Association of cumulative cholesterol-HDL-glucose index with cardiovascular disease risk in individuals with cardiovascular-kidney-metabolic syndrome stages 0–3: a nationwide prospective cohort study

Abstract Background Cardiovascular–kidney–metabolic (CKM) syndrome integrates cardiovascular disease, chronic kidney disease, and metabolic risk factors, highlighting their interaction and shared progression. The cholesterol–HDL–glucose (CHG) index is an emerging surrogate marker of insulin resistance, and growing evidence suggests its association with cardiovascular disease risk. However, the association between cumulative CHG exposure and cardiovascular disease risk in the CKM stages 0–3 population remains unclear. Methods Data were obtained from the China Health and Retirement Longitudinal Study (CHARLS). A total of 3,002 participants with CKM stages 0–3 were included. Cumulative CHG exposure was assessed using CHG values measured at Wave 1 and Wave 3. K-means clustering was applied to classify participants into three groups based on CHG change patterns. Multivariable Cox proportional hazards regression models and restricted cubic spline (RCS) analyses were used to evaluate the association between cumulative CHG and incident cardiovascular disease (CVD). Receiver operating characteristic (ROC) curve analysis was further performed to assess the predictive performance of cumulative CHG for incident CVD and to compare it with cumulative TyG. Subgroup and sensitivity analyses were conducted to examine the robustness of the results. Results Among the 3,002 participants included in the analysis, 569 (19%) developed incident CVD during a median follow-up of 5 years. In the fully adjusted model, each one-unit increase in cumulative CHG was associated with a 13% higher risk of CVD (HR = 1.13, 95% CI: 1.04–1.23). Compared with participants in the lowest quartile, those in the highest quartile had a 34% higher risk of CVD (HR = 1.34, 95% CI: 1.02–1.75). Restricted cubic spline analysis indicated a linear association between cumulative CHG and CVD risk. When categorized by CHG clusters, CVD risk increased progressively from Cluster 1 (persistently low levels) to Cluster 2 (persistently moderate levels) and Cluster 3 (high levels with a moderate decrease over time) (P for trend < 0.05). ROC analysis showed that cumulative CHG had limited but comparable discrimination ability for incident CVD compared with cumulative TyG (3-year AUC: 0.560 vs. 0.554; 5-year AUC: 0.569 vs. 0.557; all P for DeLong test > 0.05). Conclusions In individuals with CKM stages 0–3, elevated cumulative CHG is associated with an increased risk of CVD. Cumulative CHG may help identify individuals at higher risk of CVD and provide evidence to support cardiovascular risk stratification and early preventive strategies.