AIMS Public Health. 2026 Jul 20;13(3):761-782. doi: 10.3934/publichealth.2026041. eCollection 2026.
ABSTRACT
Both fatty liver/fibrosis and insulin resistance (IR) contribute to the development of Cardiovascular-Kidney-Metabolic (CKM) syndrome and elevate cardiovascular risk. This study aimed to investigate the joint associations of IR and fatty liver/fibrosis indices with major adverse cardiovascular events (MACE) and mortality in individuals with CKM syndrome stages 0-3. This study enrolled 259,699 and 6808 CKM syndrome stages 0-3 from the UK Biobank (UKB) and the National Health and Nutrition Examination Survey (NHANES). Two IR-related indices (triglyceride-glucose index, TyG; cardiometabolic index, CMI), fatty liver indices (Fatty Liver Index, FLI; Hepatic Steatosis Index, HSI), and liver fibrosis score (LiverRisk score, LRS) were calculated to construct composite indices. Multivariable Cox proportional hazards models, restricted cubic splines, Kaplan-Meier analyses, and time-dependent receiver operating characteristic curves were employed to assess prognostic associations. Mediation modeling and proteomic enrichment analyses provided a robust framework for exploring the potential pathophysiological pathways. In the UKB, elevated levels of the IR-FLI/HSI/LRS indices were significantly associated with increased risks of MACE and mortality, with consistent findings observed for all-cause and CVD mortality in the NHANES. Significant positive nonlinear relationships were established between the CMI-FLI/HSI/LRS indices and the risk of MACE. Furthermore, these composite indices demonstrated superior 10-year predictive performance compared to individual IR-related indices, and the combination of CMI and LRS showed the best performance for predicting cardiovascular mortality in both cohorts, with AUCs of 0.755 in the UKB and 0.847 in the NHANES. Mediation analysis revealed that C-reactive protein, neutrophils, and leukocytes partially mediated these associations (ratio 5.3%-14.8%). Proteomic analyses identified cytokine-cytokine receptor interactions as a primary regulatory hub, while leukocyte migration, chemotaxis, and neutrophil degranulation emerged as potential effector mechanisms implicated in this process. IR-fatty liver/fibrosis indices are significantly associated with MACE and mortality and may serve as promising biomarkers for early screening and targeted intervention in CKM stages 0-3.
PMID:42909327 | PMC:PMC13684069 | DOI:10.3934/publichealth.2026041