Article Text

Superior weight loss with once-weekly semaglutide versus other glucagon-like peptide-1 receptor agonists is independent of gastrointestinal adverse events
  1. Ildiko Lingvay1,
  2. Thomas Hansen2,
  3. Stanislava Macura2,
  4. Michel Marre3,4,
  5. Michael A Nauck5,
  6. Raymond de la Rosa6,
  7. Vincent Woo7,
  8. Emre Yildirim2,
  9. John Wilding8
  1. 1Department of Internal Medicine/Endocrinology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
  2. 2Novo Nordisk A/S, Søborg, Denmark
  3. 3Clinique Ambroise Paré, Neuilly sur Seine, France
  4. 4UMRS 1138, Metabolic Inflammation in Diabetes and its Complications Cordeliers Research Centre, Paris, France
  5. 5Diabetes Division, Katholisches Klinikum Bochum, St Josef Hospital, Bochum, Germany
  6. 6Endocrinology, Millennium Physician Group, Englewood, Florida, USA
  7. 7Endocrinology and Metabolism, University of Manitoba, Winnipeg, Manitoba, Canada
  8. 8Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
  1. Correspondence to Dr Ildiko Lingvay; Ildiko.Lingvay{at}


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.

  • body weight
  • diabetes mellitus
  • type 2
  • gastrointestinal tract
  • glucagon-like peptide 1

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  • Contributors All authors contributed to the design and conduct of the trials, the analysis and interpretation of the data and the preparation, review and approval of the manuscript.

  • Funding This study and the associated trials were supported by Novo Nordisk A/S, Denmark. Grant/award number not applicable.

  • 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.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplemental information. SUSTAIN 3: 7: SUSTAIN 10: