Comparative Effectiveness of Sulfonylurea and Metformin Monotherapy on Cardiovascular Events in Type 2 Diabetes Mellitus

BACKGROUND The effects of sulfonylureas and metformin on outcomes of cardiovascular disease (CVD) in type 2 diabetes are not well-characterized. OBJECTIVE To compare the effects of sulfonylureas and metformin on CVD outcomes (acute myocardial infarction and stroke) or death. DESIGN Retrospective cohort study. SETTING National Veterans Health Administration databases linked to Medicare files. PATIENTS Veterans who initiated metformin or sulfonylurea therapy for diabetes. Patients with chronic kidney disease or serious medical illness were excluded. MEASUREMENTS 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. RESULTS 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. LIMITATION 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. CONCLUSION Use of sulfonylureas compared with metformin for initial treatment of diabetes was associated with an increased hazard of CVD events or death. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality and the U.S. Department of Health and Human Services.

[1]  A. Hung,et al.  Initiation of sulfonylureas versus metformin is associated with higher blood pressure at one year , 2012, Pharmacoepidemiology and Drug Safety.

[2]  A. Hung,et al.  Comparative effectiveness of incident oral antidiabetic drugs on kidney function , 2012, Kidney international.

[3]  D. Mozaffarian,et al.  Heart disease and stroke statistics--2012 update: a report from the American Heart Association. , 2012, Circulation.

[4]  D. Mozaffarian,et al.  Executive summary: heart disease and stroke statistics--2012 update: a report from the American Heart Association. , 2012, Circulation.

[5]  Medicaid Services,et al.  International Classification of Diseases, Ninth Revision, Clinical Modification , 2011 .

[6]  Nisa M. Maruthur,et al.  Comparative Effectiveness and Safety of Medications for Type 2 Diabetes: An Update Including New Drugs and 2-Drug Combinations , 2011, Annals of Internal Medicine.

[7]  A. Hung,et al.  The effect of incident antidiabetic regimens on lipid profiles in veterans with type 2 diabetes: a retrospective cohort , 2011, Pharmacoepidemiology and drug safety.

[8]  Executive Summary: Standards of Medical Care in Diabetes—2011 , 2011, Diabetes Care.

[9]  G. Corrao,et al.  Multiple outcomes associated with the use of metformin and sulphonylureas in type 2 diabetes: a population-based cohort study in Italy , 2011, European Journal of Clinical Pharmacology.

[10]  John B. Carlin,et al.  Bias and efficiency of multiple imputation compared with complete‐case analysis for missing covariate values , 2010, Statistics in medicine.

[11]  A. Mackinnon,et al.  The use and reporting of multiple imputation in medical research – a review , 2010, Journal of internal medicine.

[12]  A. Hung,et al.  Glycemic and weight changes after persistent use of incident oral diabetes therapy: a veterans administration retrospective cohort study , 2010, Pharmacoepidemiology and drug safety.

[13]  John B Carlin,et al.  American Journal of Epidemiology Practice of Epidemiology Strategies for Multiple Imputation in Longitudinal Studies , 2022 .

[14]  S. Nissen,et al.  Rosiglitazone revisited: an updated meta-analysis of risk for myocardial infarction and cardiovascular mortality. , 2010, Archives of internal medicine.

[15]  Craig I Coleman,et al.  Effect of noninsulin antidiabetic drugs added to metformin therapy on glycemic control, weight gain, and hypoglycemia in type 2 diabetes. , 2010, JAMA.

[16]  B. Wells,et al.  The Risk of Overall Mortality in Patients With Type 2 Diabetes Receiving Glipizide, Glyburide, or Glimepiride Monotherapy , 2010, Diabetes Care.

[17]  P. Elliott,et al.  Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study using UK general practice research database , 2009, BMJ : British Medical Journal.

[18]  P. Gideon,et al.  An algorithm to identify incident myocardial infarction using Medicaid data , 2009, Pharmacoepidemiology and drug safety.

[19]  R. Stafford,et al.  National trends in treatment of type 2 diabetes mellitus, 1994-2007. , 2008, Archives of internal medicine.

[20]  Renee F Wilson,et al.  Cardiovascular outcomes in trials of oral diabetes medications: a systematic review. , 2008, Archives of internal medicine.

[21]  Jordi Castellsague,et al.  Validation of ICD‐9 codes with a high positive predictive value for incident strokes resulting in hospitalization using Medicaid health data , 2008, Pharmacoepidemiology and drug safety.

[22]  Shari Bolen,et al.  Systematic Review: Comparative Effectiveness and Safety of Oral Medications for Type 2 Diabetes Mellitus , 2007, Annals of Internal Medicine.

[23]  A. Lincoff,et al.  Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. , 2007, JAMA.

[24]  Changing Incident Diabetes Regimens , 2007, Diabetes Care.

[25]  C. Koro,et al.  Coronary heart disease outcomes in patients receiving antidiabetic agents , 2007, Pharmacoepidemiology and drug safety.

[26]  S. Nissen,et al.  Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. , 2007, The New England journal of medicine.

[27]  F. Weaver,et al.  Veterans’ Access to and Use of Medicare and Veterans Affairs Health Care , 2007, Medical care.

[28]  S. Normand,et al.  Positive predictive value of the diagnosis of acute myocardial infarction in an administrative database , 1999, Journal of General Internal Medicine.

[29]  B. Zinman,et al.  Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. , 2006, The New England journal of medicine.

[30]  M. Cheang,et al.  Validity of a Prescription Claims Database to Estimate Medication Adherence in Older Persons , 2006, Medical care.

[31]  S. Schneeweiss.  Sensitivity analysis and external adjustment for unmeasured confounders in epidemiologic database studies of therapeutics , 2006, Pharmacoepidemiology and drug safety.

[32]  D. Cryer,et al.  Comparative outcomes study of metformin intervention versus conventional approach the COSMIC Approach Study. , 2005, Diabetes care.

[33]  Sebastian Schneeweiss,et al.  Adjusting for Unmeasured Confounders in Pharmacoepidemiologic Claims Data Using External Information: The Example of COX2 Inhibitors and Myocardial Infarction , 2005, Epidemiology.

[34]  A. Folsom,et al.  Trends in the sensitivity, positive predictive value, false-positive rate, and comparability ratio of hospital discharge diagnosis codes for acute myocardial infarction in four US communities, 1987-2000. , 2004, American journal of epidemiology.

[35]  W. Ray,et al.  Evaluating medication effects outside of clinical trials: new-user designs. , 2003, American journal of epidemiology.

[36]  Lori S. Parsons.  Reducing Bias in a Propensity Score Matched-Pair Sample Using Greedy Matching Techniques , 2001 .

[37]  D. Rubin,et al.  Estimating and Using Propensity Scores with Partially Missing Data , 2000 .

[38]  Yang C. Yuan,et al.  Multiple Imputation for Missing Data: Concepts and New Development , 2000 .

[39]  B. Psaty,et al.  Assessment and Control for Confounding by Indication in Observational Studies , 1999, Journal of the American Geriatrics Society.

[40]  R. Holman,et al.  Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. , 1998 .

[41]  R. Holman,et al.  Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34) , 1998, The Lancet.

[42]  R. Kronmal,et al.  Assessing the sensitivity of regression results to unmeasured confounders in observational studies. , 1998, Biometrics.

[43]  Uk-Prospective-Diabetes-Study-Group.  Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) , 1998, The Lancet.

[44]  L. J. Wei,et al.  The Robust Inference for the Cox Proportional Hazards Model , 1989 .

[45]  V. Basevi.  Standards of Medical Care in Diabetes—2011 , 2011, Diabetes Care.

[46]  T. Schacker,et al.  Annals of Internal Medicine , 1992 .

[47]  G. Knatterud,et al.  The UGDP and Insulin Therapy: A Reply , 1979, Diabetes Care.

[48]  N. Freinkel,et al.  The UGDP Controversy , 1979, Diabetes.

[49]  M. P. Stern,et al.  Zespół metaboliczny jako czynnik prognostyczny ułatwiający rozpoznanie osób z ryzykiem rozwoju cukrzycy typu 2 i/lub chorób układu sercowo-naczyniowego , 1979 .

[50]  P. Forsham,et al.  "Settling the UGDP controversy"? , 1975, JAMA.

[51]  S. Schor.  Editorials: Statistical problems in clinical trials: the UGDP study revisited. , 1973, The American journal of medicine.

[52]  C. Meinert,et al.  The UGDP Controversy: Clinical Trials Versus Clinical Impressions , 1972, Diabetes.

[53]  H. Seltzer.  A Summary of Criticisms of the Findings and Conclusions of the University Group Diabetes Program (UGDP) , 1972, Diabetes.

[54]  G. Knatterud,et al.  Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. 3. Clinical implications of UGDP results. , 1971, JAMA.

[55]  C. Meinert,et al.  Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. IV. A preliminary report on phenoformin results. , 1971, JAMA.