The cholesterol, high-density lipoprotein, and glucose index and its derived indices predict cardiometabolic multimorbidity development and progression in metabolic dysfunction-associated steatotic liver disease individuals: a prospective cohort study

BACKGROUND: Dysregulation of cholesterol, high-density lipoprotein cholesterol, and glucose metabolism is thought to be an important metabolic link between metabolic dysfunction-associated steatotic liver disease (MASLD), type 2 diabetes (T2D), and cardiovascular disease. Although the cholesterol-high-density lipoprotein-glucose (CHG) index and its adiposity-derived indices have been associated with individual cardiometabolic diseases (CMDs), their associations with cardiometabolic multimorbidity (CMM), stage-specific disease progression, and risk prediction in individuals with MASLD remain unclear. METHODS: This prospective cohort study included 109,434 UK Biobank participants with MASLD and without T2D, coronary heart disease (CHD), or stroke at baseline. Eight CHG-related indices were evaluated. Incident CMM was defined as the occurrence of at least two of the three CMDs. Cox models estimated associations with incident CMM. Multistate models characterized transitions from a disease-free state to individual CMD and subsequently to CMM. Incremental prediction was assessed using the C-index, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Exploratory mediation analyses evaluated circulating biomarkers related to metabolic, inflammatory, hepatic and renal pathways. RESULTS: During a median follow-up of 16.4 years, 4225 participants developed CMM. All CHG-related indices were associated with higher CMM risk, with the strongest associations observed for CHG-waist-to-height ratio (CHG-WHtR; hazard ratio [HR] per 1-standard deviation [SD] increment, 1.61; 95% confidence interval [CI] 1.57-1.65) and CHG-waist circumference (CHG-WC; HR, 1.59; 95% CI, 1.55-1.63). Adding each index to conventional risk models improved discrimination and risk classification. CHG-WHtR and CHG-WC showed relatively favorable predictive performance, although the absolute differences between indices were modest. In multistate analyses, associations were strongest for disease-free to T2D and CHD-to-CMM transitions. Exploratory biomarker analyses showed that baseline biomarker domains related to glycemic regulation, lipid metabolism, inflammation, and hepatic and renal function were statistically linked to these associations. CONCLUSIONS: Among individuals with MASLD, CHG-related indices, particularly CHG-WHtR and CHG-WC, were associated with incident CMM and transition-specific disease progression and improved risk prediction. These readily available indices may help refine CMM risk stratification in MASLD.