GLP-1 Receptor Agonists and Kidney Protection.

Eulalia Greco,Annalisa Giandalia,Salvatore De Cosmo,Giuseppina Russo,Roberto Pontremoli,Francesca Viazzi

doi:10.3390/medicina55060233

Abstract

Type 2 diabetes mellitus (T2DM) is the leading cause of chronic kidney disease (CKD). Diabetic nephropathy (DN) is determined by specific pathological structural and functional alterations of the kidneys in patients with diabetes, and its clinical manifestations are albuminuria and decline of glomerular filtration rate (GFR). Apart from renin–angiotensin–aldosterone system (RAAS) inhibitors, no other drugs are currently available as therapy for diabetic kidney disease (DKD). Glucagon-like peptide-1 receptor (GLP-1R) agonists are a new class of anti-hyperglycemic drugs which have been demonstrated to prevent the onset of macroalbuminuria and reduce the decline of GFR in diabetic patients. These drugs may exert their beneficial actions on the kidneys through blood glucose- and blood pressure (BP)-lowering effects, reduction of insulin levels and weight loss. Clinical benefits of GLP-1R agonists were acknowledged due to data from large randomized phase III clinical trials conducted to assess their cardiovascular(CV) safety. These drugs improved renal biomarkers in placebo-controlled clinical studies, with effects supposed to be independent of the actions on glycemic control. In this review, we will focus on the actions of GLP-1R agonists on glucose metabolism and kidney physiology, and evaluate direct and indirect mechanisms through which these drugs may confer renal protection.

Highlights

Type 2 diabetes mellitus (T2DM) confers an increased risk of developing macrovascular and microvascular complications, which may result in disability for affected individuals as well as considerable costs for global health-care systems [1]
The analysis of secondary endpoints suggested that dulaglutide attenuates estimated glomerular filtration rate (eGFR) decline compared with insulin glargine in patients with T2DM and moderate-to-severe chronic kidney disease (CKD) after 52 weeks
As insulin plays a direct role in the development and progression of diabetic kidney disease (DKD), Glucagon-like peptide-1 receptor (GLP-1R) agonists may have beneficial effects for various organs including the kidneys, reducing insulin levels and improving insulin sensitivity

Summary

Introduction

Type 2 diabetes mellitus (T2DM) confers an increased risk of developing macrovascular and microvascular complications, which may result in disability for affected individuals as well as considerable costs for global health-care systems [1]. Emerging evidence suggests the potential protective actions on kidneys of GLP-1R agonists, independently of their glucose lowering effects, some of which may play a role in inhibition of development and progression of DKD [19]. GLP-1 and GLP-1R agonists have been demonstrated to reduce markers of renal RAAS activation, including angiotensin II levels and its deleterious effects in the glomerulus, which may represent other potential renoprotective mechanisms in DKD [24]. Renal improvement has been obtained without major changes in insulin secretion or glucose tolerance, supporting direct renal effects Together, these findings support the hypothesis that GLP-1R signaling may directly exert antioxidant and protective effects on the diabetic kidney. All these data for the basis for future clinical studies investigating whether GLP-1R agonists will improve renal outcomes in the setting of DKD

Evidence from Outcomes of Cardiovascular Safety Studies with GLP-1R Agonists

Results

Findings

Conclusions and Future Perspectives