SGLT2 Inhibitors Beyond Glycemic Control: Emerging Therapeutic Applications, Clinical Evidence, Safety and Future Perspectives

Sodium-glucose cotransporter 2 (SGLT2) inhibitors were initially developed as antihyperglycemic agents for the treatment of type 2 diabetes mellitus. However, accumulating evidence from large randomized controlled trials has transformed their therapeutic position from glucose-lowering medicines into important cardiorenal-metabolic agents. Pharmacological inhibition of SGLT2 decreases renal glucose and sodium reabsorption, resulting in glucosuria, natriuresis and osmotic diuresis. These effects are accompanied by alterations in tubuloglomerular feedback, intraglomerular pressure, systemic hemodynamics, myocardial metabolism, inflammatory pathways, oxidative stress and renal energy metabolism. Major cardiovascular outcome trials demonstrated reductions in hospitalization for heart failure and favorable renal outcomes in individuals with type 2 diabetes. Dedicated heart-failure trials subsequently established benefits in patients with heart failure with reduced, mildly reduced and preserved ejection fraction, including individuals without diabetes. Similarly, CREDENCE, DAPA-CKD and EMPA-KIDNEY demonstrated clinically important kidney protection and slowing of chronic kidney disease progression. These findings have substantially broadened the role of SGLT2 inhibitors in contemporary pharmacotherapy. Emerging evidence is also evaluating their potential applications in metabolic dysfunction-associated steatotic liver disease, obesity-related metabolic disorders, hyperuricemia, anemia, polycystic ovary syndrome and other conditions; however, these applications remain less established than their cardiovascular and renal indications. Despite their favorable benefit-risk profile, SGLT2 inhibitors require appropriate patient selection and monitoring because genital mycotic infections, volume depletion, hypotension and rare euglycemic diabetic ketoacidosis may occur. This review summarizes the pharmacological basis, mechanisms, established cardiovascular and renal applications, emerging therapeutic uses, major clinical evidence, safety profile, drug interactions, patient-counselling considerations, limitations and future perspectives of SGLT2 inhibitors.