Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitors in Atrial Fibrillation: Clinical Implications, Mechanisms, and Therapeutic Potential.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia worldwide and contributes substantially to morbidity, mortality, and healthcare burden, particularly among patients with diabetes and heart failure (HF). Emerging evidence suggests that sodium-glucose cotransporter-2 (SGLT-2) inhibitors, initially developed as glucose-lowering agents, confer cardiovascular (CV) benefits that extend beyond glycaemic control. Recent clinical and experimental data indicate that these agents may reduce the incidence and burden of AF through multifactorial mechanisms involving hemodynamic, metabolic, and electrophysiological modulation. SGLT-2 inhibition improves myocardial energetics, enhances diastolic relaxation, and attenuates oxidative stress, inflammation, and atrial fibrosis - key determinants of atrial structural and electrical remodeling. In addition, these agents influence ionic homeostasis by modulating sodium and calcium handling, thereby stabilizing atrial conduction and preventing arrhythmogenic substrate formation. Observational analyses and post-hoc evaluations of major CV outcome trials, including DECLARE-TIMI and DAPA-HF, consistently show lower AF event rates among patients receiving SGLT-2 inhibitors. Preclinical models corroborate these findings, demonstrating reduced atrial remodeling and fibrosis independent of glycaemic status. Although current data are largely indirect and derived from secondary analyses, they collectively suggest that SGLT-2 inhibitors exert atrial-specific protective effects. Compared with traditional antiarrhythmic therapies, SGLT-2 inhibitors offer a complementary strategy that targets upstream metabolic and structural mechanisms rather than direct electrophysiological blockade. Ongoing studies aim to clarify their role in rhythm control, interaction with β-blockers, and efficacy in patients with pre-existing AF. While the safety profile remains favourable across age and comorbidity spectra, mechanistic uncertainties and the absence of dedicated randomized trials warrant further investigation. Understanding how SGLT-2 inhibition influences atrial remodeling could unveil a novel therapeutic avenue for the prevention and management of AF in both diabetic and non-diabetic populations.