Triglyceride-glucose index demonstrates false-positive association with cardiometabolic multimorbidity progression in cardiometabolic disease patients: Observation and Mendelian randomization study

The Triglyceride-Glucose (TyG) index is a recognized predictor for incident cardiometabolic diseases (CMDs) and cardiometabolic multimorbidity (CMM) in general populations. However, its utility for predicting progression from single CMD to CMM among patients with existing CMD remains unverified. This study combined retrospective cohort analyses (cross-sectional cohorts: China Health and Retirement Longitudinal Study [CHARLS]-1, n = 5415; First Affiliated Hospital of Shantou University Medical Center, n = 544; longitudinal cohort: CHARLS-2, n = 1866) with Mendelian randomization to evaluate this relationship. Cross-sectional analyses initially indicated positive associations between elevated TyG index and CMM progression (per-standard deviation increase: CHARLS-1 adjusted odds ratio [OR] = 1.43, 95% confidence interval [CI]: 1.30-1.57; First Affiliated Hospital of Shantou University Medical Center adjusted OR = 1.75, 95% CI: 1.33-2.31). However, longitudinal analysis showed no significant association after multivariable adjustment (hazard ratio = 0.87, 95% CI: 0.73-1.02). Crucially, Mendelian randomization analysis with sequential exclusion of confounder-associated single nucleotide polymorphisms (glucose, triglycerides, and body mass index) revealed no causal relationship (Model 3 inverse-variance weighted OR = 0.647, 95% CI: 0.412-1.014). These findings demonstrate that the apparent association between TyG index and CMM progression in patients with baseline CMD is likely a false-positive result attributable to residual confounding, with no causal link supported by rigorous longitudinal or genetic evidence. Thus, while TyG is valuable for predicting initial CMD onset, it lacks clinical utility for forecasting progression to multimorbidity in established patients, necessitating exploration of alternative biomarkers for this critical transition.