Association between triglyceride-glucose index and related indicators with heart failure–related mortality in individuals with early-stage cardiovascular-kidney-metabolic syndrome

Insulin resistance is a central pathophysiological feature of cardiovascular–kidney–metabolic (CKM) syndrome and has been implicated in adverse cardiovascular outcomes. However, the association between triglyceride–glucose (TyG) index–related indicators and heart failure (HF)–related mortality in individuals with early-stage CKM syndrome remains unclear. This research conducted a prospective analysis using data from the National Health and Nutrition Examination Survey (NHANES) 2005–2018. Participants with CKM stages 0–2 and without clinical cardiovascular disease at baseline were included. TyG and related indices (TyG-BMI, TyG-WC, and TyG-WHtR) were analyzed as continuous and quartile-based variables. The primary outcome was HF-related mortality, ascertained via linkage to the National Death Index. Associations were assessed using Cox proportional hazards and Fine–Gray competing risk models with hierarchical adjustment, including additional adjustment for CKM stage in extended models. Machine learning approaches (Boruta and SHAP) were applied for covariate selection. Nonlinear associations, predictive performance, mediation by HbA1c, and subgroup effects were further evaluated. Among 14,830 participants, higher TyG-related indices were associated with increased HF-related mortality during follow-up. After full adjustment, each 1-SD increase in TyG-WC and TyG-WHtR was associated with a 2.27-fold and 2.94-fold higher risk of HF-related mortality, respectively (all P < 0.05). The associations remained consistent after additional adjustment for CKM stage. Restricted cubic spline analyses demonstrated predominantly linear dose–response relationships. TyG-WHtR exhibited the strongest discriminatory ability (AUC = 0.641, 95% CI 0.601–0.680). Mediation analyses indicated that HbA1c accounted for approximately 15%–30% of the observed associations. Associations were generally consistent across clinically relevant subgroups and remained robust in competing risk analyses and sensitivity analyses. In individuals with early-stage CKM syndrome, TyG-related indices—particularly those incorporating central adiposity—are independently associated with HF-related mortality. These findings highlight the prognostic relevance of insulin resistance–related metabolic burden in the early stages of CKM syndrome.