{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T10:25:46Z","timestamp":1784543146712,"version":"3.55.0"},"reference-count":73,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T00:00:00Z","timestamp":1755216000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Metabolic dysfunction associated steatohepatitis (MASH), formerly known as NASH, represents one of the leading causes of chronic liver disease worldwide. Its high prevalence is driven by insulin resistance, obesity and type 2 diabetes (T2D) and is associated with cardiovascular disease. The main driver of liver damage is fat accumulation in hepatocytes leading to inflammation and fibrosis development. People with MASH and clinically significant fibrosis (stage F2\/F3) are \u2018at risk\u2019 of progressing to cirrhosis and hepatocellular carcinoma and are considered in need of treatment. Metabolic drivers of MASH originating outside the liver, for example, from the adipose tissue and the gut, and genetic heterogeneity contribute to making the prevalent pathogenetic factor difficult to dissect at an individual level. In this scenario, the Food and Drug Administration's conditional approval of the liver\u2010directed thyroid hormone receptor beta agonist Resmetirom as the first pharmacological treatment for MASH last March 2024 and the expected extension of the glucagon\u2010like protein\u20101 receptor agonist Semaglutide indication from diabetes and obesity to MASH mark a key milestone. Both drugs are also under evaluation by the European Medicines Agency. The proven efficacy of these compounds in clinical trials needs to be balanced against safety profiles and patient preferences. To investigate future trajectories and possible uses as mono\u2010therapy or in combination, we examined available results of clinical trials and real\u2010life studies. Despite the need to await the final results of outcome studies to exclude any possible challenges for both compounds, safety profiles and external factors including reimbursement policies or supply limitations may currently guide the individual choice.<\/jats:p>","DOI":"10.1111\/liv.70271","type":"journal-article","created":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T13:01:44Z","timestamp":1755262904000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Safety Choice Drivers of the Coming Treatment Options for Non\u2010Cirrhotic Metabolic Steatohepatitis"],"prefix":"10.1111","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2600-3555","authenticated-orcid":false,"given":"Alessandra","family":"Mangia","sequence":"first","affiliation":[{"name":"Liver Unit Fondazione IRCCS, \u201cCasa Sollievo della Sofferenza\u201d Hospital  San Giovanni Rotondo Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca V. C.","family":"Valenti","sequence":"additional","affiliation":[{"name":"Biological Resource Center\/Biobank Fondazione \u201cCa Granda\u201d IRCCS Ospedale Maggiore Policlinico  Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,8,15]]},"reference":[{"key":"e_1_2_9_2_1","unstructured":"\u201cNovoNordisk Press Release NovoNordisk Press Release NovoNordisk Press Release \u201dhttps:\/\/www.prnewswire.com\/news\u2010releases\/essence\u2010phase\u20103\u2010trial\u2010of\u2010semaglutide\u2010showed\u2010significant\u2010improvements\u2010at\u201072\u2010weeks\u2010in\u2010adults\u2010with\u2010mash\u2010published\u2010in\u2010nejm\u2010302443359.html."},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2023.06.003"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.2337\/dci24-0003"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2023.04.035"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/HEP.0000000000000004"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhepr.2024.101271"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2019.06.021"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/liv.13185"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lanepe.2025.101320"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2023-330110"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20701"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2024.04.031"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/liv.15930"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2020.06.006"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2015.04.005"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)00634-7"},{"key":"e_1_2_9_18_1","unstructured":"Administration U S F A D \u201cFDA Approves First Treatment for Patients With Liver Scarring due to Fatty Liver Disease \u201d 2024."},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/liv.13972"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.17925\/EE.2023.19.1.60"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2309000"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02603-1"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)32517-6"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02602-2"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/apt.17734"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dld.2024.01.022"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1097\/HEP.0000000000001112"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2019.12.002"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2024.05.052"},{"issue":"1","key":"e_1_2_9_30_1","first-page":"16","article-title":"Resmetirom Effects on NASH With Liver Fibrosis in Patients With NASH Genetic Risk Alleles (AASLD Abstract 2070)","volume":"80","author":"Chalasani N.","year":"2024","journal-title":"Hepatology"},{"key":"e_1_2_9_31_1","unstructured":"Administration U S F A D \u201cNonalcoholic Steatohepatitis With Compensated Cirrhosis: Developing Drugs for Treatment Guidance for Industry \u201d 2019."},{"key":"e_1_2_9_32_1","doi-asserted-by":"crossref","unstructured":"N.Alkouri R.Taub X.Lu et\u00a0al. \u201cTreatment With Resmetirom for up to Two Years Led to Improvement in Liver Stiffness Fibrosis Biomarkers Fibrosis Sores and Portal Hypertension in 122 Patients With Compensated MASH Cirrhosis EASL 2025 \u201d May 7\u201010 Amsterdam.","DOI":"10.1016\/S0168-8278(25)00311-3"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.3390\/metabo11020073"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2023.07.033"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMe2314365"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabet.2018.12.001"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2032183"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)00213-0"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2021.3224"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2028395"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2413258"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcjd.2024.09.118"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2307563"},{"issue":"1","key":"e_1_2_9_44_1","first-page":"S1249","article-title":"Effect of Resmetirom or Placebp in Patients With <5% or \u2265\u20095% Weight Loss and\/or on Baseline GLP\u20101 in the MAESTRO\u2010NASH 52\u2010Week Serial Liver Biopsy Study (Abstract 132)","volume":"80","author":"Nourredin M.","year":"2024","journal-title":"Hepatology"},{"key":"e_1_2_9_45_1","first-page":"1","article-title":"What Is the Evidence Regarding the Safety of New Obesity Pharmacotherapies","volume":"49","author":"Vidal J.","year":"2024","journal-title":"International Journal of Obesity"},{"issue":"4","key":"e_1_2_9_46_1","first-page":"998","article-title":"Pharmacokinetics and Tolerability of Semaglutide in People With Hepatic Impairment. Diabetes, Obes","volume":"20","author":"Jensen L.","year":"2018","journal-title":"Metabolism"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-1253(23)00068-7"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1111\/dom.15794"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-02026-4"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-02996-7"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pcd.2024.06.013"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1002\/oby.23952"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2024.12.045"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2036205"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2024.04.034"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2024.156043"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(24)00437-9"},{"key":"e_1_2_9_58_1","first-page":"5021","article-title":"Efruxifermin Significantly Reduced Proportion of Participants With At\u2010Risk MASH and Led to Near\u2010Complete Histological Disease Reversal at Week 96 in the HARMONY Study","volume":"80","author":"Noureddin M.","year":"2024","journal-title":"Hepatology"},{"key":"e_1_2_9_59_1","unstructured":"M.Noureddin M. E.Rinella N.Chalasani et\u00a0al. \u201cEfruxifermin Improves Fibrosis in Participants With Compensated Cirrhosis due to MASH: Results of a 96\u2010Week Randomized Double\u2010Blind Placebo\u2010Controlled Phase 2b Trial (SYMMETRY) GS\u2010012.\u201d"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2304286"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2206038"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2401943"},{"key":"e_1_2_9_63_1","first-page":"5014","article-title":"Impact of PNPLA3 rs738409 on the Response to Tirzepatide Versus Placebo for the Treatment of Non\u2010Cirrhotic MASH","volume":"80","author":"Sanyal A.","year":"2024","journal-title":"Hepatology"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2107519"},{"key":"e_1_2_9_65_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.24945"},{"key":"e_1_2_9_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2024.06.003"},{"key":"e_1_2_9_67_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2401755"},{"key":"e_1_2_9_68_1","doi-asserted-by":"publisher","DOI":"10.1080\/13543784.2024.2441865"},{"key":"e_1_2_9_69_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2021.07.025"},{"key":"e_1_2_9_70_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(24)00429-X"},{"key":"e_1_2_9_71_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-03284-0"},{"key":"e_1_2_9_72_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-03283-1"},{"key":"e_1_2_9_73_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2024.07.003"},{"key":"e_1_2_9_74_1","volume-title":"Sustainable Innovation: Medicines and the Challenges for the Future of Our National Health Service","author":"Pani L.","year":"2016"}],"container-title":["Liver International"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/liv.70271","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T14:06:31Z","timestamp":1764597991000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/liv.70271"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,15]]},"references-count":73,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2025,9]]}},"alternative-id":["10.1111\/liv.70271"],"URL":"https:\/\/doi.org\/10.1111\/liv.70271","archive":["Portico"],"relation":{},"ISSN":["1478-3223","1478-3231"],"issn-type":[{"value":"1478-3223","type":"print"},{"value":"1478-3231","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,15]]},"assertion":[{"value":"2025-06-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-29","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-15","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70271"}}