inhibition in Sub- addition of icosapent ethyl can Summary: A Report of the American jects With Elevated Risk (FOURIER) be considered to reduce cardio- College of Cardiology/American Heart trial, which enrolled 27,564 patients with vascular risk. A Association Task Force on Clinical Practice prior ASCVD and an additional high-risk S120 Cardiovascular Disease and Risk Management Diabetes Care Volume 43, Supplement 1, January 2020

Hypertriglyceridemia should be ad- that for statin therapy (103). In a large [1.3 mmol/L]), and triglyceride levels of dressedwithdietaryandlifestyle trial in patients with diabetes, fenofi- 150–400 mg/dL (1.7–4.5 mmol/L) to changes including weight loss and ab- brate failed to reduce overall cardiovas- statin therapy plus extended-release ni- stinence from alcohol (101). Severe cular outcomes (104). acin or placebo. The trial was halted early hypertriglyceridemia (fasting triglycer- due to lack of efficacy on the primary ides $500 mg/dL and especially .1,000 Other Combination Therapy ASCVD outcome (first event of the com- mg/dL) may warrant pharmacologic ther- posite of death from CHD, nonfatal MI, Recommendations apy (fibric acid derivatives and/or fish ischemic stroke, hospitalization for an 10.32 Statin plus fibrate combination oil) to reduce the risk of acute pancre- ACS, or symptom-driven coronary or therapy has not been shown to atitis. Moderate- or high-intensity statin cerebral revascularization) and a possible improve atherosclerotic car- therapy should also be used as indicated increase in ischemic stroke in those on diovascular disease outcomes to reduce risk of cardiovascular events combination therapy (108). and is generally not recom- (see STATIN TREATMENT). In patients with The much larger Heart Protection mended. A moderate hypertriglyceridemia, lifestyle Study 2–Treatment of HDL to Reduce 10.33 Statin plus niacin combination interventions, treatment of secondary the Incidence of Vascular Events (HPS2- therapy has not been shown to factors, and avoidance of medications THRIVE) trial also failed to show a benefit provide additional cardiovas- that might raise triglycerides are recom- of adding niacin to background statin cular benefit above statin ther- mended. therapy (109). A total of 25,673 patients apy alone, may increase the The Reduction of Cardiovascular with prior vascular disease were random- risk of stroke with additional Events with Icosapent Ethyl–Intervention ized to receive 2 g of extended-release side effects, and is generally Trial (REDUCE-IT) enrolled 8,179 adults niacin and 40 mg of laropiprant (an not recommended. A Association receiving statin therapy with mod- antagonist of the prostaglandin D2 re- erately elevated triglycerides (135– ceptor DP1 that has been shown to 499 mg/dL, median baseline of 216 Statin and Fibrate Combination Therapy improve adherence to niacin therapy) fi mg/dL) who had either established car- Combination therapy (statin and brate) versus a matching placebo daily and diovascular disease (secondary preven- is associated with an increased risk for followed for a median follow-up period tion cohort) or diabetes plus at least one abnormal transaminase levels, myositis, of 3.9 years. There was no significant other cardiovascular risk factor (primary and rhabdomyolysis. The risk of rhabdo- difference in the rate of coronary death, prevention cohort). Patients were ran- myolysis is more common with higher MI, stroke, or coronary revascularization fi domized to icosapent ethyl 4 g/day (2 g doses of statins and renal insuf ciency with the addition of niacin–laropiprant twice daily with food) versus placebo. and appears to be higher when statins versus placebo (13.2% vs. 13.7%; rate fi The trial met its primary end point, are combinedDiabetes with gem brozil (com- ratio 0.96; P 5 0.29). Niacin–laropiprant fi demonstrating a 25% relative risk reduc- pared with feno brate) (105). was associated with an increased inci- tion (P , 0.001) for the primary end point In the ACCORD study, in patients dence of new-onset diabetes (absolute composite of cardiovascular death, non- with type 2 diabetes who were at high excess, 1.3 percentage points; P , 0.001) fatal myocardial infarction, nonfatal risk for ASCVD, the combination of fe- and disturbances in diabetes control fi stroke, coronary revascularization, or no brate and simvastatin did not reduce among those with diabetes. In addition, unstable angina. The composite of car- the rate of fatal cardiovascular events, there was an increase in serious adverse diovascular death, nonfatal myocardial nonfatal MI, or nonfatal stroke as com- events associated with the gastrointes- infarction, or nonfatal stroke was re- pared with simvastatin alone. Prespeci- tinal system, musculoskeletal system, fi duced by 26% (P , 0.001). Additional ed subgroup analyses suggested skin, and, unexpectedly, infection and ischemic end points were significantly heterogeneity in treatment effects bleeding. fi lower in the icosapent ethylAmerican group than in with possible bene tformenwith Therefore, combination therapy with $ the placebo group, including cardiovas- both a triglyceride level 204 mg/dL a statin and niacin is not recommended cular death, which was reduced by 20% (2.3 mmol/L) and an HDL cholesterol given the lack of efficacy on major # (P 5 0.03). The proportions of patients level 34 mg/dL (0.9 mmol/L) (106). ASCVD outcomes and increased side fi experiencing adverse events and serious A prospective trial of a newer brate effects. fi adverse events were similar between the in this speci c population of patients is active and placebo treatment groups. It ongoing (107). Diabetes Risk With Statin Use should be noted that data are lacking Statin and Niacin Combination Therapy Several studies have reported a modestly with©2019 other n-3 fatty acids, and results of The Atherothrombosis Intervention in increased risk of incident diabetes with the REDUCE-IT trial should not be ex- Metabolic Syndrome With Low HDL/ statin use (110,111), which may be lim- trapolated to other products (102). High Triglycerides: Impact on Global ited to those with diabetes risk factors. Low levels of HDL cholesterol, often Health Outcomes (AIM-HIGH) trial ran- An analysis of one of the initial studies associated with elevated triglyceride lev- domized over 3,000 patients (about suggested that although statin use was els, are the most prevalent pattern of one-third with diabetes) with established associated with diabetes risk, the cardio- dyslipidemia in individuals with type 2 ASCVD, low LDL cholesterol levels vascular event rate reduction with sta- diabetes. However, the evidence for the (,180 mg/dL [4.7 mmol/L]), low HDL tins far outweighed the risk of incident use of drugs that target these lipid frac- cholesterol levels (men ,40 mg/dL diabetes even for patients at highest tions is substantially less robust than [1.0 mmol/L] and women ,50 mg/dL risk for diabetes (112). The absolute care.diabetesjournals.org Cardiovascular Disease and Risk Management S121

risk increase was small (over 5 years of outcome was major bleeding (i.e., in- clopidogrel (75 mg/day) should follow-up, 1.2% of participants on placebo tracranial hemorrhage, sight-threatening be used. B developed diabetes and 1.5% on rosuvas- bleeding in the eye, gastrointestinal bleed- 10.36 Dual antiplatelet therapy (with tatin developed diabetes) (112). A meta- ing, or other serious bleeding). During a low-dose aspirin and a P2Y12 analysis of 13 randomized statin trials with mean follow-up of 7.4 years, there was a inhibitor) is reasonable for a 91,140 participants showed an odds ratio of significant 12% reduction in the primary year after an acute coronary 1.09 for a new diagnosis of diabetes, so that efficacy end point (8.5% vs. 9.6%; P 5 syndrome A and may have (on average) treatment of 255 patients with 0.01). In contrast, major bleeding was benefits beyond this period. B statins for 4 years resulted in one additional significantly increased from 3.2% to 10.37 Aspirin therapy (75–162 mg/day) case of diabetes while simultaneously pre- 4.1% in the aspirin group (rate ratio may be considered as a pri- venting 5.4 vascular events among those 1.29; P 5 0.003), with most of the excess mary prevention strategy in 255 patients (111). being gastrointestinal bleeding and other those with diabetes who are extracranial bleeding. There were no sig- at increased cardiovascular Lipid-Lowering Agents and Cognitive nificant differences by sex, weight, or risk, after a comprehensive dis- Function duration of diabetes or other baseline cussion with the patient on the Although concerns regarding a potential factors including ASCVD risk score. benefits versus the comparable adverse impact of lipid-lowering agents on Two other large randomized trials of increased risk of bleeding. A cognitive function have been raised, sev- aspirin for primary prevention, in pa- eral lines of evidence point against this tients without diabetes (ARRIVE [Aspirin association, as detailed in a 2018 European Risk Reduction to Reduce Risk of Initial Vascular Events]) Atherosclerosis Society Consensus Panel Aspirin has been shown to be effective in (126) andAssociation in the elderly (ASPREE [Aspirin statement (113). First, there are three large reducing cardiovascular morbidity and in Reducing Events in the Elderly]) (127), randomized trials of statin versus placebo mortality in high-risk patients with pre- which included 11% with diabetes, found where specific cognitive tests were per- vious MI or stroke (secondary preven- no benefit of aspirin on the primary efficacy formed, and no differences were seen tion) and is strongly recommended. In end point and an increased risk of bleeding. between statin and placebo (114–117). primary prevention, however, among In ARRIVE, with 12,546 patients over a pe- In addition, no change in cognitive function patients with no previous cardiovascular riod of 60 months follow-up, the primary has been reported in studies with the events, its net benefit is more contro- endpointoccurredin4.29%vs.4.48%of addition of ezetimibe (92) or PCSK9 inhib- versial (120,121). patients in the aspirin versus placebo itors (95,118) to statin therapy, including Previous randomized controlled trials groups (HR 0.96; 95% CI 0.81–1.13; P 5 among patients treated to very low LDL of aspirin specifically in patients with 0.60). Gastrointestinal bleeding events cholesterol levels. In addition, the most diabetes failed toDiabetes consistently show a (characterized as mild) occurred in 0.97% recent systematic review of the U.S. Food significant reduction in overall ASCVD of patients in the aspirin group vs. 0.46% in and Drug Administration’s(FDA’s) post- end points, raising questions about the the placebo group (HR 2.11; 95% CI 1.36– marketing surveillance databases, ran- efficacy of aspirin for primary preven- 3.28; P 5 0.0007). In ASPREE, including domized controlled trials, and cohort, tion in people with diabetes, although 19,114 persons, for the rate of cardiovas- case-control, and cross-sectional studies some sex differences were suggested cular disease (fatal CHD, MI, stroke, or evaluating cognition in patients receiving (122–124). hospitalization for heart failure) after a statins found that published data do not The Antithrombotic Trialists’ Collabo- median of 4.7 years of follow-up, the rates reveal an adverse effect of statins on ration published an individual patient– per 1,000 person-years were 10.7 vs. 11.3 cognition (119). Therefore, a concern level meta-analysis (120) of the six large events in aspirin vs. placebo groups (HR thatstatinsorotherlipid-lowering agents trials of aspirin for primary prevention 0.95; 95% CI 0.83–1.08). The rate of major might cause cognitive dysfunctionAmerican or in the general population. These trials hemorrhage per 1,000 person-years was dementia is not currently supported collectively enrolled over 95,000 partic- 8.6 events vs. 6.2 events, respectively (HR by evidence and should not deter their ipants, including almost 4,000 with di- 1.38; 95% CI 1.18–1.62; P , 0.001). use in individuals with diabetes at high abetes. Overall, they found that aspirin Thus, aspirin appears to have a modest risk for ASCVD (119). reduced the risk of serious vascular effect on ischemic vascular events, with events by 12% (relative risk 0.88 [95% the absolute decrease in events depend- ANTIPLATELET AGENTS CI 0.82–0.94]). The largest reduction was ing on the underlying ASCVD risk. The Recommendations for nonfatal MI, with little effect on CHD main adverse effect is an increased risk ©2019 death (relative risk 0.95 [95% CI 0.78– 10.34 Use aspirin therapy (75–162 of gastrointestinal bleeding. The excess 1.15]) or total stroke. mg/day) as a secondary pre- risk may be as high as 5 per 1,000 per Most recently, the ASCEND (A Study of vention strategy in those with year in real-world settings. However, for Cardiovascular Events iN Diabetes) trial diabetes and a history of ath- adults with ASCVD risk .1% per year, the randomized 15,480 patients with diabe- erosclerotic cardiovascular tes but no evident cardiovascular disease number of ASCVD events prevented will disease. A to aspirin 100 mg daily or placebo (125). be similar to the number of episodes 10.35 For patients with atheroscle- The primary efficacy end point was vas- ofbleeding induced, although thesecom- rotic cardiovascular disease and cular death, MI, or stroke or transient plications do not have equal effects on documented aspirin allergy, ischemic attack. The primary safety long-term health (128). S122 Cardiovascular Disease and Risk Management Diabetes Care Volume 43, Supplement 1, January 2020

Recommendations for using aspirin as platelets from patients with diabetes does not improve outcomes as primary prevention include both men have altered function, it is unclear long as atherosclerotic cardio- and women aged $50 years with di- what, if any, effect that ﬁnding has on vascular disease risk factors are abetes and at least one additional major the required dose of aspirin for cardio- treated. A risk factor (family history of premature protective effects in the patient with 10.39 Consider investigations for cor- ASCVD, hypertension, dyslipidemia, smok- diabetes. Many alternate pathways for onary artery disease in the pres- ing, or chronic kidney disease/albuminuria) platelet activation exist that are inde- ence of any of the following: who are not at increased risk of bleeding pendent of thromboxane A and thus are 2 atypical cardiac symptoms (e.g., (e.g., older age, anemia, renal disease) not sensitive to the effects of aspirin unexplained dyspnea, chest dis- (129–132).Noninvasiveimagingtechniques (137). “Aspirin resistance” has been de- comfort); signs or symptoms of such as coronary calcium scoring may scribed in patients with diabetes when associated vascular disease in- potentially help further tailor aspirin ther- measured by a variety of ex vivo and in cluding carotid bruits, transient apy, particularly in those at low risk (133) vitro methods (platelet aggregometry, ischemic attack, stroke, claudi- (134). For patients over the age of 70 years measurement of thromboxane B ) 2 cation, or peripheral arterial (with or without diabetes), the balance (138), but other studies suggest no im- disease; or electrocardiogram appears to have greater risk than beneﬁt pairment in aspirin response among pa- abnormalities (e.g., Q waves). E (125,127). Thus, for primary prevention, the tients with diabetes (139). A recent trial use of aspirin needs to be carefully con- suggested that more frequent dosing sidered and may generally not be recom- regimens of aspirin may reduce platelet Treatment

mended. Aspirin may be considered in the reactivity in individuals with diabetes Recommendations context of high cardiovascular risk with low (140); however, these observations 10.40AssociationInpatients with known athero- bleeding risk, but generally not in older alone are insufficient to empirically rec- sclerotic cardiovascular dis- adults. Aspirin therapy for primary preven- ommend that higher doses of aspirin ease, consider ACE inhibitor tion may be considered in the context of beusedin thisgroup atthis time. Another or angiotensin receptor blocker shared decision-making, which carefully recent meta-analysis raised the hypoth- therapy to reduce the risk of weighs the cardiovascular benefits with esis that low-dose aspirin efficacy is cardiovascular events. B the fairly comparable increase in risk of reduced in those weighing more than 10.41 In patients with prior myocardial bleeding. For patients with documented 70 kg (141); however, the ASCEND trial infarction, b-blockers should ASCVD, use of aspirin for secondary pre- found benefit of low-dose aspirin in be continued for at least 2 years vention has far greater benefitthanrisk;for those in this weight range, which would after the event. B this indication, aspirin is still recommended thus not validate this suggested hypoth- 10.42 In patients with type 2 diabe- (120). esis (125). It appearsDiabetes that 75–162 mg/day tes with stable heart failure, is optimal. Aspirin Use in People <50 Years of Age metformin may be continued Aspirin is not recommended for those at Indications for P2Y12 Receptor for glucose lowering if esti- fi low risk of ASCVD (such as men and Antagonist Use mated glomerular ltration women aged ,50 years with diabetes A P2Y12 receptor antagonist in com- rate remains .30 mL/min with no other major ASCVD risk factors) bination with aspirin is reasonable for but should be avoided in as the low benefit is likely to be out- at least 1 year in patients following an unstable or hospitalized pa- weighed by the risks of bleeding. Clinical ACSandmayhavebenefits beyond this tients with heart failure. B judgment should be used for those at period. Evidence supports use of either 10.43 Among patients with type 2 intermediate risk (younger patients with ticagrelor or clopidogrel if no percu- diabetes who have established one or more risk factors orAmerican older patients taneous coronary intervention was atherosclerotic cardiovascular withnoriskfactors) untilfurther research performed and clopidogrel, ticagrelor, disease or established kidney is available. Patients’ willingness to un- or prasugrel if a percutaneous coro- disease, a sodium–glucose co- dergo long-term aspirin therapy should nary intervention was performed transporter 2 inhibitor or glu- also be considered (135). Aspirin use in (142). In patients with diabetes and cagon-like peptide 1 receptor patients aged ,21 years is generally prior MI (1–3 years before), adding agonist with demonstrated contraindicated due to the associated ticagrelor to aspirin significantly re- cardiovascular disease benefit risk of Reye syndrome. duces the risk of recurrent ischemic (Table 10.3B and Table 10.3C) ©2019 events including cardiovascular and is recommended as part of the Aspirin Dosing glucose-lowering regimen. A Average daily dosages used in most CHD death (143). 10.43a In patients with type 2 diabe- clinical trials involving patients with di- tes and established atheroscle- abetes ranged from 50 mg to 650 mg but CARDIOVASCULAR DISEASE rotic cardiovascular disease, were mostly in the range of 100–325 mg/ Screening multiple atherosclerotic cardio- day. There is little evidence to support Recommendations vascular disease risk factors, any specific dose, but using the lowest 10.38 In asymptomatic patients, rou- or diabetic kidney disease, a possible dose may help to reduce side tinescreeningforcoronaryartery sodium–glucose cotransporter effects (136). In the U.S., the most com- disease is not recommended as it 2 inhibitor with demonstrated mon low-dose tablet is 81 mg. Although care.diabetesjournals.org Cardiovascular Disease and Risk Management S123

established as an independent predictor Diabetes (Look AHEAD) trial may be con- cardiovascular benefit is rec- of future ASCVD events in patients with sidered for improving glucose control, fit- ommended to reduce the risk diabetes and is consistently superior to ness, and some ASCVD risk factors (157). of major adverse cardiovascu- both the UK Prospective Diabetes Study Patients at increased ASCVD risk should lar events and heart failure (UKPDS)riskengineandtheFraming- receive statin, ACE inhibitor, or ARB therapy hospitalization. A ham Risk Score in predicting risk in this if the patient has hypertension, and 10.43b In patients with type 2 diabe- population (148–150). However, a ran- possibly aspirin, unless there are contra- tesandestablishedatheroscle- domized observational trial demon- indications to a particular drug class. rotic cardiovascular disease strated no clinical benefit to routine While clear benefit exists for ACE inhib- or multiple risk factors for screening of asymptomatic patients itor or ARB therapy in patients with atherosclerotic cardiovascular with type 2 diabetes and normal diabetic kidney disease or hypertension, disease, a glucagon-like pep- ECGs (151). Despite abnormal myo- the benefits in patients with ASCVD in the tide 1 receptor agonist with cardial perfusion imaging in more than absence of these conditions are less demonstrated cardiovascular one in five patients, cardiac outcomes clear, especially when LDL cholesterol benefit is recommended to were essentially equal (and very low) in is concomitantly controlled (158,159). reduce the risk of major ad- screened versus unscreened patients. In patients with prior MI, active angina, verse cardiovascular events. A Accordingly, indiscriminate screening is or HFrEF, b-blockers should be used 10.43c In patients with type 2 diabe- not considered cost-effective. Studies (160). tes and established heart have found that a risk factor–based failure, a sodium–glucose co- approach to the initial diagnostic evalu- transporter 2 inhibitor may be GLUCOSE-LOWERING THERAPIES ation and subsequent follow-up for cor- considered to reduce risk of AND CARDIOVASCULARAssociation onary artery disease fails to identify heart failure hospitalization. C OUTCOMES which patients with type 2 diabetes In 2008, the FDA issued a guidance for will have silent ischemia on screening industry to perform cardiovascular out- CARDIAC TESTING tests (152,153). comes trials for all new medications for Candidates for advanced or invasive car- Any benefit of newer noninvasive cor- thetreatmentfortype2diabetesamid diac testing include those with 1) typical onary artery disease screening methods, concerns of increased cardiovascular risk or atypical cardiac symptoms and 2)an such as computed tomography calcium (161). Previously approved diabetes med- abnormal resting electrocardiogram scoring and computed tomography an- ications were not subject to the guidance. (ECG). Exercise ECG testing without or giography, to identify patient subgroups Recently published cardiovascular out- with echocardiography may be used as for different treatmentDiabetes strategies re- comestrialshaveprovidedadditional the initial test. In adults with diabetes $ mains unproven in asymptomatic pa- data on cardiovascular outcomes in pa- 40 years of age, measurement of coro- tients with diabetes, though research tients with type 2 diabetes with car- nary artery calcium is also reasonable for is ongoing. Although asymptomatic pa- diovascular disease or at high risk for cardiovascular risk assessment. Pharma- tients with diabetes with higher coronary cardiovascular disease (see Table 10.3A, cologic stress echocardiography or nu- disease burden have more future cardiac Table 10.3B, and Table 10.3C). Cardio- clear imaging should be considered in events (148,154,155), the role of these vascular outcomes trials of dipeptidyl individualswithdiabetesinwhomresting tests beyond risk stratification is not peptidase 4 (DPP-4) inhibitors have all, ECG abnormalities preclude exercise clear. so far, not shown cardiovascular bene- stress testing (e.g., left bundle branch While coronary artery screening fits relative to placebo. However, results block or ST-T abnormalities). In addition, methods, such as calcium scoring, from other new agents have provided a individuals whorequirestress testing and may improve cardiovascular risk assess- mix of results. are unable to exercise shouldAmerican undergo ment in people with type 2 diabetes pharmacologic stress echocardiography (156), their routine use leads to radia- SGLT2 Inhibitor Trials or nuclear imaging. tion exposure and may result in unnec- The BI 10773 (Empagliflozin) Cardiovas- essary invasive testing such as coronary cular Outcome Event Trial in Type 2 Di- SCREENING ASYMPTOMATIC angiography and revascularization pro- abetes Mellitus Patients (EMPA-REG PATIENTS cedures. The ultimate balance of ben- OUTCOME) trial was a randomized, dou- The screening of asymptomatic patients efit, cost, and risks of such an approach ble-blind trial that assessed the effect with high ASCVD risk is not recommen- in asymptomatic patients remains con- of empagliflozin, an SGLT2 inhibitor, ded (144),©2019 in part because these high-risk troversial, particularly in the modern versus placebo on cardiovascular outpatients should already be receiving in- setting of aggressive ASCVD risk factor comes in 7,020 patients with type 2 tensive medical therapydan approach control. diabetes and existing cardiovascular dis- that provides similar benefit as invasive ease. Study participants had a mean age revascularization (145,146). There is also LIFESTYLE AND PHARMACOLOGIC of 63 years, 57% had diabetes for more some evidence that silent ischemia may INTERVENTIONS than 10 years, and 99% had established reverse over time, adding to the contro- Intensive lifestyle intervention focusing cardiovascular disease. EMPA-REG OUT- versy concerning aggressive screening on weight loss through decreased caloric COME showed that over a median fol- strategies (147). In prospective studies, intake and increased physical activity as low-up of 3.1 years, treatment reduced coronary artery calcium has been performedintheActionforHealthin the composite outcome of MI, stroke, S124 Cardiovascular Disease and Risk Management Diabetes Care Volume 43, Supplement 1, January 2020

Table 10.3A—Cardiovascular outcomes trials of available antihyperglycemic medications completed after the issuance of the FDA 2008 guidelines: DPP-4 inhibitors SAVOR-TIMI 53 (181) EXAMINE (186) TECOS (183) CARMELINA (184,187) (n 5 16,492) (n 5 5,380) (n 5 14,671) (n 5 6,979) Intervention Saxagliptin/placebo Alogliptin/placebo Sitagliptin/placebo Linagliptin/placebo Main inclusion criteria Type 2 diabetes and history Type 2 diabetes and ACS Type 2 diabetes Type 2 diabetes and high CV and of or multiple risk factors within 15–90 days before and preexisting renal risk for CVD randomization CVD A1C inclusion criteria (%) $6.5 6.5–11.0 6.5–8.0 6.5–10.0 Age (years)†† 65.1 61.0 65.4 65.8 Race (% white) 75.2 72.7 67.9 80.2 Sex (% male) 66.9 67.9 70.7 62.9 Diabetes duration (years)†† 10.3 7.1 11.6 14.7 Median follow-up (years) 2.1 1.5 3.0 2.2 Statin use (%) 78 91 80 71.8 Metformin use (%) 70 66 82 54.8 Prior CVD/CHF (%) 78/13 100/28 74/18 57/26.8 Mean baseline A1C (%) 8.0 8.0 7.2 7.9 Mean difference in A1C 20.3^ 20.3^ 20.3^ 20.36^ between groups at end of treatment (%) Association Year started/reported 2010/2013 2009/2013 2008/2015 2013/2018 Primary outcome§ 3-point MACE 3-point MACE 4-point MACE 3-point MACE 1.00 (0.89–1.12) 0.96 (95% UL #1.16) 0.98 (0.89–1.08) 1.02 (0.89–1.17) Key secondary outcome§ Expanded MACE 4-point MACE 3-point MACE Kidney composite (ESRD, 1.02 (0.94–1.11) 0.95 (95% UL #1.14) 0.99 (0.89–1.10) sustained $40% decrease in eGFR, or renal death) 1.04 (0.89–1.22) Cardiovascular death§ 1.03 (0.87–1.22) 0.85 (0.66–1.10) 1.03 (0.89–1.19) 0.96 (0.81–1.14) MI§ 0.95 (0.80–1.12) 1.08 (0.88–1.33) 0.95 (0.81–1.11) 1.12 (0.90–1.40) Stroke§ 1.11 (0.88–1.39) 0.91 (0.55Diabetes–1.50) 0.97 (0.79 –1.19) 0.91 (0.67–1.23) HF hospitalization§ 1.27 (1.07–1.51) 1.19 (0.90–1.58) 1.00 (0.83–1.20) 0.90 (0.74–1.08) Unstable angina 1.19 (0.89–1.60) 0.90 (0.60–1.37) 0.90 (0.70–1.16) 0.87 (0.57–1.31) hospitalization§ All-cause mortality§ 1.11 (0.96–1.27) 0.88 (0.71–1.09) 1.01 (0.90–1.14) 0.98 (0.84–1.13) Worsening nephropathy§|| 1.08 (0.88–1.32) ddKidney composite (see above) d, not assessed/reported; ACS, acute coronary syndrome; CHF, congestive heart failure; CV, cardiovascular; CVD, cardiovascular disease; DPP-4, dipeptidylpeptidase4;eGFR, estimatedglomerularfiltrationrate;ESRD, end-stage renaldisease;GLP-1, glucagon-likepeptide1;HF, heart failure; MACE, major adverse cardiac event; MI, myocardial infarction; UL, upper limit. Data from this table was adapted from Cefalu et al. (188) in the January 2018 issue of Diabetes Care. ††Age was reported as means in all trials except EXAMINE, which reported medians; diabetes duration was reported as means in all trials except SAVOR-TIMI 53 and EXAMINE, which reported medians. §Outcomes reported as hazard ratio (95% CI). ||Worsening nephropathy is defined as as doubling of creatinine level, initiation of dialysis, renal transplantation, or creatinine .6.0 mg/dL (530 mmol/L) in SAVOR-TIMI 53. Worsening nephropathy was a prespecified exploratory adjudicated outcome in SAVOR-TIMI 53.^SignificantAmerican difference in A1C between groups (P , 0.05).

and cardiovascular death by 14% (abso- assessed 1) the cardiovascular effects of drug (163). Thereafter, the postapproval lute rate 10.5% vs. 12.1% in the placebo treatment in patients at high risk for CANVAS-Renal (CANVAS-R) trial was group, HR in the empagliflozin group major adverse cardiovascular events, started in 2014. Combining both of these 0.86; 95% CI 0.74–0.99; P 5 0.04 for and 2) the impact of canagliflozin therapy trials, 10,142 participants with type 2 superiority)©2019 and cardiovascular death by on cardiorenal outcomes in patients with diabetes were randomized to canagliflo- 38% (absolute rate 3.7% vs. 5.9%, HR diabetes-related chronic kidney disease zin or placebo and were followed for an 0.62; 95% CI 0.49–0.77; P , 0.001) (8). have been conducted (162). First, the average 3.6 years. The mean age of The FDA added an indication for empa- Canagliflozin Cardiovascular Assessment patients was 63 years, and 66% had a gliflozin to reduce the risk of major Study (CANVAS) Program integrated data history of cardiovascular disease. The adverse cardiovascular death in adults from two trials. The CANVAS trial that combined analysis of the two trials found with type 2 diabetes and cardiovascular started in 2009 was partially unblinded that canagliflozin significantly reduced disease. prior to completion because of the the composite outcome of cardiovascu- Two large outcomes trials of the SGLT2 need to file interim cardiovascular out- lar death, MI, or stroke versus placebo inhibitor canagliflozin that separately comes data for regulatory approval of the (occurring in 26.9 vs. 31.5 participants care.diabetesjournals.org Cardiovascular Disease and Risk Management S125

Table 10.3B—Cardiovascular outcomes trials of available antihyperglycemic medications completed after the issuance of the FDA 2008 guidelines: GLP-1 receptor agonists Harmony ELIXA (170) LEADER (165) SUSTAIN-6 (166)* EXSCEL (171) Outcomes (168) REWIND (169) (n 5 6,068) (n 5 9,340) (n 5 3,297) (n 5 14,752) (n 5 9,463) (n 5 9,901) Intervention Lixisenatide/ Liraglutide/ Semaglutide/ Exenatide QW/ Albiglutide/ Dulaglutide/ placebo placebo placebo placebo placebo placebo Main inclusion Type 2 diabetes Type 2 diabetes Type 2 diabetes and Type 2 diabetes Type 2 diabetes Type 2 diabetes criteria and history of and preexisting preexisting CVD, with or without with preexisting and prior ACS (,180 days) CVD, CKD, or HF HF, or CKD at preexisting CVD CVD ASCVD event at $50 years of $50 years of age or risk factors age or CV risk at or CV risk at $60 for ASCVD $60 years of years of age age A1C inclusion 5.5–11.0 $7.0 $7.0 6.5–10.0 $7.0 #9.5 criteria (%) Age (years)†† 60.3 64.3 64.6 62 64.1 66.2 Race (% white) 75.2 77.5 83.0 75.8 84.8 75.7 Sex (% male) 69.3 64.3 60.7 62 69.4 53.7 Diabetes duration 9.3 12.8 13.9 12 13.8 10.5 (years)†† Median follow-up 2.1 3.8 2.1 3.2 1.6 Association5.4 (years) Statin use (%) 93 72 73 74 84.0 66 Metformin use (%) 66 76 73 77 73.6 81 Prior CVD/CHF (%) 100/22 81/18 60/24 73.1/16.2 100/20.2 32/9 Mean baseline 7.7 8.7 8.7 8.0 8.7 7.4 A1C (%) Mean difference in 20.3^ 20.4^ 20.7 or – 1.0^† 20.53^ 20.52^ 20.61^ A1C between groups at end of treatment (%) Year started/ 2010/2015 2010/2016 2013/2016Diabetes 2010/2017 2015/2018 2011/2019 reported Primary outcome§ 4-point MACE 3-point MACE 3-point MACE 3-point MACE 3-point MACE 3-point MACE 1.02 (0.89–1.17) 0.87 (0.78–0.97) 0.74 (0.58–0.95) 0.91 (0.83–1.00) 0.78 (0.68–0.90) 0.88 (0.79–0.99) Key secondary Expanded MACE Expanded MACE Expanded MACE Individual Expanded MACE Composite outcome§ (0.90–1.11) 0.88 (0.81–0.96) 0.74 (0.62–0.89) components of (with urgent microvascular MACE (see revascularization outcome below) for unstable (eye or renal angina) outcome) 0.78 (0.69–0.90) 0.87 (0.79–0.95) CV death or HF hospitalization American 0.85 (0.70–1.04) Individual components of MACE (see below) Cardiovascular 0.98 (0.78–1.22) 0.78 (0.66–0.93) 0.98 (0.65–1.48) 0.88 (0.76–1.02) 0.93 (0.73–1.19) 0.91 (0.78–1.06) death§ MI§ 1.03 (0.87–1.22) 0.86 (0.73–1.00) 0.74 (0.51–1.08) 0.97 (0.85–1.10) 0.75 (0.61–0.90) 0.96 (0.79–1.15) Stroke§ 1.12 (0.79–1.58) 0.86 (0.71–1.06) 0.61 (0.38–0.99) 0.85 (0.70–1.03) 0.86 (0.66–1.14) 0.76 (0.61–0.95) HF ©20190.96 (0.75 –1.23) 0.87 (0.73–1.05) 1.11 (0.77–1.61) 0.94 (0.78–1.13) d 0.93 (0.77–1.12) hospitalization§ Unstable angina 1.11 (0.47–2.62) 0.98 (0.76–1.26) 0.82 (0.47–1.44) 1.05 (0.94–1.18) d 1.14 (0.84–1.54) hospitalization§ Continued on p. S126 S126 Cardiovascular Disease and Risk Management Diabetes Care Volume 43, Supplement 1, January 2020

Table 10.3B—Continued Harmony ELIXA (170) LEADER (165) SUSTAIN-6 (166)* EXSCEL (171) Outcomes (168) REWIND (169) (n 5 6,068) (n 5 9,340) (n 5 3,297) (n 5 14,752) (n 5 9,463) (n 5 9,901) All-cause 0.94 (0.78–1.13) 0.85 (0.74–0.97) 1.05 (0.74–1.50) 0.86 (0.77–0.97) 0.95 (0.79–1.16) 0.90 (0.80–1.01) mortality§ Worsening d 0.78 (0.67–0.92) 0.64 (0.46–0.88) dd 0.85 (0.77–0.93) nephropathy§|| d, not assessed/reported; ACS, acute coronary syndrome; ASCVD, atherosclerotic cardiovascular disease; CHF, congestive heart failure; CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease; GLP-1, glucagon-like peptide 1; HF, heart failure; MACE, major adverse cardiac event; MI, myocardial infarction. Data from this table was adapted from Cefalu et al. (188) in the January 2018 issue of Diabetes Care. *Powered to rule out a hazard ratio of 1.8; superiority hypothesis not prespecified. ††Age was reported as means in all trials; diabetes duration was reported as means in all trials except EXSCEL, which reported medians. †A1C change of 0.66% with 0.5 mg and 1.05% with 1 mg dose of semaglutide. §Outcomes reported as hazard ratio (95% CI). ||Worsening nephropathy is defined as the new onset of urine albumin-to-creatinine ratio .300 mg/g creatinine or a doubling of the serum creatinine level and an estimated glomerular filtration rate of ,45 mL/min/1.73 m2, the need for continuous renal replacement therapy, or death from renal disease in LEADER and SUSTAIN-6 and as new macroalbuminuria, a sustained decline in estimated glomerular filtration rate of 30% or more from baseline, or chronic renal replacement therapy in REWIND. Worsening nephropathy was a prespecified exploratory adjudicated outcome in LEADER, SUSTAIN-6, and REWIND.^Significant difference in A1C between groups (P , 0.05).

per 1,000 patient-years; HR 0.86 [95% CI failure (HR 0.61 [95% CI 0.47–0.80]), and lowerrateofhospitalizationforheartfailureAssociation 0.75–0.97]). The specific estimates for of the composite of cardiovascular death (HR 0.73; 95% CI 0.61–0.88). No difference canagliflozin versus placebo on the or hospitalization for heart failure (HR was seen in cardiovascular death between primary composite cardiovascular out- 0.69 [95% CI 0.57–0.83]). In terms of groups. come were HR 0.88 (0.75–1.03) for safety, no significant increase in lower- the CANVAS trial and 0.82 (0.66–1.01) limb amputations, fractures, acute kidney GLP-1 Receptor Agonist Trials for CANVAS-R, with no heterogeneity injury, or hyperkalemia was noted for The Liraglutide Effect and Action in Di- found between trials. Of note, there canagliflozin relative to placebo in CRE- abetes: Evaluation of Cardiovascular was an increased risk of lower-limb am- DENCE. An increased risk for diabetic Outcome Results (LEADER) trial was a putation with canagliflozin (6.3 vs. 3.4 ketoacidosis was noted, however, with randomized, double-blind trial that participants per 1,000 patient-years; HR 2.2 and 0.2 events per 1,000 patient-years assessed the effect of liraglutide, a 1.97 [95% CI 1.41–2.75]) (9). Second, the noted in the canagliDiabetesflozin and placebo glucagon-like peptide 1 (GLP-1) receptor Canagliflozin and Renal Events in Dia- groups, respectively (HR 10.80 [95% CI agonist, versus placebo on cardiovascular betes with Established Nephropathy 1.39–83.65]) (162). outcomes in 9,340 patients with type 2 Clinical Evaluation (CREDENCE) trial ran- The Dapagliflozin Effect on Cardiovascu- diabetes at high risk for cardiovascular domized 4,401 patients with type 2 lar Events–Thrombosis in Myocardial In- disease or with cardiovascular disease. diabetes and chronic diabetes-related farction 58 (DECLARE-TIMI 58) trial was Study participants had a mean age of kidney disease (UACR .300 mg/g and another randomized, double-blind trial that 64 years and a mean duration of diabetes estimated glomerular filtration rate 30 assessed the effects of dapagliflozin versus of nearly 13 years. Over 80% of study to ,90 mL/min/1.73 m2) to canagliflozin placebo on cardiovascular and renal out- participants had established cardiovascu- 100 mg daily or placebo (162). The pri- comes in 17,160 patients with type 2 di- lardisease.Afteramedianfollow-upof3.8 mary outcome was a composite of end- abetes and established ASCVD or multiple years, LEADER showed that the primary stage kidney disease (ESKD),American doubling of risk factors for atherosclerotic cardiovascu- composite outcome (MI, stroke, or car- serum creatinine, or death from renal or lar disease (164). Study participants had a diovascular death) occurred in fewer cardiovascular causes. The trial was stop- mean age of 64 years, with ;40% of study participants in the treatment group ped early due to conclusive evidence of participants having established ASCVD at (13.0%) when compared with the pla- efficacy identified during a prespecified baselineda characteristic of this trial that cebo group (14.9%) (HR 0.87; 95% CI interim analysis with no unexpected differs from other large cardiovascular trials 0.78–0.97; P , 0.001 for noninferiority; safety signals. The risk of the primary where a majority of participants had estab- P 5 0.01 for superiority). Deaths from composite outcome was 30% lower with lished cardiovascular disease. DECLARE- cardiovascular causes were significantly canagli©2019flozin treatment when compared TIMI 58 met the prespecified criteria for reduced in the liraglutide group (4.7%) with placebo (HR 0.70 [95% CI 0.59– noninferiority to placebo with respect to compared with the placebo group 0.82]). Moreover, it reduced the prespe- MACE but did not show a lower rate of (6.0%) (HR 0.78; 95% CI 0.66–0.93; cified end point of ESKD alone by 32% (HR MACE when compared with placebo (8.8% P 5 0.007) (165). The FDA approved 0.68 [95% CI 0.54–0.86]). Canagliflozin in the dapagliflozin group and 9.4% in the theuseofliraglutidetoreducetheriskof was additionally found to have a lower placebo group; HR 0.93; 95% CI 0.84–1.03; major adverse cardiovascular events, risk of the composite of cardiovascular P 5 0.17). A lower rate of cardiovascular including heart attack, stroke, and car- death, myocardial infarction, or stroke death or hospitalization for heart failure diovascular death, in adults with type 2 (HR 0.80 [95% CI 0.67–0.95]), as well as was noted (4.9% vs. 5.8%; HR 0.83; 95% CI diabetes and established cardiovascu- lower risk of hospitalizations for heart 0.73–0.95; P 5 0.005), which reflected a lar disease. care.diabetesjournals.org Cardiovascular Disease and Risk Management S127

Table 10.3C—Cardiovascular outcomes trials of available antihyperglycemic medications completed after the issuance of the FDA 2008 guidelines: SGLT2 inhibitors EMPA-REG CANVAS (9) OUTCOME (8) DECLARE-TIMI 58 (164) (n 5 7,020) (n 5 4,330) (n 5 5,812) (n 5 17,160) Intervention Empagliflozin/ Canagliflozin/ Dapagliflozin/placebo placebo placebo Main inclusion criteria Type 2 diabetes Type 2 diabetes Type 2 diabetes and and and preexisting established ASCVD or preexisting CVD at $30 multiple risk factors CVD years of age for ASCVD or .2 CV risk factors at $50 years of age A1C inclusion criteria (%) 7.0–10.0 7.0–10.5 $6.5 Age (years)†† 63.1 63.3 64.0 Race (% white) 72.4 78.3 79.6 Sex (% male) 71.5 64.2 62.6 Diabetes duration (years)†† 57% .10 13.5 11.0 Median follow-up (years) 3.1 5.7 2.1 4.2 Statin use (%) 77 75 Association75 (statin or ezetimibe use) Metformin use (%) 74 77 82 Prior CVD/CHF (%) 99/10 65.6/14.4 40/10 Mean baseline A1C (%) 8.1 8.2 8.3 Mean difference in A1C between 20.3^‡ 20.58^ 20.43^ groups at end of treatment (%) Year started/reported 2010/2015 2009/2017 2013/2018 Primary outcome§ 3-point MACE 3-point MACE Progression to 3-point MACE 0.93 (0.84– 0.86 (0.74–0.99) 0.86 (0.75–0.97)§ albuminuria** 1.03) 0.73 (0.47–0.77) CV death or HF hospitalization 0.83 (0.73–0.95) Key secondary outcome§ 4-point MACE All-cause and CV Diabetes40% reduction in Death from any cause mortality (see composite 0.93 (0.82–1.04) below) eGFR, renal Renal composite ($40% replacement, decrease in eGFR rate to renal death 0.60 ,60 mL/min/1.73m2, new (0.47–0.77) ESRD,ordeathfromrenalor CV causes 0.76 (0.67–0.87) Cardiovascular death§ 0.62 (0.49–0.77) 0.96 (0.77–1.18)¶ 0.98 (0.82–1.17) 0.87 (0.72–1.06)# MI§ 0.87 (0.70–1.09) 0.85 (0.65–1.11) 0.85 (0.61–1.19) 0.89 (0.77–1.01) Stroke§ 1.18 (0.89–1.56) 0.97 (0.70–1.35) 0.82 (0.57–1.18) 1.01 (0.84–1.21) HF hospitalization§ American0.65 (0.50–0.85) 0.77 (0.55–1.08) 0.56 (0.38–0.83) 0.73 (0.61–0.88) Unstable angina hospitalization§ 0.99 (0.74–1.34) dd All-cause mortality§ 0.68 (0.57–0.82) 0.87 (0.74–1.01)‡‡ 0.93 (0.82–1.04) 0.90 (0.76–1.07)## Worsening nephropathy§|| 0.61 (0.53–0.70) 0.60 (0.47–0.77) 0.53 (0.43–0.66) d, not assessed/reported; CHF, congestive heart failure; CV, cardiovascular; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; HF, heart failure; MACE,major adverse cardiac event; MI, myocardial infarction; SGLT2, sodium–glucose cotransporter 2. Data from this table was adapted from Cefalu et al. (188) in the January 2018 issue of Diabetes Care. **On the basis of prespecified outcomes, the renal outcomes are not viewedas statisticallysignificant. ††Age was reportedas meansin all trials; diabetes duration was reportedas meansin alltrials except EMPA-REG©2019 OUTCOME, which reported as percentage of population with diabetes duration .10 years, and DECLARE-TIMI 58, which reported median. ‡AlC change of 0.30 in EMPA-REG OUTCOME is based on pooled results for both doses (i.e., 0.24% for 10 mg and 0.36% for 25 mg of empagliflozin). §Outcomesreportedashazardratio(95%CI).||Worseningnephropathy is definedasthe newonsetofurine albumin-to-creatinineratio.300mg/g creatinine or a doubling of the serum creatinine level and an estimated glomerular filtration rate of ,45 mL/min/1.73 m2, the need for continuous renal replacement therapy, or death from renal disease in EMPA-REG OUTCOME and as $40% decrease in estimated glomerular filtration rate to ,60 mL/min/1.73 m2, ESRD, or death from renal cause in DECLARE-TIMI 58. Worsening nephropathy was a prespecified exploratory adjudicated outcome in DECLARE-TIMI 58 but not in EMPA-REG OUTCOME. ¶Truncated data set (prespecified in treating hierarchy as the principal data set for analysis for superiority of all-cause mortality and cardiovascular death in the CANVAS Program).^Significant difference in A1C between groups (P , 0.05). #Nontruncated data set. ‡‡Truncated integrated data set (refers to pooled data from CANVAS after 20 November 2012 plus CANVAS-R; prespecified in treating hierarchy as the principal data set for analysis for superiority of all-cause mortality and cardiovascular death in the CANVAS Program). ##Nontruncated integrated data (refers to pooled data from CANVAS, including before 20 November 2012 plus CANVAS-R). S128 Cardiovascular Disease and Risk Management Diabetes Care Volume 43, Supplement 1, January 2020

Results from a moderate-sized trial of blind, placebo-controlled trial that as- disease) were randomized to receive ex- another GLP-1 receptor agonist, sema- sessed the effect of the once-weekly tended-release exenatide 2 mg or pla- glutide, were consistent with the LEADER GLP-1 receptor agonist dulaglutide ver- ceboandfollowedforamedianof3.2 trial (166). Semaglutide is a once-weekly sus placebo on MACE in ;9,990 patients years. The primary end point of cardio- GLP-1 receptor agonist approved by the with type 2 diabetes at risk for cardiovascular death, MI, or stroke occurred in FDA for the treatment of type 2 diabetes. vascular events or with a history of 839 patients (11.4%; 3.7 events per The Trial to Evaluate Cardiovascular and cardiovascular disease (169). Study par- 100 person-years) in the exenatide Other Long-term Outcomes With Sem- ticipants hada mean age of 66years and a group and in 905 patients (12.2%; 4.0 aglutide in Subjects With Type 2 Diabe- mean duration of diabetes of ;10 years. events per 100 person-years) in the tes (SUSTAIN-6) was the initial randomized Approximately 32% of participants had placebo group (HR 0.91; 95% CI 0.83– trial powered to test noninferiority of prior history of atherosclerotic cardio- 1.00; P , 0.001 for noninferiority) but semaglutide for the purpose of initial vascular events at baseline. After a me- was not superior to placebo with re- regulatory approval. In this study, 3,297 dian follow-up of 5.4 years, the primary spect to the primary end point (P50.06 for patients with type 2 diabetes were ran- composite outcome of nonfatal myocar- superiority). However, all-cause mortality domized to receive once-weekly semaglu- dial infarction, nonfatal stroke, or death was lower in the exenatide group (HR 0.86 tide (0.5 mg or 1.0 mg) or placebo for from cardiovascular causes occurred [95% CI 0.77–0.97]). The incidence of acute 2 years. The primary outcome (the first in 12.0% and 13.4% of participants in pancreatitis, pancreatic cancer, medullary occurrence of cardiovascular death, non- the dulaglutide and placebo treatment thyroid carcinoma, and serious adverse fatal MI, or nonfatal stroke) occurred in groups, respectively (HR 0.88; 95% CI events did not differ significantly between 108 patients (6.6%) in the semaglutide 0.79–0.99; P 5 0.026). These findings the two groups. group vs. 146 patients (8.9%) in theplacebo equated to incidence rates of 2.4 and 2.7 InAssociation summary, there are now numerous group (HR 0.74; 95% CI 0.58–0.95; P , events per 100 person-years, respec- large randomized controlled trials re- 0.001). More patients discontinued treat- tively. The results were consistent across porting statistically significant reductions ment in the semaglutide group because of the subgroups of patients with and within cardiovascular events for three of the adverse events, mainly gastrointestinal. out prior history of CV events. All-cause FDA-approved SGLT2 inhibitors (empa- The cardiovascular effects of the oral for- mortality did not differ between groups gliflozin, canagliflozin, and dapagliflozin) mulation of semaglutide compared with (P 5 0.067). and four FDA-approved GLP-1 receptor placebo have been assessed in Peptide The Evaluation of Lixisenatide in Acute agonists (liraglutide, albiglutide [al- Innovation for Early Diabetes Treatment Coronary Syndrome (ELIXA) trial studied though that agent was removed from (PIONEER) 6, a preapproval trial designed the once-daily GLP-1 receptor agonist the market for business reasons], sem- to rule outan unacceptable increase in in lixisenatide on cardiovascular outcomes aglutide [lower risk of cardiovascular cardiovascular risk. In this trial of 3,183 in patients withDiabetes type 2 diabetes who had events in a moderate-sized clinical trial patients with type 2 diabetes and high had a recent acute coronary event (170). but one not powered as a cardiovascu- cardiovascular risk followed for a me- A total of 6,068 patients with type 2 lar outcomes trial], and dulaglutide). dian of 15.9 months, oral semaglutide diabetes with a recent hospitalization for Meta-analyses of the trials reported was noninferior to placebo for the pri- MIorunstable angina withinthe previous to date suggest that GLP-1 receptor mary composite outcome of cardiovas- 180 days were randomized to receive agonists and SGLT2 inhibitors reducerisk cular death, nonfatal myocardial infarction, lixisenatide or placebo in addition to of atherosclerotic major adverse cardio- or nonfatal stroke (HR 0.79; 95% CI 0.57– standard care and were followed for a vascular events to a comparable degree 1.11; P , 0.001 for noninferiority) (167). median of ;2.1 years. The primary out- in patients with type 2 diabetes and The cardiovascular effects of this formu- come of cardiovascular death, MI, stroke, established ASCVD (172). SGLT2 inhib- lation of semaglutide will be further tested or hospitalization for unstable angina itors also appear to reduce risk of heart in a large, longer-term outcomesAmerican trial. occurred in 406 patients (13.4%) in the failure hospitalization and progression The Harmony Outcomes trial random- lixisenatide group vs. 399 (13.2%) in the of kidney disease in patients with es- ized 9,463 patients with type 2 diabetes placebo group (HR 1.2 [95% CI 0.89– tablished ASCVD, multiple risk factors and cardiovascular disease to once- 1.17]), which demonstrated the noninfer- for ASCVD, or diabetic kidney disease weekly subcutaneous albiglutide or match- iorityoflixisenatidetoplacebo(P,0.001) (173). In patients with type 2 diabetes ing placebo, in addition to their standard but did not show superiority (P 5 0.81). and established ASCVD, multiple ASCVD care. Over a median duration of 1.6 years, The Exenatide Study of Cardiovascu- risk factors, or diabetic kidney disease, the GLP-1 receptor agonist reduced the risk lar Event Lowering (EXSCEL) trial also an SGLT2 inhibitor with demonstrated of©2019 cardiovascular death, MI, or stroke to an reported results with the once-weekly cardiovascular benefit is recommended incidencerateof4.6eventsper100per- GLP-1 receptor agonist extended-release to reduce the risk of major adverse son-years in the albiglutide group vs. 5.9 exenatide and found that major adverse cardiovascular events and heart failure events in the placebo group (HR ratio 0.78, cardiovascular events were numeri- hospitalization. In patients with type 2 P 5 0.0006 for superiority) (168). This cally lower with use of extended-release diabetes and established ASCVD or mul- agent is not currently available for clinical exenatide compared with placebo, al- tiple risk factors for ASCVD, a glucagon- use. though this difference was not statisti- like peptide 1 receptor agonist with The Researching Cardiovascular Events cally significant (171). A total of 14,752 demonstrated cardiovascular benefitis With a Weekly Incretin in Diabetes (RE- patients with type 2 diabetes (of whom recommended to reduce the risk of ma- WIND) trial was a randomized, double- 10,782 [73.1%] had previous cardiovascular jor adverse cardiovascular events. For care.diabetesjournals.org Cardiovascular Disease and Risk Management S129

many patients, use of either an SGLT2 compared with placebo (Table 10.3B) 5. Cavender MA, Steg PG, Smith SC Jr, et al.; inhibitor or a GLP-1 receptor agonist to (165,166,169–171). REACH Registry Investigators. Impact of diabetes reduce cardiovascular risk is appropri- Reduced incidence of heart failure has mellitus on hospitalization for heart failure, cardiovascular events, and death: outcomes at ate. It is unknown whether use of both been observed with the use of SGLT2 4 years from the Reduction of Atherothrombosis classes of drugs will provide an additive inhibitors (162,164). In EMPA-REG OUT- for Continued Health (REACH) registry. Circula- cardiovascular outcomes benefit. COME, the addition of empagliflozin to tion 2015;132:923–931 standard care led to a significant 35% 6. McAllister DA, Read SH, Kerssens J, et al. reduction in hospitalization for heart Incidence of hospitalization for heart failure and Glucose-Lowering Therapies and case-fatality among 3.25 million people with and Heart Failure failure compared with placebo (8). Al- without diabetes mellitus. Circulation 2018;138: As many as 50% of patients with type 2 though the majority of patients in the 2774–2786 diabetes may develop heart failure (174). study did not have heart failure at base- 7. Lam CSP, Voors AA, de Boer RA, Solomon SD, Data on the effects of glucose-lowering line, this benefit was consistent in pa- van Veldhuisen DJ. Heart failure with preserved agents on heart failure outcomes have tients with and without a history of heart ejection fraction: from mechanisms to therapies. Eur Heart J 2018;39:2780–2792 demonstrated that thiazolidinediones failure (10). Similarly, in CANVAS and 8. Zinman B, Wanner C, Lachin JM, et al.; EMPA- have a strong and consistent relationship DECLARE-TIMI 58, there were 33% and REG OUTCOME Investigators. Empagliflozin, car- with increased risk of heart failure 27% reductions in hospitalization for diovascular outcomes, and mortality in type 2 (175–177). Therefore, thiazolidinedione heart failure, respectively, with SGLT2 diabetes. N Engl J Med 2015;373:2117–2128 use should be avoided in patients with inhibitor use versus placebo (9,164). 9. Neal B, Perkovic V, Mahaffey KW, et al.; CANVAS Program Collaborative Group. Canagli- symptomatic heart failure. Restrictions to Additional data from the CREDENCE trial flozin and cardiovascular and renal events in use of metformin in patients with med- with canagliflozin showed a 39% reduc- type 2 diabetes. N Engl J Med 2017;377:644–657 ically treated heart failure were removed tion in hospitalization for heart failure, 10. FitchettAssociation D, Butler J, van de Borne P, et al.; by the FDA in 2006 (178). In fact, obser- and 31% reduction in the composite of EMPA-REG OUTCOMEÒ trial investigators. Ef- fects of empagliflozin on risk for cardiovascu- vational studies of patients with type 2 cardiovascular death or hospitalization lar death and heart failure hospitalization across diabetes and heart failure suggest that for heart failure, in a diabetic kidney dis- the spectrum of heart failure risk in the EMPA- metformin users have better outcomes ease population with albuminuria (UACR REG OUTCOMEÒ trial. Eur Heart J 2018;39:363– than patients treated with other antihy- of .300 to 5,000 mg/g) (162). These 370 perglycemic agents (179). Metformin may combined findings from four large out- 11. Blood Pressure Lowering Treatment Trialists’ Collaboration. Blood pressure-lowering treat- comes trials of three different SGLT2 in- be used for the management of hyper- ment based on cardiovascular risk: a meta- glycemia in patients with stable heart hibitors are highly consistent and clearly analysis of individual patient data. Lancet failure as long as kidney function remains indicate robust benefits of SGLT2 inhibitors 2014;384:591–598 within the recommended range for use in the prevention of heart failure hospital- 12. Grundy SM, Stone NJ, Bailey AL, et al. 2018 (180). izations. They alsoDiabetes suggest, but do not AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/ APhA/ASPC/NLA/PCNA Guideline on the man- Recent studies examining the relation- prove, that SGLT2 inhibitors may be ben- agement of blood cholesterol: executive sum- ship between DPP-4 inhibitors and heart eficial in patients with established heart mary: a report of the American College of failure have had mixed results. The Sax- failure. This hypothesis is being specifically Cardiology/American Heart Association Task agliptinAssessmentofVascular Outcomes evaluated in several large outcomes trials Force on Clinical Practice Guidelines. J Am Recorded in Patients with Diabetes Mel- in patients with established heart failure, Coll Cardiol 2019;73:3168–3209 – 13. Muntner P, ColantonioLD, CushmanM, et al. litus Thrombolysis in Myocardial Infarc- both with and without diabetes, to de- Validation of the atherosclerotic cardiovascular tion 53 (SAVOR-TIMI 53) study showed termine the efficacy of SGLT2 inhibitors in disease Pooled Cohort risk equations. JAMA that patients treated with the DPP-4 in- the treatment of heart failure with reduced 2014;311:1406–1415 hibitor saxagliptin were more likely to be and preserved ejection fraction. 14. DeFilippisAP, Young R, McEvoyJW,et al.Risk hospitalized for heart failure than those score overestimation: the impact of individual American cardiovascular risk factors and preventive ther- givenplacebo(3.5%vs.2.8%,respectively) References apies on the performance of the American Heart (181). However, three other cardiovascu- 1. American Diabetes Association. Economic Association-American College of Cardiology-Ath- lar outcomes trials, Examination of Car- costs of diabetes in the U.S. in 2017. Diabetes erosclerotic Cardiovascular Disease risk score in a diovascular Outcomes with Alogliptin Care 2018;41:917–928 modern multi-ethnic cohort. Eur Heart J 2017;38: versus Standard of Care (EXAMINE) 2. Ali MK, Bullard KM, Saaddine JB, Cowie CC, 598–608 Imperatore G, Gregg EW.Achievement of goalsin 15. Bohula EA, Morrow DA, Giugliano RP, et al. (182), Trial Evaluating Cardiovascular Out- Atherothrombotic risk stratification and ezeti- comes with Sitagliptin (TECOS) (183), and U.S.diabetescare,1999-2010.NEnglJMed2013; 368:1613–1624 mibe for secondary prevention. J Am Coll Cardiol – the Cardiovascular and Renal Microvas- 3. Buse JB, Ginsberg HN, Bakris GL, et al.; Amer- 2017;69:911 921 ©2019 16. Bohula EA, Bonaca MP, Braunwald E, et al. cular Outcome Study With Linagliptin ican Heart Association; American Diabetes Atherothrombotic risk stratification and the ef- (CARMELINA) (184) did not find a signif- Association. Primary prevention of cardio- ficacy and safety of vorapaxar in patients with vascular diseases in people with diabetes icant increase in risk of heart failure stable ischemic heart disease and previous fi hospitalization with DPP-4 inhibitor use mellitus: a scienti c statement from the Amer- myocardial infarction. Circulation 2016;134: compared with placebo. No increased risk ican Heart Association and the American Di- 304–313 of heart failure hospitalization has been abetes Association. Diabetes Care 2007;30: 17. de Boer IH, Bangalore S, Benetos A, et al. 162–172 identified in the cardiovascular outcomes Diabetes and hypertension: a position statement 4. Gaede P, Lund-Andersen H, Parving H-H, by the American Diabetes Association. Diabetes trials of the GLP-1 receptor agonists Pedersen O. Effect of a multifactorial interven- Care 2017;40:1273–1284 lixisenatide, liraglutide, semaglutide, tion on mortality in type 2 diabetes. N Engl J Med 18. Bobrie G, Genes` N, Vaur L, et al. Is “iso- exenatide QW, albiglutide, or dulaglutide 2008;358:580–591 lated home” hypertension as opposed to S130 Cardiovascular Disease and Risk Management Diabetes Care Volume 43, Supplement 1, January 2020

“isolated office” hypertension a sign of SPRINT-eligible participants of ACCORD-BP. Di- 47. Irgens HU, Reisaeter L, Irgens LM, Lie RT. greater cardiovascular risk? Arch Intern abetes Care 2017;40:1733–1738 Long term mortality of mothers and fathers after Med 2001;161:2205–2211 33. Brouwer TF, Vehmeijer JT, Kalkman DN, et al. pre-eclampsia: population based cohort study. 19. Sega R, Facchetti R, Bombelli M, et al. Intensive blood pressure lowering in patients BMJ 2001;323:1213–1217 Prognostic value of ambulatory and home blood with and patients without type 2 diabetes: 48. Sacks FM, Svetkey LP, Vollmer WM, et al.; pressures comparedwithofficeblood pressurein a pooled analysis from two randomized trials. DASH-Sodium Collaborative Research Group. the general population: follow-up results from Diabetes Care 2018;41:1142–1148 Effects on blood pressure of reduced dietary the Pressioni Arteriose Monitorate e Loro Asso- 34. Lamprea-Montealegre JA, de Boer IH. sodium and the Dietary Approaches to Stop ciazioni (PAMELA) study. Circulation 2005;111: Reevaluating the evidence for blood pressure Hypertension (DASH) diet. N Engl J Med 2001; 1777–1783 targetsintype2diabetes.DiabetesCare2018;41: 344:3–10 20. Omboni S, Gazzola T, Carabelli G, Parati G. 1132–1133 49. James PA, Oparil S, Carter BL, et al. 2014 Clinical usefulness and cost effectiveness of 35. de Boer IH, Bakris G, Cannon CP. Individu- evidence-basedguideline forthe managementof homeblood pressuretelemonitoring: meta-anal- alizing blood pressure targets for people with high blood pressure in adults: report from the ysis of randomized controlled studies. J Hyper- diabetes and hypertension: comparing the ADA panel members appointed to the Eighth Joint tens 2013;31:455–467; discussion 467–468 and the ACC/AHA recommendations. JAMA National Committee (JNC 8). JAMA 2014;311: 21. Emdin CA, Rahimi K, Neal B, Callender T, 2018;319:1319–1320 507–520 Perkovic V, Patel A. Blood pressure lowering in 36. Basu S, Sussman JB, Rigdon J, Steimle L, Denton 50. Bakris GL, Weir MR; Study of Hypertension fi type 2 diabetes: a systematic review and meta- BT, Hayward RA. Bene t and harm of intensive and the Efficacy of Lotrel in Diabetes (SHIELD) analysis. JAMA 2015;313:603–615 blood pressure treatment: derivation and validation Investigators. Achieving goal blood pressure in 22. Arguedas JA, Leiva V, Wright JM. Blood of risk models using data from the SPRINT and patients with type 2 diabetes: conventional pressure targets for hypertension in people ACCORD trials. PLoS Med 2017;14:e1002410 versus fixed-dose combination approaches. J with diabetes mellitus. Cochrane Database 37. Phillips RA, Xu J, Peterson LE, Arnold RM, Clin Hypertens (Greenwich) 2003;5:202–209 Syst Rev 2013;10:CD008277 Diamond JA, Schussheim AE. Impact of cardio- 51. FeldmanRD,ZouGY,VandervoortMK,Wong fi 23. Ettehad D, Emdin CA, Kiran A, et al. Blood vascular risk on the relative bene t and harm of CJ, Nelson SAE, Feagan BG. A simplified approach pressure lowering for prevention of cardiovas- intensive treatment of hypertension. J Am Coll to theAssociation treatment of uncomplicated hyperten- – cular disease and death: a systematic review and Cardiol 2018;71:1601 1610 sion: a cluster randomized, controlled trial. Hy- meta-analysis. Lancet 2016;387:957–967 38. Whelton PK, Carey RM, Aronow WS, et al. pertension 2009;53:646–653 24. Brunstrom¨ M, Carlberg B. Effect of antihy- 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ 52. Webster R, Salam A, de Silva HA, Selak V, pertensive treatment at different blood pressure ASH/ASPC/NMA/PCNA guideline for the preven- Stepien S, Rajapakse S, et al. Fixed low-dose triple tion, detection, evaluation, and management of levels in patients with diabetes mellitus: system- combination antihypertensive medication vs high blood pressure in adults: a report of the aticreviewandmeta-analyses.BMJ2016;352:i717 usual care for blood pressure control in patients American College of Cardiology/American Heart 25. Bangalore S, Kumar S, Lobach I, Messerli FH. with mild to moderate hypertension in Sri Lanka: Association Task Force on Clinical Practice Guide- Blood pressure targets in subjects with type 2 a randomized clinical trial. JAMA 2018;320:566– lines. J Am Coll Cardiol 2018;71:e127–e248 diabetes mellitus/impaired fasting glucose: ob- 579 39. Wright JT Jr, Williamson JD, Whelton PK, servations from traditional and Bayesian ran- 53. Bangalore S, Kamalakkannan G, Parkar S, et al.; SPRINT Research Group. A randomized trial dom-effects meta-analyses of randomized trials. Messerli FH. Fixed-dose combinations improve of intensive versus standard blood-pressure con- Circulation 2011;123:2799–2810 medication compliance: a meta-analysis. Am J trol. N Engl J MedDiabetes 2015;373:2103–2116 26. Thomopoulos C, Parati G, Zanchetti A. Ef- Med 2007;120:713–719 40. Beddhu S, Greene T, Boucher R, et al. In- fects of blood-pressure-lowering treatment on 54. Catala-L´ opez´ F, Mac´ıas Saint-Gerons D, tensive systolic blood pressure control and in- outcome incidence in hypertension: 10 - should Gonzalez-Bermejo´ D, et al. Cardiovascular and cident chronic kidney disease in people with and blood pressure management differ in hyperten- renal outcomes of renin-angiotensin system without diabetes mellitus: secondary analyses of sive patients with and without diabetes mellitus? two randomised controlled trials. Lancet Diabe- blockade in adult patients with diabetes mellitus: Overview and meta-analyses of randomized tri- tes Endocrinol 2018;6:555–563 asystematicreviewwithnetwork meta-analyses. – als. J Hypertens 2017;35:922 944 41. Sink KM, Evans GW, Shorr RI, et al. Syncope, PLoS Med 2016;13:e1001971 27. Xie X, Atkins E, Lv J, et al. Effects of intensive hypotension, and falls in the treatment of hy- 55. Palmer SC, Mavridis D, Navarese E, et al. fi blood pressure lowering on cardiovascular and pertension: results from the randomized clinical Comparative ef cacy and safety of blood pres- renal outcomes: updated systematic review and systolic blood pressure intervention trial. J Am sure-lowering agents in adults with diabetes and – meta-analysis. Lancet 2016;387:435 443 Geriatr Soc 2018;66:679–686 kidney disease: a network meta-analysis. Lancet – 28. Cushman WC, Evans GW, Byington RP, et al.; 42. Abalos E, Duley L, Steyn DW. Antihyperten- 2015;385:2047 2056 ACCORD Study Group. Effects ofAmerican intensive blood- sive drug therapy for mild to moderate hyper- 56. Barzilay JI, Davis BR, Bettencourt J, et al.; pressure control in type 2 diabetes mellitus. N tension during pregnancy. Cochrane Database ALLHAT Collaborative Research Group. Cardio- Engl J Med 2010;362:1575–1585 Syst Rev 2014;2:CD002252 vascular outcomes using doxazosin vs. chlortha- 29. Patel A, MacMahon S, Chalmers J, et al.; 43. Magee LA, von Dadelszen P, Rey E, et al. Less- lidone for the treatment of hypertension in older ADVANCE Collaborative Group. Effects of a fixed tight versus tight control of hypertension in adults with and without glucose disorders: a re- combination of perindopril and indapamide on pregnancy. N Engl J Med 2015;372:407–417 port from the ALLHAT study. J Clin Hypertens macrovascular and microvascular outcomes in 44. Brown MA, Magee LA, Kenny LC, et al.; (Greenwich) 2004;6:116–125 patients with type 2 diabetes mellitus (the International Society for the Study of Hyper- 57. Weber MA, Bakris GL, Jamerson K, et al.; ADVANCE trial): a randomised controlled trial. tensioninPregnancy(ISSHP).Hypertensive ACCOMPLISH Investigators. Cardiovascular events Lancet 2007;370:829–840 disorders of pregnancy: ISSHP classification, during differing hypertension therapies in pa- 30.©2019 Bakris GL. The implications of blood pressure diagnosis,and management recommendations tients with diabetes. J Am Coll Cardiol 2010;56: measurement methods on treatment targets for international practice. Hypertension 2018; 77–85 for blood pressure. Circulation 2016;134:904– 72:24–43 58. Bangalore S, Fakheri R, Toklu B, Messerli FH. 905 45. American College of Obstetricians and Gy- Diabetes mellitus as a compelling indication for 31. Margolis KL, O’Connor PJ, Morgan TM, et al. necologists; Task Force on Hypertension in Preg- use of renin angiotensin system blockers: sys- Outcomes of combined cardiovascular risk factor nancy. Hypertension in pregnancy. Report of the tematic review and meta-analysis of randomized management strategies in type 2 diabetes: the American College of Obstetricians and Gynecol- trials. BMJ 2016;352:i438 ACCORD randomized trial. Diabetes Care 2014; ogists’ Task Force on Hypertension in Pregnancy. 59. Carlberg B, Samuelsson O, Lindholm LH. 37:1721–1728 Obstet Gynecol 2013;122:1122–1131 Atenolol in hypertension: is it a wise choice? 32. Buckley LF, Dixon DL, Wohlford GF 4th, 46. Al-Balas M, Bozzo P, Einarson A. Use of Lancet 2004;364:1684–1689 Wijesinghe DS, Baker WL, Van Tassell BW. In- diuretics during pregnancy. Can Fam Physician 60. Yusuf S, Teo KK, Pogue J, et al.; ONTARGET tensive versus standard blood pressure control in 2009;55:44–45 Investigators. Telmisartan, ramipril, or both in care.diabetesjournals.org Cardiovascular Disease and Risk Management S131

patients at high risk for vascular events. N Engl J in adults: a report of the American College of 86. Knopp RH, d’Emden M, Smilde JG, Pocock SJ. Med 2008;358:1547–1559 Cardiology/American Heart Association Task Efficacy and safety of atorvastatin in the pre- 61. Fried LF, Emanuele N, Zhang JH, et al.; VA Force on Practice Guidelines and The Obesity vention of cardiovascular end points in sub- NEPHRON-D Investigators. Combined angio- Society. J Am Coll Cardiol 2014;63(25 Pt B): jects with type 2 diabetes: the Atorvastatin tensin inhibition for the treatment of diabetic 2985–3023 Study for Prevention of Coronary Heart Disease nephropathy. N Engl J Med 2013;369:1892– 75. Estruch R, Ros E, Salas-Salvado´ J, et al.; Endpoints in Non-Insulin-Dependent Diabetes 1903 PREDIMED Study Investigators. Primary pre- Mellitus (ASPEN). Diabetes Care 2006;29: 62. Makani H, Bangalore S, Desouza KA, Shah A, vention of cardiovascular disease with a Med- 1478–1485 Messerli FH. Efficacy and safety of dual blockade iterranean diet supplemented with extra-virgin 87. Colhoun HM, Betteridge DJ, Durrington PN, of the renin-angiotensin system: meta-analysis olive oil or nuts. N Engl J Med 2018;378:e34 etal.; CARDSinvestigators. Primarypreventionof of randomised trials. BMJ 2013;346:f360 76. Eckel RH, Jakicic JM, Ard JD, et al.. 2013 AHA/ cardiovascular disease with atorvastatin in type 2 63. Zhao P, Xu P, Wan C, Wang Z. Evening versus ACC guidelineon lifestyle management to reduce diabetes in the Collaborative Atorvastatin Di- morning dosing regimen drug therapy for hy- cardiovascular risk: a report of the American abetes Study (CARDS): multicentre randomised pertension. Cochrane Database Syst Rev 2011; College of Cardiology/American Heart Associa- placebo-controlled trial. Lancet 2004;364:685– 10:CD004184 tion Task Force on Practice Guidelines. Circula- 696 64. Hermida RC, Ayala DE, Mojon´ A, Fernandez´ tion 2013;129:S76–S99 88. Kearney PM, Blackwell L, Collins R, et al.; JR. Influence of time of day of blood pressure- 77. Chasman DI, Posada D, Subrahmanyan L, Cholesterol Treatment Trialists’ (CTT) Collabo- lowering treatment on cardiovascular risk in Cook NR, Stanton VP Jr, Ridker PM. Pharmaco- rators. Efficacy of cholesterol-lowering therapy hypertensive patients with type 2 diabetes. Di- genetic study of statin therapy and cholesterol in 18,686 people with diabetes in 14 randomised abetes Care 2011;34:1270–1276 reduction. JAMA 2004;291:2821–2827 trials of statins: a meta-analysis. Lancet 2008; 65. Nilsson E, Gasparini A, Arnl¨ ov¨ J, et al. In- 78. Meek C, Wierzbicki AS, Jewkes C, et al. 371:117–125 cidence and determinants of hyperkalemia and Daily and intermittent rosuvastatin 5 mg ther- 89. Taylor F, Huffman MD, Macedo AF, et al. hypokalemia in a large healthcare system. Int J apy in statin intolerant patients: an observa- Statins for the primary prevention of cardiovas- Cardiol 2017;245:277–284 tional study. Curr Med Res Opin 2012;28:371– cular disease. Cochrane Database Syst Rev 2013; 66. Bandak G, Sang Y, Gasparini A, et al. Hyper- 378 1:CD004816Association kalemia after initiating renin-angiotensin system 79. Mihaylova B, Emberson J, Blackwell L, et al.; 90. Carter AA, Gomes T, Camacho X, Juurlink DN, blockade: the Stockholm Creatinine Measure- Cholesterol Treatment Trialists’ (CTT) Collabo- Shah BR, Mamdani MM. Risk of incident diabetes ments (SCREAM) project. J Am Heart Assoc 2017; rators. The effects of lowering LDL cholesterol among patients treated with statins: population 6:e005428 with statin therapy in people at low risk of based study [published correction appears in 67. Hughes-Austin JM, Rifkin DE, Beben T, et al. vascular disease: meta-analysis of individual BMJ 2013;347:f4356]. BMJ 2013;346:f2610 The relation of serum potassium concentration data from 27 randomised trials. Lancet 2012; 91. Baigent C, Blackwell L, Emberson J, et al.; with cardiovascular events and mortality in 380:581–590 Cholesterol Treatment Trialists’ (CTT) Collabora- community-living individuals. Clin J Am Soc 80. Baigent C, Keech A, Kearney PM, et al.; tion. Efficacy and safety of more intensive low- Nephrol 2017;12:245–252 Cholesterol Treatment Trialists’ (CTT) Collabo- ering of LDL cholesterol: a meta-analysis of data 68. James MT, Grams ME, Woodward M, et al.; rators. Efficacy and safety of cholesterol-lower- from 170,000 participants in 26 randomised CKD Prognosis Consortium. A meta-analysis of ing treatment: prospective meta-analysis of trials. Lancet 2010;376:1670–1681 the association of estimated GFR, albumin- data from 90,056 participants in 14 rando- 92. Cannon CP, Blazing MA, Giugliano RP, et al.; uria, diabetes mellitus, and hypertension with mised trials of statins.Diabetes Lancet 2005;366:1267– IMPROVE-IT Investigators. Ezetimibe added to acute kidney injury. Am J Kidney Dis 2015;66: 1278 statin therapy after acute coronary syndromes. N 602–612 81. Pyor˘ al¨ a¨ K, Pedersen TR, Kjekshus J, Engl J Med 2015;372:2387–2397 69. Iliescu R, Lohmeier TE, Tudorancea I, LaffinL, Faergeman O, Olsson AG, Thorgeirsson G. Cho- 93. De Ferranti SD, de Boer IH, Fonseca V, et al. Bakris GL. Renal denervation for the treatment of lesterol lowering with simvastatin improves Type 1 diabetes mellitus and cardiovascular resistant hypertension: review and clinical per- prognosis of diabetic patients with coronary disease: a scientific statement from the spective. Am J Physiol Renal Physiol 2015;309: heart disease. A subgroup analysis of the Scan- American Heart Association and American F583–F594 dinavian Simvastatin Survival Study (4S). Diabe- Diabetes Association. Circulation 2014;130: 70. Bakris GL, Agarwal R, Chan JC, et al.; Min- tes Care 1997;20:614–620 1110–1130 eralocorticoid Receptor Antagonist Tolerability 82. Collins R, Armitage J, Parish S, Sleigh P, Peto 94. Cannon CP, Braunwald E, McCabe CH, et al.; Study–Diabetic Nephropathy (ARTS-DN) Study R; Heart Protection Study Collaborative Group. Pravastatin or Atorvastatin Evaluation and In- Group. Effect of finerenone on albuminuria in MRC/BHF Heart Protection Study of cholesterol- fection Therapy-Thrombolysis in Myocardial In- patients with diabetic nephropathy: a random- lowering with simvastatin in 5963 people with farction 22 Investigators. Intensive versus ized clinical trial. JAMA 2015;314:884American–894 diabetes: a randomised placebo-controlled trial. moderate lipid lowering with statins after acute 71. Williams B, MacDonald TM, Morant S, et al.; Lancet 2003;361:2005–2016 coronary syndromes. N Engl J Med 2004;350: British Hypertension Society’s PATHWAY Stud- 83. Goldberg RB, Mellies MJ, Sacks FM, et al.; 1495–1504 ies Group. Spironolactone versus placebo, biso- The Care Investigators. Cardiovascular events 95. Sabatine MS, Giugliano RP, Keech AC, et al.; prolol, and doxazosin to determine the optimal and their reduction with pravastatin in dia- FOURIER Steering Committee and Investigators. treatment for drug-resistant hypertension betic and glucose-intolerant myocardial infarc- Evolocumab and clinical outcomes in patients (PATHWAY-2): a randomised, double-blind, tion survivors with average cholesterol levels: with cardiovascular disease. N Engl J Med 2017; crossover trial. Lancet 2015;386:2059–2068 subgroup analyses in the Cholesterol and Re- 376:1713–1722 72. Filippatos G, Anker SD, Bohm¨ M, et al. A current Events (CARE) trial. Circulation 1998;98: 96. Giugliano RP, Cannon CP, Blazing MA, et al.; randomized controlled study of finerenone vs. 2513–2519 IMPROVE-IT (Improved Reduction of Outcomes: eplerenone©2019 in patients with worsening chronic 84. Shepherd J, Barter P, Carmena R, et al. Effect Vytorin Efficacy International Trial) Investiga- heart failure and diabetes mellitus and/or of lowering LDL cholesterol substantially below tors. Benefit of adding ezetimibe to statin ther- chronic kidney disease. Eur Heart J 2016;37: currently recommended levels in patients with apy on cardiovascular outcomes and safety in 2105–2114 coronary heart disease and diabetes: the Treat- patients with versus without diabetes mellitus: 73. Bomback AS, Klemmer PJ. Mineralocorticoid ing to New Targets (TNT) study. Diabetes Care results from IMPROVE-IT (Improved Reduction receptor blockade in chronic kidney disease. 2006;29:1220–1226 of Outcomes: Vytorin Efficacy International Tri- Blood Purif 2012;33:119–124 85. Sever PS, Poulter NR, Dahlof¨ B, et al. Re- al). Circulation 2018;137:1571–1582 74. Jensen MD, Ryan DH, Apovian CM, et al.; duction in cardiovascular events with atorvas- 97. Das SR, Everett BM, Birtcher KK, et al. 2018 American College of Cardiology/American Heart tatin in 2,532 patients with type 2 diabetes: ACC expert consensus decision pathway on novel Association Task Force on Practice Guidelines; Anglo-Scandinavian Cardiac Outcomes Trial– therapies for cardiovascular risk reduction in Obesity Society. 2013 AHA/ACC/TOS guideline lipid-lowering arm (ASCOT-LLA). Diabetes Care patients with type 2 diabetes and atherosclerotic for the management of overweight and obesity 2005;28:1151–1157 cardiovascular disease: a report of the American S132 Cardiovascular Disease and Risk Management Diabetes Care Volume 43, Supplement 1, January 2020

College of Cardiology Task Force on Expert 112. RidkerPM,PradhanA,MacFadyenJG,Libby 125. ASCEND Study Collaborative Group. Effects Consensus Decision Pathways. J Am Coll Cardiol P, Glynn RJ. Cardiovascular benefits and diabetes of aspirin for primary prevention in persons with 2018;72:3200–3223 risks of statin therapy in primary prevention: an diabetes mellitus. N Engl J Med 2018;379:1529– 98. Moriarty PM, Jacobson TA, Bruckert E, et al. analysis from the JUPITER trial. Lancet 2012;380: 1539 Efficacy and safety of alirocumab, a monoclonal 565–571 126. Gaziano JM, Brotons C, Coppolecchia R, et al.; antibody to PCSK9, in statin-intolerant patients: 113. Mach F, Ray KK, Wiklund O, et al.; European ARRIVE Executive Committee. Use of aspirin to design and rationale of ODYSSEY ALTERNATIVE, a Atherosclerosis Society Consensus Panel. Ad- reduce risk of initial vascular events in patients randomized phase 3 trial. J Clin Lipidol 2014;8: verse effects of statin therapy: perception vs. at moderate risk of cardiovascular disease (ARRIVE): 554–561 the evidence – focus on glucose homeostasis, a randomised, double-blind, placebo-controlled 99. Zhang X-L, Zhu Q-Q, Zhu L, et al. Safety and cognitive, renal and hepatic function, haemor- trial. Lancet 2018;392:1036–1046 fi ef cacy of anti-PCSK9 antibodies: a meta-anal- rhagic stroke and cataract. Eur Heart J 2018;39: 127. McNeilJJ,WolfeR,WoodsRL,etal.; ASPREE – ysis of 25 randomized, controlled trials. BMC 2526 2539 Investigator Group. Effect of aspirin on cardio- Med 2015;13:123 114. Heart Protection Study Collaborative vascular events and bleeding in the healthy 100. Sabatine MS, Leiter LA, Wiviott SD, et al. Group. MRC/BHF Heart Protection Study of cho- elderly. N Engl J Med 2018;379:1509–1518 fi Cardiovascular safety and ef cacy of the PCSK9 lesterol lowering with simvastatin in 20,536 high- 128. Pignone M, Earnshaw S, Tice JA, Pletcher inhibitor evolocumab in patients with and with- risk individuals: a randomised placebo-controlled MJ. Aspirin, statins, or both drugs for the primary out diabetes and the effect of evolocumab on trial. Lancet 2002;360:7–22 prevention of coronary heart disease events in glycaemia and risk of new-onset diabetes: a pre- 115. Shepherd J, Blauw GJ, Murphy MB, et al.; men:acost-utilityanalysis.Ann InternMed2006; specified analysis of the FOURIER randomised PROSPER study group. PROspective Study of 144:326–336 controlled trial. Lancet Diabetes Endocrinol Pravastatin in the Elderly at Risk. Pravastatin 129. Huxley RR, Peters SAE, Mishra GD, 2017;5:941–950 in elderly individuals at risk of vascular disease Woodward M. Risk of all-cause mortality and 101. Berglund L, Brunzell JD, Goldberg AC, et al.; (PROSPER): a randomised controlled trial. Lancet Endocrine Society. Evaluation and treatment of 2002;360:1623–1630 vascular events in women versus men with type 1 hypertriglyceridemia: an Endocrine Society clin- 116. Trompet S, van Vliet P, de Craen AJM, et al. diabetes: a systematic review and meta-analysis. – ical practice guideline. J Clin Endocrinol Metab Pravastatin and cognitive function in the elderly. LancetAssociation Diabetes Endocrinol 2015;3:198 206 2012;97:2969–2989 Results of the PROSPER study. J Neurol 2010;257: 130. Peters SAE, Huxley RR, Woodward M. Di- 102. Bhatt DL, Steg PG, Miller M, et al.; REDUC- 85–90 abetes as risk factor for incident coronary E-IT Investigators. Cardiovascular risk reduction 117. Yusuf S, Bosch J, Dagenais G, et al.; HOPE-3 heartdiseaseinwomencomparedwithmen: with icosapent ethyl for hypertriglyceridemia. N Investigators. Cholesterol lowering in interme- a systematic review and meta-analysis of 64 Engl J Med 2019;380:11–22 diate-risk persons without cardiovascular dis- cohorts including 858,507 individuals and 103. Singh IM, Shishehbor MH, Ansell BJ. High- ease. N Engl J Med 2016;374:2021–2031 28,203 coronary events. Diabetologia 2014; density lipoprotein as a therapeutic target: a sys- 118. Giugliano RP, Mach F, Zavitz K, et al.; 57:1542–1551 tematic review. JAMA 2007;298:786–798 EBBINGHAUS Investigators. Cognitive function 131. Kalyani RR, Lazo M, Ouyang P, et al. Sex 104. Keech A, Simes RJ, Barter P, et al.; FIELD inarandomizedtrial ofevolocumab.N EnglJ Med differences in diabetes and risk of incident cor- study investigators. Effects of long-term fenofi- 2017;377:633–643 onary artery disease in healthy young and middle- brate therapy on cardiovascular events in 119. Richardson K, Schoen M, French B, et al. aged adults. Diabetes Care 2014;37:830–838 9795 people with type 2 diabetes mellitus Statins and cognitive function: a systematic re- 132. Peters SAE, Huxley RR, Woodward M. Di- (the FIELD study): randomised controlled trial. view. Ann InternDiabetes Med 2013;159:688–697 abetes as a risk factor for stroke in women Lancet 2005;366:1849–1861 120. Baigent C, Blackwell L, Collins R, et al.; compared with men: a systematic review and 105. Jones PH, Davidson MH. Reporting rate of Antithrombotic Trialists’ (ATT) Collaboration. meta-analysis of 64 cohorts, including 775,385 rhabdomyolysis with fenofibrate 1 statin versus Aspirin in the primary and secondary prevention individuals and 12,539 strokes. Lancet 2014;383: gemfibrozil 1 any statin. Am J Cardiol 2005;95: of vascular disease: collaborative meta-analysis 1973–1980 120–122 of individual participant data from randomised 133. Miedema MD, Duprez DA, Misialek JR, et al. 106. Ginsberg HN, Elam MB, Lovato LC, et al.; trials. Lancet 2009;373:1849–1860 Use of coronary artery calcium testing to guide ACCORD Study Group. Effects of combination 121. Perk J, De Backer G, Gohlke H, et al.; aspirin utilization for primary prevention: esti- lipid therapy in type 2 diabetes mellitus. N Engl J European Association for Cardiovascular Pre- mates from the multi-ethnic study of athero- – Med 2010;362:1563 1574 vention & Rehabilitation (EACPR); ESC Commit- sclerosis. Circ Cardiovasc Qual Outcomes 2014;7: fi 107. Kowa Research Institute, Inc. Pema brate tee for Practice Guidelines (CPG). European 453–460 to Reduce Cardiovascular OutcoMes by Reducing Guidelines on cardiovascular disease preven- 134. Dimitriu-Leen AC, Scholte AJHA, van Triglycerides IN patiENts With diabeTes (PROM- tion in clinical practice (version 2012). The Fifth Rosendael AR, et al. Value of coronary com- INENT) In: ClinicalTrials.gov [Internet]. Bethesda, Joint Task Force of the European Society of American puted tomography angiography in tailoring MD, National Library of Medicine. NLM Identi- Cardiology and OtherSocietieson Cardiovascular aspirin therapy for primary prevention of fier: NCT03071692. Accessed 8 October 2018. Disease Prevention in Clinical Practice (consti- atherosclerotic events in patients at high risk Available from https://clinicaltrials.gov/ct2/ tuted by representatives of nine societies and with diabetes mellitus. Am J Cardiol 2016;117: show/NCT03071692 by invited experts). Eur Heart J 2012;33:1635– – 108. Boden WE, Probstfield JL, Anderson T, et al.; 1701 887 893 135. Mora S, Ames JM, Manson JE. Low-dose AIM-HIGH Investigators. Niacin in patients withlow 122. Belch J, MacCuish A, Campbell I, et al. The HDL cholesterol levels receiving intensive statin prevention of progression of arterial disease and aspirin in the primary prevention of cardiovas- therapy. N Engl J Med 2011;365:2255–2267 diabetes (POPADAD) trial: factorial randomised cular disease: shared decision making in clinical – 109. Landray MJ, Haynes R, Hopewell JC, et al.; placebo controlled trial of aspirin and antiox- practice. JAMA 2016;316:709 710 HPS2-THRIVE©2019 Collaborative Group. Effects of idants in patients with diabetes and asymptom- 136. Campbell CL, Smyth S, Montalescot G, extended-release niacin with laropiprant in atic peripheral arterial disease. BMJ 2008;337: Steinhubl SR. Aspirin dose for the prevention high-risk patients. N Engl J Med 2014;371: a1840 of cardiovascular disease: a systematic review. 203–212 123. Zhang C, Sun A, Zhang P, et al. Aspirin for JAMA 2007;297:2018–2024 110. Rajpathak SN, Kumbhani DJ, Crandall J, primary prevention of cardiovascular events in 137. Dav`ı G, Patrono C. Platelet activation and Barzilai N, Alderman M, Ridker PM. Statin therapy patients with diabetes: a meta-analysis. Diabetes atherothrombosis. N Engl J Med 2007;357:2482– and risk of developing type 2 diabetes: a meta- Res Clin Pract 2010;87:211–218 2494 analysis. Diabetes Care 2009;32:1924–1929 124. DeBerardis G,Sacco M,Strippoli GFM,et al. 138. Larsen SB, Grove EL, Neergaard-Petersen S, 111. Sattar N, Preiss D, Murray HM, et al. Statins Aspirin for primary prevention of cardiovascular Wurtz¨ M, HvasA-M, KristensenSD.Determinants and risk of incident diabetes: a collaborative events in people with diabetes: meta-analysis of of reduced antiplatelet effect of aspirin in pa- meta-analysis of randomised statin trials. Lancet randomised controlled trials. BMJ 2009;339: tients with stable coronary artery disease. PLoS 2010;375:735–742 b4531 One 2015;10:e0126767 care.diabetesjournals.org Cardiovascular Disease and Risk Management S133

139. Zaccardi F, Rizzi A, Petrucci G, et al. In vivo 153. Scognamiglio R, Negut C, Ramondo A, 166. Marso SP, Bain SC, Consoli A, et al.; platelet activation and aspirin responsiveness in Tiengo A, Avogaro A. Detection of coronary SUSTAIN-6 Investigators. Semaglutide and type 1 diabetes. Diabetes 2016;65:503–509 artery disease in asymptomatic patients with cardiovascular outcomes in patients with 140. Bethel MA, Harrison P, Sourij H, et al. type 2 diabetes mellitus. J Am Coll Cardiol 2006; type 2 diabetes. N Engl J Med 2016;375: Randomized controlled trial comparing impact 47:65–71 1834–1844 on platelet reactivity of twice-daily with once- 154. Hadamitzky M, Hein F, Meyer T, et al. 167. Husain M,Birkenfeld AL,Donsmark M,et al. daily aspirin in people with type 2 diabetes. Prognostic value of coronary computed tomo- Oralsemaglutideand cardiovascular outcomes in Diabet Med 2016;33:224–230 graphic angiography in diabetic patients without patients with type 2 diabetes. N Engl J Med 2019; 141. Rothwell PM, Cook NR, Gaziano JM, et al. known coronary artery disease. Diabetes Care 381:841–851 Effects of aspirin on risks of vascular events and 2010;33:1358–1363 168. Hernandez AF, Green JB, Janmohamed S, cancer according to bodyweight and dose: anal- 155. ChoiE-K,ChunEJ,ChoiS-I,etal.Assessment et al. Albiglutide and cardiovascular outcomes in ysis of individual patient data from randomised of subclinical coronary atherosclerosis in asymp- patients with type 2 diabetes and cardiovascular trials. Lancet 2018;392:387–399 tomatic patients with type 2 diabetes mellitus disease (Harmony Outcomes): a double-blind, 142. Vandvik PO, Lincoff AM, Gore JM, et al. with single photon emission computed tomog- randomised placebo-controlled trial. Lancet Primary and secondary prevention of cardiovas- raphy and coronary computed tomography an- 2018;392:1519–1529 cular disease: Antithrombotic Therapy and Pre- giography. Am J Cardiol 2009;104:890–896 169. Gerstein HC, Colhoun HM, Dagenais GR, vention of Thrombosis, 9th ed: American College 156. Malik S, Zhao Y, Budoff M, et al. Coronary et al.; REWIND Investigators. Dulaglutide and of Chest Physicians Evidence-Based Clinical Prac- artery calcium score for long-term risk classifi- cardiovascular outcomes in type 2 diabetes (RE- tice Guidelines Guidelines [published correction cation in individuals with type 2 diabetes and WIND): a double-blind, randomised placebo- appears in Chest 2012;141:1129]. Chest 2012; metabolic syndrome from the multi-ethnic study controlled trial. Lancet 2019;394:121–130 141(Suppl.):e637S–e668S of atherosclerosis. JAMA Cardiol 2017;2:1332– 170. Pfeffer MA, Claggett B, Diaz R, et al.; ELIXA 143. Bhatt DL, Bonaca MP, Bansilal S, et al. 1340 Investigators. Lixisenatide in patients with type 2 Reduction in ischemic events with ticagrelor 157. Wing RR, Bolin P, Brancati FL, et al.; Look diabetes and acute coronary syndrome. N Engl J in diabetic patients with prior myocardial in- AHEAD Research Group. Cardiovascular effects Med 2015;373:2247–2257 farction in PEGASUS-TIMI 54. J Am Coll Cardiol of intensive lifestyle intervention in type 2 di- 171. HolmanAssociation RR, Bethel MA, Mentz RJ, et al.; 2016;67:2732–2740 abetes. N Engl J Med 2013;369:145–154 EXSCEL Study Group. Effects of once-weekly ex- 144. Bax JJ, Young LH, Frye RL, Bonow RO, 158. Braunwald E, Domanski MJ, Fowler SE, enatide on cardiovascular outcomes in type 2 Steinberg HO, Barrett EJ; ADA. Screening for et al.; PEACE Trial Investigators. Angiotensin- diabetes. N Engl J Med 2017;377:1228–1239 coronaryartery diseasein patients with diabetes. converting-enzyme inhibition in stable coronary 172. Zelniker TA, Wiviott SD, Raz I, et al. Com- Diabetes Care 2007;30:2729–2736 artery disease. N Engl J Med 2004;351:2058– parison of the effects of glucagon-like peptide 145. Boden WE, O’Rourke RA, Teo KK, et al.; 2068 receptor agonists and sodium-glucose cotrans- COURAGETrial Research Group. Optimal medical 159. Telmisartan Randomised AssessmeNt porter 2 inhibitors for prevention of major therapy with or without PCI for stable coronary Study in ACE iNtolerant subjects with cardiovas- adverse cardiovascular and renal outcomes in disease. N Engl J Med 2007;356:1503–1516 cular Disease (TRANSCEND) Investigators, Yusuf type 2 diabetes mellitus. Circulation 2019;139: 146. BARI 2D Study Group, Frye RL, August P, S, Teo K, et al. Effects of the angiotensin-receptor 2022–2031 et al. A randomized trial of therapies for type 2 blocker telmisartan on cardiovascular events 173. Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 diabetes and coronary artery disease. N Engl J in high-risk patients intolerant to angiotensin- inhibitors for primary and secondary prevention of Med 2009;360:2503–2015 converting enzyme inhibitors:Diabetes a randomised cardiovascular and renal outcomes in type 2 diabetes: 147. Wackers FJT, Chyun DA, Young LH, et al.; controlled trial. Lancet 2008;372:1174–1183 a systematic review and meta-analysis of cardiovas- Detection of Ischemia in Asymptomatic Diabetics 160. Kezerashvili A, Marzo K, De Leon J. Beta cular outcome trials. Lancet 2019;393:31–39 (DIAD) Investigators. Resolution of asymptom- blocker use after acute myocardial infarction in 174. Kannel WB, Hjortland M, Castelli WP. Role atic myocardial ischemia in patients with type 2 the patient with normal systolic function: when is of diabetes in congestive heart failure: the diabetes in the Detection of Ischemia in Asymp- it “ok” to discontinue? Curr Cardiol Rev 2012;8: Framingham study. Am J Cardiol 1974;34:29–34 tomatic Diabetics (DIAD) study. Diabetes Care 77–84 175. Dormandy JA, Charbonnel B, Eckland DJA, 2007;30:2892–2898 161. U.S. Food and Drug Administration. Guid- et al.; PROactive Investigators. Secondary pre- 148. Elkeles RS, Godsland IF, Feher MD, et al.; ance for industry. Diabetes mellitusdevaluating vention of macrovascular events in patients with PREDICT Study Group. Coronary calcium mea- cardiovascular risk in new antidiabetic thera- type 2 diabetes in the PROactive Study (PRO- surement improves prediction of cardiovascular pies to treat type 2 diabetes. Silver Spring, spective pioglitAzone Clinical Trial In macroVas- events in asymptomatic patients with type 2 MD, 2008. Accessed 3 November 2017. Avail- cular Events): a randomised controlled trial. diabetes: the PREDICT study. Eur Heart J 2008;29: able from http://www.fda.gov/downloads/Drugs/ Lancet 2005;366:1279–1289 2244–2251 AmericanGuidanceComplianceRe gulatoryInformation/ 176. Singh S,LokeYK, FurbergCD.Long-termrisk 149. Raggi P, Shaw LJ, Berman DS, Callister TQ. Guidances/ucm071627.pdf of cardiovascular events with rosiglitazone: Prognostic value of coronary artery calcium 162. Perkovic V, Jardine MJ, Neal B, et al. Can- a meta-analysis. JAMA 2007;298:1189–1195 screening in subjects with and without diabetes. agliflozin and renal outcomes in type 2 diabetes 177. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. J Am Coll Cardiol 2004;43:1663–1669 and nephropathy. N Engl J Med 2019;380:2295– Pioglitazone and risk of cardiovascular events in 150. Anand DV, Lim E, Hopkins D, et al. Risk 2306 patientswithtype2diabetesmellitus: ameta-analysis stratification in uncomplicated type 2 diabetes: 163. Neal B, Perkovic V, Matthews DR, et al.; of randomized trials. JAMA 2007;298:1180–1188 prospective evaluation of the combined use of CANVAS-R Trial Collaborative Group. Ratio- 178. Inzucchi SE, Masoudi FA, McGuire DK. coronary artery calcium imaging and selective nale, design and baseline characteristics of Metformin in heart failure. Diabetes Care myocardial perfusion scintigraphy. Eur Heart J the CANagliflozin cardioVascular Assessment 2007;30:e129–e129 2006;27:713©2019–721 Study-Renal (CANVAS-R): a randomized, placebo- 179. Eurich DT, Majumdar SR, McAlister FA, 151. Young LH, Wackers FJT, Chyun DA, et al.; controlled trial. Diabetes Obes Metab 2017;19: Tsuyuki RT, Johnson JA. Improved clinical out- DIAD Investigators. Cardiac outcomes after 387–393 comes associated with metformin in patients screening for asymptomatic coronary artery 164. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, with diabetes and heart failure. Diabetes Care disease in patients with type 2 diabetes: the Kato ET, Cahn A, et al. Dapagliflozin and cardio- 2005;28:2345–2351 DIAD study: a randomized controlled trial. JAMA vascular outcomes in type 2 diabetes. N Engl J 180. U.S. Food and Drug Administration. FDA 2009;301:1547–1555 Med 2019;380:347–357 drug safety communication: FDA revises warn- 152. Wackers FJT, Young LH, Inzucchi SE, et al.; 165. Marso SP, Daniels GH, Brown-Frandsen K, ings regarding use of the diabetes medicine Detection of Ischemia in Asymptomatic Diabetics et al.; LEADER Steering Committee; LEADER Trial metformin in certain patients with reduced Investigators. Detection of silent myocardial ische- Investigators. Liraglutide and cardiovascular out- kidney function, 2016. Accessed 14 October mia in asymptomatic diabetic subjects: the DIAD comes in type 2 diabetes. N Engl J Med 2016;375: 2016. Available from http://www.fda.gov/ study. Diabetes Care 2004;27:1954–1961 311–322 Drugs/DrugSafety/ucm493244.htm S134 Cardiovascular Disease and Risk Management Diabetes Care Volume 43, Supplement 1, January 2020

181. Scirica BM, Bhatt DL, Braunwald E, et al.; 184. Rosenstock J, Perkovic V, Johansen OE, coronary syndrome in patients with type 2 di- SAVOR-TIMI 53 Steering Committee and Investiga- et al. Effect of linagliptin vs placebo on major abetes. N Engl J Med 2013;369:1327–1335 tors. Saxagliptin and cardiovascular outcomes in cardiovascular events in adults with type 2 di- 187. Rosenstock J, Perkovic V, Alexander JH, patients with type 2 diabetes mellitus. N Engl J Med abetes and high cardiovascular and renal risk: the et al. Rationale, design, and baseline character- 2013;369:1317–1326 CARMELINA randomized clinical trial. JAMA istics of the CArdiovascular safety and Renal 182. Zannad F, Cannon CP, Cushman WC, et al.; 2019;321:69–79 Microvascular outcomE study with LINAgliptin EXAMINE Investigators. Heart failure and mortality 185. Hansson L, Zanchetti A, Carruthers SG, (CARMELINA): a randomized, double-blind, placebo- outcomes in patients with type 2 diabetes taking et al.; HOT Study Group. Effects of intensive controlled clinical trial in patients with type 2 alogliptinversusplaceboinEXAMINE:amulticentre, blood-pressure lowering and low-dose aspirin diabetes and high cardio-renal risk. Cardiovasc randomised, double-blind trial. Lancet 2015;385: in patients with hypertension: principal results Diabetol 2018;17:39 2067–2076 of the Hypertension Optimal Treatment (HOT) 188. Cefalu WT, Kaul S, Gerstein HC, et al. 183. Green JB, Bethel MA, Armstrong PW, et al.; randomised trial. Lancet 1998;351:1755– Cardiovascular outcomes trials in type 2 diabe- TECOS Study Group. Effect of sitagliptin on 1762 tes: where do we go from here? Reﬂections cardiovascular outcomes in type 2 diabetes. N 186. White WB, Cannon CP, Heller SR, et al.; from a Diabetes Care Editors’ Expert Forum. Engl J Med 2015;373:232–242 EXAMINE Investigators. Alogliptin after acute Diabetes Care 2018;41:14–31

Association

Diabetes

American

11. Microvascular Complications American Diabetes Association and Foot Care: Standards of Medical Care in Diabetes22020

Diabetes Care 2020;43(Suppl. 1):S135–S151 | https://doi.org/10.2337/dc20-s011 1 IRVSUA OPIAIN N OTCARE FOOT AND COMPLICATIONS MICROVASCULAR 11. The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes” includes the ADA’s current clinical practice recommendations and is intended to Association provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc20- SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc20-SINT). Readers who wish to comment on the Standards of Care are invited todosoatprofessional.diabetes.org/SOC.Diabetes For prevention and management of diabetes complications in children and adolescents, please refer to Section 13 “Children and Adolescents” (https://doi.org/10.2337/ dc20-S013).

CHRONIC KIDNEY DISEASE Screening

Recommendations 11.1 At least once a year, assess urinary albumin (e.g., spot urinary albumin-to- creatinine ratio) and estimated glomerular ﬁltration rate (eGFR) in patients with type 1 diabetes withAmerican duration of $5 years and in all patients with type 2 diabetes regardless of treatment. B Patients with urinary albumin .30 mg/g creatinine and/or an eGFR ,60 mL/min/1.73 m2 should be monitored twice annually to guide therapy. C

Treatment

Recommendations 11.2 Optimize glucose control to reduce the risk or slow the progression of ©2019chronic kidney disease. A 11.3 For patients with type 2 diabetes and diabetic kidney disease, consider use Suggested citation: American Diabetes Associa- of a sodium–glucose cotransporter 2 inhibitor in patients with an estimated tion. 11. Microvascular complications and glomerular ﬁltration rate $30 mL/min/1.73 m2 and urinary albumin .30 foot care: Standards of Medical Care in d . Diabetes 2020. Diabetes Care 2020;43(Suppl. mg/g creatinine, particularly in those with urinary albumin 300 mg/g 1):S135–S151 creatinine, to reduce risk of chronic kidney disease (CKD) progression, A © 2019 by the American Diabetes Association. cardiovascular events, or both. In patients with CKD who are at increased Readers may use this article as long as the work risk for cardiovascular events, use of a glucagon-like peptide 1 receptor is properly cited, the use is educational and agonist may reduce risk of progression of albuminuria, cardiovascular not for proﬁt, and the work is not altered. events, or both (Table 9.1). C More information is available at http://www .diabetesjournals.org/content/license. S136 Microvascular Complications and Foot Care Diabetes Care Volume 43, Supplement 1, January 2020

or very high albuminuria (1,2,10,11). 11.4 Optimize blood pressure con- about the etiology of kidney Exercise within 24 h, infection, fever, trol to reduce the risk or slow disease, difficult management congestive heart failure, marked hyper- the progression of chronic kid- issues, and rapidly progressing glycemia, menstruation, and marked ney disease. A kidney disease. A hypertension may elevate UACR inde- 11.5 Do not discontinue renin-an- pendently of kidney damage (12). giotensin system blockade for eGFR should be calculated from serum minor increases in serum cre- Epidemiology of Diabetes and Chronic creatinine using a validated formula. The atinine (,30%) in the absence Kidney Disease Chronic kidney disease (CKD) is diag- Chronic Kidney Disease Epidemiology of volume depletion. B nosed by the persistent presence of Collaboration (CKD-EPI) equation is 11.6 For people with nondialysis- elevated urinary albumin excretion (al- generally preferred (2). eGFR is routinely dependent chronic kidney dis- buminuria), low estimated glomerular reported by laboratories with serum ease, dietary protein intake should filtration rate (eGFR), or other manifes- creatinine, and eGFR calculators are be approximately 0.8 g/kg body tations of kidney damage (1,2). In this available online at nkdep.nih.gov. An weight per day (the recommen- section, the focus will be on CKD eGFR persistently ,60 mL/min/1.73 m2 ded daily allowance). A For pa- attributed to diabetes (diabetic kidney is considered abnormal, though optimal tients on dialysis, higher levels of disease), which occurs in 20–40% of thresholds for clinical diagnosis are de- dietary protein intake should be patients with diabetes (1,3–5). CKD typ- bated in older adults (2,13). considered, since malnutrition ically develops after diabetes duration is a major problem in some of 10 years in type 1 diabetes but may Diagnosis of Diabetic Kidney Disease dialysis patients. B be present at diagnosis of type 2 di- Diabetic kidney disease is usually a clin- 11.7 In nonpregnant patients with Association abetes. CKD can progress to end-stage ical diagnosis made based on the pres- diabetes and hypertension, ei- renal disease (ESRD) requiring dialysis ence of albuminuria and/or reduced ther an ACE inhibitor or an or kidney transplantation and is the eGFRintheabsenceofsignsorsymptoms angiotensin receptor blocker leading cause of ESRD in the U.S. (6). of other primary causes of kidney dam- is recommended for those In addition, among people with type 1 or age. The typical presentation of diabetic with modestly elevated urinary 2 diabetes, the presence of CKD mark- kidney disease is considered to include a albumin-to-creatinine ratio edly increases cardiovascular risk and long-standing duration of diabetes, ret- (30–299 mg/g creatinine) B and health care costs (7). inopathy, albuminuria without gross is strongly recommended for hematuria, and gradually progressive those with urinary albumin-to- loss of eGFR. However, signs of CKD $ Assessment of Albuminuria and creatinine ratio 300 mg/g Diabetesmay be present at diagnosis or without creatinine and/or estimated Estimated Glomerular Filtration Rate Screening for albuminuria can be most retinopathy in type 2 diabetes, and re- glomerular filtration rate ,60 easily performed by urinary albumin-to- duced eGFR without albuminuria has mL/min/1.73 m2. A creatinine ratio (UACR) in a random spot been frequently reported in type 1 11.8 Periodically monitor serum urine collection (1,2). Timed or 24-h and type 2 diabetes and is becoming creatinine and potassium lev- collections are more burdensome and more common over time as the prev- els for the development of add little to prediction or accuracy. Mea- alence of diabetes increases in the U.S. increased creatinineor changes surement of a spot urine sample for (3,4,14,15). in potassium when ACE inhibi- albuminalone(whetherbyimmunoassay An active urinary sediment (containing tors, angiotensin receptor block- or by using a sensitive dipstick test red or white blood cells or cellular ers, or diuretics are used. B specific for albuminuria) without simul- casts), rapidly increasing albuminuria or 11.9 An ACE inhibitor or an angio- Americantaneously measuring urine creatinine nephrotic syndrome, rapidly decreasing tensin receptor blocker is not (Cr) is less expensive but susceptible eGFR, or the absence of retinopathy (in recommended for the primary to false-negative and false-positive de- type 1 diabetes) suggests alternative or prevention of chronic kidney terminations as a result of variation in additional causes of kidney disease. For disease in patients with diabetes urine concentration due to hydration. patients with these features, referral to a who have normal blood pres- Normal UACR is defined as ,30 mg/g nephrologist for further diagnosis, in- sure, normal urinary albumin- Cr, and high urinary albumin excretion is cluding the possibility of kidney biopsy, to-creatinine ratio (,30 mg/g defined as $30 mg/g Cr. However, UACR should be considered. It is rare for pa- creatinine), and normal estimated ©2019 is a continuous measurement, and differ- tients with type 1 diabetes to develop glomerular filtration rate. A ences within the normal and abnormal kidney disease without retinopathy. In 11.10 Patients should be referred for ranges are associated with renal and type 2 diabetes, retinopathy is only mod- evaluation by a nephrologist if cardiovascular outcomes (7–9). Further- erately sensitive and specific for CKD they have an estimated glo- more, because of high biological variabil- caused by diabetes, as confirmed by merular filtration rate ,30 ity of .20% between measurements in kidney biopsy (16). mL/min/1.73 m2. A urinary albumin excretion, two of three 11.11 Promptly refer to a physician specimens of UACR collected within a 3- experienced in the care of Staging of Chronic Kidney Disease to 6-month period should be abnormal Stages 1–2 CKD have been defined by kidney disease for uncertainty before considering a patient to have high evidence of high albuminuria with care.diabetesjournals.org Microvascular Complications and Foot Care S137

Association

Figure 11.1—Risk of chronic kidney disease (CKD) progression, frequency of visits, and referral to nephrology according to glomerular filtration rate (GFR)andalbuminuria.TheGFRandalbuminuriagriddepictsthe riskofprogression,morbidity,andmortality bycolor,frombesttoworst(green,yellow, orange, red, dark red). The numbers in the boxes are a guide to the frequency of visits (number of times per year). Green can reflect CKD with normal eGFR and albumin-to-creatinine ratio only in the presence of other markers of kidney damage, such as imaging showing polycystic kidney disease or kidney biopsyabnormalities,with follow-upmeasurements annually; yellow requirescaution and measurements at least once per year;orange requires measurements twice per year; red requires measurements three times per year; and dark red requires measurements four times per year. These are general parameters only, based on expert opinion, and underlying comorbid conditions and disease state as well as the likelihood of impacting a change in management for any individual patient must be taken into account. “Refer” indicates that nephrology services are recommended. *Referring cliniciansmaywishtodiscusswiththeirnephrologyservice,dependingonlocal arrangements regardingtreating orreferring.Reprintedwith permission from Vassalotti et al. (188). Diabetes eGFR $60 mL/min/1.73 m2, while stages progression and other adverse health particularly when combined with diu- 3–5 CKD have been defined by progres- outcomes) and cause of kidney damage retics or other medications that reduce sively lower ranges of eGFR (17) (Fig. (including possible causes other than glomerular filtration; however, this 11.1). At any eGFR, the degree of albu- diabetes) may also affect these decisions has not been found to be true in ran- minuria is associated with risk of cardio- (20). domized clinical outcome trials of ad- vascular disease (CVD), CKD progression, vanced kidney disease (24) or high and mortality (7). Therefore, Kidney Acute Kidney Injury cardiovascular disease risk with normal Disease: Improving Global Outcomes Acute kidney injury (AKI) is diagnosed kidney function (25–27). Timely iden- (KDIGO) recommends a more compre- by a 50% or greater sustained increase tification and treatment of AKI is im- hensive CKD staging that incorporates in serum creatinine over a short period portant because AKI is associated with albuminuria at all stages ofAmerican eGFR; this of time, which is also reflected as a rapid increased risks of progressive CKD and system is more closely associated with decrease in eGFR (21,22). People with other poor health outcomes (28). risk but is also more complex and does diabetes are at higher risk of AKI than Small elevations in serum creatinine not translate directly to treatment deci- those without diabetes (23). Other risk (up to 30% from baseline) with renin- sions (2). Thus, based on the current factors for AKI include preexisting CKD, angiotensin system blockers (such as classification system, both eGFR and the use of medications that cause ACE inhibitors and ARBs) must not be albuminuria must be quantified to guide kidney injury (e.g., nonsteroidal anti- confused with AKI (29). An analysis treatment decisions. This is also impor- inflammatory drugs), and the use of oftheActiontoControlCardiovascu- tant©2019 since eGFR levels are essential to medications that alter renal blood flow lar Risk in Diabetes Blood Pressure modify drug dosage or restrictions of use and intrarenal hemodynamics. In partic- (ACCORD BP) trial demonstrates that those (Fig. 11.1) (18,19). The degree of albu- ular, many antihypertensive medications randomized to intensive blood pressure minuria may influence choice of antihy- (e.g., diuretics, ACE inhibitors, and an- lowering with up to a 30% increase in pertensive (see Section 10 “Cardiovascular giotensin receptor blockers [ARBs]) can serum creatinine did not have any in- Disease and Risk Management,” https:// reduce intravascular volume, renal blood crease in mortality or progressive kidney doi.org.10.2337/dc20-S010) or glucose- flow, and/or glomerular filtration. There disease (30–32). Moreover, a measure of lowering medications (see below). Ob- was concern that sodium–glucose co- markers for AKI showed no significant served history of eGFR loss (which transporter 2 (SGLT2) inhibitors may increase of any markers with increased is also associated with risk of CKD promote AKI through volume depletion, creatinine (32). Accordingly, ACE inhibitors S138 Microvascular Complications and Foot Care Diabetes Care Volume 43, Supplement 1, January 2020

Table 11.1—Selected complications of chronic kidney disease recommended because it does not alter Complication Medical and laboratory evaluation glycemic measures, cardiovascular risk measures, or the course of GFR decline (39). . Elevated blood pressure 140/90 mmHg Blood pressure, weight Restriction of dietary sodium (to ,2,300 Volume overload History, physical examination, weight mg/day) may be useful to control blood Electrolyte abnormalities Serum electrolytes pressure and reduce cardiovascular risk Metabolic acidosis Serum electrolytes (40,41), and restriction of dietary potas- Anemia Hemoglobin; iron testing if indicated sium may be necessary to control se- Metabolic bone disease Serum calcium, phosphate, PTH, vitamin 25(OH)D rum potassium concentration (23,33–35). Complications of chronic kidney disease (CKD) generally become prevalent when estimated These interventions may be most important glomerular filtration rate falls below 60 mL/min/1.73 m2 (stage 3 CKD or greater) and become more for patients with reduced eGFR, for whom common and severe as CKD progresses. Evaluation of elevated blood pressure and volume urinary excretion of sodium and potassium overload should occur at every clinical contact possible; laboratory evaluations are generally indicated every 6–12 months for stage 3 CKD, every 3–5 months for stage 4 CKD, and every 1– may be impaired. For patients on dialysis, 3 months for stage 5 CKD, or as indicated to evaluate symptoms or changes in therapy. PTH, higher levels of dietary protein intake should parathyroid hormone; 25(OH)D, 25-hydroxyvitamin D. be considered, since malnutrition is a major problem in some dialysis patients (42). Recommendations for dietary sodium and and ARBs should not be discontinued for 2 diabetes, reducing albuminuria from potassium intake should be individualized , $ minor increases in serum creatinine ( 30%), levels 300 mg/g Cr has been associated on the basis of comorbid conditions, med- in the absense of volume depletion. with improved renal and cardiovascular ication use, blood pressure, and labora- outcomes, leading some to suggest that toryAssociation data. Surveillance medications should be titrated to min- Albuminuria and eGFR should be mon- imize UACR. However, this approach has Glycemic Targets itored regularly to enable timely diagno- not been formally evaluated in prospec- Intensive glycemic control with the goal sis of CKD, monitor progression of CKD, tive trials. In type 1 diabetes, remission of achieving near-normoglycemia has detect superimposed kidney diseases of albuminuria may occur spontane- beenshowninlargeprospective random- including AKI, assess risk of CKD compli- ously and cohort studies evaluating ized studies to delay the onset and pro- cations, dose drugs appropriately, and associations of change in albuminuria gression of albuminuria and reduced determine whether nephrology referral with clinical outcomes have reported eGFR in patients with type 1 diabetes is needed. Among people with existing inconsistent results (36,37). (43,44) and type 2 diabetes (1,45–51). kidney disease, albuminuria and eGFR The prevalence of CKD complications Insulin alone was used to lower blood may change due to progression of CKD, correlates withDiabetes eGFR (38). When eGFR glucose in the Diabetes Control and , 2 development of a separate superim- is 60 mL/min/1.73 m , screening for Complications Trial (DCCT)/Epidemiol- Table posed cause of kidney disease, AKI, or complications of CKD is indicated ( ogy of Diabetes Interventions and Com- 11.1 other effects of medications, as noted ). Early vaccination against hepatitis plications (EDIC) study of type 1 diabetes, above. Serum potassium should also B virus is indicated in patients likely to while a variety of agents were used in “ be monitored for patients treated with progress to ESRD (see Section 4 Com- clinical trials of type 2 diabetes, support- ACE inhibitors, ARBs, and diuretics be- prehensive Medical Evaluation and As- ing the conclusion that glycemic control ” cause these medications can cause hy- sessment of Comorbidities, https://doi itself helps prevent CKD and its progres- perkalemia or hypokalemia, which are .org/10.2337/dc20-S004, for further in- sion. The effects of glucose-lowering associated with cardiovascular risk and formation on immunization). therapies on CKD have helped define mortality (33–35). For patients with A1C targets (see Table 6.2). eGFR ,60 mL/min/1.73 mAmerican2, appropriate Interventions The presence of CKD affects the risks medication dosing should be verified, Nutrition and benefits of intensive glycemic con- exposure to nephrotoxins (e.g., nonste- For people with nondialysis-dependent trol and a number of specific glucose- roidal anti-inflammatory drugs and io- CKD, dietary protein intake should be lowering medications. In the Action to dinated contrast) should be minimized, ;0.8 g/kg body weight per day (the Control Cardiovascular Risk in Diabetes and potential CKD complications should recommended daily allowance) (1). (ACCORD) trial of type 2 diabetes, ad- be evaluated (Table 11.1). Compared with higher levels of dietary verse effects of intensive glycemic con- The need for annual quantitative as- protein intake, this level slowed GFR trol (hypoglycemia and mortality) were sessment©2019 of albumin excretion after di- decline with evidence of a greater effect increased among patients with kidney agnosis of albuminuria, institution of ACE over time. Higher levels of dietary pro- disease at baseline (52,53). Moreover, inhibitors or ARB therapy, and achiev- tein intake (.20% of daily calories from there is a lag time of at least 2 years in ing blood pressure control is a subject protein or .1.3 g/kg/day) have been type 2 diabetes to over 10 years in type 1 of debate. Continued surveillance can associated with increased albuminuria, diabetes for the effects of intensive glu- assess both response to therapy and more rapid kidney function loss, and cose control to manifest as improved disease progression and may aid in as- CVD mortality and therefore should be eGFR outcomes (49,54,55). Therefore, in sessing adherence to ACE inhibitor or avoided. Reducing the amount of di- some patients with prevalent CKD and ARB therapy. In addition, in clinical trials etary protein below the recommended substantial comorbidity, target A1C levels of ACE inhibitors or ARB therapy in type daily allowance of 0.8 g/kg/day is not maybelessintensive(1,56). care.diabetesjournals.org Microvascular Complications and Foot Care S139

Direct Renal Effects of Glucose-Lowering constraints, metformin should be con- In addition, subgroup analyses of CANVAS Medications sidered the first-line treatment for all and LEADER suggested that the renal Some glucose-lowering medications also patients with type 2 diabetes, including benefits of canagliflozin and liraglutide have effects on the kidney that are direct, those with CKD. were as great or greater for participants i.e., not mediated through glycemia. For SGLT2 inhibitors and GLP-1 RAs should with CKD at baseline(27,66) and in CANVAS example, SGLT2 inhibitors reduce renal be considered for patients with type 2 were similar for participants with or with- tubular glucose reabsorption, weight, diabetes and CKD who require another out atherosclerotic cardiovascular disease systemic blood pressure, intraglomerular drug added to metformin to attain target (ASCVD) at baseline (72). pressure, and albuminuria and slow GFR A1C or cannot use or tolerate metformin. Several large clinical trials of SGLT2 loss through mechanisms that appear SGLT2 inhibitors reduce risks of CKD inhibitors focused on patients with ad- independent of glycemia (26,57–60). progression, CVD events, and hypogly- vanced CKD, and assessment of primary Moreover, recent data support the cemia. GLP-1 RAs are suggested because renal outcomes are completed or ongo- notion that SGLT2 inhibitors reduce ox- they reduce risks of CVD events and ing. Canagliflozin and Renal End points in idative stress in the kidney by .50% and hypoglycemia and appear to possibly Diabetes with Established Nephropa- blunt increases in angiotensinogen as slow CKD progression. thy Clinical Evaluation (CREDENCE), a well as reduce NLRP3 inflammasome A number of large cardiovascular out- placebo-controlled trial of canagliflozin activity (61–63). Glucagon-like peptide comes trials in patients with type 2 di- among 4,401 adults with type 2 diabetes, 1 receptor agonists (GLP-1 RAs) also have abetes at high risk for CVD or with UACR $300 mg/g Cr, and mean eGFR direct effects on the kidney and have existing CVD examined kidney effects 56 mL/min/1.73 m2 with a mean albu- been reported to improve renal out- as secondary outcomes. These trials minuria level of over 900 mg/day, has a comes compared with placebo (64–67). include EMPA-REG OUTCOME [BI primaryAssociation composite end point of ESRD, Renal effects should be considered when 10773 (Empagliflozin) Cardiovascular doubling of serum creatinine, or renal or selecting antihyperglycemia agents (see Outcome Event Trial in Type 2 Diabetes cardiovascular death (24,73). It was stop- Section 9 “Pharmacologic Approaches to Mellitus Patients], CANVAS (Canagliflozin ped early due to positive efficacy and Glycemic Treatment,” https://doi.org/10 Cardiovascular Assessment Study), showed a 32% risk reduction for devel- .2337/dc20-S009). LEADER (Liraglutide Effect and Action opment of ESRD over control (24). in Diabetes: Evaluation of Cardiovascular Additionally, the development of the Selection of Glucose-Lowering Medications Outcome Results), and SUSTAIN-6 (Trial primary end point, which included for Patients With Chronic Kidney Disease to Evaluate Cardiovascular and Other chronic dialysis for $30 days, kidney For patients with type 2 diabetes and Long-term Outcomes With Semaglutide transplantation or eGFR ,15 mL/min/ established CKD, special considerations in Subjects With Type 2 Diabetes) 1.73 m2 sustained for $30 days by forthe selectionofglucose-lowering med- (59,64,67,71). SpeciDiabetesfically, compared central laboratory assessment, doubling ications include limitations to available with placebo, empagliflozin reduced from the baseline serum creatinine av- medications when eGFR is diminished the risk of incident or worsening ne- erage sustained for $30 days by central and a desire to mitigate high risks of phropathy (a composite of progression laboratory assessment, or renal death or CKD progression, CVD, and hypoglycemia to UACR .300 mg/g Cr, doubling of cardiovascular death, was reduced by (68,69). Drug dosing may require modifi- serum creatinine, ESRD, or death from 30%. This benefit was on background cation with eGFR ,60 mL/min/1.73 m2 (1). ESRD) by 39% and the risk of doubling ACE inhibitor or ARB therapy in .99% of The U.S. Food and Drug Administration of serum creatinine accompanied by the patients (24). Moreover, in this ad- (FDA) revised its guidance for the use of eGFR #45 mL/min/1.73 m2 by 44%; vanced CKD group, there were clear metformin in CKD in 2016 (70), recom- canagliflozin reduced the risk of progres- benefits on cardiovascular outcomes mending use of eGFR instead of serum sion of albuminuria by 27% and the risk demonstrating a 31% reduction in car- creatinine to guide treatmentAmerican and ex- of reductionin eGFR,ESRD, or death from diovascular death or heart failure hos- panding the pool of patients with kidney ESRD by 40%; liraglutide reduced the risk pitalization and a 20% reduction in disease for whom metformin treatment of new or worsening nephropathy (a cardiovascular death, nonfatal myocar- should be considered. The revised FDA composite of persistent macroalbumin- dial infarction, or nonfatal stroke (24,74). guidance states that metformin is uria, doubling of serum creatinine, ESRD, In addition to renal effects, some contraindicated inpatientswithan or death from ESRD) by 22%; and sema- SGLT2 inhibitors and GLP-1 RAs have eGFR ,30 mL/min/1.73 m2; eGFR should glutide reduced the risk of new or wors- demonstrated cardiovascular benefits. be monitored while taking metformin; ening nephropathy (a composite of Namely, in EMPA-REG OUTCOME, CANVAS, the©2019 benefits and risks of continuing persistent UACR .300 mg/g Cr, doubling and LEADER, empagliflozin, canagliflozin, treatment should be reassessed when of serum creatinine, or ESRD) by 36% and liraglutide, respectively, each reduced eGFR falls ,45 mL/min/1.73 m2;met- (each P , 0.01). cardiovascular events,evaluatedas primary formin should not be initiated for These analyses were limited by eval- outcomes, compared with placebo (see patients with an eGFR ,45 mL/min/ uation of study populations not selected Section 10 “Cardiovascular Disease and 1.73 m2; and metformin should be primarily for CKD and examination of Risk Management,” https://doi.org/10 temporarily discontinued at the time renal effects as secondary outcomes. .2337/dc20-S010 for further discussion). of or before iodinated contrast imag- However, all of these trials included large While the glucose-lowering effects ing procedures in patients with eGFR numbers of people with stage 3a (eGFR of SGLT2 inhibitors are blunted with 30–60 mL/min/1.73 m2. Within these 45–59 mL/min/1.73 m2) kidney disease. eGFR ,45 mL/min/1.73 m2,therenal S140 Microvascular Complications and Foot Care Diabetes Care Volume 43, Supplement 1, January 2020

and cardiovascular benefits were still Cardiovascular Disease and Blood Pressure blockers (92). In a trial of people with seen down to eGFR levels of 30 mL/ Hypertension is a strong risk factor for type 2 diabetes and normal urine albumin/1.73 m2 with no significant change the development and progression of CKD min excretion, an ARB reduced or sup- in glucose (24,26,43,45,52,56,71). Most (78). Antihypertensive therapy reduces pressed the development of albuminuria participants with CKD in these trials the risk of albuminuria (79–82), and but increased the rate of cardiovascular also had diagnosed ASCVD at baseline, among patients with type 1 or 2 diabetes events (93).Ina trial of people with type 1 though ;28% of CANVAS participants with established CKD (eGFR ,60 mL/ diabetes exhibiting neither albuminuria with CKD did not have diagnosed min/1.73 m2 and UACR $300 mg/g Cr), nor hypertension, ACE inhibitors or ARBs ASCVD (27). ACE inhibitor or ARB therapy reduces the did not prevent the development of Based on evidence from the CREDENCE risk of progression to ESRD (83–85). diabetic glomerulopathy assessed by kid- trial and secondary analyses of cardio- Moreover, antihypertensive therapy re- ney biopsy (90) This was further sup- vascular outcomes trials with SGLT2 duces risks of cardiovascular events (79). ported by a similar trial in patients with inhibitors, cardiovascular and renal Blood pressure levels ,140/90 mmHg type 2 diabetes (91). Therefore, ACE events are reduced with SGLT2 inhibitor are generally recommended to reduce inhibitors or ARBs are not recommended useinpatientsdowntoaneGFRof CVD mortality and slow CKD progres- for patients without hypertension to pre- 30 mL/min/1.73 m2 even independent sion among all people with diabetes vent the development of CKD. of glucose-lowering effects (75). (82). Lower blood pressure targets Two clinical trials studied the combi- While there is clear cardiovascular risk (e.g., ,130/80 mmHg) should be con- nations of ACE inhibitors and ARBs and reduction associated with GLP-1 RA use sidered for patients based on individual found no benefits on CVD or CKD, and the in patients with type 2 diabetes and CKD, anticipated benefits and risks. Patients drug combination had higher adverse the proof of benefit on renal outcome with CKD are at increased risk of CKD eventAssociation rates (hyperkalemia and/or AKI) will come with the results of the ongoing progression (particularly those with al- (94,95). Therefore, the combined useof ACE FLOW (A Research Study to See How buminuria) and CVD and therefore may inhibitors and ARBs should be avoided. Semaglutide Works Compared to Pla- be suitable in some cases for lower blood Mineralocorticoid receptor antago- cebo in People With Type 2 Diabetes pressure targets, especially in those nists (spironolactone, eplerenone, and and Chronic Kidney Disease) trial with with $300 mg/day albuminuria. finerenone) in combination with ACE injectable semaglutide (76). As noted ACE inhibitors or ARBs are the pre- inhibitors or ARBs remain an area of above, published data address a limited ferred first-line agent for blood pressure great interest. Mineralocorticoid recep- group of CKD patients, mostly with coex- treatment among patients with diabe- tor antagonists are effective for man- isting ASCVD. Renal events have been tes, hypertension, eGFR ,60 mL/min/ agementofresistanthypertension,have 2 examined, however, as both primary and 1.73 m , and UACR $300 mg/g Cr be- been shown to reduce albuminuria in secondary outcomes in published large cause of theirDiabetes proven benefits for pre- short-term studies of CKD, and may trials. Also, adverse event profiles of vention of CKD progression (83–86). In have additional cardiovascular benefits these agents must be considered. Please general, ACE inhibitors and ARBs are (96–98). There has been, however, an fi refer to Table 9.1 for drug-specific considered to have similar bene ts increase in hyperkalemic episodes in factors, including adverse event infor- (87,88) and risks. In the setting of lower those on dual therapy, and larger, longer – mation, for these agents. Additional levels of albuminuria (30 299 mg/g Cr), trials with clinical outcomes are needed clinical trials focusing on CKD and car- ACE inhibitor or ARB therapy has been before recommending such therapy. diovascular outcomes in CKD patients demonstrated to reduce progression to Referral to a Nephrologist are ongoing and will be reported in the more advanced albuminuria ($300 mg/g next few years. Cr) and cardiovascular events but not Consider referral to a physician experi- For patients with type 2 diabetes and progression to ESRD (86,89). While ACE enced in the care of kidney disease when CKD, the selection of speciAmericanfic agents may inhibitors or ARBs are often prescribed there is uncertainty about the etiology fi depend on comorbidity and CKD stage. for high albuminuria without hyperten- of kidney disease, for dif cult manage- SGLT2 inhibitors may be more useful for sion, outcome trials have not been per- ment issues (anemia, secondary hyper- patients at high risk of CKD progression formed in this setting to determine parathyroidism, metabolic bone disease, (i.e., with albuminuria or a history of whether this improves renal outcomes. resistant hypertension, or electrolyte dis- documented eGFR loss) (Fig. 9.1) be- Moreover, two long-term, double-blind turbances), or when there is advanced cause they appear to have large bene- studies demonstrate no renoprotective kidney disease (eGFR ,30 mL/min/ 2 ficial effects on CKD incidence. The SGLT2 effect of either ACE inhibitors or ARBs in 1.73 m ) requiring discussion of renal inhibitors©2019 canagliflozin, empagliflozin, type 1 and type 2 diabetes among those replacement therapy for ESRD (2). The and dapagliflozin are approved by the who were normotensive with or without threshold for referral may vary depending FDA for use with eGFR $45 mL/min/ high albuminuria (formerly microalbu- on the frequency with which a provider 1.73 m2 (though pivotal trials for each minuria) (90,91). encounters patients with diabetes and included participants with eGFR $30 Absent kidney disease, ACE inhibitors kidney disease. Consultation with a ne- mL/min/1.73 m2 and demonstrated or ARBs are useful to control blood phrologist when stage 4 CKD develops benefit in subgroups with low eGFR) pressure but have not proven superior (eGFR ,30 mL/min/1.73 m2) has been (26,27,77). Some GLP-1 RAs may be used to alternative classes of antihypertensive found to reduce cost, improve quality of with lower eGFR, but most require dose therapy, including thiazide-like diuretics care, and delay dialysis (99). However, adjustment. and dihydropyridine calcium channel other specialists and providers should care.diabetesjournals.org Microvascular Complications and Foot Care S141

also educate their patients about the Diabetic retinopathy is a highly specific 11.18 Women with preexisting type progressive nature of CKD, the kidney vascular complication of both type 1 and 1ortype2diabeteswhoare preservation benefits of proactive treat- type 2 diabetes, with prevalence strongly planning pregnancy or who are mentofbloodpressureandbloodglucose, related to both the duration of diabetes pregnant should be counseled and the potential need for renal replace- and the level of glycemic control (100). on the risk of development and/ ment therapy. Diabetic retinopathy is the most frequent or progression of diabetic reti- cause of new cases of blindness among nopathy. B adults aged 20–74 years in developed DIABETIC RETINOPATHY 11.19 Eye examinations should occur countries. Glaucoma, cataracts, and other before pregnancy or in the first Recommendations disorders of the eye occur earlier and 11.12 trimester in patients with pre- Optimize glycemic control to more frequently in people with diabetes. existing type 1 or type 2 di- reduce the risk or slow the In addition to diabetes duration, fac- abetes, and then patients progression of diabetic reti- tors that increase the risk of, or are A should be monitored every tri- nopathy. associated with, retinopathy include 11.13 mester and for 1 year postpar- Optimize blood pressure and chronic hyperglycemia (101), nephropa- tum as indicated by the degree serum lipid control to reduce thy (102), hypertension (103), and of retinopathy. B the risk or slow the progression dyslipidemia (104). Intensive diabetes A of diabetic retinopathy. management with the goal of achieving Treatment near-normoglycemia has been shown in large prospective randomized studies to Screening Recommendations prevent and/or delay the onset and pro- Recommendations 11.20 Promptly refer patients with Association gression of diabetic retinopathy and po- 11.14 Adults with type 1 diabetes any level of macular edema, tentially improve patient reported visual should have an initial dilated severe nonproliferative dia- function (46,105–107). and comprehensive eye exam- betic retinopathy (a precursor Several case series and a controlled ination by an ophthalmologist of proliferative diabetic reti- prospective study suggest that preg- or optometrist within 5 years nopathy), or any proliferative nancy in patients with type 1 diabe- after the onset of diabetes. B diabetic retinopathy to an oph- tes may aggravate retinopathy and 11.15 Patients with type 2 diabetes thalmologist who is knowl- threaten vision, especially when gly- should have an initial dilated edgeable and experienced in cemic control is poor at the time of and comprehensive eye exam- the management of diabetic conception (108,109). Laser photocoagu- ination by an ophthalmologist retinopathy. A Diabeteslation surgery can minimize the risk of or optometrist at the time of 11.21 The traditional standard treat- vision loss (109). the diabetes diagnosis. B ment, panretinal laser photo- 11.16 If there is no evidence of ret- coagulation therapy, is indicated inopathy for one or more an- to reduce the risk of vision loss Screening The preventive effects of therapy and nual eye exams and glycemia is in patients with high-risk prolif- the fact that patients with proliferative well controlled, then screening erative diabetic retinopathy and, diabetic retinopathy (PDR) or macular every 1–2 years may be con- in some cases, severe nonproli- edema may be asymptomatic provide sidered. If any level of diabetic ferative diabetic retinopathy. A strong support for screening to detect retinopathy is present, subse- 11.22 Intravitreousinjectionsofanti– diabetic retinopathy. quent dilated retinal examina- vascular endothelial growth fac- Diabetic retinopathy screening should tions should be repeated at least tor ranibizumab are not inferior American be performed using validated ap- annually by an ophthalmologist to traditional panretinal laser proaches and methodologies. Youth or optometrist. If retinopathy is photocoagulation and are also with type 1 or type 2 diabetes are progressing or sight-threatening, indicatedtoreducetheriskof also at risk for complications and need then examinations will be revision loss in patients with pro- to be screened for diabetic retinopathy quired more frequently. B liferative diabetic retinopathy. A (110). If diabetic retinopathy is evident 11.17 Programs that use retinal pho- 11.23 Intravitreousinjectionsofanti– on screening, prompt referral to an oph- tography (with remote reading vascular endothelial growth thalmologist is recommended. Subse- or use of a validated assess- factor are indicated for central ©2019 quent examinations for patients with ment tool) to improve access involveddiabeticmacularedema, type 1 or type 2 diabetes are generally to diabetic retinopathy screen- which occurs beneath the foveal repeated annually for patients with min- ing can be appropriate screen- center and may threaten reading imal to no retinopathy. Exams every 1–2 ing strategies for diabetic vision. A years may be cost effective after one or retinopathy. Such programs 11.24 The presence of retinopathy is more normal eye exams, and in a pop- need to provide pathways not a contraindication to aspirin ulation with well controlled type 2 di- for timely referral for a com- therapy for cardioprotection, as abetes, there was essentially no risk of prehensive eye examination aspirin does not increase the risk development of significant retinopathy when indicated. B of retinal hemorrhage. A with a 3-year interval after a normal S142 Microvascular Complications and Foot Care Diabetes Care Volume 43, Supplement 1, January 2020

examination (111). Less frequent intervals comprehensive eye examination at the growth factor (anti-VEGF) agent, specif- have been found in simulated modeling time of diagnosis. ically ranibizumab, resulted in visual acu- to be potentially effective in screening for Pregnancy ity outcomes that were not inferior to diabetic retinopathy in patients without Pregnancy is associated with a rapid those observed in patients treated with diabetic retinopathy(112).Morefrequent progression of diabetic retinopathy panretinal laser at 2 years of followup examinations by the ophthalmologist will (117,118). Women with preexisting (121). In addition, it was observed that be required if retinopathy is progressing. type 1 or type 2 diabetes who are plan- patients treated with ranibizumab Retinal photography with remote ning pregnancy or who have become tended to have less peripheral visual fi reading by experts has great potential pregnant should be counseled on the eld loss, fewer vitrectomy surgeries to provide screening services in areas risk of development and/or progression for secondary complications from their fi where quali ed eye care professionals of diabetic retinopathy. In addition, rapid proliferative disease, and a lower risk of are not readily available (105,106). High implementation of intensive glycemic developing diabetic macular edema. quality fundus photographs can detect management in the setting of retinopa- However, a potential drawback in using fi most clinically signi cant diabetic reti- thy is associated with early worsening anti-VEGF therapy to manage prolifer- nopathy. Interpretation of the images of retinopathy (109). Women who de- ative disease is that patients were re- should be performed by a trained eye velop gestational diabetes mellitus do quired to have a greater number of visits care provider. Retinal photography may not require eye examinations during and received a greater number of fi also enhance ef ciency and reduce pregnancy and do not appear to be treatments than is typically required costs when the expertise of ophthalmol- at increased risk of developing diabetic for management with panretinal laser, ogistscanbeusedformorecomplex retinopathy during pregnancy (119). which may not be optimal for some pa- examinations and for therapy (113,114). tients.Association Other emerging therapies for In-person exams are still necessary Treatment retinopathy that may use sustained intra- when the retinal photos are of unaccept- Two of the main motivations for screen- vitreal delivery of pharmacologic agents able quality and for follow-up if abnor- ing for diabetic retinopathy are to pre- are currently under investigation. The FDA malities are detected. Retinal photos are vent loss of vision and to intervene with approved ranibizumab for the treatment not a substitute for comprehensive eye treatment when vision loss can be pre- of diabetic retinopathy in 2017. exams, which should be performed at vented or reversed. While the ETDRS (122) established the least initially and at intervals thereafter benefit of focal laser photocoagulation Photocoagulation Surgery as recommended by an eye care pro- surgery in eyes with clinically significant Two large trials, the Diabetic Retinop- fessional. Artificial intelligence systems macularedema (definedasretinaledema athy Study (DRS) in patients with PDR that detect more than mild diabetic located at or within 500 mm of the center and the Early Treatment Diabetic Ret- retinopathy and diabetic macular edema Diabetesof the macula), current data from well- inopathy Study (ETDRS) in patients with authorized for use by the FDA represent designed clinical trials demonstrate that macular edema, provide the strongest an alternative to traditional screening intravitreal anti-VEGF agents provide a support for the therapeutic benefits approaches (115). However, the bene- more effective treatment regimen for of photocoagulation surgery. The DRS fits and optimal utilization of this type central-involved diabetic macular edema (120) showed in 1978 that panretinal of screening have yet to be fully de- than monotherapy or even combination photocoagulation surgery reduced the termined. Artificial intelligence systems therapy with laser (123,124). There risk of severe vision loss from PDR from should not be used for patients with are currently three anti-VEGF agents 15.9% in untreated eyes to 6.4% in known retinopathy, prior retinopathy commonlyusedtotreateyeswith treated eyes with the greatest benefit treatment, or symptoms of vision central-involved diabetic macular ratio in those with more advanced base- impairment. Results of eye examina- edemadbevacizumab, ranibizumab, line disease (disc neovascularization tions should be documentedAmerican and trans- and aflibercept (100). or vitreous hemorrhage). In 1985, the mitted to the referring health care In both the DRS and the ETDRS, laser ETDRS also verified the benefits of professional. photocoagulation surgery was beneficial panretinal photocoagulation for high- in reducing the risk of further visual loss Type 1 Diabetes risk PDR and in older-onset patients in affected patients but generally not Because retinopathy is estimated to with severe nonproliferative diabetic beneficial in reversing already dimin- take at least 5 years to develop after retinopathy or less-than-high-risk PDR. ished acuity. Anti-VEGF therapy im- the onset of hyperglycemia, patients Panretinal laser photocoagulation is still proves vision and has replaced the with type 1 diabetes should have an commonly used to manage compli- ©2019 need for laser photocoagulation in initial dilated and comprehensive eye ex- cations of diabetic retinopathy that in- the vast majority of patients with di- amination within 5 years after the diagnosis volve retinal neovascularization and its abetic macular edema (125). Most of diabetes (116). complications. patients require near-monthly admin- Type 2 Diabetes Anti–Vascular Endothelial Growth Factor istration of intravitreal therapy with Patients with type 2 diabetes who may Treatment anti-VEGF agents during the first 12 have had years of undiagnosed diabetes Recent data from the Diabetic Retinop- months of treatment, with fewer injec- and have a significant risk of prevalent athy Clinical Research Network and tions needed in subsequent years to diabetic retinopathy at the time of di- others demonstrate that intravitreal in- maintain remission from central-involved agnosis should have an initial dilated and jections of anti–vascular endothelial diabetic macular edema. care.diabetesjournals.org Microvascular Complications and Foot Care S143

Adjunctive Therapy loss of protective sensation (LOPS). 11.30 Pregabalin, duloxetine, or ga- Lowering blood pressure has been shown LOPS indicates the presence of distal bapentin are recommended as to decrease retinopathy progression, al- sensorimotor polyneuropathy and is a initial pharmacologic treat- though tight targets (systolic blood risk factor for diabetic foot ulceration. ments for neuropathic pain pressure ,120 mmHg) do not impart The following clinical tests may be used in diabetes. A additional benefit (106). ACE inhibitors to assess small- and large-fiber function and ARBs are both effective treatments and protective sensation: The diabetic neuropathies are a hetero- in diabetic retinopathy (126). In patients geneous group of disorders with diverse with dyslipidemia, retinopathy progres- 1. Small-fiber function: pinprick and tem- clinical manifestations. The early recog- perature sensation sion may be slowed by the addition of nition and appropriate management of fi 2. Large-fiber function: vibration percep- feno brate, particularly with very mild neuropathy in the patient with diabetes tion and 10-g monofilament nonproliferative diabetic retinopathy at is important. baseline (104,127). 3. Protective sensation: 10-g monofilament 1. Diabetic neuropathy is a diagnosis of These tests not only screen for the pres- exclusion. Nondiabetic neuropathies NEUROPATHY ence of dysfunction but also predict future may be present in patients with di- Screening risk of complications. Electrophysiological abetes and may be treatable. testing or referral to a neurologist is rarely Recommendations 2. Numerous treatment options exist for needed, except in situations where the 11.25 All patients should be assessed symptomatic diabetic neuropathy. clinical features are atypical or the di- for diabetic peripheral neurop- 3. Up to 50% of diabetic peripheral neu- agnosis is unclear. athy starting at diagnosis of ropathy (DPN) may be a symptomatic. Association In all patients with diabetes and DPN, type 2 diabetes and 5 years If not recognized and if preventive foot causes of neuropathy other than diabetes after the diagnosis of type 1 care is not implemented, patients are should be considered, including toxins diabetes and at least annually at risk for injuries to their insensate (e.g., alcohol), neurotoxic medications thereafter. B feet. (e.g., chemotherapy), vitamin B12 defi- 11.26 Assessment for distal symmet- 4. Recognition and treatment of auto- ciency, hypothyroidism, renal disease, ric polyneuropathy should nomic neuropathy may improve malignancies (e.g., multiple myeloma, bron- include a careful history and symptoms, reduce sequelae, and im- assessment of either temper- chogenic carcinoma), infections (e.g., prove quality of life. fl ature or pinprick sensation HIV), chronic in ammatory demyelinat- ing neuropathy, inherited neuropathies, (small fiber function) and vi- Specific treatment for the underlying Diabetesand vasculitis (131). See the American bration sensation using a nerve damage, other than improved Diabetes Association (ADA) position 128-Hz tuning fork (for large- glycemic control, is currently not avail- statement “Diabetic Neuropathy” for fiber function). All patients should able. Glycemic control can effectively more details (130). have annual 10-g monofila- prevent DPN and cardiac autonomic ment testing to identify feet neuropathy (CAN) in type 1 diabetes Diabetic Autonomic Neuropathy at risk for ulceration and am- (128,129) and may modestly slow their The symptoms and signs of autonomic B putation. progression in type 2 diabetes (48), but it neuropathy should be elicited carefully 11.27 Symptoms and signs of auto- does not reverse neuronal loss. Thera- during the history and physical exami- nomic neuropathy should be peutic strategies (pharmacologic and nation. Major clinical manifestations assessed in patients with mi- nonpharmacologic) for the relief of pain- of diabetic autonomic neuropathy in- E crovascular complications.Americanful DPN and symptoms of autonomic clude hypoglycemia unawareness, rest- neuropathy can potentially reduce pain ing tachycardia, orthostatic hypotension, (130) and improve quality of life. gastroparesis, constipation, diarrhea, fe- Treatment cal incontinence, erectile dysfunction, Recommendations Diagnosis neurogenic bladder, and sudomotor dys- 11.28 Optimize glucose control to Diabetic Peripheral Neuropathy function with either increased or de- prevent or delay the develop- Patients with type 1 diabetes for 5 or more creased sweating. mentof neuropathy in patients years and all patients with type 2 diabetes Cardiac Autonomic Neuropathy. CAN is with type 1 diabetes A and to ©2019 should be assessed annually for DPN associated with mortality independently slow the progression of neu- using the medical history and simple of other cardiovascular risk factors ropathy in patients with type 2 clinical tests (130). Symptoms vary ac- (132,133). In its early stages, CAN may diabetes. B cording to the class of sensory fibers be completely asymptomatic and de- 11.29 Assess and treat patients to involved. The most common early symp- tected only by decreased heart rate var- reduce pain related to diabetic toms are induced by the involvement of iability with deep breathing. Advanced peripheral neuropathy B and small fibers and include pain and dys- disease may be associated with resting symptoms of autonomic neu- esthesia(unpleasantsensations ofburn- tachycardia (.100 bpm) and orthostatic ropathy and to improve quality ing and tingling). The involvement of hypotension (a fall in systolic or dia- of life. E large fibers may cause numbness and stolic blood pressure by .20 mmHg or S144 Microvascular Complications and Foot Care Diabetes Care Volume 43, Supplement 1, January 2020

.10 mmHg, respectively, upon standing a modest slowing of progression without expensive, although it is not FDA ap- without an appropriate increase in heart reversal of neuronal loss (48,139). Specific proved for this indication (154). rate). CAN treatment is generally focused glucose-lowering strategies may have dif- Duloxetine is a selective norepineph- on alleviating symptoms. ferent effects. In a post hoc analysis, par- rine and serotonin reuptake inhibitor. Gastrointestinal Neuropathies. Gastroin- ticipants, particularly men, in the Bypass Doses of 60 and 120 mg/day showed testinal neuropathies may involve any Angioplasty Revascularization Investigation efficacy in the treatment of pain associ- portion of the gastrointestinal tract with in Type 2 Diabetes (BARI 2D) trial treated ated with DPN in multicenter randomized manifestations including esophageal with insulin sensitizers had a lower inci- trials, although some of these had dysmotility, gastroparesis, constipation, dence of distal symmetric polyneuropathy high drop-out rates (143,145,150,152). diarrhea, and fecal incontinence. Gastro- over4yearsthanthosetreatedwith insulin/ Duloxetine also appeared to improve paresis should be suspected in individ- sulfonylurea (140). neuropathy-related quality of life (155). uals with erratic glycemic control or with In longer-term studies, a small increase in upper gastrointestinal symptoms with- Neuropathic Pain A1C was reported in people with diabetes out another identified cause. Exclusion of Neuropathic pain can be severe and can treated with duloxetine compared with organic causes of gastric outlet obstruc- impact quality of life, limit mobility, and placebo (156). Adverse events may be tion or peptic ulcer disease (with esoph- contribute to depression and social dys- more severe in older people but may be agogastroduodenoscopy or a barium function (141). No compelling evidence attenuated with lower doses and slower study of the stomach) is needed before exists in support of glycemic control or titrations of duloxetine. considering a diagnosis of or specialized lifestyle management as therapies for Tapentadol is a centrally acting opioid testing for gastroparesis. The diagnostic neuropathic pain in diabetes or predia- analgesic that exerts its analgesic effects gold standard for gastroparesis is the betes, which leaves only pharmaceutical throughAssociation both m-opioid receptor agonism measurement of gastric emptying with interventions (142). and noradrenaline reuptake inhibition. scintigraphy of digestible solids at Pregabalin and duloxetine have re- Extended-release tapentadol was ap- 15-min intervals for 4 h after food intake. ceived regulatory approval by the FDA, proved by the FDA for the treatment The use of 13C octanoic acid breath test Health Canada, and the European Med- of neuropathic pain associated with is emerging as a viable alternative. icines Agency for the treatment of neu- diabetes based on data from two mul- ropathic pain in diabetes. The opioid ticenter clinical trials in which partici- Genitourinary Disturbances. Diabetic auto- tapentadol has regulatory approval in pants titrated to an optimal dose of nomic neuropathy may also cause gen- the U.S. and Canada, but the evidence tapentadol were randomly assigned to itourinary disturbances, including sexual of its use is weaker (143). Comparative continue that dose or switch to placebo dysfunction and bladder dysfunction. In effectiveness studies and trials that in- (157,158). However, both used a design men, diabetic autonomic neuropathy clude quality-of-lifeDiabetes outcomes are rare, enriched for patients who responded to may cause erectile dysfunction and/or so treatment decisions must consider tapentadol and therefore their results are retrograde ejaculation (130). Female each patient’s presentation and comor- not generalizable. A recent systematic sexual dysfunction occurs more frequently bidities and often follow a trial-and-error review and meta-analysis by the Special in those with diabetes and presents as approach. Given the range of partially Interest Group on Neuropathic Pain of the decreased sexual desire, increased pain effective treatment options, a tailored International Association for the Study of during intercourse, decreased sexual and stepwise pharmacologic strategy Pain found the evidence supporting the arousal, and inadequate lubrication with careful attention to relative symp- effectiveness of tapentadol in reducing (134). Lower urinary tract symptoms tom improvement, medication adher- neuropathic pain to be inconclusive (143). manifest as urinary incontinence and ence, and medication side effects is Therefore, given the high risk for addiction bladder dysfunction (nocturia, frequent recommended to achieve pain reduction and safety concerns compared with the urination, urination urgency,American and weak – and improve quality of life (144 146). relatively modest pain reduction, the use urinary stream). Evaluation of bladder a d Pregabalin, a calcium channel 2- of extended release tapentadol is not function should be performed for indi- subunit ligand, is the most extensively generally recommended as a first- or viduals with diabetes who have recurrent studied drug for DPN. The majority of second-line therapy. The use of any urinary tract infections, pyelonephritis, studies testing pregabalin have reported opioids for management of chronic neu- incontinence, or a palpable bladder. favorable effects on the proportion of ropathic pain carries the risk of addiction participants with at least 30–50% im- and should be avoided. Treatment provement in pain (143,145,147–150). Tricyclic antidepressants, venlafaxine, Glycemic©2019 Control However, not all trials with pregabalin carbamazepine, and topical capsaicin, Near-normal glycemic control, imple- have been positive (143,145,151,152), although not approved for the treatment mented early in the course of diabetes, especially when treating patients with has been shown to effectively delay or advanced refractory DPN (149). Adverse of painful DPN, may be effective and prevent the development of DPN and effects may be more severe in older considered for the treatment of painful CAN in patients with type 1 diabetes patients (153) and may be attenuated DPN (130,143,145). (135–138). Although the evidence for by lower starting doses and more gradual Orthostatic Hypotension the benefit of near-normal glycemic titration. The related drug, gabapentin, Treating orthostatic hypotension is chal- control is not as strong for type 2 di- has also shown efficacy for pain control lenging. The therapeutic goal is to min- abetes, some studies have demonstrated in diabetic neuropathy and may be less imize postural symptoms rather than care.diabetesjournals.org Microvascular Complications and Foot Care S145

to restore normotension. Most patients Medicines Agency. It should be reserved be referred for ankle-brachial require both nonpharmacologic mea- for severe cases that are unresponsive to index and for further vascular sures (e.g., ensuring adequate salt intake, other therapies (166). Other treatment assessment as appropriate. C avoiding medications that aggravate hy- options include domperidone (available 11.36 A multidisciplinary approach is potension,orusingcompressivegarments outside of the U.S.) and erythromycin, recommended for individuals over the legs and abdomen) and phar- which is only effective for short-term use with foot ulcers and high-risk macologic measures. Physical activity and due to tachyphylaxis (167,168). Gastric feet (e.g., dialysis patients and exercise should be encouraged to avoid electrical stimulation using a surgically those with Charcot foot or deconditioning, which is known to exac- implantable device has received approval prior ulcers or amputation). B from the FDA, although its efficacy is erbate orthostatic intolerance, and vol- 11.37 Refer patients who smoke or who fl variable and use is limited to patients ume repletion with uids and salt is have histories of prior lower- with severe symptoms that are refractory critical. There have been clinical studies extremity complications, loss of to other treatments (169). that assessed the impact of an approach protective sensation, structural incorporating the aforementioned non- Erectile Dysfunction abnormalities, or peripheral arte- pharmacologic measures. Additionally, rial disease to foot care special- supine blood pressure tends to be In addition to treatment of hypogonadism if present, treatments for erectile ists for ongoing preventive care much higher in these patients, often re- and lifelong surveillance. C quiring treatment of blood pressure at dysfunction may include phosphodies- terase type 5 inhibitors, intracorporeal 11.38 Provide general preventive bedtime with shorter-acting drugs that foot self-care education to also affect baroreceptor activity such as or intraurethral prostaglandins, vacuum devices, or penile prostheses. As with all patients with diabetes. B guanfacine or clonidine, shorter-acting DPN treatments, these interventions do 11.39AssociationThe use of specialized therapeu- calcium blockers (e.g., isradipine), or not change the underlying pathology tic footwear is recommended for shorter-acting b-blockers such as atenolol and natural history of the disease pro- high-risk patients with diabetes or metoprolol tartrate. Alternatives can cess but may improve the patient’s including those with severe neu- include enalapril if patients are unable ropathy, foot deformities, ulcers, – quality of life. to tolerate preferred agents (159 161). callousformation,poorperipheral Midodrine and droxidopa are approved circulation, or history of amputa- by the FDA for the treatment of ortho- FOOT CARE tion. B static hypotension. Recommendations Gastroparesis 11.31 Perform a comprehensive foot Foot ulcers and amputation, which are Treatment for diabetic gastroparesis evaluationDiabetes at least annually to consequences of diabetic neuropathy may be very challenging. A low-fiber, identify risk factors for ulcers and/or peripheral arterial disease B low-fat eating plan provided in small and amputations. (PAD), are common and represent major 11.32 frequent meals with a greater propor- Patients with evidence of sen- causes of morbidity and mortality in tion of liquid calories may be useful sory loss or prior ulceration or people with diabetes. (162–164). In addition, foods with amputation should have their Early recognition and treatment of B smallparticlesizemayimprovekey feet inspected at every visit. patients with diabetes and feet at risk 11.33 symptoms (165). Withdrawing drugs Obtain a prior history of ulcer- for ulcers and amputations can delay or with adverse effects on gastrointestinal ation, amputation, Charcot foot, prevent adverse outcomes. motility including opioids, anticholiner- angioplasty or vascular surgery, The risk of ulcers or amputations is gics, tricyclic antidepressants, GLP-1 RAs, cigarette smoking, retinopathy, increased in people who have the fol- pramlintide, and possiblyAmerican dipeptidyl and renal disease and assess lowing risk factors: peptidase 4 inhibitors may also im- current symptoms of neuropa- prove intestinal motility (162,166). In thy (pain, burning, numbness) c Poor glycemic control cases of severe gastroparesis, pharma- andvasculardisease(legfatigue, c Peripheral neuropathy with LOPS B cologic interventions are needed. Only claudication). c Cigarette smoking 11.34 metoclopramide, a prokinetic agent, is The examination should include c Foot deformities approved by the FDA for the treatment inspection of the skin, assess- c Preulcerative callus or corn of gastroparesis. However, the level of ment of foot deformities, neu- c PAD rological assessment (10-g evidence©2019 regarding the bene fits of me- c History of foot ulcer monofilament testing with at toclopramide for the management of c Amputation least one other assessment: gastroparesis is weak, and given the risk c Visual impairment pinprick, temperature, vibra- for serious adverse effects (extrapyra- c CKD (especially patients on dialysis) tion), and vascular assess- midal signs such as acute dystonic ment including pulses in the fi reactions, drug-induced parkinsonism, Moreover, there is suf cient good- legs and feet. B akathisia, and tardive dyskinesia), its quality evidence to support use of ap- 11.35 Patients with symptoms of use in the treatment of gastroparesis propriate therapeutic footwear with claudication or decreased or beyond 12 weeks is no longer recomm- demonstrated pressure relief that is absent pedal pulses should ended by the FDA or the European worn by the patient to prevent plantar S146 Microvascular Complications and Foot Care Diabetes Care Volume 43, Supplement 1, January 2020

foot ulcer recurrence or worsening. How- ulcer and peripheral arterial disease consideration and a thorough workup ever, there is very little evidence for the should be performed: skin perfusion should be performed when patients with use of interventions to prevent a first foot pressure ($40 mmHg), toe pressure neuropathy present with the acute onset ulcer or heal ischemic, infected, non- ($30 mmHG), or transcutaneous oxygen of a red, hot, swollen foot or ankle, and plantar, or proximal foot ulcers (170). pressure (TcPO2 $25 mmHg). Urgent Charcot neuroarthropathy should be ex- Studies on specific types of footwear vascular imaging and revascularization cluded. Early diagnosis and treatment of demonstrated that shape and barefoot should be considered in a patient with Charcot neuroarthropathy is the best plantar pressure–based orthoses were a diabetic foot ulcer and an ankle pres- way to prevent deformities that increase more effective in reducing submeta- sure (ankle-brachial index) ,50 mmHg, the risk of ulceration and amputation. tarsal head plantar ulcer recurrence toe pressure ,30 mmHg, or a TcPO2 The routine prescription of therapeutic than current standard-of-care orthoses ,25 mmHg (130,175). footwear is not generally recommended. (171). However, patients should be provided Clinicians are encouraged to review Patient Education adequate information to aid in selection ADA screening recommendations for fur- All patients with diabetes and partic- of appropriate footwear. General foot- ther details and practical descriptions of ularly those with high-risk foot condi- wear recommendations include a broad how to perform components of the com- tions (history of ulcer or amputation, and square toe box, laces with three or prehensive foot examination (172). deformity, LOPS, or PAD) and their four eyes per side, padded tongue, qual- families should be provided general ity lightweight materials, and sufficient Evaluation for Loss of Protective education about risk factors and ap- size to accommodate a cushioned insole. Sensation propriate management (176). Patients Use of custom therapeutic footwear can All adults with diabetes should undergo a at risk should understand the implica- help reduce the risk of future foot ulcers comprehensive foot evaluation at least Association tions of foot deformities, LOPS, and in high-risk patients (173,176). annually. Detailed foot assessments may Most diabetic foot infections are poly- occur more frequently in patients with PAD; the proper care of the foot, in- microbial, with aerobic gram-positive histories of ulcers or amputations, foot cluding nail and skin care; and the cocci. Staphylococci and streptococci deformities, insensate feet, and PAD importance of foot monitoring on a are the most common causative organ- (173,174).Toassessrisk, clinicians should daily basis. Patients with LOPS should isms. Wounds without evidence of soft ask about history of foot ulcers or am- be educated on ways to substitute tissue or bone infection do not require putation, neuropathic and peripheral other sensory modalities (palpation or visual inspection using an unbreak- antibiotic therapy. Empiric antibiotic vascular symptoms, impaired vision, re- able mirror) for surveillance of early therapy can be narrowly targeted at nal disease, tobacco use, and foot care foot problems. gram-positive cocci in many patients practices. A general inspection of skin The selectionDiabetes of appropriate footwear with acute infections, but those at risk integrity and musculoskeletal deform- and footwear behaviors at home should for infection with antibiotic-resistant ities should be performed. Vascular as- ’ organisms or with chronic, previously sessment should include inspection and also be discussed. Patients understand- treated, or severe infections require palpation of pedal pulses. ing of these issues and their physical broader-spectrum regimens and should The neurological exam performed as ability to conduct proper foot surveil- be referred to specialized care centers part of the foot examination is designed lance and care should be assessed. Pa- fi (177). Foot ulcers and wound care may to identify LOPS rather than early neu- tients with visual dif culties, physical require care by a podiatrist, orthopedic ropathy. The 10-g monofilament is the constraints preventing movement, or cognitive problems that impair their abil- or vascular surgeon, or rehabilitation most useful test to diagnose LOPS. ity to assess the condition of the foot and specialist experienced in the manage- Ideally, the 10-g monofilament test to institute appropriate responses will ment of individuals with diabetes (177). should be performed with at least Americanneed other people, such as family mem- Hyperbaric oxygen therapy (HBOT) in one other assessment (pinprick, tem- bers, to assist with their care. patients with diabetic foot ulcers has perature or vibration sensation using a mixed evidence supporting its use as 128-Hz tuning fork, or ankle reflexes). an adjunctive treatment to enhance Absent monofilament sensation sug- Treatment People with neuropathy or evidence of wound healing and prevent amputation gests LOPS, while at least two normal increased plantar pressures (e.g., ery- (178–181). A well-conducted random- tests (and no abnormal test) rules out thema, warmth, or calluses) may be ized controlled study performed in LOPS. adequately managed with well-fitted 103 patients found that HBOT did not Evaluation©2019 for Peripheral Arterial walking shoes or athletic shoes that reduce the indication for amputation or Disease cushion the feet and redistribute pres- facilitate wound healing compared with Initial screening for PAD should include a sure. People with bony deformities comprehensive wound care in patients history of decreased walking speed, leg (e.g., hammertoes, prominent metatar- with chronic diabetic foot ulcers (182). fatigue, claudication, and an assessment sal heads, bunions) may need extra Moreover, a systematic review by the of the pedal pulses. Ankle-brachial index wide or deep shoes. People with bony International Working Group on the Di- testing should be performed in patients deformities, including Charcot foot, who abetic Foot of interventions to improve with symptoms or signs of PAD. Addi- cannot be accommodated with com- the healing of chronic diabetic foot ulcers tionally, at least one of the following mercial therapeutic footwear, will re- concluded that analysis of the evidence tests in a patient with a diabetic foot quire custom-molded shoes. Special continues to present methodological care.diabetesjournals.org Microvascular Complications and Foot Care S147

challenges as randomized controlled type 2 diabetes. J Am Soc Nephrol 2013;24:302– 24. Perkovic V, Jardine MJ, Neal B, et al. Canagli- studies remain few, with a majority being 308 flozin and renal outcomes in type 2 diabetes and – of poor quality (179). Thus, HBOT does 9. Groop P-H, Thomas MC, Moran JL, et al.; nephropathy. N Engl J Med 2019;380:2295 2306 FinnDiane Study Group. The presence and se- 25. Nadkarni GN, Ferrandino R, Chang A, et al. not have a significant effect on health- verity of chronic kidney disease predicts all-cause Acute kidney injury in patients on SGLT2 inhib- related quality of life in patients with mortality in type 1 diabetes. Diabetes 2009;58: itors: a propensity-matched analysis. Diabetes diabetic foot ulcers (183,184). A recent 1651–1658 Care 2017;40:1479–1485 review concluded that the evidence to 10. Gomes MB, Gonçalves MF. Is there a phys- 26. Wanner C, Inzucchi SE, Lachin JM, et al.; iological variability for albumin excretion rate? EMPA-REG OUTCOME Investigators. Empagli- date remains inconclusive regarding the Study in patients with diabetes type 1 and non- flozin and progression of kidney disease in clinical and cost-effectiveness of HBOT as diabetic individuals. Clin Chim Acta 2001;304: type 2 diabetes. N Engl J Med 2016;375:323– an adjunctive treatment to standard 117–123 334 wound care for diabetic foot ulcers 11. Naresh CN, Hayen A, Weening A, Craig JC, 27. Neuen BL, Ohkuma T, Neal B, et al. Cardio- fl (185). Results from the Dutch DAMOCLES Chadban SJ. Day-to-day variability in spot urine vascular and renal outcomes with canagli ozin albumin-creatinine ratio. Am J Kidney Dis 2013; according to baseline kidney function: data from (Does Applying More Oxygen Cure 62:1095–1101 the CANVAS Program. Circulation 2018;138: Lower Extremity Sores?) trial demon- 12. Tankeu AT, Kaze FF, Noubiap JJ, Chelo D, 1537–1550 strated that HBOT in patients with di- Dehayem MY, Sobngwi E. Exercise-induced albu- 28. Thakar CV, Christianson A, Himmelfarb J, abetes and ischemic wounds did not minuria and circadian blood pressure abnormalities Leonard AC. Acute kidney injury episodes and – significantly improve complete wound intype 2diabetes.WorldJNephrol2017;6:209 216 chronic kidney disease risk in diabetes mellitus. 13. Delanaye P, Glassock RJ, Pottel H, Rule AD. Clin J Am Soc Nephrol 2011;6:2567–2572 healing and limb salvage (186). While An age-calibrated definition of chronic kidney 29. Bakris GL, Weir MR. Angiotensin-converting the Centers for Medicare & Medicaid disease: rationale and benefits. Clin Biochem Rev enzyme inhibitor-associated elevations in serum Services currently covers HBOT for di- 2016;37:17–26 creatinine: is this a cause for concern? Arch abetic foot ulcers that have failed a 14. Kramer HJ, Nguyen QD, Curhan G, Hsu C-Y. Intern Med 2000;160:685–693 fi Association standard course of wound therapy Renal insuf ciency in the absence of albuminuria 30. Beddhu S, Greene T, Boucher R, et al. In- and retinopathy among adults with type 2 di- tensive systolic blood pressure control and in- when there are no measurable signs abetes mellitus. JAMA 2003;289:3273–3277 cident chronic kidney disease in people with and of healing for at least 30 consecutive 15. Molitch ME, Steffes M, Sun W, et al.; Epide- without diabetes mellitus: secondary analyses of days (187), given the data not support- miology of Diabetes Interventions and Com- two randomised controlled trials. Lancet Diabe- inganeffect,suchanapproachisnot plications Study Group. Development and progression tes Endocrinol 2018;6:555–563 of renal insufficiency with and without albu- 31. Collard D, Brouwer TF, Peters RJG, Vogt L, currently warranted. HBOT should be a minuria in adults with type 1 diabetes in the van den Born BH. Creatinine rise during blood topic of shared decision-making before Diabetes Control and Complications Trial and pressure therapy and the risk of adverse clinical treatment is considered for selected the Epidemiology of Diabetes Interventions and outcomes in patients with type 2 diabetes mel- patients with diabetic foot ulcers (187). Complications study. Diabetes Care 2010;33: litus. Hypertension 2018;72:1337–1344 1536–1543 32. Malhotra R, Craven T, Ambrosius WT, et al.; 16. He F, Xia X, Wu XF,Diabetes Yu XQ, Huang FX. Diabetic SPRINT Research Group. Effects of intensive References retinopathy in predicting diabetic nephropathy blood pressure lowering on kidney tubule injury 1. Tuttle KR, Bakris GL, Bilous RW, et al. Diabetic in patients with type 2 diabetes and renal in CKD: a longitudinal subgroup analysis in kidney disease: a report from an ADA Consensus disease: a meta-analysis. Diabetologia 2013; SPRINT. Am J Kidney Dis 2019;73:21–30 – Conference. Diabetes Care 2014;37:2864 2883 56:457–466 33. Hughes-Austin JM, Rifkin DE, Beben T, et al. 2. National Kidney Foundation. KDIGO 2012 clin- 17. Levey AS, Coresh J, Balk E, et al.; National The relation of serum potassium concentration ical practice guideline for the evaluation and Kidney Foundation. National Kidney Foundation with cardiovascular events and mortality in management of chronic kidney disease. Kidney practice guidelines for chronic kidney disease: community-living individuals. Clin J Am Soc Int Suppl 2013;3:1–150 evaluation, classification, and stratification. Ann Nephrol 2017;12:245–252 3. Afkarian M, Zelnick LR, Hall YN, et al. Clinical Intern Med 2003;139:137–147 34. Bandak G, Sang Y, Gasparini A, et al. Hyper- manifestations of kidney disease among US 18. Flynn C, Bakris GL. Noninsulin glucose- kalemia after initiating renin-angiotensin system Adults with diabetes, 1988-2014. JAMA 2016; lowering agents for the treatment of patients blockade: the Stockholm Creatinine Measure- 316:602–610 on dialysis. Nat Rev Nephrol 2013;9:147–153 ments (SCREAM) project. J Am Heart Assoc 2017; 4. de Boer IH, Rue TC, Hall YN, Heagerty PJ, Weiss 19. Matzke GR, Aronoff GR, Atkinson AJ Jr, et al. 6:e005428 NS, Himmelfarb J. Temporal trendsAmerican in the prev- Drug dosing consideration in patients with acute 35. Nilsson E, Gasparini A, Arnl¨ ov¨ J, et al. In- alence of diabetic kidney disease in the United and chronic kidney disease-a clinical update from cidence and determinants of hyperkalemia and States. JAMA 2011;305:2532–2539 Kidney Disease: Improving Global Outcomes hypokalemia in a large healthcare system. Int J 5. de Boer IH; DCCT/EDIC Research Group. Kid- (KDIGO). Kidney Int 2011;80:1122–1137 Cardiol 2017;245:277–284 ney disease and related findings in the Diabetes 20. Coresh J, Turin TC, Matsushita K, et al. De- 36. de Boer IH, Gao X, Cleary PA, et al.; Diabetes Control and Complications Trial/Epidemiology of cline in estimated glomerular filtration rate and Control and Complications Trial/Epidemiology Diabetes Interventions and Complications study. subsequent risk of end-stage renal disease and of Diabetes Interventions and Complications Diabetes Care 2014;37:24–30 mortality. JAMA 2014;311:2518–2531 (DCCT/EDIC) Research Group. Albuminuria 6. United States Renal Data System. Annual Data 21. Zhou J, Liu Y, Tang Y, et al. A comparison of changes and cardiovascular and renal outcomes Report:©2019 Epidemiology of Kidney Disease in the RIFLE, AKIN, KDIGO, and Cys-C criteria for the intype1diabetes:theDCCT/EDICstudy.ClinJAm United STates. Bethesda, MD, National Institutes definition of acute kidney injury in critically ill Soc Nephrol 2016;11:1969–1977 of Health, National Institute of Diabetes and patients. Int Urol Nephrol 2016;48:125–132 37. Sumida K, Molnar MZ, Potukuchi PK, et al. Digestive and Kidney Diseases, 2016 22. Hoste EAJ, Kellum JA, Selby NM, et al. Global Changes in albuminuria and subsequent risk of 7. Fox CS, Matsushita K, Woodward M, et al.; epidemiology and outcomes of acute kidney incident kidney disease. Clin J Am Soc Nephrol Chronic Kidney Disease Prognosis Consortium. injury. Nat Rev Nephrol 2018;14:607–625 2017;12:1941–1949 Associations of kidney disease measures with 23. James MT, Grams ME, Woodward M, et al.; 38. Inker LA, Grams ME, Levey AS, et al.; CKD mortality and end-stage renal disease in indi- CKD Prognosis Consortium. A meta-analysis of Prognosis Consortium. Relationship of estimated viduals with and without diabetes: a meta- the association of estimated GFR, albuminuria, GFR and albuminuria to concurrent laboratory analysis. Lancet 2012;380:1662–1673 diabetes mellitus, and hypertension with abnormalities: an individual participant data 8. Afkarian M, Sachs MC, Kestenbaum B, et al. acute kidney injury. Am J Kidney Dis 2015; meta-analysis in a global consortium. Am J Kidney disease and increased mortality risk in 66:602–612 Kidney Dis 2019;73:206–217 S148 Microvascular Complications and Foot Care Diabetes Care Volume 43, Supplement 1, January 2020

39. Klahr S, Levey AS, Beck GJ, et al.; Modifica- Veterans Affairs Diabetes Trial (VADT). Diabeto- 66. Mann JFE, Ørsted DD, Brown-Frandsen K, tion of Diet in Renal Disease Study Group. The logia 2018;61:295–299 et al.; LEADER Steering Committee and Inves- effects of dietary protein restriction and blood- 52. Miller ME, Bonds DE, Gerstein HC, et al.; tigators.. Liraglutide and renal outcomes in pressure control on the progression of chronic ACCORD Investigators. The effects of baseline type 2 diabetes. N Engl J Med 2017;377:839– renal disease. N Engl J Med 1994;330:877–884 characteristics, glycaemia treatment approach, 848 40. Mills KT, Chen J, Yang W, et al.; Chronic Renal and glycated haemoglobin concentration on the 67. Marso SP, Bain SC, Consoli A, et al.; SUSTAIN- Insufficiency Cohort (CRIC) Study Investigators. risk of severe hypoglycaemia: post hoc epide- 6 Investigators. Semaglutide and cardiovascular Sodium excretion and the risk of cardiovascular miological analysis of the ACCORD study. BMJ outcomes in patients with type 2 diabetes. N Engl disease in patients with chronic kidney disease. 2010;340:b5444 J Med 2016;375:1834–1844 jama 2016;315:2200–2210 53. Papademetriou V, Lovato L, Doumas M, 68. Karter AJ, Warton EM, Lipska KJ, et al. De- 41. Whelton PK, Carey RM, Aronow WS, et al. et al.; ACCORD Study Group. Chronic kidney velopment and validation of a tool to identify 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ disease and intensive glycemic control increase patients with type 2 diabetes at high risk of ASH/ASPC/NMA/PCNA guideline for the preven- cardiovascular risk in patients with type 2 di- hypoglycemia-related emergency department or tion, detection, evaluation, and management of abetes. Kidney Int 2015;87:649–659 hospital use. JAMA Intern Med 2017;177:1461– high blood pressure in adults: executive sum- 54. Perkovic V, Heerspink HL, Chalmers J, et al.; 1470 mary: a report of the American College of ADVANCECollaborativeGroup. Intensiveglucose 69. Moen MF, Zhan M, Hsu VD, et al. Frequency Cardiology/American Heart Association Task control improves kidney outcomes in patients of hypoglycemia and its significance in chronic Force on Clinical Practice Guidelines. Hyperten- with type 2 diabetes. Kidney Int 2013;83:517– kidney disease. Clin J Am Soc Nephrol 2009;4: sion 2018;71:1269–1324 523 1121–1127 42. Murray DP, Young L, Waller J, et al. Is dietary 55. Wong MG, Perkovic V, Chalmers J, et al.; 70. U.S. Food and Drug Administration. FDA protein intake predictive of 1-year mortality in ADVANCE-ON Collaborative Group. Long-term drug safety communication: FDA revises warn- dialysis patients? Am J Med Sci 2018;356:234– benefits of intensive glucose control for prevent- ings regarding use of the diabetes medicine 243 ing end-stage kidney disease: ADVANCE-ON. metformin in certain patients with reduced 43. DCCT/EDIC research group. Effect of inten- Diabetes Care 2016;39:694–700 kidney function, 2016. Accessed 4 November sive diabetes treatment on albuminuria in type 1 56. National Kidney Foundation. KDOQI clinical 2019.Association Available from http://www.fda.gov/ diabetes: long-term follow-up of the Diabetes practiceguidelinefor diabetesandCKD:2012Up- Drugs/DrugSafety/ucm493244.htm Control and Complications Trial and Epidemiol- date. Am J Kidney Dis 2012;60:850–886 71. Zinman B, WannerC,Lachin JM,et al.; EMPA- ogy of Diabetes Interventions and Complications 57. Cherney DZI, Perkins BA, Soleymanlou N, REG OUTCOME Investigators. Empagliflozin, car- study. Lancet Diabetes Endocrinol 2014;2:793– et al. Renal hemodynamic effect of sodium- diovascular outcomes, and mortality in type 2 800 glucose cotransporter 2 inhibition in patients diabetes. N Engl J Med 2015;373:2117–2128 44. de Boer IH, Sun W, Cleary PA, et al.; DCCT/ with type 1 diabetes mellitus. Circulation 2014; 72. Mahaffey KW, Neal B, Perkovic V, et al.; EDIC Research Group. Intensive diabetes therapy 129:587–597 CANVAS Program Collaborative Group. Canagli- and glomerular filtration rate in type 1 diabetes. 58. Heerspink HJL, Desai M, Jardine M, Balis D, flozin for primary and secondary prevention of N Engl J Med 2011;365:2366–2376 Meininger G, Perkovic V. Canagliflozin slows cardiovascular events: results from the CANVAS 45. UK Prospective Diabetes Study (UKPDS) progression of renal function decline indepen- program (Canagliflozin Cardiovascular Assess- Group. Effect of intensive blood-glucose control dently of glycemic effects. J Am Soc Nephrol ment Study). Circulation 2018;137:323–334 with metformin on complications in overweight 2017;28:368–375 73. Jardine MJ, Mahaffey KW, Neal B, et al.; patients with type 2 diabetes (UKPDS 34). Lancet 59. Neal B, PerkovicDiabetes V, Mahaffey KW, et al.; CREDENCE study investigators. The Canagliflozin 1998;352:854–865 CANVAS Program Collaborative Group. Canagliflozin and Renal Endpoints in Diabetes with Established 46. UK Prospective Diabetes Study (UKPDS) and cardiovascular and renal events in type 2 Nephropathy Clinical Evaluation (CREDENCE) Group. Intensive blood-glucose control with diabetes. N Engl J Med 2017;377:644–657 study rationale, design, and baseline character- sulphonylureas or insulin compared with con- 60. Zelniker TA, Braunwald E. Cardiac and renal istics. Am J Nephrol 2017;46:462–472 ventional treatment and risk of complications in effects of sodium-glucose co-transporter 2 inhib- 74. Mahaffey KW, Jardine MJ, Bompoint S, et al. patients with type 2 diabetes (UKPDS 33). Lancet itors in diabetes: JACC state-of-the-art review. Canagliflozin and cardiovascular and renal out- 1998;352:837–853 J Am Coll Cardiol 2018;72:1845–1855 comes in type 2 diabetes mellitus and chronic 47. Patel A, MacMahon S, Chalmers J, et al.; 61. Woods TC, Satou R, Miyata K, et al. Canagli- kidney disease in primary and secondary cardio- ADVANCE Collaborative Group. Intensive blood flozin prevents intrarenal angiotensinogen aug- vascular prevention groups. Circulation 2019; glucose control and vascular outcomes in pa- mentation and mitigates kidney injury and 140:739–750 tients with type 2 diabetes. N Engl J Med 2008; hypertension in mouse model of type 2 diabetes 75. Bakris GL. Major advancements in slowing 358:2560–2572 mellitus. Am J Nephrol 2019;49:331–342 diabetic kidney disease progression: focus on 48. Ismail-Beigi F, Craven T, Banerji MA, et al.; 62. Heerspink HJL, Perco P, Mulder S, et al. SGLT2 inhibitors. Am J Kidney Dis. 28 June ACCORD trial group. Effect ofAmerican intensive treat- Canagliflozin reduces inflammation and fibrosis 2019 [Epub ahead of print]. DOI: 10.1053/ ment of hyperglycaemia on microvascular out- biomarkers: a potential mechanism of action for j.ajkd.2019.05.009 comes in type 2 diabetes: an analysis of the beneficial effects of SGLT2 inhibitors in diabetic 76. Novo Nordisk A/S. A research study to see ACCORDrandomised trial. Lancet 2010;376:419– kidney disease. Diabetologia 2019;62:1154– how semaglutide works compared to placebo in 430 1166 people with type 2 diabetes and chronic kidney 49. Zoungas S, Chalmers J, Neal B, et al.; 63. Yaribeygi H, Butler AE, Atkin SL, Katsiki N, disease (FLOW). In: ClinicalTrials.gov. Bethesda, ADVANCE-ON Collaborative Group. Follow-up Sahebkar A. Sodium-glucose cotransporter 2 in- MD, National Library of Medicine, 2019. Ac- of blood-pressure lowering and glucose control hibitors and inflammation in chronic kidney cessed 11 September 2019. Available from in type 2 diabetes. N Engl J Med 2014;371:1392– disease: possible molecular pathways. J Cell https://clinicaltrials.gov/ct2/show/NCT03819153 1406©2019 Physiol 2018;234:223–230 77. Franki, L. FDA approves label extension 50. Zoungas S, Arima H, Gerstein HC, et al.; 64. Marso SP, Daniels GH, Brown-Frandsen K, for dapagliflozin. Accessed 11 September Collaborators on Trials of Lowering Glucose et al.; LEADER Steering Committee; LEADER Trial 2019. Available from https://www.mdedge (CONTROL) group. Effects of intensive glucose Investigators. Liraglutide and cardiovascular out- .com/endocrinology/article/195314/diabetes/ control on microvascular outcomes in patients comes in type 2 diabetes. N Engl J Med 2016;375: fda-approves-label-extension-dapagliflozin with type 2 diabetes: a meta-analysis of individ- 311–322 78. Leehey DJ, Zhang JH, Emanuele NV, et al.; VA ual participant data from randomised controlled 65. Cooper ME, Perkovic V, McGill JB, et al. NEPHRON-D Study Group. BP and renal out- trials. Lancet Diabetes Endocrinol 2017;5:431– Kidney disease end points in a pooled analysis comes in diabetic kidney disease: the Veterans 437 of individual patient-level data from a large Affairs Nephropathy in Diabetes Trial. Clin J Am 51. Agrawal L, Azad N, Bahn GD, et al.; VADT clinical trials program of the dipeptidyl peptidase Soc Nephrol 2015;10:2159–2169 Study Group. Long-term follow-up of intensive 4 inhibitor linagliptin in type 2 diabetes. Am J 79. Emdin CA, Rahimi K, Neal B, Callender T, glycaemic control on renal outcomes in the Kidney Dis 2015;66:441–449 Perkovic V, Patel A. Blood pressure lowering in care.diabetesjournals.org Microvascular Complications and Foot Care S149

type 2 diabetes: a systematic review and meta- 94. Yusuf S, Teo KK, Pogue J, et al.; ONTARGET function outcomes in the Diabetes Control analysis. JAMA 2015;313:603–615 Investigators. Telmisartan, ramipril, or both in and Complications Trial/Epidemiology of Diabe- 80. Cushman WC, Evans GW, Byington RP, et al.; patients at high risk for vascular events. N Engl J tes Interventions and Complications (DCCT/ ACCORD Study Group. Effects of intensive blood- Med 2008;358:1547–1559 EDIC) cohort. JAMA Ophthalmol 2016;134: pressure control in type 2 diabetes mellitus. N 95. Fried LF, Emanuele N, Zhang JH, et al.; VA 137–145 Engl J Med 2010;362:1575–1585 NEPHRON-D Investigators. Combined angioten- 108. Fong DS, Aiello LP, Ferris FL 3rd, Klein R. 81. UK Prospective Diabetes Study Group. sin inhibition for the treatment of diabetic Diabetic retinopathy. Diabetes Care 2004;27: Tight blood pressure control and risk of macro- nephropathy. N Engl J Med 2013;369:1892–1903 2540–2553 vascular and microvascular complications in 96. Bakris GL, Agarwal R, Chan JC, et al.; Min- 109. Diabetes Control and Complications Trial type 2 diabetes: UKPDS 38. BMJ 1998;317:703– eralocorticoid Receptor Antagonist Tolerability Research Group. Effect of pregnancy on micro- 713 Study–Diabetic Nephropathy (ARTS-DN) Study vascular complications in the Diabetes Control 82. de Boer IH, Bangalore S, Benetos A, et al. Group. Effect of finerenone on albuminuria in and Complications Trial. Diabetes Care 2000;23: Diabetes and hypertension: a position statement patients with diabetic nephropathy: a random- 1084–1091 by the American Diabetes Association. Diabetes ized clinical trial. JAMA 2015;314:884–894 110. Dabelea D, Stafford JM, Mayer-Davis EJ, Care 2017;40:1273–1284 97. Williams B, MacDonald TM, Morant S, et al.; SEARCH for Diabetes in Youth Research 83. Brenner BM, Cooper ME, de Zeeuw D, et al.; et al.; British Hypertension Society’s PATHWAY Group. Association of type 1 diabetes vs type 2 RENAAL Study Investigators. Effects of losartan Studies Group. Spironolactone versus placebo, diabetes diagnosed during childhood and ado- on renal and cardiovascular outcomes in patients bisoprolol, and doxazosin to determine the lescence with complications during teenage with type 2 diabetes and nephropathy. N Engl J optimal treatment for drug-resistant hyperten- years and young adulthood. JAMA 2017;317: Med 2001;345:861–869 sion (PATHWAY-2): a randomised, double-blind, 825–835 84. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD; crossover trial. Lancet 2015;386:2059–2068 111. AgardhE,Tababat-KhaniP.Adopting3-year The Collaborative Study Group. The effect of 98. Filippatos G, Anker SD, Bohm¨ M, et al. A screening intervals for sight-threatening retinal angiotensin-converting-enzyme inhibition on di- randomized controlled study of finerenone vs. vascular lesions in type 2 diabetic subjects with- abetic nephropathy. N Engl J Med 1993;329: eplerenone in patients with worsening chronic out retinopathy. Diabetes Care 2011;34:1318– 1456–1462 heart failure and diabetes mellitus and/or chronic 1319 Association 85. Lewis EJ, Hunsicker LG, Clarke WR, et al.; kidney disease. Eur Heart J 2016;37:2105–2114 112. Nathan DM, Bebu I, Hainsworth D, et al.; Collaborative Study Group. Renoprotective ef- 99. Smart NA, Dieberg G, Ladhani M, Titus T. DCCT/EDIC Research Group. Frequency of fect of the angiotensin-receptor antagonist Early referral to specialist nephrology services for evidence-based screening for retinopathy in irbesartan in patients with nephropathy due preventing the progression to end-stage kidney type 1 diabetes. N Engl J Med 2017;376: to type 2 diabetes. N Engl J Med 2001;345:851– disease. Cochrane Database Syst Rev 2014;6: 1507–1516 860 CD007333 113. Daskivich LP, Vasquez C, Martinez C Jr, 86. Heart Outcomes Prevention Evaluation 100. Solomon SD, Chew E, Duh EJ, et al. Diabetic Tseng C-H, Mangione CM. Implementation Study Investigators. Effects of ramipril on car- retinopathy: a position statement by the Amer- and evaluation of a large-scale teleretinal di- diovascular and microvascular outcomes in peo- ican Diabetes Association. Diabetes Care 2017; abetic retinopathy screening program in the Los ple with diabetes mellitus: results of the HOPE 40:412–418 Angeles County Department of Health Services. study and MICRO-HOPE substudy. Lancet 2000; 101. Klein R. Hyperglycemia and microvascular JAMA Intern Med 2017;177:642–649 355:253–259 and macrovascular disease in diabetes. Diabetes 114. Sim DA, Mitry D, Alexander P, et al. The 87. Barnett AH, Bain SC, Bouter P, et al.; Dia- Care 1995;18:258–268Diabetesevolution of teleophthalmology programs in the betics Exposed to Telmisartan and Enalapril 102. Estacio RO, McFarling E, Biggerstaff S, United Kingdom: beyond diabetic retinopathy Study Group. Angiotensin-receptor blockade Jeffers BW, Johnson D, Schrier RW. Overt albu- screening. J Diabetes Sci Technol 2016;10: versus converting-enzyme inhibition in type 2 minuria predicts diabetic retinopathy in His- 308–317 diabetes and nephropathy. N Engl J Med 2004; panics with NIDDM. Am J Kidney Dis 1998;31: 115. Abramoff` MD, Lavin PT, Birch M, Shah N, 351:1952–1961 947–953 Folk JC. Pivotal trial of an autonomous AI-based 88. Wu H-Y, Peng C-L, Chen P-C, et al. Compar- 103. Leske MC, Wu S-Y, Hennis A, et al.; Barba- diagnostic system for detection of diabetic ret- ative effectiveness of angiotensin-converting dos Eye Study Group. Hyperglycemia, blood inopathy in primary care offices. NPJ Digit Med enzyme inhibitors versus angiotensin II receptor pressure, and the 9-year incidence of diabetic 2018;1:39 blockers for major renal outcomes in patients retinopathy: the Barbados Eye Studies. Ophthal- 116. Hooper P, Boucher MC, Cruess A, et al. with diabetes: A 15-year cohort study. PLoS One mology 2005;112:799–805 Canadian Ophthalmological Society evidence- 2017;12:e0177654 104. Chew EY, Davis MD, Danis RP, et al.; Action based clinical practice guidelines for the 89. Parving HH, Lehnert H, Brochner-Mortensen¨ to Control Cardiovascular Risk in Diabetes Eye management of diabetic retinopathy. Can J J, Gomis R, Andersen S, Arner P; Irbesartan in Study Research Group. The effects of medical Ophthalmol 2012;47(Supp. 1):S1–S30 Patients with Type 2 Diabetes andAmerican Microalbu- management on the progression of diabetic 117. Axer-Siegel R, Hod M, Fink-Cohen S, et al. minuria Study Group. The effect of irbesartan on retinopathy in persons with type 2 diabetes: Diabetic retinopathy during pregnancy. Ophthal- the development of diabetic nephropathy in the Action to Control Cardiovascular Risk in mology 1996;103:1815–1819 patients with type 2 diabetes. N Engl J Med Diabetes (ACCORD) Eye Study. Ophthalmology 118. Best RM, Chakravarthy U. Diabetic retinop- 2001;345:870–878 2014;121:2443–2451 athy in pregnancy. Br J Ophthalmol 1997;81:249– 90. Mauer M, Zinman B, Gardiner R, et al. Renal 105. Nathan DM, Genuth S, Lachin J, et al.; 251 and retinal effects of enalapril and losartan Diabetes Control and Complications Trial Re- 119. Gunderson EP, Lewis CE, Tsai A-L, et al. A in type 1 diabetes. N Engl J Med 2009;361:40–51 search Group. The effect of intensive treatment 20-year prospective study of childbearing and 91. Weil EJ, Fufaa G, Jones LI, et al. Effect of of diabetes on the development and progression incidence of diabetes in young women, con- losartan©2019 on prevention and progression of early of long-term complications in insulin-dependent trolling for glycemia before conception: the diabetic nephropathy in American Indians with diabetes mellitus. N Engl J Med 1993;329:977– Coronary Artery Risk Development in Young type 2 diabetes. Diabetes 2013;62:3224–3231 986 Adults (CARDIA) Study. Diabetes 2007;56: 92. Bangalore S, Fakheri R, Toklu B, Messerli FH. 106. Chew EY, Ambrosius WT, Davis MD, et al.; 2990–2996 Diabetes mellitus as a compelling indication for ACCORD Study Group; ACCORD Eye Study Group. 120. The Diabetic Retinopathy Study Research use of renin angiotensin system blockers: sys- Effects of medical therapies on retinopathy pro- Group. Preliminary report on effects of photo- tematic review and meta-analysis of randomized gression in type 2 diabetes. N Engl J Med 2010; coagulation therapy. Am J Ophthalmol 1976;81: trials. BMJ 2016;352:i438 363:233–244 383–396 93. HallerH,ItoS,IzzoJLJr,etal.;ROADMAPTrial 107. Gubitosi-Klug RA, Sun W, Cleary PA, et al.; 121. Gross JG, Glassman AR, Jampol LM, et al.; Investigators. Olmesartan for the delay or pre- Writing Team for the DCCT/EDIC Research Writing Committee for the Diabetic Retinopathy ventionof microalbuminuriaintype2 diabetes. N Group. Effects of prior intensive insulin therapy Clinical Research Network. Panretinal photo- Engl J Med 2011;364:907–917 and risk factors on patient-reported visual coagulation vs intravitreous ranibizumab for S150 Microvascular Complications and Foot Care Diabetes Care Volume 43, Supplement 1, January 2020

proliferative diabetic retinopathy: a random- Diabetes Control and Complications Trial. Ann 147. Freeman R, Durso-Decruz E, Emir B. Effi- ized clinical trial. JAMA 2015;314:2137–2146 Neurol 1995;38:869–880 cacy, safety, and tolerability of pregabalin treat- 122. Early Treatment Diabetic Retinopathy Study 136. CDC Study Group. The effect of intensive ment for painful diabetic peripheral neuropathy: research group. Photocoagulation for diabetic diabetes therapy on measures of autonomic findings from seven randomized, controlled trials macular edema. Early Treatment Diabetic Reti- nervous system function in the Diabetes Control across a range of doses. Diabetes Care 2008;31: nopathy Study report number 1. Arch Ophthalmol and Complications Trial (DCCT). Diabetologia 1448–1454 1985;103:1796–1806 1998;41:416–423 148. Moore RA, Straube S, Wiffen PJ, Derry S, 123. Elman MJ, Bressler NM, Qin H, et al.; Di- 137. Albers JW, Herman WH, Pop-Busui R, et al.; McQuayHJ.Pregabalinforacuteandchronicpain abetic Retinopathy Clinical Research Network. Diabetes Control and Complications Trial /Epi- in adults. Cochrane Database Syst Rev 2009 (3): Expanded 2-year follow-up of ranibizumab plus demiology of Diabetes Interventions and Com- CD007076 prompt or deferred laser or triamcinolone plus plications Research Group. Effect of prior 149. Raskin P,HuffmanC,TothC,et al. Pregabalin prompt laser for diabetic macular edema. Oph- intensive insulin treatment during the Diabetes in patients with inadequately treated painful di- thalmology 2011;118:609–614 Control and Complications Trial (DCCT) on pe- abetic peripheral neuropathy: a randomized with- 124. Mitchell P, Bandello F, Schmidt-Erfurth U, ripheral neuropathy in type 1 diabetes during drawal trial. Clin J Pain 2014;30:379–390 et al.; RESTORE study group. The RESTORE study: the Epidemiology of Diabetes Interventions and 150. Tesfaye S, Wilhelm S, Lledo A, et al. Dulox- ranibizumab monotherapy or combined with Complications (EDIC) study. Diabetes Care 2010; etine and pregabalin: high-dose monotherapy or laser versus laser monotherapy for diabetic 33:1090–1096 their combination? The “COMBO-DN study”–a macular edema. Ophthalmology 2011;118: 138. Pop-Busui R, Low PA, Waberski BH, et al.; multinational, randomized, double-blind, parallel- 615–625 DCCT/EDIC Research Group. Effects of prior in- group study in patients with diabetic peripheral 125. Nguyen QD, Brown DM, Marcus DM, et al.; tensive insulin therapy on cardiac autonomic neuropathic pain. Pain 2013;154:2616–2625 RISE and RIDE Research Group. Ranibizumab for nervous system function in type 1 diabetes 151. Ziegler D, Duan WR, An G, Thomas JW, diabetic macular edema: results from 2 phase III mellitus: the Diabetes Control and Complications Nothaft W. A randomized double-blind, placebo-, randomized trials:RISEandRIDE.Ophthalmology Trial/Epidemiology of Diabetes Interventions and active-controlled study of T-type calcium 2012;119:789–801 and Complications study (DCCT/EDIC). Circula- channel blocker ABT-639 in patients with diabetic 126. Shih C-J, Chen H-T, Kuo S-C, et al. Compar- tion 2009;119:2886–2893 peripheralAssociation neuropathic pain. Pain 2015;156:2013– ative effectiveness of angiotensin-converting- 139. Callaghan BC,Little AA, FeldmanEL, Hughes 2020 enzyme inhibitors and angiotensin II receptor RAC. Enhanced glucose control for preventing 152. Quilici S, Chancellor J, Lothgren¨ M, et al. blockers in patients with type 2 diabetes and and treating diabetic neuropathy. Cochrane Da- Meta-analysis of duloxetine vs. pregabalin and retinopathy. CMAJ 2016;188:E148–E157 tabase Syst Rev 2012;6:CD007543 gabapentin in the treatment of diabetic periph- 127. Shi R, Zhao L, Wang F, et al. Effects of lipid- 140. Pop-Busui R, Lu J, Brooks MM, et al.; BARI eral neuropathic pain. BMC Neurol 2009;9:6 lowering agents on diabetic retinopathy: a meta- 2D Study Group. Impact of glycemic control 153. Dworkin RH, Jensen MP, Gammaitoni AR, analysis and systematic review. Int J Ophthalmol strategies on the progression of diabetic periph- Olaleye DO, Galer BS. Symptom profiles differ 2018;11:287–295 eral neuropathy in the Bypass Angioplasty Re- in patients with neuropathic versus non- 128. Ang L, Jaiswal M, Martin C, Pop-Busui R. vascularization Investigation 2 Diabetes (BARI neuropathic pain. J Pain 2007;8:118–126 Glucosecontrolanddiabeticneuropathy: lessons 2D) Cohort. Diabetes Care 2013;36:3208–3215 154. Wiffen PJ, Derry S, Bell RF, et al. Gabapentin from recent large clinical trials. Curr Diab Rep 141. Sadosky A, Schaefer C, Mann R, et al. for chronic neuropathic pain in adults. Cochrane 2014;14:528 Burden of illness associated with painful diabetic Database Syst Rev 2017;6:CD007938 129. Martin CL, Albers JW, Pop-Busui R; DCCT/ peripheral neuropathyDiabetes among adults seeking 155. Wernicke JF, Pritchett YL, D’Souza DN, et al. EDIC Research Group. Neuropathy and related treatment in the US: results from a retrospective A randomized controlled trial of duloxetine in findings in the diabetes control and complica- chart review and cross-sectional survey. Diabetes diabetic peripheral neuropathic pain. Neurology tions trial/epidemiology of diabetes interven- Metab Syndr Obes 2013;6:79–92 2006;67:1411–1420 tions and complications study. Diabetes Care 142. Waldfogel JM, Nesbit SA, Dy SM, et al. 156. Hardy T, Sachson R, Shen S, Armbruster M, 2014;37:31–38 Pharmacotherapy for diabetic peripheral neu- BoultonAJM.Doestreatment withduloxetinefor 130. Pop-Busui R, Boulton AJM, Feldman EL, ropathy pain and quality of life: a systematic neuropathic pain impact glycemic control? Di- et al. Diabetic neuropathy: a position statement review. Neurology 2017;88:1958–1967 abetes Care 2007;30:21–26 by the American Diabetes Association. Diabetes 143. Finnerup NB, Attal N, Haroutounian S, et al. 157. Schwartz S, Etropolski M, Shapiro DY, et al. Care 2017;40:136–154 Pharmacotherapy for neuropathic pain in adults: Safety and efficacy of tapentadol ER in patients 131. Freeman R. Not all neuropathy in diabetes a systematic review and meta-analysis. Lancet with painful diabetic peripheral neuropathy: re- is of diabetic etiology: differential diagnosis of Neurol 2015;14:162–173 sults of a randomized-withdrawal, placebo-con- diabetic neuropathy. Curr Diab Rep 2009;9:423– 144. Bril V, England J, Franklin GM, et al.; Amer- trolled trial. Curr Med Res Opin 2011;27:151–162 431 ican Academy of Neurology; American Associa- 158. Vinik AI, Shapiro DY, Rauschkolb C, et al. 132. Pop-Busui R, Evans GW, GersteinAmerican HC, et al.; tion of Neuromuscular and Electrodiagnostic A randomized withdrawal, placebo-controlled Action to Control Cardiovascular Risk in Diabetes Medicine; American Academy of Physical Med- study evaluating the efficacy and tolerability Study Group. Effects of cardiac autonomic dys- icine and Rehabilitation. Evidence-based guide- of tapentadol extended release in patients function on mortality risk in the Action to Control line: treatment of painful diabetic neuropathy: with chronic painful diabetic peripheral neurop- Cardiovascular Risk in Diabetes (ACCORD) trial. report of the American Academy of Neurology, athy. Diabetes Care 2014;37:2302–2309 Diabetes Care 2010;33:1578–1584 the American Association of Neuromuscular 159. Briasoulis A, Silver A, Yano Y, Bakris GL. 133. Pop-Busui R, Cleary PA, Braffett BH, et al.; and Electrodiagnostic Medicine, and the Amer- Orthostatic hypotension associated with baro- DCCT/EDIC Research Group. Association be- ican Academy of Physical Medicine and Re- receptor dysfunction: treatment approaches. J tween cardiovascular autonomic neuropathy habilitation [published correction appears in Clin Hypertens (Greenwich) 2014;16:141–148 and©2019 left ventricular dysfunction: DCCT/EDIC Neurology 2011;77:603]. Neurology 2011;76: 160. Figueroa JJ, Basford JR, Low PA. Preventing study (Diabetes Control and Complications Tri- 1758–1765 and treating orthostatic hypotension: As easy as al/Epidemiology of Diabetes Interventions and 145. Griebeler ML, Morey-Vargas OL, Brito JP, A, B, C. Cleve Clin J Med 2010;77:298–306 Complications). J Am Coll Cardiol 2013;61:447– et al. Pharmacologic interventions for painful 161. Jordan J, Fanciulli A, Tank J, et al. Manage- 454 diabetic neuropathy: an umbrella systematic re- ment of supine hypertension in patients with 134. Smith AG, Lessard M, Reyna S, Doudova M, view and comparative effectiveness network neurogenic orthostatic hypotension: scientific Singleton JR. The diagnostic utility of Sudoscan meta-analysis.Ann Intern Med2014;161:639–649 statement of the American Autonomic Society, for distal symmetric peripheral neuropathy. J 146. Ziegler D, Fonseca V. From guideline to European Federation of Autonomic Societies, Diabetes Complications 2014;28:511–516 patient: a review of recent recommendations and the European Society of Hypertension. J 135. Diabetes Control and Complications Trial for pharmacotherapy of painful diabetic neu- Hypertens 2019;37:1541–1546 (DCCT) Research Group. Effect of intensive di- ropathy. J Diabetes Complications 2015;29: 162. Camilleri M, Parkman HP, Shafi MA, Abell TL, abetes treatment on nerve conduction in the 146–156 Gerson L; American College of Gastroenterology. care.diabetesjournals.org Microvascular Complications and Foot Care S151

Clinical guideline: management of gastroparesis. 172. BoultonAJM, ArmstrongDG, AlbertSF, etal.; oxygen therapy for chronic wounds. Cochrane Am J Gastroenterol 2013;108:18–37 American Diabetes Association; American Associ- Database Syst Rev 20156:CD004123 163. Parrish CR, Pastors JG. Nutritional manage- ation of Clinical Endocrinologists. Comprehensive 181. Londahl¨ M, Katzman P, Nilsson A, ment of gastroparesis in people with diabetes. foot examination and risk assessment: a report of Hammarlund C. Hyperbaric oxygen therapy fa- Diabetes Spectr 2007;20:231–234 the task force of the foot care interest group of the cilitates healing of chronic foot ulcers in pa- 164. Parkman HP, Yates KP, Hasler WL, et al.; AmericanDiabetesAssociation,withendorsement tients with diabetes. Diabetes Care 2010;33: NIDDK Gastroparesis Clinical Research Consor- by the American Association of Clinical Endocri- 998–1003 tium. Dietary intake and nutritional deficiencies nologists. Diabetes Care 2008;31:1679–1685 182. Fedorko L, Bowen JM, Jones W, et al. in patients with diabetic or idiopathic gastro- 173. Hingorani A, LaMuraglia GM, Henke P, et al. Hyperbaric oxygen therapy does not reduce paresis. Gastroenterology 2011;141:486–498, The management of diabetic foot: a clinical prac- indications for amputation in patients with di- 498.e1–498.e7 ticeguidelinebytheSocietyforVascularSurgeryin abetes with nonhealing ulcers of the lower 165. Olausson EA, Storsrud¨ S, Grundin H, collaboration withthe American Podiatric Medical limb: a prospective, double-blind, randomized Isaksson M, Attvall S, Simren´ M. A small particle Association and the Society for Vascular Medicine. controlled clinical trial. Diabetes Care 2016;39: size diet reduces upper gastrointestinal symp- J Vasc Surg 2016;63(Suppl.):3S–21S 392–399 toms in patients with diabetic gastroparesis: 174. Litzelman DK, Slemenda CW, Langefeld CD, 183. Li G, Hopkins RB, Levine MAH, et al. arandomized controlledtrial.Am JGastroenterol et al. Reduction of lower extremity clinical Relationship between hyperbaric oxygen ther- 2014;109:375–385 abnormalities in patients with non-insulin- apy and quality of life in participants with 166. Umpierrez GE, Ed. Therapy for Diabetes dependent diabetes mellitus. A randomized, chronic diabetic foot ulcers: data from a ran- Mellitus and RelatedDisorders. 6thed. Alexandria, controlled trial. Ann Intern Med 1993;119:36–41 domized controlled trial. Acta Diabetol 2017; VA, American Diabetes Association, 2014 175. IWGDF. IWGDF Guidelines on the pre- 54:823–831 167. Sugumar A, Singh A, Pasricha PJ. A system- vention and management of diabetic foot 184. Boulton AJM. The Diabetic Foot, 2000. atic review of the efficacy of domperidone for the disease. Accessed 12 September 2019. Available South Dartmouth, MA, MDText.com, Inc.Ac- treatment of diabetic gastroparesis. Clin Gastro- from https://iwgdfguidelines.org/wp-content/ cessed 4 November 2019. Available from enterol Hepatol 2008;6:726–733 uploads/2019/05/IWGDF-Guidelines-2019.pdf http://www.ncbi.nlm.nih.gov/books/NBK409609/ 168. Maganti K, Onyemere K, Jones MP. Oral 176. Bonner T, Foster M, Spears-Lanoix E. Type 185. HyperbaricAssociation Oxygen Therapy for the Treat- erythromycin and symptomatic relief of gastro- 2 diabetes-related foot care knowledge and foot ment of Diabetic Foot Ulcers. A health technol- paresis: a systematic review. Am J Gastroenterol self-care practice interventions in the United ogy assessment. Ont Health Technol Assess Ser 2003;98:259–263 States: a systematic review of the literature. 2017;17:1–142 169. McCallum RW, Snape W, Brody F, Wo J, Diabet Foot Ankle 2016;7:29758 186. Stoekenbroek RM, Santema TB, Koelemay Parkman HP, Nowak T. Gastric electrical stimula- 177. Lipsky BA, Berendt AR, Cornia PB, et al.; MJ, et al. Is additional hyperbaric oxygen tion with Enterra therapy improves symptoms Infectious Diseases Society of America. 2012 therapy cost-effective for treating ische- from diabetic gastroparesis in a prospective study. Infectious Diseases Society of America clinical mic diabetic ulcers? Study protocol for the Dutch Clin Gastroenterol Hepatol 2010;8:947–954 practice guideline for the diagnosis and treat- DAMOCLES multicenter randomized clini- 170. Bus SA, van Deursen RW, Armstrong DG, ment of diabetic foot infections. Clin Infect Dis cal trial. J Diabetes 2015;7:125–132 Lewis JE, Caravaggi CF, Cavanagh PR; Interna- 2012;54:e132–e173 187. Huang ET, Mansouri J, Murad MH, et al.; tional Working Group on the Diabetic Foot. 178. Elraiyah T, Tsapas A, Prutsky G, et al. A UHMS CPG Oversight Committee. A clinical Footwear and offloading interventions to pre- systematic review and meta-analysis of adjunc- practice guideline for the use of hyperbaric vent and heal foot ulcers and reduce plantar tive therapies in diabeticDiabetes foot ulcers. J Vasc Surg oxygen therapy in the treatment of diabetic pressure in patients with diabetes: a systematic 2016;63(2 Suppl.):46S–58S.e1–2 foot ulcers. Undersea Hyperb Med 2015;42: review. Diabetes Metab Res Rev 2016;32(Suppl. 179. Game FL, Apelqvist J, Attinger C, et al.; 205–247 1):99–118 International Working Group on the Diabetic 188. Vassalotti JA, Centor R, Turner BJ, Greer 171. Ulbrecht JS, Hurley T, Mauger DT, Cavanaugh Foot. Effectiveness of interventions to enhance RC, Choi M, Sequist TD; National Kidney Foun- PR. Prevention of recurrent foot ulcers with healing of chronic ulcers of the foot in diabetes: dation Kidney Disease Outcomes Quality Ini- plantar pressure–based in-shoe orthoses: the a systematic review. Diabetes Metab Res Rev tiative. Practical approachtodetectionand CareFUL Prevention multicenter randomized 2016;32(Suppl. 1):154–168 management of chronic kidney disease for controlled trial. Diabetes Care 2014;37:1982– 180. Kranke P, Bennett MH, Martyn-St James M, the primary care clinician. Am J Med 2016; 1989 Schnabel A, Debus SE, Weibel S. Hyperbaric 129:153–162.e7 American

12. Older Adults: Standards of American Diabetes Association Medical Care in Diabetesd2020

Diabetes Care 2020;43(Suppl. 1):S152–S162 | https://doi.org/10.2337/dc20-S012

12. OLDER ADULTS are invited to do so at professional.diabetes.org/SOC. Diabetes Recommendations 12.1 Consider the assessment of medical, psychological, functional (self- management abilities), and social geriatric domains in older adults to provide a framework to determine targets and therapeutic approaches for diabetes management. B 12.2 Screen for geriatric syndromes (i.e., polypharmacy, cognitive impairment, depression, urinary incontinence, falls, and persistent pain) in older adults as they may affect diabetes self-management and diminish quality of life. B

Diabetes is an importantAmerican health condition for the aging population. Approximately one-quarter of people over the age of 65 years have diabetes and one-half of older adults have prediabetes (1), and the number of older adults living with these conditions is expected to increase rapidly in the coming decades. Dia- betes management in older adults requires regular assessment of medical, psychological, functional, and social domains. Older adults with diabetes have higher rates of premature death, functional disability, accelerated muscle loss, and coexisting illnesses, such as hypertension, coronary heart disease, and stroke, than those without©2019 diabetes. Screening for diabetes complications in older adults should be individualized and periodically revisited, as the results of screening tests may impact Suggested citation: American Diabetes Associa- targets and therapeutic approaches (2–4). At the same time, older adults with tion. 12. Older adults: Standards of Medical Care diabetes also are at greater risk than other older adults for several common in Diabetesd2020. Diabetes Care 2020;43(Suppl. geriatric syndromes, such as polypharmacy, cognitive impairment, depression, 1):S152-S162 urinary incontinence, injurious falls, and persistent pain (5). These conditions © 2019 by the American Diabetes Association. may impact older adults’ diabetes self-management abilities and quality of life if Readers may use this article as long as the work “ is properly cited, the use is educational and not left unaddressed (2,6,7). See Section 4 Comprehensive Medical Evaluation and for proﬁt, and the work is not altered. More infor- Assessment of Comorbidities” (https://doi.org/10.2337/dc20-S004) for comorbid- mation is available at http://www.diabetesjournals ities to consider when caring for older adults with diabetes. .org/content/license. care.diabetesjournals.org Older Adults S153

The comprehensive assessment de- cognitive function or in preventing cog- referral to a behavioral health provider scribed above may provide a framework nitive decline (17). Pilot studies in pa- for formal cognitive/neuropsychological to determine targets and therapeutic tients with mild cognitive impairment evaluation (28). approaches (8–10), including whether evaluating the potential benefits of referral for diabetes self-management intranasal insulin therapy and metfor- education is appropriate (when compli- min therapy provide insights for future HYPOGLYCEMIA cating factors arise or when transitions in clinical trials and mechanistic studies Recommendation care occur) or whether the current reg- (18–20). 12.4 Hypoglycemiashouldbeavoided imen is too complex for the patient’s Despite the paucity of therapies to in older adults with diabetes. It self-management ability or the care- prevent or remedy cognitive decline, shouldbeassessedandmanaged givers providing care. Particular atten- identifying cognitive impairment early by adjusting glycemic targets and tion should be paid to complications has important implications for diabe- pharmacologic regimens. B that can develop over short periods of tes care. The presence of cognitive im- time and/or would significantly impair pairment can make it challenging for functional status, such as visual and clinicians to help their patients reach Older adults are at higher risk of hypo- lower-extremity complications. Please individualized glycemic, blood pressure, glycemia for many reasons, including refer to the American Diabetes Associ- and lipid targets. Cognitive dysfunction insulin deficiency necessitating insulin ation (ADA) consensus report “Diabetes makes it difficult for patients to perform therapy and progressive renal insuffi- in Older Adults” for details (2). complex self-care tasks (21), such as ciency (29). As described above, older monitoring glucose and adjusting insu- adults have higher rates of unidentified lin doses. It also hinders their ability cognitiveAssociation impairment and dementia NEUROCOGNITIVE FUNCTION to appropriately maintain the timing leading to difficulties in adhering to Recommendation of meals and content of diet. When complex self-care activities (e.g., glu- 12.3 Screening for early detection of clinicians are managing patients with cose monitoring, insulin dose ad- mild cognitive impairment or cognitive dysfunction, it is critical to justment, etc.). Cognitive decline has dementia should be performed simplify drug regimens and to facilitate been associated with increased risk of for adults 65 years of age or and engage the appropriate support hypoglycemia and, conversely, severe older at the initial visit and structure to assist the patient in all hypoglycemia has been linked to annually as appropriate. B aspects of care. increased risk of dementia (30,31). Older adults with diabetes should be Therefore, as discussed under recom- Older adults with diabetes are at carefully screened and monitored for mendation 12.3, it is important to rou- higher risk of cognitive decline and in- cognitive impairmentDiabetes (2) (see Table 4.1 tinely screen older adults for cognitive stitutionalization (11,12). The presen- for cognitive screening recommenda- impairment and dementia and discuss tation of cognitive impairment ranges tions). Several simple assessment tools findings with the patients and their from subtle executive dysfunction to are available to screen for cognitive caregivers. memory loss and overt dementia. Peo- impairment (22,23), such as the Mini- Patients should be monitored for hy- ple with diabetes have higher incidences Mental State Examination (24), Mini-Cog poglycemia; glycemic targets and phar- of all-cause dementia, Alzheimer disease, (25), and the Montreal Cognitive Assess- macologic regimens may need to be and vascular dementia than people with ment (26), which may help to identify adjusted to minimize the occurrence normal glucose tolerance (13). The ef- patients requiring neuropsychological of hypoglycemic events (2). Of note, it fects of hyperglycemia and hyperinsuli- evaluation, particularly those in whom is important to prevent hypoglycemia nemia on the brain are areas of intense dementia is suspected (i.e., experiencing to reduce the risk of cognitive decline research. Poor glycemic controlAmerican is asso- memory loss and decline in their basic (30) and other major adverse outcomes ciated witha declinein cognitivefunction and instrumental activities of daily liv- (32). Intensive glucose control in the (14), and longer duration of diabetes is ing). Annual screening is indicated for Action to Control Cardiovascular Risk associated with worsening cognitive adults 65 years of age or older for early in Diabetes-Memory in Diabetes study function. There are ongoing studies eval- detection of mild cognitive impairment (ACCORD-MIND) was not found to ben- uating whether preventing or delaying or dementia (4,27). Screening for cogni- efit brain structure or cognitive function diabetes onset may help to maintain tive impairment should additionally be during follow-up (15). In the Diabetes cognitive function in older adults. How- considered when a patient presents Control and Complications Trial (DCCT), ever,©2019 studies examining the effects of with a significant decline in clinical status no significant long-term declines in cog- intensive glycemic and blood pressure due to increased problems with self-care nitive function were observed, despite control to achieve specific targets have activities, such as errors in calculating participants’ relatively high rates of re- not demonstrated a reduction in brain insulin dose, difficulty counting carbohy- current severe hypoglycemia (33). To function decline (15,16). drates, skipped meals, skipped insulin achieve the appropriate balance be- Clinical trials of specific interventionsd doses, and difficulty recognizing, pre- tween glycemic control and risk for hy- including cholinesterase inhibitors and venting, or treating hypoglycemia. Peo- poglycemia, it is important to carefully glutamatergic antagonistsdhave not ple who screen positive for cognitive assess and reassess patients’ risk for shown positive therapeutic benefitin impairment should receive diagnostic worsening of glycemic control and func- maintaining or significantly improving assessment as appropriate, including tional decline. S154 Older Adults Diabetes Care Volume 43, Supplement 1, January 2020

TREATMENT GOALS with diabetes have little comorbidity a patient needs a referral for cognitive and are active. Life expectancies are and physical functional assessment, us- Recommendations highly variable but are often longer ing age-normalized evaluation tools, as 12.5 Older adults who are otherwise than clinicians realize. Providers caring well as help establishing a support struc- healthy with few coexisting for older adults with diabetes must take ture for diabetes care (3,28). chronic illnesses and intact cog- this heterogeneity into consideration nitive function and functional when setting and prioritizing treatment Patients With Complications and status should have lower glyce- goals (9,10) (Table 12.1). In addition, Reduced Functionality , mic goals (such as A1C 7.5% older adults with diabetes should be For patients with advanced diabetes [58 mmol/mol]), while those assessed for disease treatment and complications, life-limiting comorbid ill- with multiple coexisting chronic self-management knowledge, health nesses, or substantial cognitive or func- illnesses, cognitive impairment, literacy, and mathematical literacy (nu- tional impairments, it is reasonable to set or functional dependence should meracy) at the onset of treatment. See less intensive glycemic goals (Table 12.1). have less-stringent glycemic Fig. 6.2 for patient- and disease-related Factors to consider in individualizing , – goals (such as A1C 8.0 8.5% factors to consider when determining glycemic goals are outlined in Fig. 6.2. – C [64 69 mmol/mol]). individualized glycemic targets. These patients are less likely to benefit 12.6 Glycemic goals for some older A1C is used as the standard biomarker from reducing the risk of microvascular adults might reasonably be re- for glycemic control in all patients with complications and more likely to suffer laxed as part of individualized diabetes but may have limitations in serious adverse effects from hypoglyce- care, but hyperglycemia lead- patients who have medical conditions mia. However, patients with poorly con- ing to symptoms or risk of that impact red blood cell turnover (see trolledAssociation diabetes may be subject to acute acute hyperglycemia compli- Section 2 “Classification and Diagnosis of complications of diabetes, including cations should be avoided in Diabetes” https://doi.org/10.2337/dc20- dehydration, poor wound healing, and C all patients. S002, for additional details on the limi- hyperglycemic hyperosmolar coma. Gly- 12.7 Screening for diabetes compli- tations of A1C) (37). Many conditions cemic goals should, at a minimum, avoid cations should be individualized associated with increased red blood cell these consequences. in older adults. Particular atten- turnover, such as hemodialysis, recent tion should be paid to compli- blood loss or transfusion, or erythropoi- Vulnerable Patients at the End of Life cations that would lead to etin therapy, are commonly seen in older For patients receiving palliative care and C functional impairment. adults with functional limitations and end-of-life care, the focus should be to 12.8 Treatment of hypertension to can falsely increase or decrease A1C. In reduce the burdens and avoid the side individualized target levels is these instances,Diabetes plasma blood glucose effects of glycemic management. Thus, C indicated in most older adults. and fingerstick readings should be used when organ failure develops, several agents 12.9 Treatment of other cardiovas- for goal setting (Table 12.1). will have to be deintensified or discontin- cular risk factors should be ued. For the dying patient, most agents individualized in older adults Healthy Patients With Good for type 2 diabetes may be removed (38). considering the time frame of Functional Status There is, however, no consensus for the fi bene t. Lipid-lowering therapy There are few long-term studies in older management of type 1 diabetes in this fi and aspirin therapy may bene t adults demonstrating the benefits of in- scenario (39). See END-OF-LIFE CARE, below, those with life expectancies at tensive glycemic, blood pressure, and for additional information. least equal to the time frame of lipid control. Patients who can be ex- primary prevention or second- pected to live long enough to reap the Beyond Glycemic Control ary intervention trials.AmericanE benefits of long-term intensive diabetes Although hyperglycemia control may be management, who have good cognitive important in older individuals with dia- The care of older adults with diabetes is and physical function, and who choose to betes, greater reductions inmorbidityand complicated by their clinical, cognitive, do so via shared decision-making may be mortality are likely to result from control and functional heterogeneity. Some treated using therapeutic interventions of other cardiovascular risk factors rather older individuals may have developed and goals similar to those for younger than from tight glycemic control alone. diabetes years earlier and have signifi- adults with diabetes (Table 12.1). Thereisstrongevidencefromclinicaltrials cant complications, others are newly As with all patients with diabetes, di- of the value of treating hypertension in diagnosed©2019 and may have had years of abetes self-management education and older adults (40,41), with treatment of undiagnosed diabetes with resultant ongoing diabetes self-management sup- hypertension to individualized target lev- complications, and still other older adults portare vitalcomponents ofdiabetes care els indicated in most. There is less evi- may have truly recent-onset disease with for older adults and their caregivers. Self- dence for lipid-lowering therapy and few or no complications (34). Some older management knowledge and skills should aspirin therapy, although the benefits adults with diabetes have other under- be reassessed when regimen changes are of these interventions for primary pre- lying chronic conditions, substantial made or an individual’s functional abili- vention and secondary intervention are diabetes-related comorbidity, limited ties diminish. In addition, declining or likely to apply to older adults whose life cognitive or physical functioning, or impaired ability to perform diabetes self- expectancies equal or exceed the time frailty (35,36). Other older individuals care behaviors may be an indication that frames of the clinical trials. care.diabetesjournals.org Older Adults S155

Table 12.1—Framework for considering treatment goals for glycemia, blood pressure, and dyslipidemia in older adults with diabetes Patient Fasting or characteristics/ Reasonable preprandial Blood health status Rationale A1C goal‡ glucose Bedtime glucose pressure Lipids Healthy (few Longer remaining life ,7.5% 90–130 mg/dL 90–150 mg/dL ,140/90 mmHg Statin unless coexisting chronic expectancy (58 mmol/mol) (5.0–7.2 mmol/L) (5.0–8.3 contraindicated illnesses, intact mmol/L) or not tolerated cognitive and functional status) Complex/ Intermediate ,8.0% 90–150 mg/dL 100–180 mg/dL ,140/90 mmHg Statin unless intermediate remaining life (64 mmol/mol) (5.0–8.3 mmol/L) (5.6–10.0 contraindicated (multiple expectancy, high mmol/L) or not tolerated coexisting chronic treatment burden, illnesses* or 21 hypoglycemia instrumental ADL vulnerability, impairments or fall risk mild-to-moderate cognitive impairment) Very complex/poor Limited remaining life ,8.5%† 100–180 mg/dL 110–200 mg/dL ,150/90 mmHg Consider health (LTC or end- expectancy makes (69 mmol/mol) (5.6–10.0 (6.1–11.1 likelihood of stage chronic benefit uncertain mmol/L) mmol/L) Associationbenefit with illnesses** or statin moderate-to- (secondary severe cognitive prevention impairment or 21 more so than ADL dependencies) primary) This table represents a consensus framework for considering treatment goals for glycemia, blood pressure, and dyslipidemia in older adults with diabetes. The patient characteristic categories are general concepts. Not every patient will clearly fall into a particular category. Consideration of patient and caregiver preferences is an important aspect of treatment individualization. Additionally, a patient’s health status and preferences may change over time. ADL, activities of daily living; LTC, long-term care. ‡A lower A1C goal may be set for an individual if achievable without recurrent or severe hypoglycemia or undue treatment burden. *Coexisting chronic illnesses are conditions serious enough to require medications or lifestyle management and may include arthritis, cancer, congestive heart failure, depression, emphysema, falls, hypertension, incontinence, stage 3 or worse chronicDiabetes kidney disease, myocardial infarction, and stroke. “Multiple” meansatleastthree,butmanypatientsmayhavefive or more (54). **The presence of a single end-stage chronic illness, such as stage 3–4 congestive heart failure or oxygen-dependent lung disease, chronic kidney disease requiring dialysis, or uncontrolled metastatic cancer, may cause significant symptoms or impairment of functional status and significantly reduce life expectancy. †A1C of 8.5% (69 mmol/mol) equates to an estimated average glucose of ;200 mg/dL (11.1 mmol/L). Looser A1C targets above 8.5% (69 mmol/mol) are not recommended, as they may expose patients to more frequent higher glucose values and acute risks from glycosuria, dehydration, hyperglycemic hyperosmolar syndrome, and poor wound healing. Adapted from Kirkman et al. (2).

LIFESTYLE MANAGEMENT functional, or psychosocial stressors. 12.13 Deintensification (or simplifi- Inadequate nutritional intake, partic- Recommendation cation) of complex regimens ularly inadequate protein intake, can 12.10 Optimal nutrition and protein is recommended to reduce increase the risk of sarcopenia and intake is recommendedAmerican for the risk of hypoglycemia and frailty in older adults. Management of older adults; regular exercise, polypharmacy, if it can be frailty in diabetes includes optimal including aerobic activity and achieved within the individu- nutrition with adequate protein intake resistance training, should be alized A1C target. B combined with an exercise program that encouraged in all older adults 12.14 Consider costs of care and in- includes aerobic and resistance training who can safely engage in such surance coverage rules when (44,45). activities. B developing treatment plans in PHARMACOLOGIC THERAPY order to reduce risk of cost- ©2019 related nonadherence. B Diabetes in the aging population is asso- Recommendations ciated with reduced muscle strength, 12.11 In older adults with type 2 poor muscle quality, and accelerated Special care is required in prescribing diabetes at increased risk loss of muscle mass, resulting in sarco- and monitoring pharmacologic thera- of hypoglycemia, medication penia (42,43). Diabetes is also recog- pies in older adults (46). See Fig. 9.1 classes with low risk of hypo- nized as an independent risk factor for for general recommendations regard- glycemia are preferred. B frailty. Frailty is characterized by decline ing glucose-lowering treatment for adults 12.12 Overtreatment of diabetes is in physical performance and an in- with type 2 diabetes and Table 9.1 for common in older adults and creased risk of poor health outcomes patient- and drug-specificfactorsto should be avoided. B due to physiologic vulnerability to clinical, consider when selecting glucose-lowering S156 Older Adults Diabetes Care Volume 43, Supplement 1, January 2020

agents. Cost may be an important con- may impair their ability to follow their the dose of insulin may not be ade- sideration, especially as older adults regimen safely. Individualized glycemic quate (55). Simplification of the insulin tend to be on many medications and goals should be established (Fig. 6.3)and regimen to match an individual’sself- live on fixed incomes (47). Accordingly, periodically adjusted based on coexist- management abilities and their avail- the costs of care and insurance coverage ing chronic illnesses, cognitive function, able social and medical support in these rules should be considered when devel- and functional status (2). Tight glycemic situations has been shown to reduce oping treatment plans to reduce the risk control in older adults with multiple hypoglycemia and disease-related dis- of cost-related nonadherence (48,49). medical conditions is considered over- tress without worsening glycemic con- See Tables 9.2 and 9.3 for median treatment and is associated with an trol (56–58). Fig. 12.1 depicts an monthly cost in the U.S. of noninsulin increased risk of hypoglycemia; unfor- algorithm that can be used to simplify glucose-lowering agents and insulin, re- tunately, overtreatment is common in the insulin regimen (56). There are spectively. It is important to match com- clinical practice (50–54). Deintensifica- now multiple studies evaluating de- plexity of the treatment regimen to the tion of regimens in patients taking non- intensification protocols; in general, self-management ability of older pa- insulin glucose-lowering medications the studies demonstrate that de- tients and their available social and can be achieved by either lowering intensification is safe and possibly medical support. Many older adults the dose or discontinuing some medi- beneficial for older adults (59). Table with diabetes struggle to maintain the cations, so long as the individualized 12.2 provides examples of and rationale frequent blood glucose testing and insu- glycemic target is maintained. When pa- for situations where deintensification lin injection regimens they previously fol- tients are found to have an insulin and/or insulin regimen simplifica- lowed, perhaps for many decades, as regimen with complexity beyond their tion may be appropriate in older they develop medical conditions that self-management abilities, lowering adults.Association

Diabetes

American

Figure 12.1—Algorithm to simplify insulin regimen for older patients with type 2 diabetes. eGFR, estimated glomerular ﬁltration rate. *Basal insulins: glargine U-100 and U-300, detemir, degludec, and human NPH. **See Table 12.1. UMealtime insulins: short-acting (regular human insulin) or rapid- acting (lispro, aspart, and glulisine). §Premixed insulins: 70/30, 75/25, and 50/50 products. Adapted with permission from Munshi and colleagues (56,82,83). care.diabetesjournals.org Older Adults S157

Table 12.2—Considerations for treatment regimen simplification and deintensification/deprescribing in older adults with diabetes (56,82) Patient When may treatment characteristics/health Reasonable A1C/ When may regimen deintensification/ status treatment goal Rationale/considerations simplification be required? deprescribing be required? Healthy (few A1C ,7.5% c Patients can generally c If severe or recurrent c If severe or recurrent coexisting chronic (58 mmol/mol) perform complex tasks to hypoglycemia occurs in hypoglycemia occurs in illnesses, intact maintain good glycemic patients on insulin therapy patients on noninsulin cognitive and control when health is stable (even if A1C is appropriate) therapies with high risk functional status) c During acute illness, patients c If wide glucose excursions of hypoglycemia (even if may be more at risk for are observed A1C is appropriate) administration or dosing c If cognitive or functional c If wideglucoseexcursions errors that can result in decline occurs following are observed hypoglycemia, falls, fractures, acute illness c In the presence of etc. polypharmacy Complex/ A1C ,8.0% c Comorbidities may affect self- c If severe or recurrent c If severe or recurrent intermediate (64 mmol/mol) management abilities and hypoglycemia occurs in hypoglycemia occurs in (multiple coexisting capacity to avoid patients on insulin therapy patients on noninsulin chronic illnesses or hypoglycemia (even if A1C is appropriate) therapies with high risk 21 instrumental c Long-acting medication c If unable to manage of hypoglycemia (even if ADL impairments or formulations may decrease complexity of an insulin A1C is appropriate) mild-to-moderate pill burden and complexity of regimen c If wideglucoseexcursions cognitive medication regimen c If there is a significantAssociationare observed impairment) change in social c In the presence of circumstances, such as loss polypharmacy of caregiver, change in living situation, or financial difficulties Community-dwelling Avoid reliance c Glycemic control is important c If treatment regimen c If the hospitalization for patients receiving on A1C for recovery, wound healing, increased in complexity acute illness resulted in care in a skilled hydration, and avoidance of during hospitalization, it is weight loss, anorexia, nursing facility for infections reasonable, in many cases, short-term cognitive short-term Glucose target: c Patients recovering from to reinstate the decline, and/or loss of rehabilitation 100–200 mg/dL illness may not have returned prehospitalization physical functioning (5.55–11.1 mmol/L) to baseline cognitiveDiabetes function medication regimen during at the time of discharge the rehabilitation c Consider the type of support the patient will receive at home Very complex/poor A1C ,8.5% c No benefits of tight glycemic c If on an insulin regimen and c If on noninsulin agents health (long-term (69 mmol/)† control in this population the patient would like to with a high hypoglycemia care or end-stage c Hypoglycemia should be decrease the number of risk in the context of chronic illnesses or avoided injections and fingerstick cognitive dysfunction, moderate-to- c Most important outcomes are blood glucose monitoring depression, anorexia, or severe cognitive maintenance of cognitive and events each day inconsistent eating impairment or 21 functional status c If the patient has an pattern ADL dependencies) American inconsistent eating pattern c If taking any medications without clear benefits Patients at end of life Avoid hypoglycemia c Goal is to provide comfort and c If there is pain or c If taking any medications and symptomatic avoid tasks or interventions discomfort caused by without clear benefits in hyperglycemia that cause pain or discomfort treatment (e.g., injections improving symptoms c Caregivers are important in or fingersticks) and/or comfort providing medical care and c If there is excessive maintaining quality of life caregiver stress due to treatment complexity Treatment©2019 regimen simplification refers to changing strategy to decrease the complexity of a medication regimen, e.g., fewer administration times, fewer fingerstick readings, decreasing the need for calculations (such as sliding scale insulin calculations or insulin-carbohydrate ratio calculations). Deintensification/deprescribing refers to decreasing the dose or frequency of administration of a treatment or discontinuing a treatment altogether. ADL, activities of daily living. †Consider adjustment of A1C goal if the patient has a condition that may interfere with erythrocyte life span/turnover.

Metformin glomerular filtration rate $30 mL/min/ hepatic function or congestive heart fail- Metformin is the first-line agent for older 1.73 m2 (60). However, it is contra- ure because of the increased risk of lactic adults with type 2 diabetes. Recent indicated in patients with advanced acidosis. Metformin may be temporarily studies have indicated that it may be renal insufficiency and should be used discontinued before procedures, during used safely in patients with estimated with caution in patients with impaired hospitalizations, and when acute illness S158 Older Adults Diabetes Care Volume 43, Supplement 1, January 2020

may compromise renal or liver function. be convenient for older adults with their own medications, whereas those Additionally, metformin can cause gas- diabetes. In patients with established living in a nursing home (community trointestinal side effects and a reduc- atherosclerotic cardiovascular disease, living centers) may rely completely on tion in appetite that can be problematic these agents have shown cardiovascular the care plan and nursing support. for some older adults. Reduction or benefits (64). This class of agents has also Those receiving palliative care (with or elimination of metformin may be nec- been found to be beneficial for patients without hospice) may require an ap- essaryforpatientsexperiencinggas- with heart failure and to slow the pro- proach that emphasizes comfort and trointestinal side effects. gression of chronic kidney disease. See symptom management, while de- Section 9 “Pharmacologic Approaches emphasizing strict metabolic and blood Thiazolidinediones to Glycemic Treatment” (https://doi.org/ pressure control. Thiazolidinediones, if used at all, should 10.2337/dc20-S009) for a more extensive be used very cautiously in those with, or discussion regarding the indications for SPECIAL CONSIDERATIONS at risk for, congestive heart failure, os- this class of agents. While understand- FOR OLDER ADULTS WITH teoporosis, falls or fractures, and/or mac- ing of the clinical benefits of this class is TYPE 1 DIABETES ular edema (61,62). evolving, side effects such as volume Dueinparttothesuccessofmodern Insulin Secretagogues depletion may be more common among diabetes management, patients with Sulfonylureas and other insulin secreta- older patients. type 1 diabetes are living longer and gogues are associated with hypoglyce- the population of these patients over mia and should be used with caution. If Insulin Therapy 65 years of age is growing (65–67). Many The use of insulin therapy requires that used, sulfonylureas with a shorter dura- of the recommendations in this section patients or their caregivers have good tion of action, such as glipizide or glime- regarding a comprehensive geriatric as- visual and motor skills and cognitive Association piride, are preferred. Glyburide is a sessment and personalization of goals ability. Insulin therapy relies on the longer-acting sulfonylurea and should and treatments are directly applicable ability of the older patient to admin- be avoided in older adults (63). to older adults with type 1 diabetes; ister insulin on their own or with the however, this population has unique Incretin-Based Therapies assistance of a caregiver. Insulin doses challenges and requires distinct treat- Oral dipeptidyl peptidase 4 (DPP-4) inhib- should be titrated to meet individu- ment considerations (68). Insulin is an itors have few side effects and minimal alized glycemic targets and to avoid essential life-preserving therapy for pa- risk of hypoglycemia, but their cost may hypoglycemia. tients with type 1 diabetes, unlike for be a barrier to some older patients. DPP-4 Once-daily basal insulin injection ther- those with type 2 diabetes. In order inhibitors do not increase major adverse apy is associated with minimal side ef- to avoid diabetic ketoacidosis, older cardiovascular outcomes (64). fects and may beDiabetes a reasonable option in adults with type 1 diabetes need some Glucagon-like peptide 1 (GLP-1) re- many older patients. Multiple daily inform of basal insulin even when they are ceptor agonists have demonstrated jections of insulin may be too complex unable to ingest meals. Insulin may be cardiovascular benefits among patients for the older patient with advanced di- delivered through insulin pump or injec- with established atherosclerotic car- abetes complications, life-limiting co- tions. Continuous glucose monitoring diovascular disease, and newer trials existing chronic illnesses, or limited (CGM) is approved for use by Medicare Fig. 12.1 are expanding our understanding of functional status. provides a and can play a critical role in improving their benefits in other populations potential approach to insulin regimen A1C, reducing glycemic variability, and fi (64). See Section 9 “Pharmacologic simpli cation. reducing risk of hypoglycemia (69) (see Approaches to Glycemic Treatment” Section 7 “Diabetes Technology,” (https://doi.org/10.2337/dc20-S009) Other Factors to Consider https://doi.org/10.2337/dc20-S007, for a more extensive discussionAmerican regarding The needs of older adults with diabetes and section 9 “Pharmacologic Approaches thespecificindicationsforthisclass.While and their caregivers should be evaluated to Glycemic Treatment,” https://doi.org/ the benefits of this class are emerging, to construct a tailored care plan. Im- 10.2337/dc20-S009). In the older patient thesedrugsareinjectableagents(withthe paired social functioning may reduce with type 1 diabetes, administration of exception of oral semaglutide), which these patients’ quality of life and increase insulin may become more difficult as require visual, motor, and cognitive skills the risk of functional dependency (7). The complications, cognitive impairment, for appropriate administration. They may patient’s living situation must be consid- and functional impairment arise. This also be associated with nausea, vomiting, ered as it may affect diabetes manage- increases the importance of caregivers and©2019 diarrhea. Given the gastrointestinal ment and support needs. Social and in the lives of these patients. Many older side effects of this class, GLP-1 receptor instrumental support networks (e.g., patients with type 1 diabetes require agonists may not be preferred in older adult children, caretakers) that pro- placementin long-termcare(LTC)settings patients who are experiencing unex- vide instrumental or emotional sup- (i.e., nursing homes and skilled nursing plained weight loss. port for older adults with diabetes facilities) and, unfortunately, these pa- should be included in diabetes manage- tients encounter providers that are un- Sodium–Glucose Cotransporter ment discussions and shared decision- familiar with insulin pumps or CGM. Some 2 Inhibitors making. providers may be unaware of the distinc- Sodium–glucose cotransporter 2 inhibi- Older adults in assisted living facilities tion between type 1 and type 2 diabetes. In tors are administered orally, which may may not have support to administer these instances, the patient or the patient’s care.diabetesjournals.org Older Adults S159

family may be more familiar with di- inadvertently lead to decreased food (16.7 mmol/L) over 2 consecutive abetes management than the providers. intake and contribute to unintentional days, Education of relevant support staff and weight loss and undernutrition. Diets d) any reading is too high for the providers in rehabilitation and LTC set- tailored to a patient’s culture, preferen- glucometer, or tings regarding insulin dosing and use of ces, and personal goals may increase e) the patient is sick, with vomiting, pumps and CGM is recommended as quality of life, satisfaction with meals, symptomatic hyperglycemia, or part of general diabetes education (see and nutrition status (72). It may be help- poor oral intake. recommendations 12.15 and 12.16). ful to give insulin after meals to ensure that the dose is appropriate for the END-OF-LIFE CARE TREATMENT IN SKILLED NURSING amount of carbohydrate the patient Recommendations FACILITIES AND NURSING HOMES consumed in the meal. 12.17 When palliative care is needed Recommendations in older adults with diabetes, 12.15 Consider diabetes education Hypoglycemia providers should initiate con- for the staff of long-term care Older adults with diabetes in LTC are versations regarding the goals and rehabilitation facilities especially vulnerable to hypoglycemia. and intensity of care. Strict to improve the management They have a disproportionately high glucose and blood pressure of older adults with diabetes. number of clinical complications and control may not be necessary E comorbidities that can increase hypogly- E, and reduction of therapy 12.16 Patients with diabetes residing cemia risk: impaired cognitive and renal may be appropriate. Similarly, in long-term care facilities function, slowed hormonal regulation the intensity of lipid manage- need careful assessment to and counterregulation, suboptimal hy- Associationment can be relaxed, and establish individualized glyce- dration, variable appetite and nutri- withdrawal of lipid-lowering mic goals and to make tional intake, polypharmacy, and slowed therapy may be appropriate. A appropriate choices of glucose- intestinal absorption (73). Oral agents 12.18 Overall comfort, prevention loweringagentsbasedontheir may achieve similar glycemic out- of distressing symptoms, and clinical and functional status. E comes in LTC populations as basal insu- preservation of quality of life lin (50,74). and dignity are primary goals Management of diabetes in the LTC Another consideration for the LTC for diabetes management at setting is unique. Individualization of setting is that, unlike in the hospital the end of life. C health care is important in all patients; setting, medical providers are not re- however, practical guidance is needed quired to evaluateDiabetes the patients daily. for medical providers as well as the LTC According to federal guidelines, assess- The management of the older adult staff and caregivers (70). Training should ments should be done at least every at the end of life receiving palliative fi include diabetes detection and institu- 30 days for the rst 90 days after ad- medicine or hospice care is a unique tional quality assessment. LTC facilities mission and then at least once every situation. Overall, palliative medicine should develop their own policies and 60 days. Although in practice the patients promotes comfort, symptom control procedures for prevention and manage- may actually be seen more frequently, and prevention (pain, hypoglycemia, ment of hypoglycemia. the concern is that patients may have hyperglycemia, and dehydration), and uncontrolled glucose levels or wide ex- preservation of dignity and quality of life cursions without the practitioner being in patients with limited life expectancy Resources notified. Providers may make adjust- (71,75). In the setting of palliative care, Staff of LTC facilities should receive ap- ments to treatment regimens by tele- providers should initiate conversations propriate diabetes educationAmerican to improve phone, fax, or in person directly at the regarding the goals and intensity of the management of older adults with LTC facilities provided they are given diabetes care; strict glucose and blood diabetes. Treatments for each patient timely notification of blood glucose man- pressure control may not be consistent should be individualized. Special management issues from a standardized with achieving comfort and quality of agement considerations include the alert system. life. In a multicenter trial, withdrawal of need to avoid both hypoglycemia and The following alert strategy could be statins among patients in palliative care the complications of hyperglycemia considered: has been found to improve quality of (2,71). For more information, see the life, while similar evidence for glucose ADA©2019 position statement “ Management 1. Call provider immediately in cases of and blood pressure control are not yet of Diabetes in Long-term Care and Skilled low blood glucose levels (,70 mg/dL available (76–78). A patient has the Nursing Facilities” (70). [3.9 mmol/L]). right to refuse testing and treatment, 2. Call as soon as possible when whereas providers may consider with- Nutritional Considerations a) glucose values are 70–100 mg/dL drawing treatment and limiting diag- An older adult residing in an LTC facility (3.9 and 5.6 mmol/L) (regimen nostic testing, including a reduction may have irregular and unpredictable mayneedtobeadjusted), in the frequency of fingerstick testing meal consumption, undernutrition, an- b) glucose values are .250 mg/dL (79,80). Glucose targets should aim orexia, and impaired swallowing. Fur- (13.9 mmol/L) within a 24-h period, to prevent hypoglycemia and hyperglyce- thermore, therapeutic diets may c) glucose values are .300 mg/dL mia. Treatment interventions need to be S160 Older Adults Diabetes Care Volume 43, Supplement 1, January 2020

mindful of quality of life. Careful mon- from https://www.niddk.nih.gov/about-niddk/ MIND randomised trial. Diabetologia 2017;60: itoring of oral intake is warranted. The strategic-plans-reports/diabetes-in-america-3rd- 69–80 decision process may need to involve edition 17. Ghezzi L, Scarpini E, Galimberti D. Disease- 2. Kirkman MS, Briscoe VJ, Clark N, et al. Di- modifying drugs in Alzheimer’s disease. Drug Des the patient, family, and caregivers, abetes in older adults. Diabetes Care 2012;35: Devel Ther 2013;7:1471–1478 leading to a care plan that is both 2650–2664 18. CraftS,Baker LD, MontineTJ,etal. Intranasal convenient and effective for the goals 3. Young-Hyman D, de Groot M, Hill-Briggs F, insulin therapy for Alzheimer disease and am- of care (81). The pharmacologic therapy Gonzalez JS, Hood K, Peyrot M. Psychosocial care nestic mild cognitive impairment: a pilot clinical for people with diabetes: a position statement – may include oral agents as first line, trial. Arch Neurol 2012;69:29 38 of the American Diabetes Association. Diabetes 19. Freiherr J, Hallschmid M, Frey WH 2nd, et al. followed by a simplified insulin regi- Care 2016;39:2126–2140 Intranasal insulin as a treatment for Alzheimer’s men. If needed, basal insulin can be 4. Institute of Medicine of the National Acad- disease: a review of basic research and clinical implemented, accompanied by oral emies. Cognitive Aging: Progress in Understand- evidence. CNS Drugs 2013;27:505–514 agents and without rapid-acting insulin. ing and Opportunities for Action, 2015. Accessed 20. Alagiakrishnan K, Sankaralingam S, Ghosh M, 31 October 2019. Available from http:// Mereu L, Senior P. Antidiabetic drugs and their Agents that can cause gastrointestinal nationalacademies.org/hmd/Reports/2015/ potential role in treating mild cognitive impair- symptoms such as nausea or excess Cognitive-Aging.aspx ment and Alzheimer’s disease. Discov Med 2013; weight loss may not be good choices 5. Kimbro LB, Mangione CM, Steers WN, et al. 16:277–286 in this setting. As symptoms progress, Depression and all-cause mortality in persons 21. Tomlin A, Sinclair A. The influence of cog- some agents may be slowly tapered and with diabetes mellitus: are older adults at higher nition on self-management of type 2 diabetes in risk? Results from the Translating Research Into older people. Psychol Res Behav Manag 2016;9: discontinued. Action for Diabetes Study. J Am Geriatr Soc 2014; 7–20 Different patient categories have been 62:1017–1022 22. National Institute on Aging. Assessing cog- proposed for diabetes management in 6. Sudore RL, Karter AJ, Huang ES, et al. Symp- nitive impairment in older patients. Accessed those with advanced disease (39). tom burden of adults with type 2 diabetes across 27 AugustAssociation 2019. Available from https://www.nia the disease course: diabetes & aging study. J Gen .nih.gov/health/assessing-cognitive-impairment- – A stable patient Intern Med 2012;27:1674 1681 older-patients 1. : Continue with the 7. Laiteerapong N, Karter AJ, Liu JY, et al. Cor- 23. Alzheimer’s Association. Cognitive assess- patient’s previous regimen, with a relates of quality of life in older adults with ment Accessed 27 August 2019. Available focus on the prevention of hypoglyce- diabetes: the Diabetes & Aging Study. Diabetes from https://alz.org/professionals/healthcare- mia and the management of hyper- Care 2011;34:1749–1753 professionals/cognitive-assessment “ glycemia using blood glucose 8. McClintockMK,DaleW,LaumannEO,WaiteL. 24. Folstein MF, Folstein SE, McHugh PR. Mini- Empirical redefinition of comprehensive health mental state”: a practical method for grading the testing, keeping levels below the and well-being in the older adults of the United cognitive state of patients for the clinician. J renal threshold of glucose. There States. Proc Natl Acad Sci U S A 2016;113:E3071– Psychiatr Res 1975;12:189–198 is very little role for A1C monitoring 3080 25. Borson S, ScanlanJM, Chen P, GanguliM.The and lowering. 9. Laiteerapong N, Iveniuk J, John PM, Laumann Mini-Cog as a screen for dementia: validation 2. A patient with organ failure: Prevent- EO, Huang ES. ClassiDiabetesfication of older adults who in a population-based sample. J Am Geriatr Soc have diabetes by comorbid conditions, United 2003;51:1451–1454 ing hypoglycemia is of greater sig- States, 2005–2006. Prev Chronic Dis 2012;9:E100 26. Nasreddine ZS, Phillips NA, Bedirian´ V, nificance. Dehydration must be 10. Blaum C, Cigolle CT, Boyd C, et al. Clinical et al. The Montreal Cognitive Assessment, prevented and treated. In people complexity in middle-aged and older adults with MoCA: a brief screening tool for mild cognitive with type 1 diabetes, insulin admin- diabetes: the Health and Retirement Study. Med impairment. J Am Geriatr Soc 2005;53:695– – istration may be reduced as the oral Care 2010;48:327 334 699 11. Cukierman T, Gerstein HC, Williamson JD. 27. Moreno G, Mangione CM, Kimbro L, intake of food decreases but should Cognitive decline and dementia in diabetesd Vaisberg E; American Geriatrics Society Expert not be stopped. For those with type 2 systematic overview of prospective observational Panel on Care of Older Adults with Diabetes diabetes, agents that may cause hy- studies. Diabetologia 2005;48:2460–2469 Mellitus. Guidelines abstracted from the Amer- poglycemia should be reduced in 12. Roberts RO, Knopman DS, Przybelski SA, ican Geriatrics Society Guidelines for Improving dose. The main goal is to avoid hy- et al. Association of type 2 diabetes with brain the Care of Older Adults with Diabetes Mellitus: Americanatrophy and cognitive impairment. Neurology 2013 update. J Am Geriatr Soc 2013;61:2020– poglycemia, allowing for glucose val- 2014;82:1132–1141 2026 ues in the upper level of the desired 13. Xu WL, von Strauss E, Qiu CX, Winblad B, 28. American Psychological Association. Guide- target range. Fratiglioni L. Uncontrolled diabetes increases lines for the evaluation of dementia and age- 3. A dying patient: For patients with the risk of Alzheimer’s disease: a population- related cognitive change. Accessed 31 October type 2 diabetes, the discontinuation based cohort study. Diabetologia 2009;52: 2019. Available from http://www.apa.org/ 1031–1039 practice/guidelines/dementia.aspx of all medications may be a reason- 14. Yaffe K, Falvey C, Hamilton N, et al. Diabetes, 29. Lee AK, Lee CJ, Huang ES, Sharrett AR, Coresh able approach, aspatients are unlikely glucose control, and 9-year cognitive decline J, Selvin E. Risk factors for severe hypoglycemia in to have any oral intake. In patients among older adults without dementia. Arch black and white adults with diabetes: the Ath- ©2019with type 1 diabetes, there is no Neurol 2012;69:1170–1175 erosclerosis Risk in Communities (ARIC) Study. – consensus, but a small amount of 15. Launer LJ, Miller ME, Williamson JD, et al.; Diabetes Care 2017;40:1661 1667 ACCORD MIND investigators. Effects of intensive 30. Feinkohl I, Aung PP, Keller M, et al.; Edin- basal insulin may maintain glucose glucose lowering on brain structure and func- burgh Type 2 Diabetes Study (ET2DS) Investiga- levels and prevent acute hyperglyce- tion in people with type 2 diabetes (ACCORD tors. Severe hypoglycemia and cognitive decline mic complications. MIND): a randomised open-label substudy. in older people with type 2 diabetes: the Edin- Lancet Neurol 2011;10:969–977 burgh type 2 diabetes study. Diabetes Care 2014; 16. Murray AM, Hsu F-C, Williamson JD, et al.; 37:507–515 References Action to Control Cardiovascular Risk in Diabetes 31. Lee AK, Rawlings AM, Lee CJ, et al. Severe 1. National Institute of Diabetes and Digestive Follow-On Memory in Diabetes (ACCORDION hypoglycaemia, mild cognitive impairment, de- and Kidney Diseases. Diabetes in America, 3rd MIND) Investigators. ACCORDION MIND: results mentia and brain volumes in older adults with edition, 2018. Accessed 27 August 2019. Available of the observational extension of the ACCORD type 2 diabetes: the Atherosclerosis Risk in care.diabetesjournals.org Older Adults S161

Communities (ARIC) cohort study. Diabetologia 48. Schmittdiel JA, Steers N, Duru OK, et al. 63. American Geriatrics Society 2015 Beers 2018;61:1956–1965 Patient-provider communication regarding drug Criteria Update Expert Panel. American Geri- 32. Lee AK, Warren B, Lee CJ, et al. The asso- costs in Medicare Part D beneficiaries with diatrics Society 2015 updated beers criteria for ciation of severe hypoglycemia with incident abetes: a TRIAD Study. BMC Health Serv Res potentially inappropriate medication use in cardiovascular events and mortality in adults 2010;10:164 older adults. J Am Geriatr Soc 2015;63:2227– with type 2 diabetes. Diabetes Care 2018;41: 49. Patel MR, Resnicow K, Lang I, Kraus K, Heisler 2246 104–111 M. Solutions to address diabetes-related finan- 64. Davies MJ, D’Alessio DA, Fradkin J, et al. 33. Jacobson AM, Musen G, Ryan CM, et al.; cial burden and cost-related nonadherence: re- Management of hyperglycemia in type 2 diabe- Diabetes Control and Complications Trial/ sults from a pilot study. Health Educ Behav 2018; tes, 2018. A consensus report by the American Epidemiology of Diabetes Interventions and 45:101–111 Diabetes Association (ADA) and the European Complications Study Research Group. Long- 50. Andreassen LM, Sandberg S, Kristensen GBB, Association for the Study of Diabetes (EASD). term effect of diabetes and its treatment on Sølvik UØ, Kjome RLS. Nursing home patients Diabetes Care 2018;41:2669–2701 cognitive function. N Engl J Med 2007;356: with diabetes: prevalence, drug treatment and 65. Livingstone SJ, Levin D, Looker HC, et al.; 1842–1852 glycemic control. Diabetes Res Clin Pract 2014; Scottish Diabetes Research Network epide- 34. Selvin E, Coresh J, Brancati FL. The burden 105:102–109 miology group; Scottish Renal Registry. Esti- and treatment of diabetes in elderly individ- 51. Lipska KJ, Ross JS, Miao Y, Shah ND, Lee SJ, mated life expectancy in a Scottish cohort uals in the U.S. Diabetes Care 2006;29:2415– Steinman MA. Potential overtreatment of di- with type 1 diabetes, 2008-2010. JAMA 2015; 2419 abetesmellitusin older adultswith tight glycemic 313:37–44 35. Bandeen-Roche K, Seplaki CL, Huang J, et al. control. JAMA Intern Med 2015;175:356–362 66. Miller RG, Secrest AM, Sharma RK, Songer TJ, Frailty in older adults: a nationally representative 52. Thorpe CT, Gellad WF, Good CB, et al. Tight Orchard TJ. Improvements in the life expectancy profile in the United States. J Gerontol A Biol Sci glycemic control and use of hypoglycemic med- of type 1 diabetes: the Pittsburgh Epidemiology Med Sci 2015;70:1427–1434 ications in older veterans with type 2 diabetes of Diabetes Complications study cohort. Diabe- 36. Kalyani RR, Tian J, Xue Q-L, et al. Hypergly- and comorbid dementia. Diabetes Care 2015;38: tes 2012;61:2987–2992 cemia and incidence of frailty and lower extrem- 588–595 67. Bullard KM, Cowie CC, Lessem SE, et al. ity mobility limitations in older women. J Am 53. McAlister FA, Youngson E, Eurich DT. Treat- PrevalenceAssociation of diagnosed diabetes in adults by Geriatr Soc 2012;60:1701–1707 ment deintensification is uncommon in adults diabetes typedUnited States, 2016. MMWR 37. NGSP. Factors that interfere with HbA1c with type 2 diabetes mellitus: a retrospective Morb Mortal Wkly Rep 2018;67:359–361 test results. Accessed 31 October 2019. Available cohort study. Circ Cardiovasc Qual Outcomes 68. Heise T, Nosek L, Rønn BB, et al. Lower from http://www.ngsp.org/factors.asp 2017;10:e003514 within-subject variability of insulin detemir in 38. Sinclair A, Dunning T, Colagiuri S. IDF Global 54. Arnold SV, Lipska KJ, Wang J, Seman L, Mehta comparison to NPH insulin and insulin glargine in Guideline For Managing Older People With SN, Kosiborod M. Use of intensive glycemic people with type 1 diabetes. Diabetes 2004;53: Type 2 Diabetes. Brussels, Belgium, International management in older adults with diabetes mel- 1614–1620 Diabetes Federation, 2013 litus. J Am Geriatr Soc 2018;66:1190–1194 69. Ruedy KJ, Parkin CG, Riddlesworth TD, 39. Angelo M, Ruchalski C, Sproge BJ. An ap- 55. Weiner JZ, Gopalan A, Mishra P, et al. use Graham C; DIAMOND Study Group. Continuous proach to diabetes mellitus in hospice and and discontinuation of insulin treatment among glucose monitoring in older adults with type palliative medicine. J Palliat Med 2011;14: adults aged 75 to 79 years with type 2 diabetes. 1 and type 2 diabetes using multiple daily in- 83–87 JAMA Intern Med. 23 September 2019 [Epub jections of insulin: results from the DIAMOND 40. Beckett NS, Peters R, Fletcher AE, et al.; ahead of print]. DOI:Diabetes 10.1001/jamainternmed. trial. J Diabetes Sci Technol 2017;11:1138–1146 HYVET Study Group. Treatment of hypertension 2019.3759 70. Munshi MN, Florez H, Huang ES, et al. in patients 80 years of age or older. N Engl J Med 56. Munshi MN, Slyne C, Segal AR, Saul N, Lyons Management of diabetes in long-term care and 2008;358:1887–1898 C, Weinger K. Simplification of insulin regimen in skilled nursing facilities: a position statement of 41. de Boer IH, Bangalore S, Benetos A, et al. older adults and risk of hypoglycemia. JAMA the American Diabetes Association. Diabetes Care Diabetes and hypertension: a position statement Intern Med 2016;176:1023–1025 2016;39:308–318 by the American Diabetes Association. Diabetes 57. Sussman JB, Kerr EA, Saini SD, et al. Rates of 71. Sinclair A, Morley JE, Rodriguez-Manas~ L, Care 2017;40:1273–1284 deintensification of blood pressure and glycemic et al. Diabetes mellitus in older people: position 42. Park SW, Goodpaster BH, Strotmeyer ES, medication treatment based on levels of control statement on behalf of the International Asso- et al. Decreased muscle strength and quality in and life expectancy in older patients with di- ciation of Gerontology and Geriatrics (IAGG), the older adults with type 2 diabetes: the health, abetes mellitus. JAMA Intern Med 2015;175: European Diabetes Working Party for Older aging, and body composition study. Diabetes 1942–1949 People (EDWPOP), and the International Task 2006;55:1813–1818 58. Abdelhafiz AH, Sinclair AJ. Deintensification Force of Experts in Diabetes. J Am Med Dir Assoc 43. Park SW, Goodpaster BH, StrotmeyerAmerican ES, of hypoglycaemic medications-use of a system- 2012;13:497–502 et al.; Health, Aging, and Body Composition atic review approach to highlight safety concerns 72. Dorner B, Friedrich EK, Posthauer ME. Prac- Study. Accelerated loss of skeletal muscle in older people with type 2 diabetes. J Diabetes tice paper of the American Dietetic Association: strength in older adults with type 2 diabetes: Complications 2018;32:444–450 individualized nutrition approaches for older the Health, Aging, and Body Composition Study. 59. Seidu S, Kunutsor SK, Topsever P, Hambling adults in health care communities. J Am Diet Diabetes Care 2007;30:1507–1512 CE, Cos FX, Khunti K. Deintensification in older Assoc 2010;110:1554–1563 44. Villareal DT, Chode S, Parimi N, et al. Weight patients with type 2 diabetes: a systematic re- 73. Migdal A, Yarandi SS, Smiley D, Umpierrez loss, exercise, or both and physical function in view of approaches, rates and outcomes. Di- GE. Update on diabetes in the elderly and in obese older adults. N Engl J Med 2011;364:1218– abetes Obes Metab 2019;21:1668–1679 nursing home residents. J Am Med Dir Assoc 1229 60. Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, 2011;12:627–632.e2 45. Villareal©2019 DT, Aguirre L, Gurney AB, et al. McGuire DK. Metformin in patients with type 2 74. Pasquel FJ, Powell W, Peng L, et al. A Aerobic or resistance exercise, or both, in dieting diabetes and kidney disease: a systematic review. randomized controlled trial comparing treat- obese older adults. N Engl J Med 2017;376:1943– JAMA 2014;312:2668–2675 ment with oral agents and basal insulin in elderly 1955 61. Schwartz AV, Chen H, Ambrosius WT, et al. patients with type 2 diabetes in long-term care 46. Valencia WM, Florez H. Pharmacological Effects of TZD use and discontinuation on frac- facilities. BMJ Open Diabetes Res Care 2015;3: treatment of diabetes in older people. Diabetes ture rates in ACCORD bone study. J Clin Endo- e000104 Obes Metab 2014;16:1192–1203 crinol Metab 2015;100:4059–4066 75. Quinn K, Hudson P, Dunning T. Diabetes 47. Zhang JX, Bhaumik D, Huang ES, Meltzer DO. 62. Billington EO, Grey A, Bolland MJ. The effect management in patients receiving palliativecare. Change in insurance status and cost-related of thiazolidinediones on bone mineral density J Pain Symptom Manage 2006;32:275–286 medication non-adherence among older U.S. and bone turnover: systematic review and 76. Kutner JS, Blatchford PJ, Taylor DH Jr, et al. adults with diabetes from 2010 to 2014. J Health meta-analysis. Diabetologia 2015;58:2238– Safetyandbenefitof discontinuingstatintherapy Med Econ 2018;4:7 2246 in the setting of advanced, life-limiting illness: S162 Older Adults Diabetes Care Volume 43, Supplement 1, January 2020

a randomized clinical trial. JAMA Intern Med 79. Ford-Dunn S, Smith A, Quin J. Management diabetes: from the Diabetes Care Program of 2015;175:691–700 of diabetes during the last days of life: attitudes Nova Scotia (DCPNS) and the Palliative and 77. Dunning T, Martin P. Palliative and end of life of consultant diabetologists and consultant pal- Therapeutic Harmonization (PATH) program. care of people with diabetes: issues, challenges liative care physicians in the UK. Palliat Med J Am Med Dir Assoc 2013;14:801–808 and strategies. Diabetes Res Clin Pract 2018;143: 2006;20:197–203 82. Munshi MN, Slyne C, Segal AR, Saul N, Lyons 454–463 80. Petrillo LA, Gan S, Jing B, Lang-Brown S, C, Weinger K. Liberating A1C goals in older 78. Bouça-Machado R, Rosario´ M, Alarcão J, Boscardin WJ, Lee SJ. Hypoglycemia in hospice adults may not protect against the risk of Correia-Guedes L, Abreu D, Ferreira JJ. Clinical patients with type 2 diabetes in a national sample of hypoglycemia. J Diabetes Complications 2017; trials in palliative care: a systematic review of nursing homes.JAMA InternMed2018;178:713–715 31:1197–1199 their methodological characteristics and of the 81. Mallery LH, Ransom T, Steeves B, Cook B, 83. Leung E, Wongrakpanich S, Munshi MN. quality of their reporting. BMC Palliat Care 2017; Dunbar P, Moorhouse P. Evidence-informed guide- Diabetes management in the elderly. Diabetes 16:10 lines for treating frail older adults with type 2 Spectr 2018;31:245–253

Association

Diabetes

American

13. Children and Adolescents: American Diabetes Association Standards of Medical Care in Diabetes22020

Diabetes Care 2020;43(Suppl. 1):S163–S182 | https://doi.org/10.2337/dc20-S013

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes” Association ADOLESCENTS AND CHILDREN 13. includes the ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc20-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence- grading system for ADA’s clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc20-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.Diabetes Themanagementofdiabetes in childrenandadolescents cannotsimplybederivedfrom care routinely provided to adults with diabetes. The epidemiology, pathophysiology, developmental considerations, and response to therapy in pediatric-onset diabetes are different from adult diabetes. There are also differences in recommended care for children and adolescents with type 1 as opposed to type 2 diabetes. This section firstaddressescareforchildrenandadolescentswithtype1diabetesandnextaddresses care for children and adolescents with type 2 diabetes. Figure 13.1 provides guidance on managing new-onset diabetes in youth with overweight or obesity before type 1 or type 2 diabetes is diagnosed and so applies to all youth with overweight or obesity. Lastly, guidance is provided in this section on transition of care from pediatric to adult providers to ensure thatAmerican the continuum of care is appropriate as the child withdiabetesdevelopsinto adulthood. Due tothe nature ofclinicalresearchinchildren, the recommendations for children and adolescents with diabetes are less likely to be based on clinical trial evidence. However, expert opinion and a review of available and relevant experimental data are summarized in the American Diabetes Association (ADA) position statements “Type 1 Diabetes in Children and Adoles- cents” (1) and “Evaluation and Management of Youth-Onset Type 2 Diabetes” (2). TheADAconsensusreport“Youth-Onset Type 2DiabetesConsensusReport:Current Status,©2019 Challenges, and Priorities ” (3) characterizes type 2 diabetes in children and evalu- ates treatment options but also discusses knowledge gaps and recruitment challenges in clinical and translational research in youth-onset type 2 diabetes. Suggested citation: American Diabetes Associa- tion. 13. Children and adolescents: Standards of Monogenic diabetes (neonatal diabetes and maturity-onset diabetes in the young Medical Care in Diabetesd2020. Diabetes Care [MODY]),whichoftenpresentinyouth,arediscussedinsection2“Classification and 2020;43(Suppl. 1):S163–S182 Diagnosis of Diabetes” (https://doi.org/10.2337/dc20-S002). © 2019 by the American Diabetes Association. Readers may use this article as long as the work TYPE 1 DIABETES is properly cited, the use is educational and not for profit, and the work is not altered. More infor- Type 1 diabetes is the most common form of diabetes in youth (4), although mation is available at http://www.diabetesjournals recent data suggest that it may account for a large proportion of cases diagnosed in .org/content/license. S164 Children and Adolescents Diabetes Care Volume 43, Supplement 1, January 2020

adult life (5). The provider must consider diabetes management throughout child- Physical Activity and Exercise the unique aspects of care and manage- hood and adolescence. Health care Recommendations ment of children and adolescents with providers in the diabetes care team 13.5 Exercise is recommended for all type 1 diabetes, such as changes in insu- who care for children and adolescents youth with type 1 diabetes with must be capable of evaluating the edu- lin sensitivity related to physical growth the goal of 60 min of moderate- cational, behavioral, emotional, and and sexual maturation, ability to pro- to-vigorous intensity aerobic psychosocial factors that impact imple- vide self-care, supervision in the childcare activity daily, with vigorous mentation of a treatment plan and must and school environment, neurological muscle-strengthening and bone- work with the individual and family to vulnerability to hypoglycemia and hy- strengthening activities at least overcome barriers or redefine goals as perglycemia in young children, and pos- 3 days per week. C appropriate. Diabetes self-management sible adverse neurocognitive effectsof 13.6 Education about frequent pat- education and support requires peri- diabetic ketoacidosis (DKA) (6,7). Atten- terns of glycemia during and odic reassessment, especially as the tion to family dynamics, developmental after exercise, which may in- youth grows, develops, and acquires the stages, and physiologic differences re- clude initial transient hyperglyce- need for greater independent self-care lated to sexual maturity is essential in mia followed by hypoglycemia, skills. In addition, it is necessary to as- developing and implementing an optimal is essential. Families should sess the educational needs and skills of diabetes treatment plan (8). also receive education on pre- day careproviders,school nurses, orother A multidisciplinary team of special- vention and management of school personnel who participate in the ists trained in pediatric diabetes man- hypoglycemia during and after care of the child with diabetes (9). agement and sensitive to the challenges exercise, including ensuring of children and adolescents with type Associationpatients have a preexercise glu- 1 diabetes and their families should Nutrition Therapy cose level of 90–250 mg/dL (5.0– 13.9 mmol/L) and accessible provide care for this population. It is Recommendations essential that diabetes self-management carbohydrates before engaging 13.2 Individualized medical nutrition education and support, medical nutri- in activity, individualized accord- therapy is recommended for tion therapy, and psychosocial support ing to the type/intensity of the children and adolescents with be provided at diagnosis and regularly planned physical activity. E type 1 diabetes as an essential thereafter in a developmentally appro- 13.7 Patients should be educated on component of the overall treat- priate format that builds on prior knowl- strategies to prevent hypoglyce- ment plan. A edge by individuals experienced with the mia during exercise, after exercise, 13.3 Monitoring carbohydrate in- biological, educational, nutritional, be- and overnight following exercise, take, whetherDiabetes by carbohydrate havioral, and emotional needs of the which may include reducing pran- counting or experience-based growing child and family. The appropri- dial insulin dosing for the meal/ estimation, is key to achieving ate balance between adult supervision snack preceding (and, if needed, optimal glycemic control. B and independent self-care should be de- following) exercise, reducing basal 13.4 Comprehensive nutrition edu- fined at the first interaction and reeval- insulin doses, increasing carbohy- cation at diagnosis, with annual uated at subsequent visits, with the drate intake, eating bedtime updates, by an experienced reg- expectation that it will evolve as the snacks, and/or using continuous istered dietitian nutritionist is adolescent gradually becomes an emerg- glucose monitoring. C recommended to assess caloric ing young adult. 13.8 Frequent glucose monitoring and nutrition intake in relation before, during, and after exer- to weight status and cardiovas- Diabetes Self-Management Education cise, with or without use of Americancular disease risk factors and to and Support continuous glucose monitoring, inform macronutrient choices. E Recommendation is important to prevent, detect, and treat hypoglycemia and hy- 13.1 Youth with type 1 diabetes and Dietary management should be individ- perglycemia with exercise. C parents/caregivers (for patients ualized: family habits, food preferences, aged ,18 years) should receive religious or cultural needs, finances, culturally sensitive and develop- schedules, physical activity, and the pa- Exercise positively affects insulin sensitivity, mentally appropriate individual- tient’s and family’s abilities in numeracy, physical fitness, strength building, weight ©2019ized diabetes self-management literacy, and self-management should be management, social interaction, mood, educationandsupportaccording considered. Visits with a registered di- self-esteem building, and creation of to national standards at diagno- etitian nutritionist should include assess- healthful habits for adulthood, but it sis and routinely thereafter. B ment for changes in food preferences also has the potential to cause both over time, access to food, growth and hypoglycemia and hyperglycemia. No matter how sound the medical reg- development, weight status, cardiovas- See below for strategies to mitigate imen,itcanonlybeeffectiveifthe cular risk, and potential for eating dis- hypoglycemia risk and minimize hyper- family and/or affected individuals are orders. Dietary adherence is associated glycemia with exercise. For an in-depth able to implement it. Family involve- with better glycemic control in youth discussion, see recently published re- ment is a vital component of optimal with type 1 diabetes (10). views and guidelines (11–13). care.diabetesjournals.org Children and Adolescents S165

Overall, it is recommended that In addition, obesity is as common in 13.13 Assess youth with diabetes for youth with type 1 diabetes participate children and adolescents with type 1 psychosocial and diabetes- in60 min ofmoderate (e.g.,brisk walking, diabetes as in those without diabetes. related distress, generally start- dancing) to vigorous (e.g., running, jump- It is associated with higher frequency of ing at 7–8 years of age. B ing rope) intensity aerobic activity daily, cardiovascular risk factors, and it dispro- 13.14 Offer adolescents time by including resistance and flexibility train- portionately affects racial/ethnic minor- themselves with their care ing (14). Although uncommon in the ities in the U.S. (21–25). Therefore, provider(s) starting at age 12 pediatric population, patients should diabetes care providers should monitor years, or when developmen- be medically evaluated for comorbid weight status and encourage a healthy tally appropriate. E conditions or diabetes complications diet, exercise, and healthy weight as key 13.15 Starting at puberty, precon- that may restrict participation in an components of pediatric type 1 diabetes ception counseling should be exercise program. As hyperglycemia can care. incorporated into routine di- occur before, during, and after physi- abetes care for all girls of child- cal activity, it is important to ensure School and Child Care ’ bearing potential. A that the elevated glucose level is not As a large portion of a child s day is spent 13.16 Begin screening youth with related to insulin deficiency that would in school, close communication with and type 1 diabetes for eating dis- lead to worsening hyperglycemia with the cooperation of school or day care orders between 10 and 12 exercise and ketosis risk. Intense activ- personnel are essential for optimal di- years of age. The Diabetes Eat- ity should be postponed with marked abetes management, safety, and maxi- ing Problems Survey-Revised hyperglycemia (glucose $350 mg/dL mal academic opportunities. Refer to the “ (DEPS-R) is a reliable, valid, [19.4 mmol/L]), moderate to large urine ADA position statements Diabetes Care ” “ Associationand brief screening tool for ketones, and/or b-hydroxybutyrate in the School Setting (26) and Care of identifying disturbed eating (B-OHB) .1.5 mmol/L. Caution may Young Children With Diabetes in the ” behavior. B be needed when B-OHB levels are Child Care Setting (27) for additional $0.6 mmol/L (10,11). details. Rapid and dynamic cognitive, develop- The prevention and treatment of mental, and emotional changes occur hypoglycemia associated with physical Psychosocial Issues during childhood, adolescence, and activity include decreasing the pran- Recommendations emerging adulthood. Diabetes manage- dial insulin for the meal/snack before 13.9 At diagnosis and during rou- ment during childhood and adolescence exercise and/or increasing food intake. tine follow-up care, assess psy- places substantial burdens on the youth Patients on insulin pumps can lower chosocial issues and family basal rates by ;10–50% or more or Diabetesand family, necessitating ongoing as- stresses that could impact di- suspend for 1–2 h during exercise (15). sessment of psychosocial status and abetes management and pro- Decreasing basal rates or long-acting diabetes distress in the patient and vide appropriate referrals to insulin doses by ;20% after exercise the caregiver during routine diabetes trained mental health profes- – may reduce delayed exercise-induced hy- visits (28 34). It is important to consider sionals, preferably experi- poglycemia (16). Accessible rapid-acting the impact of diabetes on quality of life enced in childhood diabetes. E carbohydrates and frequent blood glu- as well as the development of mental 13.10 Mental health professionals cose monitoring before, during, and health problems related to diabetes should be considered inte- after exercise, with or without contin- distress, fear of hypoglycemia (and hy- gral members of the pediat- uous glucose monitoring, maximize perglycemia), symptoms of anxiety, dis- ric diabetes multidisciplinary safety with exercise. ordered eating behaviors and eating team. E Blood glucose targets priorAmerican to exercise disorders, and symptoms of depression 13.11 Encourage developmentally should be 90–250 mg/dL (5.0–13.9 (35). Consider assessing youth for di- appropriate family involve- mmol/L). Consider additional carbo- abetes distress, generally starting at 7 or ment in diabetes management hydrate intake during and/or after 8 years of age (36). Consider screening tasks for children and adoles- exercise, depending on the duration for depression and disordered eating cents, recognizing that prema- and intensity of physical activity, to behaviors using available screening ture transfer of diabetes care prevent hypoglycemia. For low-to- tools (28,37). Early detection of depres- to the child can result in di- moderate intensity aerobic activities sion, anxiety, eating disorders, and abetes burnout nonadherence (30–©201960 min), and if the patient is learning disabilities can facilitate ef- and deterioration in glycemic fasting, 10–15 g of carbohydrate fective treatment options and help control. A may prevent hypoglycemia (17). After minimize adverse effects on diabetes 13.12 Providers should consider insulin boluses (relative hyperinsuli- management and disease outcomes asking youth and their par- nemia), consider 0.5–1.0 g of carbohy- (33,36). There are validated tools, ents about social adjustment drates/kg per hour of exercise (;30– such as the Problem Areas in Diabetes- (peer relationships) and school 60 g), which is similar to carbohydrate Teen (PAID-T) and Parent (P-PAID-Teen) performance to determine requirements to optimize performance (34), that can be used in assessing di- whether further intervention in athletes without type 1 diabetes abetes-specificdistressinyouthstart- is needed. B (18–20). ing at age 12 years and in their parent S166 Children and Adolescents Diabetes Care Volume 43, Supplement 1, January 2020

caregivers. Furthermore, the complex- recognize the unique and dangerous 13.22 Less-stringent A1C goals (such ities of diabetes management require disordered eating behavior of insulin as ,7.5% [58 mmol/mol]) may ongoing parental involvement in care omission for weight control in type 1 be appropriate for patients throughout childhood with develop- diabetes (47) using tools such as the Di- who cannot articulate symp- mentally appropriate family teamwork abetes Eating Problems Survey-Revised toms of hypoglycemia; have between the growing child/teen and (DEPS-R) to allow for early diagnosis hypoglycemia unawareness; parent in order to maintain adherence and intervention (37,48–50). lack access to analog insulins, and to prevent deterioration in glycemic The presence of a mental health pro- advanced insulin delivery tech- control (38,39). As diabetes-specific fessional on pediatric multidisciplinary nology, and/or continuous glu- family conflict is related to poorer teams highlights the importance of at- cose monitors; cannot check adherence and glycemic control, it is tending to the psychosocial issues of blood glucose regularly; or appropriate to inquire about such diabetes. These psychosocial factors have nonglycemic factors that conflict during visits and to either are significantly related to self-manage- increase A1C (e.g., high glyca- help to negotiate a plan for resolution ment difficulties, suboptimal glycemic tors). B or refer to an appropriate mental control, reduced quality of life, and 13.23 Even less-stringent A1C goals health specialist (40). Monitoring of higher rates of acute and chronic di- (such as ,8% [64 mmol/mol]) social adjustment (peer relationships) abetes complications. may be appropriate for pa- andschoolperformancecanfacili- tients with a history of severe tate both well-being and academic Glycemic Control hypoglycemia, limited life ex- achievement (41). Suboptimal glyce- Recommendations pectancy, or extensive comor- mic control is a risk factor for under- 13.17 The majority of children and Associationbid conditions. B performance at school and increased adolescents with type 1 diabe- 13.24 Providers may reasonably sug- absenteeism (42). tes should be treated with gest more-stringent A1C goals Shared decision-making with youth intensive insulin regimens, (such as ,6.5% [48 mmol/ regarding the adoption of regimen com- either via multiple daily injec- mol]) for selected individ- ponents and self-management behav- tions or continuous subcuta- ual patients if they can be iors can improve diabetes self-efficacy, neous insulin infusion. A achieved without significant adherence, and metabolic outcomes 13.18 All children and adolescents hypoglycemia, negative im- (22,43). Although cognitive abilities with type 1 diabetes should pacts on well-being, or undue vary, the ethical position often adopted self-monitorglucoselevelsmul- burden of care, or in those is the “mature minor rule,” whereby tiple times daily (up to 6–10 who have nonglycemic factors children after age 12 or 13 years who Diabetes times/day), including premeal, that decrease A1C (e.g., lower appear to be “mature” have the right to prebedtime, and as needed for erythrocyte life span). Lower consent or withhold consent to general safety in specificsituations such targets may also be appropri- medical treatment, except in cases in as exercise, driving, or the pres- ate during the honeymoon which refusal would significantly endan- ence of symptoms of hypogly- phase. B ger health (44). cemia. B Beginning at the onset of puberty or at 13.19 Continuous glucose monitor- diagnosis of diabetes, all adolescent girls Current standards for diabetes man- ing (CGM) should be consid- and women with childbearing potential agement reflect the need to lower glu- ered in all children and should receive education about the risks cose as safely as possible. This should be adolescents with type 1 diabe- of malformations associated with poor done with stepwise goals. When estab- tes, whether using injections metabolic control and theAmerican use of effective lishing individualized glycemic targets, or continuous subcutaneous contraception to prevent unplanned preg- special consideration should be given insulin infusion, as an addi- nancy. Preconception counseling using to the risk of hypoglycemia in young tional tool to help improve developmentally appropriate educa- children (aged ,6 years) who are often glucose control. Benefits of tional tools enables adolescent girls unable to recognize, articulate, and/or CGM correlate with adherence to make well-informed decisions (45). manage hypoglycemia. However, regis- to ongoing use of the device. B Preconception counseling resources tai- try data indicate that A1C targets can be 13.20 Automated insulin delivery lored for adolescents are available at no achieved in children, including those ,6 systems appear to improve cost©2019 through the ADA (46). Refer to the years, without increased risk of severe glycemic control and reduce ADA position statement “Psychosocial Care hypoglycemia (51,52). Recent data have hypoglycemia in children and for People With Diabetes” for further de- demonstrated that the use of continuous should be considered in chil- tails (36). glucose monitors lowered A1C and dren with type 1 diabetes. B Youth with type 1 diabetes have an increased time in range in adolescents 13.21 A1C goals must be individual- increased risk of disordered eating be- and young adults, and, in children ,8 ized and reassessed over time. havior as well as clinical eating disorders years old, was associated with lower risk An A1C of ,7% (53 mmol/mol) with serious short-term and long-term of hypoglycemia (53,54). Please refer to is appropriate for many chil- negative effects on diabetes outcomes Section 7 “Diabetes Technology” (https:// dren. B and health in general. It is important to doi.org/10.2337/dc20-S007) for more care.diabetesjournals.org Children and Adolescents S167

information on the use of blood glucose continuous glucose monitors are not other autoimmune conditions, such as meters, continuous glucose monitors, and currently approved for use in children Addison disease (primary adrenal insuf- insulin pumps. More information on in- and adolescents. A strong relationship ficiency), autoimmune hepatitis, autoim- sulin injection technique can be found exists between frequency of blood glu- mune gastritis, dermatomyositis, and in Section 9 “Pharmacologic Approaches cose monitoring and glycemic stability myasthenia gravis, occur more com- to Glycemic Treatment (https://doi.org/ (77–86). Recent data with newer devi- monly in the population with type 1 10.2337/dc20-S009).” ces and insulins indicate that the risk of diabetes than in the general pediatric The Diabetes Control and Complica- hypoglycemia with lower A1C is less than population and should be assessed and tions Trial (DCCT), which did not enroll it was before (52,76,87–94). Some data monitored as clinically indicated. In ad- children ,13 years of age, demonstrated suggest that there could be a threshold dition, relatives of patients should be that near normalization of blood glucose where lower A1C is associated with more offered testing for islet autoantibodies levels was more difficult to achieve in hypoglycemia (95,96); however, the con- through research studies (e.g., TrialNet) adolescents than in adults. Nevertheless, fidence intervals were large, suggesting for early diagnosis of preclinical type 1 the increased use of basal-bolus regi- great variability. diabetes (stages 1 and 2). mens, insulin pumps, frequent blood In selecting glycemic targets, the glucose monitoring, goal setting, and long-term health benefits of achieving a Thyroid Disease improved patient education in youth lower A1C should be balanced against from infancy through adolescence has the risks of hypoglycemia and the de- Recommendations 13.26 been associated with more children velopmental burdens of intensive regi- Consider testing children with reaching the blood glucose targets rec- mens in children and youth. In addition, type 1 diabetes for antithyroid ommended by ADA (55–58), particularly achieving lower A1C levels is likely fa- Associationperoxidase and antithyroglob- in patients of families in which both the cilitated by setting lower A1C targets ulin antibodies soon after B parents and the child with diabetes par- (51,97). Lower goals may be possible diagnosis. 13.27 ticipate jointly to perform the required during the “honeymoon” phase of type 1 Measure thyroid-stimulating diabetes-related tasks. Furthermore, diabetes. hormone concentrations at di- studies documenting neurocognitive agnosis when clinically stable imaging differences related to hy- Key Concepts in Setting Glycemic or soon after glycemic control perglycemia in children provide an- Targets has been established. If nor- c Targets should be individualized, and other motivation for lowering glycemic mal, suggest rechecking every lower targets may be reasonable based – targets (6). 1 2 years or sooner if the on a benefit-risk assessment. Lower A1C in adolescence and young patient has positive thyroid c Blood glucose targets should be adulthood is associated with lower risk Diabetes antibodies or develops symp- modified in children with frequent and rate of microvascular and macro- toms or signs suggestive of hypoglycemia or hypoglycemia un- vascular complications, as shown in stud- thyroid dysfunction, thyrome- awareness. ies in youth (59–62) and in studies that galy, an abnormal growth rate, c Postprandial blood glucose values include youth and adults and demon- or unexplained glycemic vari- should be measured when there is B strate the effects of metabolic memory ability. a discrepancy between preprandial (63–66). blood glucose values and A1C levels In addition, type 1 diabetes can be and to assess preprandial insulin Autoimmune thyroid disease is the associated with adverse effects on cog- doses in those on basal-bolus or pump most common autoimmune disorder nition during childhood and adoles- regimens. associated with diabetes, occurring in cence (6,67,68). DKA has been shown 17–30% of patients with type 1 diabetes to cause adverse effects onAmerican brain de- (99,103,104). At the time of diagnosis, velopment and function. Additional fac- Autoimmune Conditions ;25% of children with type 1 diabe- tors (69–72) that contribute to adverse Recommendation tes have thyroid autoantibodies (105); effects on brain development and func- 13.25 Assess for additional autoim- their presence is predictive of thyroid tion include young age, severe hypo- mune conditions soon after dysfunctiondmost commonly hypoglycemia at ,6 years of age, and chronic the diagnosis of type 1 diabe- thyroidism, although hyperthyroid- hyperglycemia (73,74). However, me- tes and if symptoms develop. B ; ticulous use of new therapeutic modal- ism occurs in 0.5% of patients with ities©2019 such as rapid- and long-acting Because of the increased frequency of type 1 diabetes (106,107). For thyroid insulin analogs, technological advances other autoimmune diseases in type 1 autoantibodies, a study from Sweden (e.g., continuous glucose monitors, low- diabetes, screening for thyroid dysfunc- indicated that antithyroid peroxidase glucose suspend insulin pumps, and tion and celiac disease should be con- antibodies were more predictive than automated insulin delivery systems), and sidered (98–102). Periodic screening in antithyroglobulin antibodies in multi- intensive self-management education asymptomatic individuals has been rec- variate analysis (108). Thyroid function now make it more feasible to achieve ommended, but the optimal frequency tests may be misleading (euthyroid sick excellent glycemic control while reduc- of screening is unclear. syndrome) if performed at the time of ing the incidence of severe hypoglyce- Although much less common than diagnosis owing to the effect of previous mia (75–84). Intermittently scanned thyroid dysfunction and celiac disease, hyperglycemia, ketosis or ketoacidosis, S168 Children and Adolescents Diabetes Care Volume 43, Supplement 1, January 2020

weight loss, etc. Therefore, if performed IgA deficiency, screening can include Management of Cardiovascular Risk at diagnosis and slightly abnormal, thy- measuring IgG tissue transglutaminase Factors roid function tests should be repeated antibodies or IgG deamidated gliadin Hypertension Screening peptide antibodies. Because most cases soon after a period of metabolic stability Recommendations of celiac disease are diagnosed within and achievement of glycemic targets. 13.31 Blood pressure should be mea- the first 5 years after the diagnosis of Subclinical hypothyroidism may be suredateachroutinevisit.Chil- type 1 diabetes, screening should be associated with increased risk of symp- dren found to have elevated considered at the time of diagnosis and tomatic hypoglycemia (109) and reduced blood pressure (systolic blood repeated at 2 and then 5 years (112) or linear growth rate. Hyperthyroidism pressure or diastolic blood if clinical symptoms indicate, such as alters glucose metabolism and usu- pressure $90th percentile for poor growth or increased hypoglycemia ally causes deterioration of glycemic age,sex,andheightor,in (113,115). control. adolescents $13 years, systolic Although celiac disease can be di- blood pressure 120–129 mmHg agnosed more than 10 years after di- with diastolic blood pressure Celiac Disease abetes diagnosis, there are insufficient ,80 mmHg) or hypertension data after 5 years to determine the Recommendations (systolic blood pressure or di- optimal screening frequency. Measure- 13.28 Screen children with type 1 astolic blood pressure $95th ment of tissue transglutaminase antidiabetes for celiac disease by percentile for age, sex, and body should be considered at other measuring IgA tissue transglu- height or, in adolescents $13 times in patients with symptoms sug- taminase (tTG) antibodies, years, systolic blood pressure gestive of celiac disease (112). Moni- with documentation of normal Association$130 mmHg or diastolic blood toring for symptoms should include total serum IgA levels, soon pressure $80 mmHg) should assessment of linear growth and weight after the diagnosis of diabetes, have elevated blood pressure gain (113,115). A small bowel biopsy or IgG to tTG and deamida- confirmed on three separate in antibody-positive children is recom- ted gliadin antibodies if IgA B fi days. deficient. B mended to con rm the diagnosis (119). 13.29 Repeat screening within European guidelines on screening for fi 2 years of diabetes diagno- celiac disease in children (not speci cto Hypertension Treatment children with type 1 diabetes) suggest sis and then again after Recommendations that biopsy may not be necessary in 5yearsandconsidermore 13.32 Initial treatment of elevated frequent screening in chil- symptomatic children with high antibody titers (i.e.,Diabetes greater than 10 times blood pressure (systolic blood dren who have symptoms pressure or diastolic blood or a first-degree relative with the upper limit of normal) provided that fi pressure consistently $90th celiac disease. B further testing is performed (veri cation of endomysial antibody positivity percentile for age, sex, and 13.30 Individuals with biopsy- $ on a separate blood sample). Whether height or 120/80 mmHg in confirmed celiac disease should $ this approach may be appropriate adolescents 13 years) in- be placed on a gluten-free cludes dietary modification diet for treatment and to avoid for asymptomatic children in high- risk groups remains an open question, and increased exercise, if ap- complications; they should also propriate, aimed at weight have a consultation with a die- though evidence is emerging (120). It is also advisable to check for celiac control. If target blood pres- titian experienced in manag- – disease–associated HLA types in pa- sure is not reached within 3 ing both diabetesAmerican and celiac 6 months of initiating lifestyle disease. B tients who are diagnosed without a small intestinal biopsy. In symptomatic intervention, pharmacologic children with type 1 diabetes and con- treatment should be consid- Celiac disease is an immune-mediated E firmed celiac disease, gluten-free diets ered. disorder that occurs with increased fre- 13.33 fi reduce symptoms and rates of hypogly- In addition to lifestyle modi - quency in patients with type 1 diabe- cemia (121).The challenging dietary re- cation, pharmacologic treat- – tes (1.6 16.4% of individuals compared strictions associated with having both ment of hypertension (systolic – with 0.3 1% in the general population) type 1 diabetes and celiac disease blood pressureordiastolicblood – $ (98,101,102,110©2019114). Screening pa- place a significant burden on individuals. pressure consistently 95th per- tients with type 1 diabetes for celiac Therefore, a biopsy to confirm the di- centile for age, sex, and height or $ disease is further justified by its associ- agnosis of celiac disease is recommen- 140/90 mmHg in adolescents $ ation with osteoporosis, iron deficiency, ded, especially in asymptomatic children, 13 years) should be considered growth failure, and potential increased before establishing a diagnosis of celiac as soon as hypertension is con- fi E risk of retinopathy and albuminuria disease (122) and endorsing significant rmed. 13.34 (115–118). dietary changes. A gluten-free diet was ACE inhibitors or angioten- Screening for celiac disease includes beneficial in asymptomatic adults with sin receptor blockers should measuring serum levels of IgA and tissue positive antibodies confirmed by biopsy be considered for the initial transglutaminase antibodies, or, with (123). pharmacologic treatment of care.diabetesjournals.org Children and Adolescents S169

be accurately calculated in a nonfasting hypertension E in children 13.39 After the age of 10 years, addi- state and is therefore practical to obtain and adolescents, following tion of a statin may be consid- in clinical practice as a screening test reproductive counseling due ered in patients who, despite (133). Youth with type 1 diabetes have a to the potential teratogenic medical nutrition therapy and high prevalence of lipid abnormalities effects of both drug classes. E lifestyle changes, continue to (126,134). 13.35 The goal of treatment is blood have LDL cholesterol .160 Even if normal, screening should be pressure consistently ,90th mg/dL (4.1 mmol/L) or LDL repeated within 3 years, as glycemic percentile for age, sex, and cholesterol .130 mg/dL (3.4 control and other cardiovascular risk height or ,120/,80 mmHg mmol/L) and one or more car- factors can change dramatically during in children $13 years. E diovascular disease risk factors, adolescence (135). following reproductive counsel- Treatment. Pediatric lipid guidelines pro- Blood pressure measurements should ing because of the potential vide some guidance relevant to children be performed using the appropriate size teratogenic effects of statins. E with type 1 diabetes (124,132,136,137); cuff with the child seated and relaxed. 13.40 The goal of therapy is an LDL however, there are few studies on Hypertension should be confirmed on at cholesterol value ,100 mg/dL modifying lipid levels in children with least three separate days. Evaluation (2.6 mmol/L). E type 1 diabetes. A 6-month trial of di- should proceed as clinically indicated etary counseling produced a signifi- (124). Treatment is generally initiated Population-based studies estimate that cant improvement in lipid levels (138); with an ACE inhibitor, but an angiotensin 14–45% of children with type 1 diabe- likewise, a lifestyle intervention trial receptor blocker can be used if the ACE tes have two or more atherosclerotic with 6 months of exercise in adoles- inhibitor is not tolerated (e.g., due to cardiovascular disease (ASCVD) risk Association cents demonstrated improvement in cough) (125). – factors (126 128), and the prevalence lipid levels (139). Data from the SEARCH of cardiovascular disease (CVD) risk factors for Diabetes in Youth (SEARCH) study Dyslipidemia Testing increases with age (128) and among racial/ show that improved glucose over a 2-year ethnic minorities (21), with girls having a Recommendations period is associated with a more favor- higher risk burden than boys (127). 13.36 able lipid profile; however, improved gly- Initial lipid testing should be Pathophysiology. The atherosclerotic pro- performed when initial glyce- cemia alone will not normalize lipids in cess begins in childhood, and although youth with type 1 diabetes and dys- mic control has been achieved ASCVD events are not expected to occur and age is $2 years. If initial lipidemia (135). during childhood, observations using a LDL cholesterol is #100 mg/dL Although intervention data are sparse, variety of methodologiesDiabetes show that (2.6 mmol/L), subsequent test- the American Heart Association catego- youth with type 1 diabetes may have ing should be performed at rizes children with type 1 diabetes in the subclinical CVD within the first decade of 9-11 years of age. B Initial highest tier for cardiovascular risk and – testing may be done with diagnosis (129 131). Studies of carotid recommends both lifestyle and pharma- a nonfasting non-HDL choles- intima-media thickness have yielded in- cologictreatment forthose withelevated terol level with confirmatory consistent results (124,125). LDL cholesterol levels (137,140). Initial testing with a fasting lipid Screening. Diabetes predisposes to de- therapy should be with a nutrition plan panel. velopment of accelerated arteriosclero- that restricts saturated fat to 7% of to- 13.37 If LDL cholesterol values are sis. Lipid evaluation for these patients tal calories and dietary cholesterol to within the accepted risk level contributes to risk assessment and iden- 200 mg/day. Data from randomized clin- fi (,100 mg/dL [2.6 mmol/L]),American a ti es an important proportion of those ical trials in children as young as 7 months lipid profile repeated every with dyslipidemia. Therefore, initial of age indicate that this diet is safe and 3 years is reasonable. E screening should be done soon after does not interfere with normal growth diagnosis. If the initial screen is normal, and development (141). subsequent screening may be done at Neither long-term safety nor cardio- Dyslipidemia Treatment 9–11 years of age, which is a stable time vascular outcome efficacy of statin ther- for lipid assessment in children (132). apy has been established for children; Recommendations Non-HDL cholesterol level has been however, studies have shown short-term 13.38 If lipids are abnormal, initial identified as a significant predictor of safety equivalent to that seen in adults therapy should consist of op- ©2019 the presence of atherosclerosisdas pow- and efficacy in lowering LDL cholesterol timizing glucose control and erful as any other lipoprotein cholesterol levels in familial hypercholesterolemia or medical nutrition therapy to measure in children and adolescents. For severe hyperlipidemia, improving endo- limit the amount of calories both children and adults, non-HDL cho- thelial function and causing regression fromfatto25–30%,saturated lesterol level seems to be more predictive of carotid intimal thickening (142,143). fat to ,7%, cholesterol ,200 of persistent dyslipidemia and, therefore, Statins are not approved for patients mg/day, avoidance of trans atherosclerosis and future events than aged ,10 years, and statin treatment fats, and aim for ;10% calo- total cholesterol, LDL cholesterol, or HDL should generally not be used in chil- ries from monounsaturated cholesterol levels alone. A major advan- dren with type 1 diabetes before this fats. A tage of non-HDL cholesterol is that it can age. Statins are contraindicated in S170 Children and Adolescents Diabetes Care Volume 43, Supplement 1, January 2020

pregnancy; therefore, prevention of un- effects of exercise) spot urine $11 years or puberty has planned pregnancies is of paramount im- sampleforalbumin-to-creatinine started, whichever is earlier. B portance for postpubertal girls (see ratioshouldbeconsideredat 13.46 After the initial examination, “ Section 14 Management of Diabetes in puberty or at age .10 years, repeat dilated and compre- ” Pregnancy, https://doi.org/10.2337/dc20- whichever is earlier, once the hensive eye examination every S014, for more information). The multi- child has had diabetes for 5 2 years. Less frequent exami- center, randomized, placebo-controlled years. B nations, every 4 years, may Adolescent Type 1 Diabetes Cardio-Renal be acceptable on the advice Intervention Trial (AdDIT) provides safety Nephropathy Treatment of an eye care professional data on pharmacologic treatment with Recommendations and based on risk factor as- an ACE inhibitor and statin in adolescents 13.44 An ACE inhibitor or an angio- sessment, including a history with type 1 diabetes. tensin receptor blocker, titrated of glycemic control with A1C to normalization of albumin ex- ,8%. B Smoking cretion,maybeconsideredwhen Recommendations elevated urinary albumin-to- Retinopathy (like albuminuria) most commonly occurs after the onset of 13.41 Elicit a smoking history at initial creatinine ratio (.30 mg/g) is puberty and after 5–10 years of diabetes and follow-up diabetes visits; documented (two of three urine duration (154). It is currently recognized discourage smoking in youth samples obtained over a 6- who do not smoke and encour- month interval following ef- that there is low risk of development of age smoking cessation in those forts to improve glycemic vision-threateningAssociation retinal lesions prior to who do smoke. A control and normalize blood 12 years of age (155,156). A 2019 publi- 13.42 E-cigarette use should be dis- pressure). E cation based on the follow-up of the couraged. A DCCT adolescent cohort supports lower Data from 7,549 participants ,20 years frequency of eye examinations than pre- The adverse health effects of smoking of age in the T1D Exchange clinic reg- viously recommended, in particular in are well recognized with respect to fu- istry emphasize the importance of adolescents with A1C closer to the tar- ture cancer and CVD risk. Despite this, good glycemic and blood pressure conget range (157,158). Referrals should smoking rates are significantly higher trol, particularly as diabetes duration be made to eye care professionals among youth with diabetes than among increases, in order to reduce the risk with expertise in diabetic retinopathy youth without diabetes (144,145). In of diabetic kidney disease. The data also and experience in counseling pediatric youth with diabetes, it is important to underscore theDiabetes importance of routine patients and families on the importance of prevention, early detection, and in- avoid additional CVD risk factors. Smok- screening to ensure early diagnosis and tervention. ing increases the risk of onset of albu- timely treatment of albuminuria (151). minuria; therefore, smoking avoidance is An estimation of glomerular filtration Neuropathy important to prevent both microvascu- rate (GFR), calculated using GFR estimat- lar and macrovascular complications ing equations from the serum creatinine, Recommendation 13.47 (132,146). Discouraging cigarette smok- height, age, and sex (152), should be Consider an annual compre- ing, including e-cigarettes (147,148), is considered at baseline and repeated as hensive foot exam at the start an important part of routine diabetes of puberty or at age $10 years, indicated based on clinical status, age, care. In light of recent Centers for Dis- whichever is earlier, once the diabetes duration, and therapies. Im- ease Control and Prevention evidence youth has had type 1 diabetes proved methods are needed to screen of deaths related to e-cigaretteAmerican use for 5 years. B (149,150), no persons should be advised for early GFR loss, since estimated GFR is . 2 tousee-cigarettes, eitherasawaytostop inaccurate at GFR 60 mL/min/1.73 m Diabetic neuropathy rarely occurs in smoking tobacco or as a recreational (152,153). The AdDIT study in adoles- prepubertal children or after only 1–2 drug. In younger children, it is important cents with type 1 diabetes demonstrated years of diabetes (154), although data to assess exposure to cigarette smoke in safety of ACE inhibitor treatment, but the suggest a prevalence of distal peripheral the home because of the adverse effects treatment did not change the albumin- neuropathy of 7% in 1,734 youth with of secondhand smoke and to discourage to-creatinine ratio over the course of the type 1 diabetes and associated with the youth©2019 from ever smoking if exposed to study (124). presence of CVD risk factors (159,160). A smokers in childhood. comprehensive foot exam, including in- Retinopathy spection, palpation of dorsalis pedis and Microvascular Complications Recommendations posterior tibial pulses, and determina- Nephropathy Screening 13.45 An initial dilated and compre- tion of proprioception, vibration, and fi Recommendations hensive eye examination is rec- mono lament sensation, should be performed annually along with an assess- 13.43 Annual screening for albumin- ommended once youth have ment of symptoms of neuropathic pain uria with a random (morning had type 1 diabetes for 3–5 (160). Foot inspection can be performed sample preferred to avoid years, provided they are aged at each visit to educate youth regarding care.diabetesjournals.org Children and Adolescents S171

theimportanceoffootcare(seeSec- Diagnostic Challenges children and adolescents after tion 11 “Microvascular Complications the onset of puberty or $10 Given the current obesity epidemic, dis- and Foot Care,” https://doi.org/10.2337/ years of age, whichever oc- tinguishing between type 1 and type 2 dc20-S011). fi curs earlier, with overweight diabetes in children can be dif cult. (BMI$85th percentile)orobe- Overweight and obesity are common TYPE 2 DIABETES sity (BMI $95thpercentile)and in children with type 1 diabetes (23), For information on testing for type 2 who have one or more addi- and diabetes-associated autoantibodies diabetes and prediabetes in children tional risk factors for diabetes and ketosis may be present in pediatric and adolescents, please refer to Sec- (see Table 2.4 for evidence patients with features of type 2 diabetes tion 2 “Classification and Diagnosis grading of other risk factors). (including obesity and acanthosis nigri- of Diabetes” (https://doi.org/10.2337/ 13.49 If tests are normal, repeat test- cans) (171). The presence of islet auto- dc20-S002). For additional support for ing at a minimum of 3-year antibodies has been associated with fi these recommendations, see the ADA intervals E, or more frequently faster progression to insulin de ciency ; position statement “Evaluation and Man- if BMI is increasing. C (171). At onset, DKA occurs in 6% of – agement of Youth-Onset Type 2 Di- 13.50 Fasting plasma glucose, 2-h youth aged 10 19 years with type 2 diabetes” (2). plasma glucose during a 75-g abetes (176). Although uncommon, type 2 Type 2 diabetes in youth has increased oralglucose tolerancetest,and diabetes has been observed in prepuber- over the past 20 years, and recent esti- A1C can be used to test for tal childrenunder theageof10, andthus it mates suggest an incidence of ;5,000 prediabetes or diabetes in chil- should be part of the differential in chil- new cases per year in the U.S. (161). The dren and adolescents. B dren with suggestive symptoms (177). Centers for Disease Control and Preven- 13.51 Children and adolescents with Finally,Association obesity (178) contributes to the tion published projections for type 2 overweight or obesity in whom development of type 1 diabetes in some diabetes prevalence using the SEARCH the diagnosis of type 2 diabe- individuals, which further blurs the lines database; assuming a 2.3% annual in- tes is being considered should between diabetes types. However, accu- crease, the prevalence in those under have a panel of pancreatic rate diagnosis is critical, as treatment regi- 20 years of age will quadruple in 40 years autoantibodies tested to ex- mens, educational approaches, dietary (162,163). clude the possibility of auto- advice, and outcomes differ markedly be- Evidence suggests that type 2 diabetes immune type 1 diabetes. B tweenpatientswiththetwodiagnoses. fi fi in youth is different not only from type 1 The signi cant diagnostic dif culties diabetes but also from type 2 diabe- In the last decade, the incidence posed by MODY are discussed in sec- “ fi tes in adults and has unique features, and prevalence of type 2 diabetes in tion 2 Classi cation and Diagnosis of Diabetes ” such as a more rapidly progressive decline adolescents has increased dramatically, Diabetes (https://doi.org/10.2337/dc20- in b-cell function and accelerated de- especially in racial and ethnic minority S002). In addition, there are rare and atypical diabetes cases that represent velopment of diabetes complications populations (132,169). A few recent a challenge for clinicians and researchers. (2,164).Type 2 diabetes disproportion- studies suggest oral glucose tolerance ately impacts youth of ethnic and ra- tests or fasting plasma glucose values as Management cial minorities and can occur in complex more suitable diagnostic tests than A1C Lifestyle Management psychosocial and cultural environments, in the pediatric population, especially which may make it difficult to sustain among certain ethnicities (170), al- Recommendations healthy lifestyle changes and self- though fasting glucose alone may over- 13.52 All youth with type 2 diabetes management behaviors (22,165–168). diagnose diabetes in children (171,172). and their families should re- Additional risk factors associatedAmerican with In addition, many of these studies do not ceive comprehensive diabe- type 2 diabetes in youth include adiposity, recognize that diabetes diagnostic crites self-management education fi family history of diabetes, female sex, and teria are based on long-term health and support that is speci c low socioeconomic status (164). outcomes, and validations are not cur- to youth with type 2 diabe- As with type 1 diabetes, youth with rently available in the pediatric popu- tes and is culturally compe- B type 2 diabetes spend much of the day in lation (173). ADA acknowledges the tent. 13.53 school. Therefore, close communication limited data supporting A1C for diag- Youthwithoverweight/obesity with and the cooperation of school per- nosing type 2 diabetes in children and and type 2 diabetes and their sonnel©2019 are essential for optimal diabetes adolescents. Although A1C is not rec- families should be provided with developmentally and management, safety, and maximal aca- ommended for diagnosis of diabetes in culturally appropriate compre- demic opportunities. childrenwithcysticfibrosisorsymptoms hensive lifestyle programs that suggestive of acute onset of type 1 di- are integrated with diabetes Screening and Diagnosis abetes, and only A1C assays without management to achieve 7–10% interference are appropriate for chil- Recommendations decrease in excess weight. C dren with hemoglobinopathies, ADA 13.48 Risk-based screening for pre- 13.54 Given the necessity of long- continues to recommend A1C for diabetes and/or type 2 diabe- term weight management for diagnosis of type 2 diabetes in this tes should be considered in children and adolescents with population (174,175). S172 Children and Adolescents Diabetes Care Volume 43, Supplement 1, January 2020

type 2 diabetes, lifestyle inter- 13.61 A1C targets for patients on carcinoma or multiple endo- vention should be based on insulin should be individual- crine neoplasia type 2. A a chronic care model and of- ized, taking into account the 13.68 Patients treated with basal in- feredinthecontextofdiabe- relatively low rates of hypogly- sulin up to 1.5 units/kg/day tes care. E cemia in youth-onset type 2 who do not meet A1C target 13.55 Youth with diabetes, like all diabetes. E should be moved to multiple children, should be encouraged daily injections with basal and to participate in at least 30–60 Pharmacologic Management premeal bolus insulins. E min of moderate-to-vigorous 13.69 In patients initially treated with Recommendations physical activity at least 5 days insulin and metformin who are 13.62 Initiate pharmacologic therapy, per week (and strength train- meeting glucose targets based in addition to lifestyle therapy, ing on at least 3 days/week) B on home blood glucose moni- at diagnosis of type 2 diabetes. and to decrease sedentary be- A toring, insulin can be tapered havior. C over 2–6 weeks by decreasing 13.63 In incidentally diagnosed or 13.56 Nutrition for youth with type the insulin dose 10–30% every metabolically stable patients 2 diabetes, like for all chil- few days. B (A1C ,8.5% [69 mmol/mol] and dren, should focus on healthy 13.70 Use of medications not ap- asymptomatic),metforministhe eating patterns that empha- proved by the U.S. Food and initial pharmacologic treatment size consumption of nutrient- Drug Administration for youth of choice if renal function is dense, high-quality foods and with type 2 diabetes is not normal. A decreased consumption of cal- Associationrecommended outside of re- 13.64 Youth with marked hypergly- orie-dense, nutrient-poor foods, search trials. B cemia (blood glucose $250 particularly sugar-added bever- mg/dL [13.9 mmol/L], A1C ages. B $8.5% [69 mmol/mol]) with- Treatment of youth-onset type 2 diabe- out acidosis at diagnosis who tes should include lifestyle management, Glycemic Targets are symptomatic with polyuria, diabetes self-management education, and pharmacologic treatment. Initial Recommendations polydipsia, nocturia, and/or treatment of youth with obesity and 13.57 Home self-monitoring of blood weight loss should be treated diabetes must take into account that glucose regimens should be in- initially with basal insulin while diabetes type is often uncertain in the dividualized, taking into consid- metformin is initiated and ti- DiabetesB fi rst few weeks of treatment, due to eration the pharmacologic trated. 13.65 overlap in presentation, and that a sub- treatment of the patient. E In patients with ketosis/ stantial percentage of youth with type 2 13.58 A1C should be measured every ketoacidosis, treatment with diabetes will present with clinically sig- 3 months. E subcutaneous or intravenous nificant ketoacidosis (180). Therefore, 13.59 A reasonable A1C target for insulin should be initiated to initial therapy should address the hyper- most children and adolescents rapidly correct the hypergly- glycemia and associated metabolic de- with type 2 diabetes treated cemia and the metabolic de- rangements irrespective of ultimate with oral agents alone is rangement. Once acidosis is diabetes type, with adjustment of ther- ,7% (53 mmol/mol). More resolved, metformin should be apy once metabolic compensation has stringent A1C targets (such initiated while subcutane- been established and subsequent infor- as ,6.5% [48 mmol/mol]) ous insulin therapy is contin- American A mation, such as islet autoantibody results, may be appropriate for se- ued. 13.66 becomes available. Figure 13.1 provides lected individual patients if In individuals presenting with an approach to initial treatment of new- they can be achieved without severe hyperglycemia (blood $ onset diabetes in youth with overweight significant hypoglycemia or glucose 600 mg/dL [33.3 or obesity. other adverse effects of treat- mmol/L]), consider assessment Glycemic targets should be individu- ment.Appropriatepatientsmight for hyperglycemic hyperosmo- A alized, taking into consideration long- include those with short dura- lar nonketotic syndrome. 13.67 term health benefits of more stringent tion of diabetes and lesser If glycemic targets are no ©2019 targets and risk for adverse effects, degrees of b-cell dysfunction longer met with metformin such as hypoglycemia. A lower target and patients treated with life- (with or without basal insu- A1C in youth with type 2 diabetes when style or metformin only who lin), liraglutide (a glucagon-like compared with those recommended achieve significant weight im- peptide 1 receptor agonist) in type 1 diabetes is justified by lower provement. E therapy should be considered risk of hypoglycemia and higher risk of 13.60 Less-stringent A1C goals (such in children 10 years of age or complications (181–184). as 7.5% [58 mmol/mol]) may older if they have no past Patients and their families must pri- be appropriate if there is in- medical history or family his- oritize lifestyle modifications such creased risk of hypoglycemia. E tory of medullary thyroid as eating a balanced diet, achieving care.diabetesjournals.org Children and Adolescents S173

Association

Diabetes Figure 13.1—Management of new-onset diabetes in youth with overweight or obesity. A1C 8.5% 5 69 mmol/mol. Adapted from the ADA position statement “Evaluation and Management of Youth-Onset Type 2 Diabetes” (2). DKA, diabetic ketoacidosis; HHNK, hyperosmolar hyperglycemic nonketotic syndrome; MDI, multiple daily injections. and maintaining a healthy weight, and (185–187), initial treatment must include recommended. The Treatment Options exercising regularly. A family-centered management of comorbidities such as for Type 2 Diabetes in Adolescents and approach to nutrition and lifestyle obesity, dyslipidemia, hypertension, and Youth (TODAY) study found that metfor- modiﬁcation is essential in children microvascular complications. min alone provided durable glycemic with type 2 diabetes, and nutrition rec- Current pharmacologic treatment op- control (A1C #8% [64 mmol/mol] for ommendations should be culturally ap- tions for youth-onset type 2 diabetes 6 months) in approximately half of the propriate and sensitiveAmerican to family are limited to three approved drugsd subjects (189). The RISE Consortium resources (see Section 5 “Facilitating insulin, metformin, and liraglutide (2). study did not demonstrate differences Behavior Change and Well-being to Im- Presentation with ketoacidosis or marked in measures of glucose or b-cell function prove Health Outcomes,” https://doi ketosis requires a period of insulin ther- preservation between metformin and .org/10.2337/dc20-S005). Given the com- apy until fasting and postprandial glyce- insulin, but there was more weight gain plex social and environmental context mia have been restored to normal or with insulin (190). surrounding youth with type 2 diabetes, near-normal levels. Metformin therapy To date, the TODAY study is the only individual-levellifestyleinterventionsmay may be used as an adjunct after resolu- trial combining lifestyle and metformin not be©2019 sufﬁcient to target the complex tion of ketosis/ketoacidosis. Initial treat- therapy in youth with type 2 diabetes; interplay of family dynamics, mental health, ment should also be with insulin when the combination did not perform better community readiness, and the broader the distinction between type 1 diabetes than metformin alone in achieving du- environmental system (2). and type 2 diabetes is unclear and in rable glycemic control (189). A multidisciplinary diabetes team, patients who have random blood glu- A recent randomized clinical trial in including a physician, diabetes nurse cose concentrations $250 mg/dL (13.9 children aged 10–17 years with type 2 educator, registered dietitian, and psy- mmol/L) and/or A1C $8.5% (69 mmol/mol) diabetes demonstrated the addition of chologist or social worker, is essential. (188). subcutaneous liraglutide (up to 1.8 mg In addition to achieving glycemic tar- When insulin treatment is not daily) to metformin (with or without gets and self-management education required, initiation of metformin is basal insulin) as safe and effective to S174 Children and Adolescents Diabetes Care Volume 43, Supplement 1, January 2020

decrease A1C (estimated decrease of Assessment of Bariatric Surgery (Teen- 13.81 In nonpregnant patients with 1.06 percentage points at 26 weeks LABS) Study, have demonstrated the ef- diabetes and hypertension, and 1.30 at 52 weeks), although it did fectiveness of metabolic surgery in ado- either an ACE inhibitor or an increase the frequency of gastrointesti- lescents (199–205). angiotensin receptor blocker nal side effects (191). In June 2019, the is recommended for those U.S. Food and Drug Administration ap- Prevention and Management of with modestly elevated uri- proved liraglutide injection for treatment Diabetes Complications nary albumin-to-creatinine ra- of pediatric patients aged 10 years or Nephropathy tio (30–299 mg/g creatinine) older with type 2 diabetes (192). Recommendations and is strongly recommended Metabolic Surgery 13.73 Blood pressure should be mea- for those with urinary albumin- sured at every visit. A to-creatinine ratio .300 mg/g Recommendations 13.74 Blood pressure should be op- creatinine and/or estimated 13.71 Metabolic surgery may be con- timized to reduce risk and/or glomerular filtration rate ,60 sidered for the treatment of slow the progression of dia- mL/min/1.73 m2. E adolescents with type 2 diabe- betic kidney disease. A 13.82 For those with nephropathy, tes who are markedly obese 13.75 If blood pressure is $90th per- continued monitoring (yearly (BMI .35 kg/m2)andwhohave centile for age, sex, and height urinary albumin-to-creatinine uncontrolled glycemia and/or or, in adolescents $13 years, ratio, estimated glomerular fil- serious comorbidities despite blood pressure is $120/80 tration rate, and serum potas- lifestyle and pharmacologic mmHg, increased emphasis sium) may aid in assessing intervention. A should be placed on lifestyle Associationadherence and detecting pro- 13.72 Metabolic surgery should be managementto promoteweight gression of disease. E performed only by an experi- loss. If blood pressure remains 13.83 Referral to nephrology is rec- enced surgeon working as part above the 90th percentile or, ommended in case of uncer- of a well-organized and en- in adolescents $13 years, tainty of etiology, worsening gaged multidisciplinary team blood pressure is $120/80 urinary albumin-to-creatinine including a surgeon, endocri- after 6 months, antihyperten- ratio, or decrease in estimated nologist, nutritionist, behavioral sive therapy should be initi- glomerular filtration rate. E A health specialist, and nurse. ated. C 13.76 In addition to lifestyle modi- The results of weight-loss and lifestyle Neuropathy fication, pharmacologic treat- interventions for obesity in children and Diabetes ment of hypertension (systolic Recommendations adolescents have been disappointing, bloodpressureordiastolicblood 13.84 Youth with type 2 diabetes and no effective and safe pharmacologic pressure consistently $95th should be screened for the intervention is available or approved by percentile for age, sex, and presence of neuropathy by foot the U.S. Food and Drug Administration in height or $140/90 mmHg in examination at diagnosis and youth. Over the last decade, weight-loss adolescents $13 years) should annually.Theexaminationshould surgery has been increasingly performed be considered as soon as hy- include inspection, assess- in adolescents with obesity. Small retro- pertension is confirmed. E ment of foot pulses, pinprick spective analyses and a recent prospec- 13.77 Initial therapeutic options in- and 10-g monofilament sensa- tive multicenter nonrandomized study clude ACE inhibitors or angio- tion tests, testing of vibra- suggest that bariatric or metabolic sur- tensin receptor blockers. Other tion sensation using a 128-Hz gery may have benefits inAmerican obese adoles- blood pressure–lowering agents tuning fork, and ankle reflex cents with type 2 diabetes similar to maybeaddedasneeded.C tests. C those observed in adults. Teenagers ex- 13.78 Protein intake should be at the 13.85 Prevention should focus on perience similar degrees of weight loss, recommended daily allowance achieving glycemic targets. C diabetes remission, and improvement of of 0.8 g/kg/day. E cardiometabolic risk factors for at least 13.79 Urine albumin-to-creatinine ra- 3 years after surgery (193). No random- Retinopathy tio should be obtained at the ized trials, however, have yet compared time of diagnosis and annually Recommendations the©2019 effectiveness and safety of surgery thereafter. An elevated urine 13.86 Screening for retinopathy should to those of conventional treatment albumin-to-creatinine ratio (.30 be performed by dilated fundo- options in adolescents (194). The guide- mg/g creatinine) should be scopy or retinal photography lines used as an indication for metabolic confirmed on two of three at or soon after diagnosis and surgery in adolescents generally include samples. B annually thereafter. C BMI .35 kg/m2 with comorbidities or 13.80 Estimated glomerular filtration 13.87 Optimizing glycemia is recom- BMI .40 kg/m2 with or without comor- rate should be determined at mended to decrease the risk or bidities (195–206). A number of grou- the time of diagnosis and an- slow the progression of reti- ps, including the Pediatric Bariatric nually thereafter. E nopathy. B Study Group and the Teen Longitudinal care.diabetesjournals.org Children and Adolescents S175

Dyslipidemia a dilated eye examination should be 13.88 Less frequent examination (ev- performed at diagnosis. Thereafter, ery 2 years) may be consid- Recommendations screening guidelines and treatment rec- ered if there is adequate 13.96 Lipid testing should be per- ommendations for hypertension, dys- glycemic control and a normal formed when initial glycemic lipidemia, urine albumin excretion, and eye exam. C control has been achieved and annually thereafter. B retinopathy are similar to those for youth with type 1 diabetes. Addi- Nonalcoholic Fatty Liver Disease 13.97 Optimal goals are LDL cholesterol ,100 mg/dL (2.6 mmol/L), tional problems that may need to be Recommendations HDL cholesterol .35 mg/dL addressed include polycystic ovary dis- 13.89 Evaluation for nonalcoholic fatty (0.91 mmol/L), and triglycer- ease and other comorbidities associ- liver disease (by measuring AST ides ,150 mg/dL (1.7 mmol/L). ated with pediatric obesity, such as and ALT) should be done at E sleep apnea, hepatic steatosis, ortho- diagnosis and annually there- 13.98 If lipids are abnormal, initial pedic complications, and psychosocial after. B therapy should consist of op- concerns. The ADA position statement “ 13.90 Referral to gastroenterology timizing glucose control and Evaluation and Management of Youth- ” should be considered for per- medical nutritional therapy Onset Type 2 Diabetes (2) provides sistently elevated or worsen- to limit the amount of calories guidance on the prevention, screening, ing transaminases. B from fat to 25–30%, satu- and treatment of type 2 diabetes and its rated fat to ,7%, cholesterol comorbidities in children and adolescents. Obstructive Sleep Apnea ,200 mg/day, avoid trans fats, and aim for ;10% cal- Youth-onsetAssociation type 2 diabetes is asso- Recommendation fi ories from monounsaturated ciated with signi cant microvascular 13.91 Screening for symptomsof sleep fats for elevated LDL. For and macrovascular risk burden and a apnea should be done at each elevated triglycerides, medi- substantial increase in the risk of car- visit, and referral to a pediat- cal nutrition therapy should diovascular morbidity and mortality at ric sleep specialist for evalu- also focus on decreasing simple an earlier age than those diagnosed ation and a polysomnogram, sugar intake and increasing di- later in life (208). The higher complica- if indicated, is recommen- etary n-3 fatty acids in addition tion risk in earlier-onset type 2 diabetes ded. Obstructive sleep apnea to the above changes. A is likely related to prolonged lifetime should be treated when docu- 13.99 If LDL cholesterol remains exposure to hyperglycemia and other mented. B .130 mg/dLDiabetes after 6 months atherogenic risk factors, including in- of dietary intervention, initi- sulinresistance,dyslipidemia,hyperten- fl Polycystic Ovary Syndrome ate therapy with statin, with a sion, and chronic in ammation. There is goal of LDL ,100 mg/dL. B low risk of hypoglycemia in youth with Recommendations type 2 diabetes, even if they are being 13.92 13.100 If triglycerides are .400 mg/ Evaluate for polycystic ovary treated with insulin (209), and there are syndrome in female adoles- dL (4.7 mmol/L) fasting or . high rates of complications (181–184). cents with type 2 diabetes, in- 1,000 mg/dL (11.6 mmol/ L) nonfasting, optimize glyce- These diabetes comorbidities also appear cluding laboratory studies when to be higher than in youth with type 1 B mia and begin fibrate, with indicated. diabetes despite shorter diabetes dura- 13.93 agoalof,400 mg/dL (4.7 Oral contraceptive pills for tion and lower A1C (207). In addition, the treatment of polycystic ovary mmol/L) fasting (to reduce risk for pancreatitis). C progression of vascular abnormalities syndrome are not contraindi-American appears to be more pronounced in cated for girls with type 2 di- youth-onset type 2 diabetes compared C abetes. Cardiac Function Testing with type 1 diabetes of similar dura- 13.94 Metformin in addition to life- tion, including ischemic heart disease fi Recommendation style modi cation is likely to and stroke (210). improve the menstrual cyclic- 13.101 Routine screening for heart disease with electrocardio- ity and hyperandrogenism in Psychosocial Factors girls with type 2 diabetes. E gram, echocardiogram, or ©2019 stress testing is not recom- Recommendations 13.102 Providers should assess social Cardiovascular Disease mended in asymptomatic youthwithtype2diabetes.B context, including potential Recommendation food insecurity, housing sta- 13.95 Intensive lifestyle interventions bility, and financial barriers, Comorbidities may already be present focusing on weight loss, dyslipi- and apply that information to at the time of diagnosis of type 2 di- demia, hypertension, and dys- treatment decisions. E abetes in youth (164,207). Therefore, glycemia are important to 13.103 Use patient-appropriate stan- blood pressure measurement, a fast- prevent overt macrovascular dardized and validated tools ing lipid panel, assessment of random disease in early adulthood. E to assess for diabetes distress urine albumin-to-creatinine ratio, and S176 Children and Adolescents Diabetes Care Volume 43, Supplement 1, January 2020

a miscarriage, stillbirth, or intrauterine health care quality, cost, and outcomes and mental/behavioral health death, and 20.5% of the liveborn infants (226). Worsening diabetes health out- in youth with type 2 diabetes, had a major congenital anomaly. comes during transition to adult care with attention to symptoms of and early adulthood have been docu- depression and eating disor- mented (227,228). ders, and refer to specialty TRANSITION FROM PEDIATRIC TO Although scientiﬁc evidence is limited, care when indicated. B ADULT CARE it is clear that comprehensive and co- 13.104 When choosing glucose- Recommendations ordinated planning that begins in early lowering or other medications 13.107 Pediatric diabetes providers adolescence is necessary to facilitate a for youth with overweight or should begin to prepare seamless transition from pediatric to obesity and type 2 diabetes, youth for transition to adult adult health care (222,223,229,230). consider medication-taking health care in early adoles- New technologies and other interven- behavior and their effect on cence and, at the latest, at tions are being tried to support transi- weight. E least 1 year before the tran- tion to adult care in young adulthood 13.105 Starting at puberty, precon- sition. E (231–235) A comprehensive discussion ception counseling should 13.108 Both pediatric and adult di- regarding the challenges faced during be incorporated into routine abetes care providers should this period, including speciﬁc recommen- diabetes clinic visits for all provide support and resour- dations, is found in the ADA position females of childbearing po- ces for transitioning young statement “Diabetes Care for Emerging tential because of the ad- adults. E Adults: Recommendations for Transition verse pregnancy outcomes 13.109 Youth with type 2 diabetes From Pediatric to Adult Diabetes Care in this population. A Association should be transferred to an Systems” (223). 13.106 Patients should be screened adult-oriented diabetes spe- The Endocrine Society in collaboration for smoking and alcohol use cialist when deemed appro- with the ADA and other organizations has at diagnosis and regularly priate by the patient and developed transition tools for clinicians thereafter. C provider. E and youth and families (230).

Most youth with type 2 diabetes come Care and close supervision of diabetes from racial/ethnic minority groups, management are increasingly shifted References have low socioeconomic status, and from parents and other adults to the 1. Chiang JL, Maahs DM, Garvey KC, et al. Type often experience multiple psychoso- youth with type 1 or type 2 diabetes 1 diabetes in children and adolescents: a posi- cial stressors (22,36,165–168). Consid- throughout childhoodDiabetes and adolescence. tion statement by the American Diabetes Asso- ciation. Diabetes Care 2018;41:2026–2044 eration of the sociocultural context The shift from pediatric to adult health 2. Arslanian S, Bacha F, Grey M, Marcus MD, and efforts to personalize diabetes man- care providers, however, often occurs White NH, Zeitler P. Evaluation and manage- agement are of critical importance to abruptly as the older teen enters the next ment of youth-onset type 2 diabetes: a posi- minimize barriers to care, enhance ad- developmental stage, referred to as tion statement by the American Diabetes herence, and maximize response to emerging adulthood (221), which is a Association. Diabetes Care 2018;41:2648– treatment. critical period for young people who 2668 3. Nadeau KJ, Anderson BJ, Berg EG, et al. Youth- Evidence about psychiatric disorders have diabetes. During this period of onset type 2 diabetes consensus report: current and symptoms in youth with type 2 di- major life transitions, youth begin to status, challenges, and priorities. Diabetes Care abetes is limited (211–215), but given the move out of their parents’ homes and 2016;39:1635–1642 sociocultural context for many youth and must become fully responsible for their 4. Mayer-Davis EJ, Lawrence JM, Dabelea D, the medical burden andAmerican obesity associ- diabetes care. Their new responsibilities et al.; SEARCH for Diabetes in Youth Study. ated with type 2 diabetes, ongoing sur- include self-management of their diabe- Incidence trends of type 1 and type 2 diabetes among youths, 2002–2012. N Engl J Med 2017; veillance of mental health/behavioral tes, making medical appointments, and 376:1419–1429 health is indicated. Symptoms of depres- financing health care, once they are no 5. Thomas NJ, Jones SE, Weedon MN, Shields sion and disordered eating are common longer covered by their parents’ health BM, Oram RA, Hattersley AT. Frequency and and associated with poorer glycemic insurance plans (ongoing coverage until phenotype of type 1 diabetes in the first six control (212,216,217). age 26 years is currently available under decades of life: a cross-sectional, genetically fi Many of the drugs prescribed for di- provisions of the U.S. Affordable Care strati ed survival analysis from UK Biobank. ©2019 Lancet Diabetes Endocrinol 2018;6:122–129 abetes and psychiatric disorders are as- Act). In addition to lapses in health care, 6. Barnea-Goraly N, Raman M, Mazaika P, et al.; sociated with weight gain and can increase this is also a period associated with Diabetes Research in Children Network (Direc- patients’ concerns about eating, body deterioration in glycemic stability; in- Net). Alterations in white matter structure in shape, and weight (218,219). creased occurrence of acute complica- young children with type 1 diabetes. Diabetes The TODAY study documented (220) tions; psychosocial, emotional, and Care 2014;37:332–340 that despite disease- and age-specific behavioral challenges; and the emer- 7. Cameron FJ, Scratch SE, Nadebaum C, et al.; DKA Brain Injury Study Group. Neurological counseling, 10.2% of the females in gence of chronic complications (222–225). consequences of diabetic ketoacidosis at initial the cohort became pregnant over an av- The transition period from pediatric to adult presentation of type 1 diabetes in a prospective erage of 3.8 years of study participation. care is prone to fragmentation in health cohort study of children. Diabetes Care 2014;37: Of note, 26.4% of pregnancies ended in care delivery, which may adversely impact 1554–1562 care.diabetesjournals.org Children and Adolescents S177

8. Markowitz JT, Garvey KC, Laffel LMB. De- and Diabetes Prospective Follow-up Registry. 38. Katz ML, Volkening LK, Butler DA, Anderson velopmental changes in the roles of patients Obesity in youth with type 1 diabetes in Ger- BJ, Laffel LM. Family-based psychoeducation and and families in type 1 diabetes management. many, Austria, and the United States. J Pediatr Care Ambassador intervention to improve gly- Curr Diabetes Rev 2015;11:231–238 2015;167:627–632.e4 cemic control in youth with type 1 diabetes: 9. Driscoll KA, Volkening LK, Haro H, et al. Are 24. Corbin KD, Driscoll KA, Pratley RE, Smith SR, a randomized trial. Pediatr Diabetes 2014;15: children with type 1 diabetes safe at school? Maahs DM, Mayer-Davis EJ; Advancing Care for 142–150 Examining parent perceptions. Pediatr Diabetes Type 1 Diabetes and Obesity Network (ACT1ON). 39. Laffel LMB, Vangsness L, Connell A, Goebel- 2015;16:613–620 Obesity in type 1 diabetes: pathophysiology, Fabbri A, Butler D, Anderson BJ. Impact of 10. Mehta SN, Volkening LK, Anderson BJ, et al.; clinical impact, and mechanisms. Endocr Rev ambulatory, family-focused teamwork interven- Family Management of Childhood Diabetes 2018;39:629–663 tion on glycemic control in youth with type 1 Study Steering Committee. Dietary behaviors 25. Redondo MJ, Foster NC, Libman IM, et al. diabetes. J Pediatr 2003;142:409–416 predict glycemic control in youth with type 1 Prevalence of cardiovascular risk factors in youth 40. Anderson BJ, Vangsness L, Connell A, Butler diabetes. Diabetes Care 2008;31:1318–1320 with type 1 diabetes and elevated body mass D, Goebel-Fabbri A, Laffel LMB. Family conflict, 11. Riddell MC, Gallen IW, Smart CE, et al. index. Acta Diabetol 2016;53:271–277 adherence, and glycaemic control in youth with Exercise management in type 1 diabetes: a con- 26. Jackson CC, Albanese-O’Neill A, Butler KL, short duration type 1 diabetes. Diabet Med 2002; sensus statement. Lancet Diabetes Endocrinol et al. Diabetes care in the school setting: a po- 19:635–642 2017;5:377–390 sition statement of the American Diabetes As- 41. Helgeson VS, Palladino DK. Implications of 12. Colberg SR, Sigal RJ, Yardley JE, et al. Physical sociation. Diabetes Care 2015;38:1958–1963 psychosocial factors for diabetes outcomes activity/exercise and diabetes: a position state- 27. Siminerio LM, Albanese-O’Neill A, Chiang JL, among children with type 1 diabetes: a review. ment of the American Diabetes Association. et al.; American Diabetes Association. Care of Soc Personal Psychol Compass 2012;6:228–242 Diabetes Care 2016;39:2065–2079 young children with diabetes in the child care 42. McCarthy AM, Lindgren S, Mengeling MA, 13. Robertson K, Adolfsson P, Scheiner G, Hanas setting: a position statement of the American Tsalikian E, Engvall J. Factors associated with R, Riddell MC. Exercise in children and adoles- Diabetes Association. Diabetes Care 2014;37: academic achievement in children with type 1 cents with diabetes. Pediatr Diabetes 2009; 2834–2842 diabetes. Diabetes Care 2003;26:112–117 10(Suppl. 12):154–168 28. Corathers SD, Kichler J, Jones N-HY, et al. 43. KutherAssociation TL. Medical decision-making and 14. U.S. Department of Health and Human Serv- Improving depression screening for adolescents minors: issues of consent and assent. Adoles- ices. 2008 physical activity guidelines for Amer- with type 1 diabetes. Pediatrics 2013;132: cence 2003;38:343–358 icans: index. Accessed 29 October 2019. Available e1395–e1402journal 44. Coleman DL, Rosoff PM. The legal authority from https://health.gov/paguidelines/guidelines/ 29. Hood KK, Beavers DP, Yi-Frazier J, et al. of mature minors to consent to general medical default.aspx Psychosocial burden and glycemic control during treatment. Pediatrics 2013;131:786–793 15. Tsalikian E, Kollman C, Tamborlane WB, the first 6 years of diabetes: results from the 45. Charron-Prochownik D, Sereika SM, Becker et al.; Diabetes Research in Children Network SEARCH for Diabetes in Youth study. J Adolesc D, et al. Long-term effects of the booster- (DirecNet) Study Group. Prevention of hypogly- Health 2014;55:498–504 enhancedREADY-Girls preconception counseling cemia during exercise in children with type 1 30. Ducat L, Philipson LH, Anderson BJ. The program on intentions and behaviors for family diabetes by suspending basal insulin. Diabetes mental health comorbidities of diabetes. planning in teens with diabetes. Diabetes Care Care 2006;29:2200–2204 JAMA 2014;312:691–692 2013;36:3870–3874 16. Taplin CE, Cobry E, Messer L, McFann K, Chase 31. Hagger V, Hendrieckx C, Sturt J, Skinner TC, 46. Charron-Prochownik D, Downs J. Diabetes HP, Fiallo-Scharer R. Preventing post-exercise noc- Speight J. Diabetes distressDiabetes among adolescents and Reproductive Health for Girls. Alexandria, VA, turnal hypoglycemia in children with type 1 di- with type 1 diabetes: a systematic review. Curr American Diabetes Association, 2016 abetes. J Pediatr 2010;157:784–788.e1 Diab Rep 2016;16:9 47. Wisting L, Frøisland DH, Skrivarhaug T, 17. Riddell MC, Milliken J. Preventing exercise- 32. Anderson BJ, Laffel LM, Domenger C, et al. Dahl-Jørgensen K, Rø O. Disturbed eating be- induced hypoglycemia in type 1 diabetes using Factors associated with diabetes-specific health- havior and omission of insulin in adolescents real-time continuous glucose monitoring and a related quality of life in youth with type 1 di- receiving intensified insulin treatment: a nation- new carbohydrate intake algorithm: an obser- abetes: the global TEENs study [published wide population-based study. Diabetes Care vational field study. Diabetes Technol Ther 2011; correction appears in Diabetes Care 2018;41: 2013;36:3382–3387 13:819–825 640]. Diabetes Care 2017;40:1002–1009 48. Goebel-Fabbri AE. Disturbed eating behav- 18. Francescato MP, Stel G, Stenner E, Geat M. 33. Hilliard ME, De Wit M, Wasserman RM, et al. iors and eating disorders in type 1 diabetes: Prolonged exercise in type 1 diabetes: perfor- Screening and support for emotional burdens of clinical significance and treatment recommen- mance of a customizable algorithm to estimate youth with type 1 diabetes: strategies for di- dations. Curr Diab Rep 2009;9:133–139 the carbohydrate supplements to minimize gly- abetes care providers. Pediatr Diabetes 2018;19: 49. Atik Altınok Y, Ozg¨ ur¨ S, Meseri R, Ozen¨ S, cemic imbalances. PLoS One 2015;10:e0125220American534–543 Darcan S¸,Goks¸en¨ D. Reliability and validity of the 19. Adolfsson P, Mattsson S, Jendle J. Evaluation 34. Shapiro JB, Vesco AT, Weil LEG, Evans MA, diabetes eating problem survey in Turkish chil- of glucose control when a new strategy of in- Hood KK, Weissberg-Benchell J. Psychometric dren and adolescents with type 1 diabetes creased carbohydrate supply is implemented properties of the Problem Areas in Diabetes: mellitus. J Clin Res Pediatr Endocrinol 2017;9: during prolonged physical exercise in type 1 Teen and Parent of Teen versions. J Pediatr 323–328 diabetes. Eur J Appl Physiol 2015;115:2599–2607 Psychol 2018;43:561–571 50. Saßmann H, Albrecht C, Busse-Widmann P, 20. Baker LB, Rollo I, Stein KW, Jeukendrup AE. 35. Lawrence JM, Yi-Frazier JP, Black MH, et al.; et al. Psychometric properties of the German Acute effects of carbohydrate supplementation SEARCH for Diabetes in Youth Study Group. version of the Diabetes Eating Problem Survey- on intermittent sports performance. Nutrients Demographic and clinical correlates of diabe- Revised: additional benefit of disease-specific 2015;7:5733–5763 tes-related quality of life among youth with screening in adolescents with Type 1 diabetes. 21. Redondo©2019 MJ, Libman I, Cheng P, et al.; type 1 diabetes. J Pediatr 2012;161:201–207.e2 Diabet Med 2015;32:1641–1647 Pediatric Diabetes Consortium. Racial/ethnic mi- 36. Young-Hyman D, de Groot M, Hill-Briggs F, 51. Maahs DM, Hermann JM, DuBose SN, et al.; nority youth with recent-onset type 1 diabetes Gonzalez JS, Hood K, Peyrot M. Psychosocial care DPV Initiative; T1D Exchange Clinic Network. have poor prognostic factors. Diabetes Care for people with diabetes: a position statement of Contrasting the clinical care and outcomes of 2018;41:1017–1024 the American Diabetes Association. Diabetes 2,622 children with type 1 diabetes less than 22. Liu LL, Lawrence JM, Davis C, et al.; SEARCH Care 2016;39:2126–2140 6 years of age in the United States T1D Exchange for Diabetes in Youth Study Group. Prevalence of 37. Markowitz JT, Butler DA, Volkening LK, and German/Austrian DPV registries. Diabetolo- overweight and obesity in youth with diabetes in Antisdel JE, Anderson BJ, Laffel LMB. Brief screen- gia 2014;57:1578–1585 USA: the SEARCH for Diabetes in Youth study. ing tool for disordered eating in diabetes: internal 52. HaynesA,Hermann JM,Miller KM,et al.; T1D Pediatr Diabetes 2010;11:4–11 consistency and external validity in a contempo- Exchange, WACDD and DPV registries. Severe 23. DuBose SN, Hermann JM, Tamborlane WV, rary sample of pediatric patients with type 1 hypoglycemia rates are not associated with HbA1c: et al.; Type 1 Diabetes Exchange Clinic Network diabetes. Diabetes Care 2010;33:495–500 a cross-sectional analysis of 3 contemporary S178 Children and Adolescents Diabetes Care Volume 43, Supplement 1, January 2020

pediatric diabetes registry databases. Pediatr Di- Interventions and Complications Research 78. Abraham MB, Davey R, O’Grady MJ, et al. abetes 2017;18:643–650 Group. Sustained effect of intensive treatment Effectiveness of a predictive algorithm in the 53. Jaeb Center for Health Research. CGM In- of type 1 diabetes mellitus on development prevention of exercise-induced hypoglycemia in tervention in Teens and Young Adults With and progression of diabetic nephropathy: the type 1 diabetes. Diabetes Technol Ther 2016;18: Type 1 Diabetes (T1D) (CITY). In: ClinicalTrials Epidemiology of Diabetes Interventions and 543–550 .gov. Bethesda, MD, National Library of Medi- Complications (EDIC) study. JAMA 2003;290: 79. Buckingham BA, Bailey TS, Christiansen M, cine. Accessed 3 October 2019. Available from 2159–2167 et al. Evaluation of a predictive low-glucose https://clinicaltrials.gov/ct2/show/NCT03263494 65. Writing Team for the DCCT/EDIC Research management system in-clinic. Diabetes Technol 54. Jaeb Center for Health Research. Strategies Group, Gubitosi-Klug RA, Sun W, et al. Effects of Ther 2017;19:288–292 to Enhance New CGM Use in Early Childhood prior intensive insulin therapy and risk factors on 80. Nimri R, Muller I, Atlas E, et al. MD-Logic (SENCE). In: ClinicalTrials.gov. Accessed 3 Octo- patient-reported visual function outcomes in overnight control for 6 weeks of home use in ber 2019. Available from https://clinicaltrials the Diabetes Control and Complications Trial/ patients with type 1 diabetes: randomized cross- .gov/ct2/show/NCT02912728 Epidemiology of Diabetes Interventions and over trial. Diabetes Care 2014;37:3025–3032 55. Rosenbauer J, Dost A, Karges B, et al.; DPV Complications (DCCT/EDIC) cohort. JAMA Oph- 81. Thabit H, Tauschmann M, Allen JM, et al. Initiative and the German BMBF Competence thalmol 2016;134:137–145 Home use of an artificial beta cell in type 1 Network Diabetes Mellitus. Improved metabolic 66. Orchard TJ, Nathan DM, Zinman B, et al.; diabetes. N Engl J Med 2015;373:2129–2140 control in children and adolescents with type 1 Writing Group for the DCCT/EDIC Research 82. Bergenstal RM, Garg S, Weinzimer SA, et al. diabetes: a trend analysis using prospective Group. Association between 7 years of intensive Safety of a hybrid closed-loop insulin delivery multicenter data from Germany and Austria. treatment of type 1 diabetes and long-term system in patients with type 1 diabetes. JAMA Diabetes Care 2012;35:80–86 mortality. JAMA 2015;313:45–53 2016;316:1407–1408 56. Cameron FJ, de Beaufort C, Aanstoot HJ, 67. Foland-Ross LC, Reiss AL, Mazaika PK, et al.; 83. Kovatchev B, Cheng P, Anderson SM, et al. et al.; Hvidoere International Study Group. Les- Diabetes Research in Children Network (Direc- Feasibility of long-term closed-loop control: sons from the Hvidoere International Study Net). Longitudinal assessment of hippocampus a multicenter 6-month trial of 24/7 automated Group on childhood diabetes: be dogmatic about structurein childrenwith type 1diabetes. Pediatr insulin delivery. Diabetes Technol Ther 2017;19: outcome and flexible in approach. Pediatr Di- Diabetes 2018;19:1116–1123 18–Association24 abetes 2013;14:473–480 68. Mauras N, Mazaika P, Buckingham B, et al.; 84. El-Khatib FH, Balliro C, Hillard MA, et al. 57. Nimri R, Weintrob N, Benzaquen H, Ofan R, Diabetes Research in Children Network (Direc- Homeuseofabihormonalbionicpancreasversus Fayman G, Phillip M. Insulin pump therapy in Net). Longitudinal assessment of neuroanatom- insulin pump therapy in adults with type 1 di- youth with type 1 diabetes: a retrospective ical and cognitive differences in young children abetes:a multicentre randomised crossover trial. paired study. Pediatrics 2006;117:2126–2131 with type 1 diabetes: association with hypergly- Lancet 2017;389:369–380 58. Doyle EA, Weinzimer SA, Steffen AT, Ahern cemia. Diabetes 2015;64:1770–1779 85. Levine BS, Anderson BJ, Butler DA, Antisdel JAH, Vincent M, Tamborlane WVA. A random- 69. Pourabbasi A, Tehrani-Doost M, Qavam SE, JE, Brackett J, Laffel LM. Predictors of glycemic ized, prospective trial comparing the efficacy of Arzaghi SM, Larijani B. Association of diabetes control and short-term adverse outcomes in continuous subcutaneous insulin infusion with mellitus and structural changes in the central youth with type 1 diabetes. J Pediatr 2001; multiple daily injections using insulin glargine. nervous system in children and adolescents: 139:197–203 Diabetes Care 2004;27:1554–1558 a systematic review. J Diabetes Metab Disord 86. Miller KM, Beck RW, Bergenstal RM, et al.; 59. Diabetes Control and Complications Trial 2017;16:10 T1D Exchange Clinic Network. Evidence of a Research Group. Effect of intensive diabetes 70. Perantie DC, WuDiabetes J, Koller JM, et al. Regional strong association between frequency of self- treatment on the development and progression brain volume differences associated with hyper- monitoring of blood glucose and hemoglobin of long-term complications in adolescents with glycemia and severe hypoglycemia in youth with A1c levels in T1D Exchange clinic registry par- insulin-dependent diabetes mellitus: Diabetes type 1 diabetes. Diabetes Care 2007;30:2331– ticipants. Diabetes Care 2013;36:2009–2014 Control and Complications Trial. J Pediatr 1994; 2337 87. Haynes A, Hermann JM, Clapin H, et al.; 125:177–188 71. Arbelaez AM, Semenkovich K, Hershey T. WACDD and DPV registries. Decreasing trends in 60. White NH, Cleary PA, Dahms W, Goldstein D, Glycemic extremes in youth with T1DM: the mean HbA1c are not associated with increasing Malone J, Tamborlane WV; Diabetes Control and structural and functional integrity of the de- rates of severe hypoglycemia in children: a lon- Complications Trial (DCCT)/Epidemiology of Di- veloping brain. Pediatr Diabetes 2013;14:541– gitudinal analysis of two contemporary popula- abetes Interventions and Complications (EDIC) 553journal tion-based pediatric type 1 diabetes registries Research Group. Beneficial effects of intensive 72. Broadley MM, White MJ, Andrew B. A from Australia and Germany/Austria between therapy of diabetes during adolescence: out- systematic review and meta-analysis of execu- 1995 and 2016. Diabetes Care 2019;42:1630– comes after the conclusion of the Diabetes tive function performance in type 1 diabetes 1636 Control and Complications TrialAmerican (DCCT). J Pediatr mellitus. Psychosom Med 2017;79:684–696 88. Fredheim S, Johansen A, Thorsen SU, et al.; 2001;139:804–812 73. Ryan CM. Why is cognitive dysfunction Danish Society for Diabetes in Childhood and 61. Samuelsson U, Steineck I, Gubbjornsdottir S. associated with the development of diabetes Adolescence. Nationwide reduction in the fre- A high mean-HbA1c value 3-15 months after early in life? The diathesis hypothesis. Pediatr quency of severe hypoglycemia by half. Acta diagnosis of type 1 diabetes in childhood is Diabetes 2006;7:289–297 Diabetol 2015;52:591–599 related to metabolic control, macroalbuminuria, 74. Cameron FJ. The impact of diabetes on brain 89. Birkebaek NH, Drivvoll AK, Aakeson K, et al. and retinopathy in early adulthood–apilot function in childhood and adolescence. Pediatr Incidence of severe hypoglycemia in children study using two nation-wide population based Clin North Am 2015;62:911–927 with type 1 diabetes in the Nordic countries in quality registries. Pediatr Diabetes 2014;15: 75. Campbell MS, Schatz DA, Chen V, et al.; T1D the period 2008-2012: association with hemo- 229–235 Exchange Clinic Network. A contrast between globin A 1c and treatment modality. BMJ Open 62.©2019 Carlsen S, Skrivarhaug T, Thue G, et al. children and adolescents with excellent and poor Diabetes Res Care 2017;5:e000377 Glycemic control and complications in patients control: the T1D Exchange clinic registry expe- 90. Ly TT, Nicholas JA, Retterath A, Lim EM, Davis with type 1 diabetes - a registry-based longitu- rience. Pediatr Diabetes 2014;15:110–117 EA, Jones TW. Effect of sensor-augmented insulin dinal study of adolescents and young adults. 76. Cooper MN, O’Connell SM, Davis EA, Jones pump therapy and automated insulin suspen- Pediatr Diabetes 2017;18:188–195 TW. A population-based study of risk factors for sion vs standard insulin pump therapy on hypo- 63. Genuth SM, Backlund J-YC, Bayless M, et al.; severe hypoglycaemia in a contemporary cohort glycemia in patients with type 1 diabetes: DCCT/EDIC Research Group. Effects of prior in- of childhood-onset type 1 diabetes. Diabetologia a randomized clinical trial. JAMA 2013;310: tensive versus conventional therapy and history 2013;56:2164–2170 1240–1247 of glycemia on cardiac function in type 1 diabetes 77. Bergenstal RM, Klonoff DC, Garg SK, et al.; 91. Downie E, Craig ME, Hing S, Cusumano J, in the DCCT/EDIC. Diabetes 2013;62:3561–3569 ASPIRE In-Home Study Group. Threshold-based Chan AKF, Donaghue KC. Continued reduction in 64. Writing Team for the Diabetes Control and insulin-pump interruption for reduction of hy- the prevalence of retinopathy in adolescents Complications Trial/Epidemiology of Diabetes poglycemia. N Engl J Med 2013;369:224–232 with type 1 diabetes: role of insulin therapy care.diabetesjournals.org Children and Adolescents S179

and glycemic control. Diabetes Care 2011;34: 105. Triolo TM, Armstrong TK, McFann K, et al. celiac disease: a multicenter longitudinal analysis 2368–2373 Additional autoimmune disease found in 33% of of 56,514 patients from the German-Austrian 92. Karges B, Rosenbauer J, Kapellen T, et al. patients at type 1 diabetes onset. Diabetes Care DPV database. Diabetes Care 2015;38:801– Hemoglobin A1c levels and risk of severe hy- 2011;34:1211–1213 807 poglycemia in children and young adults with 106. Kordonouri O, Deiss D, Danne T, Dorow A, 118. Mollazadegan K, Kugelberg M, Montgomery type 1 diabetes from Germany and Austria: Bassir C, Gruters-Kieslich¨ A. Predictivity of thy- SM,SandersDS,LudvigssonJ,LudvigssonJF.A a trend analysis in a cohort of 37,539 patients roid autoantibodies for the development of population-based study of the risk of diabetic between 1995 and 2012. PLoS Med 2014;11: thyroid disorders in children and adolescents retinopathy in patients with type 1 diabetes and e1001742 with type 1 diabetes. Diabet Med 2002;19:518– celiac disease. Diabetes Care 2013;36:316–321 93. Johnson SR, Cooper MN, Jones TW, Davis EA. 521 119. Rubio-Tapia A, Hill ID, Kelly CP, Calderwood Long-term outcome of insulin pump therapy in 107. Dost A, Rohrer TR, Frohlich-Reiterer¨ E, AH, Murray JA; American College of Gastroen- children with type 1 diabetes assessed in a large et al.; DPV Initiative and the German Compe- terology. ACG clinical guidelines: diagnosis and population-based case-control study. Diabetolo- tence Network Diabetes Mellitus. Hyperthyroid- management of celiac disease. Am J Gastro- gia 2013;56:2392–2400 ism in 276 children and adolescents with type 1 enterol 2013;108:656–676; quiz 677 94. Karges B, Kapellen T, Wagner VM, et al.; DPV diabetes from Germany and Austria. Horm Res 120. Paul SP, Sandhu BK, Spray CH, Basude D, Initiative. Glycated hemoglobin A1c as a risk Paediatr 2015;84:190–198 Ramani P. Evidence supporting serology-based factor for severe hypoglycemia in pediatric 108. Jonsdottir B, Larsson C, Carlsson A, et al.; pathway for diagnosing celiac disease in asymp- type 1 diabetes. Pediatr Diabetes 2017;18:51–58 Better Diabetes Diagnosis Study Group. Thyroid tomatic children from high-risk groups. J Pediatr 95. Saydah S, Imperatore G, Divers J, et al. and islet autoantibodies predict autoimmune Gastroenterol Nutr 2018;66:641–644 Occurrence of severe hypoglycaemic events thyroid disease at type 1 diabetes diagnosis. J 121. Abid N, McGlone O, Cardwell C, McCallion among US youth and young adults with Clin Endocrinol Metab 2017;102:1277–1285 W, Carson D. Clinical and metabolic effects of type 1 or type 2 diabetes. Endocrinol Diabetes 109. Mohn A, Di Michele S, Di Luzio R, Tumini S, gluten free diet in children with type 1 diabetes Metab 2019;2:e00057 Chiarelli F. The effect of subclinical hypothyroid- and coeliac disease. Pediatr Diabetes 2011;12: 96. Ishtiak-Ahmed K, Carstensen B, Pedersen- ism on metabolic control in children and ado- 322–325 Bjergaard U, Jørgensen ME. Incidence trends and lescents with type 1 diabetes mellitus. Diabet 122. HusbyAssociation S, Koletzko S, Korponay-Szabo´ IR, predictors of hospitalization for hypoglycemia in Med 2002;19:70–73 et al.; ESPGHAN Working Group on Coeliac 17,230 adult patients with type 1 diabetes: 110. Holmes GKT. Screening for coeliac disease Disease Diagnosis; ESPGHAN Gastroenterology a Danish Register linkage cohort study. Diabetes in type 1 diabetes. Arch Dis Child 2002;87:495– Committee; European Society for Pediatric Gas- Care 2017;40:226–232 498 troenterology, Hepatology, and Nutrition. Euro- 97. Swift PGF, Skinner TC, de Beaufort CE, et al.; 111. Rewers M, Liu E, Simmons J, Redondo MJ, pean Society for Pediatric Gastroenterology, Hvidoere Study Group on Childhood Diabetes. Hoffenberg EJ. Celiac disease associated with Hepatology, and Nutrition guidelines for the Target setting in intensive insulin management is type 1 diabetes mellitus. Endocrinol Metab Clin diagnosis of coeliac disease. J Pediatr Gastro- associated with metabolic control: the Hvidoere North Am 2004;33:197–214, xi enterol Nutr 2012;54:136–160 childhood diabetes study group centre differ- 112. Pham-Short A, Donaghue KC, Ambler G, 123. Kurppa K, Paavola A, Collin P, et al. Benefits ences study 2005. Pediatr Diabetes 2010;11: Phelan H, Twigg S, Craig ME. Screening for celiac of a gluten-free diet for asymptomatic patients 271–278 disease in type 1 diabetes: a systematic review. with serologic markers of celiac disease. Gastro- 98. Warncke K, Frohlich-Reiterer¨ EE, Thon A, Pediatrics 2015;136:e170–e176 enterology 2014;147:610–617.e1 Hofer SE, Wiemann D, Holl RW; DPV Initiative of 113. Craig ME, Prinz N,Diabetes Boyle CT, et al.; Austral- 124. Marcovecchio ML, Chiesa ST, Bond S, et al.; the German Working Group for Pediatric Dia- asian Diabetes Data Network (ADDN); T1D Ex- AdDIT Study Group. ACE inhibitors and statins in betology; German BMBF Competence Network change Clinic Network (T1DX); National adolescents with type 1 diabetes. N Engl J Med for Diabetes Mellitus. Polyendocrinopathy in Paediatric Diabetes Audit (NPDA) and the Royal 2017;377:1733–1745 children, adolescents, and young adults with College of Paediatrics and Child Health; Pro- 125. de Ferranti SD, de Boer IH, Fonseca V, et al. type 1 diabetes: a multicenter analysis of spective Diabetes Follow-up Registry (DPV) ini- Type 1 diabetes mellitus and cardiovascular 28,671 patients from the German/Austrian tiative. Prevalence of celiac disease in 52,721 disease:ascientific statementfromthe American DPV-Wiss database. Diabetes Care 2010;33: youth with type 1 diabetes: international com- Heart Association and American Diabetes Asso- 2010–2012 parison across three continents. Diabetes Care ciation. Circulation 2014;130:1110–1130 99. Nederstigt C, Uitbeijerse BS, Janssen LGM, 2017;40:1034–1040 126. Rodriguez BL, Fujimoto WY, Mayer-Davis Corssmit EPM, de Koning EJP, Dekkers OM. 114. Cerutti F, Bruno G, Chiarelli F, Lorini R, EJ, et al. Prevalence of cardiovascular disease risk Associated auto-immune disease in type 1 di- Meschi F, Sacchetti C; Diabetes Study Group of factors in U.S. children and adolescents with abetes patients: a systematic review and meta- the Italian Society of Pediatric Endocrinology diabetes: the SEARCH for Diabetes in Youth analysis. Eur J Endocrinol 2019;180:135American–144 and Diabetology. Younger age at onset and study. Diabetes Care 2006;29:1891–1896 100. KozhakhmetovaA,WyattRC,CaygillC,etal. sex predict celiac disease in children and 127. Margeirsdottir HD, Larsen JR, Brunborg C, A quarter of patients with type 1 diabetes have adolescents with type 1 diabetes: an Italian Overby NC, Dahl-Jørgensen K; Norwegian Study co-existing non-islet autoimmunity: the findings multicenter study. Diabetes Care 2004;27: Group for Childhood Diabetes. High prevalence of a UK population-based family study. Clin Exp 1294–1298 of cardiovascular risk factors in children and Immunol 2018;192:251–258 115. Simmons JH, Foster NC, Riddlesworth TD, adolescents with type 1 diabetes: a popula- 101. Hughes JW, Riddlesworth TD, DiMeglio LA, et al.; T1D Exchange Clinic Network. Sex- and tion-based study. Diabetologia 2008;51:554–561 Miller KM, Rickels MR, McGill JB. Autoimmune age-dependent effects of celiac disease on 128. Schwab KO, Doerfer J, Hecker W, et al.; DPV diseases in children and adults with type 1 di- growthandweightgaininchildrenwith Initiative of the German Working Group for abetes from the T1D Exchange Clinic Registry. type 1 diabetes: analysis of the Type 1 Diabetes Pediatric Diabetology. Spectrum and prevalence J Clin©2019 Endocrinol Metab 2016;101:4931 –4937 Exchange Clinic Registry.Pediatr Diabetes2018; of atherogenic risk factors in 27,358 children, 102. Kahaly GJ, Hansen MP. Type 1 diabetes 19:741–748 adolescents, and young adults with type 1 di- associated autoimmunity. Autoimmun Rev 2016; 116. Margoni D, Chouliaras G, Duscas G, et al. abetes: cross-sectional data from the German 15:644–648 Bone health in children with celiac disease diabetes documentation and quality manage- 103. Roldan´ MB, Alonso M, Barrio R. Thyroid assessed by dual x-ray absorptiometry: effect ment system (DPV). Diabetes Care 2006;29:218– autoimmunity in children and adolescents with of gluten-free diet and predictive value of serum 225 type 1 diabetes mellitus. Diabetes Nutr Metab biochemical indices. J Pediatr Gastroenterol Nutr 129. Singh TP, Groehn H, Kazmers A. Vascular 1999;12:27–31 2012;54:680–684 function and carotid intimal-medial thickness in 104. Shun CB, Donaghue KC, Phelan H, Twigg 117. Rohrer TR, Wolf J, Liptay S, et al.; DPV children with insulin-dependent diabetes melli- SM, Craig ME. Thyroid autoimmunity in type 1 Initiative and the German BMBF Competence tus. J Am Coll Cardiol 2003;41:661–665 diabetes: systematic review and meta-analysis. Network Diabetes Mellitus. Microvascular com- 130. Haller MJ, Stein J, Shuster J, et al. Peripheral Diabet Med 2014;31:126–135 plications in childhood-onset type 1 diabetes and artery tonometry demonstrates altered endothelial S180 Children and Adolescents Diabetes Care Volume 43, Supplement 1, January 2020

function in children with type 1 diabetes. Pediatr 140. McCrindle BW, Urbina EM, Dennison BA, 152. Schwartz GJ, Work DF. Measurement and Diabetes 2007;8:193–198 et al.; American Heart Association Atheroscle- estimation of GFR in children and adolescents. 131. Urbina EM, Wadwa RP, Davis C, et al. rosis, Hypertension, and Obesity in Youth Com- Clin J Am Soc Nephrol 2009;4:1832–1843 Prevalence of increased arterial stiffness in chil- mittee; American Heart Association Council of 153. Inker LA, Schmid CH, Tighiouart H, et al.; dren with type 1 diabetes mellitus differs by Cardiovascular Disease in the Young; American CKD-EPI Investigators. Estimating glomerular fil- measurement site and sex: the SEARCH for Di- Heart Association Council on Cardiovascular tration rate from serum creatinine and cysta- abetes in Youth Study. J Pediatr 2010;156:731– Nursing. Drug therapy of high-risk lipid abnor- tin C. N Engl J Med 2012;367:20–29 737.e1 malities in children and adolescents: a scientific 154. Cho YH, Craig ME, Hing S, et al. Microvas- 132. Expert Panel on Integrated Guidelines for statement from the American Heart Association cular complications assessment in adolescents Cardiovascular Health and Risk Reduction in Atherosclerosis, Hypertension, and Obesity in with 2- to 5-yr duration of type 1 diabetes from Children and Adolescents; National Heart, Youth Committee, Council of Cardiovascular 1990 to 2006. Pediatr Diabetes 2011;12:682–689 Lung, and Blood Institute. Expert Panel on In- Disease in the Young, with the Council on Car- 155. Scanlon PH, Stratton IM, Bachmann MO, tegrated Guidelines for Cardiovascular Health diovascular Nursing. Circulation 2007;115:1948– Jones C, Leese GP; Four Nations Diabetic Reti- and Risk Reduction in Children and Adolescents: 1967 nopathy Screening Study Group. Risk of diabetic summary report. Pediatrics 2011;128(Suppl. 5): 141. Salo P, Viikari J, Ham¨ al¨ ainen¨ M, et al. Serum retinopathy at first screen in children at 12 and S213–S256 cholesterol ester fatty acids in 7- and 13-month- 13 years of age. Diabet Med 2016;33:1655–1658 133. Blaha MJ, Blumenthal RS, Brinton EA, old children in a prospective randomized trial of a 156. Beauchamp G, Boyle CT, Tamborlane WV, Jacobson TA; National Lipid Association Task- low-saturated fat, low-cholesterol diet: the STRIP et al.; T1D Exchange Clinic Network. Treatable forceonNon-HDLCholesterol. Theimportanceof baby project: Special Turku coronary Risk factor diabetic retinopathy is extremely rare among non-HDL cholesterol reporting in lipid manage- Intervention Project for children. Acta Paediatr pediatric T1D Exchange clinic registry partici- ment. J Clin Lipidol 2008;2:267–273 1999;88:505–512 pants. Diabetes Care 2016;39:e218–e219 134. Kershnar AK, Daniels SR, Imperatore G, 142. McCrindle BW, Ose L, Marais AD. Efficacy 157. Nathan DM, Bebu I, Hainsworth D, et al.; et al. Lipid abnormalities are prevalent in youth and safety of atorvastatin in children and ado- DCCT/EDIC Research Group. Frequency of evi- with type 1 and type 2 diabetes: the SEARCH for lescents with familial hypercholesterolemia or dence-based screening for retinopathy in type 1 Diabetes in Youth Study. J Pediatr 2006;149:314– severe hyperlipidemia: a multicenter, random- diabetes.Association N Engl J Med 2017;376:1507–1516 319 ized, placebo-controlled trial. J Pediatr 2003;143: 158. Gubitosi-Klug RA, Bebu I, White NH, et al.; 135. Maahs DM, Dabelea D, D’Agostino RB Jr, 74–80 DiabetesControlandComplicationsTrial (DCCT)/ et al.; SEARCH for Diabetes in Youth Study. 143. Wiegman A, Hutten BA, de Groot E, et al. Epidemiology of Diabetes Interventions and Glucose control predicts 2-year change in lipid Efficacy and safety of statin therapy in children Complications (EDIC) Research Group*. Screen- profile in youth with type 1 diabetes. J Pediatr with familial hypercholesterolemia: a random- ing eye exams in youth with type 1 diabetes 2013;162:101–107.e1 ized controlled trial. JAMA 2004;292:331–337 under 18 years of age: once may be enough? 136. Daniels SR, Greer FR; Committee on Nu- 144. Karter AJ, Stevens MR, Gregg EW, et al. Pediatr Diabetes 2019;20:743–749 trition. Lipid screening and cardiovascular health Educational disparities in rates of smoking 159. Jaiswal M, Divers J, Dabelea D, et al. Prev- in childhood. Pediatrics 2008;122:198–208 among diabetic adults: the translating research alence of and risk factors for diabetic peripheral 137. Kavey R-EW, Allada V, Daniels SR, et al.; into action for diabetes study. Am J Public Health neuropathy in youth with type 1 and type 2 American Heart Association Expert Panel on 2008;98:365–370 diabetes: SEARCH for Diabetes in Youth Study. Population and Prevention Science; American 145. Reynolds K, Liese AD, Anderson AM, et al. Diabetes Care 2017;40:1226–1232 Heart Association Council on Cardiovascular Prevalence of tobaccoDiabetes use and association be- 160. Pop-Busui R, Boulton AJM, Feldman EL, Disease in the Young; American Heart Associa- tween cardiometabolic risk factors and cigarette et al. Diabetic neuropathy: a position statement tion Council on Epidemiology and Prevention; smoking in youth with type 1 or type 2 diabetes by the American Diabetes Association. Diabetes American Heart Association Council on Nutrition, mellitus. J Pediatr 2011;158:594–601.e1 Care 2017;40:136–154 Physical Activity and Metabolism; American 146. Scott LJ, Warram JH, Hanna LS, Laffel LM, 161. LawrenceJM,Imperatore G,PettittDJ,etal. HeartAssociation Councilon High Blood Pressure Ryan L, Krolewski AS. A nonlinear effect of Incidence of diabetes in United States youth by Research; American Heart Association Council on hyperglycemia and current cigarette smoking diabetes type, race/ethnicity, and age, 2008– Cardiovascular Nursing; American Heart Associ- are major determinants of the onset of micro- 2009 (Abstract). Diabetes 2014;63(Suppl. 1): ation Council on the Kidney in Heart Disease; albuminuria in type 1 diabetes. Diabetes 2001; A407 Interdisciplinary Working Group on Quality of 50:2842–2849 162. Imperatore G, Boyle JP, Thompson TJ, et al.; Care and Outcomes Research. Cardiovascular 147. Chaffee BW, Watkins SL, Glantz SA. Elec- SEARCH for Diabetes in Youth Study Group. risk reduction in high-risk pediatric patients: tronic cigarette use and progression from exper- Projections of type 1 and type 2 diabetes burden a scientific statement from the American Heart imentation to established smoking. Pediatrics in the U.S. population aged ,20 years through Association Expert Panel on PopulationAmerican and Pre- 2018;141:e20173594 2050: dynamic modeling of incidence, mortality, vention Science; the Councils on Cardiovascu- 148. Audrain-McGovern J, Stone MD,Barrington- and population growth. Diabetes Care 2012;35: lar Disease in the Young, Epidemiology and Trimis J, Unger JB, Leventhal AM. Adolescent 2515–2520 Prevention, Nutrition, Physical Activity and Me- e-cigarette, hookah, and conventional cigarette 163. Pettitt DJ, Talton J, Dabelea D, et al.; tabolism, High Blood Pressure Research, Cardio- use and subsequent marijuana use. Pediatrics SEARCH for Diabetes in Youth Study Group. vascular Nursing, and the Kidney in Heart 2018;142:e20173616 Prevalence of diabetes in U.S. youth in 2009: Disease; and the Interdisciplinary Working Group 149. Centers for Disease Control and Preven- the SEARCH for diabetes in youth study. Diabetes on Quality of Care and Outcomes Research: tion. Outbreak of lung injury associated with Care 2014;37:402–408 endorsed by the American Academy of Pediat- e-cigarette use, or vaping. Accessed 27 Septem- 164. Copeland KC, Zeitler P, Geffner M, et al.; rics. Circulation 2006;114:2710–2738 ber 2019. Available from https://www.cdc.gov/ TODAY Study Group. Characteristics of adoles- 138.©2019 Cadario F, Prodam F, Pasqualicchio S, et al. tobacco/basic_information/e-cigarettes/severe- cents and youth with recent-onset type 2 di- Lipid profile and nutritional intake in children and lung-disease.html abetes: the TODAY cohort at baseline. J Clin adolescents with Type 1 diabetes improve after a 150. Miech R, Johnston L, O’Malley PM, Endocrinol Metab 2011;96:159–167 structured dietician training to a Mediterranean- Bachman JG, Patrick ME. Trends in adolescent 165. Arslanian SA. Metabolic differences be- style diet. J Endocrinol Invest 2012;35:160– vaping, 2017-2019.N Engl J Med 2019;381:1490– tween Caucasian and African-American children 168 1491 and the relationship to type 2 diabetes mellitus. J 139. Salem MA, AboElAsrar MA, Elbarbary NS, 151. Daniels M, DuBose SN, Maahs DM, et al.; Pediatr Endocrinol Metab 2002;15(Suppl. 1): ElHilaly RA, Refaat YM. Is exercise a therapeutic T1D Exchange Clinic Network. Factors associated 509–517 tool for improvement of cardiovascular risk with microalbuminuria in 7,549 children and 166. Naughton MJ, Ruggiero AM, Lawrence JM, factors in adolescents with type 1 diabetes adolescents with type 1 diabetes in the T1D et al.; SEARCH for Diabetes in Youth Study Group. mellitus? A randomised controlled trial. Diabetol Exchange clinic registry. Diabetes Care 2013;36: Health-related quality of life of children and Metab Syndr 2010;2:47 2639–2645 adolescents with type 1 or type 2 diabetes care.diabetesjournals.org Children and Adolescents S181

mellitus: SEARCH for Diabetes in Youth Study. 183. TODAY Study Group. Lipid and inflamma- Pediatric Bariatric Study Group. J Pediatr Surg Arch Pediatr Adolesc Med 2008;162:649–657 tory cardiovascular risk worsens over 3 years in 2006;41:137–143; discussion 137–143 167. Wadden TA, Webb VL, Moran CH, BailerBA. youth with type 2 diabetes: the TODAY clinical 200. Inge TH, Zeller M, Harmon C, et al. Teen- Lifestyle modification for obesity: new develop- trial. Diabetes Care 2013;36:1758–1764 Longitudinal Assessment of Bariatric Surgery: ments in diet, physical activity, and behavior 184. TODAY Study Group. Rapid rise in hyper- methodological features of the first prospective therapy. Circulation 2012;125:1157–1170 tension and nephropathy in youth with type 2 multicenter study of adolescent bariatric sur- 168. WhalenDJ, BeldenAC, TillmanR, BarchDM, diabetes: the TODAY clinical trial. Diabetes Care gery. J Pediatr Surg 2007;42:1969–1971 Luby JL. Early adversity, psychopathology, and 2013;36:1735–1741 201. Ells LJ, Mead E, Atkinson G, et al. Surgery for latent class profiles of global physical health from 185. Grey M, Schreiner B, Pyle L. Development the treatment of obesity in children and ado- preschool through early adolescence. Psycho- of a diabetes education program for youth with lescents. Cochrane Database Syst Rev 2015;6: som Med 2016;78:1008–1018 type 2 diabetes. Diabetes Educ 2009;35:108–116 CD011740 169. Dabelea D, Mayer-Davis EJ, Saydah S, et al.; 186. American Diabetes Association. Be Healthy 202. Michalsky MP, Inge TH, Simmons M, et al.; SEARCH for Diabetes in Youth Study. Prevalence Today; Be Healthy For Life. Accessed 29 October Teen-LABSConsortium.Cardiovascularriskfactors of type 1 and type 2 diabetes among children and 2019. Available from http://main.diabetes.org/ in severely obese adolescents: the Teen Longitu- adolescents from 2001 to 2009. JAMA 2014;311: dorg/PDFs/Type-2-Diabetes-in-Youth/Type-2- dinal Assessment of Bariatric Surgery (Teen-LABS) 1778–1786 Diabetes-in-Youth.pdf study. JAMA Pediatr 2015;169:438–444 170. Buse JB, Kaufman FR, Linder B, Hirst K, El 187. Atkinson A, Radjenovic D. Meeting quality 203. Zeinoddini A, Heidari R, Talebpour M. Ghormli L, Willi S; HEALTHY Study Group. Di- standards for self-management education in Laparoscopic gastric plication in morbidly obese abetes screening with hemoglobin A(1c) versus pediatric type 2 diabetes. Diabetes Spectr adolescents:aprospectivestudy.SurgObesRelat – – fasting plasma glucose in a multiethnic middle- 2007;20:40 46 Dis 2014;10:1135 1139 school cohort. Diabetes Care 2013;36:429–435 188. Copeland KC, Silverstein J, Moore KR, et al. 204. Gothberg¨ G, Gronowitz E, Flodmark C-E, 171. Klingensmith GJ, Pyle L, Arslanian S, et al.; Management of newly diagnosedtype 2 diabetes et al. Laparoscopic Roux-en-Y gastric bypass in – TODAY Study Group. The presence of GAD and mellitus (T2DM) in children and adolescents. adolescents with morbid obesity surgical as- – IA-2 antibodies in youth with a type 2 diabetes Pediatrics 2013;131:364 382 pects and clinical outcome. Semin Pediatr – phenotype: results from the TODAY study. Di- 189. Zeitler P, Hirst K, Pyle L, et al.; TODAY Study Surg 2014;23:11Association16 abetes Care 2010;33:1970–1975 Group. A clinical trial to maintain glycemic con- 205. Inge TH, Prigeon RL, Elder DA, et al. Insulin b 172. Hannon TS, Arslanian SA. The changing face trol in youth with type 2 diabetes. N Engl J Med sensitivity and -cell function improve after – ofdiabetesinyouth:lessonslearnedfromstudies 2012;366:2247 2256 gastric bypass in severely obese adolescents. J 190. RISE Consortium. Impact of insulin and – of type 2 diabetes. Ann N Y Acad Sci 2015;1353: Pediatr 2015;167:1042 1048.e1 metformin versus metformin alone on b-cell 206. Styne DM, Arslanian SA, Connor EL, et al. 113–137 function in youth with impaired glucose toler- Pediatric obesity-assessment, treatment, and pre- 173. Kapadia C, Zeitler P; Drugs and Therapeu- ance or recently diagnosed type 2 diabetes. vention: an Endocrine Society clinical practice guide- tics Committee of the Pediatric Endocrine Soci- Diabetes Care 2018;41:1717–1725 line. J Clin Endocrinol Metab 2017;102:709–757 ety. Hemoglobin A1c measurement for the 191. Tamborlane WV, Barrientos-Perez´ M, 207. Eppens MC, Craig ME, Cusumano J, et al. diagnosis of type 2 diabetes in children. Int J Fainberg U, et al.; Ellipse Trial Investigators. Prevalence of diabetes complications in adoles- Pediatr Endocrinol 2012;2012:31 Liraglutide in children and adolescents with cents with type 2 compared with type 1 diabetes. 174. Kester LM, Hey H, Hannon TS. Using hemo- type 2 diabetes. N Engl J Med 2019;381:637– Diabetes Care 2006;29:1300–1306 globin A1c for prediabetes and diabetes diagnosis 646journal Diabetes208. Song SH, Hardisty CA. Early onset type 2 in adolescents: can adult recommendations be 192. U.S. Food and Drug Administration. FDA diabetes mellitus: a harbinger for complica- upheld for pediatric use? J Adolesc Health 2012; approves new treatment for pediatric patients tions in later years–clinical observation from a – 50:321 323 with type 2 diabetes. Accessed 20 September secondary care cohort. QJM 2009;102:799– 175. Wu E-L, Kazzi NG, Lee JM. Cost-effectiveness 2019. Available from http://www.fda.gov/news- 806 of screening strategies for identifying pediatric events/press-announcements/fda-approves- 209. ZeitlerP,Fu J,TandonN,etal.; International diabetes mellitus and dysglycemia. JAMA Pediatr new-treatment-pediatric-patients-type-2-diabetes Society for Pediatric and Adolescent Diabetes. – 2013;167:32 39 193. Inge TH, Courcoulas AP, Jenkins TM, et al.; ISPAD Clinical Practice Consensus Guidelines 176. Dabelea D, Rewers A, Stafford JM, et al.; Teen-LABS Consortium. Weight Loss and Health 2014.Type2diabetesinthe childandadolescent. SEARCH for Diabetes in Youth Study Group. Status 3 Years after Bariatric Surgery in Adoles- Pediatr Diabetes 2014;15(Suppl. 20):26–46 Trends in the prevalence of ketoacidosis at di- cents. N Engl J Med 2016;374:113–123 210. Song SH. Complication characteristics be- abetes diagnosis: the SEARCH for Diabetes in 194. Rubino F, Nathan DM, Eckel RH, et al.; tween young-onset type 2 versus type 1 diabetes – Youth Study. Pediatrics 2014;133:e938 e945 Delegates of the 2nd Diabetes Surgery Summit. in a UK population. BMJ Open Diabetes Res Care 177. Hutchins J, Barajas RA, Hale D,American Escaname E, Metabolic surgery in the treatment algorithm for 2015;3:e000044 Lynch J. Type 2 diabetes in a 5-year-old and single type 2 diabetes: a joint statement by interna- 211. Cefalu WT. “TODAY” reflects on the chang- center experience of type 2 diabetes in youth tional diabetes organizations. Diabetes Care ing “faces” of type 2 diabetes. Diabetes Care under 10. Pediatr Diabetes 2017;18:674–677 2016;39:861–877 2013;36:1732–1734 178. Ferrara CT, Geyer SM, Liu Y-F, et al.; Type 195. Pratt JSA, Lenders CM, Dionne EA, et al. 212. Lawrence JM, Standiford DA, Loots B, et al.; 1 Diabetes TrialNet Study Group. Excess BMI in Best practice updates for pediatric/adolescent SEARCH for Diabetes in Youth Study. Prevalence childhood: a modifiable risk factor for type 1 weight loss surgery. Obesity (Silver Spring) 2009; and correlates of depressed mood among youth diabetes development? Diabetes Care 2017;40: 17:901–910 with diabetes: the SEARCH for Diabetes in Youth 698–701 196. Dolan K, Creighton L, Hopkins G, Fielding G. study. Pediatrics 2006;117:1348–1358 179. Reference removed during proofreading Laparoscopic gastric banding in morbidly obese 213. Levitt Katz LE, Swami S, Abraham M, et al. 180.©2019 Pinhas-Hamiel O, Dolan LM, Zeitler PS. adolescents. Obes Surg 2003;13:101–104 Neuropsychiatric disorders at the presentation Diabetic ketoacidosis among obese African- 197. Sugerman HJ, Sugerman EL, DeMaria EJ, of type 2 diabetes mellitus in children. Pediatr American adolescents with NIDDM. Diabetes et al. Bariatric surgery for severely obese ado- Diabetes 2005;6:84–89 Care 1997;20:484–486 lescents. J Gastrointest Surg 2003;7:102–108 214. Lewis-Fernandez´ R, Rotheram-Borus MJ, 181. TODAY Study Group. Safety and tolerability 198. Inge TH, Garcia V, Daniels S, et al. A Betts VT, et al. Rethinking funding priorities in of the treatment of youth-onset type 2 diabetes: multidisciplinary approach to the adolescent mental health research. Br J Psychiatry 2016; the TODAY experience. Diabetes Care 2013;36: bariatric surgical patient. J Pediatr Surg 2004; 208:507–509 1765–1771 39:442–447; discussion 446–447 215. Reinehr T. Type 2 diabetes mellitus in 182. TODAY Study Group. Retinopathy in 199. Lawson ML, Kirk S, Mitchell T, et al.; Pe- children and adolescents. World J Diabetes youth with type 2 diabetes participating in diatricBariatricStudyGroup.One-yearoutcomes 2013;4:270–281 the TODAY clinical trial. Diabetes Care 2013; of Roux-en-Y gastric bypass for morbidly obese 216. Pinhas-Hamiel O, Hamiel U, Levy-Shraga Y. 36:1772–1774 adolescents: a multicenter study from the Eating disorders in adolescents with type 1 S182 Children and Adolescents Diabetes Care Volume 43, Supplement 1, January 2020

diabetes: challenges in diagnosis and treatment. Endocrinologists, the American Osteopathic U.S. national sample of young adults with type 1 World J Diabetes 2015;6:517–526 Association, the Centers for Disease Control diabetes. Diabetes Care 2017;40:317–324 217. Wilﬂey D, Berkowitz R, Goebel-Fabbri A, and Prevention, ChildrenwithDiabetes,The 230. The Endocrine Society. Managing the tran- et al.; TODAY Study Group. Binge eating, mood, Endocrine Society, the International Society for sition of care for patients with type 1 diabetes. and quality of life in youth with type 2 diabetes: Pediatric and Adolescent Diabetes, Juvenile Accessed 29 October 2019. Available from baseline data from the today study. Diabetes Diabetes Research Foundation International, https://www.endocrine.org/guidelines-and-clinical- – Care 2011;34:858 860 the National Diabetes Education Program, practice/quality-improvement-resources/clinical- 218. Shelton RC. Depression, antidepressants, and the Pediatric Endocrine Society (formerly practice-resources/transition-of-care and weight gain in children. Obesity (Silver Lawson Wilkins Pediatric Endocrine Society). 231. Reid MW, Krishnan S, Berget C, et al. Spring) 2016;24: 2450–2450 Diabetes Care 2011;34:2477–2485 CoYoT1 Clinic: home telemedicine increases 219. Baeza I, Vigo L, de la Serna E, et al. The 224. Bryden KS, Peveler RC, Stein A, Neil A, effects of antipsychotics on weight gain, weight- Mayou RA, Dunger DB. Clinical and psychological young adult engagement in diabetes care. Di- – related hormones and homocysteine in children course of diabetes from adolescence to young abetes Technol Ther 2018;20:370 379 and adolescents: a 1-year follow-up study. Eur adulthood: a longitudinal cohort study. Diabetes 232. Spaic T, Robinson T, Goldbloom E, et al.; Child Adolesc Psychiatry 2017;26:35–46 Care 2001;24:1536–1540 JDRF Canadian Clinical Trial CCTN1102 Study 220. Klingensmith GJ, Pyle L, Nadeau KJ, et al.; 225. Laing SP, Jones ME, Swerdlow AJ, Burden Group. Closing the gap: results of the multi- TODAY Study Group. Pregnancy outcomes in AC, Gatling W. Psychosocial and socioeconomic center canadian randomized controlled trial youth with type 2 diabetes: the TODAY study risk factors for premature death in young people of structured transition in young adults with experience. Diabetes Care 2016;39:122–129 with type 1 diabetes. Diabetes Care 2005;28: type 1 diabetes. Diabetes Care 2019;42:1018– 221. Arnett JJ. Emerging adulthood: a theory of 1618–1623 1026 development from the late teens through the 226. Mays JA, Jackson KL, Derby TA, et al. An 233. White M, O’Connell MA, Cameron FJ. Clinic twenties. Am Psychol 2000;55:469–480 evaluation of recurrent diabetic ketoacidosis, attendance and disengagement of young adults 222. Weissberg-BenchellJ,WolpertH,Anderson fragmentation of care, and mortality across with type 1 diabetes after transition of care from – BJ. Transitioning from pediatric to adult care: Chicago, Illinois. Diabetes Care 2016;39:1671 paediatric to adult services (TrACeD): a rando- a new approach to the post-adolescent young 1676 mised,Association open-label, controlled trial. Lancet Child person with type 1 diabetes. Diabetes Care 2007; 227. Lotstein DS, Seid M, Klingensmith G, et al.; Adolesc Health 2017;1:274–283 30:2441–2446 SEARCH for Diabetes in Youth Study Group. 234. Schultz AT, Smaldone A. Components of 223. Peters A, Laffel L; American Diabetes Transition from pediatric to adult care for youth interventions that improve transitions to adult Association Transitions Working Group. Diabe- diagnosed with type 1 diabetes in adolescence. tes care for emerging adults: recommendations Pediatrics 2013;131:e1062–e1070 care for adolescents with type 1 diabetes. J – for transition from pediatric to adult diabetes 228. Lyons SK, Becker DJ, Helgeson VS. Transfer Adolesc Health 2017;60:133 146 care systems: a position statement of the from pediatric to adult health care: effects on 235. Sequeira PA, Pyatak EA, Weigensberg MJ, American Diabetes Association, with represen- diabetes outcomes. Pediatr Diabetes 2014;15: et al. Let’s Empower and Prepare (LEAP): eval- tation by the American College of Osteopathic 10–17 uation of a structured transition program for Family Physicians, the American Academy of 229. GarveyKC,FosterNC,AgarwalS,etal.Health young adults with type 1 diabetes. Diabetes Care Pediatrics, the American Association of Clinical care transition preparationDiabetes and experiences in a 2015;38:1412 –1419

American

14. Management of Diabetes in American Diabetes Association Pregnancy: Standards of Medical Care in Diabetesd2020

Diabetes Care 2020;43(Suppl. 1):S183–S192 | https://doi.org/10.2337/dc20-S014 4 AAEETO IBTSI PREGNANCY IN DIABETES OF MANAGEMENT 14. The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes” Association includes the ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc20-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence- grading system for ADA’s clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc20-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.Diabetes DIABETES IN PREGNANCY The prevalence of diabetes in pregnancy has been increasing in the U.S. in parallel with the worldwide epidemic of obesity. Not only is the prevalence of type 1 diabetes and type 2 diabetes increasing in women of reproductive age, but there is also a dramatic increase in the reported rates of gestational diabetes mellitus. Diabetes confers signiﬁcantly greater maternal and fetal risk largely related to the degree of hyperglycemia but also related to chronic complications and comorbidities of diabetes. In general, speciﬁc risks of diabetes in pregnancy include spontaneous abortion, fetal anomalies, preeclampsia, fetal demise, macrosomia, neonatal hypoglycemia, hyperbilirubinemia, and neonatal respiratory distress syndrome, among others. In addition, diabetesAmerican in pregnancy may increase the risk of obesity, hypertension, and type 2 diabetes in offspring later in life (1,2).

PRECONCEPTION COUNSELING

Recommendations 14.1 Starting at puberty and continuing in all women with diabetes and reproductive potential, preconception counseling should be incorporated into routine diabetes care. A 14.2©2019Family planning should be discussed, and effective contraception (with consideration of long-acting, reversible contraception) should be prescribed and used Suggested citation: American Diabetes Associa- until a woman’s treatment regimen and A1C are optimized for pregnancy. A tion. 14. Management of diabetes in pregnancy: 14.3 Preconception counseling should address the importance of achieving Standards of Medical Care in Diabetesd2020. glucose levels as close to normal as is safely possible, ideally Diabetes Care 2020;43(Suppl. 1):S183-S192 A1C ,6.5% (48 mmol/mol), to reduce the risk of congenital anomalies, © 2019 by the American Diabetes Association. preeclampsia, macrosomia, and other complications. B Readers may use this article as long as the work is properly cited, the use is educational and not for proﬁt, and the work is not altered. More infor- All women of childbearing age with diabetes should be informed about the mation is available at http://www.diabetesjournals importance of achieving and maintaining as near euglycemia as safely possible prior .org/content/license. S184 Management of Diabetes in Pregnancy Diabetes Care Volume 43, Supplement 1, January 2020

to conception and throughout preg- additional details on elements of pre- multidisciplinary clinic including nancy. Observational studies show an conception care (15,17). Counseling an endocrinologist, maternal-fetal increased risk of diabetic embryopathy, on the specificrisksofobesityinpreg- medicine specialist, registered di- especially anencephaly, microcephaly, nancy and lifestyle interventions to etitian nutritionist, and diabetes congenital heart disease, renal anoma- prevent and treat obesity, including educator, when available. B lies, and caudal regression, directly pro- referral to a registered dietitian nutri- 14.5 In addition to focused attention portional to elevations in A1C during the tionist (RD/RDN), is recommended when on achieving glycemic targets A, first 10 weeks of pregnancy (3). Although indicated. standard preconception care observational studies are confounded Diabetes-specific counseling should should be augmented with ex- by the association between elevated include an explanation of the risks to tra focus on nutrition, diabetes periconceptional A1C and other poor mother and fetus related to pregnancy education, and screening for di- self-care behavior, the quantity and con- and the ways to reduce risk including abetes comorbidities and com- sistency of data are convincing and sup- glycemic goal setting, lifestyle manage- plications. E port the recommendation to optimize ment, and medical nutrition therapy. The 14.6 Women with preexisting type 1 glycemia prior to conception, given most important diabetes-specific com- or type 2 diabetes who are that organogenesis occurs primarily ponent of preconception care is the planning pregnancy or who at 5–8 weeks of gestation, with an attainment of glycemic goals prior to have become pregnant should A1C ,6.5% (48 mmol/mol) being as- conception. Diabetes-specifictesting be counseled on the risk of de- sociated with the lowest risk of con- should include A1C, creatinine, and uri- velopment and/or progression genital anomalies (3–6). nary albumin-to-creatinine ratio. Special of diabetic retinopathy. Dilated There are opportunities to educate all attention should be paid to the review of eye examinations should occur Association women and adolescents of reproductive the medication list for potentially harm- ideally before pregnancy or in age with diabetes about the risks of ful drugs (i.e., ACE inhibitors [18], angio- the first trimester, and then unplanned pregnancies and about im- tensin receptor blockers [18], and statins patients should be monitored provedmaternalandfetaloutcomeswith [19,20]). A referral for a comprehensive every trimester and for 1 year pregnancy planning (7). Effective pre- eye exam is recommended. Women with postpartum as indicated by the conception counseling could avert sub- preexisting diabetic retinopathy will need degree of retinopathy and as stantial health and associated cost close monitoring during pregnancy to as- recommended by the eye care burdens in offspring (8). Family planning sess for progression of retinopathy and provider. B should be discussed, including the ben- provide treatment if indicated (21). The efits of long-acting, reversable contra- use of aspirin (81–150 mg) can be consid- The importance of preconception care ception, and effective contraception Diabetesered preconception as it is recommended for all women is highlighted by the should be prescribed and used until a for all pregnant women with diabetes (if no American College of Obstetricians and woman is prepared and ready to become contraindication) by 16 weeks of gesta- Gynecologists (ACOG) committee opin- pregnant (9–13). tion to reduce the risk of preeclampsia. ion 762, Prepregnancy Counseling (15). To minimize the occurrence of com- Please see PREECLAMPSIA AND ASPIRIN for more A key point is the need to incorporate plications, beginning at the onset of information. a question about a woman’s plans for puberty or at diagnosis, all girls and Several studies have shown improved pregnancy into routine primary and gy- women with diabetes of childbearing diabetes and pregnancy outcomes when necologic care. The preconception care potential should receive education about care has been delivered from preconcep- 1) the risks of malformations associated of women with diabetes should include tion through pregnancy by a multidisci- with unplanned pregnancies and even the standard screenings and care recom- plinary group focused on improved mild hyperglycemia and 2American)theuseofef- mended for all women planning preg- glycemic control (22–25). One study fective contraception at all times when nancy (15). Prescription of prenatal showed that care of preexisting diabetes preventing a pregnancy. Preconception vitamins (with at least 400 mg of folic in clinics that included diabetes and m counseling using developmentally ap- acid and 150 g of potassium iodide [16]) obstetric specialists improved care propriate educational tools enables is recommended prior to conception. (25). However, there is no consensus adolescent girls to make well-informed Review and counseling on the use of on the structure of multidisciplinary decisions (7). Preconception counseling nicotine products, alcohol, and recrea- team care for diabetes and pregnancy, resources tailored for adolescents are tional drugs, including marijuana, is and there is a lack of evidence on the available©2019 at no cost through the American important. Standard care includes impact on outcomes of various methods Diabetes Association (ADA) (14). screening for sexually transmitted dis- of health care delivery (26). eases and thyroid disease, recommended Preconception Care vaccinations, routine genetic screen- GLYCEMIC TARGETS IN ing, a careful review of all prescription Recommendations PREGNANCY and nonprescription medications and 14.4 Women with preexisting diabe- Recommendations supplements used, and a review of travel tes who are planning a preg- 14.7 Fasting and postprandial self- history and plans with special attention nancy should ideally be managed monitoring of blood glucose to areas known to have Zika virus, as beginning in preconception in a are recommended in both outlined by ACOG. See Table 14.1 for care.diabetesjournals.org Management of Diabetes in Pregnancy S185

Table 14.1—Checklist for preconception care for women with diabetes (15,17) Preconception education should include: ☐ Comprehensive nutrition assessment and recommendations for: c Overweight/obesity or underweight c Meal planning c Correction of dietary nutritional deficiencies c Caffeine intake c Safe food preparation technique ☐ Lifestyle recommendations for: c Regular moderate exercise c Avoidance of hyperthermia (hot tubs) c Adequate sleep ☐ Comprehensive diabetes self-management education ☐ Counseling on diabetes in pregnancy per current standards, including: natural history of insulin resistance in pregnancy and postpartum; preconception glycemic targets; avoidance of DKA/severe hyperglycemia; avoidance of severe hypoglycemia; progression of retinopathy; PCOS (if applicable); fertility in patients with diabetes; genetics of diabetes; risks to pregnancy including miscarriage, still birth, congenital malformations, macrosomia, preterm labor and delivery, hypertensive disorders in pregnancy, etc. ☐ Supplementation c Folic acid supplement (400 mg routine) c Appropriate use of over-the-counter medications and supplements Medical assessment and plan should include: ☐ General evaluation of overall health ☐ Evaluation of diabetes and its comorbidities and complications, including: DKA/severe hyperglycemia; severe hypoglycemia/ hypoglycemic unawareness; barriers to care; comorbidities such as hyperlipidemia, hypertension, NAFLD,Association PCOS, and thyroid dysfunction; complications such as macrovascular disease, nephropathy, neuropathy (including autonomic bowel and bladder dysfunction), and retinopathy ☐ Evaluation of obstetric/gynecologic history, including history of: cesarean section, congenital malformations or fetal loss, current methods of contraception, hypertensive disorders of pregnancy, postpartum hemorrhage, preterm delivery, previous macrosomia, Rh incompatibility, and thrombotic events (DVT/PE) ☐ Review of current medications and appropriateness during pregnancy Screening should include: ☐ Diabetescomplicationsandcomorbidities,including: comprehensivefootexam;comprehensiveophthalmologicexam;ECGinwomenstartingat age 35 years who have cardiac signs/symptoms or risk factors, and if abnormal, further evaluation; lipid panel; serum creatinine; TSH; and urine protein-to-creatinine ratio ☐ Anemia Diabetes ☐ Genetic carrier status (based on history): c Cystic fibrosis c Sickle cell anemia c Tay-Sachs disease c Thalassemia c Others if indicated ☐ Infectious disease c Neisseria gonorrhea/Chlamydia trachomatis c Hepatitis C c HIV c Pap smear c Syphilis Immunizations should include: American ☐ Rubella ☐ Varicella ☐ Hepatitis B ☐ Influenza ☐ Others if indicated Preconception plan should include: ☐ Nutrition and medication plan to achieve glycemic targets prior to conception, including appropriate implementation of monitoring, continuous glucose monitoring, and pump technology ☐©2019Contraceptive plan to prevent pregnancy until glycemic targets are achieved ☐ Management plan for general health, gynecologic concerns, comorbid conditions, or complications, if present, including: hypertension, nephropathy, retinopathy; Rh incompatibility; and thyroid dysfunction DKA, diabetic ketoacidosis; DVT/PE, deep vein thrombosis/pulmonary embolism; ECG, electrocardiogram; NAFLD, nonalcoholic fatty liver disease; PCOS, polycystic ovary syndrome; TSH, thyroid-stimulating hormone. S186 Management of Diabetes in Pregnancy Diabetes Care Volume 43, Supplement 1, January 2020

diabetogenic placental hormones. In pa- c Fasting glucose ,95 mg/dL (5.3 gestational diabetes mellitus tients with preexisting diabetes, glycemic mmol/L) and either and preexisting diabetes in targets are usually achieved through a com- c One-hour postprandial glucose ,140 pregnancy to achieve optimal bination of insulin administration and med- mg/dL (7.8 mmol/L) or glucose levels. Glucose targets ical nutrition therapy. Because glycemic c Two-hour postprandial glucose ,120 are fasting plasma glucose ,95 targets in pregnancy are stricter than in mg/dL (6.7 mmol/L) mg/dL (5.3 mmol/L) and either nonpregnant individuals, it is important 1-h postprandial glucose ,140 that women with diabetes eat consistent These values represent optimal control if mg/dL(7.8mmol/L)or2-hpost- amounts of carbohydrates to match with they can be achieved safely. In practice, prandial glucose ,120 mg/dL insulin dosage and to avoid hyperglycemia it may be challenging for women with (6.7 mmol/L). Some women or hypoglycemia. Referral to a registered type 1 diabetes to achieve these with preexisting diabetes should dietitian nutritionist is important in order targets without hypoglycemia, particu- also test blood glucose prepran- to establish a food plan and insulin-to- larly women with a history of recurrent dially. B carbohydrate ratio and to determine hypoglycemia or hypoglycemia unaware- 14.8 Due to increased red blood cell weight gain goals. ness. If women cannot achieve these turnover, A1C is slightly lower targets without significant hypoglyce- in normal pregnancy than in mia, the ADA suggests less-stringent normal nonpregnant women. Insulin Physiology Given that early pregnancy is a time of targets based on clinical experience and Ideally, the A1C target in preg- enhanced insulin sensitivity and lower glu- individualization of care. nancy is ,6% (42 mmol/mol) if cose levels, many women with type 1 di- this can be achieved without abetes will have lower insulin requirements significant hypoglycemia, but A1CAssociation in Pregnancy and increased risk for hypoglycemia (27). The In studies of women without preexisting the target may be relaxed to situation rapidly reverses by approximately diabetes, increasing A1C levels within the ,7%(53mmol/mol)ifnecessary 16weeksasinsulinresistance increases normal range are associated with ad- to prevent hypoglycemia. B exponentially during the second and early verse outcomes (33). In the Hyperglyce- 14.9 When used in addition to pre- thirdtrimestersto2–3 times the preprandial mia and Adverse Pregnancy Outcome and postprandial self-monitoring requirement. The insulin requirement levels (HAPO) study, increasing levels of glyce- of blood glucose, continuous off toward the end of the third trimester mia were also associated with worsen- glucose monitoring can help with placental aging. A rapid reduction ing outcomes (34). Observational studies to achieve A1C targets in dia- in insulin requirements can indicate the in preexisting diabetes and pregnancy betes and pregnancy. B development of placental insufficiency show the lowest rates of adverse fetal 14.10 When used in addition to self- (28). In womenDiabetes with normal pancreatic outcomes in association with A1C ,6– monitoring of blood glucose function, insulin production is sufficient 6.5% (42–48 mmol/mol) early in gesta- targeting traditional pre- and to meet the challenge of this physiolog- tion (4–6,35). Clinical trials have not postprandial targets, continu- ical insulin resistance and to maintain evaluated the risks and benefits of ous glucose monitoring can normal glucose levels. However, in achieving these targets, and treatment reduce macrosomia and neo- women with diabetes, hyperglycemia goals should account for the risk of natal hypoglycemia in preg- occurs if treatment is not adjusted ap- maternal hypoglycemia in setting an nancy complicated by type 1 propriately. individualized target of ,6% (42 diabetes. B mmol/mol) to ,7% (53 mmol/mol). Due 14.11 Continuous glucose monitor- to physiological increases in red blood ing metrics should not be Glucose Monitoring Reflecting this physiology, fasting and cell turnover, A1C levels fall during nor- used as a substitute for self- Americanpostprandial monitoring of blood glucose mal pregnancy (36,37). Additionally, as monitoring of blood glucose to is recommended to achieve metabolic A1C represents an integrated measure achieve optimal pre- and post- control in pregnant womenwith diabetes. of glucose, it may not fully capture postprandial glycemic targets. E Preprandial testing is also recommended prandial hyperglycemia, which drives 14.12 Commonly used estimated A1C when using insulin pumps or basal-bolus macrosomia. Thus, although A1C may and glucose management indi- therapy so that premeal rapid-acting in- be useful, it should be used as a second- catorcalculations should notbe sulindosagecanbeadjusted.Postprandial ary measure of glycemic control in preg- used in pregnancy as estimates monitoring is associated with better gly- nancy, after self-monitoring of blood of A1C. C ©2019 cemiccontrolandlowerriskofpreeclamp- glucose. sia (29–31). There are no adequately In the second and third trimesters, Pregnancy in women with normal glu- powered randomized trials comparing A1C ,6% (42 mmol/mol) has the lowest cose metabolism is characterized by fast- different fasting and postmeal glycemic risk of large-for-gestational-age in- ing levels of blood glucose that are targets in diabetes in pregnancy. fants (35,38,39), preterm delivery (40), lower than in the nonpregnant state Similar to the targets recommended and preeclampsia (1,41). Taking all of due to insulin-independent glucose up- by ACOG (the same as for GDM; de- this into account, a target of ,6% take by the fetus and placenta and by scribed below) (32), the ADA-recommended (42 mmol/mol) is optimal during preg- mild postprandial hyperglycemia and targets for women with type 1 or type 2 nancy if it can be achieved without carbohydrate intolerance as a result of diabetes are as follows: significant hypoglycemia. The A1C target care.diabetesjournals.org Management of Diabetes in Pregnancy S187

in a given patient should be achieved between the woman and an RD/RDN fa- medications lack long-term without hypoglycemia, which, in addition miliar with the management of GDM safety data. to the usual adverse sequelae, may in- (50,51). The food plan should provide 14.15 Metformin, when used to treat crease the risk of low birth weight (42). adequate calorie intake to promote polycystic ovary syndrome and Given the alteration in red blood cell fetal/neonatal and maternal health, induce ovulation, should be kinetics during pregnancy and physiolog- achieve glycemic goals, and promote discontinued by the end of ical changes in glycemic parameters, A1C weight gain according to 2009 Institute the first trimester. A levels may need to be monitored more of Medicine recommendations (52). frequently than usual (e.g., monthly). There is no definitive research that GDM is characterized by increased risk identifies a specific optimal calorie intake Continuous Glucose Monitoring in of macrosomia and birth complications for women with GDM or suggests that Pregnancy and an increased risk of maternal type 2 their calorie needs are different from CONCEPTT (Continuous Glucose Moni- diabetes after pregnancy. The associa- those of pregnant women without toring in Pregnant Women With Type 1 tion of macrosomia and birth complica- GDM. The food plan should be based Diabetes Trial) was a randomized con- tions with oral glucose tolerance test on a nutrition assessment with guidance trolled trial of continuous glucose mon- (OGTT) results is continuous with no from the Dietary Reference Intakes fl itoring (CGM) in addition to standard clear in ection points (34). In other (DRI). The DRI for all pregnant women care, including optimization of pre- words, risks increase with progressive recommends a minimum of 175 g of and postprandial glucose targets versus hyperglycemia. Therefore, all women carbohydrate, a minimum of 71 g of standard care for pregnant women with should be tested as outlined in Sec- protein, and 28 g of fiber. The diet should “ fi type 1 diabetes. It demonstrated the tion 2 Classi cation and Diagnosis of not be high in saturated fat. As is true ” Association value of CGM in pregnancy complicated Diabetes (https://doi.org/10.2337/dc20- for all nutrition therapy in patients with by type 1 diabetes by showing a mild S002). Although there is some heteroge- diabetes, the amount and type of car- improvement in A1C without an increase neity, many randomized controlled trials bohydrate will impact glucose levels. in hypoglycemia and reductions in large- (RCTs) suggest that the risk of GDM may be Simple carbohydrates will result in higher for-gestational-age births, length of stay, reduced by diet, exercise, and lifestyle postmeal excursions. and neonatal hypoglycemia (43). An ob- counseling, particularly when interven- Pharmacologic Therapy servational cohort study that evaluated tions are started during the first or early Treatment of GDM with lifestyle and the glycemic variables reported using in the second trimester (46–48). insulin has been demonstrated to im- CGM and their association with large- Lifestyle Management prove perinatal outcomes in two large for-gestational-age births found that After diagnosis, treatment starts with randomized studies as summarized in a mean glucose had a greater association Diabetes medical nutrition therapy, physical ac- U.S. Preventive Services Task Force re- than time in range, time below range, or tivity, and weight management depend- view (53). Insulin is the first-line agent time above range (44). Using the CGM- ing on pregestational weight, as outlined recommended for treatment of GDM in reported mean glucose is superior to the in the section below on preexisting type 2 the U.S. While individual RCTs support use of estimated A1C, glucose manage- diabetes, and glucose monitoring aiming limited efficacy of metformin (54,55) and ment indicator, and other calculations for the targets recommended by the Fifth glyburide (56) in reducing glucose levels to estimate A1C given the changes to International Workshop-Conference on for the treatment of GDM, these agents A1C that occur in pregnancy (45). Gestational Diabetes Mellitus (48): are not recommended as first-line treatment for GDM because they are known to MANAGEMENT OF GESTATIONAL c Fasting glucose ,95 mg/dL (5.3 cross the placenta and data on long-term DIABETES MELLITUS Americanmmol/L) and either safety for offspring is of some concern Recommendations c One-hour postprandial glucose ,140 (32). Furthermore, glyburide and met- 14.13 Lifestyle behavior change is an mg/dL (7.8 mmol/L) or formin failed to provide adequate glyce- essential component of man- c Two-hour postprandial glucose ,120 mic control in separate randomized agement of gestational diabe- mg/dL (6.7 mmol/L) controlled trials, failing in 23% and tes mellitus and may suffice for 25–28% of women with GDM, respec- the treatment of many women. Depending on the population, studies tively (57,58). Insulinshouldbeaddedifneeded suggest that 70–85% of women diag- Sulfonylureas to achieve glycemic targets. A nosed with GDM under Carpenter- ©2019 Sulfonylureas are known to cross the 14.14 Insulin is the preferred medi- Coustan can control GDM with lifestyle placenta and have been associated cation for treating hyperglyce- modification alone; it is anticipated with increased neonatal hypoglycemia. mia in gestational diabetes that this proportion will be even higher Concentrations of glyburide in umbilical mellitus. Metformin and gly- if the lower International Association of cord plasma are approximately 50–70% buride should not be used as Diabetes and Pregnancy Study Groups of maternal levels (57,58). Glyburide first-line agents, as both cross (49) diagnostic thresholds are used. was associated with a higher rate of the placenta to the fetus. A neonatal hypoglycemia and macrosomia Other oral and noninsulin Medical Nutrition Therapy Medical nutrition therapy for GDM is an than insulin or metformin in a 2015 meta- injectable glucose-lowering individualized nutrition plan developed analysis and systematic review (59). S188 Management of Diabetes in Pregnancy Diabetes Care Volume 43, Supplement 1, January 2020

More recently, glyburide failed to be cost, language barriers, comprehension, While many providers prefer insulin found noninferior to insulin based on a or cultural influences, may not be able to pumps in pregnancy, it is not clear that composite outcome of neonatal hypogly- use insulin safely or effectively in preg- they are superior to multiple daily cemia, macrosomia, and hyperbilirubine- nancy. Oral agents may be an alternative injections (88–90). Closed-loop technol- mia (60). Long-term safety data for in these women after a discussion of ogy that is U.S. Food and Drug Admin- offspring exposed to glyburide are not the known risks and the need for more istration approved outside of pregnancy available (60). long-term safety data in offspring. How- can only target a glucose of 120 mg/dL at Metformin ever, due to the potential for growth this time, which is likely to be too high for Metformin was associated with a lower restriction or acidosis in the setting optimal nocturnal control in pregnancy. fi fi risk of neonatal hypoglycemia and less of placental insuf ciency, metformin However, given potential bene ts, on- maternal weight gain than insulin in should not be used in women with hy- going work is being done in this area. systematic reviews (59,61,62,65). How- pertension, preeclampsia, or at risk for intrauterine growth restriction (78,79). Type 1 Diabetes ever, metformin readily crosses the pla- Women with type 1 diabetes have an centa, resulting in umbilical cord blood Insulin increased risk of hypoglycemia in the first levels of metformin as high or higher than Insulin use should follow the guidelines trimester and, like all women, have al- simultaneous maternal levels (66,67). In below. Both multiple daily insulin injec- tered counterregulatory response in the Metformin in Gestational Diabetes: tions and continuous subcutaneous in- pregnancy that may decrease hypogly- The Offspring Follow-Up (MiG TOFU) sulin infusion are reasonable delivery cemia awareness. Education for patients study’s analyses of 7- to 9-year-old off- strategies, and neither has been shown and family members about the preven- spring, the 9-year-old offspring exposed to be superior to the other during preg- tion, recognition, and treatment of hy- to metformin in the Auckland cohort for nancy (80). poglycemiaAssociation is important before, during, the treatment of GDM were heavier and and after pregnancy to help to prevent had a higher waist-to-height ratio and MANAGEMENT OF PREEXISTING and manage the risks of hypoglycemia. waist circumference than those exposed TYPE 1 DIABETES AND TYPE Insulin resistance drops rapidly with de- to insulin (68). This was not found in the 2 DIABETES IN PREGNANCY livery of the placenta. Adelaide cohort. In two RCTs of metfor- Insulin Use Pregnancy is a ketogenic state, and min use in pregnancy for polycystic ovary women with type 1 diabetes, and to a Recommendations syndrome, follow-up of 4-year-old off- lesser extent those with type 2 diabetes, 14.16 Insulin is the preferred agent spring demonstrated higher BMI and are at risk for diabetic ketoacidosis (DKA) for management of both type 1 increased obesity in the offspring ex- at lower blood glucose levels than in the diabetes and type 2 diabetes in posed to metformin (69,70). A follow-up nonpregnant state. Women with type 1 pregnancy.DiabetesE – diabetes should be prescribed ketone study at 5 10 years showed that the 14.17 Either multiple daily injections strips and receive education on diabetic offspring had higher BMI, weight-to- or insulin pump technology ketoacidosis prevention and detection. height ratios, waist circumferences, can be used in pregnancy com- DKA carries a high risk of stillbirth. and a borderline increase in fat mass plicated by type 1 diabetes. C (70,71). Metformin is being studied in Women in DKA who are unable to eat often require 10% dextrose with an in- two ongoing trials in type 2 diabetes The physiology of pregnancy necessi- sulin drip to adequately meet the higher (Metformin in Women with Type 2 Di- tates frequent titration of insulin to carbohydrate demands of the placenta abetes in Pregnancy Trial [MiTY] [72] and match changing requirements and and fetus in the third trimester in order to Medical Optimization of Management of underscores the importance of daily resolve their ketosis. Type 2 Diabetes Complicating Pregnancy and frequent self-monitoring of blood Retinopathy is a special concern in [MOMPOD] [73]), butAmerican long-term off- glucose. Due to the complexity of insulin pregnancy. Rapid implementation of eu- spring data will not be available for management in pregnancy, referral to a glycemia in the setting of retinopathy is some time. A recent meta-analysis con- specialized center offering team-based associated with worsening of retinopa- cluded that metformin exposure resulted care (with team members including thy (21). in smaller neonates with acceleration of maternal-fetal medicine specialist, en- postnatal growth resulting in higher BMI docrinologist, or other provider experi- Type 2 Diabetes in childhood (68,69). enced in managing pregnancy in women Type 2 diabetes is often associated with Randomized, double-blind, controlled with preexisting diabetes, dietitian, obesity. Recommended weight gain dur- trials©2019 comparing metformin with other nurse, and social worker, as needed) ing pregnancy for overweight women is therapies for ovulation induction in is recommended if this resource is 15–25lband forobese womenis10–20lb women with polycystic ovary syndrome available. (52). There is no adequate data on op- have not demonstrated benefit in pre- None of the currently available human timal weight gain versus weight mainte- venting spontaneous abortion or GDM insulin preparations have been demon- nance in women with a BMI .35 kg/m2. (74), and there is no evidence-based strated to cross the placenta (80–86). A Glycemic control is often easier to need to continue metformin in such recent Cochrane systematic review was achieve in women with type 2 diabetes patients (75–77). not able to recommend any specific in- than in those with type 1 diabetes but There are some women with GDM sulin regimen over another for the treat- can require much higher doses of insulin, requiring medical therapy who, due to ment of diabetes in pregnancy (87). sometimes necessitating concentrated care.diabetesjournals.org Management of Diabetes in Pregnancy S189

insulin formulations. As in type 1 diabe- at conception and avoided in requirements for the initial tes, insulin requirements drop dramati- sexually active women of child- few days postpartum. C cally after delivery. bearing age who are not using 14.22 A contraceptive plan should be The risk for associated hypertension reliable contraception. B discussed and implemented and other comorbidities may be as high with all women with diabetes or higher with type 2 diabetes as with of reproductive potential. C type 1 diabetes, even if diabetes is better In normal pregnancy, blood pressure is 14.23 Screen women with a recent controlled and of shorter apparent du- lower than in the nonpregnant state. In a history of gestational diabetes ration, with pregnancy loss appearing to pregnancy complicated by diabetes and mellitus at 4–12 weeks post- be more prevalent in the third trimester chronic hypertension, a target goal blood , partum, using the 75-g oral in women with type 2 diabetes compared pressure of 135/85 mmHg is reason- glucose tolerancetestandclin- with the first trimester in women with able (98,99). Blood pressure targets ically appropriate nonpreg- type 1 diabetes (91,92). lower than 120/80 mmHg may be associated with impaired fetal growth, nancy diagnostic criteria. B especially in the setting of placental in- 14.24 Women with a history of ges- PREECLAMPSIA AND ASPIRIN sufficiency. In a 2015 study targeting tational diabetes mellitus found Recommendation diastolic blood pressure of 100 mmHg to have prediabetes should re- 14.18 Women with type 1 or type 2 versus 85 mmHg in pregnant women, ceive intensive lifestyle inter- diabetes should be prescribed only 6% of whom had GDM at enroll- ventions and/or metformin to low-dose aspirin 60–150 mg/ ment, there was no difference in preg- prevent diabetes. A day (usual dose 81 mg/day) by nancy loss, neonatal care, or other 14.25 Womenwithahistoryofgesta- the end of the first trimester neonatal outcomes, although women Associationtional diabetes mellitus should in order to lower the risk of in the less intensive treatment group have lifelong screening for the preeclampsia. A had a higher rate of uncontrolled hyper- development of type 2 diabetes tension (100). or prediabetes at least every B Diabetes in pregnancy is associated with During pregnancy, treatment with 3 years. 14.26 an increased risk of preeclampsia (93). ACE inhibitors and angiotensin receptor Women with a history of ges- Based upon the results of clinical trials blockers is contraindicated because tational diabetes mellitus should and meta-analyses (94), the U.S. Preven- they may cause fetal renal dysplasia, seek preconception screen- tive Services Task Force recommends the oligohydramnios, pulmonary hypoplasia, ing for diabetes and precon- use of low-dose aspirin (81 mg/day) as a and intrauterine growth restriction (18). ception care to identify and treat preventive medication at 12 weeks of AntihypertensiveDiabetes drugs known to be hyperglycemia and prevent con- E gestation in women who are at high risk effective and safe in pregnancy include genital malformations. 14.27 for preeclampsia (95). A cost-benefit methyldopa, nifedipine, labetalol, diltia- Postpartum care should in- analysis has concluded that this approach zem, clonidine, and prazosin. Atenolol is clude psychosocial assessment E would reduce morbidity, save lives, and not recommended, but other b-blockers and support for self-care. lower health care costs (96). However, may be used, if necessary. Chronic diuretic use during pregnancy is not rec- more study is needed to assess the long- Gestational Diabetes Mellitus ommended as it has been associated term effects of prenatal aspirin exposure Initial Testing with restricted maternal plasma volume, on offspring (97). Because GDM often represents previ- which may reduce uteroplacental perfu- ously undiagnosed prediabetes, type 2 sion (101). On the basis of available PREGNANCY AND DRUG diabetes, maturity-onset diabetes of the evidence, statins should also be avoided CONSIDERATIONS American young, or even developing type 1 di- in pregnancy (102). abetes, women with GDM should be Recommendations See PREGNANCY AND ANTIHYPERTENSIVE MEDI- tested for persistent diabetes or predi- 14.19 In pregnant patients with di- CATIONS in Section 10 “Cardiovascular Dis- abetes at 4–12 weeks postpartum with a abetes and hypertension or ease and Risk Management” (https://doi 75-g OGTT using nonpregnancy criteria significant proteinuria, a consis- .org/10.2337/dc20-s010) for more infor- as outlined in Section 2 “Classification tent blood pressure .135/85 mation on managing blood pressure in and Diagnosis of Diabetes” (https://doi mmHg should be treated in pregnancy. ©2019the interest of optimizing long- .org/10.2334/dc20-S002). term maternal health. Blood POSTPARTUM CARE Postpartum Follow-up pressure targets should range The OGTT is recommended over A1C at no lower than 120/80 mmHg, Recommendations 4–12 weeks postpartum because A1C as lower blood pressure tar- 14.21 Insulin resistance decreases may be persistently impacted (lowered) gets may impair fetal growth. C dramatically immediately post- by the increased red blood cell turnover 14.20 Potentially harmful medications partum, and insulin require- related to pregnancy, by blood loss at in pregnancy (i.e., ACE inhibi- ments need to be evaluated delivery, or by the preceding 3-month tors, angiotensin receptor block- and adjusted as they are often glucose profile. The OGTT is more sen- ers, statins) should be stopped roughly half the prepregnancy sitive at detecting glucose intolerance, S190 Management of Diabetes in Pregnancy Diabetes Care Volume 43, Supplement 1, January 2020

including both prediabetes and diabetes. following 1–2 weeks. In women taking pregnancy outcome in 933 women with type 1 Women of reproductive age with pre- insulin, particular attention should be diabetes. Diabetes Care 2009;32:1046–1048 diabetes may develop type 2 diabetes by directed to hypoglycemia prevention in 5. Nielsen GL, Møller M, Sørensen HT. HbA1c in early diabetic pregnancy and pregnancy out- the time of their next pregnancy and will the setting of breastfeeding and erratic comes: a Danish population-based cohort study need preconception evaluation. Because sleep and eating schedules (111). of 573 pregnancies in women with type 1 di- GDM is associated with an increased abetes. Diabetes Care 2006;29:2612–2616 lifetime maternal risk for diabetes esti- Lactation 6. Suhonen L, Hiilesmaa V, Teramo K. Glycaemic mated at 50–70% after 15–25 years control during early pregnancy and fetal In light of the immediate nutritional and malformations in women with type I diabetes (103,104), women should also be tested immunological benefits of breastfeeding mellitus. Diabetologia 2000;43:79–82 every 1–3 years thereafter if the 4– for the baby, all women including those 7. Charron-Prochownik D, Sereika SM, Becker D, 12 weeks postpartum 75-g OGTT is with diabetes should be supported in et al. Long-term effects of the booster-enhanced normal. Ongoing evaluation may be attempts to breastfeed. Breastfeeding READY-Girls preconception counseling program performedwithanyrecommendedgly- on intentions and behaviors for family planning may also confer longer-term metabolic in teens with diabetes. Diabetes Care 2013;36: cemic test (e.g., annual A1C, annual benefits to both mother (112) and off- 3870–3874 fasting plasma glucose, or triennial spring (113) However, lactation can 8. Peterson C, Grosse SD, Li R, et al. Preventable 75-g OGTT using nonpregnant thresh- increase the risk of overnight hypogly- health and cost burden of adverse birth outcomes olds). cemia, and insulin dosing may need to associated with pregestational diabetes in the United States. Am J Obstet Gynecol 2015;212: be adjusted. 74.e1–74.e9 Gestational Diabetes Mellitus and 9. Britton LE, Hussey JM, Berry DC, Crandell JL, Type 2 Diabetes Contraception Brooks JL, Bryant AG. Contraceptive use among Women with a history of GDM have a A major barrier to effective preconcep- womenAssociation with prediabetes and diabetes in a US greatly increased risk of conversion to tion care is the fact that the majority of national sample. J Midwifery Womens Health 2019;64:36–45 type 2 diabetes over time (103). In the pregnancies are unplanned. Planning prospective Nurses’ Health Study II (NHS 10. Morris JR, Tepper NK. Description and com- pregnancy is critical in women with pre- parison of postpartum use of effective contra- II), subsequent diabetes risk after a his- existing diabetes due to the need for ception among women with and without diabetes. fi tory of GDM was signi cantly lower in preconception glycemic control to pre- Contraception. 1 September 2019 [Epub ahead women who followed healthy eating vent congenital malformations and re- of print]. DOI: 10.1016/j.contraception.2019 .08.008 patterns (105). Adjusting for BMI mod- duce the risk of other complications. erately, but not completely, attenuated 11. Goldstuck ND, Steyn PS. The intrauterine Therefore, all women with diabetes of device in women with diabetes mellitus type I this association. Interpregnancy or post- childbearing potential should have family and II: a systematic review. ISRN Obstet Gynecol partum weight gain is associated with planning options reviewed at regular 2013. Accessed 3 October 2019. Available increased risk of adverse pregnancy out- intervals to makeDiabetes sure that effective from https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC3874344/ comes in subsequent pregnancies (106) contraception is implemented and main- and earlier progression to type 2 diabe- 12. Wu JP, Moniz MH, Ursu AN. Long-acting tained. This applies to women in the reversible contraception-highly efficacious, safe, tes. immediate postpartum period. Women and underutilized. JAMA 2018;320:397–398 Both metformin and intensive lifestyle with diabetes have the same contracep- 13. ACOG Practice Bulletin No. 201: Pregesta- intervention prevent or delay progres- tion options and recommendations as tional Diabetes Mellitus. Obstet Gynecol 2018; 132:e228–e248 sion to diabetes in women with predia- those without diabetes. Long-acting, re- betes and a history of GDM. Of women 14. Charron-Prochownik D, Downs J. Diabetes versable contraception may be ideal for andReproductiveHealthforGirls.Alexandria,VA, with a history of GDM and prediabetes, many women. The risk of an unplanned American Diabetes Association, 2016 – only 5 6 women need to be treated with pregnancy outweighs the risk of any 15. ACOG Committee Opinion No. 762: Prepreg- either intervention to prevent one case given contraception option. nancy Counseling. Obstet Gynecol 2019;133: of diabetes over 3 yearsAmerican (107). In these e78–e89 women, lifestyle intervention and met- 16. Alexander EK, Pearce EN, Brent GA, et al. References 2017 guidelines of the American Thyroid Asso- formin reduced progression to diabetes 1. Dabelea D, Hanson RL, Lindsay RS, et al. ciation for the diagnosis and management of by 35% and 40%, respectively, over Intrauterine exposure to diabetes conveys risks thyroid disease during pregnancy and the post- 10 years compared with placebo (108). for type 2 diabetes and obesity: a study of partum. Thyroid 2017;27:315–389 If the pregnancy has motivated the adop- discordant sibships. Diabetes 2000;49:2208– 17. Ramos DE. Preconception health: changing the paradigm on well-woman health. Obstet tion of a healthier diet, building on these 2211 2. Holmes VA, Young IS, Patterson CC, et al.; Gynecol Clin North Am 2019;46:399–408 gains to support weight loss is recom- Diabetes and Pre-eclampsia Intervention Trial 18. Bullo M, Tschumi S, Bucher BS, Bianchetti mended©2019 in the postpartum period. Study Group. Optimal glycemic control, pre- MG, Simonetti GD. Pregnancy outcome following eclampsia, and gestational hypertension in exposure to angiotensin-converting enzyme in- women with type 1 diabetes in the Diabetes hibitors or angiotensin receptor antagonists: Preexisting Type 1 and Type 2 Diabetes and Pre-eclampsia Intervention Trial. Diabetes a systematic review. Hypertension 2012;60: Insulin sensitivity increases dramatically Care 2011;34:1683–1688 444–450 with delivery of the placenta. In one 3. Guerin A, Nisenbaum R, Ray JG. Use of 19. Taguchi N, Rubin ET, Hosokawa A, et al. study, insulin requirements in the imme- maternal GHb concentration to estimate the Prenatal exposure to HMG-CoA reductase inhib- diate postpartum period are roughly 34% risk of congenital anomalies in the offspring itors: effects on fetal and neonatal outcomes. of women with prepregnancy diabetes. Diabetes Reprod Toxicol 2008;26:175–177 lower than prepregnancy insulin require- Care 2007;30:1920–1925 20. Bateman BT, Hernandez-Diaz S, Fischer MA, ments (109,110). Insulin sensitivity then 4. Jensen DM, Korsholm L, Ovesen P, et al. Peri- et al. Statins and congenital malformations: co- returns to prepregnancy levels over the conceptional A1C and risk of serious adverse hort study. BMJ 2015;350:h1035 care.diabetesjournals.org Management of Diabetes in Pregnancy S191

21. Chew EY, Mills JL, Metzger BE, et al.; National and adverse pregnancy outcomes. N Engl J Med diagnosis of gestational diabetes. Am J Obstet Institute of Child Health and Human Develop- 2008;358:1991–2002 Gynecol 2015;212:224.e1–224.e9 ment Diabetes in Early Pregnancy Study. Met- 35. Maresh MJA, Holmes VA, Patterson CC, 50. Han S, Crowther CA, Middleton P, Heatley E. abolic control and progression of retinopathy: et al.; Diabetesand Pre-eclampsiaIntervention Different types of dietary advice for women with the Diabetes in Early Pregnancy Study. Diabetes Trial Study Group. Glycemic targets in the gestational diabetes mellitus. Cochrane Data- Care 1995;18:631–637 second and third trimester of pregnancy for base Syst Rev 2013;3:CD009275 22. McElvy SS, Miodovnik M, Rosenn B, et al. A womenwithtype1diabetes.DiabetesCare 51. Viana LV, Gross JL, Azevedo MJ. Die- focused preconceptional and early pregnancy 2015;38:34–42 tary intervention in patients with gestational program in women with type 1 diabetes reduces 36. Nielsen LR, Ekbom P, Damm P, et al. HbA1c diabetes mellitus: a systematic review and perinatal mortality and malformation rates to levels are significantly lower in early and late meta-analysis of randomized clinical trials on general population levels. J Matern Fetal Med pregnancy. Diabetes Care 2004;27:1200–1201 maternal and newborn outcomes. Diabetes Care 2000;9:14–20 37. Mosca A, Paleari R, Dalfra` MG, et al. Ref- 2014;37:3345–3355 23. Murphy HR, Roland JM, Skinner TC, et al. erence intervals for hemoglobin A1c in pregnant 52. Institute of Medicine and National Research Effectiveness of a regional prepregnancy care women: data from an Italian multicenter study. Council. Weight Gain During Pregnancy: Reex- program in women with type 1 and type 2 Clin Chem 2006;52:1138–1143 amining the Guidelines. Washington, D.C., Na- diabetes: benefits beyond glycemic control. Di- 38. Hummel M, Marienfeld S, Huppmann M, tional Academies Press, 2009 abetes Care 2010;33:2514–2520 et al. Fetal growth is increased by maternal type 1 53. Hartling L, Dryden DM, Guthrie A, Muise M, 24. ElixhauserA, WeschlerJM, Kitzmiller JL, et al. diabetes and HLA DR4-related gene interactions. Vandermeer B, Donovan L. Benefits and harms Cost-benefit analysis of preconception care for Diabetologia 2007;50:850–858 of treating gestational diabetes mellitus: a system- women with established diabetes mellitus. Di- 39. Cyganek K, Skupien J, Katra B, et al. Risk of atic review and meta-analysis for the U.S. Preven- abetes Care 1993;16:1146–1157 macrosomia remains glucose-dependent in a tiveServicesTaskForceandtheNational Institutes 25. Owens LA, Avalos G, Kirwan B, Carmody L, cohort of women with pregestational type 1 of Health Office of Medical Applications of Re- Dunne F. ATLANTIC DIP: closing the loop: diabetes and good glycemic control. Endocrine search. Ann Intern Med 2013;159:123–129 a change in clinical practice can improve out- 2017;55:447–455 54. Rowan JA, Hague WM, Gao W, Battin MR, comes for women with pregestational diabetes. 40. Abell SK, Boyle JA, de Courten B, et al. Impact Moore MP;Association MiG Trial Investigators. Metformin Diabetes Care 2012;35:1669–1671 of type 2 diabetes, obesity and glycaemic control versus insulin for the treatment of gestational 26. Taylor C, McCance DR, Chappell L, Nelson- on pregnancy outcomes. Aust N Z J Obstet diabetes. N Engl J Med 2008;358:2003–2015 Piercy C, Thorne SA, Ismail KMK, et al. Imple- Gynaecol 2017;57:308–314 55. Gui J, Liu Q, Feng L. Metformin vs insulin in mentation of guidelines for multidisciplinary 41. Temple RC, Aldridge V, Stanley K, Murphy the managementof gestationaldiabetes:a meta- team management of pregnancy in women HR. Glycaemic control throughout pregnancy analysis. PLoS One 2013;8:e64585 with pre-existing diabetes or cardiac conditions: and risk of pre-eclampsia in women with type 56. Langer O, Conway DL, Berkus MD, Xenakis results from a UK national survey. BMC Preg- I diabetes. BJOG 2006;113:1329–1332 EM-J, Gonzales O. A comparison of glyburide nancy Childbirth 2017;17:434 42. Combs CA, Gunderson E, Kitzmiller JL, Gavin and insulin in women with gestational diabetes 27. Garc´ıa-Patterson A, Gich I, Amini SB, LA, Main EK. Relationship of fetal macrosomia to mellitus. N Engl J Med 2000;343:1134–1138 Catalano PM, de Leiva A, Corcoy R. Insulin maternal postprandial glucose control during 57. Hebert MF, Ma X, Naraharisetti SB, et al.; requirements throughout pregnancy in women pregnancy. Diabetes Care 1992;15:1251–1257 Obstetric-Fetal Pharmacology Research Unit with type 1 diabetes mellitus: three changes of 43. FeigDS,DonovanLE,CorcoyR,etal.;CONCEPTT Network. Are we optimizing gestational diabetes direction. Diabetologia 2010;53:446–451 Collaborative Group. ContinuousDiabetes glucose mon- treatment with glyburide? The pharmacologic 28. Padmanabhan S, Lee VW, Mclean M, et al. itoring in pregnant women with type 1 diabetes basis for better clinical practice. Clin Pharmacol The association of falling insulin requirements (CONCEPTT): a multicentre international ran- Ther 2009;85:607–614 with maternal biomarkers and placental dys- domised controlled trial. Lancet 2017;390: 58. Malek R, Davis SN. Pharmacokinetics, effi- function: a prospective study of women with 2347–2359 cacy and safety of glyburide for treatment of preexisting diabetes in pregnancy. Diabetes 44. Kristensen K, Ogge¨ LE, Sengpiel V, et al. gestational diabetes mellitus. Expert Opin Drug Care 2017;40:1323–1330 Continuous glucose monitoring in pregnant Metab Toxicol 2016;12:691–699 29. Manderson JG, Patterson CC, Hadden DR, women with type 1 diabetes: an observational 59. Balsells M, Garc´ıa-Patterson A, Sola` I, Roque´ Traub AI, Ennis C, McCance DR. Preprandial cohort study of 186 pregnancies. Diabetologia M, Gich I, Corcoy R. Glibenclamide, metformin, versus postprandial blood glucose monitoring 2019;62:1143–1153 and insulin for the treatment of gestational in type 1 diabetic pregnancy: a randomized 45. Law GR, Gilthorpe MS, Secher AL, et al. diabetes: a systematic review and meta-analysis. controlled clinical trial. Am J Obstet Gynecol Translating HbA1c measurements into estimated BMJ 2015;350:h102 2003;189:507–512 average glucose values in pregnant women with 60. Senat´ M-V, Affres H, Letourneau A, et al.; 30. de Veciana M, Major CA, MorganAmerican MA, et al. diabetes. Diabetologia 2017;60:618–624 Groupe de Recherche en Obstetrique´ et Postprandial versus preprandial blood glucose 46. Koivusalo SB, Ron¨ o¨ K, Klemetti MM, et al. Gynecologie´ (GROG). Effect of glyburide vs sub- monitoring in women with gestational diabetes Gestational diabetes mellitus can be prevented cutaneous insulin on perinatal complications mellitus requiring insulin therapy. N Engl J Med by lifestyle intervention: the Finnish Gesta- among women with gestational diabetes: a ran- 1995;333:1237–1241 tional Diabetes Prevention Study (RADIEL): domized clinical trial. JAMA 2018;319:1773–1780 31. Jovanovic-Peterson L, Peterson CM, Reed a randomized controlled trial. Diabetes Care 61. Silva JC, Pacheco C, Bizato J, de Souza BV, GF, et al. Maternal postprandial glucose levels 2016;39:24–30 Ribeiro TE, Bertini AM. Metformin compared and infant birth weight: the Diabetes in Early 47. Wang C, Wei Y, Zhang X, et al. A randomized with glyburide for the management of gesta- Pregnancy Study. The National Institute of Child clinical trial of exercise during pregnancy to tional diabetes. Int J Gynaecol Obstet 2010;111: Health and Human Development–Diabetes in prevent gestational diabetes mellitus and im- 37–40 Early©2019 Pregnancy Study. Am J Obstet Gynecol prove pregnancy outcome in overweight and 62. Nachum Z, Zafran N, Salim R, et al. Glyburide 1991;164:103–111 obese pregnant women. Am J Obstet Gynecol versus metformin and their combination for the 32. ACOG Practice Bulletin No. 190: Gesta- 2017;216:340–351 treatment of gestational diabetes mellitus: a ran- tional Diabetes. Obstet Gynecol 2018;131: 48. Metzger BE, Buchanan TA, Coustan DR, et al. domized controlled study. Diabetes Care 2017; e49–e64 Summary and recommendations of the Fifth 40:332–337 33. Ho Y-R, Wang P, Lu M-C, Tseng S-T, Yang C-P, International Workshop-Conference on Gesta- 63. Reference removed during proofreading. Yan Y-H. Associations of mid-pregnancy HbA1c tional Diabetes Mellitus. Diabetes Care;2007; 64. Reference removed during proofreading. with gestational diabetes and risk of adverse 30(Suppl._2):S251–S260 65. Jiang Y-F, Chen X-Y, Ding T, Wang X-F, Zhu pregnancy outcomes in high-risk Taiwanese 49. Mayo K, Melamed N, Vandenberghe H, Z-N, Su S-W. Comparative efficacy and safety of women. PLoS One 2017;12:e0177563 Berger H. The impact of adoption of the in- OADs in management of GDM: network meta- 34. Metzger BE, Lowe LP, Dyer AR, et al.; HAPO ternational association of diabetes in pregnancy analysis of randomized controlled trials. J Clin Study Cooperative Research Group. Hyperglycemia study group criteria for the screening and Endocrinol Metab 2015;100:2071–2080 S192 Management of Diabetes in Pregnancy Diabetes Care Volume 43, Supplement 1, January 2020

66. Vanky E, Zahlsen K, Spigset O, Carlsen SM. and a personalized approach. Diabetes Care 97. Voutetakis A, Pervanidou P, Kanaka-Gantenbein Placental passage of metformin in women with 2019;42:396–399 C. Aspirin for the prevention of preeclampsia and polycystic ovary syndrome. Fertil Steril 2005;83: 80. Farrar D, Tuffnell DJ, West J, West HM. potential consequences for fetal brain develop- 1575–1578 Continuous subcutaneous insulin infusion ver- ment. JAMA Pediatr 2019;173:619–620 67. Charles B, Norris R, Xiao X, Hague W. Pop- sus multiple daily injections of insulin for preg- 98. Brown MA, Magee LA, Kenny LC, et al.; ulation pharmacokinetics of metformin in late nant women with diabetes. Cochrane Database International Society for the Study of Hyper- pregnancy. Ther Drug Monit 2006;28:67–72 Syst Rev 2016;6:CD005542 tensioninPregnancy(ISSHP).Hypertensive 68. Rowan JA, Rush EC, Plank LD, et al. Met- 81. Reference removed during proofreading. disorders of pregnancy: ISSHP classification, formin in gestational diabetes: the offspring 82. Pollex EK, Feig DS, LubetskyA,YipPM,KorenG. diagnosis, and management recommenda- follow-up (MiG TOFU): body composition and Insulin glargine safetyinpregnancy:atransplacental tions for international practice. Hypertension metabolic outcomes at 7-9 years of age. BMJ transfer study. Diabetes Care 2010;33:29–33 2018;72:24–43 Open Diabetes Res Care 2018;6:e000456 83. Holcberg G, Tsadkin-Tamir M, Sapir O, et al. 99. ACOG Practice Bulletin No. 203: Chronic 69. Hanem LGE, Stridsklev S, Jul´ ´ıusson PB, et al. Transfer of insulin lispro across the human Hypertension in Pregnancy. Obstet Gynecol Metformin use in PCOS pregnancies increases placenta. Eur J Obstet Gynecol Reprod Biol 2019;133:e26–e50 the risk of offspring overweight at 4 years of age: 2004;115:117–118 100. Magee LA, von Dadelszen P, Rey E, et al. follow-up of two RCTs. J Clin Endocrinol Metab 84. Boskovic R, Feig DS, Derewlany L, Knie B, Less-tight versus tight control of hypertension in 2018;103:1612–1621 Portnoi G, Koren G. Transfer of insulin lispro pregnancy. N Engl J Med 2015;372:407–417 70. Tarry-Adkins JL, Aiken CE, Ozanne SE. Neo- across the human placenta: in vitro perfusion 101. Sibai BM. Treatment of hypertension in preg- natal, infant, and childhood growth following studies. Diabetes Care 2003;26:1390–1394 nant women. N Engl J Med 1996;335:257–265 metformin versus insulin treatment for gesta- 85. McCance DR, Damm P, Mathiesen ER, et al. 102. Kazmin A, Garcia-Bournissen F, Koren G. tional diabetes: a systematic review and meta- Evaluation of insulin antibodies and placental Risks of statin use during pregnancy: a systematic analysis. PLoS Med 2019;16:e1002848 transfer of insulin aspart in pregnant women review. J Obstet Gynaecol Can 2007;29:906–908 71. Hanem LGE, Salvesen Ø, Juliusson PB, et al. with type 1 diabetes mellitus. Diabetologia 103. Kim C, Newton KM, Knopp RH. Gestational Intrauterine metformin exposure and offspring 2008;51:2141–2143 diabetes and the incidence of type 2 diabetes: cardiometabolic risk factors (PedMet study): 86. Suffecool K, Rosenn B, Niederkofler EE, et al. a systematicAssociation review. Diabetes Care 2002;25: a 5-10 year follow-up of the PregMet randomised Insulin detemir does not cross the human pla- 1862–1868 controlled trial. Lancet Child Adolesc Health centa. Diabetes Care 2015;38:e20–e21 104. Drury MI. Carbohydrate metabolism in 2019;3:166–174 87. O’Neill SM, Kenny LC, Khashan AS, West HM, pregnancy and the newborn. Sutherland HW, 72. Mount Sinai Hospital, Canada. Metformin in Smyth RM, Kearney PM. Different insulin types Stowers JM, Eds. Edinburgh, Churchill Living- Women With Type 2 Diabetes in Pregnancy Trial and regimens for pregnant women with pre- stone, 1984 (MiTy). In: ClinicalTrials.gov. Bethesda, MD, Na- existing diabetes. Cochrane Database Syst Rev 105. Tobias DK, Hu FB, Chavarro J, Rosner B, tional Library of Medicine, 2019. Accessed 3 Oc- 2017;2:CD011880 Mozaffarian D, Zhang C. Healthful dietary patterns tober 2019. Available from https://clinicaltrials 88. Carta Q, Meriggi E, Trossarelli GF, et al. and type 2 diabetes mellitus risk among women .gov/ct2/show/NCT01353391 Continuous subcutaneous insulin infusion versus with a history of gestational diabetes mellitus. 73. University of North Carolina, Chapel Hill. intensive conventional insulin therapy in type I Arch Intern Med 2012;172:1566–1572 Medical Optimization of Management of and type II diabetic pregnancy. Diabete Metab 106. Villamor E, Cnattingius S. Interpregnancy Type 2 Diabetes Complicating Pregnancy (MOMPOD). 1986;12:121–129 weight change and risk of adverse pregnancy In: ClinicalTrials.gov. Bethesda, MD, National 89. Kernaghan D,Diabetes Farrell T, Hammond P, Owen P. outcomes: a population-based study. Lancet Library of Medicine, 2019. Accessed 3 October Fetal growth in women managed with insulin 2006;368:1164–1170 2019. Available from https://clinicaltrials.gov/ pump therapy compared to conventional insulin. 107. Ratner RE, Christophi CA, Metzger BE, et al.; ct2/show/NCT02932475 Eur J Obstet Gynecol Reprod Biol 2008;137:47–49 Diabetes Prevention Program Research Group. 74. Vanky E, Stridsklev S, Heimstad R, et al. 90. Feig DS, Corcoy R, Donovan LE, et al.; CON- Prevention of diabetes in women with a history Metformin versus placebo from first trimester CEPTT Collaborative Group. Pumps or multiple daily of gestational diabetes: effects of metformin to delivery in polycystic ovary syndrome: a ran- injections in pregnancy involving type 1 diabetes: and lifestyle interventions. J Clin Endocrinol domized, controlled multicenter study. J Clin aprespecified analysis of the CONCEPTT random- Metab 2008;93:4774–4779 Endocrinol Metab 2010;95:E448–E455 ized trial. Diabetes Care 2018;41:2471–2479 108. Aroda VR, Christophi CA, Edelstein SL, et al.; 75. Legro RS, Barnhart HX, Schlaff WD, et al.; 91. Clausen TD, Mathiesen E, Ekbom P, Hellmuth Diabetes Prevention Program Research Group. Cooperative Multicenter Reproductive Medi- E, Mandrup-Poulsen T, Damm P. Poor pregnancy The effect of lifestyle intervention and metfor- cine Network. Clomiphene, metformin, or both outcome in women with type 2 diabetes. Di- min on preventing or delaying diabetes among for infertility in the polycystic ovary syndrome. abetes Care 2005;28:323–328 women with and without gestational diabetes: N Engl J Med 2007;356:551–566 92. Cundy T, Gamble G, Neale L, et al. Differing the Diabetes Prevention Program outcomes 76. Palomba S, Orio F Jr, FalboAmerican A, et al. Prospec- causes of pregnancy loss in type 1 and type 2 study 10-year follow-up. J Clin Endocrinol Metab tive parallel randomized, double-blind, double- diabetes. Diabetes Care 2007;30:2603–2607 2015;100:1646–1653 dummy controlled clinical trial comparing 93. Duckitt K, Harrington D. Risk factors for pre- 109. Achong N, Duncan EL, McIntyre HD, clomiphene citrate and metformin as the eclampsia at antenatal booking: systematic re- Callaway L. Peripartum management of glycemia first-line treatment for ovulation induction view of controlled studies. BMJ 2005;330:565 in women with type 1 diabetes. Diabetes Care in nonobese anovulatory women with poly- 94. Roberge S, Bujold E, Nicolaides KH. Aspirin 2014;37:364–371 cystic ovary syndrome. J Clin Endocrinol for the prevention of preterm and term pre- 110. Roeder HA, Moore TR, Ramos GA. Changes Metab 2005;90:4068–4074 eclampsia: systematic review and metaanalysis. in postpartum insulin requirements for patients 77. Palomba S, Orio F Jr, Nardo LG, et al. Met- Am J Obstet Gynecol 2018;218:287–293.e1 with well-controlled type 1 diabetes. Am J Peri- formin©2019 administration versus laparoscopic ovar- 95. Henderson JT, Whitlock EP, O’Conner E, natol 2016;33:683–687 ian diathermy in clomiphene citrate-resistant Senger CA, Thompson JH, Rowland MG. Low- 111. Riviello C, Mello G, Jovanovic LG. Breastfeed- women with polycystic ovary syndrome: a pro- dose aspirin for the prevention of morbidity and ing and the basal insulin requirement in type 1 spective parallel randomized double-blind mortality from preeclampsia: a systematic evi- diabetic women. Endocr Pract 2009;15:187–193 placebo-controlled trial. J Clin Endocrinol dence review for the U.S. Preventive Services 112. Stuebe AM, Rich-Edwards JW, Willett WC, Metab 2004;89:4801–4809 Task Force, 2014. Rockville, MD, Agency for Manson JE, Michels KB. Duration of lactation and 78. Barbour LA, Scifres C, Valent AM, et al. A Healthcare Research and Quality (Report No. incidence of type 2 diabetes. JAMA 2005;294: cautionary response to SMFM statement: phar- 14-05207-EF-1) 2601–2610 macological treatment of gestational diabetes. 96. Werner EF, Hauspurg AK, Rouse DJ. A cost- 113. Pereira PF, Alfenas RdeCG, Araujo´ RMA. Does Am J Obstet Gynecol 2018;219:367.e1–367.e7 benefit analysis of low-dose aspirin prophylaxis breastfeeding influence the risk of developing di- 79. Barbour LA, Feig DS. Metformin for gesta- for the prevention of preeclampsia in the United abetes mellitus in children? A review of current tional diabetes mellitus: progeny, perspective, States. Obstet Gynecol 2015;126:1242–1250 evidence. J Pediatr (Rio J) 2014;90:7–15 Diabetes Care Volume 43, Supplement 1, January 2020 S193

15. Diabetes Care in the Hospital: American Diabetes Association Standards of Medical Care in Diabetesd2020

Diabetes Care 2020;43(Suppl. 1):S193–S202 | https://doi.org/10.2337/dc20-S015

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes” includes the ADA’s current clinical practice recommendations and is intended to Association HOSPITAL THE IN CARE DIABETES 15. provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc20- SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi .org/10.2337/dc20-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC. Diabetes Among hospitalized patients, both hyperglycemia and hypoglycemia are associated with adverse outcomes, including death (1–4). Therefore, careful management of inpatients with diabetes has direct and immediate beneﬁts. Hospital management of diabetes is facilitated by preadmission treatment of hyperglycemia in patients having elective procedures, a dedicated inpatient diabetes service applying well-developed standards, and careful transition out of the hospital to prearranged outpatient management. These steps can shorten hospital stays and reduce the need for readmission, as well as improve patient outcomes. Some in-depth reviews of hospital care for patients with diabetes have been published (5,6). HOSPITAL CARE DELIVERYAmerican STANDARDS

Recommendations 15.1 Perform an A1C test on all patients with diabetes or hyperglycemia (blood glucose .140 mg/dL [7.8 mmol/L]) admitted to the hospital if not performed in the prior 3 months. B 15.2 Insulin should be administered using validated written or computerized protocols that allow for predeﬁned adjustments in the insulin dosage based ©2019on glycemic ﬂuctuations. C

Suggested citation: American Diabetes Associa- Considerations on Admission tion. 15. Diabetes care in the hospital: Standards High-quality hospital care for diabetes requires standards for care delivery, which of Medical Care in Diabetesd2020. Diabetes are best implemented using structured order sets, and quality assurance for Care 2020;43(Suppl. 1):S193-S202 process improvement. Unfortunately, “best practice” protocols, reviews, and © 2019 by the American Diabetes Association. guidelines (2) are inconsistently implemented within hospitals. To correct this, Readers may use this article as long as the work is properly cited, the use is educational and not medical centers striving for optimal inpatient diabetes treatment should establish for proﬁt, and the work is not altered. More infor- protocols and structured order sets, which include computerized physician order mation is available at http://www.diabetesjournals entry (CPOE). .org/content/license. S194 Diabetes Care in the Hospital Diabetes Care Volume 43, Supplement 1, January 2020

Initial orders should state the type of following hospitalization that has been and Diagnosis of Diabetes,” https://doi diabetes (i.e., type 1, type 2, gestational attributed to diabetes can be reduced, .org/10.2337/dc20-S002) (2,25). Hypo- diabetes mellitus, pancreatic diabetes) and costs saved, when inpatient care glycemia in hospitalized patients is cate- when it is known. Because inpatient is provided by a specialized diabetes gorized by blood glucose concentration treatment and discharge planning are management team (20,21). In a cross- and clinical correlates (Table 6.4)(26): more effective if based on preadmission sectional comparison of usual care to Level 1 hypoglycemia is a glucose concen- glycemia, an A1C should be measured on management by specialists who re- tration 54–70 mg/dL (3.0–3.9 mmol/L). all patients with diabetes or hyperglyce- viewed cases and made recommenda- Level 2 hypoglycemia is a blood glucose mia admitted to the hospital if the test tions solely through the electronic concentration ,54 mg/dL (3.0 mmol/L), has not been performed in the previous medical record, rates of both hyper- which is typically the threshold for neuro- 3 months (7–10). In addition, diabetes and hypoglycemia were reduced 30– glycopenic symptoms. Level 3 hypoglyce- self-management knowledge and behav- 40% by electronic “virtual care” (22). mia is a clinical event characterized by iors should be assessed on admission Details of team formation are available altered mental and/or physical function- and diabetes self-management educa- in The Joint Commission Standards for ing that requires assistance from another tion provided, if appropriate. Diabetes programs and from the Society of Hos- person for recovery. Levels 2 and 3 self-management education should in- pital Medicine (23,24). require immediate correction of low clude appropriate skills needed after Even the best orders may not be blood glucose. discharge, such as medication dosing and carried out in a way that improves qual- administration, glucose monitoring, and ity, nor are they automatically updated Glycemic Targets recognition and treatment of hypogly- when new evidence arises. To this end, In a landmark clinical trial, Van den cemia (2). There is evidence to support the Joint Commission has an accredita- BergheAssociation et al. (27) demonstrated that preadmission treatment of hyperglyce- tion program for the hospital care of an intensive intravenous insulin regimen mia in patients scheduled for elective diabetes (23), and the Society of Hospital to reach a target glycemic range of 80– surgery as an effective means of reducing Medicine has a workbook for program 110 mg/dL (4.4–6.1 mmol/L) reduced adverse outcomes (11–13). development (24). mortality by 40% compared with a stan- The National Academy of Medicine dard approach targeting blood glucose of recommends CPOE to prevent medication- GLYCEMIC TARGETS IN 180–215 mg/dL (10–12 mmol/L) in crit- related errors and to increase efficiency HOSPITALIZED PATIENTS ically ill patients with recent surgery (4). in medication administration (14). A This study provided robust evidence that Recommendations Cochrane review of randomized con- active treatment to lower blood glucose 15.4 trolled trials using computerized advice Insulin therapy should be initi- in hospitalized patients had immediate to improve glucose control in the hospital ated forDiabetes treatment of persistent bene fits. However, a large, multicenter found significant improvement in the hyperglycemia starting at a thresh- follow-up study, the Normoglycemia in $ percentage of time patients spent in old 180 mg/dL (10.0 mmol/L). Intensive Care Evaluation and Survival the target glucose range, lower mean Once insulintherapy is started, a Using Glucose Algorithm Regulation – blood glucose levels, and no increase in target glucose range of 140 180 (NICE-SUGAR) trial (28), led to a recon- – hypoglycemia (15). Thus, where feasible, mg/dL (7.8 10.0 mmol/L) is rec- sideration of the optimal target range for there should be structured order sets ommended for the majority of glucose lowering in critical illness. In this that provide computerized advice for critically ill patients and non- trial critically ill patients randomized A glucose control. Electronic insulin critically ill patients. to intensive glycemic control (80–110 15.5 – order templates also improve mean More stringent goals, such as 110 mg/dL) derived no significant treatment – glucose levels without increasing hy- 140 mg/dL (6.1 7.8 mmol/L), advantage compared with a group with poglycemia in patientsAmerican with type 2 may be appropriate for selected more moderate glycemic targets (140– diabetes, so structured insulin order patients if they can be achieved 180 mg/dL [7.8–10.0 mmol/L]) and in fact fi sets should be incorporated into the without signi cant hypoglyce- had slightly but significantly higher mor- C CPOE (16,17). mia. tality (27.5% vs. 25%). The intensively treated group had 10- to 15-fold greater Diabetes Care Providers in the Hospital Standard Definitions of Glucose rates of hypoglycemia, which may have Recommendation Abnormalities contributed to the adverse outcomes 15.3 When caring for hospitalized Hyperglycemia in hospitalized patients is noted. The findings from NICE-SUGAR ©2019patients with diabetes, consult defined as blood glucose levels .140 are supported by several meta-analyses, with a specialized diabetes or mg/dL (7.8 mmol/L) (2,25). Blood glu- some of which suggest that tight glyce- glucose management team when cose levels persistently above this level mic control increases mortality com- possible. C should prompt conservative interven- pared with more moderate glycemic tions, such as alterations in diet or targets and generally causes higher rates Appropriately trained specialists or spe- changes to medications that cause hy- of hypoglycemia (29–31). Based on these cialty teams may reduce length of stay, perglycemia. An admission A1C value results, insulin therapy should be initi- improve glycemic control, and improve $6.5% (48 mmol/mol) suggests that ated for treatment of persistent hyper- outcomes (11,18,19). In addition, the the onset of diabetes preceded hospi- glycemia $180 mg/dL (10.0 mmol/L) greater risk of 30-day readmission talization (see Section 2 “Classification and targeted to a glucose range of care.diabetesjournals.org Diabetes Care in the Hospital S195

140–180 mg/dL (7.8–10.0 mmol/L) for Administration (FDA) has established GLUCOSE-LOWERING TREATMENT the majority of critically ill patients (2). standards for capillary (fingerstick) blood IN HOSPITALIZED PATIENTS Although not as well supported by data glucose meters used in the ambulatory Recommendations from randomized controlled trials, these setting, as well as standards to be 15.6 Basal insulin or a basal plus bolus recommendations have been extended applied for POC measures in the correction insulin regimen is the to hospitalized patients without critical hospital (34). The balance between preferred treatment for noncriti- illness. More stringent goals, such as analytic requirements (e.g., accuracy, cally ill hospitalized patients with – – 110 140 mg/dL (6.1 7.8 mmol/L), may precision, interference) and clinical re- poor oral intake or those who are be appropriate for selected patients (e.g., quirements (rapidity, simplicity, point of taking nothing by mouth. A An critically ill postsurgical patients or pa- care) has not been uniformly resolved insulin regimen with basal, pran- tients with cardiac surgery), as long as (33,35), and most hospitals/medical dial, and correction components is fi they can be achieved without signi cant centers have arrived at their own policies the preferred treatment for non- hypoglycemia. On the other hand, glu- to balance these parameters. It is criti- critically ill hospitalized patients . cose concentrations 180 mg/dL (10 cally important that devices selected for with good nutritional intake. A fl mmol/L) may be acceptable in terminally in-hospital use, and the work ow 15.7 Use of only a sliding scale insulin ill patients, in patients with severe co- through which they are applied, have regimen in the inpatient hospi- morbidities, and in inpatient care set- careful analysis of performance and re- tal setting is strongly discour- tings where frequent glucose monitoring liability and ongoing quality assess- aged. A or close nursing supervision is not fea- ments. Recent studies indicate that sible. In these patients less aggressive POC measures provide adequate infor- In most instances, insulin is the preferred insulin regimens to minimize glucosuria, mation for usual practice, with only rare treatmentAssociation for hyperglycemia in hospital- dehydration, and electrolyte disturban- instances where care has been com- ized patients (2). However, in certain ces are often more appropriate. Clinical promised (36,37). Good practice dic- circumstances, it may be appropriate judgment combined with ongoing as- tates that any glucose result that does to continue home regimens including ’ sessment of clinical status, including not correlate with the patient sclinical oral glucose-lowering medications (42). fi changes in the trajectory of glucose status should be con rmed through If oral medications are held in the hos- measures, illness severity, nutritional measurement of a serum sample in the pital, there should be a protocol for status, or concomitant medications clinical laboratory. resuming them 1–2 days before dis- that might affect glucose levels (e.g., charge. For patients using insulin, recent glucocorticoids), should be incorporated Continuous Glucose Monitoring reports indicate that inpatient use of into the day-to-day decisions regarding Real-time continuousDiabetes glucose monitor- insulin pens is safe and may be associated insulin dosing (2). ing (CGM) provides frequent measure- with improved nurse satisfaction com- ments of interstitial glucose levels, as pared with the use of insulin vials and BEDSIDE BLOOD GLUCOSE well as direction and magnitude of glu- syringes (43–45). Insulin pens have been MONITORING cose trends. It has theoretical advantages the subject of an FDA warning because In hospitalized patients with diabetes over POC glucose testing in detecting and of potential blood-borne diseases; the who are eating, glucose monitoring reducing the incidence of hypoglycemia warning “For single patient use only” should be performed before meals; in in the hospital setting that have been should be rigorously followed (46). those not eating, glucose monitoring borne out in some but not all studies is advised every 4–6 h (2). More frequent (38,39). Several inpatient studies have Insulin Therapy blood glucose testing ranging from every shown that CGM use did not improve Critical Care Setting 30 min to every 2 h is the required glucose control but detected a greater In the critical care setting, continuous standard for safe use of intravenousAmericannumber of hypoglycemic events than intravenous insulin infusion is the most insulin. Safety standards for blood glu- POC glucose testing (40,41). However, effective method for achieving glycemic cose monitoring that prohibit the sharing at present, there are insufficient data on targets. Intravenous insulin infusions of lancets, other testing materials, and clinical outcomes, safety, or cost effec- should be administered based on vali- needles are mandatory (32). tiveness to recommend widespread use dated written or computerized protocols The vast majority of hospital glucose of CGM in hospitalized patients (38,40). that allow for predefined adjustments in monitoring is performed using standard In particular, more research is needed the infusion rate, accounting for glycemic glucose monitors and capillary blood to support application of CGM for crit- fluctuations and insulin dose (2). taken©2019 from fingersticks, similar to the ical care (41). In patients who use CGM process used by outpatients for home in the ambulatory setting for self- Noncritical Care Setting glucose monitoring (33). Point-of-care management of diabetes, use of CGM Outside of critical care units, scheduled (POC) meters are not as accurate or as for this purpose during hospitalization insulin regimens are recommended to precise as laboratory glucose analyzers, can be appropriate but requires hospitals manage hyperglycemia in patients with and capillary blood glucose readings are to have protocols for guidance, as well as diabetes. Regimens using insulin analogs subject to artifact due to perfusion, access to specialist care (39). For more and human insulin result in similar glyce- edema, anemia/erythrocytosis, and sev- information on CGM, see Section 7 “Di- mic control in the hospital setting (47). The eral medications commonly used in the abetes Technology” (https://doi.org/10 use of subcutaneous rapid- or short-acting hospital (4,34). The U.S. Food and Drug .2337/dc20-S007). insulin before meals, or every 4–6hifno S196 Diabetes Care in the Hospital Diabetes Care Volume 43, Supplement 1, January 2020

mealsaregivenorifthepatientisreceiving Transitioning Intravenous to preventing and treating hypo- continuous enteral/parenteral nutrition, is Subcutaneous Insulin glycemia should be established indicated to correct hyperglycemia (2). When discontinuing intravenous insulin, for each patient. Episodes of Basal insulin, or a basal plus bolus cor- a transition protocol is associated with hypoglycemia in the hospital rection regimen, is the preferred treat- less morbidity and lower costs of care should be documented in the ment for noncritically ill hospitalized (53) and is therefore recommended. A medical record and tracked. E patients with poor oral intake or those patient with type 1 or type 2 diabetes 15.9 The treatment regimen should who are restricted from oral intake. An being transitioned to an outpatient sub- be reviewed and changed as nec- insulin regimen with basal, prandial, and cutaneous regimen should receive a dose essary to prevent further hypo- correction components is the preferred of subcutaneous basal insulin 2–4 h be- glycemia when a blood glucose treatment fornoncritically illhospitalized fore the intravenous infusion is discon- value of ,70 mg/dL (3.9 mmol/L) patients with good nutritional intake. tinued. Converting to basal insulin at is documented. C For patients who are eating, insulin 60–80% of the daily infusion dose is an injections should align with meals. In effective approach (2,53,54). For patients Patients with or without diabetes may such instances, POC glucose testing transitioning to regimens with concen- experience hypoglycemia in the hospital shouldbeperformedimmediately before trated insulin (U-200, U-300, or U-500) in setting. While hypoglycemia is associated meals. If oral intake is poor, a safer the inpatient setting, it is important to with increased mortality (65), in many procedure is to administer prandial in- ensure correct dosing by utilizing an cases it is a marker of underlying disease sulin immediately after the patient eats, individual pen and cartridge for each rather than the cause of fatality. However, with the dose adjusted to be appropriate patient and by meticulous supervision hypoglycemia is a severe consequence of for the amount ingested (47). of the dose administered (55,56). New dysregulatedAssociation metabolism and/or diabetes A randomized controlled trial has studies support the use of closed-loop treatment, and it is imperative that it be shown that basal-bolus treatment im- insulin delivery with linked pump/sensor minimized in hospitalized patients. Many proved glycemic control and reduced devices to control blood glucose in se- episodes of hypoglycemia among inpa- hospital complications compared with lected groups of hospitalized patients tients are preventable. Therefore, a hy- reactive, or sliding scale, insulin regimens with type 2 diabetes (57,58). The effect poglycemia prevention and management (i.e., dosing given in response to elevated of closed-loop treatment on clinical out- protocol should be adopted and imple- glucose rather than pre-emptively) in comes, the best application of these mented by each hospital or hospital general surgery patients with type 2 di- devices, and cost-effectiveness of this system. A standardized hospital-wide, abetes(48).Prolongeduseof slidingscale approach are still to be determined. nurse-initiated hypoglycemia treatment insulin regimens as the sole treatment of protocol should be in place to immedi- hyperglycemic inpatients is strongly dis- Noninsulin TherapiesDiabetes ately address blood glucose levels of ,70 couraged (2,19). The safety and efficacy of noninsulin mg/dL (3.9 mmol/L). In addition, individ- While there is evidence for using pre- glucose-lowering therapies in the hospital ualized plans for preventing and treating mixed insulin formulations in the outpa- setting is an area of active research (59). hypoglycemia for each patient should tient setting (49), a recent inpatient study Several recent randomized trials have also be developed. An American Diabetes of 70/30 NPH/regular insulin versus basal- demonstrated the potential effectiveness Association (ADA) consensus statement bolus therapy showed comparable glyce- of glucagon-like peptide 1 receptor ago- recommends that a patient’s treatment mic control but significantly increased nists and dipeptidyl peptidase 4 inhibitors regimen be reviewed any time a blood hypoglycemia in the group receiving pre- in specific groups of hospitalized patients glucose value of ,70 mg/dL (3.9 mmol/L) mixed insulin (50). Therefore, premixed (60–63). However, an FDA bulletin states occurs, because such readings often pre- insulin regimens are not routinely recom- that providers should consider discon- dict subsequent level 3 hypoglycemia (2). mended for in-hospital use.Americantinuing saxagliptin and alogliptin in peo- Episodes of hypoglycemia in the hospital ple who develop heart failure (64). should be documented in the medical Type 1 Diabetes Sodium–glucose transporter 2 (SGLT2) record and tracked (2). For patients with type 1 diabetes, dosing inhibitors should be avoided in cases of insulin based solely on premeal glucose severe illness, in patients with ketonemia levels does not account for basal insulin or ketonuria, and during prolonged fast- Triggering Events and Prevention of requirements or caloric intake, increasing and surgical procedures (5). Until Hypoglycemia ing the risk of both hypoglycemia and safety and effectiveness are established, Insulin is one of the most common drugs hyperglycemia.©2019 Typically, basal insulin SGLT2 inhibitors are not recommended causing adverse events in hospitalized dosing schemes are based on body for routine in-hospital use. patients, and errors in insulin dosing weight, with some evidence that patients and/or administration occur relatively with renal insufficiency should be treated HYPOGLYCEMIA frequently (66,67). Beyond insulin dosing with lower doses (51,52). An insulin Recommendations errors, common preventable sources of regimen with basal and correction com- iatrogenic hypoglycemia are improper 15.8 A hypoglycemia management pro- ponents is necessary for all hospitalized prescribing of other glucose-lowering tocol should be adopted and patients with type 1 diabetes, with the medications, inappropriate management implemented by each hospital addition of prandial insulin if the patient of the first episode of hypoglycemia, and or hospital system. A plan for is eating. nutrition-insulin mismatch, often related care.diabetesjournals.org Diabetes Care in the Hospital S197

to an unexpected interruption of nutri- reduce rates of hypoglycemia in hospi- management is appropriate. If CSII or tion. A recent study describes acute kid- talized patients. CGM is to be used, hospital policy and ney injury as an important risk factor for procedures delineating guidelines for hypoglycemiainthehospital(68),possibly MEDICAL NUTRITION THERAPY IN CSII therapy, including the changing of as a result of decreased insulin clearance. THE HOSPITAL infusion sites, are advised (39,81). Studies of “bundled” preventive thera- The goals of medical nutrition therapy in pies, including proactive surveillance of the hospital are to provide adequate STANDARDS FOR SPECIAL glycemic outliers and an interdisciplinary calories to meet metabolic demands, SITUATIONS data-driven approach to glycemic man- optimize glycemic control, address per- Enteral/Parenteral Feedings agement, showed that hypoglycemic sonal food preferences, and facilitate For patients receiving enteral or paren- episodes in the hospital could be pre- creation of a discharge plan. The ADA teral feedings who require insulin, the vented. Compared with baseline, two does not endorse any single meal plan or regimen should include coverage of such studies found that hypoglycemic specified percentages of macronutrients. basal, prandial, and correctional needs. events fell by 56–80% (69,70). The Joint Current nutrition recommendations ad- It is particularly important that patients Commission recommends that all hypo- vise individualization based on treatment with type 1 diabetes continue to receive glycemic episodes be evaluated for a goals, physiological parameters, and basal insulin even if feedings are discon- root cause and the episodes be aggre- medication use. Consistent carbohydrate tinued. A reasonable estimate of basal gated and reviewed to address systemic meal plans are preferred by many hos- needs can be made from the preadmis- issues (23). pitals as they facilitate matching the sion dose of long-acting or intermediate In addition to errors with insulin treat- prandial insulin dose to the amount of insulin or a percentage of the total daily ment, iatrogenic hypoglycemia may be carbohydrate consumed (77). For enteral requirementsAssociation established in the hospital induced by a sudden reduction of corti- nutritional therapy, diabetes-specific for- (usually 30–50% of the total daily dose of costeroid dose, reduced oral intake, eme- mulas appear to be superior to standard insulin). In the absence of previous in- sis, inappropriate timing of short- or rapid- formulas in controlling postprandial glu- sulin dosing, a reasonable starting point acting insulin in relation to meals, re- cose, A1C, and the insulin response (78). is to use 5 units of NPH/detemir insulin duced infusion rate of intravenous When the nutritional issues in the subcutaneously every 12 h or 10 units of dextrose, unexpected interruption of hospital are complex, involvement of a insulin glargine every 24 h (82). enteral or parenteral feedings, and al- registered dietitian nutritionist can con- For patients receiving continuous tube tered ability of the patient to report tribute to patient care by integrating feedings, the total daily nutritional com- symptoms (5). information about the patient’s clinical ponent may be calculated as 1 unit of condition, meal planning,Diabetes and lifestyle insulin for every 10–15 g carbohydrate Predictors of Hypoglycemia habits and by establishing realistic treat- per day or as a percentage of the total In ambulatory patients with diabetes, it ment goals after discharge. Orders should daily dose of insulin when the patient is is well established that an episode of also indicate that the meal delivery and being fed (usually 50–70% of the total severe hypoglycemia increases the risk nutritional insulin coverage should be daily dose of insulin). Correctional insulin for a subsequent event, in part be- coordinated, as their variability often should also be administered subcutane- cause of impaired counterregulation creates the possibility of hyperglycemic ously every 6 h using human regular (71,72). This relationship also holds for and hypoglycemic events. insulin or every 4 h using a rapid-acting inpatients. For example, in a study of insulin such as lispro, aspart, or glulisine. hospitalized patients treated for hyper- SELF-MANAGEMENT IN THE For patients receiving enteral bolus glycemia, 84% who had an episode of HOSPITAL feedings, approximately 1 unit of regular “severe hypoglycemia” (defined as ,40 Diabetes self-management in the hospi- human insulin or rapid-acting insulin per mg/dL [2.2 mmol/L]) had aAmerican preceding tal may be appropriate for specific pa- 10–15 g carbohydrate should be given episode of hypoglycemia (,70 mg/dL tients (79,80). Candidates include both subcutaneously before each feeding. [3.9 mmol/L]) during the same admission adolescent and adult patients who suc- Correctional insulin coverage should (73). In another study of hypoglyce- cessfully conduct self-management of be added as needed before each feeding. mic episodes (defined as ,50 mg/dL diabetes at home, and whose cognitive For patients receiving continuous pe- [2.8 mmol/L]), 78% of patients were and physical skills needed to successfully ripheral or central parenteral nutrition, using basal insulin, with the incidence self-administer insulin and perform self- human regular insulin may be added to of hypoglycemia©2019 peaking between mid- monitoring of blood glucose are not the solution, particularly if .20 units of night and 6:00 A.M. Despite recognition of compromised. In addition, they should correctional insulin have been required hypoglycemia, 75% of patients did not have adequate oral intake, be proficient in the past 24 h. A starting dose of 1 unit have their dose of basal insulin changed in carbohydrate estimation, use multiple of human regular insulin for every 10 g before the next insulin administration (74). daily insulin injections or continuous sub- dextrose has been recommended (83), Recently, several groups have devel- cutaneous insulin infusion (CSII), have stable and should be adjusted daily in the oped algorithms to predict episodes of insulin requirements, and understand sick- solution. Correctional insulin should be hypoglycemia among inpatients (75,76). day management. If self-management is to administered subcutaneously. For full Models such as these are potentially be used, a protocol should include a re- enteral/parenteral feeding guidance, important and, once validated for gen- quirement that the patient, nursing staff, the reader is encouraged to consult re- eral use, could provide a valuable tool to and physician agree that patient self- view articles detailing this topic (2,84). S198 Diabetes Care in the Hospital Diabetes Care Volume 43, Supplement 1, January 2020

Glucocorticoid Therapy A recent review concluded that peri- down units (97), an approach that The prevalence of glucocorticoid therapy operative glycemic control tighter than may be safer and more cost-effective in hospitalized patients can approach 80–180 mg/dL (4.4–10.0 mmol/L) did not than treatment with intravenous insulin 10%, and these medications can induce improve outcomes and was associated (98). If subcutaneous insulin adminis- hyperglycemia in patients with and with- with more hypoglycemia (89); therefore, tration is used, it is important to pro- out antecedent diabetes (85). Glucocor- in general, tighter glycemic targets are vide adequate fluid replacement, ticoid type and duration of action must not advised. Evidence from a recent frequent bedside testing, appropriate be considered in determining insulin study indicates that compared with usual treatment of any concurrent infections, treatment regimens. Daily ingestion of dosing, a reduction of insulin given the and appropriate follow-up to avoid re- short-acting glucocorticoids such as evening before surgery by ;25% was current DKA. Several studies have shown prednisone reach peak plasma levels more likely to achieve perioperative that the use of bicarbonate in patients in 4–6 h (86) but have pharmacologic blood glucose levels in the target range with DKA made no difference in resolu- actions that last through the day. Pa- with lower risk for hypoglycemia (90). tion of acidosis or time to discharge, and tients on morning steroid regimens have In noncardiac general surgery pa- its use is generally not recommended disproportionate hyperglycemia during tients, basal insulin plus premeal short- (99). For further information regarding the day, but they frequently reach nor- or rapid-acting insulin (basal-bolus) treatment, refer to recent in-depth re- mal blood glucose levels overnight re- coverage has been associated with im- views (5). gardless of treatment (85). In subjects proved glycemic control and lower rates on once-daily steroids, prandial insulin of perioperative complications compared TRANSITION FROM THE HOSPITAL dosing, often with intermediate-acting with the reactive, sliding scale regimens TO THE AMBULATORY SETTING (NPH) insulin, is a standard approach. For (short- or rapid-acting insulin coverage RecommendationAssociation long-acting glucocorticoids such as dexa- only with no basal insulin dosing) (48,91). 15.10 There should be a structured dis- methasone and multidose or continuous charge plan tailored to the in- glucocorticoid use, long-acting insulin Diabetic Ketoacidosis and dividual patient with diabetes. B may be required to control fasting blood Hyperosmolar Hyperglycemic State glucose (42,84). For higher doses of There is considerable variability in the A structured discharge plan tailored to glucocorticoids, increasing doses of pran- presentation of diabetic ketoacidosis the individual patient may reduce length dial and correctional insulin, sometimes (DKA) and hyperosmolar hyperglycemic of hospital stay and readmission rates in extraordinary amounts, are often states, ranging from euglycemia or mild and increase patient satisfaction (100). needed in addition to basal insulin hyperglycemia and acidosis to severe Discharge planning should begin at ad- (87). Whatever orders are started, ad- hyperglycemia, dehydration, and coma; mission and be updated as patient needs justments based on anticipated changes therefore, individualizationDiabetes of treatment change. in glucocorticoid dosing and POC glucose based on a careful clinical and laboratory Transition from the acute care setting test results are critical. assessment is needed (92–95). presents risks for all patients. Inpatients Management goals include restora- may be discharged to varied settings, Perioperative Care tion of circulatory volume and tissue including home (with or without visiting Many standards for perioperative care perfusion, resolution of hyperglycemia, nurse services), assisted living, rehabili- lack a robust evidence base. However, and correction of electrolyte imbalance tation, or skilled nursing facilities. For the the following approach (88) may be and acidosis. It is also important to treat patient who is discharged to home or to considered: any correctable underlying cause of assisted living, the optimal program will DKA such as sepsis, myocardial infarction, need to consider diabetes type and se- 1. The target range for blood glucose in or stroke. In critically ill and mentally verity, effects of the patient’s illness on the perioperative periodAmerican should be obtunded patients with DKA or hyper- blood glucose levels, and the patient’s 80–180 mg/dL (4.4–10.0 mmol/L). osmolar hyperglycemia, continuous in- capacities and preferences. See Section 2. A preoperative risk assessment should travenous insulin is the standard of care. 12 “Older Adults” (https://doi.org/10 be performed for patients with diabe- Successful transition of patients from .2337/dc20-S012) for more information. tes who are at high risk for ischemic intravenous to subcutaneous insulin re- An outpatient follow-up visit with the heart disease and those with auto- quires administration of basal insulin primary care provider, endocrinologist, nomic neuropathy or renal failure. 2–4 h prior to the intravenous insulin or diabetes educator within 1 month of 3. Metformin should be withheld on the being stopped to prevent recurrence of discharge is advised for all patients ex- ©2019day of surgery. ketoacidosis and rebound hyperglycemia periencing hyperglycemia in the hospital. 4. Withhold any other oral glucose-lowering (95). There is no significant difference in If glycemic medications are changed or agents the morning of surgery or pro- outcomes for intravenous human regular glucose control is not optimal at dis- cedure and give half of NPH dose or insulin versus subcutaneous rapid-acting charge, an earlier appointment (in 1– 60–80% doses of long-acting analog or analogs when combined with aggressive 2 weeks) is preferred, and frequent pump basal insulin. fluid management for treating mild or contact may be needed to avoid hyper- 5. Monitor blood glucose at least every moderate DKA (96). Patients with un- glycemia and hypoglycemia. A recently 4–6 h while patient is taking nothing by complicated DKA may sometimes be described discharge algorithm for glyce- mouth and dose with short- or rapid- treated with subcutaneous insulin in mic medication adjustment based on acting insulin as needed. the emergency department or step- admission A1C was found useful to care.diabetesjournals.org Diabetes Care in the Hospital S199

guide treatment decisions and signif- c Information on making healthy food patients 80 years of age or older are icantly improved A1C after discharge choices at home and referral to an more than twice as likely as those 45–64 (8). Therefore, if an A1C from the prior outpatient registered dietitian nutri- years of age to visit the emergency 3 months is unavailable, measuring the tionist to guide individualization of department and nearly five times as A1C in all patients with diabetes or hy- meal plan, if needed. If relevant, likely to be admitted for insulin-related perglycemia admitted to the hospital is when and how to take blood glucose– hypoglycemia (110). One approach to recommended. lowering medications, including insulin reducing insulin-related morbidity in Clear communication with outpatient administration. older adults with type 2 diabetes is to providers either directly or via hospital c Sick-day management. substitute oral agents for insulin in discharge summaries facilitates safe c Proper use and disposal of needles and patients in whom these drugs are transitions to outpatient care. Providing syringes. effective. Among elderly patients in information regarding the cause of hy- long-term care facilities, there was no perglycemia (or the plan for determining It is important that patients be pro- significant difference in glycemic control the cause), related complications and vided with appropriate durable med- between those taking basal insulin and comorbidities, and recommended treat- ical equipment, medications, supplies those on oral glucose-lowering medica- ments can assist outpatient providers as (e.g., blood glucose test strips), and tions (111). In addition, many older they assume ongoing care. prescriptions along with appropriate adults with diabetes are overtreated The Agency for Healthcare Research education at the time of discharge in (112), with half of those maintaining an and Quality (AHRQ) recommends that, order to avoid a potentially dangerous A1C ,7% (53 mmol/mol) being treated at a minimum, discharge plans include hiatus in care. with insulin or a sulfonylurea, which the following (101): are associatedAssociation with hypoglycemia. To PREVENTING ADMISSIONS AND further lower the risk of hypoglycemia- READMISSIONS relatedadmissionsinolderadults, Medication Reconciliation In patients with diabetes, the hospital providers should consider relaxing c The patient’s medications must be cross-checked to ensure that no readmission rate is between 14% and A1C targets to 8% (64 mmol/mol) or chronic medications were stopped and 20%, nearly twice that in patients without 8.5% (69 mmol/mol) in patients with fl to ensure the safety of new prescriptions. diabetes (102,103). This re ects increased shortened life expectancies and signif- disease burden for patients and has im- icant comorbidities (refer to Section c Prescriptions for new or changed med- fi “ ” ication should be filled and reviewed portant nancial implications. Of patients 12 Older Adults, https://doi.org/10 with the patient and family at or with diabetes who are hospitalized, 30% .2337/dc20-S012, for detailed criteria). before discharge. havetwoormorehospitalstays,andthese admissions accountDiabetes for over 50% of in- References 1. Clement S, Braithwaite SS, Magee MF, et al.; Structured Discharge Communication patient costs for diabetes (104). Factors Diabetes in Hospitals Writing Committee. Man- c contributing to readmission include Information on medication changes, agement of diabetes and hyperglycemia in pending tests and studies, and follow- male sex, longer duration of prior hos- hospitals [published corrections appear in Di- up needs must be accurately and pitalization, number of previous hospital- abetes Care 2004;27:856 and Diabetes Care promptly communicated to outpa- izations, number and severity of 2004;27:1255]. Diabetes Care 2004;27:553– tient physicians. comorbidities, and lower socioeconomic 591 2. Moghissi ES, Korytkowski MT, DiNardo M, c Discharge summaries should be and/or educational status; scheduled et al.; American Association of Clinical Endocri- transmitted to the primary care pro- home health visits and timely outpatient nologists; American Diabetes Association. Amer- vider as soon as possible after dis- follow-up reduce rates of readmission ican Association of Clinical Endocrinologists and charge. (102,103). While there is no standard American Diabetes Association consensus statement on inpatient glycemic control. Diabetes c Scheduling follow-up appointmentsAmericanto prevent readmissions, several success- Care 2009;32:1119–1131 prior to discharge increases the likeli- ful strategies have been reported (103). 3. Reference removed in proof hood that patients will attend. These include targeting ketosis-prone 4. Reference removed in proof patients with type 1 diabetes (105), in- 5. Umpierrez G, Korytkowski M. Diabetic It is recommended that the following sulintreatment of patients withadmission emergenciesdketoacidosis, hyperglycaemic hy- areas of knowledge be reviewed and A1C .9% (75 mmol/mol) (106), and use perosmolar state and hypoglycaemia. Nat Rev En- docrinol 2016;12:222–232 addressed prior to hospital discharge: of a transitional care model (107). For 6. Bogun M, Inzucchi SE. Inpatient management people with diabetic kidney disease, of diabetes and hyperglycemia. Clin Ther 2013; c Identi©2019fication of the health care pro- collaborative patient-centered medical 35:724–733 vider who will provide diabetes care homes may decrease risk-adjusted read- 7. Pasquel FJ, Gomez-Huelgas R, Anzola I, et al. after discharge. mission rates (108). A recently published Predictive value of admission hemoglobin A1c on inpatient glycemic control and response to in- c Level of understanding related to the algorithm based on patient demographic sulin therapy in medicine and surgery patients diabetes diagnosis, self-monitoring of and clinical characteristics had only mod- with type 2 diabetes. Diabetes Care 2015;38: blood glucose, home blood glucose erate predictive power but identifies a e202–e203 goals, and when to call the provider. promising future strategy (109). 8. Umpierrez GE, Reyes D, Smiley D, et al. Hospital discharge algorithm based on admission c Definition, recognition, treatment, Age is also an important risk factor in HbA1c for the management of patients with and prevention of hyperglycemia and hospitalization and readmission among type 2 diabetes. Diabetes Care 2014;37:2934– hypoglycemia. patients with diabetes. 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9. Carpenter DL, Gregg SR, Xu K, Buchman TG, Accessed 28 October 2019. Available from use of continuous glucose monitoring. J Diabetes Coopersmith CM. Prevalence and impact of un- https://www.hospitalmedicine.org/clinical-topics/ Sci Technol 2017;11:1036–1044 known diabetes in the ICU. Crit Care Med 2015; glycemic-control/ 39. Umpierrez GE, Klonoff DC. Diabetes tech- 43:e541–e550 25. Umpierrez GE, Hellman R, Korytkowski MT, nology update: use of insulin pumps and con- 10. Rhee MK, Safo SE, Jackson SL, et al. Inpatient et al.; Endocrine Society. Management of tinuous glucose monitoring in the hospital. glucose values: determining the nondiabetic hyperglycemia in hospitalized patients in Diabetes Care 2018;41:1579–1589 range and use in identifying patients at high non-critical care setting: an Endocrine Society 40. Gomez AM, Umpierrez GE. Continuous glu- risk for diabetes. Am J Med 2018;131:443.e11– clinical practice guideline. J Clin Endocrinol Metab cose monitoring in insulin-treated patients in 443.e24 2012;97:16–38 non-ICU settings. J Diabetes Sci Technol 2014;8: 11. Garg R, Schuman B, Bader A, et al. Effect of 26. Agiostratidou G, Anhalt H, Ball D, et al. 930–936 preoperative diabetes management on glycemic Standardizing clinically meaningful outcome 41. Krinsley JS, Chase JG, Gunst J, et al. Contin- control and clinical outcomes after elective measures beyond HbA1c for type 1 diabetes: uous glucose monitoring in the ICU: clinical surgery. Ann Surg 2018;267:858–862 a consensus report of the American Association considerations and consensus. Crit Care 2017; 12. van den Boom W, Schroeder RA, Manning of Clinical Endocrinologists, the American Asso- 21:197 MW, Setji TL, Fiestan G-O, Dunson DB. Effect of ciation of Diabetes Educators, the American 42. Maynard G, Wesorick DH, O’Malley C, A1C and glucose on postoperative mortality in Diabetes Association, the Endocrine Society, Inzucchi SE; Society of Hospital Medicine Glyce- noncardiac and cardiac surgeries. Diabetes Care JDRF International, The Leona M. and Harry B. mic Control Task Force. Subcutaneous insulin 2018;41:782–788 Helmsley Charitable Trust, the Pediatric Endo- order sets and protocols: effective design and 13. Setji T, Hopkins TJ, Jimenez M, et al. Ration- crine Society, and the T1D Exchange. Diabetes implementation strategies. J Hosp Med 2008; alization, development, and implementation of a Care 2017;40:1622–1630 3(Suppl.):29–41 preoperative diabetes optimization program de- 27. van den Berghe G, Wouters P, Weekers F, 43. Brown KE, Hertig JB. Determining current signed to improve perioperative outcomes and et al. Intensive insulin therapy in critically ill insulin pen use practices and errors in the in- reduce cost. Diabetes Spectr 2017;30:217–223 patients. N Engl J Med 2001;345:1359–1367 patient setting. Jt Comm J Qual Patient Saf 2016; 14. Institute of Medicine. Preventing Medica- 28. Finfer S, Chittock DR, Su SY, et al.; NICE- 42:568–575 tion Errors. Aspden P, Wolcott J, Bootman JL, SUGAR Study Investigators. Intensive versus 44.Association HorneJ,BondR,SarangarmP.Comparisonof Cronenwett LR, Eds. Washington, DC, National conventional glucose control in critically ill pa- inpatient glycemic control with insulin vials Academies Press, 2007 tients. N Engl J Med 2009;360:1283–1297 versus insulin pens in general medicine patients. 15. Gillaizeau F, Chan E, Trinquart L, et al. Com- 29. Kansagara D, Fu R, Freeman M, Wolf F, Hosp Pharm 2015;50:514–521 puterized advice on drug dosage to improve Helfand M. Intensive insulin therapy in hospi- 45. Veronesi G, Poerio CS, Braus A, et al. Deter- prescribing practice. Cochrane Database Syst talized patients: a systematic review. Ann Intern minants of nurse satisfaction using insulin pen Rev 2013;11:CD002894 Med 2011;154:268–282 devices with safety needles: an exploratory factor 16. Wexler DJ, Shrader P, Burns SM, Cagliero E. 30. Sathya B, Davis R, Taveira T, Whitlatch H, Wu analysis. Clin Diabetes Endocrinol 2015;1:15 Effectiveness of a computerized insulin order W-C. Intensity of peri-operative glycemic control 46. U.S. Food and Drug Administration. FDA template in general medical inpatients with and postoperative outcomes in patients with Drug Safety Communication: FDA requires label type 2 diabetes: a cluster randomized trial. Di- diabetes: a meta-analysis. Diabetes Res Clin Pract warnings to prohibit sharing of multi-dose diabetes Care 2010;33:2181–2183 2013;102:8–15 abetes pen devices among patients. Accessed 28 17. Schnipper JL, Liang CL, Ndumele CD, 31. Umpierrez G, Cardona S, Pasquel F, et al. October 2019. Available from https://www.fda Pendergrass ML. Effects of a computerized order Randomized controlledDiabetes trial of intensive versus .gov/Drugs/DrugSafety/ucm435271.htm set on the inpatient management of hypergly- conservative glucose control in patients under- 47. Bueno E, Benitez A, Rufinelli JV, et al. Basal- cemia: a cluster-randomized controlled trial. going coronary artery bypass graft surgery: bolus regimen with insulin analogues versus Endocr Pract 2010;16:209–218 GLUCO-CABG trial. Diabetes Care 2015;38: human insulin in medical patients with type 2 18. Wang YJ, Seggelke S, Hawkins RM, et al. 1665–1672 diabetes: a randomized controlled trial in Latin Impact of glucose management team on out- 32. Cobaugh DJ, Maynard G, Cooper L, et al. America. Endocr Pract 2015;21:807–813 comes of hospitalization in patients with type 2 Enhancing insulin-use safety in hospitals: prac- 48. Umpierrez GE, Smiley D, Jacobs S, et al. diabetes admitted to the medical service. Endocr tical recommendations from an ASHP Founda- Randomized study of basal-bolus insulin ther- Pract 2016;22:1401–1405 tion expert consensus panel. Am J Health Syst apy in the inpatient management of patients 19. Draznin B, Gilden J, Golden SH, et al.; PRIDE Pharm 2013;70:1404–1413 with type 2 diabetes undergoing general sur- investigators. Pathways to quality inpatient man- 33. Rice MJ, Coursin DB. Glucose meters: here gery (RABBIT 2 surgery). Diabetes Care 2011;34: agement of hyperglycemia and diabetes: a call to today, gone tomorrow? Crit Care Med 2016;44: 256–261 action. Diabetes Care 2013;36:1807–1814 e97–e100 49. Giugliano D, Chiodini P, Maiorino MI, 20. Bansal V, Mottalib A, Pawar TK, et al. In- 34. Rice MJ, Smith JL, Coursin DB. Glucose Bellastella G, Esposito K. Intensification of insulin patient diabetes managementAmerican by specialized measurement in the ICU: regulatory intersects therapy with basal-bolus or premixed insulin diabetes team versus primary service team in reality. Crit Care Med 2017;45:741–743 regimens in type 2 diabetes: a systematic review non-critical care units: impact on 30-day read- 35. Klonoff DC, Draznin B, Drincic A, et al. PRIDE and meta-analysis of randomized controlled mission rate and hospital cost. BMJ Open Di- statement on the need for a moratorium on the trials. Endocrine 2016;51:417–428 abetes Res Care 2018;6:e000460 CMS plan to cite hospitals for performing point- 50. Bellido V, Suarez L, Rodriguez MG, et al. 21. Ostling S, Wyckoff J, Ciarkowski SL, et al. The of-care capillary blood glucose monitoring on Comparison of basal-bolus and premixed insulin relationship between diabetes mellitus and critically ill patients. J Clin Endocrinol Metab regimens in hospitalized patients with type 2 30-day readmission rates. Clin Diabetes Endo- 2015;100:3607–3612 diabetes. Diabetes Care 2015;38:2211–2216 crinol 2017;3:3 36. DuBois JA, Slingerland RJ, Fokkert M, et al. 51. Baldwin D, Zander J, Munoz C, et al. A 22.©2019 Rushakoff RJ, Sullivan MM, MacMaster HW, Bedside glucose monitoringdis it safe? A new, randomized trial of two weight-based doses et al. Association between a virtual glucose regulatory-compliant risk assessment evaluation of insulin glargine and glulisine in hospital- management service and glycemic control in protocol in critically ill patient care settings. Crit ized subjects with type 2 diabetes and renal hospitalized adult patients: an observational Care Med 2017;45:567–574 insufficiency. Diabetes Care 2012;35:1970– study. Ann Intern Med 2017;166:621–627 37. Zhang R, Isakow W, Kollef MH, Scott MG. 1974 23. Arnold P, Scheurer D, Dake AW, et al. Hos- Performance of a modern glucose meter in ICU 52. Iyengar R, Franzese J, Gianchandani R In- pital guidelines for diabetes management and and general hospital inpatients: 3 years of real- patient glycemic management in the setting of the Joint Commission-American Diabetes Asso- world paired meter and central laboratory re- renal insufficiency/failure/dialysis. Curr Diab Rep ciation inpatient diabetes certification. Am J sults. Crit Care Med 2017;45:1509–1514 2018;18:75 Med Sci 2016;351:333–341 38. Wallia A, Umpierrez GE, Rushakoff RJ, et al.; 53. Schmeltz LR, DeSantis AJ, Thiyagarajan V, 24. Society of Hospital Medicine. Clinical Tools, DTS Continuous Glucose Monitoring in the Hos- et al. Reduction of surgical mortality and mor- Glycemic Control Implementation Toolkit. pital Panel. Consensus statement on inpatient bidity in diabetic patients undergoing cardiac care.diabetesjournals.org Diabetes Care in the Hospital S201

surgery with a combined intravenous and sub- 67. Alwan D, Chipps E, Yen P-Y, Dungan K. 84. Corsino L, Dhatariya K, Umpierrez G. Man- cutaneous insulin glucose management strategy. Evaluation of the timing and coordination of agement of diabetes and hyperglycemia in hos- Diabetes Care 2007;30:823–828 prandial insulin administration in the hospital. pitalized patients. In Endotext. Accessed 28 54. Shomali ME, Herr DL, Hill PC, Pehlivanova M, Diabetes Res Clin Pract 2017;131:18–32 October 2019. Available from http://www.ncbi Sharretts JM, Magee MF. Conversion from in- 68. Hung AM, Siew ED, Wilson OD, et al. Risk of .nlm.nih.gov/books/NBK279093/ travenous insulin to subcutaneous insulin after hypoglycemia following hospital discharge in 85. Roberts A, James J, Dhatariya K; Joint British cardiovascular surgery: transition to target study. patients with diabetes and acute kidney injury. Diabetes Societies (JBDS) for Inpatient Care. Diabetes Technol Ther 2011;13:121–126 Diabetes Care 2018;41:503–512 Management of hyperglycaemia and steroid 55. Tripathy PR, Lansang MC. U-500 regular 69. Maynard G, Kulasa K, Ramos P, et al. Impact (glucocorticoid) therapy: a guideline from the insulin use in hospitalized patients. Endocr Pract of a hypoglycemia reduction bundle and a sys- Joint British Diabetes Societies (JBDS) for In- 2015;21:54–58 tems approach to inpatient glycemic manage- patient Care group. Diabet Med 2018;35: 56. Lansang MC, Umpierrez GE. Inpatient hy- ment. Endocr Pract 2015;21:355–367 1011–1017 perglycemia management: a practical review for 70. Milligan PE, Bocox MC, Pratt E, Hoehner CM, 86. Kwon S, Hermayer KL, Hermayer K. Glucocorticoid- primary medical and surgical teams. Cleve Clin J Krettek JE, Dunagan WC. Multifaceted approach induced hyperglycemia. Am J Med Sci 2013;345: Med 2016;83(Suppl. 1):S34–S43 to reducing occurrence of severe hypoglycemia 274–277 57. Bally L, Thabit H, Hartnell S, et al. Closed-loop in a large healthcare system. Am J Health Syst 87. BradyV, Thosani S,Zhou S,BassettR, Busaidy insulin delivery for glycemic control in noncritical Pharm 2015;72:1631–1641 NL, Lavis V. Safe and effective dosing of basal- care. N Engl J Med 2018;379:547–556 71. Dagogo-Jack S. Hypoglycemia in type 1 di- bolus insulin in patients receiving high-dose 58. Boughton CK, Bally L, Martignoni F, et al. abetes mellitus: pathophysiology and preven- steroids for hyper-cyclophosphamide, doxorubi- Fully closed-loop delivery in inpatients receiving tion. Treat Endocrinol 2004;3:91–103 cin, vincristine, and dexamethasone chemother- nutritional support. a two-centre, open-label, 72. Rickels MR. Hypoglycemia-associated auto- apy. Diabetes Technol Ther 2014;16:874–879 randomised controlled trial. Lancet Diabetes nomic failure, counterregulatory responses, and 88. Smiley DD, Umpierrez GE. Perioperative Endocrinol 2019;7:368–377 therapeutic options in type 1 diabetes. Ann N Y glucose control in the diabetic or nondiabetic 59. Pasquel FJ, Fayfman M, Umpierrez GE. De- Acad Sci. 6 August 2019 [Epub ahead of print]. patient. South Med J 2006;99:580–589 bate on insulin vs non-insulin use in the hospital DOI: 10.1111/nyas.14214 89. BuchleitnerAssociation AM, Mart´ınez-Alonso M, settingdis it time to revise the guidelines for 73. Dendy JA, Chockalingam V, Tirumalasetty Hernandez´ M, Sola` I, Mauricio D. Perioperative the management of inpatient diabetes? Curr NN, et al. Identifying risk factors for severe glycaemic control for diabetic patients under- Diab Rep 2019;19:65 hypoglycemia in hospitalized patients with di- going surgery. Cochrane Database Syst Rev 2012; 60. Fushimi N, Shibuya T, Yoshida Y, Ito S, abetes. Endocr Pract 2014;20:1051–1056 9:CD007315 Hachiya H, Mori A. Dulaglutide-combined basal 74. Ulmer BJ, Kara A, Mariash CN. Temporal 90. Demma LJ, Carlson KT, Duggan EW, Morrow plus correction insulin therapy contributes to occurrences and recurrence patterns of hypo- JG III, Umpierrez G. Effect of basal insulin dosage ideal glycemic control in non-critical hospitalized glycemia during hospitalization. Endocr Pract on blood glucose concentration in ambulatory patients. J Diabetes Investig. 5 June 2019 [Epub 2015;21:501–507 surgery patients with type 2 diabetes. J Clin ahead of print]. DOI:10.1111/jdi.13093 75. Shah BR, Walji S, Kiss A, James JE, Lowe JM. Anesth 2017;36:184–188 61. Fayfman M, Galindo RJ, Rubin DJ, et al. A Derivation and validation of a risk-prediction 91. Umpierrez GE, Smiley D, Hermayer K, et al. randomized controlled trial on the safety and tool for hypoglycemia in hospitalized adults Randomized study comparing a basal-bolus efficacy of exenatide therapy for the inpatient with diabetes: the Hypoglycemia During Hospi- with a basal plus correction insulin regimen management of general medicine and surgery talization (HyDHo) score.Diabetes Can J Diabetes 2019;43: for the hospital management of medical and patients with type 2 diabetes. Diabetes Care 278–282.e1 surgical patients with type 2 diabetes: basal plus 2019;42:450–456 76. Mathioudakis NN, Everett E, Routh S, et al. trial. Diabetes Care 2013;36:2169–2174 62. Perez-Belmonte´ LM, Osuna-Sanchez´ J, Development and validation of a prediction 92. Kitabchi AE, Umpierrez GE, Miles JM, Fisher Millan-G´ omez´ M, et al. Glycaemic efficacy and model for insulin-associated hypoglycemia in JN. Hyperglycemic crises in adult patients with safety of linagliptin for the management of non- non-critically ill hospitalized adults. BMJ Open diabetes. Diabetes Care 2009;32:1335–1343 cardiac surgery patients with type 2 diabetes in a Diabetes Res Care 2018;6:e000499 93. Vellanki P, Umpierrez GE. Diabetic ketoaci- real-world setting: Lina-Surg study. Ann Med 77. Curll M, Dinardo M, Noschese M, dosis: a common debut of diabetes among 2019;51:252–261 Korytkowski MT. Menu selection, glycaemic con- African Americans with type 2 diabetes. Endocr 63. Vellanki P, Rasouli N, Baldwin D, et al.; trol and satisfaction with standard and patient- Pract 2017;23:971–978 Linagliptin Inpatient Research Group. Glycaemic controlled consistent carbohydrate meal plans in 94. Harrison VS, Rustico S, Palladino AA, Ferrara efficacy and safety of linagliptin compared to hospitalised patients with diabetes. Qual Saf C, Hawkes CP. Glargine co-administration with basal-bolus insulin regimen in patients with Health Care 2010;19:355–359 intravenous insulin in pediatric diabetic ketoa- type 2 diabetes undergoing non-cardiac surgery: 78. Ojo O, Brooke J. Evaluation of the role of cidosis is safe and facilitates transition to a a multicenter randomized clinical trial.American Diabetes enteral nutrition in managing patients with di- subcutaneous regimen. Pediatr Diabetes 2017; Obes Metab. 20 November 2018 [Epub ahead of abetes: a systematic review. Nutrients 2014;6: 18:742–748 print]. DOI: 10.1111/dom.13587 5142–5152 95. Hsia E, Seggelke S, Gibbs J, et al. Subcuta- 64. U.S. Food and Drug Administration. FDA 79. Mabrey ME, Setji TL. Patient self-management neous administration of glargine to diabetic Drug Safety Communication: FDA adds warnings of diabetes care in the inpatient setting: pro. J patients receiving insulin infusion prevents re- about heart failure risk to labels of type 2 di- Diabetes Sci Technol 2015;9:1152–1154 bound hyperglycemia. J Clin Endocrinol Metab abetes medicines containing saxagliptin and 80. Shah AD, Rushakoff RJ. Patient self-management 2012;97:3132–3137 alogliptin. Accessed 28 October 2019. Avail- of diabetes care in the inpatient setting: con. J 96. Andrade-CastellanosCA,Colunga-LozanoLE, able from http://www.fda.gov/Drugs/DrugSafety/ Diabetes Sci Technol 2015;9:1155–1157 Delgado-Figueroa N, Gonzalez-Padilla DA. Sub- ucm486096.htm©2019 81. Houlden RL, Moore S. In-hospital manage- cutaneous rapid-acting insulin analogues for di- 65. Akirov A, Grossman A, Shochat T, Shimon I. ment of adults using insulin pump therapy. Can J abetic ketoacidosis. Cochrane Database Syst Rev Mortality among hospitalized patients with Diabetes 2014;38:126–133 2016;1:CD011281 hypoglycemia: insulin related and noninsulin 82. Umpierrez GE. Basal versus sliding-scale 97. Kitabchi AE, Umpierrez GE, Fisher JN, related. J Clin Endocrinol Metab 2017;102: regular insulin in hospitalized patients with hy- Murphy MB, Stentz FB. Thirty years of personal 416–424 perglycemia during enteral nutrition therapy. experience in hyperglycemic crises: diabetic ke- 66. AmoriRE,PittasAG,SiegelRD,etal.Inpatient Diabetes Care 2009;32:751–753 toacidosis and hyperglycemic hyperosmolar medical errors involving glucose-lowering medi- 83. Pichardo-Lowden AR, Fan CY, Gabbay state. J Clin Endocrinol Metab 2008;93:1541– cations and their impact on patients: review of RA. Management of hyperglycemia in the 1552 2,598 incidents from a voluntary electronic non-intensive care patient: featuring subcu- 98. UmpierrezGE,Latif K,StoeverJ,etal.Efficacy error-reporting database. Endocr Pract 2008; taneous insulin protocols. Endocr Pract 2011;17: of subcutaneous insulin lispro versus continuous 14:535–542 249–260 intravenous regular insulin for the treatment of S202 Diabetes Care in the Hospital Diabetes Care Volume 43, Supplement 1, January 2020

patients with diabetic ketoacidosis. Am J Med importance of an interdisciplinary approach. Consensus Conference. Diabetes Care 2014;37: 2004;117:291–296 Curr Diab Rep 2018;18:54 2864–2883 99. Duhon B, Attridge RL, Franco-Martinez AC, 104. Jiang HJ, Stryer D, Friedman B, Andrews R. 109. Rubin DJ, Recco D, Turchin A, Zhao H, Maxwell PR, Hughes DW. Intravenous sodium Multiple hospitalizations for patients with di- Golden SH. External validation of the Diabetes bicarbonate therapy in severely acidotic diabetic abetes. Diabetes Care 2003;26:1421–1426 Early Re-admission Risk Indicator (DERRIÔ). En- ketoacidosis. Ann Pharmacother 2013;47:970–975 105. Maldonado MR, D’Amico S, Rodriguez L, docr Pract 2018;24:527–541 100. Shepperd S, Lannin NA, Clemson LM, Iyer D, Balasubramanyam A. Improved outcomes 110. Bansal N, Dhaliwal R, Weinstock RS. Man- McCluskey A, Cameron ID, Barras SL. Discharge in indigent patients with ketosis-prone diabetes: agement of diabetes in the elderly. Med Clin planning from hospital to home. Cochrane Da- effect of a dedicated diabetes treatment unit. North Am 2015;99:351–377 tabase Syst Rev 1996;1:CD000313 Endocr Pract 2003;9:26–32 111. Pasquel FJ, Powell W, Peng L, et al. A ran- 101. Agency for Healthcare Research and Qual- 106. WuEQ,ZhouS,YuA,etal.Outcomesassociated domized controlled trial comparing treatment with ity. Readmissions and adverse events after dis- with post-discharge insulin continuity in US patients oral agents and basal insulininelderlypatientswith charge. Accessed 28 October 2019. Available with type 2 diabetes mellitus initiating insulin in the type 2 diabetes in long-term care facilities. BMJ from https://psnet.ahrq.gov/primers/primer/11 hospital. Hosp Pract (1995) 2012;40:40–48 Open Diabetes Res Care 2015;3:e000104 102. Rubin DJ. Hospital readmission of patients 107. HirschmanKB,BixbyMB.Transitionsincare 112. Lipska KJ, Ross JS, Miao Y, Shah ND, Lee SJ, with diabetes. Curr Diab Rep 2015;15:17 from the hospital to home for patients with Steinman MA. Potential overtreatment of di- 103. Gregory NS, Seley JJ, Dargar SK, Galla N, diabetes. Diabetes Spectr 2014;27:192–195 abetes mellitus in older adults with tight gly- Gerber LM, Lee JI. Strategies to prevent read- 108. Tuttle KR, Bakris GL, Bilous RW, et al. Di- cemic control. JAMA Intern Med 2015;175:356– mission in high-risk patients with diabetes: the abetic kidney disease: a report from an ADA 362

Association

Diabetes

American

16. Diabetes Advocacy: Standards American Diabetes Association of Medical Care in Diabetesd2019

Diabetes Care 2020;43(Suppl. 1):S203–S204 | https://doi.org/10.2337/dc20-S016

The American Diabetes Association position statements. The ADA publishes Diabetes Care in the School Setting (ADA) “Standards of Medical Care in evidence-based, peer-reviewed state- A sizable portion of a child’s day is spent in Diabetes” includes the ADA’s current ments on topics such as diabetes and school, so close communication with and clinical practice recommendations and employment, diabetes and driving, in- cooperation of school personnel are esis intended to provide the components sulin access and affordability, and dia- sential to optimize diabetes management, of diabetes care, general treatment betes management in certain settings safety, and academic opportunities. See goals and guidelines, and tools to eval- such as schools, childcare programs, and the following ADA position statement for uate quality of care. Members of the correctional institutions. In addition to the diabetes management information for ADA Professional Practice Committee, ADA’s clinical documents, these advocacy students with diabetes in the elementary a multidisciplinary expert committee statements are important tools in educating and secondaryAssociation school settings.

schools, employers, licensing agencies, ADVOCACY DIABETES 16. (https://doi.org/10.2337/dc20-SPPC), Jackson CC, Albanese-O’Neill A, Butler KL, are responsible for updating the Stand- policy makers, and others about the intersection of diabetes medicine and et al.; American Diabetes Association. ards of Care annually, or more fre- the law and for providing scientifically Diabetes care in the school setting: quently as warranted. For a detailed supported policy recommendations. a position statement of the American description of ADA standards, state- Diabetes Association. Diabetes Care ments, and reports, as well as the evi- – ADVOCACY STATEMENTS 2015;38:1958 1963; https://doi.org/ dence-grading system for ADA’sclinical 10.2337/dc15-1418 (first publication The following is a partial list of advocacy practice recommendations, please refer 1998; latest revision 2015) statements ordered by publication date, to the Standards of Care Introduction with the most recent statement appear- (https://doi.org/10.2337/dc20-SINT). Diabetes ing first. Care of Young Children With Readers who wish to comment on the Diabetes in the ChildCare Setting Standards of Care are invited to do so at Insulin Access and Affordability Very young children with diabetes have professional.diabetes.org/SOC. The ADA’s Insulin Access and Affordabil- legal protections and can be safely ity Working Group compiled public in- cared for by childcare providers with formation and convened a series of appropriate training, access to resources, Managing the daily health demands of meetings with stakeholders throughout and a system of communication with diabetes can be challenging. People living theinsulin supplychain tolearn how each parents and the child’s diabetes pro- with diabetes should not have to face entity affects the cost of insulin for the vider. See the following ADA position state- discrimination due to diabetes. By advo- consumer. Their conclusions and recom- ment for information on young children cating for the rights of those with di- mendations are published in the follow- aged ,6 years in settings such as day abetes at all levels, ADA canAmerican help to ing ADA statement. care centers, preschools, camps, and ensure that they live a healthy and pro- other programs. ductive life. A strategic goal of the ADA Cefalu WT, Dawes DE, Gavlak G, et al.; is for more children and adults with di- Insulin Access and Affordability Working Siminerio LM, Albanese-O’Neill A, Chiang abetes to live free from the burden of Group. Insulin Access and Affordability JL, et al.; American Diabetes Association. discrimination. The ADA is also focused Working Group: conclusions and recom- Care of young children with diabetes in on making sure cost is not a barrier to mendations. Diabetes Care 2018;41:1299– the childcare setting: a position statement successful diabetes management. 1311 [published correction appears in of the American Diabetes Association. One©2019 tactic for achieving these goals Diabetes Care 2018;41:1831]; https://doi Diabetes Care 2014;37:2834–2842; https:// has been to implement the ADA Stan- .org/10.2337/dci18-0019 (first publication doi.org/10.2337/dc14-1676 (first publication dards of Care through advocacy-oriented 2018) 2014)

Suggested citation: American Diabetes Association. 16. Diabetes advocacy: Standards of Medical Care in Diabetesd2020. Diabetes Care 2020; 43(Suppl. 1):S203–S204 © 2019 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for proﬁt, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license. S204 Diabetes Advocacy Diabetes Care Volume 43, Supplement 1, January 2020

Diabetes and Driving Diabetes and Employment (first publication 1984; latest revision People with diabetes who wish to oper- Anypersonwithdiabetes,whether 2009) ate motor vehicles are subject to a great insulin treated or noninsulin treated, variety of licensing requirements applied should be eligible for any employment Diabetes Care in Correctional by both state and federal jurisdictions. for which he or she is otherwise qualified. Institutions For an overview of existing licensing rules Employment decisions should never be People with diabetes in correctional for people with diabetes, factors that based on generalizations or stereotypes facilities should receive care that meets impact driving for this population, and regarding the effects of diabetes. For a general guidelines for assessing driver national standards. Correctional insti- general set of guidelines for evaluating fitness and determining appropriate li- tutions should have written policies and censing restrictions, see the following individuals with diabetes for employ- procedures for the management of di- ADA position statement. ment, including how an assessment abetes and for the training of medical Editor’s note: Federal commercial driving should be performed and what changes and correctional staff in diabetes care rules for individuals with insulin-related di- (accommodations) in the workplace practices. For a general set of guidelines abetes changed on 19 November 2018. may be needed for an individual with for diabetes care in correction institutions, see the following ADA position These changes will be reflected in diabetes, see the following ADA position statement. a future updated ADA statement. statement. Lorber D, Anderson J, Arent S, et al.; American Diabetes Association. Diabetes fi American Diabetes Association. Diabetes Anderson JE, Greene MA, Grif nJW management in correctional institutions. and driving. Diabetes Care 2014;37- Jr, et al.; American Diabetes Associa- Diabetes Care 2014;37(Suppl. 1):S104– (Suppl. 1):S97–S103; https://doi.org/ tion. Diabetes and employment. Dia- S111;Association https://doi.org/10.2337/dc14-S104 10.2337/dc14-S097 (first publication betes Care 2014;37(Suppl. 1):S112–S117; (first publication 1989; latest revision 2012) https://doi.org/10.2337/dc14-S112 2008)

Diabetes

American

Disclosures: Standards of Medical Care in Diabetesd2020

Diabetes Care 2020;43(Suppl. 1):S205–S206 | https://doi.org/10.2337/dc20-SDIS

Committee members disclosed the following covering the period 12 months before December 2019 Other Speakers’ research bureau/ Ownership Consultant/advisory Member Employment Research grant support honoraria interest board Other Professional Practice Committee Joshua J. Neumiller, Washington State None None Diabetes Spectrum, None None None PharmD, CDE, University Associate FASCP, Chair Editorship George Bakris, MD University of Chicago Bayer, Janssen, Vascular None None None Novo Nordisk, Merck, None Medicine Dynamics# KBP Biosciences William T. Cefalu, MD National Institute of None None None None NoneAssociationNone Diabetes and Digestive and Kidney Diseases Jill Crandall, MD Albert Einstein College None None None None None None of Medicine DISCLOSURES David D’Alessio, MD Duke University, Division Merck, Eli Lilly None Novo Nordisk None Lilly, Intarcia Endocrine Society of Endocrinology Meeting Committee Jennifer Green, MD Duke University, Division Boehringer Ingelheim None None None Boehringer None of Endocrinology Ingelheim*, Novo Nordisk, Astra Zeneca Elbert Huang, MD, University of Chicago None None None GlaxoSmithKline* None Medical Research MPH, FACP Medicine Analytics and Informatics Alliance, Diabetes Board of Directors; The Institute for Clinical and Economic Review, Midwest Comparative Effectiveness Public Advisory Council Kathryn Evans Duke University Medical None None None None Amgen None Kreider, DNP, Center, Division of APRN, FNP- BC, Endocrinology BC-ADM Christine G. Lee, MD, National Institute of None None None None None ADA Precision Medicine MS Diabetes and Digestive and Diabetes Task Force and Kidney Diseases, Steering Committee Division of Diabetes, Endocrinology, and Metabolic Diseases Nisa Maruthur, MD, Johns Hopkins AmericanNone None None None None None MHS University, Division of General Internal Medicine Anne Peters, MD Keck School of Medicine Dexcom#, vTv Therapeutics# None ADA Scientific Stock options Abbott Diabetes Care, None of University of Sessions 2019 Boehringer Ingelheim, Southern California (honorarium Eli Lilly, Lexicon, returned to Livongo, ADA as charitable Medscape*, donation) MannKind, Novo ©2019 Nordisk, Sanofi* Maria Jose Redondo, Texas Children’s Caladrius# None ADA Scientific None None TrialNet Steering MD, PhD, MPH Hospital-Baylor Sessions 2019 Committee member College of Medicine Jane Reusch, MD University of Colorado None None Sanofi keynote None Medtronic None address# Emily Weatherup, University of Michigan None None ADA Scientific None None None MS, RDN, CDE Sessions 2019 Jennifer Wyckoff, University of Michigan None None ADA speaker None EPIC Endocrine None MD honoraria Steering Committee member S206 Disclosures Diabetes Care Volume 43, Supplement 1, January 2020

Other Speakers’ research bureau/ Ownership Consultant/advisory Member Employment Research grant support honoraria interest board Other

Deborah Young- National Institutes of None None None None None None Hyman, PhD, Health, Ofﬁce of CDE Behavioral Health and Social Science Research

American College of CardiologydDesignated Representatives (Section 10) Sandeep Das, MD, University of Texas None None Circulation None None None MPH, FACC Southwestern Medical (Associate Center Editor) Mikhail Saint Luke’s Mid AstraZeneca*, AstraZeneca*# None None AstraZeneca*, None Kosiborod, America Heart Boehringer Sanofi*, MD, FACC Institute Ingelheim* GlaxoSmithKline, Amgen*, Boehringer Ingelheim*, Novo Nordisk*, Merck (Diabetes)*, Eisai*, Glytec, Janssen*, Intarcia Therapeutics, Novartis, Bayer, AssociationApplied Therapeutics American Diabetes Association Staff Kenneth P. American Diabetes None None None First Samurai None None Moritsugu, MD, Association, First Consulting, LLC MPH Samurai Consulting, LLC Mindy Saraco, MHA American Diabetes None None None None None None Association Malaika I. Hill, MA American Diabetes None None None None None None Association Matthew P. Petersen American Diabetes None None None None None None Association Shamera Robinson, American Diabetes None None None None None None MPH, RDN Association Diabetes *$$10,000 per year from company to individual. #Grant or contract is to university or other employer. William T. Cefalu, MD, joined the Professional Practice Committee in August 2019 subsequent to his resignationasChiefScientific,Medical,andMissionOfficerofADA.KennethP. Moritsugu,MD,MPH,FACPM,iscurrentlytheInterimChiefScientificandMedicalOfficerofADAandcontinueshisworkwith First Samurai Consulting, LLC. Prior to joining ADA in September 2019, Malaika I. Hill, MA, was the principal of MD Writing & Editing Solutions, LLC. Jane Reusch, MD, joined the Professional Practice Committee in April 2019. Christine Lee, MD, joined the Professional Practice Committee in June 2019.

American

Index

A1C, S15–S17, S66–S71. see also Glycemic targets alpha-glucosidase inhibitors, S106 physical therapy, S54–S56 age and, S16 Alzheimer disease, S153 psychosocial issues, S57–S60 at hospital admission, S193–S194 ambulatory glucose report (AGP), S5, S69 revisions summary, S5 at hospital discharge, S199 amputations, foot, S145 smoking cessation, S56–S57 cardiovascular disease outcomes and, amylin mimetic, S106 in type 2 diabetes prevention/delay, S68–S71 angiotensin receptor blockers (ARBs) S32–S34 differences in children, S67, S167 in CKD patients, S141 b blockers, S115, S145, S189 differences in ethnic populations, S67–S68 in diabetic retinopathy, S143 b cell demise/dysfunction, S15 glucose assessment, S68 for hypertension, S114–S117 bevacizumab, S142 goals, S68–S71, S166 in pregnancy, S114, S184, S189 biguanides. see also metformin, S106 hemoglobinopathies, S16 anti-vascular endothelial growth factor bile acid sequestrant, S106 HIV and, S44 (anti-VEGF) treatment, S142 blood glucose monitoring, bedside, S195 in hospitalized patients, S193 antibiotic therapy blood glucose self-monitoring (SMBG), S5 limitations of, S67 for diabetic foot infections, S144 blood pressure targets, S5. see also hypertension mean glucose and, S67 antihyperglycemics in children/adolescents with type 1, microvascular complications and, S68 in obesity management, S91 S168–S169 other conditions affecting, S16 selection of, S101 body mass index (BMI), S5, S20, S89–S90 periodontal disease and, S45 for type 2 diabetes, S101 bolus calculators, S82 physical activity benefits, S55 antihypertensives, S115–S117 bone mineral density, S44 in prediabetes, S18 bedtime dosing, S115 bromocriptine,Association S106 in pregnancy, S184, S186–S187 classes of, S115 bupropion/naltrexone, S93 race/ethnicity, S16 hyperkalemia and AKI, S115 recommendations, S66 initial number of, S115 setting individualized goals, S70–S71 multiple-drug therapy, S115 calcium channel blockers, S115–S117 target in CKD, S138 in pregnancy, S189 canagliflozin, S105, S106, S124, S126, S127, S128, testing frequency, S66 resistant hypertension, S115–117 S129, S139 validity in children/adolescents, S22 antiplatelet agents, S121–S122 cancer, S42 acanthosis nigricans, S18 antipsychotics, S60 CANVAS trial, S124, S126, S127, S129, S139 acarbose, S106 antiretrovial therapies, S44 CANVAS-R trial, S124, S126, S127 access to care, S9, S203 anxiety disorders, S5, S58–S59 capsaicin, topical, S144 ACCORD BP trial, S112–S113, S137 ASCEND trial, S122 carbamazepine, S144 ACCORD MIND study, SS153 ascorbic acid, S79 Diabetescarbohydrates, S51, S52–S53 ACCORD study, S69, S70, S71, S120, S138 Asian Americans cardiovascular disease, S5, S111–S134 ACE inhibitors BMI cut point, S20, S90, S92 A1C and outcomes of, S69–S71 in CKD patients, S141 metabolic surgery in, S92, S94 ACCORD study, S69 in diabetic retinopathy, S143 risk-based screening, S20, S21 ADVANCE study, S69 for hypertension, S114–S117 Aspart, S107 antiplatelet agents, S121–S122 in pregnancy, S114, S184, S189 aspirin aspirin, S121–S122 acetaminophen, S79 cardiovascular disease and, S121–S122 blood pressure control, S112–117 acute kidney injury (AKI), S6, S115, S137–S138 dosing, S122 cardiac testing, S123 ADA evidence-grading system, S2 with P2Y12 receptor antagonist, S122 glucose-lowering therapies and, ADA statements, S1, S203–S204 in people less than 50 years of age, S122 S123–S129 ADAG study, S71, S73 preeclampsia and, S189 history of, S18 adolescents. see children and adolescents. resistance, S122 hypertension, S112 ADVANCE BP trial, S69, S70, S113 assisted living facilities, S158 hypoglycemia as risk factor for, S70 advocacy statements, S6, S203–S204Americanatenolol, S145, S189 lifestyle and pharmacologic interventions, aerobic exercise, S55 Atherosclerotic cardiovascular disease. see S123 affordability, of insulin, S203 cardiovascular disease lipid management, S117–S121 Affordable Care Act (ACA), S9 atorvastatin, S118 outcomes trials, S105 aflibercept, S142 atypical antipsychotics, S60 prevention of, in prediabetes, S3 African Americans autoimmune conditions, S4, S42, S167–S168 revisions summary, S5 A1C variability in, S16, S67 automated insulin delivery, S84 risk management in children/adolescents, BMI cut point in, S20 autonomic neuropathy, S56 S168–S170 exercise targets in, S54 screening, S122–S123 food insecurity in, S10 trials of glucose-lowering therapies, ©2019 – hypoglycemia risk in, S72 BARI 2D trial, S144 S123 S129 risk-based screening, S21 bariatric surgery, S92, S174 VADT study, S69 Age basal insulin analogs, S89–S90, S99, S105–S106 care delivery systems, S8–S9 A1C and, S16 bedside blood glucose monitoring, S195 access and quality improvement, S9

in screening and testing, S20 behavior change, S5, S11, S48–S65, S114–S115 behaviors and well-being, S9 INDEX Aging. see Older adults cardiovascular disease and, S123 care teams, S8–S9 AIM-HIGH trial, S120 DSMES, S48–S50 chronic care model, S8 Albiglutide, S125–S126, S128 in gestational diabetes mellitus, S187 cost considerations, S9 Albuminuria, S136, S137 in hypertension management, S114–S115 telemedicine, S9 alcohol intake, S51, S54 medical nutrition therapy, S50–S54 CARMELINA trial, S124, S129 alogliptin, S106, S124, S196 in obesity management, S90–S91 Caucasians, S94. see also ethnicity S208 Index Diabetes Care Volume 43, Supplement 1, January 2020

celiac disease, S4, S168 clopidogrel, S122 diabetes self-management education and cerebrovascular disease. see cardiovascular closed-loop pump system, S84, S196 support (DSMES), S9 disease cognitive impairment, S42–S43 in children/adolescents with type 1, S164 Charcot neuroarthropathy of foot, S56, S146 evaluation, S42–S43 facilitation of, S48–S50 child care settings in older adults, S153 in prediabetes, S35 ADA statement of diabetes care in, S203 statins and, S121 recommendations, S48–S49 children with type 1 diabetes, S165 colesevelam, S106 reimbursement, S50 children and adolescents, S6, S163–S182 community health workers, S11 diabetic ketoacidosis (DKA) A1C validity in, S22 community screening, S20, S22 in children with type 1, S167 autoimmune conditions, S167–S168 community support, S11 due to intercurrent illness, S74 cardiac function testing, S175 comorbidities, S4, S42–S45 in hospitalized patients, S198 cardiovascular disease, S175 computerized physician order entry (CPOE), in type 1 diabetes, S17–S18 cardiovascular risk factor management, S193–S194 diabetic kidney disease S168–S170 CONCEPTT study, S187 exercise in presence of, S56 celiac disease, S168 congenital diabetes. see neonatal diabetes protein intake, S53 complications, S174–S175 consensus reports, S1–S2 Diabetic Retinopathy Study (DRS), S142 diabetes care in child care setting, S203 continuous glucose monitoring (CGM), S5, S68, diabetic retinopathy. see retinopathy diabetes care in school setting, S203 S79–S82 diagnosis, S4, S15–S31 DSMES in, S164 blinded (professional) devices, S82 A1C, S15–S16 dyslipidemia, S169–S170, S175 in children/adolescents, S81, S167 chronic kidney disease, S136 exercise and, S55 devices, S80 confirming, S17 glycemic control, S166–S167 glucose assessment using, S68 cystic fibrosis-related diabetes, S22 glycemic targets, S172 in hospitals, S195 fasting and 2-hour plasma glucose, hypertension, S168–S169 in hypoglycemia prevention, S73–S74 S15–S16 intermittent CGM use in, S81 impact of frequency on, S81 Associationgestational diabetes mellitus, S25–S27 lifestyle management, S171–S172 intermittent, S81 monogenic diabetes syndromes, S23, metabolic surgery, S174 in pregnancy, S81, S187 S24–S25 microvascular complications, S170–S171 real-time, S80–S82 posttransplantation diabetes mellitus, nephropathy, S170, S174 recommendations, S79 S22–S24 neuropathy, S170–S171, S174 side effects, S82 type 1 diabetes, S17–S18 nonalcoholic fatty liver disease, S175 standardized metrics for clinical care, type 2 diabetes and prediabetes, S18–S22 nutrition therapy in, S164 S68 diet. see also medical nutrition therapy obstructive sleep apnea, S175 continuous subcutaneous insulin infusion (CSII), for weight loss, S90–S91 pharmacologic management, S172–S174 S98, S99. see also pumps, insulin digital health technology, S84 physical activity and exercise, S164–S165 contraception, S183–S184, S190 dihydropyridine calcium channel blockers, polycystic ovary syndrome, S175 Coronary heart disease. see cardiovascular S115–S117 psychosocial issues, S165–S166, S175–S176 disease diltiazem, S189 real-time CGM use in, S81 correctional institutions,Diabetes ADA statement on discharge planning, S198–S199 retinopathy, S170, S174–S175 diabetes care in, S204 diuretics, S114 revisions summary, S6 cost considerations, S9, S34, S106, S107, DKA. see diabetic ketoacidosis. school and child care, S165 S155–S156, S203 domperidone, S145 screening and testing, S22, S171 counseling, preconception, S166, S183–S184 dopamine-2 agonist, S106 smoking, S170 CREDENCE trial, S6, S129 DPP-4 inhibitors, S101, S106 thyroid disease, S167–S168 cystic fibrosis-related diabetes (CFRD), S4, S14, cardiovascular outcome trials, S124 transition from pediatric toadult care,S176 S22 heart failure and, S129 type 1 diabetes in, S63–S171 dapagliflozin, S105, S106, S126, S127, S128 in hospital care, S196 type 2 diabetes in, S171–S176 DASH diet, S114 in older adults, S158 CHIPS study, S114 DECLARE-TMI trial, S126, S127, S129 driving, ADA statement on diabetes and, chronic care model, S8, S37 degludec, S99, S107 S203–S204 chronic kidney disease, S6, S135–S141 degludec/liraglutide, S107 droxidopa, S145 acute kidney injury, S137–S138 deintensification of regimens, S155–S157 dulaglutide, S105, S106, S125–S126, S128 albuminuria assessment,American S136 delay, type 2 diabetes, S4, S32–S36 duloxetine, S144 complications, S138 cardiovascular disease prevention, S35 Dying patients, end-of-life/palliative care, diagnosis, S136 lifestyle interventions, S32–S34 S159–S160 epidemiology, S136 pharmacologic interventions, S34–S35 dyslipidemia, S35, S169–S170 estimated GFR, S136 revisions summary, S4 glycemic targets, S138 self-management/support, S35 interventions, S138–S141 dementia, S42–S43, S153. see also cognitive e-cigarettes, S5, S56–S57, S170 nutrition, S138 impairment/dementia eating disorders, S166 referral to nephrologist, S140–S141 dental practices, screening in, S22 eating patterns, S50–S52 ©2019renal effects of glucose-lowering agents, DEPS-R study, S166 EDIC study, S138 S139 Detemir, S107 electrocardiogram, S123 risk assessment, S137 Diabetes Control and Complications Trial (DCCT), ELIXA trial, S125, S128 screening recommendations, S135 S15, S16, S44, S71, S98–S99, S138, S153 EMPA-REG OUTCOME trial, S123–S124, S127, selection of glucose-lowering agents, diabetes distress, S57–S58 S129, S139 S139–S140 diabetes plate method, S52 empagliflozin, S105, S106, S123–S124, S127, staging, S136–S137 Diabetes Prevention Program (DPP), S33, S34, S128, S129, S139 surveillance, S138 S84 employment, ADA statement on diabetes and, treatment recommendations, S135–S136 Diabetes Prevention Program Outcomes Study S204 cigarettes, S34, S56, S170 (DPPOS), S34 enalapril, S145 classification, S4, S14–S15 Diabetes Prevention Recognition Program (DPRP), end-of-life care, S159–S160 clonidine, S145, S189 S534 end-stage renal disease, S136, S139, S140 care.diabetesjournals.org Index S209

enteral/parenteral feedings, S197 use in older adults, S158 Human NPH, S107 epidemiology, of diabetes and CKD, S136 glucocorticoid therapy, S198 Human Regular insulin, S107 eplerenone, S140 glucose assessment Hydralazine, S114 erectile dysfunction, S146 recommendations, S68 hyperbaric oxygen therapy, S146–S147 ertugliflozin, S106 using CGM, S68 hyperglycemia erythromycin, S145 Glucose Management Indicator, S68 definition in hospitalized patients, S194 ETDRS study, S142 glucose meters. see self-monitoring of blood effects on cognition, S43 ethnicity, S16, S18, S20. see also specific glucose in HIV, S44 ethnicities glucose monitoring. see also self- monitoring with intercurrent illness, S74 evidence-grading system, S2 in pregnancy, S186 posttransplant, S23 EXAMINE trial, S124, S129 glulisine, S107 hyperkalemia, S115 exenatide, S100, S106, S125–S126, S128 glyburide, S106, S158, S187–S188 hyperosmolar hyperglycemic states, S198 exercise. see physical activity glycemic control hypertension, S18, S35, S112–S117 exocrine pancreas disease, S14–S15, S25 in diabetic neuropathy, S144 in children/adolescents, S168–S169 EXSCEL trial, S125, S128 physical activity and, S55 intensive versus standard treatment, ezetimibe, S119 real-time CGM impact on, S81 S112–113 glycemic targets, S5, S66–S76 lifestyle interventions, S114–S115 A1C goals, S68–S71 pharmacologic interventions, S115–S117 family planning, S183–S184 A1C testing, S66–S68 pregnancy and antihypertensives, S114 fasting plasma glucose (FPG) test, S15, S19 assessment of, S66–S68 recommendations, S116 fats, dietary, S51, S53 in children/adolescents with type 1 resistant, S115–S117 fenofibrate, S120, S143 diabetes, S166–S167 screening and diagnosis, S117 fibrates, S120 in chronic kidney disease, S138 treatment goals, S112–114 finerenone, S140 in hospitalized patients, S194–S195 treatment strategies, S114–117 first-degree relatives, with diabetes, S18 hypoglycemia, S71–S74 hypertriglyceridemia, S119–S120 fl Association uvastatin, S118 individualization of, S70–S71 hypoglycemia, S71–S74 food insecurity, S10 intercurrent illness, S74 CGM in prevention, S73–S74 foot care, S6, S145–S147 in pregnancy, S184, S186–S187 classification, S72 loss of protective sensation, S144 preprandial, S73 definition in hospitalized patients, S194 patient education, S144 revisions summary, S5 effects on cognition, S43 peripheral arterial disease, S144 summary of recommendations, S72 glucagon, S73 recommendations, S145 guanfacine, S145 glucose for, S71, S72 revisions summary, S6 hospital management, S96–S197 treatment, S144–S145 in older adults, S153 ulcers, S56, S145 HAPO study, S26, S186 postprandial after RYGB surgery, S94 fractures, S44 Harmony Outcomes trial, S125, S128 predictors of, S197 FRAX score, S45 hearing impairment. see sensory impairment prevention, S73 heart failure. see alsoDiabetescardiovascular disease real-time CGM impact on, S821 glucose-lowering therapies and, S129 recommendations, S71 galactose, S79 hemoglobinopathies, S16 risk assessment, S41 gastroparesis, S145 hepatitis B vaccination, S42 symptoms, S72 fi gem brozil, S120 hepatitis C virus infection, S4, S43 treatment, S73 genetic causes, MODY, S23, S24 hip fractures, S44 triggering events, S196–S197 genetic testing, S25 HIV, S44 unawareness, S72 – gestational diabetes mellitus (GDM), S4, S14 S15, homelessness, S10 in young children with type 1 diabetes, S73 S25–S27, S187–S188 hospital care, S6, S74, S193–S202 definition, S25–S26 admission considerations, S193–S194 diagnosis, S25–S27 bedside blood glucose monitoring, S105 idiopathic diabetes, S17 lifestyle management, S187 CGM, S195 illness, intercurrent, S74 medical nutrition therapy, S187 delivery standards, S193–S194 immune-mediated diabetes, S17 one-step strategy, S26–S27 diabetes care providers, S194 immunizations, S39, S41–S42, S185 pharmacologic therapy, S187American–S188 discharge planning, S198–S199 impaired fasting glucose (IFG), S15 postpartum care, S189–S190 DKA, S198 impaired glucose tolerance (IPG), S15 postpartum conversion to type 2, S190 enteral/parenteral feedings, S197 IMPROVE-IT trial, S119 screening, S26 glucocorticoid therapy, S198 incretin-based therapies, S158. see also DPP4 two-step strategy, S27 glucose-lowering treatment in, S195–S196 inhibitors and GLP-1 receptor antagonists GI surgery. see metabolic surgery glycemic targets, S194–S195 Indian Diabetes Prevention Program (IDPP-1), S35 glargine, S99, S107 hyperosmolar hyperglycemic state, S198 influenza vaccination, S42 glargine/lixisenatide, S107 hypoglycemia in, S196–S197 inhaled insulin, S99, S107 glimepiride, S106 insulin therapy, S195–S196 inherited diabetes, S23, S24 glinides,©2019 S106 medical nutrition therapy in, S197 injectable therapies glipizide, S106 noninsulin therapies, S196 injection technique, S99–S100 glomerular filtration rate (GFR), S102, S124, S127, perioperative care, S198 intensifying to, S104 S135, S136, S137, S138, S139, S140, S156, S170 preventing admissions/readmissions, S199 site rotation, S100 glucagon, S73 revisions summary, S6 inpatient care. see Hospital care glucagon-like peptide 1 (GLP-1) receptor self-management in, S197 insulin, S101 agonists, S5, S6, S70, S100, S101, S105, S106, standards for special situations, S197–S198 access and affordability, S203 S126–S129, S196 transition to ambulatory setting, S198– analog, S101 cardiovascular outcome trials with, S199 basal, S89–S90, S99, S105–S106 S125–S126 type 1 diabetes, S196 concentrated, S106–S107 direct renal effects, S139 HOT trial, S113 human, S101 use in CKD patients, S139–S140 HPS2-THRIVE trial, S120 physiology in pregnancy, S186 S210 Index Diabetes Care Volume 43, Supplement 1, January 2020

prandial, S106 maturity-onset diabetes of the young (MODY), neuropathy, S143–S145 insulin delivery, S82–S85 S14–S15, S23, S24–S25 revisions summary, S6 combined pump and sensor systems, meal planning, S50–S52 midodrine, S145 S83–S84 medical devices, for weight loss, S92 MiG TOFU study, S188 digital health technology, S84 medical evaluation, S4, S37–S47 miglitol, S106 future of, S84–S85 assessment and treatment plan, S41 migrant farmworkers, S4, S10–S11 injection technique, S99–S100 comorbidities assessment, S42–S45 mineralocorticoid receptor antagonists, S115, inpatient care, S84 components of, S37–S40 S116, S140 patch, S82 immunizations, S41–S42 MiTY study, S188 pumps, S82–S83 recommendations, S40 MOMPOD study, S188 recommendations, S82, S83 referrals, S41–S42 monogenic diabetes syndromes, S14–S15, S23, syringes and pens, S82 medical nutrition therapy, S4, S5, S50–S54. see S24–S25 transitioning from IV to subcutaneous, also nutrition S196 alcohol, S54 insulin secretagogues, S158 carbohydrates, S52–S53 naltrexone/bupropion, S93 insulin sensitizers, S144 inchildren/adolescentswithtype1diabetes, nateglinide, S106 insulin therapy S164 National Diabetes Education Program, S8, S9 basal, SMBG in patents using, S78–S79 in chronic kidney disease, S138 National Health and Nutrition Examination carbohydrates intake and, S53 eating patterns, S50–S52 Survey (NHANES), S44 in critical care setting, S195 in gestational diabetes mellitus, S187 National Institute of Diabetes and Digestive and intensifying to injectable, S104, S105 goals for adults, S48 Kidney Diseases, S9 in noncritical care setting, S195–S196 in the hospital, S197 national policy in pregnancy, S188–S189 macronutrient distribution, S50–S52 in diabetes prevention/delay, S34 simplification of, for older adults, S156, S158 meal planning, S50–S52 neonatal diabetes, S14–S15, S23, S24 for type 1 diabetes, S98–S100 micronutrients and supplements, S53–S54 nephropathy.Associationsee also chronic kidney disease, for type 2 diabetes, S104–S108 nonnutritive sweeteners, S54 S170 intensification, S108 protein, S53 neurocognitive function intravenous insulin therapy, S196 revisions summary, S5 in older adults, S153 intravitreal therapy, S142 sodium, S53 neuropathy, diabetic, S143–S145 islet autotransplantation, S43–S44 in type 2 diabetes prevention/delay, S33 autonomic, S143 islet transplantation, S100 weight management, S52 cardiac autonomic, S143–S144 isradipine, S145 medications. see also pharmacologic interven- in children/adolescents, S170–S171 tions diagnosis, S143 considerations in pregnancy, S189 erectile dysfunction, S145 KDIGO, S137 with increased diabetes risk, S20 gastrointestinal, S144 ketoacidosis. see diabetic ketoacidosis Mediterranean diet, S50 gastroparesis, S145 kidney disease. see chronic kidney disease and meglitinides, S106 genitourinary, S144 diabetic kidney disease mental health Diabetes glycemic control, S144 Kumamoto study, S69 anxiety disorders, S58–S59 neuropathic pain, S144 depression, S59 orthostatic hypotension, S144–S145 disordered eating behavior, S59–S60 peripheral, S143 L-dopa, S79 in metabolic surgery candidates, S94 screening, S143–S144 labetalol, S114, S189 treatment, S143, S144–S145 lactation, S190 psychosocial/emotional distress, S58 new-onset diabetes after transplantation, S23 language barriers, S11 referrals for, S58 niacin, S120 laser photocoagulation surgery, S142 screening, S57 NICE-SUGAR study, S194 latent autoimmune diabetes in adults, S15 serious mental illness, S60 S92–S94 nifedipine, long-acting, S114, S189 Latinos metabolic surgery, S40 exercise targets in, S54 adverse effects, S94 nonalcoholic fatty liver disease, food insecurity in, S10 in children/adolescents, S174 nonnutritive sweeteners, S51, S54 migrant farmworkers, S4, S10-S11 recommendations, S92 nursing homes, S158, S159 risk-based screening, S18-S21Americanmetformin nutrition. see also medical nutrition therapy LEADER trial, S125, S126, S128, S139 cardiovascular effects, S129 effects on cognition, S43 lifestyle management. see behavior changes for CKD patients, S139 linagliptin, S106, S124 for gestational diabetes mellitus, S188, – obesity management, S5, S89–S97 Lipid management, S117–S121 S157 S158 approved medications, S92 lifestyle intervention, S117 median monthly cost, S106 – assessing safety and efficacy, S92 ongoing therapy and monitoring, S117 for older adults, S157 S158 S34–S35 assessment, S89–S90 statins, S117–S121 to prevent/delay type 2 diabetes, behavioral therapy, S90–S91 liraglutide, S93, S100, S105, S106, S107, for type 1 diabetes, S100 in children/adolescents, S174 S125–S126, S127, S128, S139 for type 2 diabetes, S101, S105 S91–S92 lixisenatide,©2019 S106, S107, S125 –S126, S128 methyldopa, S114, S190 concomitant medications, S90–S91 long-term care facilities, S158, S159 metoclopramide, S145 diet, longer-acting insulin analogs, S99 metoprolol, S145 glucose-lowering therapy, S91 Look AHEAD trial, S45, S90–S91 micronutrients, S51, S53–S54 lifestyle interventions, S91 S92 lorcaserin, S93 microvascular complications, S6, S135–S151 medical devices for, S92–S94, lorcaserin XR, S93 A1C and, S69 metabolic surgery, S174 S91–S92 loss of protective sensation (LOPS), S146 in children/adolescents with type diabetes, pharmacotherapy, lovastatin, S118 S170–S171 physical activity, S90–S91 chronic kidney disease, S135–S141 revisions summary, S5 diabetic retinopathy, S141–S143 weight management, S52, S174 macronutrient distribution, S50–S52 exercise in presence of, S56 obstructive sleep apnea, S45 macular edema, S142 foot care, S145–S147 olanzapene, S60 care.diabetesjournals.org Index S211

older adults, S6, S152–S162 in type 2 diabetes prevention/delay, subcutaneous insulin infusion, S98, S99 deintensification/deprescribing, S155–S157 S33–S34 in type 2 diabetes, S83 end-of-life care, S159–S160 physical inactivity, S18 hypoglycemia in, S73, S153 pioglitazone, S106 quality improvement, 59 lifestyle management, S155 PIONEER trial, S128 neurocognitive function, S153 pitavastatin, S118 pharmacologic therapy, S155–S158 plant-based diet, S50 race, S16, S18 recommendations, S152 pneumococcal pneumonia vaccination, S42 ranibizumab, S142 revisions summary, S6 polycystic ovary syndrome, S18 rapid-acting insulin analogs, S99, S107 simplification of insulin therapy,S156,S157 population health, S4, S7–S13 real-time CGM in skilled nursing facilities/nursing homes, care delivery systems, S8–S9 in adults, S80–S81 S159 recommendations, S7 in children/adolescents, S81 treatment goals, S154–S155 revisions summary, S4, S9–S11 in pregnancy, S81 with type 1 diabetes, S158–S160 social context, S9–S11 in type 1 diabetes, S80–S81 one-step strategy, GDM, S26–S27 postpartum care, S189–190 in type 2 diabetes, S81 fi oral agents. see also speci c medications postsurgical diabetes, S44 REDUCE-IT, S5, S120 – SMBG in patients using, S78 79 posttransplantation diabetes mellitus, S22–S24 referrals oral glucose tolerance test (OGTT), S15, S16, S23, pramlintide, S100, S106 for initial care management, S42 S26 prandial insulin, S106 to nephrologist for CKD, S140–S141 organ failure, end-of-life/palliative care, S160 prasugrel, S122 reimbursement, for DSMES, S50 orlistat, S93 pravastatin, S118 repaglinide, S106 – orthostatic hypotension, S144 S145 prazosin, S189 resistance exercise, S55 P2Y12 receptor antagonist, S122 preconception counseling, S166, S183–S184 retinopathy, S141–S143 pain, neuropathic, S144 prediabetes adjunctive therapy, S143 – palliative care, S159 S160 children and adolescents, S22 in children/adolescents with type 1 S100 Association pancreas transplantation, criteria, S19 diabetes, S170 – pancreatectomy, S43 S44 diagnosis, S18–S19 exercise in presence of, S56 – S25 pancreatic-related diabetes, S4, S14 S15, nutrition and, S4 focal laser photocoagulation surgery, S142 pancreatitis, S43–S44 screening/testing, S19, S21 macular edema in, S141S6 parenteral feedings, S197 preeclampsia, S189 in pregnancy, S141, S142 patch, insulin, S82 pregabalin, S144 retinal photography, S142 pathophysiology, S15 pregnancy, S6, S183–S192 revisions summary, S6 patient education, on foot care, S146 – antihypertensive medications in, screening, S141 S142 patient-centered care, collaborative model, treatment, S141, S142–S143 S37–S40 S114-S116 CHIPS study, S114 in type 1 diabetes, S141, S142 PCSK9 inhibitors, S119 drug considerations, S189 in type 2 diabetes, S142 pens, insulin, S82 gestational diabetes, S187–S188 REWIND trial, S125, S128 periodontal disease, S4, S22, S45 Diabetesrosiglitazone, S106 glycemic targets in, S184, S186–S187 perioperative care, S198 postpartum care, S189–S190 rosuvastatin, S118 peripheral arterial disease. see also roux-en-Y gastric bypass, S92, S94 cardiovascular disease preconception care, S184, S185 – evaluation of foot for, S146 preconception counseling, S183 S184 peripheral neuropathy preeclampsia and aspirin, S189 SAVOR-TIMI trial, S124 exercise in presence of, S56 with preexisting type 1 diabetes, saxagliptin, S106, S124, S129, S196 foot evaluation for, S146 S188 schizophrenia, S60 pharmacologic interventions, S5, S91–S92, with preexisting type 2 diabetes, school settings – S98–S110. see also specific medications, S188 S189 ADA statement on diabetes care in, S203 medication classes real-time CGM in, S81 children/adolescents with type 1 diabetes, approved medications, S92, S93 revisions summary, S6 S165 S32–S36 assessing safety and efficacy, S92 prevention, type 2 diabetes, S4, scientific evidence-grading system, S2 for cardiovascular disease, S123 cardiovascular disease, S35 scientific review, S2 concomitant medications, S91American–S92 lifestyle interventions, S32–S34 screening costs of noninsulin medications, S106 pharmacologic interventions, S34–S35 asymptomatic adults, S20–S22 glucose-lowering therapy, S91 revisions summary, S4 for cardiovascular disease, S123 revisions summary, S5 self-management education/support, children and adolescents, S22 for type 1 diabetes, S98–S100 S36 community, S20, S22 for type 2 diabetes, S100–S108 Professional Practice Committee, S3 in dental practices, S22 in type 2 diabetes prevention/delay, protein, S51, S53 SEARCH study, S169 S34–S35 psychosocial/emotional disorders, S4, S57–S60 second-generation antipsychotics, S60 phentermine, S92, S93 anxiety disorders, S58–S59 self-management. see DSMES phentermine/topiramate,©2019 S92, S93 in children/adolescents with type 1 self-monitoring of blood glucose (SMBG), S5, photocoagulation surgery, S142 diabetes, S165–166 S68, S77–S79 physical activity, S54–S56 depression, S59 with basal insulin and/or oral agents, in obesity management, S90–S91 diabetes distress, S57–S58 S78–S79 physical activity, S54-S56 disordered eating behavior, S59–S60 glucose meter accuracy, S79, S80 in children/adolescents with type 1 screening, S57 hypoglycemia prevention with, S73 diabetes, S164–S165 serious mental illness, S60 with intensive insulin regimens, S78 exercise and children, S55 pumps, insulin, S82–S84 interfering substances for, S79 frequency and types of, S55 combined with sensor systems, S83–S84 meter standards, S79 hypoglycemia and, S56 do-it-yourself systems, S84 optimizing monitor use, S78 with microvascular complications, S56 in older adults, S83 preprandial versus postprandial, S71 pre-exercise evaluation, S55–S56 in pediatric patients, S83 recommendations, S77–S78 S212 Index Diabetes Care Volume 43, Supplement 1, January 2020

semaglutide, S5, S105, S106, S125–S126, S128, subcutaneous insulin infusion, continuous (CSII), real-timeCGMinchildren/adolescents,S81 S139, S158 S98, S99 screening for risk, S17–S18, S21 sensory impairment, S4, S44 sulfonylureas, 2nd generation, S100, S106, S158, staging, S15 SGLT2 inhibitors S187–S188 surgical treatment, S100 AKI and, S137 supplements, S51, S53–S54 type 2 diabetes cardiovascular outcomes trials, S105, S111, surgical treatment, for type 1 diabetes, S100 A1C and cardiovascular disease in, S69–S71 S123–S129 SUSTAIN trial, S126, S128, S139 cardiovascular outcomes trials, S105 costs of, S106 sweeteners, nonnutritive, S51, S54 children and adolescents, S22 direct renal effects, S139 syringes, insulin, S82 in children and adolescents, S171–S176 hospital care, S196 classification, S14–S15 revisions, S5–S6 combination therapy, S102 use in CKD patients, S139–S140 tai chi, S55 diagnosis, S19–S22, S171 use in older adults, S158 tapentadol, S144 DPP-4 inhibitors and cardiovascular out- S77–S88 short-acting insulins, S107 technology, S5, come trials, S124 – simvastatin, S118 for CGM, S79 S82 GLP1 receptor agonists and cardiovascular sitagliptin, S106, S124 in diabetes prevention/delay, S34 outcome trials, S125–S126 – skilled nursing facilities, S158, S159 for insulin delivery, S82 S85 initial therapy, S102 hypoglycemia, S159 overall recommendations, S77 intensifying to injectable therapies, S104 nutritional considerations, S159 revisions summary, S5 intermittent CGM in adults, S81 for SMBG, S77–S79 resources, S159 lifestyle management, S171–S172 S45 TECOS trial, S124, S129 sleep, obstructive sleep apnea, metabolic surgery, S174 S56–S57 TEDDY study, S18 smoking cessation, metabolic surgery in, S92, S94 telemedicine, S9 e-cigarettes, S57 overall approach, S103 temperature, effect on SMBG, S79 tobacco, S56 pharmacologic therapy, S100–S108 in type 2 diabetes prevention/delay, S34 testosterone, low, S44–S45 – Associationpostpartum conversion of GDM to, S190 in youth, S170 thiazide-like diuretics, S115 S117 preexisting, in pregnancy, S188–S189 social context, S9–S11 thiazolidinediones, S44, S100, S106, S129, S158 prevention/delay, S32–S36 sodium, S51, S53 thought disorders, S60 real-time CGM in adults, S81 spironolactone, S114, S140 thyroid disease, S167–S168 screening/testing, S20–S22, S171 SPRINT trial, S113 ticagrelor, S122 staging, of CKD, S136–S137 tobacco use smoking cessation, S56–S57 statins U-300 glargine, S99 in type 2 diabetes prevention/delay, S34 in children, S169 UK Prospective Diabetes Study (UKPDS), S69, topiramate/phentremine, S93 cognition, effects on, S43 S71, S123 tricyclic antidepressants, S144 cognitive function and, S11 uric acid, S79 in combination treatment, S119 triglycerides diabetes risk with use of, S120–S21 elevated, S119–S120 ezetimibe and, S119 REDUCE-IT trial,DiabetesS5, S120 vaccinations, S39, S41–S42 fibrates and, S120 two-hour plasma glucose (2-h PG), S15 vascular dementia, S153 niacin and, S120 in prediabetes, S18 Vegetarian diet, S50 PCSK9 inhibitors and, S119 two-step strategy, GDM, S27 venlafaxine, S144 in pregnancy, S184, S189 type 1 diabetes VERIFY trial, S5 – primary prevention with, S117, S118 S119 A1C and cardiovascular disease in, S69 Veterans Affairs Diabetes Trial (VADT), S69, S70 randomized trials, S119 in children and adolescents, S163–S171 revisions summary, S5 classification, S14–S15 risk-based therapy, S118 daily insulin requirements, S99 water intake, S54 secondary prevention with, S117–S118, hospitalized, insulin therapy in, S196 weight loss. see obesity management S119 hypoglycemia in young children with, S73 well-being, S9 in type 1 diabetes, S118–S119 idiopathic, S17 whites. see Caucasians stroke immune-mediated, S17 wound care, for diabetic foot infections, S144 GLP-1 receptor agonists and, S125–S126, insulin therapy, S98–S100 S127–S129 Americanintermittent CGM in adults, S81 risk reduction, S113, S114, S118, S119, intermittent CGM in children/adolescents, xylose, S79 S120, S121, S122 S81 SGLT2 inhibitors and, S123–S124, S126, pharmacologic therapy, S98–S100 S127 preexisting, in pregnancy, S188 yoga, S55 ©2019 Association

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