SGLT2 Inhibitors Produce Cardiorenal Benefits by Promoting Adaptive Cellular Reprogramming to Induce a State of Fasting Mimicry: A Paradigm Shift in Understanding Their Mechanism of Action

There is compelling evidence that sodium–glucose cotransporter 2 (SGLT2) inhibitors exert cardioprotective and renoprotective effects that are far greater than expected based on their effects on glycemia or glycosuria. In large-scale randomized controlled trials, SGLT2 inhibitors reduce the risk of hospitalizations for heart failure by ∼30% and often decrease the risk of cardiovascular death (1). This benefit is particularly striking in patients who have the most marked impairment of systolic function prior to treatment. In parallel, SGLT2 inhibitors also reduce the risk of end-stage renal events, including the occurrence of renal death and the need for dialysis or renal transplantation by ∼30% (2). This benefit is seen even when glomerular filtration rates are sufficiently low to abolish the glycosuric effect of these drugs. These cardiorenal benefits cannot be explained by an action of SGLT2 inhibitors to lower blood glucose, since similar effects are not seen with antidiabetes drugs that have greater antihyperglycemic actions. Additionally, they cannot be ascribed to a natriuretic action, since these drugs exert only a modest effect on plasma volume or on circulating natriuretic peptides (3). In 2016, two articles published in Diabetes Care proposed the “thrifty fuel hypothesis” to explain the cardiorenal benefits of SGLT2 inhibitors. Ferrannini et al. (4) and Mudaliar et al. (5) postulated that the action of SGLT2 inhibitors to promote ketogenesis might account for their favorable effects on the heart and kidney because enhanced ketone bodies formation might possibly provide an efficient fuel that could boost the energy state of organs under stress. However, type 2 diabetes represents a state of nutrient overabundance and not energy deprivation, as is evidenced by the enhancement of molecular pathways that promote both energy retention (e.g., through SGLT2 upregulation) and energy storage (6,7). In fact, the stressed heart already preferentially utilizes ketone bodies, …