Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are new antidiabetic drugs that were originally developed for the management of type 2 diabetes mellitus. SGLT2is exert glucosuric effects, leading to increased glucagon synthesis, enhanced fatty acid oxidation, and promoted adipose tissue mobilization, which modestly increase systemic ketone levels. For energy production under normal conditions, the healthy adult heart relies minimally on glucose but strongly on fatty acid oxidation, which contributes to between 60% and 90% of the cardiac adenosine triphosphate yield. Ketones play a minor role in adenosine triphosphate production under normal conditions. Notably, trends toward heart failure and cardiac hypertrophy can decelerate glucose metabolism, prompting a shift to ketones as alternative fuels. This transition is crucial for meeting the energy demands of cardiac cells. Furthermore, both exogenous and endogenous ketones confer protection against kidney damage and disease. Consequently, ketones are regarded as evolutionarily conserved fuels for cellular metabolism, designed to supply energy during periods of nutritional stress. In addition, ketones may improve myocardial and renal functions. The ketone β-hydroxybutyrate exerts intrinsic anti-inflammatory, antioxidative, and antifibrotic effects and can mitigate adverse left ventricular and renal remodeling or fibrosis. The cardiorenal benefits of SGLT2is are partially attributed to the occurrence of chronic low-grade hyperketonemia and a shift in myocardial and renal fuel metabolisms from relatively energy-inefficient fatty acid oxidation to energy-efficient ketone metabolism. However, SGLT2i-induced excessive ketogenesis is detrimental to certain patients, such as those with type 2 diabetes mellitus and severe acute illness and those with type 1 diabetes mellitus with substantial insulin dose reductions. This narrative review summarizes currently available evidence to provide potential mechanisms underlying the SGLT2i-induced positive and negative effects of ketones on the cardiorenal system.
