Semaglutide as a promising treatment for metabolic dysfunction‑associated steatotic liver disease

Authors

DOI:

https://doi.org/10.20883/medical.e1219

Keywords:

metabolic dysfunction-associated steatotic liver disease, semaglutide, liver cirrhosis

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent liver disorder globally, and if left untreated, it may progress to liver cirrhosis and even hepatocellular carcinoma. As of 2024, the European Association for the Study of the Liver Guidelines have recommended resmetirom as the only pharmacological treatment for adults with non-cirrhotic MASLD who have significant fibrosis (stage ≥2). However, lifestyle interventions and management of comorbidities, such as type 2 diabetes and obesity, remain the cornerstone of treatment. Glucagon-like peptide-1 receptor agonists, particularly semaglutide, have shown emerging promise in treating MASLD. Notably, the Phase III ESSENCE trial, presented in late 2024, demonstrated semaglutide's potential in improving liver fibrosis, confirmed through histological evaluation, marking a possible breakthrough for MASLD management. This review aims to synthesise current evidence on the efficacy of semaglutide in treating MASLD, highlighting its potential to fill a significant gap in the therapeutic options available for this growing global health concern.

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References

Younossi ZM, Golabi P, Paik JM, Henry A, Van Dongen C, Henry L. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology. 2023 Apr 1;77(4):1335-1347. doi: 10.1097/HEP.0000000000000004.

Rinella ME, Lazarus JV, Ratziu V, Francque SM, Sanyal AJ, Kanwal F, Romero D, Abdelmalek MF, Anstee QM, Arab JP, Arrese M, Bataller R, Beuers U, Boursier J, Bugianesi E, Byrne CD, Castro Narro GE, Chowdhury A, Cortez-Pinto H, Cryer DR, Cusi K, El-Kassas M, Klein S, Eskridge W, Fan J, Gawrieh S, Guy CD, Harrison SA, Kim SU, Koot BG, Korenjak M, Kowdley KV, Lacaille F, Loomba R, Mitchell-Thain R, Morgan TR, Powell EE, Roden M, Romero-Gómez M, Silva M, Singh SP, Sookoian SC, Spearman CW, Tiniakos D, Valenti L, Vos MB, Wong VW, Xanthakos S, Yilmaz Y, Younossi Z, Hobbs A, Villota-Rivas M, Newsome PN; NAFLD Nomenclature consensus group. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology. 2023 Dec 1;78(6):1966-1986. doi: 10.1097/HEP.0000000000000520.

Younossi Z, Tacke F, Arrese M, Chander Sharma B, Mostafa I, Bugianesi E, Wai-Sun Wong V, Yilmaz Y, George J, Fan J, Vos MB. Global Perspectives on Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis. Hepatology. 2019 Jun;69(6):2672-2682. doi: 10.1002/hep.30251.

Barb D, Repetto EM, Stokes ME, Shankar SS, Cusi K. Type 2 diabetes mellitus increases the risk of hepatic fibrosis in individuals with obesity and nonalcoholic fatty liver disease. Obesity (Silver Spring). 2021 Nov;29(11):1950-1960. doi: 10.1002/oby.23263.

Gruben N, Shiri-Sverdlov R, Koonen DP, Hofker MH. Nonalcoholic fatty liver disease: A main driver of insulin resistance or a dangerous liaison? Biochim Biophys Acta. 2014 Nov;1842(11):2329-2343. doi: 10.1016/j.bbadis.2014.08.004.

European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. Diabetologia. 2016 Jun;59(6):1121-40. doi: 10.1007/s00125-016-3902-y.

European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines on the Management of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Obes Facts. 2024;17(4):374-444. doi: 10.1159/000539371. Epub 2024 Jun 7. Erratum in: Obes Facts. 2024;17(6):658. doi: 10.1159/000541386.

Kanwal F, Shubrook JH, Adams LA, Pfotenhauer K, Wai-Sun Wong V, Wright E, Abdelmalek MF, Harrison SA, Loomba R, Mantzoros CS, Bugianesi E, Eckel RH, Kaplan LM, El-Serag HB, Cusi K. Clinical Care Pathway for the Risk Stratification and Management of Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology. 2021 Nov;161(5):1657-1669. doi: 10.1053/j.gastro.2021.07.049.

Sorli C, Harashima SI, Tsoukas GM, Unger J, Karsbøl JD, Hansen T, Bain SC. Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial. Lancet Diabetes Endocrinol. 2017 Apr;5(4):251-260. doi: 10.1016/S2213-8587(17)30013-X.

Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, Lingvay I, Rosenstock J, Seufert J, Warren ML, Woo V, Hansen O, Holst AG, Pettersson J, Vilsbøll T; SUSTAIN-6 Investigators. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016 Nov 10;375(19):1834-1844. doi: 10.1056/NEJMoa1607141.

Nauck MA, Meier JJ. MANAGEMENT OF ENDOCRINE DISEASE: Are all GLP-1 agonists equal in the treatment of type 2 diabetes? Eur J Endocrinol. 2019 Dec;181(6):R211-R234. doi: 10.1530/EJE-19-0566.

Yabut JM, Drucker DJ. Glucagon-like Peptide-1 Receptor-based Therapeutics for Metabolic Liver Disease. Endocr Rev. 2023 Jan 12;44(1):14-32. doi: 10.1210/endrev/bnac018.

Chen Y, Xu YN, Ye CY, Feng WB, Zhou QT, Yang DH, Wang MW. GLP-1 mimetics as a potential therapy for nonalcoholic steatohepatitis. Acta Pharmacol Sin. 2022 May;43(5):1156-1166. doi: 10.1038/s41401-021-00836-9.

Yuan X, Gao Z, Yang C, Duan K, Ren L, Song G. Comparing the effectiveness of long-term use of daily and weekly glucagon-like peptide-1 receptor agonists treatments in patients with nonalcoholic fatty liver disease and type 2 diabetes mellitus: a network meta-analysis. Front Endocrinol (Lausanne). 2023 Jun 5;14:1170881. doi: 10.3389/fendo.2023.1170881.

Newsome PN, Buchholtz K, Cusi K, Linder M, Okanoue T, Ratziu V, Sanyal AJ, Sejling AS, Harrison SA; NN9931-4296 Investigators. A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. N Engl J Med. 2021 Mar 25;384(12):1113-1124. doi: 10.1056/NEJMoa2028395.

Ratziu V, Francque S, Behling CA, Cejvanovic V, Cortez-Pinto H, Iyer JS, Krarup N, Le Q, Sejling AS, Tiniakos D, Harrison SA. Artificial intelligence scoring of liver biopsies in a phase II trial of semaglutide in nonalcoholic steatohepatitis. Hepatology. 2024 Jul 1;80(1):173-185. doi: 10.1097/HEP.0000000000000723.

Novo Nordisk A/S: Semaglutide 2.4mg demonstrates superior improvement in both liver fibrosis and MASH resolution in the ESSENCE trial n.d. https://www.novonordisk.com/news-and-media/news-and-ir-materials/news-details.html?id=171971 (accessed January 11, 2025).

Xie C, Alkhouri N, Elfeki MA. Role of incretins and glucagon receptor agonists in metabolic dysfunction-associated steatotic liver disease: Opportunities and challenges. World J Hepatol. 2024 May 27;16(5):731-750. doi: 10.4254/wjh.v16.i5.731.

Gad AI, Ibrahim NF, Almadani N, Mahfouz R, Nofal HA, El-Rafey DS, Ali HT, El-Hawary AT, Sadek AMEM. Therapeutic Effects of Semaglutide on Nonalcoholic Fatty Liver Disease with Type 2 Diabetes Mellitus and Obesity: An Open-Label Controlled Trial. Diseases. 2024 Aug 17;12(8):186. doi: 10.3390/diseases12080186.

Flint A, Andersen G, Hockings P, Johansson L, Morsing A, Sundby Palle M, Vogl T, Loomba R, Plum-Mörschel L. 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 Nov;54(9):1150-1161. doi: 10.1111/apt.16608.

Loomba R, Abdelmalek MF, Armstrong MJ, Jara M, Kjær MS, Krarup N, Lawitz E, Ratziu V, Sanyal AJ, Schattenberg JM, Newsome PN; NN9931-4492 investigators. Semaglutide 2·4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled phase 2 trial. Lancet Gastroenterol Hepatol. 2023 Jun;8(6):511-522. doi: 10.1016/S2468-1253(23)00068-7.

Volpe S, Lisco G, Fanelli M, Racaniello D, Colaianni V, Triggiani D, Donghia R, Crudele L, Rinaldi R, Sabbà C, Triggiani V, De Pergola G, Piazzolla G. Once-Weekly Subcutaneous Semaglutide Improves Fatty Liver Disease in Patients with Type 2 Diabetes: A 52-Week Prospective Real-Life Study. Nutrients. 2022 Nov 4;14(21):4673. doi: 10.3390/nu14214673.

Kitsunai H, Shinozaki Y, Furusawa S, Kitao N, Ito M, Kurihara H, Oba-Yamamoto C, Takeuchi J, Nakamura A, Takiyama Y, Nomoto H. The Effects of Oral Semaglutide on Hepatic Fibrosis in Subjects with Type 2 Diabetes in Real-World Clinical Practice: A Post Hoc Analysis of the Sapporo-Oral SEMA Study. Pharmaceuticals (Basel). 2025 Jan 19;18(1):129. doi: 10.3390/ph18010129.

Arai T, Atsukawa M, Tsubota A, Ono H, Kawano T, Yoshida Y, Okubo T, Hayama K, Nakagawa-Iwashita A, Itokawa N, Kondo C, Nagao M, Iwakiri K. Efficacy and safety of oral semaglutide in patients with non-alcoholic fatty liver disease complicated by type 2 diabetes mellitus: A pilot study. JGH Open. 2022 Jun 16;6(7):503-511. doi: 10.1002/jgh3.12780.

Alkhouri N, Herring R, Kabler H, Kayali Z, Hassanein T, Kohli A, Huss RS, Zhu Y, Billin AN, Damgaard LH, Buchholtz K, Kjær MS, Balendran C, Myers RP, Loomba R, Noureddin M. Safety and efficacy of combination therapy with semaglutide, cilofexor and firsocostat in patients with non-alcoholic steatohepatitis: A randomised, open-label phase II trial. J Hepatol. 2022 Sep;77(3):607-618. doi: 10.1016/j.jhep.2022.04.003.

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2025-03-31

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1.
Zasadzińska M, Borowski G. Semaglutide as a promising treatment for metabolic dysfunction‑associated steatotic liver disease. JMS [Internet]. 2025 Mar. 31 [cited 2025 Apr. 4];94(1):e1219. Available from: https://jmsnew.ump.edu.pl/index.php/JMS/article/view/1219