SGLT2 inhibitors: Do they have antiarrhythmic properties?

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) represent the cornerstone of therapy in patients with type 2 diabetes (T2D), heart failure (HF), or chronic kidney disease (CKD). These patients present a high risk of cardiac arrhythmias, particularly when these comorbidities coexist. In experimental models, SGLT2i exert antiarrhythmic effects and clinical studies and meta-analyses strongly suggest that they reduce new-onset and recurrences of atrial fibrillation in patients with HF or CKD irrespective of the diabetic status. Although some trials and meta-analyses suggest that SGLT2i could decrease the risk of ventricular arrhythmias and sudden cardiac arrest, the evidence is weak, and their potential remains to be confirmed. Thus, clinical evidence so far should be considered as hypothesis-generating. Although the exact mechanism underlying their antiarrhythmic effects remains uncertain and much research is needed, multiple direct cardiac and extracardiac effects may be involved. They improve cardiac electrical (via changes in ion channels and transporters; maintenance of Na+ and Ca2+ homeostasis), structural (reduce hypertrophy, fibrosis, inflammation, and epicardial fat; improve mitochondrial function and energetic metabolism), and autonomic (reduce sympathetic hyperactivity) remodelling. Indirect extracardiac effects related to an improvement in cardiovascular risk factors and haemodynamics, together with their protective renal and vascular effects, may also play a role. This narrative review summarises the experimental and clinical evidence of their antiarrhythmic effects, potential underlying mechanisms, limitations of present evidence, and gaps of knowledge that should be filled before SGLT2i can be recommended for the prevention and treatment of arrhythmias in patients for whom these drugs are indicated.