# 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

## TL;DR

This study compares the cardiovascular risks of different diabetes drugs, finding that low-affinity sulfonylureas are as safe as DPP-4 inhibitors, while high-affinity ones increase risk.

## Contribution

The study provides direct evidence comparing cardiovascular risks of low- and high-affinity sulfonylureas using a neutral comparator, DPP-4 inhibitors.

## Key findings

- Low-affinity sulfonylureas showed no increased cardiovascular risk compared to DPP-4 inhibitors.
- High-affinity sulfonylureas were linked to 1.17–1.31-fold higher risks of major adverse cardiovascular events and mortality.
- Low-affinity sulfonylureas may be a safer alternative when newer therapies are unavailable.

## Abstract

To individually evaluate the cardiovascular safety of low‐ and high‐affinity cardiac mitochondrial ATP‐sensitive potassium (mitoKATP) 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.

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.

The study cohort included 466 158, 83 031, and 473 539 new users of low‐affinity mitoKATP‐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.

Initiating low‐affinity mitoKATP‐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.