Population burden across cardiovascular-kidney-metabolic syndrome stages in the community

Abstract Introduction Cardiovascular-kidney-metabolic (CKM) syndrome is a newly clinical concept integrating the mutual effects of cardiovascular, renal, and metabolic diseases on cardiometabolic conditions. Current evidence is lacking on the population-level impact of CKM stages, including potential sex-based differences, on disease burden. Purpose To quantify the population-attributable fractions (PAFs) of CKM for 15-year risks of cardiovascular disease (CVD), atherosclerotic CVD (ASCVD), and all-cause mortality (ACM), and to determine any sex-based differences. Methods We analyzed 5,752 adults from a prospective cohort study. CKM stages 0–4 were defined as: Stage 0, no CKM risk factors; Stage 1, excess/dysfunctional adiposity; Stage 2, metabolic risk factors and/or moderate- to high-risk CKD; Stage 3, very high-predicted CVD risk per SCORE2 or very high-risk CKD; and Stage 4, clinical CVD. Adjusted PAFs were computed for each outcome using standard formulas applied to multivariable Cox models, overall and by sex. Result PAFs were derived incrementally by contrasting each CKM stage with the stage immediately preceding it. The largest incremental population burden was observed for the transition from Stage 1 to Stage 2, with 40–45% of CVD/ASCVD events within Stages 1–2 attributable to Stage-2–level risk (52% for ASCVD in women). The incremental PAF for Stage 3 relative to Stage 2 was modest (6–7%), consistent with the substantially lower prevalence of Stage 3 despite its higher individual risk. For all-cause mortality, Stage 2 contributed 19% of deaths among individuals in Stages 1–2 (43% in women), whereas Stages 3–4 added only minimal incremental mortality burden. Conclusion In this population-based cohort, CKM Stage 2 constituted the predominant contributor to population-level CVD, ASCVD, and mortality burden, with pronounced sex-specific heterogeneity. Prioritizing people in CKM stage 2 for preventive interventions is likely to produce the greatest public-health impact, particularly for reducing cardiovascular events in men and mortality in women.For image description, please refer to the figure legend and surrounding text. For image description, please refer to the figure legend and surrounding text.