Amir Qaseem, MD, PhD, MHA; Michael J. Barry, MD; Linda L. Humphrey, MD, MPH; Mary Ann Forciea, MD; for the Clinical Guidelines Committee of the American College of Physicians (*)
Note: Clinical practice guidelines are “guides” only and may not apply to all patients and all clinical situations. Thus, they are not intended to override clinicians' judgment. All ACP clinical practice guidelines are considered automatically withdrawn or invalid 5 years after publication or once an update has been issued.
Disclaimer: The authors of this article are responsible for its contents, including any clinical or treatment recommendations.
Financial Support: Financial support for the development of this guideline comes exclusively from the ACP operating budget.
Disclosures: Dr. Barry reports grants, personal fees, and nonfinancial support from Informed Medical Decisions Foundation and Healthwise, both nonprofits, outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M16-1860. All financial and intellectual disclosures of interest were declared and potential conflicts were discussed and managed. Drs. Boyd, Iorio, and Vijan were recused from voting on this guideline because of active intellectual conflicts. Dr. Manaker was recused from voting on this guideline because of an active indirect financial conflict. A record of disclosures and management of conflicts of interest is kept for each Clinical Guidelines Committee meeting and conference call and can be viewed at www.acponline.org/clinical_information/guidelines/guidelines/conflicts_cgc.htm.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.
Requests for Single Reprints: Amir Qaseem, MD, PhD, MHA, American College of Physicians, 190 N. Independence Mall West, Philadelphia, PA 19106; e-mail, email@example.com.
Current Author Addresses: Dr. Qaseem: American College of Physicians, 190 N. Independence Mall West, Philadelphia, PA 19106.
Dr. Barry: Massachusetts General Hospital, 50 Staniford Street, Boston, MA 02114.
Dr. Humphrey: Oregon Health and Science University, 3710 Southwest U.S. Veterans Hospital Road, Portland, OR 97201.
Dr. Forciea: University of Pennsylvania Health System, 3615 Chestnut Street, Philadelphia, PA 19104.
Author Contributions: Conception and design: A. Qaseem, M.J. Barry, L.L. Humphrey, N. Fitterman.
Analysis and interpretation of the data: A. Qaseem, M.J. Barry, L.L. Humphrey, N. Fitterman, D. Kansagara.
Drafting of the article: A. Qaseem.
Critical revision for important intellectual content: A. Qaseem, M.J. Barry, L.L. Humphrey, D. Kansagara.
Final approval of the article: A. Qaseem, M.J. Barry, L.L. Humphrey, M.A. Forciea, N. Fitterman, C. Horwitch, D. Kansagara, R. McLean, T. Wilt.
Statistical expertise: A. Qaseem.
Administrative, technical, or logistic support: A. Qaseem.
Collection and assembly of data: A. Qaseem.
Qaseem A, Barry MJ, Humphrey LL, Forciea MA, for the Clinical Guidelines Committee of the American College of Physicians. Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus: A Clinical Practice Guideline Update From the American College of Physicians. Ann Intern Med. [Epub ahead of print 3 January 2017]:. doi: 10.7326/M16-1860
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Published: Ann Intern Med. 2017.
The American College of Physicians (ACP) developed this guideline to present the evidence and provide clinical recommendations on oral pharmacologic treatment of type 2 diabetes in adults. This guideline serves as an update to the 2012 ACP guideline on the same topic. This guideline is endorsed by the American Academy of Family Physicians.
This guideline is based on a systematic review of randomized, controlled trials and observational studies published through December 2015 on the comparative effectiveness of oral medications for type 2 diabetes. Evaluated interventions included metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium–glucose cotransporter-2 (SGLT-2) inhibitors. Study quality was assessed, data were extracted, and results were summarized qualitatively on the basis of the totality of evidence identified by using several databases. Evaluated outcomes included intermediate outcomes of hemoglobin A1c, weight, systolic blood pressure, and heart rate; all-cause mortality; cardiovascular and cerebrovascular morbidity and mortality; retinopathy, nephropathy, and neuropathy; and harms. This guideline grades the recommendations by using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system.
The target audience for this guideline includes all clinicians, and the target patient population includes adults with type 2 diabetes.
ACP recommends that clinicians prescribe metformin to patients with type 2 diabetes when pharmacologic therapy is needed to improve glycemic control. (Grade: strong recommendation; moderate-quality evidence)
ACP recommends that clinicians consider adding either a sulfonylurea, a thiazolidinedione, an SGLT-2 inhibitor, or a DPP-4 inhibitor to metformin to improve glycemic control when a second oral therapy is considered. (Grade: weak recommendation; moderate-quality evidence.) ACP recommends that clinicians and patients select among medications after discussing benefits, adverse effects, and costs.
Table 1. The American College of Physicians' Guideline Grading System*
Summary of the American College of Physicians guideline on oral medications for type 2 diabetes.
DPP-4 = dipeptidyl peptidase-4; HbA1c = hemoglobin A1c; SGLT-2 = sodium–glucose cotransporter-2.
Appendix Table 1. Summary of Clinical Outcomes for Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus
Appendix Table 2. Summary of Intermediate Outcomes for Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus
Appendix Table 3. Summary of Harms for Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus
Table 2. Comparative Efficacy, Adverse Effects, and Costs for Add-on Oral Therapies to Metformin
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Silvio E. Inzucchi MD, Mikhail Kosiborod MD
Section of Endocrinology, Yale School of Medicine, New Haven, CT, Saint Luke's Mid America Heart Institute and University of Missouri-Kansas City, Kansas City, MO
January 14, 2017
Conflict of Interest:
Dr. Inzucchi has served as a consultant to Merck, Janssen, Sanofi/Lexicon, and vTv Therapeutics. He has participated on clinical trial steering or publications committees for Boehringer Ingelheim, Astra-Zeneca, and Daiichi Sankyo. He has served as a member of data monitoring committees for Novo Nordisk and Intarcia.
Dr. Kosiborod has received research grants from AstraZeneca and Boehringer Ingelheim. He has served as a consultant to AstraZeneca, Amgen, Eli Lilly, Boehringer Ingelheim, GSK, Sanofi, Novo Nordisk, Merck, ZS Pharma, and Glytec, and is on a speakers bureau for Amgen.
Comment on: Qaseem A et al. Oral Pharmacological Treatment of Type 2 Diabetes Mellitus: A Clinical Practice Guideline Update from the American College of Physicians
We read with great anticipation Qaseem et al.’s update to the ACP’s Clinical Practice Guideline for oral agent therapy in type 2 diabetes (T2D.)(1) However, as with the first iteration of this well-considered set of recommendations in 2012(2), the authors continue to focus predominantly on HbA1c control. While this has been the raison d’etre of diabetes therapy for decades, data amassed over the past 1-2 years will likely change such a traditional approach, particularly as it relates to the prevention of cardiovascular death and other adverse sequelae of cardiovascular disease (CVD). Although CVD is by far the leading cause of mortality and morbidity in patients with T2D, previous studies have demonstrated that controlling glucose alone does not reduce CVD events. Indeed, some data suggests the opposite – that overly stringent control may actually increase CVD mortality in older, at-risk patients. In contrast, four well-designed, large, prospective, placebo controlled trials over just the past 18 months have convincingly demonstrated that certain glucose lowering agents can significantly reduce major adverse CV events (MACE) and, in some instances, cardiovascular mortality, all-cause mortality and hospitalizations for heart failure. The oral SGLT2 inhibitor empagliflozin reduced MACE by 14%, cardiovascular mortality by 38%, and hospitalizations for heart failure by 35% in T2D patients with established CVD.(3) The oral thiazolidinedione pioglitazone reduced myocardial and recurrent stroke by 24% in non-diabetic patients with prior stroke or transient ischemic attack and insulin resistance.(4) Finally, two injectable GLP-1 receptor agonists, liraglutide and the currently investigational semaglutide, reduced MACE by 13% and 26%, respectively, in T2D patients at high cardiovascular risk, mostly with prior CVD.(5,6) The former also decreased cardiovascular mortality by 22%.(5) We propose that guideline committees should now consider whether these agents are preferred after metformin monotherapy in individuals with type 2 diabetes and overt CVD. Importantly, in all of these trials these benefits were realized within relatively short time period (median follow up of 2-5 years).Ultimately, the main objectives of T2D management are to prolong life, improve the quality of life, or, preferably, both. Newer treatment guidelines must, therefore, incorporate emerging data like these from large randomized clinical trials so as to encourage clinicians to develop a more comprehensive strategy in the management of their patients with T2D. The goal should not only be to lower glucose (with its anticipated long-term benefits on microvascular complications) but also to combat the most frequent and most life-threatening complication of diabetes, namely CVD.REFERENCES:1. Qaseem A, Barry MJ, Humphrey LL, Forciea MA, for the Clinical Guidelines Committee of the American College of Physicians. Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus: A Clinical Practice Guideline Update From the American College of Physicians. Ann Intern Med. [Epub ahead of print 3 January 2017] doi: 10.7326/M16-18602. Qaseem A, Humphrey LL, Sweet DE, Starkey M, Shekelle P, for the Clinical Guidelines Committee of the American College of Physicians*. Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2012;156:218-31. [PMID: 22312141] doi:10.7326/0003-4819-156-3-201202070-000113. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28. [PMID: 2637897] doi:10.1056/NEJMoa15047204. Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE , Gorman M, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. 2016;374:1321-31. [PMID:26886418] doi:10.1056/NEJMoa1506930 5. Marso SP, Daniels GH, Kirstine Brown-Frandsen K, Kristensen P, Mann JFE, Nauck MA, et al. Liraglutide and CV outcomes in type 2 diabetes. N Engl J Med. 2016;375:311-22. [PMID:27295427] doi:10.1056/NEJMoa16038276. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834-44. [PMID: 27633186] doi:10.1056/NEJMoa1607141
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