Comparative cardiovascular risk of sulfonylureas with low- and high-affinities for cardiac mitochondrial adenosine triphosphate-sensitive potassium channels versus dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes: A cohort study

Abstract

Aims: To individually evaluate the cardiovascular safety of low- and high-affinity cardiac mitochondrial ATP-sensitive potassium (mitoK_ATP) channel sulfonylureas by comparing each to dipeptidyl peptidase-4 inhibitors (DPP-4i), a generally cardiovascular-neutral comparator, given prior evidence suggesting greater cardiovascular risk with high-affinity agents and the absence of a neutral active comparator.

Methods: A new user, active comparator cohort study using propensity score-based inverse probability of treatment weighting was conducted with Taiwan's nationwide claims database (2012-2022). Patients with recent pre-entry cardiovascular events were excluded. The primary outcome was 3-point major adverse cardiovascular events (MACE: ischaemic stroke, myocardial infarction, cardiovascular death); secondary outcomes included each MACE component and all-cause mortality.

Results: The study cohort included 466 158, 83 031, and 473 539 new users of low-affinity mitoK_ATP-channel sulfonylureas (gliclazide, glimepiride), high-affinity sulfonylureas (glyburide, glipizide), and DPP-4i, respectively (mean age, 60.2 years; 55.6% male). Compared with DPP-4i, low-affinity sulfonylureas were not associated with increased risks of 3-point MACE (Hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.96-1.06), cardiovascular death (HR, 1.01; 95% CI, 0.93-1.08), or all-cause mortality (HR, 0.97; 95% CI, 0.93-1.01). Conversely, high-affinity sulfonylureas were associated with 1.17-1.31-fold increased risks of 3-point MACE, cardiovascular death, and all-cause mortality.

Conclusions: Initiating low-affinity mitoK_ATP-channel sulfonylureas demonstrated cardiovascular safety comparable to DPP-4i, whereas high-affinity sulfonylureas were linked to increased cardiovascular risk and all-cause mortality. These findings suggest low-affinity sulfonylureas are a safer alternative to high-affinity agents and as safe as DPP-4i. They may be appropriate for individuals with diabetes when newer therapies are inaccessible or unnecessary.

Keywords: cardiac mitochondrial adenosine triphosphate‐sensitive potassium channels; cohort study; dipeptidyl peptidase‐4 inhibitors; major adverse cardiovascular events; sulfonylureas; type 2 diabetes mellitus.

FIGURE 1

Forest plots showing the sensitivity and subgroup analyses of the primary analysis. aHR, adjusted hazard ratio; MACEs, major adverse cardiovascular events; MitoK_ATP, mitochondrial adenosine triphosphate sensitive‐potassium. *p < 0.05. p‐values in subgroup analyses represent the interaction analyses.