Non-alcoholic fatty liver disease and risk of fatal and non-fatal cardiovascular events: an updated systematic review and meta-analysis
Abstract
Background Studies have reported a significant association between non-alcoholic fatty liver disease (NAFLD) and increased incidence of cardiovascular disease (CVD). However, the magnitude of the risk and whether this risk changes with the severity of NAFLD remains uncertain. We performed a meta-analysis of observational studies to quantify the magnitude of the association between NAFLD and risk of incident CVD events.Methods We systematically searched PubMed, Scopus, and Web of Science from database inception to July 1, 2021, to identify eligible observational studies examining the risk of incident CVD events amongst adult (age ≥18 years) individuals with and without NAFLD and in which NAFLD was diagnosed by imaging, International Classification of Diseases codes, or liver biopsy. The primary outcomes were CVD death, non-fatal CVD events, or both. Data from selected studies were extracted, and meta-analysis was performed using random-effects models to obtain summary hazard ratios (HRs) with 95% CIs. The quality of the evidence was assessed with the Cochrane risk of bias tool. This study is registered on Open Science Framework, number osf.io/5z7gf.Findings We identified 36 longitudinal studies with aggregate data on 5 802 226 middle-aged individuals (mean age 53 years [SD 7]) and 99 668 incident cases of fatal and non-fatal CVD events over a median follow-up of 6·5 years (IQR 5·0-10·2). NAFLD was associated with a moderately increased risk of fatal or non-fatal CVD events (pooled random-effects HR 1·45, 95% CI 1·31-1·61; I 2=86·18%). This risk markedly increased across the severity of NAFLD, especially the stage of fibrosis (pooled random-effects HR 2·50, 95% CI 1·68-3·72; I 2=73·84%). All risks were independent of age, sex, adiposity measures, diabetes, and other common cardiometabolic risk factors. Sensitivity analyses did not modify these results.Interpretation NAFLD is associated with an increased long-term risk of fatal or non-fatal CVD events. CVD risk is further increased with more advanced liver disease, especially with higher fibrosis stage. These results provide evidence that NAFLD might be an independent risk factor for CVD morbidity and mortality.Funding None.
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Overall, individuals with MASLD have a higher risk of non-fatal cardiovascular disease (HR 1.40).
“Overall, individuals with MASLD have a higher risk of non-fatal cardiovascular disease (HR 1.40), 25”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [25]
The ‘NAFLD and risk of CVD events’ section (p. 9) reports a pooled HR of 1.40 for nonfatal CVD events alone. The analysis concerns people with NAFLD, however; our copy does not establish that the estimate applies specifically to people meeting MASLD criteria. (LLM, conf=0.84)
Experimental — accuracy not yet measuredSome studies indicated a higher risk of cardiovascular disease-related mortality (HR 1.30), while others did not confirm this result in the general population, but only in those with biopsy-proven MASH or other risk factors like T2D.
“Although some studies indicated a higher risk of cardiovascular disease-related mortality (HR 1.30), 25,26 others did not con fi rm this result in the general population, but only in those with biopsy-proven MASH 24 or other risk factors like T2D. 15”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [25]
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Miyamori, D., Tanaka, M., Sato, T., Endo, K., Mori, K., Mikami, T., Hosaka, I., Hanawa, N., Ohnishi, H., & Furuhashi, M. (2023) · Journal of the American Heart Association · doi:10.1161/jaha.123.030269 · Cited by 34 · see citing works
Endpoints in NASH Clinical Trials: Are We Blind in One Eye?
Lonardo, A., Ballestri, S., Mantovani, A., Targher, G., & Bril, F. (2024) · Metabolites · doi:10.3390/metabo14010040 · Cited by 34 · see citing works
Self-citationNAFLD as a continuous driver in the whole spectrum of vascular disease
Li, W., Liu, J., Cai, J., Zhang, X., Zhang, P., She, Z., Chen, S., & Li, H. (2021) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2021.10.007 · Cited by 34 · see citing works
Endothelial Dysfunction in Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis
Theofilis, P., Vordoni, A., Nakas, N., & Kalaitzidis, R. (2022) · Life · doi:10.3390/life12050718 · Cited by 34 · see citing works
Baratta, F., D’Erasmo, L., Bini, S., Pastori, D., Angelico, F., Ben, M. D., Arca, M., & Costanzo, A. D. (2022) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2022.08.011 · Cited by 34 · see citing works
- Authors
- Mantovani, A., Csermely, A., Petracca, G., Beatrice, G., Corey, K. E., Simon, T. G., Byrne, C. D., & Targher, G.
- Affiliations
- University of Verona (IT)
- Harvard University (US)
- Southampton General Hospital (GB)
- Corresponding author
- Targher, Giovanni
- ORCID
- Venue
- The Lancet Gastroenterology & Hepatology
- Publisher
- Elsevier BV
- Published
- 2021-11
- Volume
- 6
- Issue
- 11
- Pages
- 903-913
- ISSN
- 2468-1156 (ISSN-L)
- 2468-1253
- OpenAlex
- W3201276384
- Cited by
- 674
- References
- 75
- Citations by year
- 2026: 160 · 2025: 151 · 2024: 141 · 2023: 122 · 2022: 95 · 2021: 4
- FWCI
- 13.85
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- The Lancet. Gastroenterology & hepatology (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- Funders
- National Institute for Health Research Southampton Biomedical Research Centre (IS-BRC-20004)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- non-alcoholic fatty liver disease, cardiovascular disease, cardiovascular mortality, cardiovascular events, liver fibrosis, disease severity, cardiometabolic risk factors, cardiovascular risk factors, middle-aged adults, NAFLD staging
- MeSH terms
- Cardiovascular Diseases, Humans, Risk Factors, Severity of Illness Index, Models, Statistical, Survival Analysis, Observational Studies as Topic, Non-alcoholic Fatty Liver Disease
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