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The SURMOUNT-OSA master protocol comprised two, 52-week, randomized, double-blind, placebo-controlled phase 3 studies (study 1 and study 2) and demonstrated a significant reduction of a number of cardiometabolic risk measures in participants with OSA and obesity following treatment with tirzepatide. Here we report prespecified analysis of cardiometabolic risk measures in SURMOUNT-OSA. Post hoc analyses include changes in a homeostatic model assessment for insulin resistance and mediation analysis to determine the proportion of observed changes attributable to reductions in body weight, apnea\u2013hypopnea index and sleep apnea-specific hypoxic burden. In both study 1 and study 2 of SURMOUNT-OSA, tirzepatide treatment was associated with greater alleviation of cardiometabolic risk factors than placebo. Independent mediation effect of changes in OSA metrics was observed on high-sensitivity C-reactive protein, homeostatic model assessment for insulin resistance and triglycerides. The combination of changes in weight and OSA metrics, as well as weight alone, had a significant mediation effect on systolic blood pressure, but there was no significant mediation effect of weight or OSA metrics observed on diastolic blood pressure. Based on the mediation analysis, treating both sleep-disordered breathing and obesity is likely required to optimize the treatment effect on cardiometabolic benefits for patients with moderate-to-severe OSA and obesity. The ClinicalTrials.gov registration number for this study is\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT05412004\" ext-link-type=\"uri\">NCT05412004<\/jats:ext-link>\n                    .\n                  <\/jats:p>","DOI":"10.1038\/s41591-025-04071-1","type":"journal-article","created":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T10:04:15Z","timestamp":1768471455000},"page":"653-659","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Tirzepatide on obstructive sleep apnea-related cardiometabolic risk: secondary outcomes of the SURMOUNT-OSA randomized trial"],"prefix":"10.1038","volume":"32","author":[{"given":"Atul","family":"Malhotra","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald","family":"Grunstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4986-4753","authenticated-orcid":false,"given":"Ali","family":"Azarbarzin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Sands","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virend K.","family":"Somers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9890-9401","authenticated-orcid":false,"given":"Louis J.","family":"Aronne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ania M.","family":"Jastreboff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1049-0416","authenticated-orcid":false,"given":"Jitong","family":"Lou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5321-6444","authenticated-orcid":false,"given":"Sujatro","family":"Chakladar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia P.","family":"Dunn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2862-6705","authenticated-orcid":false,"given":"Mathijs C.","family":"Bunck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8695-1834","authenticated-orcid":false,"given":"Josef","family":"Bednarik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,15]]},"reference":[{"key":"4071_CR1","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1016\/S0140-6736(13)60734-5","volume":"383","author":"AS Jordan","year":"2014","unstructured":"Jordan, A. 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A.M. reports income from Eli Lilly, Livanova, Zoll and Powell Mansfield. ResMed gave a philanthropic donation to USCD. R.G. reports income from serving on the advisory board for Apnimed, the steering committee for SURMOUNT-OSA, Eli Lilly and lecture fees from Somnomed Department. He conducts sponsored studies with Eli Lilly, Alkermes, Takeda and Bod Science: Lambert Initiative. A.A. serves as a consultant for Respicardia, Eli Lilly, Inspire, Cerebra and Apnimed. Apnimed is developing pharmacological treatments for Obstructive Sleep Apnea. A.A.\u2019s interests were reviewed by Brigham and Women\u2019s Hospital and Mass General Brigham in accordance with their institutional policies. S.S. received grant support from Apnimed, Prosomnus and Dynaflex and has served as a consultant for Apnimed, Nox Medical, Inspire Medical Systems, Eli Lilly, Respicardia, LinguaFlex and Achaemenid. S.S. receives royalties for intellectual property pertaining to combination pharmacotherapy for sleep apnea via his Institution. S.S. is also the co-inventor of intellectual property pertaining to wearable sleep apnea phenotyping also via his Institution. He has received equity in Achaemenid, a company commercializing biosensor technology for monitoring oral appliance treatment efficacy. S.S. is also co-inventor of intellectual property pertaining to wearable sleep apnea phenotyping also via his Institution. His industry interactions are actively managed by his Institution. V.K.S. serves as a consultant for Eli Lilly, ApniMed, Axsome and Jazz Pharmaceuticals and on the Scientific Advisory Board for Sleep Number. L.J.A. reports receiving consulting fees from\/and serving on advisory boards for Altimmune, Atria, Boehringer Ingelheim, Carmot Therapeutics, CinFina Pharma, Corteria, Currax Pharma, Eli Lilly, Enterin, Helicore Biopharma, Jamieson Wellness, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Juvena Therapeutics, Kallyope, Morphic Medic\/GI Dynamics, Novartis, Novo Nordisk, Pfizer, Prosciento, Senda Biosciences, Skye Bio\/Cbeyond, Summit Clinical, Syntis Bio, Versanis, Veru Pharmaceuticals and Zealand Pharmaceuticals; receiving research funding from Amgen, Eli Lilly, Janssen Pharmaceuticals and Novo Nordisk; having equity interests in ERX Pharmaceuticals, Intellihealth, Jamieson Wellness, Kallyope, Mediflix, Morphic Medic\/GI Dynamics, Summit Clinical, Syntis Bio and Veru Pharmaceuticals; and serving on a board of directors for ERX Pharmaceuticals, Intellihealth and Jamieson Wellness. A.M.J. conducts multicenter trials with Amgen, Eli Lilly, Novo Nordisk and Rhythm Pharmaceuticals; serves on scientific advisory boards for Amgen, AstraZeneca, Boehringer Ingelheim, Biohaven, Eli Lilly, Intellihealth, Novo Nordisk, Pfizer, Regeneron, Rhythm Pharmaceuticals, Scholar Rock, Structure Therapeutics, Syntis Bio, Terns Pharmaceuticals, WeightWatchers and Zealand Pharmaceuticals; and receives institutional grant funding from the NIH\/NIDDK. J.L., S.C., J.P.D. and M.C.B. are employees and shareholders of Eli Lilly and Company and declare no competing interests. J.B. contributed to the paper as an employee of Eli Lilly and Company.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}