Sex Differences in Cardiovascular-Kidney-Metabolic Syndrome: 30-Year US Trends and Mortality Risks

BACKGROUND: The American Heart Association recently published guidelines on how to clinically identify and categorize individuals with cardiovascular-kidney-metabolic (CKM) syndrome. The extent to which CKM syndrome prevalence and prognosis differ by sex remains unknown. This study aimed to examine the impact of sex on trends in prevalence over 30 years and the long-term prognosis of CKM syndrome in the United States. METHODS: We analyzed nationally representative National Health and Nutrition Examination Survey 1988 to 2018 data collected from 33 868 US adults (aged ≥20 years) who were under surveillance for all-cause mortality through December 31, 2019. We examined the sex-specific prevalence of CKM syndrome and sex-specific CKM associations with all-cause mortality. RESULTS: Of the 33 868 adults studied, the mean±SD age was 48.4±18.3 years with 52% women and 56% non-White. Overall prevalence of CKM syndrome increased steadily from 1988 to 2018 in both sexes, with a larger temporal rise in prevalent stage 3 CKM seen for males (from 18.9% to 22.4%) compared with women (from 13.9% to 15.2%). Over a median follow-up of 13.3 years, there were 8745 deaths. In the multivariable Cox regression analysis, worsening CKM severity was associated with all-cause mortality ( P <0.001 for both sexes), with greater magnitudes of risk seen in women (hazards ratio, 1.24–3.33) compared with men (hazards ratio, 0.85–2.60) across all stages (likelihood ratio test χ 2 , 19.0; P interaction <0.001); results were similar for cardiovascular mortality (likelihood ratio test χ 2 , 22.3; P interaction <0.001). CONCLUSIONS: Women, compared with men, exhibited a lower prevalence of CKM stage 3 but experienced excess mortality risk across the spectrum of multisystem CKM dysfunction. These findings underscore the importance of identifying mechanisms underlying joint cardiovascular, kidney, and metabolic system pathophysiology to close a potentially widening sex disparities gap in multiorgan disease risk.