SULFONYLUREAS remain a widely prescribed second-line treatment for Type 2 diabetes (T2D), despite growing concerns about their cardiovascular safety. Previous research has yielded conflicting results, particularly when comparing individual sulfonylureas to newer agents such as dipeptidyl peptidase 4 inhibitors (DPP4is). A recent large-scale comparative effectiveness study set out to provide clarity on the cardiovascular risk associated with these drugs. A key finding was that glipizide was associated with the highest risk of adverse cardiovascular events among the drugs studied.
This research emulated a target trial using real-world data from over 48,000 adults with T2D and moderate cardiovascular risk, all of whom were previously treated with metformin monotherapy. Participants initiated a second-line therapy between 2014 and 2023 with either a sulfonylurea (glimepiride, glipizide, or glyburide) or a DPP4i. The primary outcome measured was a composite of major adverse cardiovascular events (MACE-4), including myocardial infarction, stroke, heart failure hospitalisation, and cardiovascular death. Follow-up lasted a median of 37 months, with data analysed between July 2024 and March 2025.
A total of 3,158 individuals (6.6%) experienced a MACE-4 event during the study period. The estimated 5-year risk of MACE-4 was 8.1% for DPP4i users, compared with 8.4% for glyburide, 8.6% for glimepiride, and 9.1% for glipizide. When compared to DPP4is, the 5-year risk ratio for MACE-4 was highest for glipizide at 1.13 (95% CI: 1.03–1.23). Glimepiride and glyburide showed smaller and statistically non-significant increases in risk, with risk ratios of 1.07 (95% CI: 0.96–1.16) and 1.04 (95% CI: 0.83–1.24), respectively.
These findings highlight the need for careful selection of second-line therapies in clinical practice, especially for patients with existing cardiovascular risk. Glipizide, in particular, may be less suitable for such individuals due to its higher associated risk. While observational in nature, the study benefits from robust real-world data and a trial-like design. However, limitations include residual confounding and potential misclassification in electronic health record data. Clinicians should weigh cardiovascular outcomes alongside glycaemic control when choosing between sulfonylureas and alternative agents such as DPP4is.
Reference
Turchin A et al. Cardiovascular Events in Individuals Treated With Sulfonylureas or Dipeptidyl Peptidase 4 Inhibitors. JAMA Netw Open. 2025;8(7):e2523067.
