Initiating glipizide as a second-line therapy after metformin was associated with a 13% higher 5-year risk of major adverse cardiovascular events compared with dipeptidyl peptidase 4 inhibitors in adults with type 2 diabetes and moderate cardiovascular risk, according to a nationwide comparative effectiveness study.
The study included 48,165 adults aged 30 years or older who had received metformin monotherapy for at least 3 months (median age, 61 years; 47% women). They were treated at 10 US health systems or insured by 2 national health plans between 2014 and 2023. Participants initiated glipizide (18,147), glimepiride (14,282), glyburide (1,887), or a dipeptidyl peptidase 4 inhibitors (DPP4 inhibitor) (13,849), which served as the reference given prior cardiovascular neutrality in trials. Median treatment duration was 13 months for glipizide, 14 months for glimepiride, 11 months for glyburide, and 12 months for DPP4 inhibitors.
Over a median follow-up of 37 months, estimated 5-year risks of major adverse cardiovascular events (MACE-4) were 9% for glipizide, 8.6% for glimepiride, 8.4% for glyburide, and 8% for dipeptidyl peptidase 4 (DPP4) inhibitors. Relative risk was 1.13 for glipizide, 1.07 for glimepiride, and 1.04 for glyburide. MACE-4 wasdefined as myocardial infarction, ischemic stroke, heart failure hospitalization, or cardiovascular death.
Among participants aged 65 years or older, the 5-year MACE-4 risk was 15% for glipizide compared with 13% for DPP4 inhibitors.
Component risks for glipizide users were 3% for myocardial infarction, 4% for ischemic stroke, 4% for heart failure hospitalization or fatal heart failure, and 0.5% for cardiovascular death. Results were consistent across age, sex, kidney function, and A1C subgroups, and remained robust after excluding saxagliptin from the comparator group.
“These findings suggest that glipizide may not be the optimal agent in treatment of individuals with T2D at moderate cardiovascular risk,” wrote Alexander Turchin, MD, MS, of Brigham and Women’s Hospital and Harvard Medical School, and colleagues. .
The study emulated a randomized trial using harmonized electronic health record and claims data, applying pooled logistic regression models and standardized to the distribution of baseline covariates. Mechanistically, sulfonylureas bind to sulfonylurea receptors (SURs) found not only in pancreatic β cells but also in cardiac and vascular smooth muscle tissue. However, “glipizide is not thought to have a greater affinity for either SUR 2A or SUR 2B vs pancreatic SURs (SUR 1) compared with other sulfonylureas.” the authors wrote. Glyburide, while not linked to excess cardiovascular risk, remains associated with higher hypoglycemia risk than shorter-acting agents.
Limitations included residual confounding by treatment indication, a median follow-up of just over 3 years, limited generalizability due to the predominantly privately insured population, and the absence of dose-specific analyses. The findings, investigators concluded, highlight the need to evaluate individual sulfonylureas rather than treat them as a uniform class when selecting second-line therapy for type 2 diabetes.
Source: JAMA Network Open