668-P: Body Weight Loss with Oral Semaglutide Is Predominantly Mediated by Effects Other than Gastrointestinal Adverse Events

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce body weight (BW). Evidence suggests that GLP-1RAs directly modulate appetite and reduce food intake through central mechanisms. However, GLP-1RAs are also associated with gastrointestinal (GI) adverse events (AEs), which may contribute to reduced appetite and food intake. We sought to assess whether the BW loss observed in phase 3 clinical trials with oral semaglutide was primarily due to indirect effects (defined as GI AEs, specifically nausea, vomiting, and diarrhea) or direct effects (not explained by GI AEs). Data from PIONEER 1-5, 7, and 8 were assessed and a mediation analysis (how a third variable [GI AEs] affects the relationship between two other variables [treatment and BW]) was performed to separate the overall contribution of direct and indirect effects to changes in BW. Significant total estimated treatment differences in BW loss were observed vs. all comparators with oral semaglutide 7 mg (1.0-3.7 kg vs. placebo, 1.7 kg vs. active comparator) and 14 mg (2.7-5.0 kg vs. placebo, 0.8-2.4 kg vs. active comparators). In the mediation analysis, GI AEs accounted for 0.0-0.3 kg of the BW loss across oral semaglutide doses vs. all comparators (Figure). In conclusion, GI AEs (indirect effects) appear to have no clinically relevant impact on total BW loss observed with oral semaglutide vs. placebo and most active comparators. Disclosure J. J. Meier: Advisory Panel; Self; AstraZeneca, MSD Corporation, Novo Nordisk, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, MSD Corporation, Novo Nordisk, Sanofi. R. Agesen: Employee; Self; Novo Nordisk. L. Bardtrum: Employee; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S. A. Y. Cheng: Advisory Panel; Self; Abbott, AstraZeneca, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, HLS Therapeutics Inc., Janssen Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Merck Sharp & Dohme Corp., Novo Nordisk, Sanofi, Research Support; Self; Applied Therapeutics, The Medicine Company, Speaker’s Bureau; Self; Abbott, AstraZeneca, Bausch Health, Canada, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, HLS Therapeutics Inc., Janssen Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Sanofi. S. Deenadayalan: Employee; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S. E. Montanya: Advisory Panel; Self; Sanofi, Consultant; Self; Merck Sharp & Dohme Corp., Employee; Spouse/Partner; Almirall, S. A., Research Support; Self; Menarini Group, Roche Diagnostics SL, Speaker’s Bureau; Self; Novo Nordisk A/S. R. E. Pratley: Other Relationship; Self; Hanmi Pharmaceutical, Merck Sharp & Dohme Corp., Metavention, Monster Energy Company, Inc., Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. Funding Novo Nordisk A/S