{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T17:04:50Z","timestamp":1786122290985,"version":"build-2736575974"},"reference-count":14,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100004339","name":"Sanofi","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004339","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["dom-pubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Diabetes Obesity Metabolism"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>In the AMPLITUDE O trial, efpeglenatide reduced major cardiovascular events by 27% in 4076 individuals with Type 2 diabetes and established cardiovascular or kidney disease compared to placebo during a median follow\u2010up of 1.81\u2009years. This exploratory mediation analysis evaluates the degree to which changes in measured clinical variables and biomarkers during the trial might explain the observed reduction in MACE.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>Measured variables were considered potential mediators if they were significantly changed by the intervention. The hazard (95% CI) per 1\u2010unit increase in each time\u2010updated mediator (change from baseline or updated mean) was estimated using Cox models adjusted for the same variables as in the main AMPLITUDE\u2010O results. Mediators whose hazard\u2010ratio CIs excluded 1.0 were then included in the MACE Cox model to estimate how much of efpeglenatide's effect on MACE could be statistically explained by its effect on that mediator in uni\u2010 and multivariable analyses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Change in HbA1c, weight, pulse pressure, LDL cholesterol, urinary albumin: creatinine ratio (UACR), eGFR, heart rate, lipase and amylase were modified by efpeglenatide. Of these, univariable analyses showed that only changes in HbA1c, LDL cholesterol, UACR and amylase accounted for 14%, 11%, 16% and 10%, respectively, of the effect of efpeglenatide on MACE. In the multivariable analysis, LDL cholesterol together with UACR accounted for 29.6% mediation of this effect.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>In this post hoc analysis from the AMPLITUDE\u2010O trial, changes in LDL cholesterol together with UACR but not weight were estimated to statistically account for a modest portion of the reduction in risk of MACE with efpeglenatide.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/dom.71062","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T03:55:32Z","timestamp":1782964532000},"page":"8552-8559","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Potential Mediators of Efpeglenatide's Cardiovascular Benefit: An Exploratory Analysis of the\n                    <scp>AMPLITUDE<\/scp>\n                    \u2010O Trial"],"prefix":"10.1111","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0591-3656","authenticated-orcid":false,"given":"Daniel","family":"Raaschou\u2010Oddershede","sequence":"first","affiliation":[{"name":"Institute of Cardiovascular &amp; Medical Sciences, University of Glasgow  Glasgow UK"},{"name":"Department of Clinical and Translational Research Steno Diabetes Center Copenhagen  Herlev Denmark"},{"name":"Department of Cardiology, Heart Centre Copenhagen University Hospital\u2014Rigshospitalet  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine R.","family":"Schwarz","sequence":"additional","affiliation":[{"name":"Department of Clinical and Translational Research Steno Diabetes Center Copenhagen  Herlev Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanya","family":"Kovalova","sequence":"additional","affiliation":[{"name":"Population Health Research Institute, McMaster University and Hamilton Health Sciences  Hamilton Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelley R.","family":"Branch","sequence":"additional","affiliation":[{"name":"UW Medicine Heart Institute  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Del Prato","sequence":"additional","affiliation":[{"name":"Interdisciplinary Research Center for Health Science, Sant'anna School of Advanced Studies  Pisa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1903-0018","authenticated-orcid":false,"given":"Carolyn S. P.","family":"Lam","sequence":"additional","affiliation":[{"name":"National Heart Centre Singapore and Duke\u2013NUS Medical School  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renato D.","family":"Lopes","sequence":"additional","affiliation":[{"name":"Duke Clinical Research Institute, Duke University School of Medicine  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2912-1389","authenticated-orcid":false,"given":"Richard","family":"Pratley","sequence":"additional","affiliation":[{"name":"AdventHealth Translational Research Institute  Orlando Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8324-3275","authenticated-orcid":false,"given":"Julio","family":"Rosenstock","sequence":"additional","affiliation":[{"name":"Velocity Clinical Research  Dallas Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1604-2593","authenticated-orcid":false,"given":"Naveed","family":"Sattar","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular &amp; Medical Sciences, University of Glasgow  Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8072-2836","authenticated-orcid":false,"given":"Hertzel C.","family":"Gerstein","sequence":"additional","affiliation":[{"name":"Population Health Research Institute, McMaster University and Hamilton Health Sciences  Hamilton Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1603827"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1607141"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(24)00363-2"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2108269"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc19-2251"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12933-021-01386-4"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc17-1096"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.122.063716"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12933-025-02866-7"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(24)00271-7"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.123.030131"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.8336"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-023-00849-3"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(25)01375-3"}],"container-title":["Diabetes, Obesity and Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dom-pubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/dom.71062","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/dom-pubs.onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/dom.71062","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/dom-pubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/dom.71062","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T08:52:18Z","timestamp":1786092738000},"score":1,"resource":{"primary":{"URL":"https:\/\/dom-pubs.onlinelibrary.wiley.com\/doi\/10.1111\/dom.71062"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,1]]},"references-count":14,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1111\/dom.71062"],"URL":"https:\/\/doi.org\/10.1111\/dom.71062","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.1111\/DOM.71062\/v2\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/DOM.71062\/v2\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/DOM.71062\/v2\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/DOM.71062\/v1\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/DOM.71062\/v3\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/DOM.71062\/v1\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/DOM.71062\/v1\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/DOM.71062\/v1\/review3","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/DOM.71062\/v3\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/DOM.71062\/v2\/decision1","asserted-by":"object"}]},"ISSN":["1462-8902","1463-1326"],"issn-type":[{"value":"1462-8902","type":"print"},{"value":"1463-1326","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,1]]},"assertion":[{"value":"2026-03-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-23","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-01","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}