Association of cumulative exposure and dynamic trajectories of the C-reactive protein-triglyceride-glucose and its modified indices with cardiovascular disease in individuals with cardiovascular-kidney-metabolic syndrome stages 0–3: a longitudinal analysis based on CHARLS

BACKGROUND: To evaluate the incremental predictive value of modifying the C-reactive protein-triglyceride-glucose (CTI) index with obesity parameters for incident cardiovascular disease (CVD) across Cardiovascular-Kidney-Metabolic (CKM) syndrome stages. METHODS: Based on the longitudinal CHARLS cohort, Cox proportional hazards was utilized. Predictive increments were assessed using time-dependent Nearest Neighbor Estimation (NNE) AUC with Bootstrap resampling, cNRI, and IDI. Pathophysiological mechanisms were explored via Weighted Quantile Sum (WQS) regression and causal mediation analyses. RESULTS: After adjusting for demographic and clinical confounders, CTI and its modified indices all maintained robust, independent associations with incident CVD. Specifically, except for CTI-BMI, the new index, which incorporates the obesity index, transforms the dose-response relationship from a complex, nonlinear pattern to a threshold linear association. While increments in overall discrimination (AUC) were marginal, both baseline and cumulative CTI-CVAI significantly improved risk reclassification(cNRI: 0.093-0.126, IDI: 0.024-0.026, P < 0.001). The CKM stratification reveals stage-dependent predictive effects, with amplified relative risks in CKM 0-2 stages and stronger incremental value for risk reclassification in the CKM 3 stage. WQS confirmed visceral adiposity as the dominant risk driver, and physical frailty was identified as a significant pathophysiological mediator of the observed associations. CONCLUSIONS: Incorporating obesity indicators, particularly CVAI, into the CTI framework significantly improves the reclassification of CVD risk in early to moderate CKM stages. However, the lack of significant discriminative (AUC) improvement necessitates a careful clinical trade-off between adopting complex composite metrics and maintaining screening feasibility. TRIAL REGISTRATION: Not applicable.