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 All ACP clinical practice guidelines are considered automatically withdrawn or invalid 5 years after publication or once an update has been issued.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.
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
February 13, 2017
Why is there no mention of GLP-1 receptor agonists in this guideline published last month? I see a review in July 2016 that compared all these drugs including GLP-1 agonists (Diabetes Medications as Monotherapy or Metformin-Based Combination Therapy for Type 2 Diabetes: A Systematic Review and Meta-analysis).
David S. H. Bell, MB
March 7, 2017
Conflict of Interest:
Speaker's Bureau: Novo Nordisk and Janssen, AstraZeneca
Board of Directors: AACE
Re: Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus. A Clinical Practice Guideline Update from the American College of Physician
In recommendation 2 of the updated guidelines, it is recommend that when metformin fails to achieve therapeutic goals, the clinician should consider adding either a sulfonylurea, a thiazolidinedione, an SGLT-2 inhibitor or a DPP-4 inhibitor depending upon benefits, adverse events and cost.1 While the drugs are not prioritized, the drugs are not listed in alphabetical order which implies that a sulfonylurea, which is top of the list, should be the next choice. The combination of metformin and a sulfonylurea may well be associated with increases in cardiac events. In the United Kingdom Prospective Diabetes Study (UKPDS) non-obese subjects who were failing sulfonylurea therapy after the addition of metformin had a 96% statistically significant increase in mortality, compared with those continuing sulfonylurea therapy with inferior glycemic control.2 While this was dismissed by the authors as being an artifact due to the small number of patients, it is not an isolated finding. An Israeli study showed that over 7.7 years diabetic patients with coronary artery disease compared with non-diabetic patients with coronary artery disease the mortality was increased by 22% with glyburide monotherapy, 26% with metformin monotherapy and 55% with the combination of metformin and glyburide. With the metformin/sulfonylurea combination a meta-analysis has shown an increase in mortality of 43% and in a retrospective study of a prospective observational study a higher annual mortality rate (6.2% v 3.6%).3 In addition an epidemiological study showed in patients with known CV disease there was a greater than two-fold increase in mortality with the metformin/sulfonylurea combination when compared with other oral antidiabetic agents. Also, the UK General Practitioner’s Database showed a 1.54-fold increase in mortality and a 67% increase in heart failure with the metformin/sulfonylurea combination. 4 Therefore, the metformin/sulfonylurea combination favored by third party payers based on the ADA/EASD and now the ACP guidelines, especially when utilized in the presence of ischemic heart disease (which is often silent) may be associated with an increased risk of cardiovascular events. A better recommendation is that when metformin monotherapy is no longer adequate, the use of the cardioprotective SGLT2-blockers and a GLP-1 receptor agonists as recommended by the American Association of Clinical Endocrinologists (AACE) guidelines is more appropriate.5 In addition, utilization of this combination will avoid hypoglycemia and by lowering body weight improve insulin resistance. Other cardiac risk factors such as systolic blood pressure, decelerating the decline in renal function, improvements in the lipid profile (especially non-HDL cholesterol) are also improved. That the improvement in risk factors with these drugs can result in a decrease of cardiac events, from which most diabetic subjects die, has already been documented in several studies. Therefore, rather than surreptitiously condoning the cardiotoxic combination of metformin and a sulfonylurea, the ACP guidelines should be promoting the use of GLP-1 receptor agonists and SGLT2-inhibitors to lower the risk of cardiac events.References:1) Qaseem A, Barry MJ, Humphrey LL, Forciea MA; 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(2017)166(4):279-290.2) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet(1998)352(9131):854-65.3) Evans JM, Ogston SA, Emslie-Smith A, Morris AD. Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulfonylureas and metformin. Diabetologia(2006)49(5):930-6. 4) Bell DS, Patil HR, O'Keefe JH. Divergent effects of various diabetes drugs on cardiovascular prognosis. Rev Cardiovasc Med(2013)14(2-4):e107-22.5) Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, Dagogo-Jack S, Davidson MB, Einhorn D, Garber JR, Garvey WT, Grunberger G, Handelsman Y, Hirsch IB, Jellinger PS, McGill JB, Mechanick JI, Rosenblit PD, Umpierrez G, Davidson MH. AACE/ACE comprehensive diabetes management algorithm 2015. Endocr Pract(2015)21(4):438-47.
Michael J. Barry, MD, Linda L. Humphrey, MD, MPH, Amir Qaseem, MD, PhD
March 8, 2017
IN RESPONSE: Drs. Inzucchi and Kosiborod raise the question of what outcomes are most important in trials of management of type 2 diabetes. We agree that intermediate outcomes such as hemoglobin A1c are less relevant to patients than the microvascular and macrovascular complications of diabetes. We were struck that in the systematic review on which our guideline was based, with searches through December, 2015, relatively little comparative effectiveness data were available on these outcomes, especially for the older, less expensive oral medications for diabetes (1, 2). In addition to fewer hypoglycemic episodes, evidence of reduction in all-cause and cardiovascular mortality (and low risk) was one reason we continued to recommend metformin as the agent of first choice, even though the evidence was judged to be of low quality. As far as the choice of a second agent, we indicated that our recommendations were conditional on a judged need to “improve glycemic control,” as that was the outcome most commonly included in the studies we reviewed.We believe that for most clinical outcomes, including mortality and micro- or macrovascular outcomes, the evidence is insufficient for most drugs and drug comparisons. Drs. Inzucchi and Kosiborod point out four studies that focus on more important outcomes than A1c control. Three of the four studies were published after the evidence review was completed. The randomized trial of empagiflozin, arguably the most relevant to our guideline recommendations, was not included in the evidence review, since it was a placebo-controlled rather than a head to head comparison trial (3). All of the participants in this trial had established cardiovascular disease, which is certainly common but not ubiquitous among adults with diabetes. Empagiflozin was added to participants’ baseline therapy for diabetes which most commonly (in about half of participants) was dual therapy, meaning empagiflozin was added as a third agent. In this population selected for higher cardiovascular event rates, overall mortality was reduced by an absolute 2.6% over about three years, largely reflecting a reduced risk of death from cardiovascular causes. Certainly this absolute reduction is clinically important, although given selection of participants for the trial, the results cannot be directly extrapolated to the general population of people with diabetes that our guideline addresses. We look forward to reviewing newer evidence when our guideline is next updated and strongly support the use of health outcomes, as opposed to intermediate outcomes, in evaluating the benefits and harms of pharmacologic therapies. Newer medications for diabetes, including empagliflozin, are considerably more expensive than older, time-tested alternatives. Our guideline panel, including our patient representatives, felt that cost was an important consideration in selecting therapies for diabetes. The way clinical research is funded in the United States practically ensures that only expensive new medications are studied in trials large and long enough to measure outcomes like micro- and macrovascular complications. The NIH-funded Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) (https://portal.bsc.gwu.edu/web/grade), will compare combinations of metformin with a sulfonylurea, a DPP-4 inhibitor, GLP-1 receptor agonist, or basal insulin glargine. However, a combination of metformin and an SGLT-2 inhibitor like empagliflozin is not included as a comparator, and the outcomes of the trial focus on glycemic control, rather than diabetes complications (https://clinicaltrials.gov/ct2/show/NCT01794143?term=GRADE&rank=1). Perhaps the Patient Centered Outcomes Research Institute (PCORI) could take up the question of the optimal second agent to add to metformin to improve micro- and macrovascular outcomes in people with Type 2 diabetes.Michael J. Barry, MDMassachusetts General HospitalLinda L. Humphrey, MD, MPHOregon Health and Science UniversityAmir Qaseem, MD, PhDAmerican College of PhysiciansReferences1. Maruthur NM, Tseng E, Hutfless S, et al. Diabetes medications as monotherapy or metformin-based combination therapy for type 2 diabetes: A systematic review and meta-analysis. Annals of Internal Medicine. 2016;164(11):740-51.2. Qaseem A, Barry MJ, Humphrey LL, Forciea M, for the Clinical Guidelines Committee of the American College of P. Oral pharmacologic treatment of type 2 diabetes mellitus: A clinical practice guideline update from the american college of physicians. Annals of Internal Medicine. 2017;166(4):279-90.3. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. New England Journal of Medicine. 2015;373(22):2117-28.
Amir Qaseem, Michael J. Barry, Linda L. Humphrey, Mary Ann Forciea, . Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus: A Clinical Practice Guideline Update From the American College of Physicians. Ann Intern Med. 2017;166:279–290. doi: 10.7326/M16-1860
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Published: Ann Intern Med. 2017;166(4):279-290.
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