Cardiovascular data confirm metformin over sulfonylurea as initial treatment choice in type 2 diabetes

Web Exclusives - Cardiometabolic Health
Wayne Kuznar

Two recent studies, one a randomized controlled clinical trial and the other an observational study, show potential cardiovascular advantages to using metformin over sulfonylureas in the treatment of type 2 diabetes.

Randomized controlled data favor metformin

Chinese and US researchers discovered in their clinical trial that patients with coronary artery disease who were randomized to metformin had about half the risk of cardiovascular events over a median follow-up of 5 years than did those randomized to glipizide.1 Their study is one of the first randomized controlled comparisons of the effect of these two drug classes on composite cardiovascular outcomes.

Jie Hong, MD, of Shanghai Jiao Tong University School of Medicine and colleagues enrolled 304 patients with type 2 diabetes and a history of coronary artery disease (mean age, 63.3 years). After a 2-week run-in period during which all antidiabetic agents were withdrawn, they were randomized to glipizide, 30 mg/day, or metformin, 1.5 mg/day, for 3 years. (The mean daily dose of glipizide was 28.3 mg; the mean daily dose of metformin was 1.4 g.) Insulin could be added when patients who were at the maximum dosage of study drug did not achieve the targeted glucose control level.

The targeted hemoglobin (Hb) A1c levels in both groups was 7.0%. Baseline HbA1c was 7.6% in each group; it declined to 7.1% in the glipizide group and 7.0% in the metformin group, with HbA1c levels remaining stable at these levels.

The primary end point was a composite of recurrent cardiovascular events, including death from a cardiovascular cause, death from any cause, nonfatal myocardial infarction (MI), nonfatal stroke, or arterial revascularization.

After a median follow-up of 5 years, 91 participants had 103 cardiovascular events. Events occurred in 52 patients assigned to glipizide (35.1%) and in 39 patients assigned to metformin (25.0%). There were 60 events in the glipizide arm vs. 43 in the metformin arm. The hazard ratio for the composite outcome for metformin treatment was 0.54 (a 46% reduction). There was no significant difference in mortality between the two groups.

Seventeen patients had a primary endpoint event in the first year; 9 in the glipizide group and 8 in the metformin group. Because it is unlikely that these events were caused by the effects of either treatment, the authors performed a stratified analysis looking at events only after 1 year. In this analysis, the rate of events was 52% lower in the metformin group (P <0.001).

The authors concluded, “Our study was the first to compare the effects of sulfonylureas (glipizide) and metformin on the recurrence of major cardiovascular events in a prospective, randomized, double-blind, placebo-controlled trial. We found that, compared with glipizide, metformin showed a significant reduction in composite cardiovascular endpoints.”

Observational study also consistent with metformin recommendation

In a retrospective study, the use of sulfonylureas as initial monotherapy was associated with an increase in the risk for cardiovascular events compared with metformin.2

Using data sets from the Veterans Health Administration, researchers identified 245,680 patients with type 2 diabetes who were initiated on either metformin or sulfonylurea monotherapy between 2001 and 2008. About three fourths of the cohort was white, 97% were men, and about one third had coronary artery disease or cerebrovascular disease. Follow-up continued until another antidiabetic agent was prescribed or the primary composite outcome of acute MI, stroke, or death occurred.

The median HbA1c level was 7.0% among those who began metformin therapy and 7.3% among those who began sulfonylurea therapy.

The unadjusted rates of the primary outcome were 18.2 per 1000 person-years among those prescribed sulfonylureas compared with 10.4 per 1000 person-years among the metformin recipients. After adjustment for potential confounders, the hazard ratio for the primary outcome was 1.21 for sulfonylurea as the initial prescription. The results did not differ by the type of sulfonylurea (glipizide or glyburide).

Using adjusted rate differences, the authors estimate an additional 2.2 cardiovascular disease events or deaths and 1.2 more cardiovascular disease events per 1000 person-years of sulfonylurea compared with metformin use.

“Compared with metformin, sulfonylureas are associated with increases in weight and lipid levels and greater risk for hypoglycemia but similar glycemic control,” they write. “Thus, metformin is recommended as first-line therapy for patients without contraindications.”

The reason for the difference in risk is not clear, they add.  “Whether the minor advantages in cholesterol level, weight, and blood pressure among metformin users could account for the differences in cardiovascular disease and death or whether another mechanism accounts for the risk difference observed, such as ischemic preconditioning, is currently unknown.”

The study was funded by the Agency for Healthcare Research and Quality and the US Department of Health and Human Services.


  1. Hong J, Zhang Y, Lai S, et al. Effects of metformin versus glipizide on cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease. Diabetes Care. 2012 Dec 10. [Epub ahead of print]
  2. 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.
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Last modified: February 14, 2019
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