{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T15:53:27Z","timestamp":1790610807412,"version":"4.1.0"},"reference-count":48,"publisher":"American Diabetes Association","issue":"10","license":[{"start":{"date-parts":[[2019,9,20]],"date-time":"2019-09-20T00:00:00Z","timestamp":1568937600000},"content-version":"vor","delay-in-days":42,"URL":"http:\/\/www.diabetesjournals.org\/content\/license"}],"funder":[{"DOI":"10.13039\/501100004191","name":"Novo Nordisk","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004191","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,10,1]]},"abstract":"<jats:sec><jats:title>OBJECTIVE<\/jats:title><jats:p>To explore gallbladder- and biliary tract\u2013related events reported for the liraglutide and placebo groups in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESEARCH DESIGN AND METHODS<\/jats:title><jats:p>LEADER was an international, randomized, double-blind, controlled cardiovascular (CV) outcomes trial. Participants with type 2 diabetes at high risk for CV events (n = 9,340) were randomized 1:1 to receive either liraglutide (\u22641.8 mg daily; n = 4,668) or placebo (n = 4,672), with both groups also receiving standard care (treatment period: 3.5\u20135 years). Acute gallstone disease was a medical event of special interest. This post hoc analysis categorized captured events of acute gallbladder or biliary disease into four groups: uncomplicated gallbladder stones, complicated gallbladder stones, cholecystitis, and biliary obstruction. Time to first event by treatment group was analyzed using Cox regression.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>There was an increased risk of acute gallbladder or biliary disease with liraglutide versus placebo (n = 141 of 4,668 vs. n = 88 of 4,672 patients, respectively; hazard ratio [HR] 1.60; 95% CI 1.23, 2.09; P &amp;lt; 0.001). Similar trends were observed for each of the four categories of gallbladder- or biliary tract\u2013related events. Cholecystectomy was performed more frequently in liraglutide-treated patients (HR 1.56; 95% CI 1.10, 2.20; P = 0.013) but for similar proportions of the patients who experienced gallbladder- or biliary tract\u2013related events (57% with liraglutide vs. 59% with placebo).<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>Although LEADER was not specifically designed to assess acute gallbladder or biliary disease, the trial showed an increased risk of gallbladder- or biliary tract\u2013related events with liraglutide versus placebo, which appeared to be consistent across four categories of these events. Further studies should investigate the relevant mechanisms.<\/jats:p><\/jats:sec>","DOI":"10.2337\/dc19-0415","type":"journal-article","created":{"date-parts":[[2019,8,10]],"date-time":"2019-08-10T01:15:22Z","timestamp":1565399722000},"page":"1912-1920","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":60,"title":["Effects of Liraglutide Compared With Placebo on Events of Acute Gallbladder or Biliary Disease in Patients With Type 2 Diabetes at High Risk for Cardiovascular Events in the LEADER Randomized Trial"],"prefix":"10.2337","volume":"42","clinical-trial-number":[{"clinical-trial-number":"nct01179048","registry":"10.18810\/clinical-trials-gov","type":"results"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5749-6954","authenticated-orcid":false,"given":"Michael A.","family":"Nauck","sequence":"first","affiliation":[{"name":"Diabetes Center Bochum-Hattingen, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie Louise","family":"Muus Ghorbani","sequence":"additional","affiliation":[{"name":"Novo Nordisk A\/S, S\u00f8borg, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eskil","family":"Kreiner","sequence":"additional","affiliation":[{"name":"Novo Nordisk A\/S, S\u00f8borg, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans A.","family":"Saevereid","sequence":"additional","affiliation":[{"name":"Novo Nordisk A\/S, S\u00f8borg, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John B.","family":"Buse","sequence":"additional","affiliation":[{"name":"University of North Carolina School of Medicine, Chapel Hill, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the LEADER Publication Committee on behalf of the LEADER Trial Investigators","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2019,8,9]]},"reference":[{"key":"2022031221322609300_B1","doi-asserted-by":"crossref","first-page":"834","DOI":"10.2337\/dc08-1755","article-title":"Increased risk of acute pancreatitis and biliary disease observed in patients with type 2 diabetes: a retrospective cohort study","volume":"32","author":"Noel","year":"2009","journal-title":"Diabetes Care"},{"key":"2022031221322609300_B2","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1097\/MOG.0000000000000423","article-title":"An update on the pathogenesis of cholesterol gallstone disease","volume":"34","author":"Di Ciaula","year":"2018","journal-title":"Curr Opin Gastroenterol"},{"key":"2022031221322609300_B3","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1001\/jamainternmed.2016.1531","article-title":"Association of bile duct and gallbladder diseases with the use of incretin-based drugs in patients with type 2 diabetes mellitus","volume":"176","author":"Faillie","year":"2016","journal-title":"JAMA Intern Med"},{"key":"2022031221322609300_B4","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1111\/jcpt.12373","article-title":"Incretin-based therapy and acute cholecystitis: a review of case reports and EudraVigilance spontaneous adverse drug reaction reporting database","volume":"41","author":"Pizzimenti","year":"2016","journal-title":"J Clin Pharm Ther"},{"key":"2022031221322609300_B5","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1111\/dom.12926","article-title":"Safety issues with glucagon-like peptide-1 receptor agonists (pancreatitis, pancreatic cancer and cholelithiasis): data from randomized controlled trials","volume":"19","author":"Monami","year":"2017","journal-title":"Diabetes Obes Metab"},{"key":"2022031221322609300_B6","unstructured":"European Medicines Agency. 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