Frailty as a risk-enhancing factor across the cardiovascular–kidney–metabolic framework: findings from the UK Biobank

AIMS: Frailty has been associated with increased cardiovascular disease (CVD) risk, but its role within the cardiovascular-kidney-metabolic (CKM) framework remains unclear. We examined the association between frailty and incident CVD across CKM stages. METHODS: This prospective cohort study included 408,163 UK Biobank participants free of baseline CVD. Frailty was assessed using the Fried frailty phenotype and categorized as robust, pre-frail, or frail. CKM stages (0-3) were defined according to the American Heart Association framework. Incident CVD was ascertained through hospital and mortality records. Associations were evaluated using multivariable-adjusted Cox models. RESULTS: Over a median follow-up of 15.1 years, 61,766 participants developed CVD. The 15-year cumulative incidence of CVD was 13.1% in robust individuals, 17.7% in those with pre-frailty, and 30.5% in those with frailty. After adjustment, pre-frailty and frailty were associated with higher CVD risk compared with robustness (HR 1.24, 95% CI 1.22-1.26; HR 1.85, 95% CI 1.79-1.92). These associations were observed across all CKM stages, including early-stage CKM health, with relative attenuation in CKM stage 1. CONCLUSIONS: Frailty was consistently associated with incident CVD across the CKM spectrum. When considered alongside traditional CKM variables, frailty captured additional cardiovascular vulnerability across CKM stages, supporting its role as a complementary, risk-enhancing factor within the CKM framework.