(P-498) Sulfonylureas and the Risk of Ventricular Arrhythmias Among Patients with Type 2 Diabetes: A Systematic Review of Observational Studies

Background: Sulfonylurea use is associated with an increased risk of cardiovascular death among patients with type 2 diabetes. A potential mechanism involves sulfonylurea-induced ventricular arrhythmias (VA).

Objectives: To determine whether the use of sulfonylureas, compared to the use of other antihyperglycemic therapies, is associated with the risk of VA (including ventricular tachycardia, ventricular fibrillation, and premature ventricular complexes), cardiac arrest (SCA), and sudden cardiac death among patients with type 2 diabetes.

Methods: We systematically searched MEDLINE, EMBASE, CINAHL Plus, CENTRAL, and ClinicalTrials.gov from inception to November 2020 for observational studies reporting comparisons of sulfonylureas versus other therapies or intra-class comparisons of sulfonylureas among patients with type 2 diabetes. Two independent reviewers screened potentially relevant articles, extracted data, and assessed study quality using the Cochrane Collaboration’s Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool.

Results: Our systematic review included 15 studies that met our inclusion criteria (1,374,427 participants). Comparator therapies included other oral antihyperglycemic agents (n=1), insulin (n=4), non-sulfonylurea use (n=12), and intra-class comparisons (n=3). There were few high-quality studies (ROBINS-I risk of bias: 2 moderate; 3 serious; 10 critical). All higher quality studies reporting comparisons with other therapies were consistent with an increased risk of VA. Compared with DPP-4 inhibitors, sulfonylureas were associated with a higher risk of VA (adjusted hazard ratio [aHR]: 1.31, 95% confidence interval [CI]: 0.66-2.62). Across all studies, associations of VA varied from a lower unadjusted risk (odds ratio [OR]: 0.30, 95% CI: 0.08-1.08) to a higher unadjusted risk (OR: 3.71, 95% CI: 0.85-16.20), both versus non-sulfonylurea use. One study reported discrepant results for a composite of SCA/VA versus glipizide; the Medicaid claims analysis suggested an increased risk of SCA/VA with glimepiride (aHR: 1.17, 95% CI: 0.96-1.42) and a lower risk with glyburide (aHR: 0.87, 95% CI: 0.74-1.03); these trends were not observed in the Optum claims analysis (glimepiride: aHR = 0.84, 95% CI: 0.65-1.08; glyburide: aHR = 1.11, 95% CI: 0.86-1.42).

Conclusions: Our systematic review suggests that among higher quality observational studies, sulfonylurea therapy is associated with an increased risk of VA. However, we identified few methodologically rigorous studies, underscoring the need for additional real-world safety studies of this potential drug safety issue.