Sulfonylureas Linked to Higher Cardiovascular Risk in Type 2 Diabetes: Study Shows
USA: An observational study led by Dr. Alexander Turchin of Brigham and Women's Hospital has found that sulfonylureas, when used as second-line therapy after metformin in patients with type 2 diabetes, showed a trend toward increased cardiovascular risk compared to DPP-4 inhibitors. While not always statistically significant, the risk estimates consistently moved in an unfavorable direction.
The study, published in JAMA Network Open, aimed to evaluate the cardiovascular safety profile of individual sulfonylureas—glimepiride, glipizide, and glyburide—in comparison with dipeptidyl peptidase 4 inhibitors (DPP4is) when prescribed as an add-on therapy to metformin in patients with moderate cardiovascular risk.
Researchers analyzed electronic health records and insurance claims data from over 48,000 individuals with type 2 diabetes who initiated second-line therapy after metformin between 2014 and 2023. The study included patients from 10 major U.S. healthcare systems and two large insurance providers. The primary outcome was the occurrence of major adverse cardiovascular events (MACE-4), defined as myocardial infarction, ischemic stroke, hospitalization for heart failure, or cardiovascular-related death.
Among the participants (median age 61 years; 47.1% women), 18,147 began treatment with glipizide, 14,282 with glimepiride, 1,887 with glyburide, and 13,849 with a DPP4 inhibitor.
The study led to the following findings:
- During a median follow-up of around three years, 6.6% of patients experienced a major adverse cardiovascular event (MACE-4).
- The estimated 5-year risk of MACE-4 was 9.1% for glipizide, 8.6% for glimepiride, 8.4% for glyburide, and 8.1% for DPP-4 inhibitors.
- Patients on glipizide had a significantly higher 5-year risk ratio for MACE-4 at 1.13 compared to those on DPP-4 inhibitors.
- Glimepiride and glyburide were also associated with increased risk ratios—1.07 and 1.04, respectively—but these associations were not statistically significant.
The researchers emphasized that while sulfonylureas remain widely used due to their cost-effectiveness and glucose-lowering efficacy, their cardiovascular safety profile—particularly for glipizide—warrants caution. “These results highlight the need for clinicians to carefully consider cardiovascular risks when selecting second-line glucose-lowering therapies for patients with type 2 diabetes,” the authors noted.
The study contributes to a growing body of evidence urging more personalized treatment decisions in diabetes management, especially in individuals with heightened cardiovascular risk. The findings suggest that glipizide, in particular, may not be the most suitable option for such patients when safer alternatives like DPP-4 inhibitors are available.
“In the study comparing sulfonylureas with DPP-4 inhibitors in patients with type 2 diabetes, glipizide showed the highest risk of major cardiovascular events. These findings indicate that glipizide, in particular, may not be the most suitable choice for patients with moderate cardiovascular risk,” the authors concluded.
Reference:
Turchin A, Petito LC, Hegermiller E, et al. Cardiovascular Events in Individuals Treated With Sulfonylureas or Dipeptidyl Peptidase 4 Inhibitors. JAMA Netw Open. 2025;8(7):e2523067. doi:10.1001/jamanetworkopen.2025.23067
