JAMA Netw Open

Sulfonylureas under renewed scrutiny for cardiovascular safety

July 30, 2025

Among sulfonylureas, glipizide is associated with the highest CV risk relative to DPP-4 inhibitors. For patients with T2DM at moderate CV risk, DPP-4 inhibitors, and possibly glimepiride or glyburide, may be preferred over glipizide as second-line therapy after metformin.

Study details: This comparative effectiveness research emulated a target trial using electronic health records and claims data from 48,165 adults with T2DM at moderate CV risk, all of whom initiated a second-line agent (glipizide, glimepiride, glyburide, or a DPP-4 inhibitor) after metformin between 2014 and 2023 across 10 U.S. health systems and 2 large insurers. Primary outcome was 5-year risk of a composite major adverse cardiovascular event (MACE-4: MI, ischemic stroke, HF hospitalization, or CV death).

Results: Over a median follow-up of 37 months, 6.6% experienced a MACE-4. The estimated 5-year MACE-4 risks were: DPP-4i 8.1%, glyburide 8.4%, glimepiride 8.6%, and glipizide 9.1%. Compared with DPP-4i, the risk ratio (RR) for MACE-4 was significantly higher for glipizide (RR, 1.13; 95% confidence interval [CI], 1.03–1.23), but not for glimepiride (RR, 1.07; 95% CI, 0.96–1.16) or glyburide (RR, 1.04; 95% CI, 0.83–1.24).

Source:

Turchin A, et al. (2025, July 1). JAMA Netw Open. Cardiovascular Events in Individuals Treated With Sulfonylureas or Dipeptidyl Peptidase 4 Inhibitors. https://pubmed.ncbi.nlm.nih.gov/40705329/