Sulfonylureas remain widely used for glucose-lowering in type 2 diabetes mellitus (T2DM), yet safety differences within the drug class continue to be examined. A target trial emulation, published in BMJ Open Diabetes Respiratory Care, compared risks of major adverse cardiovascular events (MACE) and severe hypoglycemia among adults with T2DM and moderate cardiovascular risk initiating different sulfonylureas.

The study included adults aged 21 years or older who initiated glimepiride, glipizide, or glyburide between 2014 and 2021 using claims data from the Optum Labs Data Warehouse and the Medicare fee-for-service 100% sample. Follow-up continued through 2022. Inverse probability of treatment weighting using propensity scores estimated with a super learner ensemble was applied, and outcomes were evaluated using weighted Cox proportional hazards models.

The weighted cohort comprised 314,699 patients with a mean age of 66.9 years; 52.0% were men, and 76.6% were non-Hispanic White. At 1 year, MACE occurred in 2.5% of patients initiating glimepiride, 2.7% initiating glipizide, and 2.8% initiating glyburide. Compared with glimepiride, glyburide was associated with a higher MACE risk (HR 1.10, 95% CI 1.05-1.16) and glipizide with a modestly higher risk (HR 1.05, 95% CI 1.03-1.07). Severe hypoglycemia occurred in 0.3%, 0.3%, and 0.4% of patients initiating glimepiride, glipizide, and glyburide, respectively. Glyburide was associated with a higher hypoglycemia risk compared with glipizide (HR 1.43, 95% CI 1.23-1.65), while glipizide was associated with a lower risk compared with glimepiride (HR 0.82, 95% CI 0.77-0.87).

In this observational target trial emulation, glimepiride was associated with the lowest MACE risk and glipizide with the lowest severe hypoglycemia risk among the three agents studied.