Associations between glucolipid metabolic indices with the risk and progression of cardiovascular-kidney-metabolic syndrome in MASLD: evidence from the UK biobank

Abstract

Metabolic dysfunction–associated steatotic liver disease (MASLD) affects nearly one-third of the global population and increases the risk of adverse hepatic and extrahepatic outcomes. However, its contribution to multimorbidity trajectories remains insufficiently defined. The current Cardiovascular -Kidney-Metabolic (CKM) framework emphasizes systemic metabolic interactions but does not explicitly account for hepatic dysfunction. We compared the predictive performance of biomarkers reflecting insulin resistance, inflammation, and metabolic dysregulation in individuals with MASLD to identify key determinants of CKM progression and assess the rationale for an expanded Cardiovascular -Kidney-Metabolic-Liver (CKML) paradigm. We analyzed 126,907 participants from the prospective UK Biobank cohort with baseline MASLD and no CKM syndrome. Indices of insulin resistance, inflammation, and metabolic dysfunction were evaluated. Associations with incident and progressive CKM were examined using Cox models, restricted cubic splines, and multi-state analyses. Discrimination was assessed by area under the curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Proteomic profiling explored molecular mediators linking leading indices to CKM outcomes. During a median follow-up of 15.7 years, 28.2% of participants developed at least one CKM condition. Indices reflecting insulin resistance showed superior predictive performance compared with inflammatory and conventional metabolic markers. Each standard deviation increase in the triglyceride–glucose index adjusted for waist-to-height ratio (TyG-WHtR) was associated with 40%, 60%, and 80% higher risks of developing one, two, and three CKM conditions, respectively (all P < 0.001); similar gradients were observed for TyG-WC. RCS analyses further revealed significant non-linear associations between indices and CKM disease risk. Multi-state analyses confirmed that TyG-WHtR, TyG-WC, and the HbA1c/HDL-C ratio predicted stepwise CKM progression and achieved higher AUC, NRI, and IDI values than comparator markers. Proteomic mediation analyses suggested partially overlapping mechanisms: PRAP1 uniquely mediated TyG-derived risk (~30%), whereas GDF15 and LGALS4 explained 18–22% of excess risk across composite indices. Composite glycolipid indices—particularly HbA1c/HDL-C and TyG-based metrics—outperformed isolated metabolic and inflammatory markers in predicting CKM progression among individuals with MASLD. These findings support incorporating hepatic metabolic dysfunction into multimorbidity risk stratification frameworks.Graphic Abstract