PMID- 33115821 OWN - NLM STAT- MEDLINE DCOM- 20210621 LR - 20240330 IS - 2052-4897 (Electronic) IS - 2052-4897 (Linking) VI - 8 IP - 2 DP - 2020 Oct TI - Superior weight loss with once-weekly semaglutide versus other glucagon-like peptide-1 receptor agonists is independent of gastrointestinal adverse events. LID - 10.1136/bmjdrc-2020-001706 [doi] LID - e001706 AB - INTRODUCTION: Gastrointestinal (GI) adverse events (AEs) are the most common AEs with glucagon-like peptide-1 receptor agonists (GLP-1RAs). Weight loss (WL) is slightly greater in people who experience GI AEs than those who do not. A previous mediation analysis of the SUSTAIN 1-5 trials indicated minor contribution of nausea/vomiting to the greater WL with once-weekly semaglutide versus comparators. Semaglutide demonstrated superior glycated hemoglobin and body weight (BW) reductions versus other GLP-1RAs in SUSTAIN 3 (versus exenatide extended release 2.0 mg), SUSTAIN 7 (versus dulaglutide) and SUSTAIN 10 (liraglutide 1.2 mg). The objective of this analysis was to assess if significantly greater WL with semaglutide versus other GLP-1RAs is mediated by nausea/vomiting and other GI AEs (diarrhea, constipation, dyspepsia) during dose escalation (baseline to week 12, when GI AEs are generally most prevalent) and from baseline to end of treatment (EOT: week 56 (SUSTAIN 3), 40 (SUSTAIN 7) or 30 (SUSTAIN 10)). RESEARCH DESIGN AND METHODS: Subjects within trials were subdivided into those who reported (yes/no) nausea/vomiting or any other GI AE. Change from baseline in BW was assessed within each trial and subgroup. A mediation analysis separated WL into direct or indirect (mediated by GI AEs) effects. RESULTS: From baseline to week 12 or EOT, the nausea/vomiting-mediated difference in WL was, respectively: 0.05 or 0.09 kg of 3.78 kg at EOT (SUSTAIN 3); 0.06 or 0.03 kg of 2.26 kg at EOT (low-dose comparison) and 0.08 or 0.04 kg of 3.55 kg at EOT (high-dose comparison) (SUSTAIN 7) and 0.05 or 0.09 kg of 3.82 kg at EOT (SUSTAIN 10). CONCLUSIONS: In SUSTAIN 3, 7 and 10, nausea/vomiting by week 12 (end of dose escalation) or throughout treatment contributed minimally (<0.1 kg) to the superior WL with semaglutide versus GLP-1RA comparators at EOT. CI - (c) Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. FAU - Lingvay, Ildiko AU - Lingvay I AUID- ORCID: 0000-0001-7006-7401 AD - Department of Internal Medicine/Endocrinology, University of Texas Southwestern Medical Center, Dallas, Texas, USA Ildiko.Lingvay@UTSouthwestern.edu. FAU - Hansen, Thomas AU - Hansen T AD - Novo Nordisk A/S, Soborg, Denmark. FAU - Macura, Stanislava AU - Macura S AD - Novo Nordisk A/S, Soborg, Denmark. FAU - Marre, Michel AU - Marre M AD - Clinique Ambroise Pare, Neuilly sur Seine, France. AD - UMRS 1138, Metabolic Inflammation in Diabetes and its Complications Cordeliers Research Centre, Paris, France. FAU - Nauck, Michael A AU - Nauck MA AD - Diabetes Division, Katholisches Klinikum Bochum, St Josef Hospital, Bochum, Germany. FAU - de la Rosa, Raymond AU - de la Rosa R AD - Endocrinology, Millennium Physician Group, Englewood, Florida, USA. FAU - Woo, Vincent AU - Woo V AD - Endocrinology and Metabolism, University of Manitoba, Winnipeg, Manitoba, Canada. FAU - Yildirim, Emre AU - Yildirim E AD - Novo Nordisk A/S, Soborg, Denmark. FAU - Wilding, John AU - Wilding J AUID- ORCID: 0000-0003-2839-8404 AD - Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - BMJ Open Diabetes Res Care JT - BMJ open diabetes research & care JID - 101641391 RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Hypoglycemic Agents) RN - 53AXN4NNHX (semaglutide) RN - 62340-29-8 (Glucagon-Like Peptides) SB - IM MH - *Diabetes Mellitus, Type 2 MH - *Glucagon-Like Peptide-1 Receptor MH - Glucagon-Like Peptides MH - Humans MH - Hypoglycemic Agents MH - Weight Loss PMC - PMC7594204 OTO - NOTNLM OT - body weight OT - diabetes mellitus OT - gastrointestinal tract OT - glucagon-like peptide 1 OT - type 2 COIS- Competing interests: IL reports receiving grants, personal fees and non-financial support from Novo Nordisk, both for and outside the submitted work; grants from Merck and Mylan; personal fees from Valeritas, TARGET Pharma, Intarcia and Mannkind; personal fees and non-financial support from Boehringer Ingelheim, Astra Zeneca, Janssen and Eli Lilly & Co; grants and non-financial support from Pfizer; grant, personal fees and non-financial support from Sanofi; all outside the submitted work. TH and SM do not have any conflicts of interest. MM reports receiving payment from Novo Nordisk for the submitted work; serving as consultant and on the advisory board of Novo Nordisk and Servier; consultant for Eli Lilly & Co and serving on the advisory board of Merck Sharp & Dohme. MAN has received fees for serving on advisory boards or lecturing for Astra Zeneca, Berlin-Chemie/Menarini, Boehringer Ingelheim, Eli Lilly & Co, Genentech, GlaxoSmithKline, Medscape, Merck Sharp&Dohme, Novo Nordisk, Sanofi-Aventis, Sun Pharma, Takeda and grant support for clinical studies from Astra Zeneca, Eli Lilly & Co, Glaxo Smith Kline, Merck Sharp & Dohme, Novo Nordisk and travel support for the above-mentioned activities. RdlR reports receiving speaker bureau honoraria from Novo Nordisk, Sanofi-Aventis and Boehringer Ingelheim. VW reports receiving grants, personal fees and other affiliations (ie, advisory boards) from Janssen, Boehringer Ingelheim, Astra Zeneca, Lilly, Novo Nordisk and Merck. EY reports being a full-time employee and minor stockholder of Novo Nordisk. JW reports grants, personal fees and fees paid into his institution from Astra Zeneca and Novo Nordisk; fees paid into his institution from Astellas, Janssen, Lilly and Rhythm Pharmaceuticals; personal fees and fees paid into his institution from Boehringer Ingelheim, Napp, Mundipharma International; grants and personal fees from Takeda. EDAT- 2020/10/30 06:00 MHDA- 2021/06/22 06:00 PMCR- 2020/10/28 CRDT- 2020/10/29 05:41 PHST- 2020/06/19 00:00 [received] PHST- 2020/09/08 00:00 [revised] PHST- 2020/09/08 00:00 [accepted] PHST- 2020/10/29 05:41 [entrez] PHST- 2020/10/30 06:00 [pubmed] PHST- 2021/06/22 06:00 [medline] PHST- 2020/10/28 00:00 [pmc-release] AID - 8/2/e001706 [pii] AID - bmjdrc-2020-001706 [pii] AID - 10.1136/bmjdrc-2020-001706 [doi] PST - ppublish SO - BMJ Open Diabetes Res Care. 2020 Oct;8(2):e001706. doi: 10.1136/bmjdrc-2020-001706.