Cardiovascular-kidney-metabolic syndrome: prevalence, risks, disease trajectories, and early-stage management

Cardiovascular-kidney-metabolic (CKM) syndrome affects approximately 90% of US adults, arising from the convergence of metabolic dysfunction, chronic kidney disease (CKD), and cardiovascular disease (CVD). These conditions create self-reinforcing cycles of multiorgan damage, substantially increasing mortality risk. The American Heart Association's 2023 staging framework stratifies CKM from stage 0 (no risk factors) through stage 4 (clinical CVD with persistent metabolic dysfunction), informing stage-specific interventions. This review synthesizes current evidence on CKM epidemiology, pathophysiology, and disease trajectories. Population-based studies reveal that stage 2 (metabolic risk factors or early CKD) represents the most prevalent category, affecting nearly half of adults in Western cohorts. Progression occurs in 34% of stage 1 individuals, with each stage transition conferring an incrementally higher cardiovascular mortality risk. We describe the biological cascade linking dysfunctional adiposity, insulin resistance, and endothelial dysfunction to renal and cardiac damage, emphasizing bidirectional organ cross talk and the emerging role of hepatic pathology [metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH)] in CKM progression. Finally, we examine stage-specific interventions, from lifestyle modification and weight-loss pharmacotherapy (GLP-1 agonists and dual agonists) in early stages to multidrug cardiorenal protection [sodium-glucose cotransporter-2 (SGLT2) inhibitors and renin-angiotensin-aldosterone system (RAAS) blockade] in advanced disease. This framework allows targeted risk stratification and evidence-based management to interrupt CKM trajectories and improve population health outcomes.