External validation reveals setting-dependent performance of TyG-related indices for HbA1c-defined prediabetes

Prediabetes defined by glycated haemoglobin (HbA1c) can occur despite fasting plasma glucose (FPG) below 100 mg/dL, leaving a discordant glycaemic phenotype that FPG-based pathways may miss. We investigated whether triglyceride-glucose (TyG)-related indices identify this phenotype and whether their comparative performance is maintained across populations.

We analysed fasting-subsample data from seven US National Health and Nutrition Examination Survey (NHANES 2005-2018) cycles and an independent health-examination cohort from Pu'er Hospital of Traditional Chinese Medicine (2020-2026). The primary index was TyG-waist-to-height ratio (TyG-WHtR). Survey-weighted and local regression models quantified adjusted associations. Candidate prediction models were benchmarked against related metabolic indices and a model retaining FPG, triglycerides and WHtR as separate terms. Repeated cross-validation was performed in NHANES, after which all fitted models, transformations and thresholds were frozen for external validation.

Among 6,930 eligible NHANES participants, 1,206 had HbA1c-defined prediabetes, corresponding to a weighted prevalence of 12.7% [95% confidence interval (CI), 11.7%-13.7%]. The local cohort included 10,791 participants and 1,139 outcomes. Each cohort-specific standard deviation increase in TyG-WHtR was associated with higher outcome prevalence in NHANES (prevalence ratio, 1.239; 95% CI, 1.158-1.326) and locally (1.482; 1.407-1.561). The raw-component model showed repeated internal validation (area under the receiver operating characteristic curve, 0.746), whereas the metabolic score for insulin resistance led to frozen external validation (0.710; 0.693-0.727). TyG-WHtR was reproducibly associated with the outcome but was not the strongest discriminator in either setting. The gains in discrimination were modest, and this cross-sectional validation does not establish clinical utility.