nach oben

Erschienen in:

06.01.2024

Emerging Drug Therapies for Metabolic Dysfunction-Associated Steatotic Liver Disease: A Glimpse into the Horizon

verfasst von: Jorge Arnold, Francisco Idalsoaga, Luis Antonio Díaz, Daniel Cabrera, Francisco Barrera, Juan Pablo Arab, Marco Arrese

Erschienen in: Current Hepatology Reports | Ausgabe 1/2024

Einloggen, um Zugang zu erhalten

Abstract

Purpose of Review

Metabolic dysfunction–associated steatotic liver disease (MASLD) and its aggressive form, metabolic dysfunction-associated steatohepatitis (MASH), are highly prevalent and can lead to fibrosis, cirrhosis, hepatocellular carcinoma, and liver failure. Currently, there is no approved pharmacological treatment for MASLD. In this review, we aim to summarize recent data on therapeutic agents under study in phase 2 and 3 trials.

Recent Findings

Building on a better understanding of MASLD/MASH pathophysiology, a myriad of drugs has been developed. Recent results from clinical trials show promise, with some candidates demonstrating positive outcomes in phase 3 trials that are predictably expected to be approved in the near future. Notably, resmetirom, a thyroid receptor β agonist, is likely to be approved in 2024.

Summary

In the coming years, results from several landmark trials will be available and will likely provide options to prevent progression to cirrhosis and adverse liver outcomes in patients with MASLD/MASH.

A recent multinational effort led by the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver, the Latin American Association for the Study of the Liver as well as other societies and organizations aimed to re-address the issue of the nomenclature and classification of hepatic steatosis (1). In the new proposal, excessive fat accumulation in the liver is now referred to as steatotic liver disease (SLD), which serves as an overarching term to encompass the various etiologies of excessive lipid accumulation in the liver. This overarching term includes steatosis due to metabolic dysfunction, now termed MASLD, steatosis in the context of alcohol-related liver disease (ALD), steatosis in the context of MASLD and increased alcohol intake (named Met-ALD), and other etiologies. The more aggressive form of MASLD is now called metabolic dysfunction–associated steatohepatitis (MASH). Initial analyses suggest that MASLD/MASH overlaps with NAFLD in 98% of the cases and therefore these terms can be used interchangeably.

•• Rinella ME, Lazarus JV, Ratziu V, Francque SM, Sanyal AJ, Kanwal F, et al. A multi-society Delphi consensus statement on new fatty liver disease nomenclature. Ann Hepatol. 2023;101133. https://doi.org/10.1016/j.aohep.2023.101133. A landmark paper describing the process leading to a new nomenclature of fatty liver diseases.

Riazi K, Azhari H, Charette JH, Underwood FE, King JA, Afshar EE, et al. The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2022;7:851–61. https://doi.org/10.1016/S2468-1253(22)00165-0.CrossRefPubMed

Le MH, Yeo YH, Li X, Li J, Zou B, Wu Y, et al. 2019 Global NAFLD prevalence: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2022;20:2809-17.e28. https://doi.org/10.1016/j.cgh.2021.12.002.CrossRefPubMed

Wong VW-S, Ekstedt M, Wong GL-H, Hagström H. Changing epidemiology, global trends, and implications for outcomes of NAFLD. J Hepatol. 2023;79:842–52. https://doi.org/10.1016/j.jhep.2023.04.036.

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;77:1335–47. https://doi.org/10.1097/HEP.0000000000000004.CrossRefPubMed

Arrese M, Barrera F, Triantafilo N, Arab JP. Concurrent nonalcoholic fatty liver disease and type 2 diabetes: diagnostic and therapeutic considerations. Expert Rev Gastroenterol Hepatol. 2019;13:849–66. https://doi.org/10.1080/17474124.2019.1649981.CrossRefPubMed

• Huang DQ, Terrault NA, Tacke F, Gluud LL, Arrese M, Bugianesi E, et al. Global epidemiology of cirrhosis - aetiology, trends, and predictions. Nat Rev Gastroenterol Hepatol. 2023;20:388–98. https://doi.org/10.1038/s41575-023-00759-2. (Important review describing changing trends in cirrhosis etiology worldwide.)CrossRefPubMedPubMedCentral

Huang DQ, Singal AG, Kono Y, Tan DJH, El-Serag HB, Loomba R. Changing global epidemiology of liver cancer from 2010 to 2019: NASH is the fastest growing cause of liver cancer. Cell Metab. 2022;34:969-77.e2. https://doi.org/10.1016/j.cmet.2022.05.003.CrossRefPubMedPubMedCentral

Majumdar A, Tsochatzis EA. Changing trends of liver transplantation and mortality from non-alcoholic fatty liver disease. Metabolism. 2020;111S:154291. https://doi.org/10.1016/j.metabol.2020.154291.CrossRefPubMed

10.

Ren Z, Wesselius A, Stehouwer CDA, Brouwers MCGJ. Cardiovascular implications of metabolic dysfunction-associated fatty liver disease. Endocrinol Metab Clin North Am. 2023;52:459–68. https://doi.org/10.1016/j.ecl.2023.01.002.CrossRefPubMed

11.

Thomas JA, Kendall BJ, Dalais C, Macdonald GA, Thrift AP. Hepatocellular and extrahepatic cancers in non-alcoholic fatty liver disease: a systematic review and meta-analysis. Eur J Cancer. 2022;173:250–62. https://doi.org/10.1016/j.ejca.2022.06.051.CrossRefPubMed

12.

Ng CH, Lim WH, Hui Lim GE, Hao Tan DJ, Syn N, Muthiah MD, et al. Mortality outcomes by fibrosis stage in nonalcoholic fatty liver disease: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2023;21:931-9.e5. https://doi.org/10.1016/j.cgh.2022.04.014.CrossRefPubMed

13.

Vilar-Gomez E, Calzadilla-Bertot L, Wai-Sun Wong V, Castellanos M, Aller-de la Fuente R, Metwally M, et al. Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi-national cohort study. Gastroenterology. 2018;155:443–57.e17. https://doi.org/10.1053/j.gastro.2018.04.034.

14.

• Younossi ZM, Zelber-Sagi S, Henry L, Gerber LH. Lifestyle interventions in nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol. 2023. https://doi.org/10.1038/s41575-023-00800-4. (Excellent review on lifestyle interventions in MASLD/MASH, which remains the cornerstone of treatment.)CrossRefPubMed

15.

•• Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, Abdelmalek MF, Caldwell S, Barb D, et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023;77:1797–835. https://doi.org/10.1097/HEP.0000000000000323. (Latest version of the American Association for the study of liver diseases guidance on NAFLD.)CrossRefPubMed

16.

Younossi ZM, Corey KE, Lim JK. AGA clinical practice update on lifestyle modification using diet and exercise to achieve weight loss in the management of nonalcoholic fatty liver disease: expert review. Gastroenterology. 2021;160:912–8. https://doi.org/10.1053/j.gastro.2020.11.051.CrossRefPubMed

17.

Long MT, Noureddin M, Lim JK. AGA clinical practice update: diagnosis and management of nonalcoholic fatty liver disease in lean individuals: expert review. Gastroenterology. 2022;163:764-74.e1. https://doi.org/10.1053/j.gastro.2022.06.023.CrossRefPubMed

18.

•• Harrison SA, Loomba R, Dubourg J, Ratziu V, Noureddin M. Clinical Trial Landscape in NASH. Clin Gastroenterol Hepatol. 2023;21:2001–14. https://doi.org/10.1016/j.cgh.2023.03.041. (Excellent review on the status of various agents for the treatment of MASH.)CrossRefPubMed

19.

Ratziu V, Friedman SL. Why do so many nonalcoholic steatohepatitis trials fail? Gastroenterology. 2023;165:5–10. https://doi.org/10.1053/j.gastro.2020.05.046.CrossRefPubMed

20.

Vuppalanchi R, Noureddin M, Alkhouri N, Sanyal AJ. Therapeutic pipeline in nonalcoholic steatohepatitis. Nat Rev Gastroenterol Hepatol. 2021;18:373–92. https://doi.org/10.1038/s41575-020-00408-y.CrossRefPubMed

21.

Tilg H, Byrne CD, Targher G. NASH drug treatment development: challenges and lessons. Lancet Gastroenterol Hepatol. 2023;8:943–54. https://doi.org/10.1016/S2468-1253(23)00159-0.CrossRefPubMed

22.

Grander C, Grabherr F, Tilg H. Non-alcoholic fatty liver disease: pathophysiological concepts and treatment options. Cardiovasc Res. 2023;119:1787–98. https://doi.org/10.1093/cvr/cvad095.CrossRefPubMedPubMedCentral

23.

Arab JP, Arrese M, Trauner M. Recent insights into the pathogenesis of nonalcoholic fatty liver disease. Annu Rev Pathol. 2018;13:321–50. https://doi.org/10.1146/annurev-pathol-020117-043617.CrossRefPubMed

24.

Arrese M, Arab JP, Barrera F, Kaufmann B, Valenti L, Feldstein AE. Insights into nonalcoholic fatty-liver disease heterogeneity. Semin Liver Dis. 2021;41:421–34. https://doi.org/10.1055/s-0041-1730927.CrossRefPubMedPubMedCentral

25.

Pal SC, Méndez-Sánchez N. Insulin resistance and adipose tissue interactions as the cornerstone of metabolic (dysfunction)-associated fatty liver disease pathogenesis. World J Gastroenterol. 2023;29:3999–4008. https://doi.org/10.3748/wjg.v29.i25.3999.CrossRefPubMedPubMedCentral

26.

Lee E, Korf H, Vidal-Puig A. An adipocentric perspective on the development and progression of non-alcoholic fatty liver disease. J Hepatol. 2023;78:1048–62. https://doi.org/10.1016/j.jhep.2023.01.024.CrossRefPubMed

27.

Dearlove DJ, Hodson L. Intrahepatic triglyceride content: influence of metabolic and genetics drivers. Curr Opin Clin Nutr Metab Care. 2022;25:241–7. https://doi.org/10.1097/MCO.0000000000000838.CrossRefPubMed

28.

Higuchi N, Kato M, Shundo Y, Tajiri H, Tanaka M, Yamashita N, et al. Liver X receptor in cooperation with SREBP-1c is a major lipid synthesis regulator in nonalcoholic fatty liver disease. Hepatol Res. 2008;38:1122–9. https://doi.org/10.1111/j.1872-034X.2008.00382.x.CrossRefPubMed

29.

Ipsen DH, Lykkesfeldt J, Tveden-Nyborg P. Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease. Cell Mol Life Sci. 2018;75:3313–27. https://doi.org/10.1007/s00018-018-2860-6.CrossRefPubMedPubMedCentral

30.

Kohjima M, Higuchi N, Kato M, Kotoh K, Yoshimoto T, Fujino T, et al. SREBP-1c, regulated by the insulin and AMPK signaling pathways, plays a role in nonalcoholic fatty liver disease. Int J Mol Med. 2008;21:507–11. https://www.ncbi.nlm.nih.gov/pubmed/18360697.

31.

Miksztowicz V, Lucero D, Zago V, Cacciagiú L, Lopez G, Gonzalez Ballerga E, et al. Hepatic lipase activity is increased in non-alcoholic fatty liver disease beyond insulin resistance. Diabetes Metab Res Rev. 2012;28:535–41. https://doi.org/10.1002/dmrr.2312.CrossRefPubMed

32.

Smith GI, Shankaran M, Yoshino M, Schweitzer GG, Chondronikola M, Beals JW, et al. Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease. J Clin Invest. 2020;130:1453–60. https://doi.org/10.1172/JCI134165.CrossRefPubMedPubMedCentral

33.

Schuster S, Cabrera D, Arrese M, Feldstein AE. Triggering and resolution of inflammation in NASH. Nat Rev Gastroenterol Hepatol. 2018;15:349–64. https://doi.org/10.1038/s41575-018-0009-6.CrossRefPubMed

34.

•• Tacke F, Puengel T, Loomba R, Friedman SL. An integrated view of anti-inflammatory and antifibrotic targets for the treatment of NASH. J Hepatol. 2023;79:552–66. https://doi.org/10.1016/j.jhep.2023.03.038. (A recent review on pathophysiological mechanisms at play in MASLD/MASH with implications for therapeutic targeting of various pathways.)CrossRefPubMed

35.

Ibrahim SH, Hirsova P, Gores GJ. Non-alcoholic steatohepatitis pathogenesis: sublethal hepatocyte injury as a driver of liver inflammation. Gut. 2018;67:963–72. https://doi.org/10.1136/gutjnl-2017-315691.CrossRefPubMed

36.

Gautheron J, Gores GJ, Rodrigues CMP. Lytic cell death in metabolic liver disease. J Hepatol. 2020;73:394–408. https://doi.org/10.1016/j.jhep.2020.04.001.CrossRefPubMedPubMedCentral

37.

Wang Y, Shi C, Guo J, Zhang Y, Gong Z. Distinct types of cell death and implications in liver diseases: an overview of mechanisms and application. J Clin Transl Hepatol. 2023;11:1413–24. https://doi.org/10.14218/JCTH.2023.00132.

38.

Shojaie L, Iorga A, Dara L. Cell death in liver diseases: a review. Int J Mol Sci. 2020;21:9682. https://doi.org/10.3390/ijms21249682.CrossRefPubMedPubMedCentral

39.

Sutti S, Albano E. Adaptive immunity: an emerging player in the progression of NAFLD. Nat Rev Gastroenterol Hepatol. 2020;17:81–92. https://doi.org/10.1038/s41575-019-0210-2.CrossRefPubMed

40.

Schwabe RF, Tabas I, Pajvani UB. Mechanisms of fibrosis development in nonalcoholic steatohepatitis. Gastroenterology. 2020;158:1913–28. https://doi.org/10.1053/j.gastro.2019.11.311.CrossRefPubMed

41.

Hammerich L, Tacke F. Hepatic inflammatory responses in liver fibrosis. Nat Rev Gastroenterol Hepatol. 2023. https://doi.org/10.1038/s41575-023-00807-x.CrossRefPubMed

42.

Tilg H, Adolph TE, Dudek M, Knolle P. Non-alcoholic fatty liver disease: the interplay between metabolism, microbes and immunity. Nat Metab. 2021;3:1596–607. https://doi.org/10.1038/s42255-021-00501-9.CrossRefPubMed

43.

Jennison E, Byrne CD. The role of the gut microbiome and diet in the pathogenesis of non-alcoholic fatty liver disease. Clin Mol Hepatol. 2021;27:22–43. https://doi.org/10.3350/cmh.2020.0129.CrossRefPubMed

44.

Loomba R, Seguritan V, Li W, Long T, Klitgord N, Bhatt A, et al. Gut microbiome-based metagenomic signature for non-invasive detection of advanced fibrosis in human nonalcoholic fatty liver disease. Cell Metab. 2019;30:607. https://doi.org/10.1016/j.cmet.2019.08.002.CrossRefPubMedPubMedCentral

45.

Aron-Wisnewsky J, Vigliotti C, Witjes J, Le P, Holleboom AG, Verheij J, et al. Gut microbiota and human NAFLD: disentangling microbial signatures from metabolic disorders. Nat Rev Gastroenterol Hepatol. 2020;17:279–97. https://doi.org/10.1038/s41575-020-0269-9.CrossRefPubMed

46.

Arab JP, Karpen SJ, Dawson PA, Arrese M, Trauner M. Bile acids and nonalcoholic fatty liver disease: molecular insights and therapeutic perspectives. Hepatology. 2017;65:350–62. https://doi.org/10.1002/hep.28709.CrossRefPubMed

47.

Carr RM, Li Y, Chau L, Friedman ES, Lee J-J, Adorini L, et al. An integrated analysis of fecal microbiome and metabolomic features distinguish Non-cirrhotic NASH from healthy control populations. Hepatology. 2023. https://doi.org/10.1097/HEP.0000000000000474.CrossRefPubMed

48.

Lefebvre P, Cariou B, Lien F, Kuipers F, Staels B. Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev. 2009;89:147–91. https://doi.org/10.1152/physrev.00010.2008.CrossRefPubMed

49.

Ferrebee CB, Dawson PA. Metabolic effects of intestinal absorption and enterohepatic cycling of bile acids. Acta Pharm Sin B. 2015;5:129–34. https://doi.org/10.1016/j.apsb.2015.01.001.CrossRefPubMedPubMedCentral

50.

Tian H, Zhang S, Liu Y, Wu Y, Zhang D. Fibroblast growth factors for nonalcoholic fatty liver disease: opportunities and challenges. Int J Mol Sci. 2023;24. https://doi.org/10.3390/ijms24054583.

51.

Puengel T, Liu H, Guillot A, Heymann F, Tacke F, Peiseler M. Nuclear receptors linking metabolism, inflammation, and fibrosis in nonalcoholic fatty liver disease. Int J Mol Sci. 2022;23. https://doi.org/10.3390/ijms23052668.

52.

Rowe IA, Wong VW-S, Loomba R. Treatment candidacy for pharmacologic therapies for NASH. Clin Gastroenterol Hepatol. 2022;20:1209–17. https://doi.org/10.1016/j.cgh.2021.03.005.

53.

Miller MJ, Harding-Theobald E, DiBattista JV, Zhao Z, Wijarnpreecha K, Lok AS, et al. Progression to cirrhosis is similar among all ages in nonalcoholic fatty liver disease, but liver-related events increase with age. Hepatol Commun. 2023;7. https://doi.org/10.1097/HC9.0000000000000148.

54.

[No title] [cited 2023 Sep 21]. https://www.fda.gov/media/127738/download.

55.

Tong X-F, Wang Q-Y, Zhao X-Y, Sun Y-M, Wu X-N, Yang L-L, et al. Histological assessment based on liver biopsy: the value and challenges in NASH drug development. Acta Pharmacol Sin. 2022;43:1200–9. https://doi.org/10.1038/s41401-022-00874-x.CrossRefPubMedPubMedCentral

56.

•• Sanyal AJ, Shankar SS, Yates KP, Bolognese J, Daly E, Dehn CA, et al. Diagnostic performance of circulating biomarkers for non-alcoholic steatohepatitis. Nat Med. 2023. https://doi.org/10.1038/s41591-023-02539-6. (An excellent update of the status of disease biomarkers in MASH.)CrossRefPubMedPubMedCentral

57.

Ampuero J, Romero-Gomez M. Stratification of patients in NASH clinical trials: a pitfall for trial success. JHEP Rep. 2020;2:100148. https://doi.org/10.1016/j.jhepr.2020.100148.CrossRefPubMedPubMedCentral

58.

Panzitt K, Wagner M. FXR in liver physiology: multiple faces to regulate liver metabolism. Biochim Biophys Acta Mol Basis Dis. 2021;1867:166133. https://doi.org/10.1016/j.bbadis.2021.166133.CrossRefPubMed

59.

Adorini L, Trauner M. FXR agonists in NASH treatment. J Hepatol. 2023. https://doi.org/10.1016/j.jhep.2023.07.034.CrossRefPubMed

60.

Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015;385:956–65. https://doi.org/10.1016/S0140-6736(14)61933-4.CrossRefPubMed

61.

Younossi ZM, Ratziu V, Loomba R, Rinella M, Anstee QM, Goodman Z, et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2019;394:2184–96. https://doi.org/10.1016/S0140-6736(19)33041-7.CrossRefPubMed

62.

Rinella ME, Dufour J-F, Anstee QM, Goodman Z, Younossi Z, Harrison SA, et al. Non-invasive evaluation of response to obeticholic acid in patients with NASH: results from the REGENERATE study. J Hepatol. 2022;76:536–48. https://doi.org/10.1016/j.jhep.2021.10.029.CrossRefPubMed

63.

Sanyal AJ, Ratziu V, Loomba R, Anstee QM, Kowdley KV, Rinella ME, et al. Results from a new efficacy and safety analysis of the REGENERATE trial of obeticholic acid for treatment of pre-cirrhotic fibrosis due to non-alcoholic steatohepatitis. J Hepatol. 2023. https://doi.org/10.1016/j.jhep.2023.07.014.CrossRefPubMed

64.

Marino L, Kim A, Ni B, Celi FS. Hormone action and liver disease, a complex interplay. Hepatology. 2023. https://doi.org/10.1097/HEP.0000000000000551.CrossRefPubMed

65.

Ritter MJ, Amano I, Hollenberg AN. Thyroid hormone signaling and the liver. Hepatology. 2020;72:742–52. https://doi.org/10.1002/hep.31296.CrossRefPubMed

66.

Zhou J, Tripathi M, Ho JP, Widjaja AA, Shekeran SG, Camat MD, et al. Thyroid hormone decreases hepatic steatosis, inflammation, and fibrosis in a dietary mouse model of nonalcoholic steatohepatitis. Thyroid. 2022;32:725–38. https://doi.org/10.1089/thy.2021.0621.CrossRefPubMed

67.

Fan H, Li L, Liu Z, Zhang P, Wu S, Han X, et al. Low thyroid function is associated with an increased risk of advanced fibrosis in patients with metabolic dysfunction-associated fatty liver disease. BMC Gastroenterol. 2023 [cited 2023 Aug 19];23:1–8. https://bmcgastroenterol.biomedcentral.com/articles/https://doi.org/10.1186/s12876-022-02612-3.

68.

Li L, Song Y, Shi Y, Sun L. Thyroid hormone receptor-β agonists in NAFLD therapy: possibilities and challenges. J Clin Endocrinol Metab. 2023;108:1602–13. https://doi.org/10.1210/clinem/dgad072.CrossRefPubMed

69.

Harrison SA, Bashir MR, Guy CD, Zhou R, Moylan CA, Frias JP, et al. Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2019;394:2012–24. https://doi.org/10.1016/S0140-6736(19)32517-6.CrossRefPubMed

70.

Harrison SA, Bashir M, Moussa SE, McCarty K, Pablo Frias J, Taub R, et al. Effects of resmetirom on noninvasive endpoints in a 36-week phase 2 active treatment extension study in patients with NASH. Hepatol Commun. 2021;5:573–88. https://doi.org/10.1002/hep4.1657.CrossRefPubMedPubMedCentral

71.

Thomas H. EASL Congress 2023. Lancet Gastroenterol Hepatol. 2023;8:700. https://doi.org/10.1016/S2468-1253(23)00202-9.CrossRefPubMed

72.

Harrison SA, Taub R, Neff GW, Lucas KJ, Labriola D, Moussa SE, et al. Resmetirom for nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled phase 3 trial. Nat Med. 2023. https://doi.org/10.1038/s41591-023-02603-1.CrossRefPubMedPubMedCentral

73.

Wu Q, Li D, Huang C, Zhang G, Wang Z, Liu J, et al. Glucose control independent mechanisms involved in the cardiovascular benefits of glucagon-like peptide-1 receptor agonists. Biomed Pharmacother. 2022;153:113517. https://doi.org/10.1016/j.biopha.2022.113517.CrossRefPubMed

74.

Jensterle M, Rizzo M, Haluzík M, Janež A. Efficacy of GLP-1 RA approved for weight management in patients with or without diabetes: a narrative review. Adv Ther. 2022;39:2452–67. https://doi.org/10.1007/s12325-022-02153-x.CrossRefPubMedPubMedCentral

75.

Krieger J-P. Intestinal glucagon-like peptide-1 effects on food intake: physiological relevance and emerging mechanisms. Peptides. 2020;131:170342. https://doi.org/10.1016/j.peptides.2020.170342.CrossRefPubMed

76.

Targher G, Mantovani A, Byrne CD. Mechanisms and possible hepatoprotective effects of glucagon-like peptide-1 receptor agonists and other incretin receptor agonists in non-alcoholic fatty liver disease. Lancet Gastroenterol Hepatol. 2023;8:179–91. https://doi.org/10.1016/S2468-1253(22)00338-7.CrossRefPubMed

77.

Yabut JM, Drucker DJ. Glucagon-like peptide-1 receptor-based therapeutics for metabolic liver disease. Endocr Rev. 2023;44:14–32. https://doi.org/10.1210/endrev/bnac018.CrossRefPubMed

78.

Ussher JR, Drucker DJ. Glucagon-like peptide 1 receptor agonists: cardiovascular benefits and mechanisms of action. Nat Rev Cardiol. 2023;20:463–74. https://doi.org/10.1038/s41569-023-00849-3.CrossRefPubMed

79.

Newsome PN, Buchholtz K, Cusi K, Linder M, Okanoue T, Ratziu V, et al. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N Engl J Med. 2021;384:1113–24. https://doi.org/10.1056/NEJMoa2028395.CrossRefPubMed

80.

Flint A, Andersen G, Hockings P, Johansson L, Morsing A, Sundby Palle M, 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;54:1150–61. https://doi.org/10.1111/apt.16608.CrossRefPubMedPubMedCentral

81.

Francque S, Szabo G, Abdelmalek MF, Byrne CD, Cusi K, Dufour J-F, et al. Nonalcoholic steatohepatitis: the role of peroxisome proliferator-activated receptors. Nat Rev Gastroenterol Hepatol. 2021;18:24–39. https://doi.org/10.1038/s41575-020-00366-5.CrossRefPubMed

82.

Staels B, Butruille L, Francque S. Treating NASH by targeting peroxisome proliferator-activated receptors. J Hepatol. 2023. https://doi.org/10.1016/j.jhep.2023.07.004.CrossRefPubMed

83.

Francque SM, Bedossa P, Ratziu V, Anstee QM, Bugianesi E, Sanyal AJ, et al. A randomized, controlled trial of the Pan-PPAR agonist lanifibranor in NASH. N Engl J Med. 2021;385:1547–58. https://doi.org/10.1056/NEJMoa2036205.CrossRefPubMed

84.

Jin L, Yang R, Geng L, Xu A. Fibroblast growth factor-based pharmacotherapies for the treatment of obesity-related metabolic complications. Annu Rev Pharmacol Toxicol. 2023;63:359–82. https://doi.org/10.1146/annurev-pharmtox-032322-093904.CrossRefPubMed

85.

Guthrie G, Vonderohe C, Burrin D. Fibroblast growth factor 15/19 expression, regulation, and function: an overview. Mol Cell Endocrinol. 2022;548:111617. https://doi.org/10.1016/j.mce.2022.111617.CrossRefPubMedPubMedCentral

86.

Harrison SA, Neff G, Guy CD, Bashir MR, Paredes AH, Frias JP, et al. Efficacy and safety of aldafermin, an engineered FGF19 analog, in a randomized, double-blind, placebo-controlled trial of patients with nonalcoholic steatohepatitis. Gastroenterology. 2021;160:219-31.e1. https://doi.org/10.1053/j.gastro.2020.08.004.CrossRefPubMed

87.

Harrison SA, Abdelmalek MF, Neff G, Gunn N, Guy CD, Alkhouri N, et al. Aldafermin in patients with non-alcoholic steatohepatitis (ALPINE 2/3): a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Gastroenterol Hepatol. 2022;7:603–16. https://doi.org/10.1016/S2468-1253(22)00017-6.CrossRefPubMed

88.

Rinella ME, Lieu HD, Kowdley KV, Goodman ZD, Alkhouri N, Lawitz E, et al. A randomized, double-blind, placebo-controlled trial of Aldafermin in patients with nonalcoholic steatohepatitis and compensated cirrhosis. Hepatology. 2023. https://doi.org/10.1097/HEP.0000000000000607.CrossRefPubMed

89.

Raptis DD, Mantzoros CS, Polyzos SA. Fibroblast growth factor-21 as a potential therapeutic target of nonalcoholic fatty liver disease. Ther Clin Risk Manag. 2023;19:77–96. https://doi.org/10.2147/TCRM.S352008.CrossRefPubMedPubMedCentral

90.

Sanyal A, Charles ED, Neuschwander-Tetri BA, Loomba R, Harrison SA, Abdelmalek MF, et al. Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial. Lancet. 2019;392:2705–17. https://doi.org/10.1016/S0140-6736(18)31785-9.CrossRefPubMed

91.

Abdelmalek MF, Sanyal AJ, Nakajima A, Neuschwander-Tetri BA, Goodman ZD, Lawitz EJ, et al. Pegbelfermin in patients with nonalcoholic steatohepatitis and compensated cirrhosis (FALCON 2): a randomized phase 2b study. Clin Gastroenterol Hepatol. 2023. https://doi.org/10.1016/j.cgh.2023.04.012.CrossRefPubMed

92.

Loomba R, Sanyal AJ, Nakajima A, Neuschwander-Tetri BA, Goodman ZD, Harrison SA, et al. Pegbelfermin in patients with nonalcoholic steatohepatitis and stage 3 fibrosis (FALCON 1): a randomized phase 2b study. Clin Gastroenterol Hepatol. 2023. https://doi.org/10.1016/j.cgh.2023.04.011.CrossRefPubMedPubMedCentral

93.

Brown EA, Minnich A, Sanyal AJ, Loomba R, Du S, Schwarz J, et al. Effect of pegbelfermin on NASH and fibrosis-related biomarkers and correlation with histological response in the FALCON 1 trial. JHEP Rep. 2023;5:100661. https://doi.org/10.1016/j.jhepr.2022.100661.CrossRefPubMedPubMedCentral

94.

Harrison SA, Ruane PJ, Freilich BL, Neff G, Patil R, Behling CA, et al. Efruxifermin in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a trial. Nat Med. 2021;27:1262–71. https://doi.org/10.1038/s41591-021-01425-3.CrossRefPubMed

95.

Harrison SA, Frias JP, Neff G, Abrams GA, Lucas KJ, Sanchez W, et al. Safety and efficacy of once-weekly efruxifermin versus placebo in non-alcoholic steatohepatitis (HARMONY): a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Gastroenterol Hepatol. 2023. https://doi.org/10.1016/S2468-1253(23)00272-8.CrossRefPubMed

96.

Mahgoub S, Newsome PN. Efruxifermin in non-alcoholic steatohepatitis. Lancet Gastroenterol Hepatol. 2023. https://doi.org/10.1016/S2468-1253(23)00285-6.CrossRefPubMed

97.

Loomba R, Sanyal AJ, Kowdley KV, Bhatt DL, Alkhouri N, Frias JP, et al. Randomized, Controlled Trial of the FGF21 Analogue Pegozafermin in NASH. N Engl J Med. 2023. https://doi.org/10.1056/NEJMoa2304286.CrossRefPubMed

98.

Rinella ME. Pegozafermin for NASH - a sprint to start a marathon. N Engl J Med. 2023;389:1044–6. https://doi.org/10.1056/NEJMe2307249.CrossRefPubMed

99.

Ahrén B. Paradigm shift in the management of metabolic diseases-next-generation incretin therapy endocrinology. 2023.https://doi.org/10.1210/endocr/bqad166.

100.

Gastaldelli A, Cusi K, Fernández Landó L, Bray R, Brouwers B, Rodríguez Á. Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial. Lancet Diabetes Endocrinol. 2022;10:393–406. https://doi.org/10.1016/S2213-8587(22)00070-5.CrossRefPubMed

101.

Sanyal AJ, Lopez P, Lawitz EJ, Lucas KJ, Loeffler J, Kim W, et al. Tropifexor for nonalcoholic steatohepatitis: an adaptive, randomized, placebo-controlled phase 2a/b trial. Nat Med. 2023;29:392–400. https://doi.org/10.1038/s41591-022-02200-8.CrossRefPubMedPubMedCentral

102.

Gawrieh S, Noureddin M, Loo N, Mohseni R, Awasty V, Cusi K, et al. Saroglitazar, a PPAR‐α/γ agonist, for treatment of NAFLD: a randomized controlled double‐blind phase 2 trial. 2021;74(4):1809–1824. https://doi.org/10.1002/hep.31843.

103.

Siddiqui MS, Idowu MO, Parmar D, Borg BB, Denham D, Loo NM, et al. A phase 2 double blinded, randomized controlled trial of Saroglitazar in patients with nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2021;19:2670–2. https://doi.org/10.1016/j.cgh.2020.10.051.CrossRefPubMed

104.

Siddiqui MS, Parmar D, Sheikh F, Sarin SK, Cisneros L, Gawrieh S, et al. Saroglitazar, a dual PPAR α/γ agonist, improves atherogenic dyslipidemia in patients with non-cirrhotic nonalcoholic fatty liver disease: a pooled analysis. Clin Gastroenterol Hepatol. 2023;21:2597-605.e2. https://doi.org/10.1016/j.cgh.2023.01.018.CrossRefPubMed

105.

Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P, Serfaty L, et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology. 2016;150:1147-59.e5. https://doi.org/10.1053/j.gastro.2016.01.038.CrossRefPubMed

106.

Lambert JE, Ramos-Roman MA, Browning JD, Parks EJ. Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease. Gastroenterology. 2014;146:726–35. https://doi.org/10.1053/j.gastro.2013.11.049.CrossRefPubMed

107.

Loomba R, Kayali Z, Noureddin M, Ruane P, Lawitz EJ, Bennett M, et al. GS-0976 reduces hepatic steatosis and fibrosis markers in patients with nonalcoholic fatty liver disease. Gastroenterology. 2018;155:1463-73.e6. https://doi.org/10.1053/j.gastro.2018.07.027.CrossRefPubMed

108.

Loomba R, Mohseni R, Lucas KJ, Gutierrez JA, Perry RG, Trotter JF, et al. TVB-2640 (FASN inhibitor) for the treatment of nonalcoholic steatohepatitis: FASCINATE-1, a randomized, placebo-controlled phase 2a trial. Gastroenterology. 2021;161:1475–86. https://doi.org/10.1053/j.gastro.2021.07.025.CrossRefPubMed

109.

Loomba R, Morgan E, Watts L, Xia S, Hannan LA, Geary RS, et al. Novel antisense inhibition of diacylglycerol O-acyltransferase 2 for treatment of non-alcoholic fatty liver disease: a multicentre, double-blind, randomised, placebo-controlled phase 2 trial. Lancet Gastroenterol Hepatol. 2020;5:829–38. https://doi.org/10.1016/S2468-1253(20)30186-2.CrossRefPubMed

110.

Ratziu V, de Guevara L, Safadi R, Poordad F, Fuster F, Flores-Figueroa J, et al. Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial. Nat Med. 2021;27:1825–35. https://doi.org/10.1038/s41591-021-01495-3.CrossRefPubMed

111.

• Wang S, Friedman SL. Found in translation-fibrosis in metabolic dysfunction-associated steatohepatitis (MASH). Sci Transl Med. 2023;15:eadi0759. https://doi.org/10.1126/scitranslmed.adi0759. An excellent update on fibrosis mechanisms in MASLD/MASH and the potential therapeutic targeting of fibrogenesis in this disease.

112.

Kram M. Galectin-3 inhibition as a potential therapeutic target in non-alcoholic steatohepatitis liver fibrosis. World J Hepatol. 2023;15:201–7. https://doi.org/10.4254/wjh.v15.i2.201.CrossRefPubMedPubMedCentral

113.

Chalasani N, Abdelmalek MF, Garcia-Tsao G, Vuppalanchi R, Alkhouri N, Rinella M, et al. Effects of belapectin, an inhibitor of galectin-3, in patients with nonalcoholic steatohepatitis with cirrhosis and portal hypertension. Gastroenterology. 2020;158:1334-45.e5. https://doi.org/10.1053/j.gastro.2019.11.296.CrossRefPubMed

114.

Harrison SA, Mayo PR, Hobbs TM, Canizares C, Foster EP, Zhao C, et al. Rencofilstat, a cyclophilin inhibitor: a phase 2a, multicenter, single-blind, placebo-controlled study in F2/F3 NASH. Hepatol Commun. 2022;6:3379–92. https://doi.org/10.1002/hep4.2100.CrossRefPubMedPubMedCentral

115.

Fromenty B, Roden M. Mitochondrial alterations in fatty liver diseases. J Hepatol. 2023;78:415–29. https://doi.org/10.1016/j.jhep.2022.09.020.CrossRefPubMed

116.

Harrison SA, Alkhouri N, Davison BA, Sanyal A, Edwards C, Colca JR, et al. Insulin sensitizer MSDC-0602K in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase IIb study. J Hepatol. 2020;72:613–26. https://doi.org/10.1016/j.jhep.2019.10.023.CrossRefPubMed

117.

Harrison SA, Thang C, Bolze S, Dewitt S, Hallakou-Bozec S, Dubourg J, et al. Evaluation of PXL065 - deuterium-stabilized (R)-pioglitazone in patients with NASH: a phase II randomized placebo-controlled trial (DESTINY-1). J Hepatol. 2023;78:914–25. https://doi.org/10.1016/j.jhep.2023.02.004.CrossRefPubMed

118.

Dufour J-F, Caussy C, Loomba R. Combination therapy for non-alcoholic steatohepatitis: rationale, opportunities, and challenges. Gut. 2020;69:1877–84. https://doi.org/10.1136/gutjnl-2019-319104.CrossRefPubMed

119.

Anstee QM, Lucas KJ, Francque S, Abdelmalek MF, Sanyal AJ, Ratziu V, et al. Tropifexor plus cenicriviroc combination versus monotherapy in nonalcoholic steatohepatitis: results from the phase 2b TANDEM study. Hepatology. 2023;78:1223–39. https://doi.org/10.1097/HEP.0000000000000439.CrossRefPubMed

120.

Loomba R, Noureddin M, Kowdley KV, Kohli A, Sheikh A, Neff G, et al. Combination therapies including cilofexor and firsocostat for bridging fibrosis and cirrhosis attributable to NASH. Hepatology. 2021;73:625–43. https://doi.org/10.1002/hep.31622.CrossRefPubMed

121.

Alkhouri N, Herring R, Kabler H, Kayali Z, Hassanein T, Kohli A, et al. 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;77:607–18. https://doi.org/10.1016/j.jhep.2022.04.003.CrossRefPubMed

122.

Lindén D, Romeo S. Therapeutic opportunities for the treatment of NASH with genetically validated targets. J Hepatol. 2023;79:1056–64. https://doi.org/10.1016/j.jhep.2023.05.007.CrossRefPubMed

123.

ElSayed NA, Aleppo G, Aroda VR, Bannuru RR, Brown FM, Bruemmer D, et al. 9. Pharmacologic approaches to glycemic treatment: standards of care in diabetes-2023. Diabetes Care. 2023;46:S140-57. https://doi.org/10.2337/dc23-S009.CrossRefPubMed

124.

Mantovani A, Petracca G, Csermely A, Beatrice G, Targher G. Sodium-glucose cotransporter-2 inhibitors for treatment of nonalcoholic fatty liver disease: a meta-analysis of randomized controlled trials. Metabolites. 2020;11. https://doi.org/10.3390/metabo11010022.

Titel: Emerging Drug Therapies for Metabolic Dysfunction-Associated Steatotic Liver Disease: A Glimpse into the Horizon
verfasst von: Jorge Arnold
Francisco Idalsoaga
Luis Antonio Díaz
Daniel Cabrera
Francisco Barrera
Juan Pablo Arab
Marco Arrese
Publikationsdatum: 06.01.2024
Verlag: Springer US
Erschienen in: Current Hepatology Reports / Ausgabe 1/2024
Elektronische ISSN: 2195-9595
DOI: https://doi.org/10.1007/s11901-023-00629-0

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

Echinokokkose medikamentös behandeln oder operieren?

06.05.2024 DCK 2024 Kongressbericht

Die Therapie von Echinokokkosen sollte immer in spezialisierten Zentren erfolgen. Eine symptomlose Echinokokkose kann – egal ob von Hunde- oder Fuchsbandwurm ausgelöst – konservativ erfolgen. Wenn eine Op. nötig ist, kann es sinnvoll sein, vorher Zysten zu leeren und zu desinfizieren.

Aquatherapie bei Fibromyalgie wirksamer als Trockenübungen

03.05.2024 Fibromyalgiesyndrom Nachrichten

Bewegungs-, Dehnungs- und Entspannungsübungen im Wasser lindern die Beschwerden von Patientinnen mit Fibromyalgie besser als das Üben auf trockenem Land. Das geht aus einer spanisch-brasilianischen Vergleichsstudie hervor.

Wo hapert es noch bei der Umsetzung der POMGAT-Leitlinie?

03.05.2024 DCK 2024 Kongressbericht

Seit November 2023 gibt es evidenzbasierte Empfehlungen zum perioperativen Management bei gastrointestinalen Tumoren (POMGAT) auf S3-Niveau. Vieles wird schon entsprechend der Empfehlungen durchgeführt. Wo es im Alltag noch hapert, zeigt eine Umfrage in einem Klinikverbund.

Das Risiko für Vorhofflimmern in der Bevölkerung steigt

02.05.2024 Vorhofflimmern Nachrichten

Das Risiko, im Lauf des Lebens an Vorhofflimmern zu erkranken, ist in den vergangenen 20 Jahren gestiegen: Laut dänischen Zahlen wird es drei von zehn Personen treffen. Das hat Folgen weit über die Schlaganfallgefährdung hinaus.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar "Chronische Unterbauch- und Viszeralschmerzen in der Praxis managen"

Springer Medizin

Abstract

Purpose of Review

Recent Findings

Summary

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 1/2024

Systemic Disease and Portal Hypertension

Sarcopenia and Frailty in Advanced Liver Disease Patients: A Comprehensive Review

Update on Hepatopulmonary Syndrome

Endocrinology for the Hepatologist

Hepatic Sarcoidosis: A Review of the Diagnosis and Management