Triglyceride-glucose-related indices and risk of cardiovascular disease and mortality in individuals with cardiovascular–kidney–metabolic (CKM) syndrome stages 0–3: a prospective cohort study of 282,920 participants in the UK Biobank

BACKGROUND: Cardiovascular-kidney-metabolic (CKM) syndrome, proposed by the American Heart Association, is strongly linked to cardiovascular disease (CVD) incidence and mortality. Triglyceride-glucose (TyG)-related indices are established predictors of CVD risk, but their associations with CVD and mortality in individuals with CKM syndrome remain understudied. METHODS: This prospective study analyzed 282,920 UK Biobank participants with CKM syndrome stages 0-3, free of CVD at baseline. Four TyG-related indices were evaluated: TyG index, TyG-body mass index (BMI), TyG-waist circumference (TyG-WC), and TyG-waist-to-height ratio (TyG-WHtR). Outcomes, including overall CVD, coronary heart disease (CHD), stroke, all-cause mortality, and cardiovascular mortality, were identified via electronic medical records and death registries. Associations were analyzed via Cox proportional hazards and restricted cubic spline (RCS) models, with incremental predictive performance evaluated by the net reclassification index (NRI), integrated discrimination improvement (IDI), and area under the curve (AUC). RESULTS: During a median follow-up of 13.6 years, 27,134 overall CVD cases, 21,658 CHD, 6,717 strokes, 19,381 all-cause deaths, and 3,466 cardiovascular deaths occurred. Compared with the lowest quartile, the fully adjusted hazard ratios (HRs) for participants in the highest TyG quartile were 1.30 (95% CI 1.25-1.35) for overall CVD. Consistent positive associations were observed for TyG-BMI (HR: 1.49, 95% CI 1.43-1.55), TyG-WC (HR: 1.58, 95% CI 1.51-1.65), and TyG-WHtR (HR: 1.58, 95% CI 1.51-1.65). For all-cause mortality, HRs (95% CIs) in the highest versus the lowest quartile were 1.11 (1.06-1.16) for TyG-BMI, 1.24 (1.18-1.31) for TyG-WC, and 1.18 (1.13-1.24) for TyG-WHtR. Similar patterns were seen for cardiovascular mortality: TyG-BMI (HR: 1.42, 95% CI 1.27-1.59); TyG-WC(HR: 1.51, 95% CI 1.33-1.72); TyG-WHtR (HR: 1.48, 95% CI 1.31-1.67). RCS analyses revealed nonlinear associations between TyG-related indices and overall CVD (all P values for nonlinearity < 0.05), except for the TyG index, which showed a linear trend. Associations with cardiovascular mortality were predominantly linear. Furthermore, TyG-WHtR, TyG-WC, and TyG-BMI exhibited significantly higher NRI, IDI, and AUC values. CONCLUSION: Higher TyG-related indices, especially TyG-BMI, TyG-WC, and TyG-WHtR, were significantly associated with a higher risk of incident CVD and mortality in individuals with CKM syndrome stage 0 to 3. Integrating TyG indices with obesity measures could enhance the incremental predictive performance for prognostic outcomes in CKM syndrome patients.