Sex differences in cardiovascular-kidney-metabolic (CKM) staging and long-term cardiovascular risk

Background Cardiovascular-kidney-metabolic (CKM) syndrome is an established contributor to cardiovascular disease (CVD), yet sex differences in CKM stage and association with CVD risk remain poorly understood. Methods We assembled an electronic health record-based sample engaged in longitudinal primary care across a large health network. We compared CKM stage distribution between men and women and examined the association of CKM stage with incident CVD using Cox models. We investigated whether sex modified the effect of CKM stage on CVD outcomes using multiplicative interaction terms and performed sex-stratified analyses. Significance was considered at p < 0.05. Results Among 23,443 adults (mean age 49 ± 16 years; 54% women), 87% had at least Stage 1 CKM syndrome. Women were more likely to have earlier stages compared to men (Stage 0: 17% vs. 8%; Stage 1: 23% vs. 19%), whereas men had higher prevalence of advanced stages (Stage 2: 57% vs. 48%; Stage 3–4: 8% vs. 6%; p < 0.0001 for all, Figure). Higher CKM stage was associated with greater CVD risk: Stage 1 vs 0 (HR 1.41, 95% CI 1.08–1.85), Stage 2 (HR 2.27, 95% CI 1.77-2.90), Stage 3 (HR 3.00, 95% CI 2.26–3.98), with no significant sex differences (p for interaction = 0.39). Conclusions CKM syndrome is highly prevalent, with women having earlier and men more advanced stages. Higher CKM stage was strongly associated with increased CVD risk across both sexes. Our findings suggest that while women have lower CKM burden, once present, CKM syndrome portends similar CVD risk as in men. Figure Legend. Top row: Pie charts showing the distribution of CKM stages (0 = no CKM, 4 = advanced CKM) in men (left in blue) and women (red). Bottom row: Kaplan–Meier curves showing cardiovascular (CV) event–free survival over 10 years by CKM stage in men (blue) and women (red). CV events include myocardial infarction, atrial fibrillation, heart failure, and stroke. Models were adjusted for age and sex where applicable. Numbers at risk by CKM stage and sex are shown below each curve. Differences between stages were assessed using the log-rank test(p<0.0001).figure--.png