Impact of empagliflozin and dapagliflozin on sudden cardiac death: A systematic review and meta-analysis of adjudicated randomized evidence

Background Sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce cardiovascular outcomes in the spectrum of cardio-renal-metabolic syndrome. Albeit basic and translational evidence support a putative anti-arrhythmic role, at the clinical level, a lack of consensus has emerged across different studies, and the true impact on sudden cardiac death (SCD) risk remains unclear. Objective The study aimed to assess the effect of empagliflozin and dapagliflozin on SCD in patients with type 2 diabetes, heart failure, or chronic kidney disease. Methods A systematic review and meta-analysis were conducted on randomized controlled trials. A total of 58,569 participants from 8 trials were included, with 30,565 patients treated with SGLT2 inhibitors and 28,104 controls assigned to placebo. The median follow-up period was 29 months. We performed pooled analysis, meta-regression, and subgroup analyses to explore the impact on SCD risk across different populations and treatment regimens. Results The pooled analysis showed a reduced risk of SCD with SGLT2 inhibitors (odds ratio: 0.82; 95% confidence interval: 0.72-0.94; P =.0104), with negligible heterogeneity (τ2 = 0.0000; I2 = 0.0%; Q = 3.17, P =.8687). Subgroup-specific estimates (age, follow-up duration, population, and SGLT2 inhibitor type) did not reach statistical significance. Meta-regression showed no significant moderation by mean age, study duration, or gender. No evidence of publication bias was detected. Conclusion Empagliflozin and dapagliflozin may reduce the relative risk of SCD. These data expand the spectrum of cardiovascular benefits attributed to SGLT2 inhibition. Further trials specifically designed to address pre-adjudicated arrhythmic end points are warranted.