{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T05:05:57Z","timestamp":1780376757815,"version":"3.54.1"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T00:00:00Z","timestamp":1780358400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve weight, glycemic control, and cardiometabolic risk factors, but randomized trials have not been powered to determine effects on advanced liver outcomes. We conducted a systematic review and exploratory meta-analysis of peer-reviewed comparative real-world cohort studies in adults with type 2 diabetes (T2D), emphasizing active-comparator designs, clinically advanced liver endpoints, and transparent limits of causal inference. PubMed\/MEDLINE and Embase were searched with citation chasing and an updated PubMed\/MEDLINE search through 25 April 2026; this evidence-identification strategy was focused rather than exhaustive. Twelve eligible comparative studies were included. In the predefined active-comparator outcome-family stratum, four studies comparing GLP-1RAs with DPP-4 inhibitors were sufficiently exchangeable for exploratory random-effects synthesis of incident cirrhosis or composite serious liver events. The primary Hartung-Knapp small-sample interval for the pooled estimate was HR 0.85 (95% CI 0.74\u20130.98); the conventional REML interval was narrower and is reported as a secondary reference estimate (95% CI 0.79\u20130.93; I\u00b2=0%; REML \u03c4\u00b2=0.000). Certainty of evidence was rated very low because all included studies were observational, outcome definitions and comparator strategies varied, and residual confounding and healthcare-engagement bias could not be excluded. GLP-1RA use shows a directionally favorable signal for advanced liver outcomes in T2D, but the evidence should be interpreted as hypothesis-supporting rather than definitive causal proof.<\/jats:p>\n                  <jats:sec>\n                    <jats:title>Systematic review registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>https:\/\/www.crd.york.ac.uk\/PROSPERO\/view\/CRD420261299499<\/jats:ext-link>\n                      , identifier CRD420261299499.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1874720","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T04:28:31Z","timestamp":1780374511000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Glucagon-like peptide-1 receptor agonists and advanced liver outcomes in type 2 diabetes: a systematic review and exploratory meta-analysis"],"prefix":"10.3389","volume":"17","author":[{"given":"Jing-Hong","family":"Hu","sequence":"first","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Yunlin Chang Gung Memorial Hospital","place":["Yunlin, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Ling","family":"Chang","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital & College of Medicine, Chang Gung University","place":["Taoyuan, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tung-Jung","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Yunlin Chang Gung Memorial Hospital","place":["Yunlin, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nai-Jen","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital & College of Medicine, Chang Gung University","place":["Taoyuan, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yung-Yu","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Chiayi Chang Gung Memorial Hospital","place":["Chiayi, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1001\/jamainternmed.2024.4661","article-title":"Glp-1 receptor agonists and risk for cirrhosis and related complications in patients with metabolic dysfunction-associated steatotic liver disease","volume":"184","author":"Kanwal","year":"2024","journal-title":"JAMA Intern Med"},{"key":"B2","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1053\/j.gastro.2024.04.029","article-title":"Association of glp-1 receptor agonists and hepatocellular carcinoma incidence and hepatic decompensation in patients with type 2 diabetes","volume":"167","author":"Wang","year":"2024","journal-title":"Gastroenterology"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1111\/liv.16132","article-title":"Impact of glp-1ra on the risk of adverse liver outcomes among patients with alcohol-associated liver disease and type 2 diabetes","volume":"45","author":"Rashid","year":"2025","journal-title":"Liver Int"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1097\/hep.0000000000000712","article-title":"Association of glucagon-like peptide-1 receptor agonists with serious liver events among patients with type 2 diabetes: a Scandinavian cohort study","volume":"79","author":"Engstr\u00f6m","year":"2024","journal-title":"Hepatology"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2023-330962","article-title":"Glucagon-like peptide-1 receptor agonists and risk of major adverse liver outcomes in patients with chronic liver disease and type 2 diabetes","volume":"73","author":"Wester","year":"2024","journal-title":"Gut"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2024-332687","article-title":"Risk of hepatic events associated with use of sodium-glucose cotransporter-2 inhibitors versus glucagon-like peptide-1 receptor agonists, and thiazolidinediones among patients with metabolic dysfunction-associated steatotic liver disease","volume":"74","author":"Bea","year":"2025","journal-title":"Gut"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.2337\/dc24-1903","article-title":"Glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors and the prevention of cirrhosis among patients with type 2 diabetes","volume":"48","author":"Pradhan","year":"2025","journal-title":"Diabetes Care"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3390\/metabo11020073","article-title":"Glucagon-like peptide-1 receptor agonists for treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: an updated meta-analysis of randomized controlled trials","volume":"11","author":"Mantovani","year":"2021","journal-title":"Metabolites"},{"key":"B9","doi-asserted-by":"publisher","first-page":"22063","DOI":"10.1038\/s41598-021-01663-y","article-title":"A meta-analysis of the effects of glucagon-like-peptide 1 receptor agonist (glp1-ra) in nonalcoholic fatty liver disease (nafld) with type 2 diabetes (t2d)","volume":"11","author":"Ghosal","year":"2021","journal-title":"Sci Rep"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhepr.2025.101661","article-title":"Impact of sglt2i and glp-1ra on liver-related events in patients with masld and type 2 diabetes: a network meta-analysis","volume":"8","author":"Li","year":"2026","journal-title":"JHEP Rep"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.n71","article-title":"The prisma 2020 statement: an updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"Bmj"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1097\/hep.0000000000000520","article-title":"A multisociety delphi consensus statement on new fatty liver disease nomenclature","volume":"78","author":"Rinella","year":"2023","journal-title":"Hepatology"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1002\/sim.1186","article-title":"Quantifying heterogeneity in a meta-analysis","volume":"21","author":"Higgins","year":"2002","journal-title":"Stat Med"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1","DOI":"10.18637\/jss.v036.i03","article-title":"Conducting meta-analyses in R with the metafor package","volume":"36","author":"Viechtbauer","year":"2010","journal-title":"J Stat Software"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.i4919","article-title":"Robins-i: a tool for assessing risk of bias in non-randomised studies of interventions","volume":"355","author":"Sterne","year":"2016","journal-title":"Bmj"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.l6890","article-title":"Synthesis without meta-analysis (swim) in systematic reviews: reporting guideline","volume":"368","author":"Campbell","year":"2020","journal-title":"Bmj"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.b2393","article-title":"Multiple imputation for missing data in epidemiological and clinical research: potential and pitfalls","volume":"338","author":"Sterne","year":"2009","journal-title":"Bmj"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2288-14-25","article-title":"The Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard Dersimonian-Laird method","volume":"14","author":"IntHout","year":"2014","journal-title":"BMC Med Res Methodol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1002\/sim.1482","article-title":"Improved tests for a random effects meta-regression with a single covariate","volume":"22","author":"Knapp","year":"2003","journal-title":"Stat Med"},{"key":"B20","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1186\/s12874-015-0091-1","article-title":"Hartung-Knapp-Sidik-Jonkman approach and its modification for random-effects meta-analysis with few studies","volume":"15","author":"R\u00f6ver","year":"2015","journal-title":"BMC Med Res Methodol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1002\/pds.3290","article-title":"Validation of three coding algorithms to identify patients with end-stage liver disease in an administrative database","volume":"21","author":"Goldberg","year":"2012","journal-title":"Pharmacoepidemiol Drug Saf"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1111\/dom.70505","article-title":"Comparative effectiveness of glp-1 receptor agonists, sglt2 inhibitors and dpp-4 inhibitors on liver outcomes in metabolic dysfunction-associated steatotic liver disease: a retrospective cohort study","volume":"28","author":"Sarker","year":"2026","journal-title":"Diabetes Obes Metab"},{"key":"B23","doi-asserted-by":"publisher","first-page":"7459","DOI":"10.1038\/s41467-025-62891-8","article-title":"A retrospective analysis of combination therapy with glp-1 receptor agonists and sglt2 inhibitors versus sglt2 inhibitor monotherapy in patients with masld","volume":"16","author":"Wu","year":"2025","journal-title":"Nat Commun"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.20524\/aog.2023.0814","article-title":"Dual metformin and glucagon-like peptide-1 receptor agonist therapy reduces mortality and hepatic complications in cirrhotic patients with diabetes mellitus","volume":"36","author":"Huynh","year":"2023","journal-title":"Ann Gastroenterol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1097\/hc9.0000000000000747","article-title":"Semaglutide versus other glp-1 receptor agonists in patients with masld","volume":"9","author":"Kuo","year":"2025","journal-title":"Hepatol Commun"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.315.7109.629","article-title":"Bias in meta-analysis detected by a simple, graphical test","volume":"315","author":"Egger","year":"1997","journal-title":"Bmj"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.7326\/m16-2607","article-title":"Sensitivity analysis in observational research: introducing the e-value","volume":"167","author":"VanderWeele","year":"2017","journal-title":"Ann Intern Med"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.39489.470347.AD","article-title":"Grade: an emerging consensus on rating quality of evidence and strength of recommendations","volume":"336","author":"Guyatt","year":"2008","journal-title":"Bmj"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1001885","article-title":"The reporting of studies conducted using observational routinely-collected health data (record) statement","volume":"12","author":"Benchimol","year":"2015","journal-title":"PloS Med"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwm324","article-title":"Immortal time bias in pharmaco-epidemiology","volume":"167","author":"Suissa","year":"2008","journal-title":"Am J Epidemiol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1080\/00273171.2011.568786","article-title":"An introduction to propensity score methods for reducing the effects of confounding in observational studies","volume":"46","author":"Austin","year":"2011","journal-title":"Multivariate Behav Res"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1111\/apt.17925","article-title":"Impacts of glucagon-like peptide-1 receptor agonists on the risk of adverse liver outcomes in patients with metabolic dysfunction-associated steatotic liver disease cirrhosis and type 2 diabetes","volume":"59","author":"Elsaid","year":"2024","journal-title":"Aliment Pharmacol Ther"},{"key":"B33","doi-asserted-by":"publisher","first-page":"697","DOI":"10.14309\/ajg.0000000000003585","article-title":"Association of glucagon-like peptide-1 receptor agonists with liver-related outcomes and all-cause mortality in patients with harmful alcohol use: a target trial emulation study","volume":"121","author":"John","year":"2026","journal-title":"Am J Gastroenterol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2028395","article-title":"A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis","volume":"384","author":"Newsome","year":"2021","journal-title":"N Engl J Med"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2023.01.004","article-title":"The postprandial actions of glp-1 receptor agonists: the missing link for cardiovascular and kidney protection in type 2 diabetes","volume":"35","author":"Thomas","year":"2023","journal-title":"Cell Metab"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24097789","article-title":"An overview of the cardioprotective effects of novel antidiabetic classes: focus on inflammation, oxidative stress, and fibrosis","volume":"24","author":"Balogh","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(15)00803-x","article-title":"Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (lean): a multicentre, double-blind, randomised, placebo-controlled phase 2 study","volume":"387","author":"Armstrong","year":"2016","journal-title":"Lancet"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v30.i43.4682","article-title":"Interplay of gut microbiota, glucagon-like peptide receptor agonists, and nutrition: new frontiers in metabolic dysfunction-associated steatotic liver disease therapy","volume":"30","author":"Guney-Coskun","year":"2024","journal-title":"World J Gastroenterol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1080\/17474124.2025.2519163","article-title":"Early portal hypertension in metabolic dysfunction-associated steatotic liver disease: a concise review","volume":"19","author":"L\u00f3pez-M\u00e9ndez","year":"2025","journal-title":"Expert Rev Gastroenterol Hepatol"},{"key":"B40","doi-asserted-by":"publisher","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":"B41","unstructured":"Fda approves treatment for serious liver disease known as mash\n          \n          \n          \n          2025"},{"key":"B42","doi-asserted-by":"publisher","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"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1874720\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T04:28:33Z","timestamp":1780374513000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1874720\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,2]]},"references-count":42,"alternative-id":["10.3389\/fendo.2026.1874720"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2026.1874720","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,2]]},"article-number":"1874720"}}