Recent Adv Inflamm Allergy Drug Discov. 2026 Jul 6. doi: 10.2174/0127722708450967260627052738. Online ahead of print.
ABSTRACT
Sodium-glucose cotransporter-2 (SGLT2) inhibitors have emerged as diseasemodifying agents in chronic kidney disease (CKD), demonstrating consistent renoprotective effects in both diabetic and non-diabetic patients. Large randomized outcome trials have shown substantial reductions in clinically significant renal endpoints. Canagliflozin reduced the risk of end-stage kidney disease, doubling of serum creatinine, or renal death by 34% (hazard ratio [HR] 0.66; 95% confidence interval [CI] 0.53-0.81) in the CREDENCE trial. Similarly, dapagliflozin reduced the risk of composite renal outcomes by 39% in DAPA-CKD (HR 0.61; 95% CI 0.51-0.72), with comparable benefits observed in non-diabetic CKD. These findings were further supported by the EMPA-KIDNEY trial, which demonstrated a 28% reduction in kidney disease progression or cardiovascular death with empagliflozin (HR 0.72; 95% CI 0.64- 0.82) across a broad range of baseline eGFR and albuminuria. Beyond their hemodynamic effects, including restoration of tubuloglomerular feedback and an early, reversible decline in eGFR, accumulating experimental and translational evidence indicates that SGLT2 inhibitors attenuate renal inflammation and fibrosis. These effects are mediated through metabolic reprogramming of proximal tubular cells, inhibition of NLRP3 inflammasome activation, improvement of mitochondrial function, and modulation of innate and adaptive immune responses. This review integrates clinical and mechanistic evidence to propose a hierarchical, time-dependent model in which early hemodynamic stabilization creates a permissive environment for sustained metabolic and immunomodulatory effects, ultimately preserving renal function over the long term. Limitations of the current evidence, including reliance on preclinical models and limited access to human kidney tissue, are also discussed.
PMID:42411217 | DOI:10.2174/0127722708450967260627052738