Sex differences in cardiovascular-kidney-metabolic syndrome and new onset cardiovascular outcomes

• There is a higher prevalence of Stage 3 CKM syndrome among men compared to women. • Subclinical ASCVD is prevalent in men, while subclinical HF predominates among women. • CHD is the most dominant cardiovascular outcome in both sexes with CKM syndrome. There is a higher prevalence of Stage 3 CKM syndrome among men compared to women. Subclinical ASCVD is prevalent in men, while subclinical HF predominates among women. CHD is the most dominant cardiovascular outcome in both sexes with CKM syndrome. Cardiovascular-Kidney-Metabolic (CKM) syndrome integrates metabolic risk factors, chronic kidney disease (CKD), and cardiovascular dysfunction, and is closely linked to cardiovascular disease (CVD) risk. We aimed to evaluate sex-specific differences in prevalence, components, and outcomes of CKM syndrome to inform strategies for personalized cardiovascular prevention. We included 6563 participants without established CVD from the Multi-Ethnic Study of Atherosclerosis (MESA). CKM stages were defined according to American Heart Association criteria. We assessed sex-specific prevalence, component distributions, and incidence of coronary heart disease (CHD), heart failure (HF), stroke, and mortality. Incidence rates (IR) per 1000 person-years and Fine-Gray subdistribution hazard ratios (SHR) were estimated. Among 3095 men and 3468 women (mean age: 62 ± 10 years), men had a higher CKM Stage 3 prevalence (42.4% vs. 36.4% in women). Within Stage 3, subclinical atherosclerotic CVD (coronary artery calcium [CAC] score ≥ 100 Agatston unit) predominated in men (70.5%), whereas subclinical HF (elevated cardiac biomarkers) was more frequent in women (70.1%). During a median follow-up of 13.7 years (IQR 9.0–15.5 years), CHD incidence was higher in men (IR: 20.9 vs. 8.9 in women), followed by HF (IR: 7.2 vs. 4.5) and stroke (IR: 6.7 vs. 6.3). Using women as the reference, SHRs (95% CI) for men were 2.28 (1.84, 2.82) for CHD, 1.66 (1.20, 2.30) for HF, and 1.07 (0.80, 1.43) for stroke. Men exhibited a higher prevalence of advanced CKM Stages and a substantially greater CHD burden, while women showed a higher subclinical HF phenotype within CKM Stage 3. These findings support sex-specific, stage-based CKM assessment as an actionable framework for early risk stratification and tailored cardiovascular prevention. Unclassifiable CKM stage included participants with components of CKM Stage 3 but without any components of CKM Stage 1 or 2. CKM Stage 4 was not included in this analysis, as MESA enrolled only participants without clinical CVD at baseline.