Triglyceride–glucose muscle-loss index and all-cause and cardiovascular mortality in cardiovascular-kidney-metabolic syndrome stages 0–3: NHANES findings with validation in CHARLS

Abstract

A composite triglyceride–glucose–muscle loss index (TyG-MLI), integrating insulin resistance (TyG) and a muscle-related metabolic reserve signal (cystatin C/creatinine ratio), may improve risk stratification in cardiometabolic–kidney–metabolic (CKM) stages 0–3, but its prognostic value is unclear. To examine associations of TyG-MLI with all-cause and cardiovascular mortality in CKM stages 0–3 and test its incremental predictive value, with external validation. Discovery–validation analyses were performed in NHANES 1999–2004 (mortality through 2019) and CHARLS 2011 (follow-up through 2020). Adults with CKM stages 0–3 and complete baseline biomarkers were included. Multivariable Cox models estimated hazard ratios (HRs). Discrimination and added value were assessed using time-dependent AUC/C-index and NRI/IDI. Mediation by estimated pulse wave velocity (ePWV) was explored. In NHANES (n=5,168; median follow-up 17.5 years), TyG-MLI (per SD) was independently associated with higher all-cause mortality (HR 2.24, 95% CI 1.35–3.71) and cardiovascular mortality (HR 2.50, 95% CI 1.69–3.70). TyG-MLI generally outperformed TyG or MLI alone for 5–15-year discrimination (all-cause AUC ~0.62–0.65) and improved all-cause reclassification beyond conventional models (NRI 0.256–0.279; IDI 0.006–0.010), whereas cardiovascular reclassification was not significant. In CHARLS (n=5,125), higher TyG-MLI remained associated with all-cause mortality (T3 vs T1 HR 2.90, 95% CI 1.69–4.99). ePWV mediation was small (≤8%). TyG-MLI independently predicts long-term mortality in CKM stages 0–3 and provides incremental information for all-cause risk stratification.2026 ESC Abstract-CZR-TyGMLI-WX