SGLT2 inhibitors and exercise in diabetic kidney disease: mechanistic rationale, emerging clinical evidence, and future perspectives

Diabetic kidney disease (DKD) is a major complication of diabetes and a leading cause of chronic kidney disease and kidney failure worldwide. Despite substantial advances in pharmacological therapy, residual risks of renal and cardiovascular disease remain considerable, underscoring the need for complementary therapeutic strategies. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as cornerstone therapies for DKD because of their glucose-independent renoprotective and cardioprotective effects. Exercise, meanwhile, provides broad metabolic, cardiovascular, anti-inflammatory, and antioxidant benefits and is recommended as an integral component of diabetes and chronic kidney disease management. Increasing evidence suggests that these two interventions may exert complementary effects on several interconnected pathways involved in DKD progression, including glomerular hyperfiltration, metabolic dysregulation, oxidative stress, inflammation, mitochondrial dysfunction, and renal fibrosis. This review summarizes the pathophysiological mechanisms underlying DKD and examines the mechanistic rationale for integrating SGLT2 inhibitors with exercise. We further discuss emerging experimental and clinical evidence regarding their potential effects on renal function, metabolic control, cardiovascular health, and exercise capacity, together with important safety considerations and challenges in individualized exercise prescription. Although available evidence provides a biologically plausible basis for potentially additive interactions between these interventions, direct clinical evidence supporting the superiority of combined therapy over either intervention alone remains limited. We therefore highlight key knowledge gaps, including the lack of adequately powered randomized controlled trials, standardized exercise protocols, and validated biomarkers for monitoring treatment response. Future studies should establish the efficacy, safety, and optimal implementation of combined SGLT2 inhibitor and exercise strategies across different stages and phenotypes of DKD, thereby facilitating their translation into individualized cardiorenal care.