{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T22:11:06Z","timestamp":1792188666299,"version":"4.4.0"},"reference-count":36,"publisher":"American Diabetes Association","issue":"12","license":[{"start":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:00:00Z","timestamp":1759968000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"funder":[{"DOI":"10.13039\/100004312","name":"Eli Lilly and Company","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004312","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,12,1]]},"abstract":"<jats:sec>\n                    <jats:title>OBJECTIVE<\/jats:title>\n                    <jats:p>To explore the relationship between metabolic and histological responses in a phase 2 trial of tirzepatide in metabolic dysfunction\u2013associated steatohepatitis (MASH).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESEARCH DESIGN AND METHODS<\/jats:title>\n                    <jats:p>This is a participant-level post hoc analysis of the 52-week, double-blind, randomized, placebo-controlled SYNERGY-NASH trial (NCT04166773). Participants (n = 190) with MASH and stage 2\/3 fibrosis were randomly assigned to receive tirzepatide (5, 10, or 15 mg) or placebo once weekly. The primary end point was MASH resolution without worsening of fibrosis. Secondary end points included fibrosis improvement by at least one stage without worsening of MASH. Metabolic changes were evaluated in responders and nonresponders for histological end points in 154 participants who completed the study on treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>At baseline, 59% had type 2 diabetes and mean BMI was 35.7 kg\/m2. Compared with nonresponders, greater body weight reductions were observed in responders for MASH resolution (\u221216.0% vs. \u22127.0%; P &amp;lt; 0.001) and for fibrosis improvement (\u221213.6% vs. \u22129.8%; P = 0.023). Reductions in HbA1c were greater for MASH responders (\u22121.2% vs. \u22120.6%; P &amp;lt; 0.001) and fibrosis responders (\u22121.2% vs. \u22120.7%; P = 0.004) than for nonresponders. Compared with nonresponders, greater improvements in liver fat and measures of adipose tissue insulin sensitivity (adipose tissue insulin resistance index and adiponectin) were observed with MASH responders (P &amp;lt; 0.001). In causal mediation analyses, normalization of liver fat was a significant mediator of both MASH resolution and fibrosis improvement.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS<\/jats:title>\n                    <jats:p>In this post hoc exploratory analysis, MASH resolution and fibrosis improvement were associated with body weight reduction, improved glycemic control, and normalization of liver fat. Weight reduction and metabolic improvements with tirzepatide treatment potentially contributed to disease modification in MASH.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/dc25-1306","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:36:35Z","timestamp":1760031395000},"page":"2074-2083","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":19,"title":["Relationship Between Metabolic and Histological Responses in People With Metabolic Dysfunction\u2013 Associated Steatohepatitis With and Without Type 2 Diabetes: Participant-Level Exploratory Analysis of the SYNERGY-NASH Trial With Tirzepatide"],"prefix":"10.2337","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8089-2907","authenticated-orcid":false,"given":"Cyrielle","family":"Caussy","sequence":"first","affiliation":[{"name":"Universite Claude Bernard Lyon1, CarMen Laboratory, INSERM 1 , INRA, Pierre-B\u00e9nite, France"},{"name":"Hospices Civils de Lyon, D\u00e9partement Endocrinologie, Diab\u00e8te et Nutrition, H\u00f4pital Lyon Sud, Pierre-B\u00e9nite 2 , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Cusi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, University of Florida 3 , Gainesville, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio","family":"Rosenstock","sequence":"additional","affiliation":[{"name":"Velocity Clinical Research at Medical City 4 , Dallas, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Bugianesi","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, University of Torino 5 , Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa K.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company 6 , Indianapolis, IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Tang","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company 6 , Indianapolis, IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kieren J.","family":"Mather","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company 6 , Indianapolis, IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohit","family":"Loomba","sequence":"additional","affiliation":[{"name":"MASLD Research Centre, Division of Gastroenterology and Hepatology, University of California San Diego 7 , San Diego, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arun J.","family":"Sanyal","sequence":"additional","affiliation":[{"name":"Virginia Commonwealth University School of Medicine 8 , Richmond, VA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark L.","family":"Hartman","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company 6 , Indianapolis, IN"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2025,10,9]]},"reference":[{"key":"2026061714575016800_B1","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1016\/j.jhep.2024.04.031","article-title":"EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD)","volume":"81","author":"European Association for the Study of the Liver","year":"2024","journal-title":"J Hepatol"},{"key":"2026061714575016800_B2","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1097\/HEP.0000000000000004","article-title":"The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review","volume":"77","author":"Younossi","year":"2023","journal-title":"Hepatology"},{"key":"2026061714575016800_B3","doi-asserted-by":"crossref","first-page":"2138","DOI":"10.1136\/gutjnl-2023-330110","article-title":"Global prevalence of non-alcoholic fatty liver disease in type 2 diabetes mellitus: an updated systematic review and meta-analysis","volume":"72","author":"En Li Cho","year":"2023","journal-title":"Gut"},{"key":"2026061714575016800_B4","article-title":"Epidemiology, screening, and co-management of type 2 diabetes mellitus and metabolic dysfunction\u2013associated steatotic liver disease","author":"Qi","year":"2024","journal-title":"Hepatology. 8 May"},{"key":"2026061714575016800_B5","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/S2468-1253(23)00157-7","article-title":"Type 2 diabetes, hepatic decompensation, and hepatocellular carcinoma in patients with non-alcoholic fatty liver disease: an individual participant-level data meta-analysis","volume":"8","author":"Huang","year":"2023","journal-title":"Lancet Gastroenterol Hepatol"},{"key":"2026061714575016800_B6","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1053\/j.gastro.2023.04.025","article-title":"Fibrosis progression rate in biopsy-proven nonalcoholic fatty liver disease among people with diabetes versus people without diabetes: a multicenter study","volume":"165","author":"Huang","year":"2023","journal-title":"Gastroenterology"},{"key":"2026061714575016800_B7","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1053\/j.gastro.2020.06.006","article-title":"Bariatric surgery provides long-term resolution of nonalcoholic steatohepatitis and regression of fibrosis","volume":"159","author":"Lassailly","year":"2020","journal-title":"Gastroenterology"},{"key":"2026061714575016800_B8","doi-asserted-by":"crossref","first-page":"1786","DOI":"10.1016\/S0140-6736(23)00634-7","article-title":"Bariatric-metabolic surgery versus lifestyle intervention plus best medical care in non-alcoholic steatohepatitis (BRAVES): a multicentre, open-label, randomised trial","volume":"401","author":"Verrastro","year":"2023","journal-title":"Lancet"},{"key":"2026061714575016800_B9","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1053\/j.gastro.2015.04.005","article-title":"Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis","volume":"149","author":"Vilar-Gomez","year":"2015","journal-title":"Gastroenterology"},{"key":"2026061714575016800_B10","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.1056\/NEJMoa2413258","article-title":"Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis","volume":"392","author":"Sanyal","year":"2025","journal-title":"N Engl J Med"},{"key":"2026061714575016800_B11","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1056\/NEJMoa2401755","article-title":"A phase 2 randomized trial of survodutide in MASH and fibrosis","volume":"391","author":"Sanyal","year":"2024","journal-title":"N Engl J Med"},{"key":"2026061714575016800_B12","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1056\/NEJMoa2401943","article-title":"Tirzepatide for metabolic dysfunction-associated steatohepatitis with liver fibrosis","volume":"391","author":"Loomba","year":"2024","journal-title":"N Engl J Med"},{"key":"2026061714575016800_B13","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/S0140-6736(21)01324-6","article-title":"Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial","volume":"398","author":"Rosenstock","year":"2021","journal-title":"Lancet"},{"key":"2026061714575016800_B14","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/S2213-8587(22)00070-5","article-title":"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","volume":"10","author":"Gastaldelli","year":"2022","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2026061714575016800_B15","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1056\/NEJMoa2206038","article-title":"Tirzepatide once weekly for the treatment of obesity","volume":"387","author":"Jastreboff","year":"2022","journal-title":"N Engl J Med"},{"key":"2026061714575016800_B16","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/S0140-6736(23)01200-X","article-title":"Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial","volume":"402","author":"Garvey","year":"2023","journal-title":"Lancet"},{"key":"2026061714575016800_B17","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1210\/clinem\/dgaa863","article-title":"Dual GIP and GLP-1 receptor agonist tirzepatide improves beta-cell function and insulin sensitivity in type 2 diabetes","volume":"106","author":"Thomas","year":"2021","journal-title":"J Clin Endocrinol Metab"},{"key":"2026061714575016800_B18","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1111\/apt.18042","article-title":"Randomised clinical trial: design of the SYNERGY-NASH phase 2b trial to evaluate tirzepatide as a treatment for metabolic dysfunction-associated steatohepatitis and modification of screening strategy to reduce screen failures","volume":"60","author":"Vuppalanchi","year":"2024","journal-title":"Aliment Pharmacol Ther"},{"key":"2026061714575016800_B19","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1093\/aje\/kwq332","article-title":"Odds ratios for mediation analysis for a dichotomous outcome","volume":"172","author":"Vanderweele","year":"2010","journal-title":"Am J Epidemiol"},{"key":"2026061714575016800_B20","article-title":"Causal mediation analysis with the CAUSALMED procedure","author":"Yung"},{"key":"2026061714575016800_B21","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1037\/a0031034","article-title":"Mediation analysis allowing for exposure-mediator interactions and causal interpretation: theoretical assumptions and implementation with SAS and SPSS macros","volume":"18","author":"Valeri","year":"2013","journal-title":"Psychol Methods"},{"key":"2026061714575016800_B22","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1097\/EDE.0000000000000121","article-title":"A unification of mediation and interaction: a 4-way decomposition","volume":"25","author":"VanderWeele","year":"2014","journal-title":"Epidemiology"},{"key":"2026061714575016800_B23","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1002\/hep.31806","article-title":"Glycemic control predicts severity of hepatocyte ballooning and hepatic fibrosis in nonalcoholic fatty liver disease","volume":"74","author":"Alexopoulos","year":"2021","journal-title":"Hepatology"},{"key":"2026061714575016800_B24","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/S2213-8587(22)00085-7","article-title":"Effects of subcutaneous tirzepatide versus placebo or semaglutide on pancreatic islet function and insulin sensitivity in adults with type 2 diabetes: a multicentre, randomised, double-blind, parallel-arm, phase 1 clinical trial","volume":"10","author":"Heise","year":"2022","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2026061714575016800_B25","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1210\/clinem\/dgac660","article-title":"Adipose tissue insulin resistance predicts the severity of liver fibrosis in patients with type 2 diabetes and NAFLD","volume":"108","author":"Kalavalapalli","year":"2023","journal-title":"J Clin Endocrinol Metab"},{"key":"2026061714575016800_B26","doi-asserted-by":"crossref","first-page":"114171","DOI":"10.1016\/j.jpeds.2024.114171","article-title":"Adipose tissue insulin resistance correlates with disease severity in pediatric metabolic dysfunction-associated steatotic liver disease: a prospective cohort study","volume":"274","author":"Heldens","year":"2024","journal-title":"J Pediatr"},{"key":"2026061714575016800_B27","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1002\/hep.23116","article-title":"Importance of changes in adipose tissue insulin resistance to histological response during thiazolidinedione treatment of patients with nonalcoholic steatohepatitis","volume":"50","author":"Gastaldelli","year":"2009","journal-title":"Hepatology"},{"key":"2026061714575016800_B28","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1002\/hep.25805","article-title":"Relationship between adipose tissue insulin resistance and liver histology in nonalcoholic steatohepatitis: a pioglitazone versus vitamin E versus placebo for the treatment of nondiabetic patients with nonalcoholic steatohepatitis trial follow-up study","volume":"56","author":"Bell","year":"2012","journal-title":"Hepatology"},{"key":"2026061714575016800_B29","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.jhep.2015.08.038","article-title":"Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis","volume":"64","author":"Armstrong","year":"2016","journal-title":"J Hepatol"},{"key":"2026061714575016800_B30","doi-asserted-by":"crossref","first-page":"1534","DOI":"10.1016\/j.cmet.2024.05.010","article-title":"Tirzepatide modulates the regulation of adipocyte nutrient metabolism through long-acting activation of the GIP receptor","volume":"36","author":"Regmi","year":"2024","journal-title":"Cell Metab"},{"key":"2026061714575016800_B31","first-page":"517","article-title":"A long-acting glucose dependent insulinotropic polypeptide receptor agonist improves insulin sensitivity and beta-cell function in subjects with type 2 diabetes","volume":"67","author":"Heise","year":"2024","journal-title":"Diabetologia"},{"key":"2026061714575016800_B32","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1016\/j.cell.2021.04.015","article-title":"Mechanisms and disease consequences of nonalcoholic fatty liver disease","volume":"184","author":"Loomba","year":"2021","journal-title":"Cell"},{"key":"2026061714575016800_B33","doi-asserted-by":"crossref","first-page":"e2231982","DOI":"10.1001\/jamanetworkopen.2022.31982","article-title":"Weight loss outcomes associated with semaglutide treatment for patients with overweight or obesity","volume":"5","author":"Ghusn","year":"2022","journal-title":"JAMA Netw Open"},{"key":"2026061714575016800_B34","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1056\/NEJMoa2032183","article-title":"Once-weekly semaglutide in adults with overweight or obesity","volume":"384","author":"Wilding","year":"2021","journal-title":"N Engl J Med"},{"key":"2026061714575016800_B35","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/S0140-6736(21)00213-0","article-title":"Semaglutide 2\u00b74 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial","volume":"397","author":"Davies","year":"2021","journal-title":"Lancet"},{"key":"2026061714575016800_B36","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1056\/NEJMoa2309000","article-title":"A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis","volume":"390","author":"Harrison","year":"2024","journal-title":"N Engl J Med"}],"container-title":["Diabetes Care"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/diabetesjournals.org\/care\/article-pdf\/48\/12\/2074\/842394\/dc251306.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/care\/article-pdf\/48\/12\/2074\/842394\/dc251306.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T18:58:01Z","timestamp":1781722681000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/care\/article\/48\/12\/2074\/163531\/Relationship-Between-Metabolic-and-Histological"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,9]]},"references-count":36,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,10,9]]},"published-print":{"date-parts":[[2025,12,1]]}},"URL":"https:\/\/doi.org\/10.2337\/dc25-1306","relation":{},"ISSN":["0149-5992","1935-5548"],"issn-type":[{"value":"0149-5992","type":"print"},{"value":"1935-5548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,9]]}}}