Insulin resistance–related indices, sarcopenia, and cardiovascular risk in CKM stages 1–3: a prospective cohort study from CHARLS

BACKGROUND: Sarcopenia often coexists with metabolic and renal dysfunction and may increase cardiovascular disease (CVD) risk. Insulin resistance (IR) is a key mechanism linking sarcopenia and cardiometabolic disorders. However, evidence on IR-related indices and CVD risk among individuals with sarcopenia across cardiovascular-kidney-metabolic (CKM) stages remains limited. This study aimed to examine associations between multiple IR-related indices and incident CVD, and to evaluate their predictive and mediating roles across CKM stages 1-3 and sarcopenia status. METHODS: We analysed 5,965 adults with CKM stages 1-3 from the China Health and Retirement Longitudinal Study (CHARLS), categorised as no sarcopenia, possible sarcopenia, or sarcopenia. We assessed associations between sarcopenia, eight IR-related indices-including triglyceride-glucose index-body mass index (TyG-BMI) and estimated glucose disposal rate (eGDR)-and incident CVD using Cox and the Fine-Gray competing risks model. Missing data were handled by multiple imputation. Dose-response relationships were evaluated with restricted cubic splines, and predictive performance was assessed with the area under the receiver operating characteristic curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Mediation and sensitivity analyses explored potential pathways and the robustness of the results. RESULTS: 63.8% of participants had possible sarcopenia or sarcopenia and were at higher risk of incident CVD and all-cause mortality. Mean follow-up was approximately 9 years. TyG-BMI was positively associated with CVD risk (HR = 3.58, 95% CI 2.50-5.14), whereas eGDR was inversely associated (HR = 0.36, 95% CI 0.28-0.47). The combined TyG-BMI and eGDR model improved CVD risk discrimination (AUC = 0.614, 95% CI 0.595-0.634), with gains in NRI (0.117, 95% CI 0.058-0.161) and IDI (0.013, 95% CI 0.007-0.023). IR-related indices accounted for 20%-46% of the association between CKM stage 3 (vs. stage 1) and CVD. CONCLUSION: Possible sarcopenia and sarcopenia were associated with increased CVD risk, particularly in CKM stage 3. IR-related indices, especially TyG-BMI and eGDR, were strongly associated with CVD risk and improved prediction, suggesting that IR may partially mediate the impact of CKM progression and sarcopenia on CVD outcomes.