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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

We re-evaluated the efficacy and safety of liraglutide, a GLP-1 analog, for use as adjunctive therapy in people with type 1 diabetes (T1D). Results from the two ADJUNCT trials suggested that residual beta-cell function is associated with more pronounced benefits and less risk of hypoglycemia. Here we analyze results of the two trials according to other baseline anthropometrics. ADJUNCT ONE (NCT01836523) and TWO (NCT02098395) were randomized controlled phase 3 trials in broad T1D populations (1398 and 835 participants, respectively) treated with liraglutide (1.8, 1.2 or 0.6 mg) or placebo. ADJUNCT ONE was a 52-week trial with a treat-to-target design and no limits on insulin titration; ADJUNCT TWO was a 26-week trial with an individual maximal insulin dose. In a post hoc analysis, we evaluated certain estimated placebo-adjusted treatment effects across clinically relevant participant subgroups. At week 26 in ADJUNCT ONE, placebo-adjusted reductions in HbA1c, body weight (BW) and daily insulin dose (up to -0.30 %-points, -5.0 kg and -12%, respectively, with liraglutide 1.8 mg) were significant (p0.05) on baseline HbA1c or BMI at neither week 26 nor 52. The risk of clinically significant hypoglycemia (symptomatic episodes with blood glucose 0.05 vs. placebo) by baseline HbA1c, BMI or insulin regimen. In ADJUNCT ONE and TWO, the efficacy and glycemic safety of liraglutide did not depend on key baseline anthropometrics. This leaves residual beta-cell function the only identified parameter impacting the treatment effect of the GLP-1 analog used as an adjunct to insulin in T1D. Together with recent progress in the understanding of T1D and of the benefits of GLP-1 receptor agonism, these findings suggest a role for GLP-1 receptor agonists in T1D, warranting further study. Disclosure T. F. Dejgaard: Advisory Panel; Self; Novo Nordisk, Consultant; Self; Boehringer Ingelheim International GmbH, Research Support; Self; AstraZeneca, Novo Nordisk, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk. L. Bardtrum: Employee; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S. E. Christiansen: None. F. Kreiner: Employee; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S. S. Madsbad: Advisory Panel; Self; AstraZeneca; Boehringer Ingelheim; Eli Lilly; Merck Sharp & Dohme; Novo Nordisk; Sanofi, Research Support; Self; Novo Nordisk, Boehringer Ingelheim, Speaker’s Bureau; Self; AstraZeneca; Boehringer Ingelheim; Merck Sharp & Dohme; Novo Nordisk; Sanofi. M. G. Von herrath: Employee; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S. B. Von scholten: Employee; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S. C. Mathieu: Advisory Panel; Self; Novo Nordisk, Sanofi, Merck Sharp and Dohme Ltd., Eli Lilly and Company, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Medtronic, ActoBio Therapeutics, Pfizer, Insulet and Zealand Pharma, Research Support; Self; Medtronic, Novo Nordisk, Sanofi and ActoBio Therapeutics, Speaker’s Bureau; Self; Novo Nordisk, Sanofi, Eli Lilly and Company, Boehringer Ingelheim, AstraZeneca and Novartis. Funding Novo Nordisk A/S