Frailty trajectories and risk of incident advanced CKM syndrome: A national cohort analysis

BACKGROUND The interplay between frailty dynamics and the newly defined Cardiovascular-Kidney-Metabolic (CKM) syndrome remains poorly understood. We aimed to quantify the association between frailty transitions and the risk of incident advanced CKM syndrome and identify modifiable drivers of frailty progression. METHODS Using data from the China Health and Retirement Longitudinal Study (CHARLS), we analyzed 8159 participants cross-sectionally and 3506 longitudinally over four years. Frailty was assessed using a deficit-accumulation index. The primary outcome was prevalent and incident advanced CKM syndrome (Stages 3-4). We employed multivariable regression models to evaluate associations and a machine learning pipeline to identify key predictors of frailty progression. RESULTS Baseline frailty showed a robust dose-response relationship with prevalent advanced CKM (OR 1.44 per 0.1-unit FI increase; 95% CI 1.38-1.51). Longitudinally, individuals progressing to a frail state had a 40% increased risk of incident advanced CKM compared to stable non-frail peers (OR 1.40; 95% CI 1.01-1.94). Notably, this risk was sex-specific, observing a significant association in men (OR 2.20; 95% CI 1.33-3.64) but not in women. Machine learning identified life satisfaction, smoking status, and sleep duration as the top predictors of frailty progression. CONCLUSIONS Frailty progression acts as a potent, sex-specific risk amplifier for advanced CKM syndrome. Integrating frailty screening into CKM care and targeting psychosocial well-being-specifically life satisfaction-alongside lifestyle factors may be important strategies to preempt frailty and potentially mitigate cardiovascular-renal-metabolic risks.