Renal Effects of SGLT2 Inhibitors: An Update

Josselin Nespoux; Volker Vallon

Disclosures

Curr Opin Nephrol Hypertens. 2020;29(2):190-198. 

In This Article

Abstract and Introduction

Abstract

Purpose of review: 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.

Recent findings: 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.

Summary: Renoprotection of SGLT2 inhibition involves blood glucose-dependent and independent effects and extends to CKD.

Introduction

Type 2 diabetes mellitus (T2DM) is a growing public health concern worldwide with increasing prevalence and high mortality rate. Normalizing blood glucose levels early on is important to lower the risk of macrovascular and microvascular complications, including diabetic nephropathy and cardiovascular disease and mortality.[1] Inhibitors of the sodium-glucose cotransporter 2 (SGLT2) are a new class of antihyperglycemic drugs recently approved in T2DM, which inhibit renal glucose reabsorption in the early proximal tubule, thereby enhancing urinary glucose excretion and lowering blood glucose levels. SGLT2 inhibitors act on their target from the extracellular surface of the brush border cell membrane,[2] which they reach by glomerular filtration. and as recently indicated for empagliflozin, also by tubular secretion.[3] The use of SGLT2 inhibitors is associated with pleiotropic beneficial effects on the renal and cardiovascular system,[4,5] and these drugs reduce the risk of renal and heart failure as demonstrated in multiple large clinical outcome trials in patients with T2DM and preserved kidney function.[6] This review aims to provide a brief update on the most recent clinical and experimental studies that shed new light on the therapeutic potential of SGLT2 inhibitors and the involved renoprotective mechanisms.

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