{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T08:48:08Z","timestamp":1790412488141,"version":"4.1.0"},"reference-count":33,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T00:00:00Z","timestamp":1758499200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Clinical trials suggest GLP\u20101 receptor agonists (RAs) and dual glucagon\u2010like peptide\u20101 (GLP\u20101)\/glucose\u2010dependent insulinotropic polypeptide (GIP) RAs improve metabolic dysfunction associated with steatohepatitis (MASH) in patients with metabolic dysfunction\u2010associated steatotic liver disease (MASLD). We aimed to compare the estimate of the relative effect of tirzepatide, semaglutide, and liraglutide in reducing the risk of major adverse liver outcomes (MALOs) in patients with type 2 diabetes (T2D).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design, Setting and Participants<\/jats:title>\n                    <jats:p>We emulated target trials based on a real\u2010world network of electronic health records (EHRs) from over 150 million patients. Three target trials were emulated, among eligible patients with T2D who had no prior MALO diagnosis, by comparing therapy involving tirzepatide, semaglutide, and liraglutide versus DPP4 inhibitor (DPP4i) therapy. We identified the first\u2010ever diagnosis of MALO occurring within a 2\u2010year follow\u2010up period and compared across the treatment groups using Kaplan\u2013Meier survival analyses. Cohorts underwent propensity score matching 1:1 for confounders. We performed sensitivity analyses relating to geographical location, combination with metformin, and by treatment adherence. We also performed head\u2010to\u2010head analyses of the incretin\u2010based therapies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>After matching, we identified three target trials comprised of 10\u2009165, 56\u2009702, and 8\u2009301 patients treated with tirzepatide, semaglutide, and liraglutide, respectively (1:1 with reference patients) for a 2\u2010year period. Tirzepatide (HR 0.53 [95% CI 0.40, 0.71]) and semaglutide (HR 0.81 [0.72, 0.90]) were associated with a significant reduction in the risk of incident MALO compared with DPP4i, whereas liraglutide was not (HR 1.04 [95% CI 0.79, 1.36]). In head\u2010to\u2010head comparisons, tirzepatide was associated with a significantly lower risk of incident MALO compared with liraglutide (HR 0.56 [95% CI 0.39, 0.79]), but not semaglutide (HR 0.83 [95% CI 0.63, 1.09]). Semaglutide was not associated with a reduced risk compared with liraglutide (HR 0.77 [95% CI 0.57, 1.05]).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Treatment with tirzepatide and, to a lesser extent, semaglutide, in patients with T2D, was associated with a lower incidence of MALO compared with DPP4i after 2\u2009years; largely driven by a reduction in the rates of compensated and decompensated cirrhosis. A reduction in MALO was not demonstrated with the use of liraglutide. These findings highlight a comparative benefit of tirzepatide (and semaglutide) versus DPP4i and should prompt more robust, longer\u2010term randomised controlled studies to evaluate their role in preventing MALO in this increasingly prevalent patient population with co\u2010existing T2D and MASLD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/liv.70367","type":"journal-article","created":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T12:23:49Z","timestamp":1758543829000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Target Trial Emulations of\n                    <scp>GLP<\/scp>\n                    \u20101 and Dual\n                    <scp>GLP<\/scp>\n                    \u20101\/\n                    <scp>GIP<\/scp>\n                    Agonists to Reduce Major Adverse Liver Outcomes in Type 2 Diabetes"],"prefix":"10.1111","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8066-9470","authenticated-orcid":false,"given":"Alex E.","family":"Henney","sequence":"first","affiliation":[{"name":"Department of Cardiovascular &amp; Metabolic Medicine University of Liverpool  Liverpool UK"},{"name":"Metabolism &amp; Nutrition Research Group Liverpool University Hospitals NHS Foundation Trust  Liverpool UK"},{"name":"Liverpool Centre for Cardiovascular Sciences University of Liverpool and Liverpool University Hospitals NHS Foundation Trust  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R.","family":"Riley","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular &amp; Metabolic Medicine University of Liverpool  Liverpool UK"},{"name":"Metabolism &amp; Nutrition Research Group Liverpool University Hospitals NHS Foundation Trust  Liverpool UK"},{"name":"Liverpool Centre for Cardiovascular Sciences University of Liverpool and Liverpool University Hospitals NHS Foundation Trust  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Anson","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular &amp; Metabolic Medicine University of Liverpool  Liverpool UK"},{"name":"Metabolism &amp; Nutrition Research Group Liverpool University Hospitals NHS Foundation Trust  Liverpool UK"},{"name":"Liverpool Centre for Cardiovascular Sciences University of Liverpool and Liverpool University Hospitals NHS Foundation Trust  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shazli","family":"Azmi","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Sciences University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uazman","family":"Alam","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular &amp; Metabolic Medicine University of Liverpool  Liverpool UK"},{"name":"Metabolism &amp; Nutrition Research Group Liverpool University Hospitals NHS Foundation Trust  Liverpool UK"},{"name":"Liverpool Centre for Cardiovascular Sciences University of Liverpool and Liverpool University Hospitals NHS Foundation Trust  Liverpool UK"},{"name":"Centre for Musculoskeletal Research, Faculty of Biology Medicine and Health The University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel J.","family":"Cuthbertson","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular &amp; Metabolic Medicine University of Liverpool  Liverpool UK"},{"name":"Metabolism &amp; Nutrition Research Group Liverpool University Hospitals NHS Foundation Trust  Liverpool UK"},{"name":"Liverpool Centre for Cardiovascular Sciences University of Liverpool and Liverpool University Hospitals NHS Foundation Trust  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9,22]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2024.02.007"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhepr.2023.100915"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc23-1937"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)00213-0"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2107519"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)01324-6"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(22)00085-7"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2015.9676"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2307563"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12933-024-02203-4"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/dom.15318"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/dom.13125"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-1253(23)00068-7"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2404881"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2401943"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2023-330962"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/apt.17925"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/alcalc\/agn099"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)61838-9"},{"key":"e_1_2_10_21_1","unstructured":"Excellence Nifhac \u201cType 2 Diabetes in Adults: Management 2025.\u201d"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.7326\/M23-2788"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0597-x"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/jamiaopen\/ooad035"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.7326\/M16-2607"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.39335.541782.AD"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.769069"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dsx.2023.102849"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2028395"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2024-334591"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1097\/HEP.0000000000000712"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/dom.16106"},{"issue":"12","key":"e_1_2_10_33_1","first-page":"756","article-title":"Nonalcoholic Steatohepatitis and Endpoints in Clinical Trials","volume":"12","author":"Hannah W. 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