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.
Aim
To determine whether the use of sulphonylurea monotherapy, compared with metformin monotherapy, is associated with an increased risk of ventricular arrhythmia (VA) among patients initiating pharmacotherapy for type 2 diabetes.
Research Design and Methods
We conducted a population‐based cohort study using electronic health data extracted from the UK's Clinical Practice Research Datalink Aurum. Using the active comparator, new‐user cohort design, we compared rates of VA among patients aged 18 years or older using sulphonylurea monotherapy with those using metformin monotherapy as their initial pharmacological treatment for type 2 diabetes from April 1998 to December 2019. We used a Cox proportional hazards model with inverse probability of treatment weighting by propensity score to estimate the adjusted hazard ratio (aHR) and a corresponding bootstrap 95% confidence interval (CI) for VA with sulphonylurea monotherapy versus metformin monotherapy.
Results
The cohort included 92 638 new users of sulphonylurea and 506 882 new users of metformin. A total of 279 VA events occurred among sulphonylurea users (rate per 10 000 person‐years: 25.5, 95% CI: 22.7 to 28.7) and 1537 VA events occurred among metformin users (rate per 10 000 person‐years: 18.5, 95% CI: 17.6 to 19.5). Compared with metformin, sulphonylureas were associated with an increased risk of VA (aHR: 1.42, 95% CI: 1.18 to 1.69).
Conclusions
Sulphonylureas are associated with an increased risk of VA when used as first‐line therapy for type 2 diabetes relative to metformin use. This increased risk should be considered when prescribing sulphonylureas as an initial treatment for type 2 diabetes.
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