Obesity &Amp; Overweight
Conditions
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.
Interventions
BIOLOGICALLiver-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
OTHERPlacebo (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
Sponsors
University Hospital, Gentofte, Copenhagen
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
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
* Anaemia * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Food intake | 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
| Measure | Time frame | Description |
|---|---|---|
| Composite score of sensation of hunger, fullness (reverse corded) and prospective food intake. | -30 to 290 minutes | Visual analogue scales (VASs) assessing appetite, satiety and hunger sensations (from 0 to 10 cm on a scale = from mimimum to maximum sensation) |
| Gastric emptying | -30 to 290 minutes | Paracetamol concentration in plasma after intake of 1.5 g paracetamol |
| Plasma concentrations of glucose | -30 to 290 minutes | Plasma glucose |
| Circulating levels of growth hormone and IGF-1 | -30 to 290 minutes | Blood samples |
| Circulating levels of acyl-ghrelin | -30 to 290 minutes | Blood samples |
Other
| Measure | Time frame | Description |
|---|---|---|
| Gallbladder motility | 290 to 310 minutes | Bed-side ultrasonography |
| Sensation of nausea, thirst, and comfort | -30 to 290 minutes | VAS |
| Heart rate | -30 to 290 minutes | Heart rate measurement |
| Systolic and diastolic blood pressure | -30 to 290 minutes | Blood pressure measurement |
| Circulating levels of LEAP2, insulin, glucagon, and other hormones and signaling molecules regulating glucose metabolism, gastrointestinal motility, energy expenditure and eating behaviour | -30 to 290 minutes | Blood samples |
| Lipids and other metabolism markers | -30 to 290 minutes | Blood samples |
| Energy expenditure | -30 to 290 minutes | Indirect calorimetry |
| Duration of ad libitum meal | 290 to 310 minutes | Ad libitum meal duration |
| Water intake during ad libitum meal | 290 minutes to 310 minutes | Ad libitum meal |
Countries
Denmark
Contacts
Primary ContactChristian Legart, MD
Outcome results
None listed