Association of triglyceride–glucose and obesity-derived indices with the risk of aortic stenosis among individuals in cardiovascular–kidney–metabolic syndrome stages 0–3: a prospective cohort study from the UK Biobank

Background: Cardiovascular-kidney-metabolic (CKM) syndrome emphasizes the interplay between metabolic dysfunction, kidney injury, and cardiovascular abnormalities. The triglyceride-glucose (TyG) and its obesity-related derivatives have emerged as simple biomarkers for insulin resistance, yet their association with aortic stenosis (AS) risk in CKM syndrome stages 0-3 remains unclear. Methods: This prospective cohort study included 363,907 participants with CKM stages 0-3 from the UK Biobank. We calculated six TyG-related indices (TyG, TyG-BMI, TyG-Waist, TyG-WHR, TyG-WHtR, and TyG-ABSI) and evaluated their associations with incident AS using Cox proportional hazards and competing risk models. Mediation analysis assessed the role of systolic blood pressure (SBP), and incremental predictive value was evaluated using C-index and net reclassification index (NRI). Results: During 15.25 years of follow-up, 3,326 AS cases occurred. After full adjustment, each 1-SD increment in TyG-related indices was associated with 8-24% increased AS risk. Compared with the lowest tertile, the highest tertile showed 1.13-1.77-fold increased risk. All indices demonstrated linear dose-response relationships with AS. SBP mediated 12.1-18.1% of these associations. TyG-WHtR showed the greatest predictive improvement (C-index: 0.806; NRI: 0.308). Conclusions: TyG-related indices, particularly TyG-WHtR, are independently associated with AS risk in CKM syndrome stages 0-3, offering potential for early risk stratification and targeted prevention strategies.