Associations of cumulative C-reactive protein–triglyceride glucose index and cumulative functional limitation burden with incident cardiovascular disease among individuals with stages 0–3 cardiovascular–kidney–metabolic syndrome: a nationwide prospective cohort study

Among adults with cardiovascular–kidney–metabolic (CKM) stages 0–3, whether cumulative metabolic-inflammatory burden and self-reported functional limitations provide complementary cardiovascular disease (CVD) prognostic information remains unclear. This China Health and Retirement Longitudinal Study (CHARLS) cohort included 4,048 participants with a 2015 landmark. Cumulative C-reactive protein–triglyceride glucose index (CTI) used 2011 and 2015 measurements; seven-task functional limitation burden used 2011, 2013, and 2015 scores and participant-specific trapezoidal integration. Incident physician-diagnosed heart disease or stroke was assessed in 2018 and 2020. Associations used mutually adjusted Cox and alternative event-time models. Internal prediction used 10-fold cross-validation and 500 full-pipeline bootstrap resamples. During follow-up, 778 participants developed CVD. Per 1-SD increment, primary mutually adjusted hazard ratios (HRs) were 1.11 (95% CI 1.03–1.20) for CTI and 1.30 (1.22–1.39) for functional limitation burden. Functional limitation HRs remained 1.30 and 1.31 in complementary log-log and interval-censored models, whereas CTI estimates were attenuated to 1.07 (0.99–1.15; P = 0.073) and 1.07 (1.00–1.16; P = 0.063), respectively. Adding functional limitation burden to conventional factors plus CTI increased the C-index by 0.0208 (95% CI 0.0102–0.0335) and integrated time-dependent area under the curve (iAUC) by 0.0230 (0.0105–0.0389). The integrated Brier score (IBS) difference, evaluated model minus comparator, was − 0.0014 (− 0.0025 to − 0.0005), indicating a small absolute reduction in prediction error. Adding CTI after functional limitation burden showed no clear additional improvement. Functional limitation burden showed consistent adjusted associations and internal prediction gains with a small absolute IBS reduction. CTI was event-time sensitive. AUC-specific superiority, clinical net benefit, and improved outcomes were not established. External validation and calibration are needed. What is currently known about this topic? CTI and reported functional limitations are associated with cardiovascular risk. What is the key research question? Do cumulative CTI and functional limitation provide complementary CVD risk information? What is new? Both cumulative measures were associated with CVD in the primary mutually adjusted model. Functional burden improved internal prediction, but the absolute IBS reduction was small. CTI was event-time sensitive; functional AUC superiority over mean/recent scores was unproven. How might this study influence clinical practice? Net benefit and better outcomes were unproven; external validation is required before clinical use.