The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity

Abstract

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.

Weight Loss and Maintenance Related to the Mechanism of Action of Glucagon-Like Peptide 1 Receptor Agonists

“…Ad libitum mean energy intake was also reduced by 35% for semaglutide 2.4 mg vs. placebo (1736 vs. 2676 kJ; estimated treatment difference [ETD], -940 kJ; p \ 0.0001). Patients receiving semaglutide 2.4 mg in this trial lost 9.9% of their body weight, compared with 0.4% in those receiving placebo [33]. In a phase II study of the longacting GLP-1RA efpeglenatide (4 mg once weekly, 6 mg once weekly, 6 mg once every 2 weeks, and 8 mg once every 2 weeks), patients with obesity and without diabetes had statistically significant reductions in body weight compared with placebo after 20 weeks of treatment (differences in least squares means were -6.3 to -7.2 kg; p \ 0.0001) [36].…”

“…Studies investigating the mechanism of action of GLP-1RA therapy for causing weight loss provide evidence that GLP-1RA treatment is associated with reductions in appetite and hunger, lower preference for energy-dense foods, alteration in food reward pathways, decrease in food cravings, and improvement in eating control (Table 2) [25,26,33,34].…”

“…Summary of clinical data on the effects of GLP-1RA therapy on energy intake, meal duration, appetite, satiety and hunger, food preferences, and gastric emptying[25,26,33] …”

Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2·4 mg for weight management: a randomised, controlled, phase 1b trial

“…14 Weight reductions with semaglutide are due to the reduction of ad libitum energy intake caused by reduced appetite, increased satiety, and improved control of eating and food preferences. 15,16 Cagrilintide (recommended international non-proprietary name for NNC0174-0833) 17 is a long-acting acylated amylin analogue with agonistic effects on both native amylin and calcitonin receptors [18][19][20] that is being investigated for weight management. Native amylin is a glucoregulatory pancreatic hormone co-secreted with insulin that is involved in the delay of gastric emptying and suppression of postprandial glucagon release.…”

GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects

“…As GLP-1Rs are expressed in multiple brain regions, and GLP-1RAs such as liraglutide and lixisenatide can penetrate the blood-brain barrier, liraglutide and exendin-4 can be vagus-dependent or independent in the suppression of the food intake ( 176 ). Semaglutide is considered to control energy intake and reduce body weight probably by activating at discrete sites in the hypothalamus to reduce food craving, or by delaying the gastric emptying to affect appetite ( 119 , 177 , 178 ). In addition, GLP-1RAs could adjust the levels of the satiety signal in the arcuate nucleus in the hypothalamus, thereby increasing satiety and reducing caloric intake ( 179 ).…”