Cumulative average metabolic indices and cardiovascular disease risk: additive predictive effects and partial mediating role of intrinsic capacity in early-stage CKM syndrome

Early stages (0–3) of cardiovascular-kidney-metabolic (CKM) syndrome represent a critical window for cardiovascular disease (CVD) prevention. Triglyceride–glucose (TyG)-derived indices reflect insulin resistance and metabolic burden, but their cumulative effects and the role of intrinsic capacity (IC) remain unclear. In this prospective study from the China Health and Retirement Longitudinal Study (CHARLS), 3,832 adults with CKM stages 0–3 and without baseline CVD were included. Fourteen cumulative average metabolic indices were derived from repeated measurements. Multivariable logistic regression and restricted cubic spline models were used to evaluate associations and dose–response relationships, with false discovery rate (FDR) correction applied for multiple comparisons. Joint effects with IC, predictive performance (AUC, calibration, decision curve analysis, NRI, and IDI), and mediation effects were assessed. During a median follow-up of 4.0 years, 303 incident CVD cases (7.9%) occurred. Five indices (TyG-BMI, TyG-WHtR, TyG-CI, TyG-CVAI, and METS-IR) were significantly associated with higher odds of new-onset CVD after full adjustment and FDR correction (per SD OR range: 1.27–1.36), with approximately linear dose–response relationships. Lower IC was associated with higher CVD risk. Individual indices showed modest discrimination (AUC range: 0.580–0.604), and incorporating IC provided incremental predictive information (AUC up to 0.621, both NRI and IDI P < 0.01). IC partially mediated these associations, with modest mediation proportions (≈ 4%–7%). Cumulative metabolic burden is independently associated with CVD risk in early-stage CKM syndrome. IC showed joint associations and modest mediating effects and provided complementary information for CVD risk assessment. Integrating metabolic and functional assessments may enhance early risk stratification.