Abstract
BackgroundCardiovascular-kidney-metabolic (CKM) syndrome represents a composite disease state driven by glucose and lipid metabolic dysregulation. The Cholesterol, High-density lipoprotein, and Glucose (CHG) index reflects the composite burden of these metabolic factors. However, its impact on the onset, stage-wise progression, and prognosis of CKM syndrome remains unclear.MethodsThis study utilized data from two large-scale prospective cohorts. In the UK Biobank (UKB) cohort, Fine-Gray proportional subdistribution hazards models were employed to investigate associations between CHG levels and the risk of incident cardiovascular disease (CVD), chronic kidney disease (CKD), and type 2 diabetes mellitus (T2DM), as well as the risk of progression from CKM Stage 0-1 to 2-3 and Stage 1-3 to 4. In the Beijing Anzhen Hospital cohort, Cox regression models assessed the impact of CHG on major adverse cardiovascular and cerebrovascular events (MACCE) in patients with CKM Stage 4 (established coronary artery disease). A causal forest algorithm was used to identify high-value subpopulations, and restricted cubic splines (RCS) characterized dose-response relationships. Sensitivity analyses were conducted to verify result robustness.ResultsThe study included 370,916 participants free of CKM diseases from UKB (median follow-up: 16.5 years) and 8,494 patients with CKM Stage 4 from Beijing Anzhen Hospital (median follow-up: 645 days). In the general population, each 1-SD increase in the CHG index was significantly associated with an increased risk of incident T2DM (HR: 1.47; 95% CI: 1.40-1.53), CVD (HR: 1.07; 1.06-1.09), and CKD (HR: 1.07; 1.04-1.10). Furthermore, elevated CHG significantly accelerated CKM progression from Stage 0-1 to 2-3 (HR: 1.16; 1.11-1.23) and from Stage 1-3 to 4 (HR: 1.06; 1.05-1.08) per 1-SD increase. In patients with established CAD (Stage 4), a 1-SD increase in CHG was associated with a higher risk of MACCE (HR: 1.12; 1.05-1.19). Machine learning analysis revealed that this prognostic impact was particularly pronounced in patients with low systemic inflammation and elevated HbA1c.ConclusionsThe CHG index demonstrates significant predictive value for the onset of component diseases, stage-wise progression, and adverse prognosis across the entire CKM syndrome continuum.Graphical abstract