Joint association of insulin resistance, fatty liver and fibrosis indices with MACE and mortality in individuals with Cardiovascular-Kidney-Metabolic syndrome stages 0–3

Yanqiu Huang; Wen Gu; Yadan Xu; Minxi Lin; Jun Lu; Chenghao Zhang; Yan Wu; Dengke Wang; Xia Shen; Yang Yang; Hui Wang; Yanqiu Huang; Wen Gu; Yadan Xu; Minxi Lin; Jun Lu; Chenghao Zhang; Yan Wu; Dengke Wang; Xia Shen; Yang Yang; Hui Wang

doi:10.3934/publichealth.2026041

AIMS Public Health

2026, Volume 13, Issue 3: 761-782. doi: 10.3934/publichealth.2026041

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Research article Special Issues

Joint association of insulin resistance, fatty liver and fibrosis indices with MACE and mortality in individuals with Cardiovascular-Kidney-Metabolic syndrome stages 0–3

Yanqiu Huang ¹,
Wen Gu ¹,
Yadan Xu ¹,
Minxi Lin ²,
Jun Lu ³,
Chenghao Zhang ¹,
Yan Wu ¹,
Dengke Wang ^{4
,
,},
Xia Shen ^{5
,
,},
Yang Yang ^{1
,
,},
Hui Wang ^{1,6
,
,}

1.
Department of Food Hygiene and Nutrition, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
2.
NO.2 high school of East China Normal University, Shanghai, China
3.
School of Political Science and International Relations, East China Normal University, Shanghai, China
4.
Luohe Center for Disease Control and Prevention, Luohe, Henan, China
5.
Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
6.
Hainan International Medical Center, Shanghai Jiao Tong University School of Medicine, Hainan, China
These authors contributed equally.

Received: 27 April 2026 Revised: 18 June 2026 Accepted: 02 July 2026 Published: 20 July 2026

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.
- insulin resistance,
- fatty liver indices,
- fibrosis index,
- MACE,
- mortality,
- UK Biobank,
- NHANES
Citation: Yanqiu Huang, Wen Gu, Yadan Xu, Minxi Lin, Jun Lu, Chenghao Zhang, Yan Wu, Dengke Wang, Xia Shen, Yang Yang, Hui Wang. Joint association of insulin resistance, fatty liver and fibrosis indices with MACE and mortality in individuals with Cardiovascular-Kidney-Metabolic syndrome stages 0–3[J]. AIMS Public Health, 2026, 13(3): 761-782. doi: 10.3934/publichealth.2026041

Related Papers:

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.

Acknowledgments

The authors express their gratitude to the participants and staff of the NHANES, UK Biobank for their invaluable contributions to this study.

Funding

This study was supported by grants from the National Natural Science Foundation of China (82403381), the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2026ZB0556800), the National Key R&D Program of China (2022YFD2101500), the Sailing Program of Shanghai Rising-Star Program (24YF2722700), and Innovative research team of high-level local universities in Shanghai, and Medical-Engineering Cross Foundation of Shanghai Jiao Tong University (YG2025LC14).

Authors' contributions

H.W. had full access to all the data in the study, take responsibility for the integrity of the data and the accuracy of the data analysis. Y.Q.H., W.G., Y.D.X., M.X.L. and J.L. contribute equally to this work. Concept and design: Y.Q.H., Y.D.X. and W.G.; Acquisition, analysis, or interpretation of data: Y.Q.H., Y.D.X., Z.Y.Z., T.W., T.Y.S., Y.L., X.S., J.L., M.X.L., C.H.Z., Y.W. and H.W.; Drafting of the article: Y.Q.H., Y.Z., Y.D.X. and Y.Y.; Critical revision of the article for important intellectual content: All authors. Statistical analysis: Y.Q.H.; Obtained funding: Y.Y. and H.W.; Administrative, technical, or material support: X.S.; Supervision: H.W.

Conflict of interest

Hui Wang is an editor-in-chief for AIMS Public Health, Yang Yang is editorial board members of AIMS Public Health, and Hui Wang is guest editor for its Special Issue. They did not engage in the editorial review or the decision to publish this article. The authors declare no conflicts of interest.

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