Obesity and type 2 diabetes (T2D) are dominant drivers of chronic kidney disease (CKD) within the cardio-kidney-metabolic (CKM) syndrome. Despite advances with renin-angiotensin system inhibitors and sodium-glucose cotransporter 2 (SGLT2) inhibitors, substantial residual cardiovascular and renal risk persists, highlighting the need for therapies targeting upstream metabolic dysfunction. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have emerged as key modulators of CKM disease through integrated metabolic, vascular, and anti-inflammatory mechanisms. Cardiovascular outcome trials first established their cardioprotective effects, while the FLOW trial definitively demonstrated kidney protection, showing a 24% reduction in major kidney outcomes in patients with T2D and CKD. Mechanistic insights from translational studies further suggest that GLP-1 receptor activation promotes metabolic decongestion, improves intrarenal hemodynamics, and attenuates inflammatory and fibrotic pathways. Beyond selective GLP-1 receptor agonism, dual (glucose-dependent insulinotropic polypeptide [GIP]/GLP-1) and triple (GIP/GLP-1/glucagon) incretin agonists, including tirzepatide and retatrutide, extend this paradigm by delivering greater weight reduction and systemic metabolic reprogramming, with emerging signals for cardiovascular and renal benefit. Contemporary CKD management is shifting toward a phenotype-driven, layered therapeutic strategy in which SGLT2 inhibitors provide foundational kidney protection and incretin-based therapies are integrated to address residual metabolic and cardiovascular risk. In this evolving CKM framework, incretin-based therapies represent a central component of multi-mechanistic disease modification, extending beyond glycemic control to coordinated protection across the heart, kidney, and metabolic systems.
