Cardiac Electrophysiological Impact of Sodium Glucose Cotransporter 2 Inhibitors: A Comprehensive Review

SGLT2i (sodium-glucose cotransporter 2 inhibitors) reduce heart failure hospitalizations, cardiovascular death, and certain arrhythmic events beyond glycemic control. However, their specific effects on cardiac autonomic function and arrhythmogenesis, as well as the potential involvement of microRNAs in mediating these benefits, remain incompletely understood. This review synthesizes clinical and preclinical evidence on the impact of SGLT2i on cardiac autonomic regulation and arrhythmias, emphasizing the interplay between SGLT2i, microRNA expression, and cardiovascular risk. We conducted a comprehensive literature search for clinical trials, meta-analyses, observational studies, and preclinical investigations. Outcomes included heart rate variability, heart rate turbulence, atrial/ventricular arrhythmias, and sudden cardiac death. Studies examining microRNA profiles associated with SGLT2i treatment and their links to cardiac fibrosis, inflammation, and arrhythmogenic substrates were analyzed in depth. Clinical evidence indicates that SGLT2i improve cardiac autonomic balance by reducing sympathetic overactivity and enhancing parasympathetic tone in patients with type 2 diabetes and cardiac autonomic neuropathy. Meta-analyses and post hoc data from cardiovascular outcome trials suggest a modest but consistent reduction in atrial fibrillation/flutter and, in some cohorts, sudden cardiac death, potentially reflecting sympathoinhibition, improved hemodynamics, and modulation of myocardial ion homeostasis. Preclinical studies support anti-arrhythmic properties through sodium-hydrogen exchanger inhibition, late sodium current suppression, and metabolic shift towards ketone utilization. SGLT2i modulate several key microRNAs implicated in heart failure and arrhythmic risk, including miR-21, miR-29, miR-30, miR-34a, and miR-92, which may partly underlie the attenuation of arrhythmogenic substrates and improved autonomic regulation. SGLT2i favorably affect cardiac autonomic function and reduce the burden of certain arrhythmias, potentially through modulation of disease-associated microRNAs. Integrating clinical autonomic outcomes with microRNA profiling provides mechanistic insights into their cardioprotective actions. Dedicated trials are warranted to clarify causality, dose-dependency, and the therapeutic potential of microRNA-SGLT2i interactions for arrhythmia prevention and management in high-risk populations.