SGLT2 Inhibitors and the Risk of Arrhythmias in Heart Failure: A Network Meta-Analysis

Background/Objectives: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have revolutionized heart failure (HF) therapies and are an essential component of guideline-directed medical therapy (GDMT); however, their significance in arrhythmia prevention is still uncertain. This meta-analysis evaluates the benefits of SGLT2i on arrhythmias in HF. Methods: A comprehensive examination was performed with PubMed, ScienceDirect, PLOS One, Cochrane, Google Scholar, and ClinicalTrials.gov from January 2014 to March 2025, complying with PRISMA guidelines. Randomized controlled trials (RCTs) comparing SGLT2i with placebo were incorporated. Primary results included ventricular arrhythmias (VA), sudden cardiac death (SCD), atrial arrhythmias, and conduction disorders. Subgroup analyses investigated the effects on arrhythmias in HF with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). Results: A total of 11 RCTs involving 23,701 patients, 11,848 on SGLT2i (mean age: 68.26 ± 10 yrs, 53.5% males) and 11,853 on placebo (mean age: 67.91 ± 10 yrs, 53% males), were analyzed with a mean follow-up of 2.71 yrs. No significant differences were reported between SGLT2i and placebo for VA [relative risk (RR): 1.02, 95% confidence interval (CI): 0.83–1.25], I2 =0%), atrial arrhythmias (RR: 0.92 [CI: 0.67–1.27], I2 = 65.3%), or conduction disorders (RR:1.22 [CI: 0.86–1.73], I2 = 10.4%). Notably, significant reductions in risk of SCD (RR: 0.68 [CI: 0.49–0.93], I2 = 0%) and in the risk of atrial arrhythmias in HFrEF (RR: 0.66 [CI: 0.49–0.89], I2 = 10.3%) were witnessed, although no such reduction was seen in HFpEF (RR: 1.14 [CI: 0.94–1.40], I2 = 33.8%). Conclusions: SGLT2i do not reduce overall arrhythmia or conduction disorder risk in HF but significantly reduce the risk of SCD and atrial arrhythmias in HFrEF patients. These results highlight potential arrhythmia prevention benefits in HFrEF, warranting further targeted studies.