NCT07171723

Studying the Influence of LEAP2 on Integrated Endocrine Control of Eating During Semaglutide Treatment

Effects of Antagonizing the Ghrelin Receptor in Individuals With Obesity on Treatment With Semaglutide

• Status: Recruiting
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 24 (estimated)
• Sponsor: University Hospital, Gentofte, Copenhagen · Academic / Other
• Sex: All
• Age: 18 Years – 65 Years
• Healthy volunteers: Not accepted

Summary

This clinical study investigates how blocking the hunger-related ghrelin receptor affects appetite and metabolism in individuals with obesity who are treated with semaglutide (a GLP-1 receptor agonist). LEAP2, a naturally occurring hormone that inhibits the ghrelin receptor, is used as the investigational compound. The objective of the study is to clarify how the ghrelin system functions when appetite is suppressed by semaglutide treatment. Participants will receive either LEAP2 or placebo during two experimental visits in a randomized, double-blind, crossover design. The investigators will assess food intake, appetite sensations, glucose metabolism, and hormonal responses. By examining the interaction between semaglutide and ghrelin signaling, the study aims to improve understanding of how multiple appetite-regulating systems interact and whether additional hunger signals remain active during GLP-1 treatment. The findings may inform the development of future treatments for individuals with obesity.

Detailed description

This study investigates the physiological role of ghrelin receptor signaling in individuals with obesity receiving stable treatment with semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist known to suppress appetite and induce weight loss. Ghrelin is the only known circulating orexigenic gut hormone, and its activity is mediated via the growth hormone secretagogue receptor (GHSR). Whether ghrelin signaling continues to contribute meaningfully to appetite regulation during pharmacological GLP-1 receptor activation remains unknown. Liver-expressed antimicrobial peptide 2 (LEAP2) is an endogenous inverse agonist and competitive antagonist of the GHSR. LEAP2 provides a highly specific and transient means of blocking ghrelin receptor activity in humans, enabling mechanistic exploration of its physiological relevance. Previous studies have demonstrated that LEAP2 infusion reduces ad libitum food intake and postprandial glucose excursions in both lean and obese individuals. However, the role of ghrelin signaling under conditions of GLP-1-induced appetite suppression has not been elucidated. The SILENCED study is a randomized, double-blind, placebo-controlled, crossover trial. Twenty-four participants with obesity who are weight-stable and on a stable dose of ≥1 mg/week semaglutide for at least 3 months will complete two experimental study days. Each participant will receive a 6-hour intravenous infusion of either LEAP2 or placebo (saline) on separate days. During each visit, appetite-related measures, food intake, glucose metabolism, gastrointestinal motility, growth hormone levels, and energy expenditure will be assessed. The primary outcome is total energy intake during a standardized ad libitum meal. Secondary and exploratory outcomes include visual analogue scale ratings of appetite, gastric emptying assessed via paracetamol absorption, postprandial glucose and hormone responses, and indirect calorimetry measurements. This study is expected to provide novel insight into whether ghrelin receptor signaling continues to play a functional role in appetite and metabolism under pharmacological GLP-1 receptor activation. The findings may inform the development of future combination therapies targeting multiple appetite-regulating pathways in the treatment of obesity.

Conditions

• Obesity &Amp; Overweight

Interventions

Type	Name	Description
BIOLOGICAL	Liver-Expressed Antimicrobial Peptide 2 (LEAP2)	Continuous intravenous infusion of LEAP2 (Liver-Expressed Antimicrobial Peptide 2), an endogenous inverse agonist and competitive antagonist of the ghrelin receptor (GHSR), administered at 40 pmol/kg/min for 6 hours. LEAP2 inhibits ghrelin-mediated signaling involved in hunger regulation, gastric motility, and growth hormone secretion. This intervention enables investigation of the physiological relevance of ghrelin receptor activity during semaglutide-induced appetite suppression
OTHER	Placebo (saline)	Continuous intravenous infusion of isotonic saline (0.9% sodium chloride) for 6 hours. This placebo comparator is used to match the volume, rate, and duration of the active intervention (LEAP2) in a randomized, double-blind, crossover design. The placebo enables assessment of the physiological effects of ghrelin receptor blockade by LEAP2 in individuals with obesity treated with semaglutide

Timeline

• Start date: 2025-09-01
• Primary completion: 2025-12-14
• Completion: 2026-02-01
• First posted: 2025-09-12
• Last updated: 2025-09-18

Locations

1 site across 1 country: Denmark