Ethan Hardy

Background: Metabolic dysfunction-associated fatty liver disease (MAFLD), formerly known as non-alcoholic fatty liver disease (NAFLD), poses a significant global health challenge, affecting approximately 32.4% of the global population.^1-4 Characterized by hepatic lipid accumulation and associated complications such as liver fibrosis and hepatocellular carcinoma, this condition underscores the need for effective treatment strategies. Glucagon-like peptide-1 (GLP-1) agonists have emerged as promising therapeutic agents for MAFLD. However, it remains unclear whether their therapeutic effects are mediated through mechanisms such as weight loss and insulin sensitivity or if a more direct mechanism exists. Exploring the mechanisms of these medications and uncovering potential direct mechanisms could provide insights into MAFLD progression, facilitate the development of new drugs, and inform the selection of currently available GLP-1 agonists best suited to treat MAFLD.³

Objective: This review aims to explore the recent advancements and persistent challenges in understanding and treating MAFLD, with a specific focus on the potential role of GLP-1 agonists and any direct mechanisms that may exist independent of their effects on weight loss and glycemic control.

Search Methods: A comprehensive literature search was conducted utilizing databases such as PubMed, focusing on articles published between 2019 and 2024. Keywords including “MAFLD,” “NAFLD,” “MCT-diet,” and “GLP-1 agonists” were employed to identify relevant studies.

Results: GLP-1 agonists hold promise in the management of MAFLD by improving glycemic control, inducing weight loss, and modulating hepatic lipid metabolism. Recent research suggests that GLP-1 agonists may exert direct hepatic actions, including modulation of ceramide species, reduction of inflammation, attenuation of fibrosis, inhibition of mTOR mediated inflammation and downstream pathways, and changes to the gut microbiota, independent of their systemic effects.^5-8 Phase 1 clinical trials indicate that the GLP-1 agonist liraglutide elicits a reduction in liver fat content at all measured time points in the 72-week period.⁹ Furthermore, in rat models, GLP-1/glucagon receptor dual-agonists demonstrate enhanced efficacy compared to GLP-1 agonists alone, indicating a potential synergistic effect that may warrant further research and human exploration in the management of MAFLD.^7,8

Conclusion: Advancements in understanding the role of GLP-1 agonists, particularly their potential direct hepatic actions, offer promising avenues for the treatment of MAFLD. However, a general lack of understanding remains regarding the direct mechanisms of GLP-1 agonists on MAFLD. It appears that multiple potential pathways are involved, necessitating further exploration. Future research and clinical trials are warranted to elucidate the long-term efficacy, safety, and underlying mechanisms of GLP-1 agonists. Additionally, dual agonists, currently limited to rat models, show promise in the management of MAFLD, with potential effects greater than those observed with GLP-1 agonists alone. Novel therapeutic strategies are imperative for addressing the escalating burden of MAFLD on a global scale.

Works Cited:

1. Nevola R, Epifani R, Imbriani S, Tortorella G, Aprea C, Galiero R, Rinaldi L, Marfella R, Sasso FC. GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives. International Journal of Molecular Sciences. 2023; 24(2):1703. https://doi.org/10.3390/ijms24021703
2. Marinko Marušić, Matej Paić, Mia Knobloch, Ana-Marija Liberati Pršo, “NAFLD, Insulin Resistance, and Diabetes Mellitus Type 2”, Canadian Journal of Gastroenterology and Hepatology, vol. 2021, Article ID 6613827, 9 pages, 2021. https://doi.org/10.1155/2021/6613827
3. Fan S, Shi X, Yao J, Zhong M, Feng P. The efficacy of glucagon-like peptide 1 receptor agonists in patients with non-alcoholic fatty liver disease: a systematic review and meta-analysis of randomized controlled trials. Revista Española de Enfermedades Digestivas. Published online 2020. https://doi.org/10.17235/reed.2020.6392/2019
4. Lee HA, Kim HY. Therapeutic Mechanisms and Clinical Effects of Glucagon-like Peptide 1 Receptor Agonists in Nonalcoholic Fatty Liver Disease. International Journal of Molecular Sciences. 2023; 24(11):9324. https://doi.org/10.3390/ijms24119324
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6. Ao N, Ma Z, Yang J, et al. Liraglutide ameliorates lipotoxicity-induced inflammation through the mTORC1 signalling pathway. Peptides. 2020;133:170375-170375. doi:https://doi.org/10.1016/j.peptides.2020.170375
7. Monfeuga T, Norlin J, Bugge A, et al. Evaluation of long acting GLP1R/GCGR agonist in a DIO and biopsy-confirmed mouse model of NASH suggest a beneficial role of GLP-1/glucagon agonism in NASH patients. Molecular Metabolism. 2024;79:101850-101850. doi:https://doi.org/10.1016/j.molmet.2023.101850
8. Boland ML, Laker RC, Mather K, et al. Resolution of NASH and hepatic fibrosis by the GLP-1R/GcgR dual-agonist Cotadutide via modulating mitochondrial function and lipogenesis. Nat Metab. 2020;2(5):413-431. doi:10.1038/s42255-020-0209-6
9. Flint A, Andersen G, Hockings P, et al. Randomised clinical trial: semaglutide versus placebo reduced liver steatosis but not liver stiffness in subjects with non-alcoholic fatty liver disease assessed by magnetic resonance imaging. Aliment Pharmacol Ther. 2021; 54: 1150–1161. https://doi.org/10.1111/apt.16608