The global rise in obesity and type 2 diabetes mellitus (T2DM) has contributed substantially to the increasing burden of chronic kidney disease (CKD), cardiovascular disease, and heart failure, highlighting the need for therapeutic strategies capable of addressing multiple components of the cardio-renal-metabolic axis. Incretin-based therapies have undergone an evolution from glucose-lowering agents to treatments with broad metabolic, cardiovascular, and renal effects. Glucagon-like peptide-1 (GLP-1) receptor agonists have demonstrated clinically meaningful reductions in cardiovascular events and have emerged as important therapies for kidney protection. Evidence from cardiovascular and kidney outcome trials, culminating in the FLOW study, has established semaglutide as a clinically relevant strategy for reducing kidney and cardiovascular risk in patients with T2DM and CKD. Beyond single-receptor agonism, the development of dual and triple incretin receptor agonists has expanded the therapeutic possibilities. Tirzepatide, a dual GLP-1/GIP receptor agonist, has demonstrated favourable kidney outcomes compared with dulaglutide, while early studies of the dual GLP-1/glucagon receptor agonist cotadutide suggest additional benefits on albuminuria and cardiorenal risk markers. Retatrutide, a triple GLP-1/GIP/glucagon receptor agonist, has shown promising effects on kidney-related parameters, although the mechanisms underlying observed increases in estimated glomerular filtration rate remain uncertain. Accumulating evidence suggests that incretin-based therapies may exert renoprotective effects through pathways extending beyond glycaemic control and weight reduction, including improvements in endothelial function, microvascular integrity, inflammation, fibrosis, and renal haemodynamics. Nevertheless, important questions remain regarding the mechanisms of kidney protection, the interpretation of kidney function changes in the setting of substantial weight loss, and the long-term renal benefits of multi-receptor modulators. Ongoing mechanistic studies and dedicated outcome trials will further define the role of incretin biology in the prevention and treatment of CKD.
