Predictive value of triglyceride-glucose-related indices for major adverse cardiovascular events in individuals with cardiovascular-kidney-metabolic syndrome stage 0–3: a prospective cohort study based on CHARLS

Cardiovascular-kidney-metabolic (CKM) syndrome, proposed by the American Heart Association in 2023, describes a progressive continuum from metabolic risk factors to end-stage cardiorenal damage. Stages 0–3 represent a critical early intervention window, yet simple risk stratification tools for this population remain limited. This study aimed to systematically compare the predictive performance of 7 triglyceride-glucose (TyG)-derived indices for major adverse cardiovascular events (MACE) and its components, and to explore potential pathophysiological pathways in middle-aged and older Chinese adults with early-stage CKM syndrome. We enrolled 6,782 participants aged ≥ 45 years with CKM stages 0–3 from the China Health and Retirement Longitudinal Study (CHARLS, 2011–2018). Cox proportional hazards models, integrated discrimination improvement (IDI), and continuous net reclassification improvement (cNRI) were used to evaluate the predictive value of each index. Exploratory mediation analysis under the counterfactual framework was performed to explore potential pathway effects. A total of 1,441 MACE events were documented during a median follow-up of 7 years. In the fully adjusted model, TyG-CVAI exhibited relatively favorable discriminative performance for composite MACE (C-statistic = 0.639, IDI = 0.0025, cNRI = 0.092). The absolute differences in discriminative performance across indices were modest, and IDI and cNRI estimates varied by index. Marked outcome-specific heterogeneity was observed: TyG-CVAI was independently associated with non-fatal myocardial infarction (HR = 1.21, 95% CI 1.12–1.31, P < 0.001) and non-fatal stroke (HR = 1.30, 95% CI 1.15–1.46, P < 0.001), while CTI showed the strongest prediction for all-cause mortality (HR = 1.55, 95% CI 1.25–1.91, P < 0.001). Systolic blood pressure accounted for the highest proportion of mediated effects, with estimated mediated proportions of 14.5%–23.4%. Modest but consistent CRP-mediated effects were also observed across 6 indices. Distinct TyG-derived indices capture different dimensions of insulin resistance-related risk and offer complementary prognostic value. These findings provide evidence to support cardiovascular risk stratification and targeted intervention in early-stage CKM syndrome.