{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T18:16:34Z","timestamp":1788459394115,"version":"build-2803163510"},"reference-count":28,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T00:00:00Z","timestamp":1753920000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T00:00:00Z","timestamp":1753920000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100004312","name":"Eli Lilly and Company","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004312","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":[[2025,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>Tirzepatide is a dual glucose\u2010dependent insulinotropic polypeptide (GIP) and glucagon\u2010like peptide\u20101 (GLP\u20101) receptor agonist for type 2 diabetes, chronic weight management and obstructive sleep apnoea (in the US). To assess the contribution of weight loss (WL) to the observed glycaemic effect, we performed mediation analysis of three randomized, controlled, parallel, 4\u2010arm SURPASS(S)\u2010trials; 1, 2 and 5, for a total of 2831 participants.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>WL dependent (WL\u2010D) and WL independent (WL\u2010IND) effects on comparator\u2010adjusted glycated haemoglobin A1c (HbA1c) reduction at Week 40 were estimated using mediation analysis, adjusted for baseline HbA1c and study\u2010specific stratification factors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The difference in mean HbA1c change from baseline at 40\u2009weeks (total effect) between tirzepatide and the placebo group ranged from \u221220.0 to \u221214.6\u2009mmol\/mol, and that between tirzepatide and semaglutide (1\u2009mg) ranged from \u22125.1 to \u22121.9\u2009mmol\/mol. In the placebo\u2010controlled trials, 12%\u201327% of the difference in HbA1c change between tirzepatide dose arms and placebo was estimated as being mediated through WL when given as monotherapy (S1), and 25%\u201345% when on the background of insulin with or without metformin (S5). Compared with semaglutide, 54%\u201371% of the difference in HbA1c change between tirzepatide and semaglutide was estimated as being WL\u2010D.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The tirzepatide\u2010induced HbA1c reductions from baseline, compared with placebo or semaglutide, were mediated through both WL\u2010D and WL\u2010IND effects. Estimated contributions of WL to the difference in glycaemic efficacy varied and were highest when tirzepatide was compared with semaglutide and less pronounced when compared with placebo. These results help to understand that other factors beyond weight reduction contribute to HbA1c reduction with tirzepatide.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/dom.16592","type":"journal-article","created":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T06:36:27Z","timestamp":1754030187000},"page":"5498-5505","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["<scp>HbA1c<\/scp>\n                    reduction with tirzepatide in people with type 2 diabetes: The contribution of weight loss assessed by a mediation analysis"],"prefix":"10.1111","volume":"27","author":[{"given":"Tina","family":"Vilsb\u00f8ll","sequence":"first","affiliation":[{"name":"Clinical Research, Steno Diabetes Centre Copenhagen Copenhagen University Hospital  Copenhagen Denmark"},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maciej T.","family":"Malecki","sequence":"additional","affiliation":[{"name":"Department of Metabolic Diseases Jagiellonian University Medical College  Krakow Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Palash","family":"Sharma","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9803-4134","authenticated-orcid":false,"given":"Vivian T.","family":"Thieu","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishna Karthik","family":"Chivukula","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0354-0558","authenticated-orcid":false,"given":"Jacek","family":"Kiljanski","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,7,31]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)02188-7"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2107519"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)01443-4"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)01324-6"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2022.0078"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.20294"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2404881"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)32260-8"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(22)00188-7"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(22)00085-7"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgae038"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/dom.15140"},{"issue":"1","key":"e_1_2_11_14_1","first-page":"S145","article-title":"8. 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