Abstract

Glucagon-like peptide-1 Receptor Agonists (GLP-1 RAs) have emerged as a cornerstone in the management of type 2 diabetes mellitus, with expanding roles in cardiovascular and renal protection. Beyond glycemic control, these agents exert pleiotropic effects that influence renal hemodynamics, tubular function, inflammation, oxidative stress, and metabolic signaling pathways. GLP-1 receptors are expressed in renal tubular and vascular tissues, particularly in proximal tubular cells, suggesting direct renal actions. GLP-1 RAs promote natriuresis and diuresis through inhibition of the Sodium-Hydrogen Exchanger 3 (NHE3), improve endothelial function, and reduce intraglomerular pressure. Additionally, they modulate mitochondrial function, lipid metabolism, inflammatory cascades, and emerging metabolic pathways involving Sirtuin 1 (SIRT1), thereby attenuating renal injury progression. Recent large-scale cardiovascular and renal outcome trials have demonstrated that GLP-1 RAs significantly reduce albuminuria and slow the decline in estimated glomerular filtration rate, although their effects are less pronounced than those of Sodium-Glucose Cotransporter 2 Inhibitors (SGLT2i) on hard renal endpoints. Nevertheless, GLP-1 RAs provide complementary benefits, especially in patients with obesity, insulin resistance, and residual cardiovascular risk. This review synthesizes current evidence on the molecular and physiological mechanisms underlying renal effects mediated by GLP-1 RAs, explores their role in metabolic reprogramming within the kidney, and evaluates their clinical impact on chronic kidney disease progression. Emerging data suggest that GLP-1 RAs may redefine nephroprotective strategies when used in combination with other agents, highlighting their importance in a multidimensional approach to cardiorenal-metabolic disease.

Keywords:Glucagon-like peptide 1; GLP-1 receptor agonists; Diabetic nephropathies; Kidney function tests; Renal insufficiency; Chronic; Sodium-hydrogen exchanger 3; Inflammation mediators; Oxidative stress

Abbreviations: GLP-1 RAs: Glucagon-Like Peptide-1 Receptor Agonists; GLP-1: Glucagon-Like Peptide-1; SGLT2: Sodium-Glucose Cotransporter 2; SIRT1: Sirtuin 1