The thyroid hormone receptor beta (THR-β) agonist resmetir for the treatment of liver fi brosis and steatohepatitis
https://doi.org/10.31146/1682-8658-ecg-244-12-113-118
Abstract
Subclinical elevations in thyroid-stimulating hormone (TSH) levels, a key indicator of thyroid dysfunction, positively correlate with biochemical markers of hepatocellular damage. The thyroid hormones triiodothyronine (T3) and thyroxine (T4) act as fundamental biochemical regulators, determining metabolic homeostasis in both hepatocytes and the body as a whole. An innovative class of drugs, THR-β agonists, target hepatocytes by selectively activating the THR-β receptor isoform, which is expressed primarily in the liver and regulates a number of metabolic processes. The high short-term efficacy and safety confirmed in the MAESTRO-NASH study have led to the consideration of resmetirom (and the THR-β agonist class as a whole) as a promising new treatment option for ASH and liver fibrosis. The antifibrotic potential of resmetirom was confirmed by the results of improvement in fibrosis stage ≥1 without worsening NAFLD activity in 24.2% of those receiving 80 mg and in 25.9% of those receiving 100 mg, versus 14.2% on placebo. A positive effect of therapy on key biochemical markers was revealed. Along with a significant decrease in the activity of liver enzymes (ALT, AST, GGT), a pronounced lipid-lowering effect on LDL was recorded: a decrease of 13.6% (80 mg) and 16.3% (100 mg) by week 24 versus a minimal change in the placebo group (+0.1%, p<0.001).
About the Authors
L. B. Lazebnik
Russian University of Medicine
Russian Federation
Russian Federation
E. V. Vinnitskaya
Moscow Clinical Scientific Center named after Loginov MHD
Russian Federation
Russian Federation
References
1. Chrysavgis L., Cholongitas E. From NAFLD to MASLD: what does it mean? Expert Review of Gastroenterology & Hepatology. 2024;18(6):217-221.
2. Hagström H. et al. 99% of patients with NAFLD meet MASLD criteria and natural history is therefore identical. Journal of hepatology. 2024;80(2): e76-e77.
3. Younossi Z.M., Zelber-Sagi S., Lazarus J.V. et al. Global Consensus Recommendations for Metabolic Dysfunction-Associated Steatotic Liver Disease and Steatohepatitis. Gastroenterology. 2025 Oct;169(5):1017-1032.e2. doi: 10.1053/j.gastro.2025.02.044.
4. Lazebnik L.B. Metabolicly associated fatty liver disease. Practical recommendations of the Scientific Society of Gastroenterologists of Russia. Part 1. Experimental and Clinical Gastroenterology. 2024;(10):5-10. (In Russ.) doi: 10.31146/1682-8658-ecg-230-10-5-10.@@ Лазебник Л.Б. Метаболически ассоциированная жировая болезнь печени. Практические рекомендации Научного общества гастроэнтерологов России. Часть 1. Экспериментальная и клиническая гастроэнтерология. 2024;(10): 5-10. doi: 10.31146/1682-8658-ecg-230-10-5-10.
5. Stepanova M., Younossi Z.M. Independent association between nonalcoholic fatty liver disease and cardiovascular disease in the US population. Clin Gastroenterol Hepatol. 2012;10(6):646-50. doi: 10.1016/j.cgh.2011.12.039.
6. Targher G., Mantovani A., Pichiri I. et al. Nonalcoholic fatty liver disease is independently associated with an increased incidence of chronic kidney disease in patients with type 1 diabetes. Diabetes Care. 2014;37(6):1729-36. doi: 10.2337/dc13-2704.
7. Ming J., Xu S., Gao B. et al. Non-alcoholic fatty liver disease predicts type 2 diabetes mellitus, but not prediabetes, in Xi’an, China: a five-year cohort study. Liver Int. 2015;35(11):2401-7. doi: 10.1111/liv.12851.
8. Sung K-C., Kim S.H.Interrelationship between fatty liver and insulin resistance in the development of type 2 diabetes. J Clin Endocrinol Metab. 2011;96(4):1093-7. doi: 10.1210/jc.2010-2190.
9. Tkachenko E.I., Grinevich V.B., Gubonina I.V., Kravchuk Y.A., Apcel V.Y., Ivanyuk E.S. Disease as a result of violations of the symbiotic relationship between the host and the microbiota with pathogens. Bulletin of the Russian Military Medical Academy. 2021;23(2):243-252. (in Russ.) doi: 10.17816/brmma58117.@@ Ткаченко Е.И., Гриневич В.Б., Губонина И.В., Кравчук Ю.А., Апчел В.Я., Иванюк Е.С. Болезни как следствие нарушений симбиотических взаимоотношений организма хозяина с микробиотой и патогенами. Вестн. Российской Военно-медицинской академии. 2021;23(2):243-252.
10. Lazebnik L.B., Turkina S.V. Enterohepatocentrism as the basis of human psychosomatic pathology. Experimental and Clinical Gastroenterology. 2023;(8):9-23. (In Russ.) doi: 10.31146/1682-8658-ecg-216-8-9-23.@@ Лазебник Л.Б., Туркина С.В. Энтерогепатоцентризм как основа психосоматической патологии человека. Экспериментальная и клиническая гастроэнтерология. 2023;216(8): 9-23. doi: 10.31146/1682-8658-ecg-216-8-9-23.
11. Mladenova I.L., Tan E.F., Ng J.Y., Sharma P. Non-alcoholic fatty liver disease (NAFLD) and its association to cardiovascular disease: A comprehensive meta-analysis. JRSM Cardiovasc Dis. 2025 Mar 21;14:20480040251325929. doi: 10.1177/20480040251325929.
12. Mladenić K. et al. The “Domino effect” in MASLD: The inflammatory cascade of steatohepatitis. European journal of immunology. 2024;54(4):2149641.
13. Solleiro-Villavicencio H. et al. Inflammation: a key mechanism connecting Metabolic-Associated Steatotic Liver Disease (MASLD) and Systemic Arterial Hypertension (SAH). Frontiers in Immunology. 2025;16:1620585.
14. Zimmerman Ya.S. Liver fibrosis: pathogenesis, diagnostic methods, treatment prospects. Clinical pharmacology and therapy. 2017;26(1):54-58.@@ Циммерман Я.С. Фиброз печени: патогенез, методы диагностики, перспективы лечения. Клиническая фармакология и терапия. 2017;26(1):54-58.
15. Lazebnik L.B., Golovanova E.V., Turkina S.V. et al. Non-alcoholic fatty liver disease in adults: clinic, diagnostics, treatment. Guidelines for therapists, third version. Experimental and Clinical Gastroenterology. 2021;1(1):4-52. (In Russ.) doi: 10.31146/1682-8658-ecg-185-1-4-52.@@ Лазебник Л.Б., Голованова Е.В., Туркина С.В. и др. Неалкогольная жировая болезнь печени у взрослых: клиника, диагностика, лечение. Рекомендации для терапевтов, третья версия. Экспериментальная и клиническая гастроэнтерология. 2021;1(1):4-52. doi: 10.31146/1682-8658-ecg-185-1-4-52.
16. Singh A., Sohal A., Batta A. GLP-1, GIP/GLP-1, and GCGR/GLP-1 receptor agonists: Novel therapeutic agents for metabolic dysfunction-associated steatohepatitis. World Journal of Gastroenterology. 2024;30(48):5205.
17. Mantovani A. et al. Glucagon-Like Peptide-1 Receptor Agonists Improve MASH and Liver Fibrosis: A Meta-Analysis of Randomised Controlled Trials. Liver International. 2025;45(9): e70256.
18. Zasadzińska M. et al. The Evolving Role of GLP-1 Receptor Agonists in MASLD: Current Evidence and Future Directions. Journal of Diabetology. 2025;16(3):214-222.
19. Gonzalez-Rellan M.J., Drucker D.J. The expanding benefits of GLP-1 medicines. Cell Reports Medicine. 2025;6(7).
20. Celletti F., Farrar J., De Regil L. World Health Organization Guideline on the Use and Indications of Glucagon-Like Peptide-1 Therapies for the Treatment of Obesity in Adults. JAMA. 2025 Dec 1. doi: 10.1001/jama.2025.24288.
21. Wang S. et al. Low thyroid function is associated with metabolic dysfunction-associated steatotic liver disease. JGH Open. 2024;8(2): e13038.
22. Krause C., Grohs M., El Gammal A.T. et al. Reduced expression of thyroid hormone receptor beta in human nonalcoholic steatohepatitis. Endocr Connect. 2018; 7(12): 1448-1456.
23. Bruinstroop E., Dalan R., Cao Y. et al. Low-dose levothyroxine reduces intrahepatic lipid content in patients with type 2 diabetes mellitus and NAFLD. Journal of Clinical Endocrinology and Metabolism. 2018. 103 2698-2706. doi: 10.1210/jc.2018-00475.
24. Mantovani, A. et al. Association between primary hypothyroidism and nonalcoholic fatty liver disease: a systematic review and meta-analysis. Thyroid. 2021;31(11), 1645-1655.
25. Sinha R.A., Singh B.K., Yen P.M. Direct effects of thyroid hormones on hepatic lipid metabolism. Nat Rev Endocrinol. 2018 May;14(5):259-269. doi: 10.1038/nrendo.2018.10.
26. Tkachenko, Elena Viktorovna. [The role of prostaglandins and constitutional hormones in the pathogenesis of chronic diseases of the hepatobiliary system: dissertation … Diss. Doctor of Medical Sciences: 03.00.04]. Moscow, 2006. 221 p. (in Russ.)@@ Ткаченко, Елена Викторовна. Роль простагландинов и конституциональных гормонов в патогенезе хронических заболеваний гепатобилиарной системы: диссертация … доктора медицинских наук: 03.00.04 / Ткаченко Елена Викторовна; [Место защиты: ГОУВПО «Российский государственный медицинский университет». - Москва, 2006. - 221 с.
27. Tkachenko EV, Varvanina GG. [Hormonal component of the gastrointestinal diseases pathogenesis]. Eksp Klin Gastroenterol. 2011;(2):27-30.Russian. PMID: 21563360.@@ Ткаченко Е.В., Варванина Г.Г. Гормональная составляющая патогенеза желудочно-кишечных заболеваний Экспериментальная и клиничнеская гастроэнтерология. 2011;(2):27-30.
28. Guo Z. et al. Association of non-alcoholic fatty liver disease with thyroid function: A systematic review and meta-analysis. Digestive and Liver Disease. 2018;50(11):1153-1162.
29. Guo W. et al. Free triiodothyronine is associated with hepatic steatosis and liver stiffness in euthyroid Chinese adults with non-alcoholic fatty liver disease. Frontiers in endocrinology. 2021;12:711956.
30. Avazova T., Rogelio P. Effects of Ursodeoxycholic Acid on Inflammatory Markers IL-6 and IL-17 in Patients with Metabolic Syndrome. Frontiers of Global Science. 2024;2(1):12-16.
31. Kim D., Yoo E.R., Li A.A. et al. Low-Normal thyroid function is associated with advanced fibrosis among adults in the United States. Clin Gastroenterol Hepatol. 2019; 17(11): 2379.
32. Harrison S.A. et al. Design of the phase 3 MAESTRO clinical program to evaluate resmetirom for the treatment of nonalcoholic steatohepatitis. Alimentary Pharmacology & Therapeutics. 2024;59(1):51-63.
33. Brennan P.N. et al. Reviewing MAESTRO-NASH and the implications for hepatology and health systems in implementation/accessibility of Resmetirom. npj Gut and Liver. 2025;2(1):3.
34. FDA Approves First Treatment for Patients with Liver Scarring Due to Fatty Liver Disease Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-patients-liver-scarring-due-fatty-liver- disease Date accessed: January 15, 2025.
35. Harrison S.A. et al. Identification and validation of pre-identified morphological baseline features for prediction of fibrosis progression in MAESTRO-NASH. J Hepatol. 2024;80(S1): S76.
36. Chen V.L. et al. Resmetirom therapy for metabolic dysfunction-associated steatotic liver disease: October 2024 updates to AASLD Practice Guidance. Hepatology. 2025;81(1):312-320.
37. Knezevic J. et al. Thyroid-gut-axis: how does the microbiota influence thyroid function? Nutrients. 2020; 12(6):1769.
38. Sun K. et al. A new mechanism of thyroid hormone receptor β agonists ameliorating nonalcoholic steatohepatitis by inhibiting intestinal lipid absorption via remodeling bile acid profiles. Acta Pharmacologica Sinica. 2024;45(10):2134-2148.
39. Udompap P. Resmetirom: Steatosis Down, Fibrosis Out, Peace of Mind In. Hepatology. 2025;81(4):1105-1106.
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For citations:
Lazebnik L.B., Vinnitskaya E.V. The thyroid hormone receptor beta (THR-β) agonist resmetir for the treatment of liver fi brosis and steatohepatitis. Experimental and Clinical Gastroenterology. 2025;(12):113-118. (In Russ.) https://doi.org/10.31146/1682-8658-ecg-244-12-113-118
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