Association of SGLT2 Inhibitors with Arrhythmias and Sudden Cardiac Death in Patients with Type 2 Diabetes or Heart Failure: A Meta-Analysis of 34 Randomized Controlled Trials.

Abstract Background Sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce hospitalizations and death from heart failure (HF), but their effect on arrhythmia expression has been poorly investigated. Objective To evaluate the association of SGLT2i with arrhythmias in patients with type 2 diabetes mellitus (T2DM) or HF. Methods We searched Pubmed and ClinicalTrials.gov. Two independent investigators identified randomized, double-blind trials that compared SGLT2i with placebo or active control for adults with T2DM or HF. Primary outcomes were incident atrial arrhythmias, ventricular arrhythmias (VA) and sudden cardiac death (SCD). Results We included 34 randomized (25 placebo-controlled and 9 active-controlled) trials with 63,166 patients (35,883 SGLT2i vs 27,273 control – mean age 53-67 years, 63% male). Medications included canagliflozin, dapagliflozin, empagliflozin or ertugliflozin. Except for one study on HF, all patients had T2DM. Follow-up ranged from 24 weeks to 5.7 years. The cumulative incidence of events was low – 3.6, 1.4 and 2.5 per 1,000 patient-years for atrial arrhythmias, VA and SCD, respectively. SGLT2i therapy was associated with a significant reduction in risk of incident atrial arrhythmias (OR, 0.81, 95% CI 0.69-0.95; P=0.008) and the “SCD” component of the SCD outcome (OR, 0.72, 95% CI 0.54-0.97; P=0.03) compared with control. There was no significant difference in incident VA or the “cardiac arrest” SCD component between groups. Conclusions SGLT2i are associated with significantly reduced risks of incident atrial arrhythmias and SCD in patients with T2DM. Prospective trials are warranted to confirm the antiarrhythmic effect of SGLT2i and whether this is a class or drug-specific effect.