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Cardiovascular Events in Individuals Treated With Sulfonylureas or Dipeptidyl Peptidase 4 Inhibitors
Journal article   Open access   Peer reviewed

Cardiovascular Events in Individuals Treated With Sulfonylureas or Dipeptidyl Peptidase 4 Inhibitors

Alexander Turchin, Lucia C Petito, Emma Hegermiller, Ryan Carnahan, Andrea DeVries, Satyender Goel, M Cecilia Lansang, Marie E McDonnell, Vinit Nair, Elisa Priest, …
JAMA network open, Vol.8(7), e2523067
07/01/2025
DOI: 10.1001/jamanetworkopen.2025.23067
PMCID: PMC12290728
PMID: 40705329
url
https://doi.org/10.1001/jamanetworkopen.2025.23067View
Published (Version of record) Open Access

Abstract

Sulfonylureas are commonly used to treat type 2 diabetes (T2D). Research findings on cardiovascular risk associated with sulfonylureas have been inconsistent. To emulate a target trial that compares the risk of cardiovascular events after initiation of treatment with individual sulfonylureas or dipeptidyl peptidase 4 inhibitors (DPP4is). This comparative effectiveness research study included individuals with T2D and moderate cardiovascular risk treated with metformin monotherapy who received care at 1 of 10 US health systems or were insured by 1 of 2 large health insurance plans between January 1, 2014, and January 1, 2023. Data were analyzed from July 2024 to March 2025. Initiation of treatment with a sulfonylurea (glimepiride, glipizide, or glyburide) or a DPP4i (reference category) as a second line therapy after metformin. The primary outcome was a 4-point composite of major adverse cardiovascular events (MACE-4): myocardial infarction, ischemic stroke, heart failure hospitalization, or cardiovascular death (from any of these conditions). The 5-year risks of each outcome were estimated. Among 48 165 eligible individuals (median [IQR] age, 61 [52-69] years; 22 674 female [47.1%]; median [IQR] hemoglobin A1C, 7.8% [7.3%-8.5%]; median [IQR] low-density lipoprotein cholesterol, 89 mg/dL [70-112 mg/dL]), 18 147 started glipizide, 14 282 started glimepiride, 1887 started glyburide, and 13 849 started a DPP4i. Over the median (IQR) follow-up of 37 (20-64) months, 3158 individuals (6.6%) experienced a MACE-4. The estimated 5-year risks of MACE-4 were 8.1% (95% CI, 7.5%-8.7%) for DPP4i, 8.4% (95% CI, 6.8%-9.9%) for glyburide, 8.6% (95% CI, 7.9%-9.2%) for glimepiride, and 9.1% (95% CI, 8.7%-9.7%) for glipizide. Compared with DPP4is, the 5-year risk ratio of MACE-4 was 1.13 (95% CI, 1.03-1.23) for glipizide, 1.07 (95% CI, 0.96-1.16) for glimepiride, and 1.04 (95% CI, 0.83-1.24) for glyburide. In this comparative effectiveness research study of sulfonylureas vs DPP4i in patients with T2D, the risk of MACE-4 events was highest for glipizide. These findings suggest that sulfonylureas, glipizide in particular, may not be the optimal agent in treatment of individuals with T2D at moderate cardiovascular risk.
 Aged Cardiovascular Diseases - chemically induced Cardiovascular Diseases - epidemiology Comparative Effectiveness Research Diabetes Mellitus, Type 2 - drug therapy Dipeptidyl-Peptidase IV Inhibitors - adverse effects Dipeptidyl-Peptidase IV Inhibitors - therapeutic use Female Glipizide - adverse effects Glipizide - therapeutic use Glyburide - adverse effects Glyburide - therapeutic use Humans Hypoglycemic Agents - adverse effects Hypoglycemic Agents - therapeutic use Male Metformin - therapeutic use Middle Aged Sulfonylurea Compounds - adverse effects Sulfonylurea Compounds - therapeutic use

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