June 7, 2026European Heart Journal418 citationsOpen Access
View Full PaperMortality 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
Key Points
- This study aims to assess the long-term mortality and cardiovascular risks of insulin secretagogues compared to metformin in type 2 diabetes.
- Nationwide study in Denmark with >20-year-old residents initiating either insulin secretagogues or metformin between 1997 and 2006.
- Follow-up period was up to 9 years, with median follow-up of 3.3 years using individual-level linkage of national registers.
- Multivariable Cox proportional-hazard analyses and propensity analyses were used to evaluate all-cause and cardiovascular mortality.
- All-cause mortality was higher for glimepiride (HR 1.32, 95% CI 1.24-1.40) compared to metformin in patients without previous MI.
- In patients with previous MI, gliblenclamide had HR 1.47 (95% CI 1.22-1.76) showing even higher risk.
- Gliclazide and repaglinide not significantly different from metformin for both all-cause and cardiovascular mortality.
Abstract
AIMS: The impact of insulin secretagogues (ISs) on long-term major clinical outcomes in type 2 diabetes remains unclear. We examined mortality and cardiovascular risk associated with all available ISs compared with metformin in a nationwide study. METHODS AND RESULTS: 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 9607 had 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 and 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. CONCLUSION: 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. Gliclazide and repaglinide appear to be associated with a lower risk than other ISs.