Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), together with newer multi-hormone receptor modulators that target glucose-dependent insulinotropic polypeptide (GIP), glucagon and amylin, have emerged as promising therapies for chronic kidney disease. This review examines the mechanisms through which these agents may protect the kidney and summarizes the emerging clinical evidence in populations without diabetes. Kidney protection appears to arise through complementary direct and indirect routes. Direct effects include natriuresis through inhibition of the sodium-hydrogen exchanger (NHE)-3, modulation of glomerular hemodynamics through effects on afferent arteriolar tone and vasoconstrictor pathways, and attenuation of renal inflammation; mechanisms that are largely independent of glucose lowering. Indirect mechanisms include reductions in the metabolic, hemodynamic and cardiac burden on the kidney through weight loss, blood pressure lowering, and improvement of heart failure. Beyond selective GLP-1R-agonism, the added hormonal components of multi-hormone receptor modulators engage distinct physiological pathways whose interactions may be additive, synergistic or counteracting, but remain incompletely understood. The efficacy of GLP-1 RAs and multi-hormone receptor modulators in people without diabetes is currently supported by results from secondary kidney endpoints in phase-3 obesity and cardiovascular outcome trials, including reductions in albuminuria and preservation of estimated glomerular filtration rate. Several dedicated outcome studies of GLP-1 RAs and multi-hormone receptor modulators are now underway and will determine whether these therapies become a new pillar of care in nondiabetic kidney disease.
