Abstract Background and Aims Cardiovascular-kidney-metabolic (CKM) syndrome is a novel disease concept; however, sex differences in its progression remain uncertain. This study aimed to quantify the risk of cardiovascular disease (CVD) events across CKM stages and to explore sex differences in this association. Methods We included 1,332,436 individuals (581,423 males and 751,013 females) from the DeSC database between 2014 and 2023 who had no prior CVD (i.e., CKM Stage 4). CKM stages were categorized as follows: Stage 0 (no CKM risk factors); Stage 1 (excess or dysfunctional adiposity); Stage 2 (metabolic risk factors and CKD), and Stage 3 (subclinical CVD). We used Cox models to examine the association of CKM stages with the risk CVD events (newly developed CKM Stage 4), including myocardial infarction, stroke, heart failure, atrial fibrillation, and peripheral artery disease. Results The progression from CKM Stages 0 to 3 showed a dose-dependent increase in adjusted hazard ratios (HR) for developing CVD events, with the highest risk at Stage 3 (1.85 95% CI 1.80-1.90). A similar pattern was observed in both males and females. However, the magnitude of associations for CKM stages 1-3 differed between the sexes: HR by Stage 1, 1.12 (1.04-1.21) vs. 1.12 (1.07-1.16); by Stage 2, 1.78 (1.69-1.88) vs 1.43 (1.39-1.48); by Stage 3, 1.99 (1.89-2.10) vs. 1.82 (1.76-1.88); and p-for-interaction values were 0.87, 0.001, and 0.005, respectively. Conclusions In this large nationwide cohort, CKM stage progression was associated with higher CVD risk in both sexes, with modest sex-specific differences. These findings highlight the value of CKM staging for early risk assessment, regardless of sex.
Ejiri et al. (Wed,) studied this question.