{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T09:24:44Z","timestamp":1784366684112,"version":"3.55.0"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,8,30]],"date-time":"2022-08-30T00:00:00Z","timestamp":1661817600000},"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. Pharmacol."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Ursodeoxycholic acid (UDCA) is currently used for the treatment of primary biliary cholangitis (PBC), but some people do not respond well to UDCA. It reported that the combination of fenofibrate and UDCA can improve the clinical indices in these patients. However, more high-quality evidence is needed to improve guideline recommendations.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> Through an updated meta-analysis, studies included were valued by the Cochrane Evaluation Manual and Robins-I. Biochemical and clinical indicator changes in UDCA-refractory PBC patients receiving combination therapy were analyzed by Revman 5.42. Then, we explored the influence of fenofibrate dose and the effectiveness and safety of long-term application by retrospective cohort study.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> Our meta-analysis included nine publications with a total of 389 patients, including 216 treated with UDCA alone and 173 who received combination therapy. The meta-analysis showed that combination therapy was more effective than UDCA monotherapy in decreasing biochemical parameters, such as ALP, GGT, IgM, and TG. However, the occurrence of pruritus and adverse events was slightly higher with combination therapy than with UDCA monotherapy. A total of 156 patients were included in our cohort study: 68 patients underwent UDCA monotherapy, and 88 patients underwent combination therapy. Among UDCA-refractory patients, fenofibrate add-on therapy significantly improved the ALP normalization rate.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> The combination of fenofibrate and UDCA can decrease biochemical parameters, of UDCA-refractory PBC patient. Furthermore, the efficacy and safety of long-term combination therapy were also confirmed in our cohort study.<\/jats:p>","DOI":"10.3389\/fphar.2022.948362","type":"journal-article","created":{"date-parts":[[2022,8,30]],"date-time":"2022-08-30T07:16:26Z","timestamp":1661843786000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Efficacy and safety of fenofibrate add-on therapy in patients with primary biliary cholangitis refractory to ursodeoxycholic acid: A retrospective study and updated meta-analysis"],"prefix":"10.3389","volume":"13","author":[{"given":"Xuan","family":"Guoyun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ding","family":"Dawei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liu","family":"Ning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hu","family":"Yinan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Fangfang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Siyuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sun","family":"Hao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Jiaqi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Ang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo","family":"Guanya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Xi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shang","family":"Yulong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Ying","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,8,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1002\/hep.510230122","article-title":"Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club","volume":"23","author":"Arroyo","year":"1996","journal-title":"Hepatology"},{"key":"B2","doi-asserted-by":"publisher","first-page":"818089","DOI":"10.3389\/fphar.2021.818089","article-title":"Fibrates for the treatment of primary biliary cholangitis unresponsive to ursodeoxycholic acid: An exploratory study","volume":"12","author":"Cancado","year":"2021","journal-title":"Front. Pharmacol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"864839","DOI":"10.1155\/2014\/864839","article-title":"Erratum to \"15-Deoxy-\u03b312, 14-prostaglandin J2 reduces liver impairment in a model of ConA-induced acute hepatic inflammation by activation of PPAR\u03b3 and reduction in NF-\u03baB activity\"","volume":"2014","author":"Chen","year":"2014","journal-title":"PPAR Res."},{"key":"B4","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1111\/apt.13465","article-title":"Combined ursodeoxycholic acid (UDCA) and fenofibrate in primary biliary cholangitis patients with incomplete UDCA response may improve outcomes","volume":"43","author":"Cheung","year":"2016","journal-title":"Aliment. Pharmacol. Ther."},{"key":"B5","doi-asserted-by":"publisher","first-page":"264","DOI":"10.3760\/cma.j.cn112138-20211112-00794-1","article-title":"Guidelines on the diagnosis and management of primary biliary cholangitis (2021)","volume":"30","year":"2022","journal-title":"Zhonghua Gan Zang Bing Za Zhi"},{"key":"B6","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1002\/hep.22428","article-title":"Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis","volume":"48","author":"Corpechot","year":"2008","journal-title":"Hepatology"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1361","DOI":"10.1016\/j.jhep.2011.02.031","article-title":"Early primary biliary cirrhosis: biochemical response to treatment and prediction of long-term outcome","volume":"55","author":"Corpechot","year":"2011","journal-title":"J. Hepatol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"2171","DOI":"10.1056\/NEJMoa1714519","article-title":"A placebo-controlled trial of bezafibrate in primary biliary cholangitis","volume":"378","author":"Corpechot","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"2527","DOI":"10.1002\/hep.31752","article-title":"Hexa histidine-tagged recombinant human cytoglobin deactivates hepatic stellate cells and inhibits liver fibrosis by scavenging reactive oxygen species","volume":"73","author":"Dat","year":"2021","journal-title":"Hepatology"},{"key":"B10","doi-asserted-by":"publisher","first-page":"894","DOI":"10.3748\/wjg.v10.i6.894","article-title":"Fenofibrate for patients with asymptomatic primary biliary cirrhosis","volume":"10","author":"Dohmen","year":"2004","journal-title":"World J. Gastroenterol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"557","DOI":"10.17235\/reed.2018.5533\/2018","article-title":"Efficacy and safety of fenofibrate add-on therapy for patients with primary biliary cholangitis and a suboptimal response to UDCA","volume":"110","author":"Duan","year":"2018","journal-title":"Rev. Esp. Enferm. Dig."},{"key":"B12","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/j.jhep.2017.03.022","article-title":"EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis","volume":"67","year":"2017","journal-title":"J. Hepatol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1030","DOI":"10.1002\/hep.26894","article-title":"Peroxisome proliferator-activated receptor alpha activates human multidrug resistance transporter 3\/ATP-binding cassette protein subfamily B4 transcription and increases rat biliary phosphatidylcholine secretion","volume":"59","author":"Ghonem","year":"2014","journal-title":"Hepatology"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1213","DOI":"10.1002\/cpt.1930","article-title":"Fenofibrate improves liver function and reduces the toxicity of the bile acid pool in patients with primary biliary cholangitis and primary sclerosing cholangitis who are partial responders to ursodiol","volume":"108","author":"Ghonem","year":"2020","journal-title":"Clin. Pharmacol. Ther."},{"key":"B15","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1111\/j.1751-2980.2012.00574.x","article-title":"Efficacy of fenofibrate in Chinese patients with primary biliary cirrhosis partially responding to ursodeoxycholic acid therapy","volume":"13","author":"Han","year":"2012","journal-title":"J. Dig. Dis."},{"key":"B16","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1016\/j.jhep.2019.04.001","article-title":"Ursodeoxycholic acid therapy and liver transplant-free survival in patients with primary biliary cholangitis","volume":"71","author":"Harms","year":"2019","journal-title":"J. Hepatol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"3037","DOI":"10.1007\/s10620-016-4250-y","article-title":"Long-term fenofibrate treatment in primary biliary cholangitis improves biochemistry but not the UK-PBC risk score","volume":"61","author":"Hegade","year":"2016","journal-title":"Dig. Dis. Sci."},{"key":"B18","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1016\/j.jhep.2020.09.011","article-title":"A placebo-controlled randomised trial of budesonide for PBC following an insufficient response to UDCA","volume":"74","author":"Hirschfield","year":"2021","journal-title":"J. Hepatol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1038\/bjp.2008.331","article-title":"Activation of peroxisome proliferator-activated receptor-alpha in mice induces expression of the hepatic low-density lipoprotein receptor","volume":"155","author":"Huang","year":"2008","journal-title":"Br. J. Pharmacol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1042\/BJ20020981","article-title":"Peroxisome proliferator-activated receptor alpha (PPARalpha)-mediated regulation of multidrug resistance 2 (Mdr2) expression and function in mice","volume":"369","author":"Kok","year":"2003","journal-title":"Biochem. J."},{"key":"B21","doi-asserted-by":"publisher","first-page":"2186","DOI":"10.1038\/ajg.2010.216","article-title":"Baseline ductopenia and treatment response predict long-term histological progression in primary biliary cirrhosis","volume":"105","author":"Kumagi","year":"2010","journal-title":"Am. J. Gastroenterol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1338","DOI":"10.1053\/j.gastro.2014.08.029","article-title":"Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow-up study","volume":"147","author":"Lammers","year":"2014","journal-title":"Gastroenterology"},{"key":"B23","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1111\/j.1365-2036.2010.04512.x","article-title":"Pilot study: fenofibrate for patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid","volume":"33","author":"Levy","year":"2011","journal-title":"Aliment. Pharmacol. Ther."},{"key":"B24","doi-asserted-by":"publisher","first-page":"120","DOI":"10.2174\/1874192401004010120","article-title":"Fenofibrate in primary biliary cirrhosis: a pilot study","volume":"4","author":"Liberopoulos","year":"2010","journal-title":"Open Cardiovasc. Med. J."},{"key":"B25","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1002\/hep.30145","article-title":"Primary biliary cholangitis: 2018 practice guidance from the American association for the study of liver diseases","volume":"69","author":"Lindor","year":"2018","journal-title":"Hepatology"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1915","DOI":"10.1016\/S0140-6736(20)31607-X","article-title":"Primary biliary cholangitis","volume":"396","author":"Lleo","year":"2020","journal-title":"Lancet"},{"key":"B27","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1007\/s00535-021-01836-6","article-title":"Environmental factors, medical and family history, and comorbidities associated with primary biliary cholangitis in Japan: a multicenter case-control study","volume":"57","author":"Matsumoto","year":"2022","journal-title":"J. Gastroenterol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"2147","DOI":"10.1111\/j.1572-0241.2002.05944.x","article-title":"Fenofibrate treatment in patients with primary biliary cirrhosis","volume":"97","author":"Ohira","year":"2002","journal-title":"Am. J. Gastroenterol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"2143","DOI":"10.1111\/j.1572-0241.2004.40397.x","article-title":"Antimitochondrial antibodies and reactivity to N. aromaticivorans proteins in Icelandic patients with primary biliary cirrhosis and their relatives","volume":"99","author":"Olafsson","year":"2004","journal-title":"Am. J. Gastroenterol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"S3","DOI":"10.1016\/S2210-7401(12)70015-3","article-title":"Ursodeoxycholic acid and bile-acid mimetics as therapeutic agents for cholestatic liver diseases: an overview of their mechanisms of action","author":"Poupon","year":"2012","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1002\/hep.21499","article-title":"Impairment of hepatic Stat-3 activation and reduction of PPARalpha activity in fructose-fed rats","volume":"45","author":"Roglans","year":"2007","journal-title":"Hepatology"},{"key":"B32","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1002\/path.1379","article-title":"High expression of MDR1, MRP1, and MRP3 in the hepatic progenitor cell compartment and hepatocytes in severe human liver disease","volume":"200","author":"Ros","year":"2003","journal-title":"J. Pathol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1945","DOI":"10.2337\/dc07-0015","article-title":"Fenofibrate therapy ameliorates fasting and postprandial lipoproteinemia, oxidative stress, and the inflammatory response in subjects with hypertriglyceridemia and the metabolic syndrome","volume":"30","author":"Rosenson","year":"2007","journal-title":"Diabetes Care"},{"key":"B34","doi-asserted-by":"publisher","first-page":"i4919","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":"B35","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1002\/hep.22670","article-title":"Comment on biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis","volume":"49","author":"Walker","year":"2009","journal-title":"Hepatology"},{"key":"B36","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1080\/00325481.2021.1885945","article-title":"Similar clinical outcome of AMA immunoblot-M2-negative compared to immunoblot-positive subjects over six years of follow-up","volume":"133","author":"Zandanell","year":"2021","journal-title":"Postgrad. Med."},{"key":"B37","doi-asserted-by":"publisher","first-page":"2757","DOI":"10.2147\/DDDT.S79837","article-title":"Combination therapy of fenofibrate and ursodeoxycholic acid in patients with primary biliary cirrhosis who respond incompletely to UDCA monotherapy: a meta-analysis","volume":"9","author":"Zhang","year":"2015","journal-title":"Drug Des. Devel. Ther."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.948362\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,30]],"date-time":"2022-08-30T07:16:31Z","timestamp":1661843791000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.948362\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,30]]},"references-count":37,"alternative-id":["10.3389\/fphar.2022.948362"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2022.948362","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,30]]},"article-number":"948362"}}