Nephroprotective Mechanisms of SGLT2i: Beyond the Glucose-Lowering Effect

Chronic kidney disease (CKD) is a fast-growing cause of death worldwide. Systemic hypertension and diabetes mellitus are the major causes of kidney damage leading to a reduction in glomerular filtration rate and to urinary protein loss. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are drugs able to address both of these deleterious effects, preventing kidney damage from progressing. Initially born as hypoglycemic agents, SGLT2is subsequently proved to have not only positive metabolic but also pleiotropic effects on the kidney and the cardiovascular system. Indeed, they improve the metabolic profile, reducing uric acid, blood sugar levels, and body weight. Moreover, they exert an anti-inflammatory and antifibrotic effect, reducing endothelial dysfunction and reactive oxygen species (ROS) production. Finally, they reduce renal hyperfiltration and control blood pressure, inducing osmotic diuresis and restoring tubulo-glomerular feedback. All these metabolic, anti-inflammatory, and hemodynamic effects contribute to significantly reducing the risk of cardiorenal events, as widely demonstrated in randomized clinical trials. The pleiotropic actions of SGLT2is together with their good tolerability make them a pillar treatment of CKD regardless of the presence of diabetes mellitus. Further studies will be needed in order to expand the indications to populations previously excluded from clinical trials such as transplant recipients or glomerulonephritis patients. This narrative review aims to summarize current knowledge regarding the nephroprotective mechanisms of SGLT2is which, after initial use as a hypoglycemic agent, have assumed a pivotal role in the actual and future management of patients with CKD.