SGLT2 inhibitors, intrarenal hypoxia and the diabetic kidney: insights into pathophysiological concepts and current evidence

Abstract

Approximately 20–40% of all diabetic patients experience chronic kidney disease, which is related to higher mortality (cardiovascular and all-cause). A large body of evidence suggests that renal hypoxia is one of the main forces that drives diabetic kidney disease, both in its early and advanced stages. It promotes inflammation, generation of intrarenal collagen, capillary rarefaction and eventually accumulation of extracellular matrix that destroys normal renal architecture. SGLT2 inhibitors are unquestionably a practice-changing drug class and a valuable weapon for patients with type 2 diabetes and chronic kidney disease. They have achieved several beneficial kidney effects after targeting multiple and interrelated signaling pathways, including renal hypoxia, independent of their antihyperglycemic activities. This manuscript discusses the pathophysiological concepts that underly their possible effects on modulating renal hypoxia. It also comprehensively investigates both preclinical and clinical studies that explored the possible role of SGLT2 inhibitors in this setting, so as to achieve long-term renoprotective benefits.