Sex differences in risk of cardiovascular disease in participants with cardiovascular-kidney-metabolic syndrome stages 0–3: parallel analyses of two prospective cohorts

Abstract Background The preclinical stages of Cardiovascular-Kidney-Metabolic (CKM) syndrome serve as an important surveillance window for cardiovascular disease (CVD) risk assessment and prevention. However, whether sex-specific differences in CVD risk exist across the CKM syndrome stages 0–3, and whether these differences would vary geographically, remain unclear. This study aimed to investigate the sex differences in developing CVD across CKM syndrome stages 0–3 and to assess whether these differences varied depending on different populations. Methods Data from UK Biobank study and China Health and Retirement Longitudinal Study (CHARLS) were used. Participants were categorized into CKM syndrome stages 0, 1, 2 or 3 in UK Biobank, and 0–1, 2 or 3 in CHARLS. Outcome was incident CVD by sex during follow-up. We used multivariable Cox models to explore the sex-CVD relationship. Results We included 352,297 participants from the UK Biobank and 7,610 CHARLS participants. A total of 32,268 (9.16%) incident CVD events occurred in the UK Biobank, among which 19,421 (12.37%) in males and 12,847 (6.58%) females. There were 1,379 (18.12%) CVD events in CHARLS: 579 (15.99%) males and 800 (20.06%) females. In the UK Biobank, males had a significantly higher risk of CVD than females in the overall population (fully-adjusted HR = 1.79; 95% CI: 1.75–1.84). Similar sex differences were observed across all CKM stages. In CHARLS, a significantly lower risk of CVD was found in males than females (fully-adjusted HR = 0.74; 95% CI: 0.62–0.87). Males had a lower CVD risk across CKM stages, although the estimate for stage 3 was imprecise and non-significant. Socioeconomic status or lifestyle behaviors partially accounted for the sex-CVD associations in both UK Biobank and CHARLS. Sensitivity analysis results supported the robustness of these findings. Conclusions While males in the UK Biobank exhibited a consistently higher risk of CVD across CKM syndrome stages 0–3, females in CHARLS had a greater CVD risk. These findings underscore the cohort-specific importance of sex differences in CKM syndrome stages and CVD risk, highlighting the necessity of localized public health surveillance and indicating the need for sex-tailored strategies to reduce the CVD burden.