Pleiotropic effects of sodium-glucose cotransporter 2 inhibitors (gliflozins) beyond diabetes mellitus: Evolution of views on cardioand nephroprotection

Sodium-glucose cotransporter 2 (SGL T2) inhibitors were developed for type 2 diabetes mellitus but now have an established role in heart failure and chronic kidney disease, including in patients without diabetes. This narrative review critically integrates outcome trials, human mechanistic studies, proteom-ics, and contemporary guidelines. Dapagliflozin and empagliflozin improve trial-specific composite out-comes across a broad range of left ventricular ejection fractions and kidney function. These clinical benefits are more firmly established than the contribution of individual molecular pathways. Renal hemodynamic effects and stimulation of erythropoiesis have human experimental support, whereas direct myocardial sodi-um-hydrogen exchanger inhibition and metabolic re-programming remain incompletely resolved. EMPER-OR proteomic studies provide translational support for coordinated changes in autophagy, iron handling, and cellular stress responses, without establishing causal mediation. Sotagliflozin is considered separately be-cause it inhibits both SGLT1 and SGLT2; its pivotal trials enrolled patients with type 2 diabetes and do not directly establish efficacy in people without diabe-tes. We propose an evidence-to-indication framework that distinguishes demonstrated clinical efficacy, sup-portive human biology, and exploratory mechanisms. This synthesis positions gliflozins as complementary components of cardiovascular and kidney care, rather than as uniquely pleiotropic drugs or interchangeable agents for every indication. The 2026 European So-ciety of Cardiology guidelines and the 2024 KDIGO guideline are integrated with the original trial popu-lations. Limitations include selective literature cover-age, heterogeneous endpoints, and incomplete mech-anistic validation. Treatment selection should follow the patient's disease phenotype and the evidence for the individual agent.