Cardiovascular-Kidney-Metabolic Syndrome and Long-Term Risk of Cardiovascular Disease and all-cause Mortality

AIMS: To examine the associations between cardiovascular-kidney-metabolic syndrome (CKM) stages and the risk of cardiovascular disease (CVD), including atherosclerotic CVD (ASCVD), and all-cause mortality (ACM), stratified by sex. METHODS AND RESULTS: Using a population-based cohort, CoLaus|PsyCoLaus, we categorized participants into CKM stages: 0 (no CKM factors), 1 (excess/dysfunctional adiposity), 2 (metabolic risk factors and/moderate- to high-risk CKD), 3 (very high predicted CVD risk per SCORE2/very high-risk CKD), and 4 (clinical CVD). Associations were assessed using generalized ordered logistic regression, Cox proportional hazards models, and population attributable fractions (PAFs). Among 5,752 participants (53.2% women; mean age: women 53.1 ± 10.7, men 52.3 ± 10.7 years), 580 CVD events (381 ASCVD), and 723 deaths occurred over 14.3 years. CKM stage distribution differed by sex (men vs women): 0 (9.9 vs 26.1%), 1 (13.3 vs 13.7%), 2 (62.6 vs 56.8%), 3 (9.4 vs 1.7%), 4 (4.8 vs 1.7%). Risk of CVD and ASCVD rose with higher CKM stage (vs stage 0), with HRs of 5.16 (95% CI, 2.61-10.19) and 3.82 (1.76-8.27) for stage 3 in men, compared with 1.92 (0.91-4.04) and 1.95 (0.79-4.81) in women. For all-cause mortality, risk peaked at stage 3 in women (3.43 [1.92-6.10]) and at stage 4 in men (2.42 [1.27-4.64]). Incremental PAFs peaked at stage 2. CONCLUSION: CKM stages were associated with a stepwise increase in risk of CVD and all-cause mortality, with important sex-specific differences observed particularly for all-cause mortality. These findings support the relevance of CKM staging for cardiovascular risk stratification and prevention in the general population.