Do effects of sodium-glucose cotransporter-2 inhibitors in patients with diabetes give insight into potential use in non-diabetic kidney disease?

Abstract

Our aim was to review the rationale for the role of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) as renoprotective therapy in patients with and without diabetes. SGLT-2i are antihyperglycemic agents, approved for treating type 2 diabetes to reduce glycosylated hemoglobin, type A1c. Primary glucoregulatory effects occur through selective inhibition of SGLT-2 at the renal proximal tubule promoting glucosuria leading to blood glucose lowering. From a hemodynamic perspective, SGLT-2 inhibition is also associated with decreased glomerular hyperfiltration, an effect that is mediated through natriuresis and tubuloglomerular feedback. With renal injury and progressive nephron loss, diabetic kidney disease, and nondiabetic chronic kidney diseases share overlapping phenotypes exhibiting single nephron hyperfiltration, along with increased proteinuria. Importantly, the impact of SGLT-2 inhibition on renal and systemic hemodynamic function, including effects on lowering blood pressure, hyperfiltration, and plasma volume, are independent of blood glucose lowering and instead are because of natriuresis. Accordingly, large clinical trials with SGLT-2i investigating the potential use of SGLT-2i in patients without diabetes are now underway. Based on prominent nonglycemic effects, the clinical use of SGLT-2i as renoprotective therapy may extend to nondiabetic chronic kidney diseases subtypes, which could help to address a large, unmet clinical need.