Mortality and Cardiovascular Risk Associated With Different Insulin Secretagogues Compared With Metformin in Type 2 Diabetes, With or Without a Previous Myocardial Infarction: A Nationwide Study

Study Questions:

What is the impact of insulin secretagogues (ISs) on long-term major clinical outcomes in type 2 diabetes?


All Danish residents >20 years, initiating single-agent ISs or metformin between 1997 and 2006, were followed for up to 9 years (median 3.3 years) by individual-level linkage of nationwide registers. All-cause mortality, cardiovascular mortality, and the composite of myocardial infarction (MI), stroke, and cardiovascular mortality associated with individual ISs were investigated in patients with or without previous MI by multivariable Cox proportional-hazard analyses including propensity analyses.


A total of 107,806 subjects were included, of whom 9,607 had a previous MI. Compared with metformin, glimepiride (hazard ratios and 95% confidence intervals): 1.32 (1.24-1.40), glibenclamide: 1.19 (1.11-1.28), glipizide: 1.27 (1.17-1.38), and tolbutamide: 1.28 (1.17-1.39) were associated with increased all-cause mortality in patients without previous MI. The corresponding results for patients with previous MI were as follows: glimepiride: 1.30 (1.11-1.44), glibenclamide: 1.47 (1.22-1.76), glipizide: 1.53 (1.23-1.89), and tolbutamide: 1.47 (1.17-1.84). Results for gliclazide [1.05 (0.94-1.16) and 0.90 (0.68-1.20)] and repaglinide [0.97 (0.81-1.15) and 1.29 (0.86-1.94)] were not statistically different from metformin in both patients without and with previous MI, respectively. Results were similar for cardiovascular mortality and for the composite endpoint.


The authors concluded that monotherapy with the most used ISs, including glimepiride, glibenclamide, glipizide, and tolbutamide, seems to be associated with increased mortality and cardiovascular risk compared with metformin.


This study demonstrated that compared with metformin, increased mortality and cardiovascular risk were associated with most first- and second-generation sulfonylureas (glimepiride, glibenclamide, glipizide, and tolbutamide). Gliclazide and repaglinide appear to be associated with a lower risk than other ISs, and the risk associated with them was not significantly different from metformin. These data suggest that the choice of a particular IS may be quite important in diabetes therapy, and highlight the need for cardiovascular efficacy and safety evaluation for all drugs used to treat type 2 diabetes mellitus.

Keywords: Carbamates, Sulfonylurea Compounds, Insulin, Myocardial Infarction, Piperidines, Diabetes Mellitus, Type 2, Cardiovascular Diseases, Risk Factors

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