Associations of baseline levels, cumulative exposure, and two-wave patterns of the combined triglyceride-glucose index and frailty index with progression from cardiovascular-kidney-metabolic syndrome stages 0–2 to stages 3–4 and stage 4: a prospective cohort study from CHARLS

BACKGROUND: The triglyceride-glucose index (TyG) and frailty index (FI) reflect metabolic dysregulation and multisystem vulnerability, respectively. However, the associations of the combined triglyceride-glucose index and frailty index (TyG-FI), its cumulative exposure, and two-wave patterns with progression from cardiovascular-kidney-metabolic (CKM) syndrome stages 0-2 to stages 3-4 and stage 4 remain unclear. METHODS: This CHARLS cohort study included 3,473 adults with CKM stages 0-2 at Wave 1 and repeat exposure and outcome assessments at Wave 3. TyG-FI was calculated as TyG × FI. Estimated cumulative TyG-FI combined the two measurements and their time interval; K-means clustering identified three two-wave patterns. Cox regression evaluated baseline TyG-FI, and logistic regression evaluated cumulative exposure and two-wave patterns. Discrimination, internal K-fold cross-validation, and sensitivity analyses were assessed. RESULTS: At Wave 3, 319 participants met CKM stage 4 criteria and 975 met CKM stages 3-4 criteria. In fully adjusted models, baseline TyG-FI was associated with stage 4 (HR per SD, 1.33; 95% CI, 1.20-1.47) and stages 3-4 (HR, 1.10; 95% CI, 1.03-1.18). The corresponding ORs for estimated cumulative TyG-FI were 1.83 (95% CI, 1.62-2.06) and 1.42 (95% CI, 1.29-1.56); highest-versus-lowest-tertile ORs were 12.40 (95% CI, 7.43-20.67) and 2.38 (95% CI, 1.86-3.04). TyG-FI pattern Class 3 was associated with stage 4 (OR, 5.93; 95% CI, 3.88-9.07) and stages 3-4 (OR, 2.30; 95% CI, 1.67-3.17). Spline associations were nonlinear. Baseline TyG-FI AUCs were 0.67 and 0.57 for the respective endpoints, with similar performance to FI. CONCLUSIONS: Higher baseline TyG-FI was associated with subsequent CKM progression, while cumulative TyG-FI and two-wave patterns were associated with progression status at follow-up. TyG-FI may provide an accessible composite measure for identifying individuals with early CKM syndrome who are at increased risk of advanced-stage progression.