{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T14:55:22Z","timestamp":1778079322876,"version":"3.51.4"},"reference-count":35,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2024,5,3]],"date-time":"2024-05-03T00:00:00Z","timestamp":1714694400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Medical and Health Guidance Projects of Xiamen","award":["3502Z20224ZD1106"],"award-info":[{"award-number":["3502Z20224ZD1106"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Nonalcoholic fatty liver disease (NAFLD) is strongly associated with type 2 diabetes mellitus (T2DM). Lifestyle intervention remains a preferred treatment modality for NAFLD. The glucagon-like peptide (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors have been developed as new glucose-lowering drugs, which can improve fatty liver via an insulin-independent glucose-lowering effect. However, studies exploring the efficacy of GLP-1 receptor agonists combined with SGLT-2 inhibitors in patients with NAFLD and T2DM are scanty. Thus, the present randomised controlled trial aims at comparing the efficacy and safety of semaglutide plus empagliflozin with each treatment alone in patients with NAFLD and T2DM.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>This 52-week double-blinded, randomised, parallel-group, active-controlled trial evaluates the effects of semaglutide, empagliflozin and semaglutide + empagliflozin in 105 eligible overweight\/obese subjects with NAFLD and T2DM. The primary outcome will be a change from baseline to week 52 in the controlled attenuation parameter, free fatty acid and glucagon. Secondary endpoints include changes in liver stiffness measurement, liver enzymes, blood glucose, lipid levels, renal function, electrolyte balances, minerals and bone metabolism, cytokines, high-sensitivity C-reactive protein, ferritin, anthropometric indicators, nonalcoholic fatty liver fibrosis score, fibrosis 4 score and homeostatic model assessment for insulin resistance. In addition, intention-to-treat, interim analysis and safety analysis will be performed.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Discussion<\/jats:title>\n<jats:p>This double-blinded, randomised, clinical trial involves a multi-disciplinary approach and aims to explore the synergistic effects of the combination of semaglutide and empagliflozin. The results can provide important insights into mechanisms of GLP-1 receptor agonists and\/or SGLT-2 inhibitors in patients with NAFLD and T2DM.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Trial registration<\/jats:title>\n<jats:p>This study has been registered with Chinese Clinical Trial Registry (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/pactr.samrc.ac.za\/\" xlink:type=\"simple\">ChiCTR2300070674<\/jats:ext-link>).<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0302155","type":"journal-article","created":{"date-parts":[[2024,5,3]],"date-time":"2024-05-03T17:26:14Z","timestamp":1714757174000},"page":"e0302155","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":14,"title":["Semaglutide combined with empagliflozin vs. monotherapy for non-alcoholic fatty liver disease in type 2 diabetes: Study protocol for a randomized clinical trial"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8244-8495","authenticated-orcid":true,"given":"Yu-Hao","family":"Lin","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhi-Jun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jin-Qing","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhi-Yi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi-Ting","family":"Peng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan-Mei","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huo-Ping","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian-Qing","family":"Tian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2024,5,3]]},"reference":[{"issue":"10290","key":"pone.0302155.ref001","doi-asserted-by":"crossref","first-page":"2212","DOI":"10.1016\/S0140-6736(20)32511-3","article-title":"Non-alcoholic fatty liver disease","volume":"397","author":"EE Powell","year":"2021","journal-title":"Lancet"},{"issue":"12","key":"pone.0302155.ref002","doi-asserted-by":"crossref","first-page":"2809","DOI":"10.1016\/j.cgh.2021.12.002","article-title":"2019 Global NAFLD Prevalence: A Systematic Review and Meta-analysis","volume":"20","author":"MH Le","year":"2022","journal-title":"Clin Gastroenterol Hepatol"},{"issue":"1","key":"pone.0302155.ref003","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1002\/hep.29466","article-title":"Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease","volume":"67","author":"C Estes","year":"2018","journal-title":"Hepatology"},{"issue":"4","key":"pone.0302155.ref004","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1016\/j.jhep.2019.06.021","article-title":"The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: A systematic review and meta-analysis","volume":"71","author":"ZM Younossi","year":"2019","journal-title":"J Hepatol"},{"issue":"2","key":"pone.0302155.ref005","doi-asserted-by":"crossref","first-page":"283","DOI":"10.2337\/dc19-1113","article-title":"Economic and Clinical Burden of Nonalcoholic Steatohepatitis in Patients With Type 2 Diabetes in the U.S","volume":"43","author":"ZM Younossi","year":"2020","journal-title":"Diabetes Care"},{"issue":"9","key":"pone.0302155.ref006","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1038\/s41575-021-00448-y","article-title":"The complex link between NAFLD and type 2 diabetes mellitus\u2014mechanisms and treatments","volume":"18","author":"G Targher","year":"2021","journal-title":"Nat Rev Gastroenterol Hepatol"},{"issue":"2","key":"pone.0302155.ref007","doi-asserted-by":"crossref","DOI":"10.3390\/biomedicines11020468","article-title":"Non-alcoholic Fatty Liver Disease (NAFLD), Type 2 Diabetes, and Non-viral Hepatocarcinoma: Pathophysiological Mechanisms and New Therapeutic Strategies","volume":"11","author":"E Vetrano","year":"2023","journal-title":"Biomedicines"},{"issue":"4","key":"pone.0302155.ref008","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.jhepr.2019.07.002","article-title":"From NASH to diabetes and from diabetes to NASH: Mechanisms and treatment options","volume":"1","author":"A Gastaldelli","year":"2019","journal-title":"JHEP Rep"},{"issue":"4","key":"pone.0302155.ref009","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/S2468-1253(21)00261-2","article-title":"Efficacy of peroxisome proliferator-activated receptor agonists, glucagon-like peptide-1 receptor agonists, or sodium-glucose cotransporter-2 inhibitors for treatment of non-alcoholic fatty liver disease: a systematic review","volume":"7","author":"A Mantovani","year":"2022","journal-title":"Lancet Gastroenterol Hepatol"},{"issue":"2","key":"pone.0302155.ref010","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1111\/joim.13531","article-title":"Current treatment of non-alcoholic fatty liver disease","volume":"292","author":"R Paternostro","year":"2022","journal-title":"J Intern Med"},{"issue":"3","key":"pone.0302155.ref011","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/j.jhep.2022.04.003","article-title":"Safety and efficacy of combination therapy with semaglutide, cilofexor and firsocostat in patients with non-alcoholic steatohepatitis: A randomised, open-label phase II trial","volume":"77","author":"N Alkhouri","year":"2022","journal-title":"J Hepatol"},{"issue":"9","key":"pone.0302155.ref012","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1111\/apt.16608","article-title":"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","volume":"54","author":"A Flint","year":"2021","journal-title":"Aliment Pharmacol Ther"},{"issue":"12","key":"pone.0302155.ref013","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1056\/NEJMoa2028395","article-title":"A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis","volume":"384","author":"PN Newsome","year":"2021","journal-title":"N Engl J Med"},{"issue":"21","key":"pone.0302155.ref014","doi-asserted-by":"crossref","DOI":"10.3390\/nu14214673","article-title":"Once-Weekly Subcutaneous Semaglutide Improves Fatty Liver Disease in Patients with Type 2 Diabetes: A 52-Week Prospective Real-Life Study","volume":"14","author":"S Volpe","year":"2022","journal-title":"Nutrients"},{"issue":"3","key":"pone.0302155.ref015","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1007\/s13300-021-01011-3","article-title":"Empagliflozin Improves Liver Steatosis and Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease and Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial","volume":"12","author":"H Chehrehgosha","year":"2021","journal-title":"Diabetes Ther"},{"issue":"8","key":"pone.0302155.ref016","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.2337\/dc18-0165","article-title":"Effect of Empagliflozin on Liver Fat in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial (E-LIFT Trial)","volume":"41","author":"MS Kuchay","year":"2018","journal-title":"Diabetes Care"},{"issue":"2","key":"pone.0302155.ref017","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1007\/s10620-019-5477-1","article-title":"Empagliflozin for the Treatment of Nonalcoholic Steatohepatitis in Patients with Type 2 Diabetes Mellitus","volume":"65","author":"LL Lai","year":"2020","journal-title":"Dig Dis Sci"},{"issue":"2","key":"pone.0302155.ref018","doi-asserted-by":"crossref","DOI":"10.3390\/biomedicines11020322","article-title":"Effects of a Combination of Empagliflozin Plus Metformin vs. Metformin Monotherapy on NAFLD Progression in Type 2 Diabetes: The IMAGIN Pilot Study","volume":"11","author":"A Caturano","year":"2023","journal-title":"Biomedicines"},{"issue":"3","key":"pone.0302155.ref019","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1111\/dom.13907","article-title":"Exenatide and dapagliflozin combination improves markers of liver steatosis and fibrosis in patients with type 2 diabetes","volume":"22","author":"A Gastaldelli","year":"2020","journal-title":"Diabetes Obes Metab"},{"issue":"9","key":"pone.0302155.ref020","doi-asserted-by":"crossref","first-page":"2286","DOI":"10.1002\/hep4.2005","article-title":"Favorable impact of long-term SGLT2 inhibitor for NAFLD complicated by diabetes mellitus: A 5-year follow-up study","volume":"6","author":"N Akuta","year":"2022","journal-title":"Hepatol Commun"},{"key":"pone.0302155.ref021","doi-asserted-by":"crossref","first-page":"e7586","DOI":"10.1136\/bmj.e7586","article-title":"SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials","volume":"346","author":"AW Chan","year":"2013","journal-title":"Bmj"},{"issue":"4","key":"pone.0302155.ref022","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1111\/1751-2980.12685","article-title":"Guidelines of prevention and treatment of nonalcoholic fatty liver disease (2018, China)","volume":"20","author":"JG Fan","year":"2019","journal-title":"J Dig Dis"},{"issue":"Suppl 1","key":"pone.0302155.ref023","first-page":"S20","article-title":"2. Diagnosis and Classification of Diabetes: Standards of Care in Diabetes-2024","volume":"47","year":"2024","journal-title":"Diabetes Care"},{"issue":"4","key":"pone.0302155.ref024","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1002\/hep.21496","article-title":"The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD","volume":"45","author":"P Angulo","year":"2007","journal-title":"Hepatology"},{"issue":"6","key":"pone.0302155.ref025","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1002\/hep.21178","article-title":"Development of a simple noninvasive index to predict significant fibrosis in patients with HIV\/HCV coinfection","volume":"43","author":"RK Sterling","year":"2006","journal-title":"Hepatology"},{"issue":"7","key":"pone.0302155.ref026","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1007\/BF00280883","article-title":"Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man","volume":"28","author":"DR Matthews","year":"1985","journal-title":"Diabetologia"},{"issue":"6","key":"pone.0302155.ref027","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.1053\/j.gastro.2019.01.042","article-title":"Accuracy of FibroScan Controlled Attenuation Parameter and Liver Stiffness Measurement in Assessing Steatosis and Fibrosis in Patients With Nonalcoholic Fatty Liver Disease","volume":"156","author":"PJ Eddowes","year":"2019","journal-title":"Gastroenterology"},{"issue":"11","key":"pone.0302155.ref028","doi-asserted-by":"crossref","first-page":"4697","DOI":"10.1007\/s12325-020-01498-5","article-title":"Effect of Empagliflozin on Liver Steatosis and Fibrosis in Patients With Non-Alcoholic Fatty Liver Disease Without Diabetes: A Randomized, Double-Blind, Placebo-Controlled Trial","volume":"37","author":"H Taheri","year":"2020","journal-title":"Adv Ther"},{"issue":"11","key":"pone.0302155.ref029","doi-asserted-by":"crossref","first-page":"1714","DOI":"10.14309\/ajg.0000000000000433","article-title":"The Impact of Obesity and Type 2 Diabetes on Chronic Liver Disease","volume":"114","author":"ZM Younossi","year":"2019","journal-title":"Am J Gastroenterol"},{"issue":"1","key":"pone.0302155.ref030","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1002\/hep.29367","article-title":"The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases","volume":"67","author":"N Chalasani","year":"2018","journal-title":"Hepatology"},{"issue":"6","key":"pone.0302155.ref031","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1016\/j.jacbts.2018.09.004","article-title":"The GLP-1 Analogs Liraglutide and Semaglutide Reduce Atherosclerosis in ApoE(-\/-) and LDLr(-\/-) Mice by a Mechanism That Includes Inflammatory Pathways","volume":"3","author":"G Rakipovski","year":"2018","journal-title":"JACC Basic Transl Sci"},{"issue":"11","key":"pone.0302155.ref032","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1002\/hep4.1562","article-title":"Nonalcoholic Fatty Liver Disease Impairs the Liver-Alpha Cell Axis Independent of Hepatic Inflammation and Fibrosis","volume":"4","author":"JS Pedersen","year":"2020","journal-title":"Hepatol Commun"},{"issue":"1","key":"pone.0302155.ref033","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1097\/MOL.0000000000000857","article-title":"The feedback cycles between glucose, amino acids and lipids and alpha cell secretion and their role in metabolic fatty liver disease","volume":"34","author":"M Winther-S\u00f8rensen","year":"2023","journal-title":"Curr Opin Lipidol"},{"issue":"9","key":"pone.0302155.ref034","doi-asserted-by":"crossref","first-page":"1852","DOI":"10.2337\/dbi22-0004","article-title":"The Liver-\u03b1-Cell Axis in Health and in Disease","volume":"71","author":"MM Richter","year":"2022","journal-title":"Diabetes"},{"key":"pone.0302155.ref035","doi-asserted-by":"crossref","first-page":"155657","DOI":"10.1016\/j.metabol.2023.155657","article-title":"SGLT2 inhibitor empagliflozin downregulates miRNA-34a-5p and targets GREM2 to inactivate hepatic stellate cells and ameliorate non-alcoholic fatty liver disease-associated fibrosis","volume":"146","author":"Y Shen","year":"2023","journal-title":"Metabolism"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0302155","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,3]],"date-time":"2024-05-03T17:26:34Z","timestamp":1714757194000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0302155"}},"subtitle":[],"editor":[{"given":"Ferdinando Carlo","family":"Sasso","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2024,5,3]]},"references-count":35,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,5,3]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0302155","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,3]]}}}