Effects of Antagonizing the Ghrelin Receptor in Individuals With Obesity on Treatment With Semaglutide
Trial Snapshot
- Phase
- Phase 1
- Status
- Recruiting
- Sponsor
- Enrollment
- 24
- Locations
- 1
- Primary Endpoint
- Food intake
Study Overview
Brief 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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Crossover
- Primary Purpose
- Treatment
- Masking
- Double (Participant, Investigator)
Eligibility Criteria
- Ages
- 18 Years to 65 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Age between 18 and 65 years old
- •Body mass index (BMI) above ≥ 25 kg/m2
- •Ongoing semaglutide treatment with a stable dose of ≥ 1 mg once weekly for a minimum of 3 months prior to inclusion
- •Weight stability, defined as a maximum variation of ±3% between the highest and lowest recorded body weight during the 3 months prior to inclusion.
- •Informed oral and written consent
Exclusion Criteria
- •Alanine aminotransferase (ALAT) > 2 times normal value
- •History of hepatobiliary and/or gastrointestinal disorder
- •Kidney disease (serum creatinine above normal range and/or urine albumin-creatinine ratio 30mg/g confirmed with two measurements)
- •Any ongoing medication that investigator evaluates would interfere with study participation
- •Any physical or psychological condition that investigators evaluate would interfere with study participation including any acute or chronic illnesses.
- •Regular tobacco smoking and/or use of other nicotine products
- •Glycated haemoglobin HbA1c > 48 and/or type 1 or type 2 diabetes medical treatment
- •Women of childbearing potential who are not using effective contraception
- •Pregnancy or breastfeeding
Arms & Interventions
LEAP2
An intravenous infusion of LEAP2, an endogenous inverse agonist and competitive antagonist of the ghrelin receptor (GHSR), will be administered at 40 pmol/kg/min for 6 hours.
Intervention: Liver-Expressed Antimicrobial Peptide 2 (LEAP2) (Biological)
Placebo
An intravenous infusion of isotonic saline (placebo) will be administered for 6 hours
Intervention: Placebo (saline) (Other)
Outcomes
Primary Outcomes
Food intake
Time Frame: 290 to 310 minutes
Difference in total energy intake during a standardized ad libitum meal. Energy intake will be quantified as kilojoules (kJ) and kJ per kilogram of body weight consumed during the meal
Secondary Outcomes
- Composite score of sensation of hunger, fullness (reverse corded) and prospective food intake.(-30 to 290 minutes)
- Gastric emptying(-30 to 290 minutes)
- Plasma concentrations of glucose(-30 to 290 minutes)
- Circulating levels of growth hormone and IGF-1(-30 to 290 minutes)
- Circulating levels of acyl-ghrelin(-30 to 290 minutes)
Investigators
Asger Lund, MD
MD, Ph.d, Head of Department, Center for Clinical Metabolic Research
University Hospital, Gentofte, Copenhagen