Cardiovascular-kidney-metabolic (CKM) syndrome reflects the complex interplay among cardiovascular disease, chronic kidney disease, type 2 diabetes, and obesity. GLP-1 receptor agonists and tirzepatide have emerged as important therapeutic options within CKM syndrome, although the strength and maturity of evidence differ across individual agents and cardiovascular and kidney outcomes. This narrative review summarizes current evidence on the cardiovascular and kidney effects of GLP-1 receptor agonists and the dual GIP/GLP-1 receptor agonist tirzepatide. Large randomized controlled trials have established reductions in major adverse cardiovascular events with several GLP-1 receptor agonists, while dedicated evidence for clinically meaningful chronic kidney disease progression is currently strongest for semaglutide. Cardiovascular benefits of semaglutide have also been demonstrated in individuals with overweight or obesity without type 2 diabetes, supporting effects beyond glucose lowering. Tirzepatide provides substantial improvements in glycemic control and body weight, with expanding evidence supporting cardiovascular benefit, including particularly encouraging findings in obesity-related heart failure with preserved ejection fraction. In contrast, its kidney evidence remains less mature and is derived predominantly from secondary and post-hoc analyses rather than from a dedicated kidney outcome trial. Collectively, these findings support a phenotype-oriented and multimodal role for incretin-based therapies in CKM syndrome management while highlighting important differences in the maturity of outcome evidence.
