Christianne L. Roumie, MD, MPH; Adriana M. Hung, MD, MPH; Robert A. Greevy, PhD; Carlos G. Grijalva, MD, MPH; Xulei Liu, MD, MS; Harvey J. Murff, MD, MPH; Tom A. Elasy, MD, MPH; Marie R. Griffin, MD, MPH
Disclaimer: The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality, the U.S. Department of Health and Human Services, or the Department of Veterans Affairs.
Grant Support: This project was funded under contract 290-05-0042 from the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services, as part of the Developing Evidence to Inform Decisions about Effectiveness program. Drs. Roumie (04-342-2) and Hung (2-031-09S) were supported by Veterans Affairs Career Development Awards. Dr. Roumie was also supported in part by the Vanderbilt Clinical Translational Scientist Award UL1 RR024975-01 from the National Center for Research Resources/National Institutes of Health. Support for Veterans Affairs/Centers for Medicare & Medicaid Services data provided by the Department of Veterans Affairs, Veterans Affairs Health Services Research and Development Service, Veterans Affairs Information Resource Center (project numbers SDR 02-237 and 98-004).
Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-0009.
Reproducible Research Statement: Study protocol and statistical code: Available from Dr. Roumie (e-mail, firstname.lastname@example.org). Data set: Not available.
Requests for Single Reprints: Christianne L. Roumie, MD, MPH, Nashville Veterans Affairs Medical Center, 1310 24th Avenue South, Geriatric Research Education Clinical Center 4A120, Nashville, TN; e-mail, email@example.com.
Current Author Addresses: Drs. Roumie and Liu: Veterans Affairs Tennessee Valley Healthcare System, 1310 24th Avenue South, Geriatric Research Education Clinical Center, Nashville, TN 37212.
Dr. Hung: Vanderbilt University Medical Center, 1161 21st Avenue South, Garland Division of Nephrology, S-3223 Medical Center North, Nashville, TN 37232.
Dr. Greevy: Vanderbilt University School of Medicine, Department of Biostatistics, 1161 21st Avenue South, S-2323 Medical Center North, Nashville, TN 37232.
Dr. Grijalva: Department of Preventive Medicine, 1500 21st Avenue South, The Village at Vanderbilt, Suite 2650, Nashville, TN 37212.
Dr. Murff: Vanderbilt Institute for Medicine and Public Health, 2525 West End Avenue, Sixth Floor, Nashville, TN 37203-1738.
Dr. Elasy: Vanderbilt University Medical Center, Medical Center East, North Tower, Suite 6000, 1215 21st Avenue South, Nashville, TN 37232-8300.
Dr. Griffin: Department of Preventive Medicine, 1500 21st Avenue South, The Village at Vanderbilt, Suite 2600, Nashville, TN 37212.
Author Contributions: Conception and design: C.L. Roumie, A.M. Hung, R.A. Greevy, C.G. Grijalva, T.A. Elasy, M.R. Griffin.
Analysis and interpretation of the data: C.L. Roumie, A.M. Hung, R.A. Greevy, C.G. Grijalva, X. Liu, H.J. Murff, T.A. Elasy, M.R. Griffin.
Drafting of the article: C.L. Roumie, R.A. Greevy, T.A. Elasy.
Critical revision of the article for important intellectual content: C.L. Roumie, A.M. Hung, R.A. Greevy, C.G. Grijalva, X. Liu, H.J. Murff, T.A. Elasy, M.R. Griffin.
Final approval of the article: C.L. Roumie, A.M. Hung, R.A. Greevy, C.G. Grijalva, H.J. Murff, T.A. Elasy, M.R. Griffin.
Statistical expertise: R.A. Greevy.
Obtaining of funding: C.L. Roumie, R.A. Greevy, C.G. Grijalva, M.R. Griffin.
Administrative, technical, or logistic support: C.L. Roumie, T.A. Elasy.
Collection and assembly of data: C.L. Roumie, R.A. Greevy.
The effects of sulfonylureas and metformin on outcomes of cardiovascular disease (CVD) in type 2 diabetes are not well-characterized.
To compare the effects of sulfonylureas and metformin on CVD outcomes (acute myocardial infarction and stroke) or death.
Retrospective cohort study.
National Veterans Health Administration databases linked to Medicare files.
Veterans who initiated metformin or sulfonylurea therapy for diabetes. Patients with chronic kidney disease or serious medical illness were excluded.
Composite outcome of hospitalization for acute myocardial infarction or stroke, or death, adjusted for baseline demographic characteristics; medications; cholesterol, hemoglobin A1c, and serum creatinine levels; blood pressure; body mass index; health care utilization; and comorbid conditions.
Among 253 690 patients initiating treatment (98 665 with sulfonylurea therapy and 155 025 with metformin therapy), crude rates of the composite outcome were 18.2 per 1000 person-years in sulfonylurea users and 10.4 per 1000 person-years in metformin users (adjusted incidence rate difference, 2.2 [95% CI, 1.4 to 3.0] more CVD events with sulfonylureas per 1000 person-years; adjusted hazard ratio [aHR], 1.21 [CI, 1.13 to 1.30]). Results were consistent for both glyburide (aHR, 1.26 [CI, 1.16 to 1.37]) and glipizide (aHR, 1.15 [CI, 1.06 to 1.26]) in subgroups by CVD history, age, body mass index, and albuminuria; in a propensity score–matched cohort analysis; and in sensitivity analyses.
Most of the veterans in the study population were white men; data on women and minority groups were limited but reflective of the Veterans Health Administration population.
Use of sulfonylureas compared with metformin for initial treatment of diabetes was associated with an increased hazard of CVD events or death.
Agency for Healthcare Research and Quality and the U.S. Department of Health and Human Services.
Diabetes increases risk for cardiovascular disease, but how metformin and sulfonylureas affect that risk is less clear.
In this analysis of a national population of veterans, new use of sulfonylureas seemed to increase incidence of and risk for cardiovascular events and death compared with metformin.
The findings apply primarily to white men.
Sulfonylureas seem to increase cardiovascular events and death compared with metformin. Whether sulfonylureas are harmful, metformin is protective, or both is unclear.
Appendix Table 1. Definitions of Comorbid Conditions and Medications, on the Basis of Codes and Prescriptions in 365 Days Before Exposure
Examination of the proportional hazards assumption using log(log survival) plots.
Appendix Table 2. Odds of Receiving Metformin Compared With Sulfonylureas
Distribution of propensity scores, by drug.
* Probability of using metformin.
Study flow diagram.
CVD = cardiovascular disease; DM = diabetes mellitus.
Table 1. Patient Characteristics in Full and Propensity Score–Matched Cohorts, by New Exposure to Metformin or Sulfonylureas
Appendix Table 3. Baseline Characteristics of Patients With Complete Covariates, by Antidiabetic Drug
Table 2. Unadjusted Incidence Rates, Adjusted Incidence Rate Difference, and Adjusted Hazard Ratios for Hazard of the Primary Composite Outcome and Secondary Outcome Among Full and Propensity Score–Matched Cohorts of New Users of Sulfonylureas Compared With Metformin
Cumulative incidence (95% CIs) of cardiovascular disease or death.
Top. Propensity score–matched cohort with persistent exposure to oral hypoglycemic medication required. Bottom. Propensity score–matched cohort with persistent exposure to oral hypoglycemic medication not required, in which patients remain in their exposure group regardless of persistence with drug therapy.
Appendix Table 4. Yearly Unadjusted Incidence Rates and Unadjusted and Adjusted Incidence Rate Differences for the Primary Composite Outcome Among a Propensity Score–Matched Cohort of New Users of Sulfonylureas Compared With Metformin
Adjusted hazard ratios for the primary composite outcome (CVD or death) and secondary outcome (CVD alone), stratified by CVD history, age, and BMI.
AMI = acute myocardial infarction; BMI = body mass index; CVD = cardiovascular disease.
* CVD defined by diagnoses or procedure codes for MI, coronary artery disease, transient ischemic attack, stroke, or surgical procedures for repair of peripheral or carotid artery disease in the baseline period.
† Results are also presented for a sample of patients (14.3%) tested for proteinuria and found positive or negative.
Appendix Table 5. Incidence Rates and Adjusted Hazard Ratios for Risk for the Primary Composite Outcome and Secondary Outcome Among the Full Cohort of New Users of Sulfonylureas Compared With Metformin, Stratified by CVD History, Age, and BMI
Appendix Table 6. Rates and Adjusted Hazard Ratios for Risk for the Primary Composite Outcome and Secondary Outcome Among Those With Complete Covariates Who Were New Users of Sulfonylureas Compared With Metformin
Appendix Table 7. Risk for CVD in the Presence of an Unmeasured Confounder With a Hazard Ratio of 1.25 for CVD and Various Prevalence Levels of the Confounder, by Exposure Group
Appendix Table 8. Risk for CVD in the Presence of an Unmeasured Confounder With a Hazard Ratio of 2.0 for CVD and Various Prevalence Levels of the Confounder, by Exposure Group
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Namitha Bhat, MD; Tuhar Shah MD, FACP; Guy Valiquette MD
New York Meical College, Valhalla, NY, 10595
December 1, 2012
Choosing the right oral anti-diabetic drug for a patient newly diagnosed with Type 2 diabetes.
We were greatly impressed as we studied the study by Roumie and colleagues (1) for the evidence based medicine presentation of our residency program. This study sought to shed new light on the age old controversy (2) of differing effects of metformin and sulfonylureas on cardiovascular events in patients with type 2 diabetes. Their study, a retrospective cohort study, utilized pharmacoepidemiologic principles along with use of available clinical measures and showed 21% increased hazard of hospitalisation for cardiovascular outcomes associated with the initiation of sulfonylurea compared with metformin. Since the publication of results of Diabetes Prevention Program (3, 4) there has been keen interest in clinical practice to use metformin to prevent development of diabetes from pre-diabetes state. Practice patterns might have changed as metformin has been found to be beneficial in those with strong risk factors for development of diabetes. We wonder if this might have been the case in this study cohort. The metformin group had lower median glycosylated haemoglobin (HbA1c) and a narrower interquartile range. Some of these patients in the metformin group might have been at high risk for diabetes and/or have pre-diabetes. Preferential use of metformin for pre-diabetes (patients and some health care providers would refer to this state as borderline diabetes) would create inherent differences in two groups in this study cohort in terms of their cardiovascular risk profile. To the authors’ credit the study also included propensity score matching in an effort to nullify the effects of these differences. However, this statistical method would not completely rectify the effects of selection bias as a contributing factor responsible for differences in the outcomes between the two groups (5).We commend the efforts put forth by Roumie and colleagues to study differences in effects on mortality and hard clinical endpoints between the two most commonly prescribed anti-diabetic drug groups. A randomized control trial would be more definitive to help settle this controversy. However, it would not be ethical to conduct such studies. The medical community would therefore have to resort to well-designed cohort studies such as this one to form stronger evidence base of comparative effectiveness and patient centred outcomes for the commonly used pharmaceutical agents.
1 Christianne L. Roumie, MD, MPH; Adriana M. Hung, MD, MPH; Robert A. Greevy, PhD; Carlos G. Grijalva, MD, MPH et al, Comparative Effectiveness of Sulfonylurea and Metformin Monotherapy on Cardiovascular Events in Type 2 Diabetes Mellitus: A Cohort Study. Ann Intern Med. 2012; 157:601-10. [PMID: 23128859]
2 Weiss IA, Valiquette G, Schwarcz MD. Impact of glycemic treatment choices on cardiovascular complications in type 2 diabetes. Cardiol Rev. 2009 17(4):165-75. [PMID: 19525678]
3 Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF et al, Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002; 346:393-403. [PMID: 11832527]
4 Diabetes Prevention Program Research Group. Effects of withdrawal from metformin on the development of diabetes in the diabetes prevention program. Diabetes Care. 2003 ; 26:977-80. [PMID: 12663559]
5 Robert J Glynn, PhD, ScD, Sebastian Schneeweiss, MD, ScD, and Til Stürmer, MD. Indications for Propensity Scores and Review of Their Use in Pharmacoepidemiology. Basic Clin Pharmacol Toxicol. 2006; 98:253–9. [PMID: 16611199]
Udaya M Kabadi, MD
Central Iowa VA Health Care System Des Moines Iowa and University of Iowa, Iowa City Iowa.
December 18, 2012
Conclusion Not Necessarily Applicable to All Sulfonylureas
Letter to Editor:
It was interesting and educational to read the article by Roumi CL et al (1).The authors deserve compliments for in depth analysis of the extensive data. However, I caution that the conclusion may not necessarily be applicable to all sulfonylureas, especially glimepiride. Several recent studies have documented better safety profile of glimepiride over glipizide and glyburide in terms of cardiovascular outcomes including deaths (2-4). The superior cardiovascular safety profile of glimepiride may be attributed to its role in being more effective in preischemic cardiac conditioning, its favorable effect on lipids, its less anti platelet aggregatory activity as well as a significantly less daily insulin requirement to attain and maintain desirable glycemic control (5-7). It is rather unfortunate that the editorial accompanying the manuscript lumps all sulfonylureas in the same bag despite contradictory evidence. After all, none of the new drugs have stood the test of time yet and therefore it would be difficult to abandon sulfonylureas.. Finally, VA system needs to be cognizant about the data regarding various sulfonylureas and alter the formulary guidelines accordingly.
1.Roumie CL, Hung AM, Greevy RA, Grijalva CG, Liu X, Murff HJ, Elasy TA, Griffin MR. Comparative effectiveness of sulfonylurea and metformin monotherapy on cardiovascular events in type 2 diabetes mellitus: a cohort study. Ann Intern Med. 2012 Nov 6;157(9):601-10. doi: 10.7326/0003-4819-157-9-201211060-00003
2.Sadikot SM, Mogensen CE Risk of coronary artery disease associated with initial sulphonylurea treatment of patients with type 2 diabetes: a matched case-control study. Diabetes Res Clin Pract. 2008 Dec;82(3):391-5. Epub 2008 Oct 21.
3.Pantalone KM, Kattan MW, Yu C, Wells BJ, Arrigain S, Jain A, Atreja A, Zimmerman RS The risk of overall mortality in patients with type 2 diabetes receiving glipizide, glyburide, or glimepiride monotherapy: a retrospective analysis. Diabetes Care. 2010 Jun;33(6):1224-9. doi: 10.2337/dc10-0017. Epub 2010 Mar 9.
4.Pantalone KM, Kattan MW, Yu C, Wells BJ, Arrigain S, Jain A, Atreja A, Zimmerman RS Increase in overall mortality risk in patients with type 2 diabetes receiving glipizide, glyburide or glimepiride monotherapy versus metformin: a retrospective analysis. Diabetes Obes Metab. 2012 Sep;14(9):803-9. doi: 10.1111/j.1463-1326.2012.01604.x. Epub 2012 Apr 29.
5.Klepzig H, Kober G, Matter C, Luus H, Schneider H, Boedeker KH, Kiowski W, Amann FW, Gruber D, Harris S, Burger Sulfonylureas and ischaemic preconditioning; a double-blind, placebo-controlled evaluation of glimepiride and glibenclamide Eur Heart J. 1999 Mar;20(6):439-46.
6.Siluk D, Kaliszan R, Haber P, Petrusewicz J, Brzozowski Z, Sut G Antiaggregatory activity of hypoglycaemic sulphonylureas. Diabetologia. 2002 Jul;45(7):1034-7. Epub 2002 Jun 12.
7.Xu DY, Zhao SP, Huang QX, Du W, Liu YH, Liu L, Xie XM Effects of Glimepiride on metabolic parameters and cardiovascular risk factors inpatients with newly diagnosed type 2 diabetes mellitus. Diabetes Res Clin Pract. 2010 Apr;88(1):71-5. Epub 2009 Dec 31.
8.Kabadi MU, Kabadi UM. Efficacy of sulfonylureas with insulin in type 2 diabetes mellitus. Annals of Pharmacotherapy. 2003;37:1572-1576,
Remy Boussageon, Theodora Bejan-Anglouvant, Catherine Cornu
Department of General Medicine, University of Poitiers, Poitiers, France 2. Clinical pharmacology department, CHRU de Tours, Tours, France; UMR 7292 CNRS, Tours, France; University Francois Rabelais,
December 22, 2012
It is time to deeply reconsider the evaluation of antidiabetic treatments
We read with interest the article by Roumie et al (1), showing that the use of sulfonylureas compared with metformin for initial treatment of type 2 diabetes (T2D) was associated with an increased hazard of cardiovascular events or death. We regret that the authors did not discuss their results in the light of recently published meta-analyses of randomized controlled trials regarding the efficacy of metformin in T2D (2,3). The efficacy of metformin to prevent death, myocardial infarction, stroke, or microvascular complications3 has not been demonstrated. The lack of evidence of metfomin’s efficacy is alarming, given the number of treated patients. The information that the use of sulfonylureas compared with metformin for initial treatment of diabetes was associated with an increased hazard of cardiovascular events or death is even more alarming. Indeed, if we consider that metformin is possibly not effective given the current evidence, then sulfonylureas are simply harmful! Sulfonylureas did not prevent cardiovascular complications in UKPDS33 (4). It would have also been interesting to study the risk associated with the combination of metformin and sulfonylurea. This risk remains unclear, however in our meta-analysis3 it was significantly increased for all-cause mortality (RR 1.55, 95% CI 1.03 to 2.33) and cardiovascular mortality (RR 2.20, 95% CI 1.20 to 4.03). The study by Roumie et al. raises important questions. We think that it is time to deeply reconsider the evaluation of antidiabetic treatments, an evaluation based on double-blind randomized controlled trials and on patient important outcomes (5).
1. Roumie CL, Hung AM, Greevy RA, Grijalva CG, Liu X, Murff HJ, Elasy TA, Griffin MR. Comparative effectiveness of sulfonylurea and metformin monotherapy on cardiovascular events in type 2 diabetes mellitus: a cohort study. Ann Intern Med. 2012 ;157:601-10
2. Lamanna C, Monami M, Marchionni N, et al. Effect of metformin on cardiovascular events and mortality: a meta-analysis of randomised clinical trials. DiabetesObesMetab 2011;13: 221-228
3. BoussageonR, Supper I, Bejan-Angoulvant T, et al. Reappraisal of Metformin Efficacy in the treatment of Type 2 Diabetes: A Meta-Analysis of Randomised Controlled Trials. PLoS Med 2012; 9(4): e1001204. i:10.1371/journal.pmed.1001204.
4. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes, UKPDS 33. Lancet. 1998; 352: 837-53.
5. Montori VM, Gandhi GY, Guyatt GH. Patient-important outcomes in diabetes--time for consensus. Lancet. 2007;370:1104-6
Roumie CL, Hung AM, Greevy RA, et al. Comparative Effectiveness of Sulfonylurea and Metformin Monotherapy on Cardiovascular Events in Type 2 Diabetes Mellitus: A Cohort Study. Ann Intern Med. 2012;157:601–610. doi: https://doi.org/10.7326/0003-4819-157-9-201211060-00003
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Published: Ann Intern Med. 2012;157(9):601-610.
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