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 Lon

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. 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. 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. 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).