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 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 6,993 participants free of cardiovascular disease at baseline from the China Health and Retirement Longitudinal Study (CHARLS, 2011–2020). Participants were classified into normal glucose tolerance (NGT, n = 2,916), prediabetes (n = 3,106), and type 2 diabetes (T2D, n = 971). Stratified multivariable Cox regression with stepwise covariate adjustment, multiplicative interaction testing, head-to-head comparison of eight metabolic indices, restricted cubic spline (RCS) dose–response analyses, subgroup analyses, and multiple sensitivity analyses were performed. Results Over a mean follow-up of 8.0 ± 2.0 years, 1,467 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 the prediabetes (HR 1.04, P = 0.43) or T2D group (HR 1.12, P = 0.17). Pairwise interaction testing confirmed effect modification (prediabetes vs. NGT P = 0.027 for MACCE). RCS analyses revealed that the dose–response relationship was consistently linear in the NGT group (all P _{non−linearity} > 0.25), whereas it shifted to a non-linear inverted-U shape in the T2D group (P _{non−linearity} = 0.017 for MACCE). In head-to-head comparisons, CTI-based indices achieved higher C-indices in the NGT group, while TyG-based indices performed better in the T2D group, demonstrating a “group-switching” phenomenon. Conclusions The predictive value of CTI-WHtR for MACCE is modified by metabolic status in both magnitude and functional form. CTI-WHtR demonstrates robust, linear, and independent predictive value in normoglycemic individuals, while the dose–response relationship transforms to an inverted-U shape in type 2 diabetes. These findings establish that metabolic status should be considered when interpreting both the strength and functional form of metabolic index–cardiovascular risk associations.