Pleiotropic effects of SGLT2 inhibitors beyond diabetes

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have transformed the therapeutic landscape of type 2 diabetes by promoting glycosuria through inhibition of renal glucose reabsorption. Beyond glycemic control, accumulating evidence supports a spectrum of extraglycemic effects, with the strongest clinical evidence for cardiorenal protection and less established evidence for neurocognitive and anticancer applications. In this review, we examine the canonical renal mechanism, compound-specific structural and pharmacological differences, and emerging non-canonical pathways that may operate partly independently of glucose lowering. Particular attention is given to ion handling, mitochondrial function, metabolic remodeling, and inflammatory signaling, while distinguishing experimentally proposed transporter-independent actions from clinically validated effects. Integrative transcriptomic, proteomic, and metabolomic studies are discussed as hypothesis-generating approaches that can prioritize pathways and biomarkers but do not by themselves establish direct binding or causal efficacy. We further consider current clinical guideline positioning, safety and tolerability, non-diabetic applications, and the limitations that constrain translation from preclinical findings. By synthesizing mechanistic, clinical, and systems-level evidence, this review provides a balanced framework for evaluating the expanding therapeutic utility of SGLT2 inhibitors.