Abstract

Diabetic kidney disease remained a leading cause of end stage renal disease globally, affecting approximately 40% of 
individuals with diabetes mellitus. Sodium glucose cotransporter 2 inhibitors represented a novel therapeutic class 
originally developed for glycemic control but have demonstrated profound renoprotective effects independent of 
glucose-lowering mechanisms. This review examined the biochemical mechanisms underlying the renoprotective 
effects of sodium glucose cotransporter 2 inhibitors, evaluated the clinical evidence supporting their use in diabetic 
kidney disease prevention, and synthesized current guideline recommendations for their implementation in clinical 
practice. A comprehensive synthesis of mechanistic studies, randomized controlled trials, meta-analyses, and 
international clinical practice guidelines published through early 2025 was conducted to evaluate sodium glucose 
cotransporter 2 inhibitor efficacy and safety in diabetic kidney disease. Sodium glucose cotransporter 2 inhibitors 
exerted renoprotection through multiple interconnected mechanisms, including restoration of tubuloglomerular 
feedback, reduction of intraglomerular pressure, attenuation of oxidative stress and inflammation, and modulation 
of renal energy metabolism. Recent evidence extended these benefits to patients with chronic kidney disease 
irrespective of diabetes status. Current guidelines recommend sodium glucose cotransporter 2 inhibitors as 
foundational therapy alongside renin angiotensin system blockade for patients with diabetic kidney disease and 
preserved ejection fraction. Sodium glucose cotransporter 2 inhibitors represented a paradigm shift in diabetic 
kidney disease management, offering robust renoprotection through pleiotropic mechanisms with an acceptable 
safety profile, though implementation barriers and knowledge gaps regarding optimal patient selection persist.