Cardioprotection by SGLT2 Inhibitors-Does It All Come Down to Na⁺?

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are emerging as a new treatment strategy for heart failure with reduced ejection fraction (HFrEF) and-depending on the wistfully awaited results of two clinical trials (DELIVER and EMPEROR-Preserved)-may be the first drug class to improve cardiovascular outcomes in patients suffering from heart failure with preserved ejection fraction (HFpEF). Proposed mechanisms of action of this class of drugs are diverse and include metabolic and hemodynamic effects as well as effects on inflammation, neurohumoral activation, and intracellular ion homeostasis. In this review we focus on the growing body of evidence for SGLT2i-mediated effects on cardiac intracellular Na⁺ as an upstream mechanism. Therefore, we will first give a short overview of physiological cardiomyocyte Na⁺ handling and its deterioration in heart failure. On this basis we discuss the salutary effects of SGLT2i on Na⁺ homeostasis by influencing NHE1 activity, late I_Na as well as CaMKII activity. Finally, we highlight the potential relevance of these effects for systolic and diastolic dysfunction as well as arrhythmogenesis.