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
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.
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The relative cardiovascular safety of gliclazide and glimepiride is somewhat supported by results of contemporary real-world data analyses.
“The relative CV safety of gliclazide and glimepiride is somewhat supported by results of contemporary real-world data analyses.186”
From 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. (2023) · cites this paper as [186]
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- Authors
- Schramm, T. K., Gislason, G. H., Vaag, A., Rasmussen, J. N., Folke, F., Hansen, M. L., Fosbøl, E. L., Køber, L., Norgaard, M. L., Madsen, M., Hansen, P. R., & Torp-Pedersen, C.
- Affiliations
- Copenhagen University Hospital (DK)
- Gentofte Hospital (DK)
- Rigshospitalet (DK)
- Statens Serum Institut (DK)
- Herlev Hospital (DK)
- University of Copenhagen (DK)
- Corresponding author
- Schramm, Tina Ken
- ORCID
- Venue
- European Heart Journal
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-04-06
- Volume
- 32
- Issue
- 15
- Pages
- 1900-1908
- ISSN
- 0195-668X (ISSN-L)
- 1522-9645
- OpenAlex
- W2150180487
- Cited by
- 418
- References
- 29
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 10 · 2023: 6 · 2022: 17 · 2021: 20 · 2020: 16 · 2019: 20 · 2018: 29 · 2017: 39 · 2016: 46 · 2015: 38 · 2014: 52 · 2013: 50 · 2012: 44
- FWCI
- 42.96
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Heart Journal (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- insulin secretagogues, type 2 diabetes, metformin, all-cause mortality, cardiovascular mortality, myocardial infarction, glimepiride, glibenclamide, glipizide, tolbutamide, gliclazide, repaglinide, sulfonylureas, long-term outcomes, old myocardial infarction
- MeSH terms
- Adult, Aged, Cause of Death, Denmark, Diabetes Mellitus, Type 2, Diabetic Angiopathies, Humans, Hypoglycemic Agents, Insulin, Metformin, Middle Aged, Myocardial Infarction, Risk Factors, Treatment Outcome, Stroke, Kaplan-Meier Estimate, Young Adult
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