Comparison of Mitochondrial Adenosine Triphosphate–Sensitive Potassium Channel High- vs Low-Affinity Sulfonylureas and Cardiovascular Outcomes in Patients With Type 2 Diabetes Treated With Metformin

IMPORTANCE: Sulfonylureas are frequently used as add-on to metformin in type 2 diabetes (T2D), and individual sulfonylurea agents carry different risks of cardiovascular disease. Sulfonylureas’ different affinities to cardiac mitochondrial adenosine triphosphate–sensitive potassium (mitoK(ATP)) channels have been speculated to account for the intraclass difference in cardiovascular risk from in vitro and ex vivo studies; however, this hypothesis has not been assessed in a general population with diabetes receiving sulfonylureas added to metformin. OBJECTIVE: To compare the risk of myocardial infarction (MI), ischemic stroke, or cardiovascular death in patients with T2D treated with mitoK(ATP) channel high-affinity sulfonylureas and low-affinity sulfonylureas as add-on to metformin. DESIGN, SETTING, AND PARTICIPANTS: This is a new-user, active-comparator, and propensity score–matched cohort study with analysis of the Taiwanese Diabetes Mellitus Health Database from 2006, to 2017. Data analysis was performed from August 2020 to July 2021. EXPOSURES: Cardiac mitoK(ATP) channel high-affinity (glyburide and glipizide) and low-affinity (gliclazide and glimepiride) sulfonylureas combined with metformin. MAIN OUTCOMES AND MEASURES: Primary outcome was major adverse cardiovascular events (MACEs), a composite of cardiovascular death or hospitalization for either MI or ischemic stroke. Secondary outcomes included individual MACE components, heart failure, arrhythmia, all-cause mortality, and severe hypoglycemia. Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs). RESULTS: Each sulfonylurea group comprised 53 714 patients (mean [SD] age, 54.7 [12.1] years; 31 962 men [59.5%]). MitoK(ATP) channel high-affinity sulfonylureas vs low-affinity sulfonylureas when combined with metformin were associated with an increased risk of MACE (aHR, 1.18; 95% CI, 1.03-1.34), MI (aHR, 1.34; 95% CI, 1.04-1.73), all-cause mortality (aHR, 1.27; 95% CI, 1.03-1.57), and severe hypoglycemia (aHR, 1.82; 95% CI, 1.58-2.10), but not with increased risks of ischemic stroke, cardiovascular death, arrhythmia, and heart failure. The duration analyses revealed the highest MACE risk during 1 to 90 days after initiation of mitoK(ATP) channel high-affinity sulfonylureas (aHR, 6.06; 95% CI, 4.86-7.55). CONCLUSIONS AND RELEVANCE: Use of mitoK(ATP) channel high-affinity sulfonylureas vs low-affinity sulfonylureas was associated with an increased MACE risk in patients with T2D concomitantly receiving metformin, suggesting that high-affinity blockage of the mitoK(ATP) channels could account for sulfonylurea-associated MACEs.