Cholesterol, high-density lipoprotein, and glucose index predict the onset, progression, and prognosis of cardiovascular-kidney-metabolic syndrome: evidence from two large prospective cohorts

Background Cardiovascular-kidney-metabolic (CKM) syndrome represents a composite disease state driven by glucose and lipid metabolic dysregulation [1]. The Cholesterol, High-density lipoprotein, and Glucose (CHG) index reflects the composite burden of these metabolic factors [2]. Purpose To investigate the impact of the CHG index on the onset, stage-wise progression, and adverse prognosis across the entire CKM syndrome continuum. Methods This study utilised 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 an independent clinical 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, CAD). A causal forest algorithm was used to identify high-value subpopulations, and restricted cubic splines (RCS) characterised dose-response relationships. Results Figure 1 outlines the study design and main findings. The study included 370,916 participants free of CKM diseases from the UKB (median follow-up: 16.5 years) and 8,494 patients with CKM Stage 4 from the clinical cohort (median follow-up: 645 days). In the general population, each 1-standard deviation (SD) increase in the CHG index was significantly associated with an increased risk of incident T2DM (hazard ratio [HR]: 1.47; 95% confidence interval [CI]: 1.40–1.53), CVD (HR: 1.07; 95% CI: 1.06–1.09), and CKD (HR: 1.07; 95% CI: 1.04–1.10). Furthermore, elevated CHG significantly accelerated CKM progression from Stage 0–1 to 2–3 (HR: 1.16; 95% CI: 1.11–1.23) and from Stage 1–3 to 4 (HR: 1.06; 95% CI: 1.05–1.08) per 1-SD increase. In patients with established CAD, a 1-SD increase in CHG was associated with a higher risk of MACCE (HR: 1.12; 95% CI: 1.05–1.19). As Figure 2, subgroup analyses revealed significant interactions of the CHG index with high-sensitivity C-reactive protein (hs-CRP, P=0.047) and glycated haemoglobin (HbA1c, P=0.038). Furthermore, a causal forest algorithm, corroborated by SHapley Additive exPlanations (SHAP) analysis, identified hs-CRP and HbA1c as the primary drivers of prognostic heterogeneity. Specifically, both the adverse impact and the discriminative performance (time-dependent area under the curve) of elevated CHG for MACCE were significantly amplified in patients with low systemic inflammation (hs-CRP < 2 mg/L) and elevated glycemic levels (HbA1c > 6.5%). Conclusion(s) The CHG index demonstrates significant predictive value for the onset of component diseases, stage-wise progression, and adverse prognosis across the CKM syndrome continuum.Figure 1Figure 2