Impact of Sodium-Glucose Cotransporter-2 Inhibitors on Cardiac Bioenergetic Properties and Cardiorespiratory Fitness: A Special Effect of SGLT2i In Heart Failure?

Recent clinical trials have highlighted the profound benefits of sodium-glucose linked transporter 2 inhibitors (SGLT2i) on cardiovascular mortality and hospitalization for heart failure patients. Modest improvements in glycemic, lipid, or blood pressure control are unlikely to contribute to these significant beneficial outcomes, generating much interest in the relevant mechanisms leading to outcome improvements. In this review, we discuss the current evidence supporting a shift in myocardial substrate utilization from carbohydrates and fat oxidation toward energy efficient ketone bodies in the failing heart and the role of SGLT2i in this key metabolic adaptation to optimize myocardial fuel energetics. Further insights into the effect of SGLT2i on the indices of cardiorespiratory fitness are outlined and provide important clues into their mechanism of benefit. This mechanistic discussion in the context of recent trials of SGLT2i denotes a promising treatment paradigm of heart failure in individuals with and without diabetes.