SGLT2 inhibitors: role in protective reprogramming of cardiac nutrient transport and metabolism

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce heart failure events by direct action on the failing heart that is independent of changes in renal tubular function. In the failing heart, nutrient transport into cardiomyocytes is increased. However, nutrient utilization is impaired, leading to deficient ATP production and the cytosolic accumulation of deleterious glucose and lipid by-products. These by-products trigger the downregulation of cytoprotective nutrient-deprivation pathways, promoting cellular stress and undermining cellular survival. SGLT2 inhibitors restore cellular homeostasis through three complementary mechanisms: they might bind directly to nutrient-deprivation and nutrient-surplus sensors to promote their cytoprotective actions; they can increase the synthesis of ATP by promoting mitochondrial health and potentially alleviate the cytosolic deficiency in ferrous iron; and they might directly inhibit glucose transporter type 1, thereby diminishing the cytosolic accumulation of toxic metabolic by-products and promoting the oxidation of long-chain fatty acids. This review describes the orchestrated interplay between nutrient transport and metabolism and nutrient deprivation and nutrient-surplus signaling to explain how SGLT2 inhibitors reverse the profound nutrient, metabolic, and cellular abnormalities observed in heart failure, thereby restoring the myocardium to a healthy molecular and cellular phenotype.