SGLT2 inhibitors and chronic kidney disease: a narrative review of nephroprotective mechanisms from hemodynamics to metabolism

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, originally designed for the treatment of type 2 diabetes, have become a critical preventive therapy for chronic kidney disease (CKD). Moreover, they exhibit substantial reductions in the risk of kidney function deterioration, progression to end-stage kidney disease, and cardiovascular mortality in a diverse patient population. This review synthesizes current evidence to clarify the complex mechanisms underlying nephroprotection, which extend beyond modest effects on glycemia and blood pressure control. The review outlines four interrelated pathways of action. SGLT2 inhibitors enhance renal hemodynamics through the activation of tubuloglomerular feedback, resulting in decreased intraglomerular hypertension. Secondly, they promote a condition of "starvation mimicry," which reconfigures cellular metabolism to alleviate glucotoxicity, increase ketogenesis, and diminish oxidative stress, with the ketone body β-hydroxybutyrate serving as both an effective energy source and an anti-inflammatory signal. Third, they demonstrate direct anti-inflammatory and anti-fibrotic effects by reducing proximal tubular workload and hypoxia, inhibiting the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome family pyrin domain-containing 3 inflammasome, and diminishing transforming growth factor-beta signaling, preventing further kidney injury and fibrosis. Putative off-target effects, such as stimulation of erythropoiesis and enhancement of local and systemic vascular endothelial function, additionally contribute to renal protection. The convergence of these pathways on the core drivers of CKD progression underpins their efficacy across diverse etiologies. This physiological rationale reinforces their significance as a fundamental component of contemporary nephroprotective strategies, operating in conjunction with renin-angiotensin-aldosterone system blockade to decelerate the advancement of CKD.