Glipizide Increases Cardiovascular Risk Compared With DPP4 Inhibitors in T2D
Patients with type 2 diabetes and moderate cardiovascular risk had a higher rate of major heart-related events when treated with sulfonylureas.
Sulfonylureas were associated with an increased risk of cardiovascular events in patients with type 2 diabetes (T2D) compared to dipeptidyl peptidase 4 (DPP4) inhibitors, according to data published in JAMA Network Open.1 The study, which found the risk was highest for glipizide, suggests sulfonylureas may not be the best choice of medication for patients with T2D who have moderate cardiovascular disease risk.
Glipizide Increases Cardiovascular Risk Compared to DPP4 Inhibitors in T2D / Martina - stock.adobe.com
Sulfonylureas are affordable and effective glucose-lowering agents used for decades in T2D management. However, concerns remain about their cardiovascular safety, based on older trials and observational studies showing higher risk compared to other medications. Additional drawbacks such as hypoglycemia, weight gain, and reduced durability challenge their use as second-line therapy.2
“Patients with type 2 diabetes are at heightened risk of adverse cardiovascular incidents such as stroke and cardiac arrest,” Alexander Turchin, MD, MS, corresponding author on the study, said in a release.3 “While sulfonylureas are popular and affordable diabetes medications, there is a lack of long-term clinical data on how they affect cardiac health in comparison to more neutral alternatives like dipeptidyl peptidase 4 inhibitors.”
Investigators from Harvard Medical School and Brigham and Women’s Hospital conducted a study to compare the risk of cardiovascular events after starting treatment with individual sulfonylureas or DPP4 inhibitors. The comparative effectiveness study included 48165 patients with T2D and moderate cardiovascular risk who were treated at 1 of 10 health systems in the United States between January 2013 and January 2023.
The patients all received metformin monotherapy and then initiated either glimepiride, glipizide, glyburide, or any DPP4 inhibitor, including alogliptin, linagliptin, saxagliptin, or sitagliptin. The primary study outcome was the 5-year risk of a 4-point composite of major adverse cardiovascular events (MACE-4), which included myocardial infarction, ischemic stroke, heart failure hospitalization, or cardiovascular death.
During the study, 18147 patients started glipizide, 14282 started glimepiride, 1887 started glyburide, and 13849 started a DPP4 inhibitor. The study found that over a median follow-up time of 37 months, 6.6% of patients experienced a MACE-4: 2.2% had myocardial infarction, 2.6% had an ischemic stroke, 3% had a heart failure hospitalization, and 0.4% died from any of the conditions. Compared with DPP4 inhibitors, the 5-year risk ratio of MACE-4 was 1.13 for glipizide, 1.07 for glimepiride, and 1.04 for glyburide.
Study limitations included short median follow-up time which made it difficult to detect further differences between the medications, that gliclazide was not in use during the study and few patients were taking glyburide, and that racial and ethnic diversity was limited.
“The potentially different cardiovascular risk between individual sulfonylureas in our study underscores the importance of evaluating each agent in a particular pharmacological class on its own merits,” the authors concluded. “These findings caution against extrapolating results of studies evaluating a single agent to the entire class, and temper concerns about the use of research and development resources for the development of multiple agents in the same pharmacological class.”
READ MORE: Diabetes Resource Center
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References
1. 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
2. Wang H, Cordiner RLM, Huang Y, et al. Cardiovascular Safety in Type 2 Diabetes With Sulfonylureas as Second-line Drugs: A Nationwide Population-Based Comparative Safety Study. Diabetes Care 1 May 2023; 46 (5): 967–977. https://doi.org/10.2337/dc22-1238
3. Study compares common type 2 diabetes drugs, finding higher cardiovascular risk for one medication. News Release. Mass General Brigham. July 24, 2025. Accessed August 5, 2025. https://www.massgeneralbrigham.org/en/about/newsroom/press-releases/cardiovascular-risk-of-diabetes-drugs
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