Sulfonylureas and the Risk of Ventricular Arrhythmias Among People with Type 2 Diabetes: A Systematic Review of Observational Studies

Abstract

Previous studies have suggested an association between sulfonylureas and an increased risk of cardiovascular death among patients with type 2 diabetes. A potential mechanism involves sulfonylurea-induced ventricular arrhythmias (VAs). We conducted a systematic review of observational studies to determine whether the use of sulfonylureas, compared with the use of other antihyperglycemic drugs, is associated with the risk of VA (ventricular tachycardia, ventricular fibrillation, and premature ventricular complexes), cardiac arrest, and sudden cardiac death among patients with type 2 diabetes. Two independent reviewers searched MEDLINE, EMBASE, CINAHL Plus, CENTRAL, and ClinicalTrials.gov from inception to July 2021 for observational studies comparing sulfonylureas vs. other antihyperglycemic therapies or intraclass comparisons of sulfonylureas. Our systematic review included 17 studies (1,607,612 patients). Per Risk Of Bias In Non-randomized Studies of Interventions (ROBINS)-I, there were few highquality studies (2 studies at moderate risk of bias; 4 at serious risk; and 11 at critical risk). All studies at a moderate or serious risk of bias reporting comparisons with other therapies were consistent with an increased risk of VA. Sulfonylureas were associated with a higher risk of arrhythmia vs. dipeptidyl peptidase-4 inhibitors (adjusted hazard ratio (aHR): 1.52, 95% confidence interval (CI): 1.27-1.80) and of VA vs. metformin (aHR: 1.52, 95% CI: 1.10-2.13). One moderate quality study reported inconsistent results for a composite of cardiac arrest/VA in analyses of US Medicaid claims and Optum claims data. Our systematic review suggests that, among higher-quality observational studies, sulfonylureas are associated with an increased risk of VA. However, we identified few methodologically rigorous studies, underscoring the need for additional real-world studies.

Methodological Quality of Retrospective Observational Studies Investigating Effects of Diabetes Monitoring Systems: a Systematic Review

“…For the other RoB domains, our ndings and those from previous reviews were relatively more consistent. For example, Islam et al (2022) con rmed that bias due to confounding and selection of the reported result were major contributors, as ten and seven of the 11 ROSs were graded as critical or serious RoB, respectively. 28 Our ndings demonstrate the barriers of applying retrospective observational studies to clinical, regulatory, or HTA decision-making.…”

“…27 In their review, seven studies were rated as having critical or serious RoB, while no study was rated as having low RoB. Similarly, Islam et al (2022) identi ed 11 retrospective studies investigating sulfonylureas in diabetic patients and rated nine of them with overall critical or serious RoB. 28 Golden et al ( 2012) did not use the ROBINS-I but the Downs and Black quality checklist supplemented with items from the Methods Guide for Effectiveness and Comparative Effectiveness Reviews.…”

Sulphonylureas versus metformin and the risk of ventricular arrhythmias among people with type 2 diabetes: A population‐based cohort study

“…Our previous systematic review identified few methodologically rigorous studies, underscoring the need for additional real‐world studies 18 . In the existing literature, one study compared the risk of VA/cardiac arrest among users of the second‐generation sulphonylureas glimepiride, glyburide and glipizide 43 .…”

“…[11][12][13][14][15][16] While several observational studies have investigated the association between sulphonylureas and the risk of VAs, many of these studies had important limitations, including time-lag bias and depletion of susceptibles (prevalent user bias). 17,18 Consequently, the effect of sulphonylureas on the risk of VAs remains unclear. Our objective was therefore to determine if sulphonylureas, relative to metformin, are associated with the risk of VAs when used as monotherapy for the initial treatment of type 2 diabetes.…”

“…Hypoglycaemia has been associated with increased risks of ventricular tachycardia and sudden cardiac death 11‐16 . While several observational studies have investigated the association between sulphonylureas and the risk of VAs, many of these studies had important limitations, including time‐lag bias and depletion of susceptibles (prevalent user bias) 17,18 . Consequently, the effect of sulphonylureas on the risk of VAs remains unclear.…”