{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T14:26:22Z","timestamp":1792765582291,"version":"4.5.0"},"reference-count":31,"publisher":"American Diabetes Association","issue":"7","license":[{"start":{"date-parts":[[2020,6,19]],"date-time":"2020-06-19T00:00:00Z","timestamp":1592524800000},"content-version":"vor","delay-in-days":46,"URL":"https:\/\/www.diabetesjournals.org\/content\/license"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,7,1]]},"abstract":"<jats:sec>\n                  <jats:title>OBJECTIVE<\/jats:title>\n                  <jats:p>The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial (ClinicalTrials.gov reg. no. NCT01179048) demonstrated a reduced risk of cardiovascular (CV) events for patients with type 2 diabetes who received the glucagon-like peptide 1 receptor agonist liraglutide versus placebo. The mechanisms behind this CV benefit remain unclear. We aimed to identify potential mediators for the CV benefit observed with liraglutide in the LEADER trial.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>RESEARCH DESIGN AND METHODS<\/jats:title>\n                  <jats:p>We performed exploratory analyses to identify potential mediators of the effect of liraglutide on major adverse CV events (MACE; composite of CV death, nonfatal myocardial infarction, or nonfatal stroke) from the following candidates: glycated hemoglobin (HbA1c), body weight, urinary albumin-to-creatinine ratio (UACR), confirmed hypoglycemia, sulfonylurea use, insulin use, systolic blood pressure, and LDL cholesterol. These candidates were selected as CV risk factors on which liraglutide had an effect in LEADER such that a reduction in CV risk might result. We used two methods based on a Cox proportional hazards model and the new Vansteelandt method designed to use all available information from the mediator and to control for confounding factors.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>Analyses using the Cox methods and Vansteelandt method indicated potential mediation by HbA1c (up to 41% and 83% mediation, respectively) and UACR (up to 29% and 33% mediation, respectively) on the effect of liraglutide on MACE. Mediation effects were small for other candidates.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>CONCLUSIONS<\/jats:title>\n                  <jats:p>These analyses identify HbA1c and, to a lesser extent, UACR as potential mediators of the CV effects of liraglutide. Whether either is a marker of an unmeasured factor or a true mediator remains a key question that invites further investigation.<\/jats:p>\n               <\/jats:sec>","DOI":"10.2337\/dc19-2251","type":"journal-article","created":{"date-parts":[[2020,5,4]],"date-time":"2020-05-04T23:05:30Z","timestamp":1588633530000},"page":"1546-1552","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":160,"title":["Cardiovascular Risk Reduction With Liraglutide: An Exploratory Mediation Analysis of the LEADER Trial"],"prefix":"10.2337","volume":"43","clinical-trial-number":[{"clinical-trial-number":"nct01179048","registry":"10.18810\/clinical-trials-gov","type":"results"},{"clinical-trial-number":"nct01179048","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9723-3876","authenticated-orcid":false,"given":"John B.","family":"Buse","sequence":"first","affiliation":[{"name":"University of North Carolina School of Medicine, Chapel Hill, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen C.","family":"Bain","sequence":"additional","affiliation":[{"name":"Swansea University Medical School, Swansea, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes F.E.","family":"Mann","sequence":"additional","affiliation":[{"name":"KfH Kidney Centre, Munich, Germany"},{"name":"Department of Nephrology, Friedrich-Alexander University of Erlangen-N\u00fcrnberg, Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5749-6954","authenticated-orcid":false,"given":"Michael A.","family":"Nauck","sequence":"additional","affiliation":[{"name":"Diabetes Center Bochum-Hattingen, St. Josef Hospital (Ruhr-Universit\u00e4t Bochum), Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven E.","family":"Nissen","sequence":"additional","affiliation":[{"name":"Cleveland Clinic, Cleveland, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart","family":"Pocock","sequence":"additional","affiliation":[{"name":"Department of Medical Statistics, London School of Hygiene & Tropical Medicine, London, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil R.","family":"Poulter","sequence":"additional","affiliation":[{"name":"School of Public Health, Imperial College London, London, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard E.","family":"Pratley","sequence":"additional","affiliation":[{"name":"AdventHealth Translational Research Institute, Orlando, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Linder","sequence":"additional","affiliation":[{"name":"Novo Nordisk A\/S, S\u00f8borg, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tea","family":"Monk Fries","sequence":"additional","affiliation":[{"name":"Novo Nordisk A\/S, S\u00f8borg, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David D.","family":"\u00d8rsted","sequence":"additional","affiliation":[{"name":"Novo Nordisk A\/S, S\u00f8borg, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0041-1876","authenticated-orcid":false,"given":"Bernard","family":"Zinman","sequence":"additional","affiliation":[{"name":"Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2020,5,4]]},"reference":[{"key":"2022031300274577900_B1","unstructured":"Novo Nordisk A\/S. Victoza (liraglutide) \u2013 Summary of Product Characteristics [Internet], 2019. Available from https:\/\/www.ema.europa.eu\/en\/documents\/product-information\/victoza-epar-product-information_en.pdf. Accessed 23 April 2020"},{"key":"2022031300274577900_B2","unstructured":"Novo Nordisk A\/S. Victoza (liraglutide) \u2013 Highlights of prescribing information [Internet], 2019. Available from https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2019\/022341s031lbl.pdf. Accessed 23 April 2020"},{"key":"2022031300274577900_B3","unstructured":"Novo Nordisk A\/S. Saxenda (liraglutide) \u2013 Summary of Product Characteristics [Internet], 2019. Available from https:\/\/www.ema.europa.eu\/en\/documents\/product-information\/saxenda-epar-product-information_en.pdf. Accessed 23 April 2020"},{"key":"2022031300274577900_B4","unstructured":"Novo Nordisk A\/S. Saxenda (liraglutide) \u2013 Highlights of prescribing information [Internet], 2018. Available from https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2018\/206321s007lbl.pdf. 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