Joint associations of the TyG index and systemic immune-inflammation index with cardiovascular disease: a cohort study

Background &Objective Previous studies have suggested that metabolic disorders and systemic inflammation may synergistically exacerbate cardiovascular disease risk. However, the combined effect of the triglyceride-glucose (TyG) index and systemic immune-inflammation index (SII) on cardiovascular disease (CVD) risk remains insufficiently investigated. This study aims to examine the joint associations of the TyG index and SII with CVD risk and mortality in a nationally representative cohort. Methodologies This prospective cohort study analyzed data from the National Health and Nutrition Examination Survey (NHANES) from 1999–2018. The participants were stratified into four groups on the basis of the TyG index and SII: low TyG/low SII, high TyG only, high SII only, and high TyG/high SII. Weighted binary logistic regression and Cox proportional hazards models were applied to assess the associations between these indices and CVD risk. Mutual mediation analysis was performed to explore potential interactions and mechanisms. Result A total of 19,168 participants were included. Compared with the low-TyG/low-SII group, high TyG alone was associated with a 49% higher CVD risk (OR 1.49, 95% CI 1.20–1.86), whereas high SII alone increased the risk by 32% (OR 1.32, 95% CI 1.04–1.67). Coexposure to both high TyG and high SII further amplified the risk of CVD (OR 1.51, 95% CI 1.21–1.88), all-cause mortality (HR 1.41, 95% CI 1.19–1.68), and cardiovascular mortality (HR 1.40, 95% CI 1.01–1.95). The results of the mediation analysis revealed that the TyG index mediated 5.2% of the association between the SII and CVD risk. Conclusion The TyG index and the SII are independent and synergistic predictors of CVD risk and mortality. Combined assessment of these biomarkers improves risk stratification, highlighting the interplay between metabolic dysfunction and chronic inflammation in CVD pathogenesis. These findings support targeted interventions addressing both metabolic dysfunction and systemic inflammation for CVD prevention.