Metabolic status modifies the predictive value of the C-reactive protein–triglyceride–glucose Index–waist-to-height ratio for major adverse cardiovascular and cerebrovascular events: a prospective cohort study from the China Health and Retirement Longitudinal Study (CHARLS)

BACKGROUND: The C-reactive protein–triglyceride–glucose index combined with the waist-to-height ratio (CTI-WHtR) is a novel composite biomarker integrating inflammation, insulin resistance, and central obesity. Whether its predictive value for major adverse cardiovascular and cerebrovascular events (MACCE) varies across metabolic states remains unknown. METHODS: We included 6993 participants free of cardiovascular disease at baseline from the China Health and Retirement Longitudinal Study (CHARLS, 2011–2020), classified into normal glucose tolerance (NGT, n = 2916), prediabetes (n = 3106), and type 2 diabetes (T2D, n = 971). Stratified Cox regression, interaction testing, head-to-head comparison of eight metabolic indices, restricted cubic spline (RCS) analyses, and multiple sensitivity analyses including multiple imputation (MICE) were performed. RESULTS: Over a mean follow-up of 8.0 ± 2.0 years, 1467 MACCE events occurred. After full adjustment including BMI, each standard deviation increase in CTI-WHtR was significantly associated with MACCE in the NGT group (HR 1.26, 95% CI 1.11–1.43, P = 0.0003), but not in prediabetes (HR 1.04, P = 0.43) or T2D (HR 1.06, P = 0.49). Multiple imputation (N = 14,606) yielded a consistent but attenuated NGT estimate (pooled HR 1.13, 95% CI 1.04–1.24, P = 0.0068). Pairwise interaction testing provided suggestive evidence of effect modification (prediabetes vs. NGT P = 0.027). RCS analyses revealed a consistently linear dose–response in the NGT group (all P-non-linearity > 0.25) but a non-linear inverted-U shape in T2D (P-non-linearity = 0.017). In head-to-head comparisons, CTI-based indices achieved higher C-indices in the NGT group while TyG-based indices performed better in T2D, suggesting a potential “group-switching” pattern warranting confirmation in larger studies. CONCLUSIONS: The predictive value of CTI-WHtR for MACCE is modified by metabolic status (operationalized as glycemic status) in both magnitude and functional form. CTI-WHtR demonstrates a statistically significant, linear association with MACCE in normoglycemic individuals (complete-case HR 1.26; multiple imputation HR 1.13), while the dose–response transforms to an inverted-U shape in T2D. These exploratory findings suggest that metabolic status may merit consideration when interpreting metabolic index–cardiovascular risk associations, pending validation in larger, multi-ethnic cohorts (overall interaction likelihood ratio test [LRT] P = 0.057).