Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors in Non-diabetic Conditions Beyond Heart Failure and Chronic Kidney Disease: Emerging Evidence, Mechanisms, and Practical Considerations

Sodium-glucose cotransporter 2 (SGLT2) inhibitors were developed as glucose-lowering agents, yet their clinical impact has expanded well beyond glycemic control. Although their benefits in heart failure and chronic kidney disease are now well established, a growing body of mechanistic and clinical evidence suggests broader utility in non-diabetic conditions such as nonalcoholic fatty liver disease (NAFLD), obesity and visceral adiposity, hypertension, hyperuricemia/gout, atrial fibrillation risk modulation, and select disorders of water balance (e.g., syndrome of inappropriate antidiuresis). These effects appear to arise from convergent pathways including natriuresis and osmotic diuresis, improved tubuloglomerular signaling, hemodynamic unloading, reductions in visceral fat and inflammation, alterations in urate handling, and shifts in substrate utilization with potential mitochondrial and endothelial benefits. This narrative review synthesizes emerging evidence for SGLT2 inhibitors in non-diabetic indications beyond heart failure and chronic kidney disease, with emphasis on biologic rationale, outcomes data, patient selection, safety in normoglycemic populations, and future research priorities.