Antiarrhythmic potential of SGLT2 inhibitors: Mechanistic insights and clinical evidence

Sodium-glucose cotransporter 2 (SGLT2) inhibitors were originally developed to treat type 2 diabetes by promoting glycosuria through inhibition of renal glucose reabsorption. However, their clinical utility has expanded rapidly following the demonstration of consistent cardiovascular and renal benefits in large-scale randomized controlled trials. These trials have shown that SGLT2 inhibitors significantly reduce adverse cardiovascular outcomes-including sudden cardiac death-in patients with diabetes, heart failure, or chronic kidney disease, irrespective of glycemic control. As clinical experience has accumulated, several unanticipated hypotheses have emerged-one of which is that SGLT2 inhibitors may exert antiarrhythmic effects. This review summarizes the current evidence for antiarrhythmic effects of SGLT2 inhibitors, from both mechanistic and clinical perspectives. Experimental studies suggest that these agents modulate arrhythmogenic substrates via multiple pathways: inhibition of sodium-hydrogen exchanger 1, suppression of the late sodium current, modulation of potassium currents, attenuation of sympathetic tone, hemodynamic improvement, and enhanced myocardial energy efficiency through increased ketone body utilization. These cellular and systemic changes may attenuate arrhythmogenic remodeling and reduce the risk of both atrial and ventricular arrhythmias. Clinically, post-hoc analyses and meta-analyses of major SGLT2 inhibitor trials have reported reductions in the incidence of atrial fibrillation/flutter and ventricular arrhythmias, although findings have been somewhat heterogeneous. A small number of prospective studies using implantable cardioverter defibrillators have also provided high-resolution evidence supporting this effect. While definitive large-scale trials with arrhythmia-specific endpoints are still lacking, the potential antiarrhythmic benefits of SGLT2 inhibitors represent a promising area for further research and may help explain their ability to reduce sudden cardiac death across a range of cardiovascular conditions.