Aim To investigate the effects of once‐weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity. Materials and Methods A double‐blind, parallel‐group trial was conducted in 72 adults with obesity, randomized to once‐weekly s.c. semaglutide (dose‐escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant‐reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch. Results The area under the concentration–time curve (AUC) for paracetamol 0 to 5 hours after a standardized meal (AUC0–5h,para; primary endpoint) was increased by 8% (P = 0.005) with semaglutide 2.4 mg versus placebo at week 20 (non‐significant when corrected for week 20 body weight; P = 0.12). No effect was seen on AUC0–1h,para, maximum observed paracetamol concentration, or time to maximum observed paracetamol concentration. Ad libitum energy intake was 35% lower with semaglutide versus placebo (1736 versus 2676 kJ; estimated treatment difference −940 kJ; P <0.0001). Semaglutide reduced hunger and prospective food consumption, and increased fullness and satiety when compared with placebo (all P <0.02). The CoEQ indicated better control of eating and fewer/weaker food cravings with semaglutide versus placebo (P <0.05). Body weight was reduced by 9.9% with semaglutide and 0.4% with placebo. Safety was consistent with the known profile of semaglutide. Conclusions In adults with obesity, once‐weekly s.c. semaglutide 2.4 mg suppressed appetite, improved control of eating, and reduced food cravings, ad libitum energy intake and body weight versus placebo. There was no evidence of delayed gastric emptying at week 20, assessed indirectly via paracetamol absorption.

No abstract

There was a slight non-statistically significant increase in semaglutide exposure when oral semaglutide was administered with omeprazole, but this is not considered clinically relevant and no dose adjustment is likely to be required.

Introduction: Oral semaglutide is a novel tablet formulation of the human glucagon-like peptide-1 analogue semaglutide. In two trials, the effects of prior food ingestion (food effect), post-dose fasting period and water volume with dosing (dosing conditions) on oral semaglutide pharmacokinetics were investigated. Methods: Subjects received once-daily oral semaglutide for 10 days. In the food-effect trial, 78 healthy subjects were randomised 1:1:1 to fed (meal 30 min pre-dose; 240 mL water with dosing), fasting (overnight until 4 h post-dose; 240 mL) or reference (fasting overnight until 30 min post-dose; 120 mL) arms. In the dosing conditions trial, 161 healthy men were randomised into eight dosing groups (overnight fasted with 50/120 mL water and 15/30/60/ 120 min post-dose fasting). Semaglutide plasma concentrations were measured frequently until 504 h after the 10th dose. Results: In the food-effect trial, limited or no measurable semaglutide exposure was observed in the fed arm, while all subjects in the fasting arm had measurable semaglutide exposure. Area under the semaglutide concentration-time curve (AUC 0-24h,semaglutide,day10 ) and maximum semaglutide concentration (C max,semaglutide,day10 ) were numerically greater by approximately 40% for the fasting versus reference arm (p = 0.082 and p = 0.080, respectively). In the dosing conditions trial, AUC 0-24h,semaglutide,day10 and C max,semaglutide,day10 were not different between water volumes (p = 0.541 and p = 0.676), but increased with longer post-dose fasting (p \ 0.001). Conclusion:Administration of oral semaglutide in the fasting state with up to 120 mL water and at least 30 min post-dose fasting results in clinically relevant semaglutide exposure. These dosing conditions have been used in the oral semaglutide phase 3 trials and are part of the approved label.Trial Registration: ClinicalTrials.gov identifiers NCT02172313, NCT01572753.

Introduction: Oral semaglutide contains the GLP-1 analog semaglutide co-formulated with the absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). Aims: This trial investigated (A) the effect of oral semaglutide and SNAC alone on the pharmacokinetics (PK) of levothyroxine (thyroxine), a frequently used oral medication with similar dosing instructions to oral semaglutide, and (B) the effect of multiple co-administered tablets on oral semaglutide PK. Methods: This was a 2-part, open-label, one-sequence crossover trial in 45 healthy subjects. Part A comprised three periods during which subjects received single-dose thyroxine 600 μg alone, with SNAC 300 mg, and with oral semaglutide 14 mg at steady-state. Primary endpoint was area under the total thyroxine (T4) serum concentration-time curve (0-48 h) after thyroxine, baseline-corrected for endogenous total T4 ( bc AUC 0-48h,T4 ). No effect of oral semaglutide or SNAC alone was declared if the 90% CI for the treatment ratio (thyroxine ± oral semaglutide or SNAC) was entirely within the pre-defined interval (0.80-1.25). In part B, oral semaglutide 14 mg at steady-state was co-administered with 5 placebo tablets (used as model tablets) once-daily for 5 weeks. Primary endpoint was area under the semaglutide plasma concentration-time curve during a 0-24 h dosing interval at steady state (AUC 0-24h ); no effect was confirmed if the 90% CI for the treatment ratio (oral semaglutide ± placebo) was entirely within the pre-defined interval (0.7000-1.4286). Safety and tolerability were also assessed. Results: In part A, co-administration of steady-state oral semaglutide with thyroxine resulted in a 33% increase in bc AUC 0-48h,T4 ; the 90% CI for the treatment ratio was not within the no effect interval. Oral semaglutide had no effect on baseline-corrected maximum total T4 concentration ( bc C max,T4 ). Co-administration of SNAC alone did not increase exposure of total T4. In part B, co-administration of multiple tablets with steady-state oral semaglutide resulted in decreased semaglutide AUC 0-24 (34%) and C max (32%); part of the treatment ratio 90% CIs were not within the no effect interval for both endpoints. The safety profile was as expected for GLP-1 receptor agonists with gastrointestinal adverse events the most frequent. Conclusion: PK of thyroxine were influenced by co-administration of steady-state oral semaglutide. However, no change in clinical practice is required as close monitoring of co-administered thyroxine is already part of medical guidance. No obvious effect was seen with SNAC alone so increased thyroxine exposure may be due to the known gastric emptying delaying effect of the GLP-1 component. Absorption...