Association Between Specificity of Sulfonylureas to Cardiac Mitochondrial KATP Channels and the Risk of Major Adverse Cardiovascular Events in Type 2 Diabetes

OBJECTIVE: Previous studies have revealed an intraclass difference in major adverse cardiovascular events (MACEs) among sulfonylureas. In vitro and ex vivo studies reported several sulfonylureas to exhibit high affinity blockage of cardiac mitochondrial adenosine triphosphate sensitive potassium (mitoK_ATP) channels and could interfere with ischemic preconditioning, the most important mechanism of self-cardiac protection. However, no studies have examined whether this varying binding affinities of sulfonylureas could account for their intraclass difference in MACE. We compared MitoK_ATP channel-high affinity versus low affinity sulfonylureas regarding the MACE risk in real-world settings.

RESEARCH DESIGN AND METHODS: Using the Taiwan nationwide healthcare claims database, patients with type 2 diabetes initiating sulfonylurea monotherapy between 2007 and 2016 were included in the cohort study. 33,727 new mitoK_ATP channel-high affinity (glyburide and glipizide) and low affinity (gliclazide and glimepiride) sulfonylurea users, respectively, were identified after 1:1 propensity score matching. Cox proportional hazard models were used to estimate adjusted hazard ratio (aHRs) and 95% confidence interval (CI).

RESULTS: MitoK_ATP channel-high affinity sulfonylureas were associated with a significantly increased risk of three-point MACEs (aHR, 1.21 [95% CI, 1.03–1.44]), ischemic stroke (aHR, 1.23 [95% CI, 1.02-1.50]), and cardiovascular death (aHR, 2.61 [95% CI, 1.31–5.20]) but not with that of MI (aHR, 1.04 [95% CI, 0.75-1.46]). The duration-response analyses revealed the highest MACE risk to be within 90 days of therapy (aHR, 4.67 [95% CI, 3.61-6.06]).

CONCLUSIONS: Cardiac mitoK_ATP channel-high affinity sulfonylureas were associated with an increased MACE risk compared with low affinity sulfonylureas in a nationwide population with diabetes.