No abstract

OBJECTIVE Previous studies have revealed an intraclass difference in major adverse cardiovascular events (MACE) among sulfonylureas (SUs). In vitro and ex vivo studies reported several sulfonylureas to exhibit high-affinity blockage of cardiac mitochondrial ATP-sensitive potassium (mitoKATP) channels and could interfere with ischemic preconditioning, the most important mechanism of self-cardiac protection. However, no studies have examined whether these varying binding affinities of sulfonylureas could account for their intraclass difference in MACE. We compared mitoKATP channel high-affinity versus low-affinity sulfonylureas regarding the MACE risk in real-world settings. RESEARCH DESIGN AND METHODS Using the Taiwan nationwide health care claims database, patients with type 2 diabetes initiating sulfonylurea monotherapy between 2007 and 2016 were included in the cohort study. A total of 33,727 new mitoKATP 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 ratios (aHRs) and 95% CI. RESULTS MitoKATP channel high-affinity sulfonylureas were associated with a significantly increased risk of three-point MACE (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 myocardial infarction (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 mitoKATP channel high-affinity sulfonylureas were associated with an increased MACE risk compared with low-affinity sulfonylureas in a nationwide population with diabetes.

ImportanceSulfonylureas 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 (mitoKATP) 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.ObjectiveTo compare the risk of myocardial infarction (MI), ischemic stroke, or cardiovascular death in patients with T2D treated with mitoKATP channel high-affinity sulfonylureas and low-affinity sulfonylureas as add-on to metformin.Design, Setting, and ParticipantsThis 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.ExposuresCardiac mitoKATP channel high-affinity (glyburide and glipizide) and low-affinity (gliclazide and glimepiride) sulfonylureas combined with metformin.Main Outcomes and MeasuresPrimary 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).ResultsEach sulfonylurea group comprised 53 714 patients (mean [SD] age, 54.7 [12.1] years; 31 962 men [59.5%]). MitoKATP 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 mitoKATP channel high-affinity sulfonylureas (aHR, 6.06; 95% CI, 4.86-7.55).Conclusions and RelevanceUse of mitoKATP 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 mitoKATP channels could account for sulfonylurea-associated MACEs.

<b>OBJECTIVE: </b>Previous studies have revealed an intraclass difference in major adverse cardiovascular events (MACEs) among sulfonylureas. <i>In vitro </i>and <i>ex vivo</i> 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. <p><b> </b></p> <p><b>RESEARCH DESIGN AND METHODS: </b>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). </p> <p> </p> <p><b>RESULTS:</b> 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]). <a>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]).</a></p> <p> </p> <p><b>CONCLUSIONS:</b> 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.</p> <b><br> </b> <p><b> </b></p>