Comparative Effectiveness of Sulfonylurea and Metformin Monotherapy on Cardiovascular Events in Type 2 Diabetes Mellitus: A Cohort Study

Study Questions:

What is the relative effect of sulfonylureas and metformin on cardiovascular disease (CVD) outcomes including acute myocardial infarction (AMI), stroke, and all-cause mortality?


A retrospective cohort study was conducted using the National Veterans Health Administration databases linked to Medicare files in patients who initiated metformin or sulfonylurea therapy for diabetes. Patients with chronic kidney disease or serious medical illness were excluded. Composite outcome was hospitalization for AMI 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.


Median age was approximately 65 years, 97% were men, and 75% were white. For those with persistent treatment exposure, follow-up was nearly 180,000 person-years with metformin and >100,000 for sulfonylureas. 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 1,000 person-years in sulfonylurea users and 10.4 per 1,000 person-years in metformin users (adjusted incidence rate difference, 2.2; 95% confidence interval [CI], 1.4-3.0), and more CVD events with sulfonylureas per 1,000 person-years (adjusted hazard ratio [aHR], 1.21; 95% CI, 1.13-1.30). Results were consistent for both glyburide (aHR, 1.26; 95% CI, 1.16-1.37) and glipizide (aHR, 1.15; CI, 1.06-1.26) in subgroups by CVD history, age, body mass index, and albuminuria; in a propensity score–matched cohort analysis; and in sensitivity analyses.


Use of sulfonylureas compared with metformin for initial treatment of diabetes was associated with an increased hazard of CVD events or death.


The study found a 21% increased hazard of hospitalization for AMI or stroke, or of death associated with initiation of sulfonylurea compared with metformin therapy. The findings do not clarify whether the difference in CVD risk is due to harm from sulfonylureas, benefit from metformin, or both. In overweight diabetics, when compared to diet alone, metformin has been shown to reduce diabetic and all-cause deaths (>35% risk reduction for each). Studies have shown that while the reduction in glycosylated hemoglobin is very similar, metformin is associated with more weight loss, decrease in low-density lipoprotein cholesterol and triglycerides, slight decrease in blood pressure, and decline of renal function. Another potential explanation for an increase in AMIs is the finding in patients and animal models that sulfonylureas impair the cardioprotective ischemic preconditioning phenomenon.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Diet

Keywords: Risk, Follow-Up Studies, Overweight, Diabetes Mellitus, Type 2, Blood Pressure, Creatinine, Hemoglobin A, Glycosylated, Sulfonylurea Compounds, Cause of Death, Cholesterol, Metformin, Cardiovascular Diseases, Medicare, United States, Myocardial Infarction, Stroke, Weight Loss, Risk Reduction Behavior, Ischemic Preconditioning, Body Mass Index, Hypoglycemic Agents, Diet, Triglycerides, Renal Insufficiency, Chronic

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