Beyond Glycemic Control: Multi-pathway Cardioprotective Mechanisms of Selective Na+/glucose Co-transporter 2 Inhibitors with Emerging Implications for Atrial Fibrillation

INTRODUCTION: Atrial fibrillation (AF) is the most common form of cardiac arrhythmia and is associated with electrocardiographic changes resulting from several complex mechanisms. While management of AF relies mainly on ion channel blockers and beta blockers for cardioversion and control of ventricular rate, many patients remain symptomatic despite the use of optimal therapy, highlighting the need for new upstream drug therapies to further improve management. METHODS: In this narrative review, we summarize and discuss key findings related to the use of selective sodium-glucose co-transporter 2 inhibitors (SGLT2i) in heart failure (HF) and their potential role in AF and the mechanisms underlying their beneficial effects. Recent landmark trials and relevant mechanistic studies were reviewed. RESULTS: Recent growing evidence suggests a cardioprotective role for SGLT2i, especially in patients with diabetes and HF with reduced (HFrEF) or preserved ejection fraction (HFpEF). At the molecular level, SGLT2i attenuate cardiac inflammation, oxidative stress, and fibrosis. In HFrEF and HFpEF patients, SGLT2i reduce the risk of HF hospitalization and cardiovascular (CV) mortality. DISCUSSION: SGLT2i may provide potential anti-arrhythmic benefits in both ventricular and atrial arrhythmias. However, it remains unclear whether these potential effects on AF and other types of arrhythmias are secondary to improved HF outcomes or result from direct effects on the myocardium. In patients with cardiac arrhythmia, SGLT2i may favorably influence cardiac structural/ electrical remodeling, oxidative stress, inflammation, and metabolic pathways. CONCLUSION: Therapeutic approaches aiming at reducing AF burden using SGLT2i may be beneficial, potentially extending beyond patients with HF or diabetes.