Associations of baseline, cumulative, and longitudinal trajectories of the C-reactive protein–triglyceride-glucose index–frailty index composite (CTI-FI) with progression from cardiovascular-kidney-metabolic syndrome stages 0–2 to stages 3–4 or stage 4: a prospective cohort study from CHARLS

Cardiovascular-kidney-metabolic (CKM) progression may reflect both metabolic-inflammatory burden and accumulated frailty. We compared baseline, cumulative, and longitudinal CTI-FI measures in adults initially classified as CKM stages 0–2. We analyzed 3,277 adults with CKM stages 0–2 at baseline in the China Health and Retirement Longitudinal Study. Baseline and cumulative CTI-FI and two-wave longitudinal trajectories of CTI, FI, and CTI-FI were examined using Cox models, restricted cubic splines, subgroup analyses, discrimination analyses, decision-curve analyses, and sensitivity analyses. During follow-up, 918 participants progressed to CKM stages 3–4, including 302 who progressed to CKM stage 4. Compared with nonprogressors, participants who developed advanced CKM stages generally had higher CTI, FI, CTI-FI, and cumulative CTI-FI values. In fully adjusted models, each 1-SD increase in baseline CTI-FI (SD = 0.829) was associated with a higher hazard of incident CKM stage 4 (HR, 1.18; 95% CI, 1.07–1.32), and the association was stronger for cumulative CTI-FI (HR, 1.36; 95% CI, 1.23–1.50). Compared with the lowest cumulative CTI-FI tertile, the highest tertile was associated with a substantially increased risk of stage 4 (HR, 3.54; 95% CI, 2.38–5.25). For incident CKM stages 3–4, the corresponding HRs per 1-SD increase were 1.05 (95% CI, 0.98–1.12) for baseline CTI-FI and 1.14 (95% CI, 1.07–1.22) for cumulative CTI-FI. Compared with trajectory Class 1, Class 2 and Class 3 were associated with stage-4 h of 2.16 and 2.82, respectively, and stages 3–4 h of 1.39 and 1.58, respectively. Restricted cubic spline analyses suggested nonlinear dose-response patterns, particularly for cumulative CTI-FI. For stage 4, cumulative FI and cumulative CTI-FI showed the highest discrimination, with an AUC of 0.66 for each. In adults with early CKM stages, higher baseline and cumulative CTI-FI and adverse two-wave CTI-FI patterns were associated with progression to stages 3–4 and stage 4. Given the modest discrimination, CTI-FI is best considered a complementary measure for population-level risk stratification and longitudinal monitoring rather than an individual diagnostic or treatment-selection tool.