Frailty as a Risk-Enhancing Factor Across the Cardiovascular-Kidney-Metabolic Framework: Findings from the UK Biobank

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.

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.

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.

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.