Renal effects of SGLT2 inhibitors: an update.

Abstract

SGLT2 inhibitors are a new class of antihyperglycemic drugs that protect kidneys and hearts of type 2 diabetic (T2DM) patients with preserved kidney function from failing. Here we discuss new insights on renal protection. Also in T2DM patients with CKD, SGLT2 inhibition causes an immediate functional reduction in glomerular filtration rate (GFR) and reduces blood pressure and preserves kidney and heart function in the long-term, despite a lesser antihyperglycemic effect. According to modeling studies, the GFR reduction reduces the tubular transport work and metabolic demand, thereby improving renal cortical oxygenation. In humans, the latter is linked to protection from CKD. Urine metabolomics in T2DM patients suggested improved renal mitochondrial function in response to SGLT2 inhibition, and experimental studies indicated improved tubular autophagy. Modeling studies predicted that also in diabetic CKD, SGLT2 inhibition is natriuretic and potentially stimulates erythropoiesis by mimicking systemic hypoxia in the kidney. Meta-analyses indicated that SGLT2 inhibition also reduces risk and severity of acute kidney injury in T2DM patients. Studies in nondiabetic mice implied inhibition of the renal urate transporter URAT1 in the uricosuric effect of SGLT2 inhibition. Renoprotection of SGLT2 inhibition involves blood glucose-dependent and independent effects and extends to CKD.