Dual clinical utility of cholesterol, high density lipoprotein, and glucose index: from advanced cardiovascular-kidney-metabolic syndrome pathogenesis to inflammatory-mediated mortality across early-transitional stages

Abstract Background Cardiovascular-kidney-metabolic (CKM) syndrome represents an emerging notion focused on the interconnection among cardiovascular, renal, and metabolic disorders. The predictive value of the cholesterol-high-density lipoprotein-glucose (CHG) index for advanced CKM syndrome and its stage-stratified mortality risk across stages 0 to 3 remains uncertain. This research aims to examine the clinical importance of the CHG and the triglyceride-glucose (TyG) indices in characterizing the development of advanced CKM syndrome and predicting mortality within the 0–3 stage. Methods We processed the data from the National Health and Nutrition Examination Survey (NHANES) 2003–2018. Associations were evaluated using multivariate logistic regression for disease progression and Cox models with restricted cubic splines (RCS) for mortality outcomes, accompanied by threshold effect and mediation analyses. Results Using multivariable logistic regression models, we found that both the CHG index and the TyG index are positively related with advanced CKM syndrome. Multivariable-adjusted modeling showed a 44% increase in the threat of all-cause mortality for each 1-unit rise in the CHG index, while no association with cardiovascular mortality was found. RCS analysis revealed a J-curve pattern in the association of the CHG index with all-cause mortality and cardiovascular mortality, with thresholds of 5.16 and 5.27. Mediation analyses identified that alkaline phosphatase, neutrophils, and the systemic immune-inflammatory index mediated between 2.1% and 17.2% of the effect in the relationship between the CHG index and all-cause mortality. Conclusions The CHG index demonstrates dual clinical utility: stratifying patients with advanced CKM syndrome and predicting nonlinear mortality across the early progressive continuum (stages 0–3). Its J-shaped association with mortality suggests complex pathophysiological relationships requiring further investigation.