Association of Frailty and Its Trajectories With the Risk of Cardiovascular–Kidney–Metabolic Syndrome Progression: A Longitudinal Cohort Study

AIMS: Frailty reflects a decline in physiological reserve and has been widely recognized as an important risk factor for cardiovascular disease (CVD). However, the relationships between frailty and the progression of the cardiovascular-kidney-metabolic (CKM) syndrome, as well as between dynamic frailty trajectories and CVD risk, have not been systematically investigated. METHODS: A total of 5624 participants from the China Health and Retirement Longitudinal Study (CHARLS) were included. The association between baseline frailty and CVD risk was analyzed using the Cox proportional hazards model and the restricted cubic spline analyses. We used Group-based trajectory modeling (GBTM) to identify trajectories of frailty development during the follow-up periods from 2011 to 2018. RESULTS: Higher baseline frailty index (FI) was significantly associated with CVD risk in individuals with CKM syndrome stages 0-3; each 0.1 increase in FI was associated with a 33% higher risk of CVD after full adjustment (HR 1.33, 95% CI 1.26-1.40). Cumulative frailty burden, assessed using the cumulative FI (cumFI), showed a strong graded association with CVD risk. Three distinct frailty trajectories were identified. Compared with the low-level increasing trajectory, moderate-level and high-level increasing trajectories were associated with higher CVD risk (HR = 4.63, 95% CI: 3.50-6.14, HR = 9.33, 95% CI: 6.89-12.64). These associations were consistent across multiple sensitivity analyses. CONCLUSIONS: Frailty is associated with the risk of CKM syndrome progression. Beyond baseline assessment, cumFI and frailty trajectories provide prognostic information for cardiovascular risk. Dynamic assessment and early intervention targeting frailty may offer a strategy for preventing CVD.