Joint Associations of Cumulative C-Reactive Protein–Triglyceride–Glucose Index and Depression with Cardiovascular Outcomes in Middle-Aged and Older Adults: A National Prospective Cohort Study

Background: The C-reactive protein–triglyceride–glucose index (CTI) and depression are each associated with elevated cardiovascular disease (CVD) risk. However, evidence on long-term cumulative CTI exposure and its joint effect with depression remains limited. Methods: This prospective cohort study included participants from the 2015 baseline of the China Health and Retirement Longitudinal Study, with follow-up in 2018 and 2020. Cox proportional hazards models were used to examine associations between a combined cumulative CTI–depression indicator and incident CVD, as well as their interaction. Restricted cubic splines were used to assess dose–response relationships across depression status. The predictive performance of the composite indicator was compared with individual components using integrated discrimination improvement and net reclassification improvement. Subgroup and sensitivity analyses were conducted. Results: Participants were categorized according to cumulative CTI level and depression status. Compared with individuals with low cumulative CTI and no depression, all other groups exhibited significantly higher risks of CVD, demonstrating a clear graded association. These associations remained robust after multivariable adjustment. In the primary fully adjusted model, participants with high cumulative CTI and depression had the highest CVD risk (HR = 1.83, 95% CI 1.53–2.20, p < 0.01). Categorical analyses suggested possible effect modification by depression status. In addition, the combined cumulative CTI–depression indicator demonstrated improved predictive performance compared with either component alone. The primary associations remained broadly consistent across subgroup and sensitivity analyses, although evidence for possible effect modification varied across alternative analytical approaches. Conclusions: The combined cumulative CTI-depression indicator was strongly and consistently associated with increased CVD risk, exhibiting graded associations with possible effect modification by depression. This joint measure captures cumulative metabolic–inflammatory burden and psychological distress and may provide complementary information for cardiovascular risk stratification beyond the individual components.