Cardiovascular event risk in type 2 diabetes: Sulfonylureas vs. DPP-4 inhibitors

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Created On: 12/11/2025

Sulfonylureas are widely prescribed for type 2 diabetes (T2D), but their cardiovascular safety remains uncertain due to conflicting evidence.

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Key take away

Compared to DPP-4 inhibitors, glipizide is linked with a higher 5-year risk of major adverse cardiovascular events in patients with type 2 diabetes on metformin.

Background

Sulfonylureas are widely prescribed for type 2 diabetes (T2D), but their cardiovascular safety remains uncertain due to conflicting evidence. Hence, a comparative trial was performed to evaluate the risk of cardiovascular events between individuals on treatment with sulfonylureas and dipeptidyl peptidase 4 (DPP4) inhibitors, aiming to guide safer treatment choices.

Method

Volunteers with T2D and moderate cardiovascular risk who were on metformin monotherapy were evaluated after initiating second-line therapy with either a sulfonylurea (glyburide, glipizide, or glimepiride) or a DPP-4 inhibitor (reference group). Data were analyzed from 10 U.S. health systems and 2 large insurance databases. The key outcome was a 4-point composite of major adverse cardiovascular events (MACE-4), including ischemic stroke, heart failure hospitalization, myocardial infarction, or cardiovascular death. Five-year event risks were calculated and analyzed.

Result

A total of 48,165 adults with T2D (median age 61 years; 47.1% female) who commenced second-line therapy after metformin were analyzed. Among them, 18,147 received glipizide, 14,282 glimepiride, 1,887 glyburide, and 13,849 a DPP4 inhibitor. Over a median follow-up of about 37 months, 3,158 participants (6.6%) experienced MACE-4. The estimated five-year MACE-4 risks were 8.1% for DPP4 inhibitors, 8.4% for glyburide, 8.6% for glimepiride, and 9.1% for glipizide. Relative to DPP-4 inhibitors, the 5-year risk ratio for MACE-4 was 1.13 with glipizide, 1.07 with glimepiride, and 1.04 with glyburide.

Conclusion

Glipizide showed the highest MACE-4 risk among sulfonylureas, implying it as a less suitable option for T2D patients with moderate cardiovascular risk.