PMID- 34514682 OWN - NLM STAT- MEDLINE DCOM- 20220331 LR - 20220721 IS - 1463-1326 (Electronic) IS - 1462-8902 (Print) IS - 1462-8902 (Linking) VI - 24 IP - 1 DP - 2022 Jan TI - Gastrointestinal tolerability of once-weekly semaglutide 2.4 mg in adults with overweight or obesity, and the relationship between gastrointestinal adverse events and weight loss. PG - 94-105 LID - 10.1111/dom.14551 [doi] AB - AIM: We evaluated gastrointestinal (GI) adverse events (AEs) with once-weekly semaglutide 2.4 mg in adults with overweight or obesity and their contribution to weight loss (WL). MATERIALS AND METHODS: AE analyses pooled data from the Semaglutide Treatment Effect in People With Obesity (STEP) 1-3 trials for participants randomized to 68 weeks of semaglutide 2.4 mg (n = 2117) or placebo (n = 1262). WL was analysed by presence/absence of GI AEs. Mediation analysis estimated WL effects mediated by and unrelated to GI AEs. GI tolerability with semaglutide 2.4 mg maintenance and cessation after dose escalation was evaluated using STEP 4 data among 803 participants tolerating 20 weeks of semaglutide run-in. RESULTS: GI AEs were more common with semaglutide 2.4 mg than placebo, with most frequently nausea (43.9% vs. 16.1% of participants), diarrhoea (29.7% vs. 15.9%), vomiting (24.5% vs. 6.3%) and constipation (24.2% vs. 11.1%). Most GI AEs with semaglutide were non-serious (99.5% of AEs), mild-to-moderate (98.1%), transient and occurred most frequently during/shortly after dose escalation. Few semaglutide-treated participants (4.3%) permanently discontinued treatment for GI AEs. In STEP 1-3, mean WL with semaglutide 2.4 mg was similar in participants without (9.6%-17.1%) versus with GI AEs (11.4%-17.7%). Consistent with this observation, mediation analysis found that GI AEs contributed little to semaglutide-induced WL: of the additional 7.6%-14.4% WL with semaglutide versus placebo, <1 percentage point was mediated by GI AEs. In STEP 4, semaglutide 2.4 mg maintenance was well tolerated. CONCLUSIONS: GI AEs were more common with semaglutide 2.4 mg than placebo, but typically mild-to-moderate and transient. Semaglutide-induced WL was largely independent of GI AEs. CI - (c) 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd. FAU - Wharton, Sean AU - Wharton S AUID- ORCID: 0000-0003-0111-1530 AD - York University, McMaster University and Wharton Weight Management Clinic, Toronto, Ontario, Canada. FAU - Calanna, Salvatore AU - Calanna S AD - Novo Nordisk A/S, Soborg, Denmark. FAU - Davies, Melanie AU - Davies M AUID- ORCID: 0000-0002-9987-9371 AD - Diabetes Research Centre, University of Leicester, Leicester, UK. AD - NIHR Leicester Biomedical Research Centre, Leicester, UK. FAU - Dicker, Dror AU - Dicker D AD - Internal Medicine Department & Obesity Clinic, Hasharon Hospital-Rabin Medical Center, Petach-Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. FAU - Goldman, Bryan AU - Goldman B AD - Novo Nordisk A/S, Soborg, Denmark. FAU - Lingvay, Ildiko AU - Lingvay I AUID- ORCID: 0000-0001-7006-7401 AD - Departments of Internal Medicine/Endocrinology and Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, Texas, USA. FAU - Mosenzon, Ofri AU - Mosenzon O AUID- ORCID: 0000-0002-5702-7584 AD - Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center; Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel. FAU - Rubino, Domenica M AU - Rubino DM AD - Washington Center for Weight Management and Research, Arlington, Virginia, USA. FAU - Thomsen, Mette AU - Thomsen M AD - Novo Nordisk A/S, Soborg, Denmark. FAU - Wadden, Thomas A AU - Wadden TA AD - Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. FAU - Pedersen, Sue D AU - Pedersen SD AD - C-ENDO Diabetes & Endocrinology Clinic Calgary, Calgary, Alberta, Canada. LA - eng PT - Journal Article PT - Randomized Controlled Trial DEP - 20211004 PL - England TA - Diabetes Obes Metab JT - Diabetes, obesity & metabolism JID - 100883645 RN - 0 (Hypoglycemic Agents) RN - 53AXN4NNHX (semaglutide) RN - 62340-29-8 (Glucagon-Like Peptides) SB - IM MH - Adult MH - *Diabetes Mellitus, Type 2/drug therapy MH - Double-Blind Method MH - Glucagon-Like Peptides/adverse effects MH - Humans MH - Hypoglycemic Agents/therapeutic use MH - Injections, Subcutaneous MH - Obesity/chemically induced/complications/drug therapy MH - *Overweight/drug therapy MH - Weight Loss PMC - PMC9293236 OTO - NOTNLM OT - GLP-1 analogue OT - antiobesity drug OT - obesity therapy OT - phase III study OT - randomized trial OT - weight control COIS- SW reports research funding, advisory/consulting fees and/or other support from AstraZeneca, Bausch Health Inc., Boehringer Ingelheim, CIHR, Janssen, Lilly and Novo Nordisk. SC is an employee of and shareholder at Novo Nordisk A/S. MD is a consultant, advisory board member and speaker for AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck Sharp & Dohme, Novo Nordisk and Sanofi-Aventis; advisory board member for Gilead Sciences Ltd. and Servier; speaker for Mitsubishi Tanabe Pharma Corporation, NAPP and Takeda Pharmaceuticals International Inc.; received research funding from AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Novo Nordisk and Sanofi-Aventis. MD is also co-funded by the NIHR Leicester Biomedical Research Centre. DD is a consultant, advisory board member and speaker for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk and Sanofi-Aventis; received research funding from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk and Sanofi-Aventis. BG is an employee of and shareholder at Novo Nordisk A/S. IL reports research funding, advisory/consulting fees and/or other support from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, GI Dynamics, Intarcia, Intercept, Janssen, Mannkind, Merck, Mylan, Novartis, Novo Nordisk, Pfizer, Sanofi, TARGETPharma, Valeritas and Zealand Pharma. OM is an advisory board member for AstraZeneca, Boehringer Ingelheim, BOL Pharma, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk and Sanofi; received research grant support through Hadassah Hebrew University Hospital from AstraZeneca and Novo Nordisk; speaker's bureau for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck Sharp & Dohme, Novo Nordisk and Sanofi. DMR is a consultant, advisory board member, speaker and clinical investigator for Novo Nordisk; clinical investigator for AstraZeneca and Boehringer Ingelheim; received honoraria from Medscape; received research funding from Obesinov and SARL; holds stock/shares in Novo Nordisk. MT is an employee of and shareholder at Novo Nordisk A/S. TAW serves on advisory boards for Novo Nordisk and WW (formerly Weight Watchers) and has received grant support, on behalf of the University of Pennsylvania, from Novo Nordisk. SDP has received consulting fees and/or speaking honoraria from Abbott, AstraZeneca, Bausch, Bayer, Boehringer Ingelheim, Dexcom, Eli Lilly, HLS, Janssen, Merck, Novo Nordisk and Sanofi; was involved in research studies for Abbott, AstraZeneca, Bausch, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk and Sanofi. EDAT- 2021/09/14 06:00 MHDA- 2022/04/01 06:00 PMCR- 2022/07/18 CRDT- 2021/09/13 07:18 PHST- 2021/08/27 00:00 [revised] PHST- 2021/06/21 00:00 [received] PHST- 2021/09/07 00:00 [accepted] PHST- 2021/09/14 06:00 [pubmed] PHST- 2022/04/01 06:00 [medline] PHST- 2021/09/13 07:18 [entrez] PHST- 2022/07/18 00:00 [pmc-release] AID - DOM14551 [pii] AID - 10.1111/dom.14551 [doi] PST - ppublish SO - Diabetes Obes Metab. 2022 Jan;24(1):94-105. doi: 10.1111/dom.14551. Epub 2021 Oct 4.