Sodium-Glucose Cotransporter 2 Inhibition: Rationale and Mechanisms for Kidney and Cardiovascular Protection in People With and Without Diabetes

Large-scale randomized trials have demonstrated the remarkable capacity of sodium-glucose cotransporter 2 inhibitors to reduce the risk of cardiovascular outcomes and kidney disease progression, irrespective of the presence or absence of type 2 diabetes mellitus. Although the results of these trials have transformed clinical practice guidelines, the mechanisms underpinning the wide-ranging benefits of this class of agents remain incompletely understood and subject to ongoing investigation. Improvements in cardiometabolic risk factors such as glucose, blood pressure, body weight, and albuminuria likely contribute. However, other direct effects on physiological and cellular function, such as restoration of tubuloglomerular feedback, improvements in kidney and cardiac oxygenation and energy efficiency, as well as restoration of normal autophagy are also likely to be important. This review summarizes the rationale and potential mechanisms for cardiorenal protection with sodium-glucose cotransporter 2 inhibitors in people with and without diabetes, their relative importance, and the experimental and clinical lines of evidence supporting these hypotheses.