Abstract / Summary
Although the cardiovascular-kidney-metabolic (CKM) syndrome framework offers a structured approach to risk stratification, the identification of individuals in early CKM stages who are at heightened risk for subsequent progression to overt cardiovascular disease (CVD) poses a persistent clinical conundrum. The current study was designed to evaluate the predictive utility of the triglyceride-glucose-normalized creatinine-to-cystatin C ratio (TyG-NCCR), a novel multidimensional composite marker, for the transition from CKM stages 0–3 to stage 4. Utilizing follow-up data from the China Health and Retirement Longitudinal Study (CHARLS) spanning 2011 to 2020, the present work included 5,474 participants categorized as CKM stages 0–3 at baseline. Cox proportional hazards models were employed to assess the association between TyG-NCCR and incident CVD events. Restricted cubic splines (RCS) were utilized to characterize dose-response relationships. The predictive performance and clinical utility of TyG-NCCR were further evaluated through the concordance index (C-index), area under the curve (AUC), net reclassification improvement (NRI), integrated discrimination improvement (IDI), and decision curve analysis (DCA). Moreover, we independently replicated our principal findings in an external cohort using the UK Biobank dataset. In adjusted Cox models, each SD increase in TyG-NCCR was associated with higher risk of CKM progression in CHARLS (HR: 1.20, 95% CI: 1.13–1.29; p < 0.001), with similar findings in the UK Biobank. Kaplan‑Meier analysis demonstrated a graded increase in the cumulative risk of incident CKM stage 4 with ascending TyG‑NCCR quartiles ( p < 0.001). Moreover, restricted cubic spline regression uncovered a notable nonlinear dose‑response trend underlying this relationship. With respect to discriminative ability, TyG‑NCCR outperformed TyG and TG/HDL‑C in terms of C‑index and dynamic AUC at 5 and 8 years, and yielded statistically significant improvements in both NRI and IDI (all p < 0.05). Furthermore, joint exposure analysis revealed that the combination of elevated TyG and reduced NCCR, reflecting a “metabolic‑structural uncoupling” phenotype, was significantly correlated with heightened risk of CKM progression. TyG-NCCR was established as an independent predictor for the progression from early CKM to clinical stage 4 disease. This integrated biomarker concurrently reflects metabolic load alongside musculoskeletal reserve, offering superior risk stratification over traditional single-parameter indicators. Future interventional studies are warranted to determine its translational clinical utility.