Sodium-glucose cotransporter 2 inhibitors in diabetic kidney disease.

Diabetic kidney disease (DKD) is a major contributor to chronic kidney disease (CKD) and end-stage kidney disease worldwide, and is strongly associated with increased cardiovascular morbidity and mortality. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, initially developed for glycemic control, are now established as key therapies for DKD patients. Large, randomized clinical trials, including CREDENCE, DAPA-CKD, and EMPA-KIDNEY, have consistently shown that SGLT2 inhibitors reduce the risk of kidney disease progression, cardiovascular events, and hospitalization for heart failure in patients with and without diabetes. These benefits extend beyond lowering glucose and are attributed to multiple complementary mechanisms, including restoration of tubuloglomerular feedback, reduction of intraglomerular pressure, natriuresis, and pleiotropic effects, such as improved metabolic efficiency, attenuation of inflammation and fibrosis, and enhanced renal oxygenation. The management of DKD is increasingly shifting toward a combination-based strategy targeting diverse pathogenic pathways. Emerging data suggest that combining SGLT2 inhibitors with other cardiorenal protective agents, such as renin-angiotensin system inhibitors, non-steroidal mineralocorticoid receptor antagonists, and glucagon-like peptide 1 receptor agonists, may provide additional benefits. Recent guidelines emphasize the use of SGLT2 inhibitors primarily for cardiorenal protection independent of glycemic control. Despite these advances, important gaps remain in underrepresented populations, including the elderly, non-albuminuric DKD, advanced CKD, kidney transplant recipients, and patients with type 1 diabetes. This review provides an overview of the key mechanisms and clinical evidence supporting the use of SGLT2 inhibitors in DKD, along with emerging insights into combination strategies and their clinical implications.