Frailty trajectories and cardiovascular disease in adults with CKM stages 0-3.

Frailty reflects multidimensional biological and functional decline beyond conventional cardiometabolic risk markers. However, evidence remains limited on the associations of baseline frailty status and longitudinal frailty index trajectories with cardiovascular disease (CVD) outcomes in adults with early cardiovascular-kidney-metabolic (CKM) syndrome. We analyzed 4219 adults aged 45 years or older with CKM stages 0-3 from the China Health and Retirement Longitudinal Study. Baseline frailty status was classified from a 32-item frailty index (FI) as robust, pre-frail, or frail and examined in relation to incident CVD using Cox proportional hazards models. The primary four-wave analysis used FI measurements from 2011 to 2018 to identify low-stable, moderate-gradual increase, and high-rapid rise trajectories; associations with CVD occurrence were estimated using logistic regression. We also conducted a wave 4 fixed interval landmark logistic analysis of events recorded at wave 5 and a wave 3 landmark Cox analysis of incident events at waves 4-5. During follow-up, 541 participants developed CVD. In the multivariable-adjusted logistic model (Model 2), compared with the low-stable trajectory, the moderate-gradual increase and high-rapid rise FI trajectories were associated with higher odds of CVD occurrence, with ORs of 1.87 (95% CI 1.51-2.32) and 3.52 (95% CI 2.55-4.87), respectively (both P < 0.001). The largest association magnitude was observed for stroke occurrence in the high-rapid rise group (OR = 4.98, 95% CI 3.01-8.24; P < 0.001). Both landmark analyses supported the primary association pattern. In the wave 3 landmark Cox analysis, associations with total CVD and stroke persisted after additional adjustment for baseline FI. In the multivariable-adjusted Cox model (Model 2), compared with robust participants, pre-frail and frail participants had higher hazards of incident CVD, with HRs of 1.61 (95% CI 1.33-1.95) and 1.63 (95% CI 1.23-2.17), respectively (both P < 0.001). Among adults with CKM stages 0-3, adverse longitudinal FI trajectories and baseline frailty were both associated with CVD outcomes. Repeated FI assessment may complement baseline frailty evaluation by characterizing persistent or accelerating deficit accumulation that may warrant closer longitudinal monitoring.