Young Adults With Early-onset Obesity Treated With Semaglutide -The RESETTLE Study (RESETTLE)

Description

Background

Alarmingly, the increment in prevalence rate for obesity is particularly pronounced among children and adolescents (1). Rates have tripled in adolescents, thus entailing increased cumulative incidences of type 2 diabetes, hypertension, and chronic kidney disease (1). In adolescents, the detrimental effects of an elevated fat accumulation have a stronger impact over the lifespan than in adult-onset obesity. Furthermore, adolescents with obesity are at a substantially elevated risk of developing morbid obesity in adulthood, as the age-dependent increments in kg/m² are substantially higher in the upper as compared to the lower body mass index (BMI) centile range (2, 3). A recent large scale meta-analysis (3) revealed that mortality increased approximately log-linearly with BMI over 25.0 kg/m² in all continents; and that this increment was greater in younger than older people (3). Furthermore, adolescents with obesity are at a substantially elevated risk of developing morbid obesity and type 2 diabetes in early adulthood (2) along with stigmatization with respect to social relationships, entry into the job market, reduced self-esteem and other psychological problems (4).

Thus, adolescents with obesity require particular medical attention, because obesity most often tracks into adulthood with detrimental effects on health and general life aspects (2).

Generally, lifestyle interventions to treat childhood obesity have yielded disappointing results (5, 6). Furthermore, the non-reversible nature of bariatric surgery and post-surgery suicidal and depression behaviors particularly for adolescents questions this obesity treatment method in adolescents (7). Although lifestyle interventions remain the method of choice for children with obesity, new effective treatment strategies targeting non-responders, with the aim to maintain weight loss over time, are urgently required.

Since 2008, The Children's Obesity Clinic (TCOC), Department of Pediatrics, Copenhagen University Hospital Holbæk has treated more than 4000 children and adolescents with overweight or obesity using the TCOC protocol which includes regular dietary, exercise, lifestyle and medical consultations. The TCOC protocol has proven successful with a reduction in BMI standard deviation score (SDS) after 1.5 years of treatment obtained in 74% of the children and adolescents (8, 9). Furthermore, the achieved relative weight loss is maintained over the course of at least 3.5 years(10). In addition, significant improvements in lipid profile (9),(11), the degree of hypertension (10), hepatic steatosis (12) and the presence of visceral fat (12) have been reported.

Although TCOC has achieved results in treating childhood obesity, 15-25% of recruited children do not respond as wished for to the structured lifestyle intervention, despite vigorous efforts. Furthermore, for the majority of the 75% of children who reduce BMI SDS, obesity remains and represents a medical and personal issue.

The reduction in BMI SDS was independent of socioeconomic status and baseline degree of obesity, but older children were more likely to drop out, highlighting the need of obesity management in adolescents and young adults (8).

Glucagon-like peptide-1 (GLP-1) is secreted from endocrine cells in the intestine upon meal intake and reduces blood glucose and food intake in a dose-dependent manner (13-16). We have previously shown that 1) people with obesity have impaired GLP-1 secretion already in the overweight state, indicating that low concentrations of GLP-1 may be part of obesity development(17), 2) weight loss induces a marked increase in GLP-1 response and this increase is part of a successfully maintained weight loss of >10 kg (18), 3) treatment with a GLP-1 receptor agonist (GLP-1 RA) facilitates long term weight loss maintenance (12 kg) accompanied by substantial improvement in metabolic health, compared to similar diet-induced weight loss maintenance (19, 20),4) appetite sensation and eating behavior are important factors in maintenance of weight loss (21) and 5) Participants with monogenic obesity, due to mutations in a central regulator of appetite, the melanocortin 4 receptor (MC4R), have limited response to standard obesity treatment, but respond to GLP-1 RA treatment (Cell metabolism, 2018)(22): Pathogenic mutations in the appetite-regulating melanocortin-4 receptor represent the most common cause of early-onset monogenic obesity (affects 2- 6% of children with obesity) with limited treatment success on standard lifestyle change (23) or even bariatric surgery (24). Interestingly, we have treated 14 adults with early-onset obesity caused by functional MC4R mutations and 28 BMI and sex matched control participants with obesity with the GLP-1 RA liraglutide 3.0 mg daily for 4 months. The two groups obtained similar significant clinically relevant weight loss (>6 kg) and reduction in glucose and triglyceride concentrations. We therefore concluded that participants with this common form of juvenile-onset obesity can be treated with GLP-1 RA (22). This, indicates that GLP-1 RA's can overrule lifestyle modification-resistant obesity due to the appetite-inhibiting effect. Recently a new GLP1-1 RA (semaglutide) was approved by the European Medical Agency (EMA) for weight management in adults obesity in January 2022. Placebo subtracted weight loss with semaglutide 2.4 mg was 13.9 % compared to 4.5% with liraglutide 3.0 mg after 68 weeks (25) in adults with overweight or obesity. Thus, semaglutide has a potentially larger treatment effect also in young adults with childhood onset obesity. The treatment effect of semaglutide 2.4 mg in young adults with lifestyle-treatment-resistant childhood onset obesity is currently unknown, why the outcomes of this study is of high clinical and socioeconomic relevance.

Study hypothesis:

We hypothesize that treatment with a GLP-1 RA will facilitate weight loss in young adults with and without treatment-resistant childhood-onset obesity.

Objectives

1. To treat young adults with obesity, who have been resistant to structured lifestyle intervention (TCOC protocol), with the GLP-1 RA, semaglutide 2.4 mg/ week. B) To treat young adults with obesity, who have responded with insufficient weight loss to the structured lifestyle intervention (TCOC protocol) and remain obese, with semaglutide 2.4 mg/ week. C) To identify underlying mechanisms of lifestyle-untreatable versus treatable childhood- onset obesity.

Endpoints

Primary endpoint:

1. Change in BMI (weight in kg/height in m^2) from before to after semaglutide treatment in non-responders to TCOC protocol compared to placebo

Secondary endpoints:

1. Change in body composition and body weight from before to after semaglutide treatment in non-responders to TCOC protocol compared to placebo
2. Change in BMI (weight in kg/height in m^2), body composition and body weight from before to after semaglutide treatment in insufficient responders to TCOC protocol compared to placebo
3. Compare BMI (weight in kg/height in m^2), body composition and body weight between excellent responders, non-responders and insufficient responders.

Other prespecified endpoints:

To determine the effect of GLP-1 RA treatment, and compare baseline data between the two intervention groups to excellent responders for the following outcomes:

1. Circulating biomarkers of metabolic regulation to evaluate metabolic health (e.g. glucose and insulin for HOMA-IR and Matsuda index, HbA1c, lipids i.e. cholesterol, HDL, LDL, triglycerides, FFA and determination of glucose-tolerance status) will be measured. Furthermore, we will measure blood pressure, pulse, and hip and waist circumference.
2. Conventional Magnetic resonance imaging (MRI) and spectroscopy is used to assess effects on fat deposits in liver, viscera, and muscle. Site-specific bone-measurements, collection of bone markers (CTX and P1NP), and DEXA scans will be performed to assess bone-health.
3. To explore the effects on appetite regulation and systemic markers of immuno-metabolism:

We will measure hormonal appetite regulation during meal tests and fasting (eg. GLP-1, Peptide YY, Glucagon, Leptin, Ghrelin, Liver-Expressed Antimicrobial Peptide 2 (LEAP2), Adiponectin) using our standard methodologies. In plasma samples we will measure various biomarkers of inflammation (eg sCD163, hsCRP, IL-1, IL-1Rap IL-6, TNF-α, SAA1, SAA2, ORM1, ORM2) and oxidation (eg malonyldialdehyde, F2-Isoprostanes, etc.), IPS and metabolomics using plasma metabolomics and proteomics technique.

4. To explore the effects on immuno-metabolic profile in human subcutaneous (sc) adipose tissue and gene expression profile of adipose tissue and in circulating inflammatory cells (PBMNCs).

5. To explore the effect on food preferences and appetite sensation: Food preferences are assessed by a picture display test where standardized pictures of food items are shown Furthermore, we will use eye tracking as well as galvanic skin response to record the participants' emotional response to the standardized food items using iMotion Software. Subjective appetite sensations will be obtained during a fixed standardized meal using electronic visual analogue scales (VAS) to record hunger, satiety, fullness, prospective food consumption, desire to eat something fatty, salty, sweet or savory, and palatability of the meals.

6. To explore the effect on brain activation using magnetic resonance (MR) imaging:

MR imaging of the brain will be conducted in a subset of participants by trained personnel at a registered clinical facility. An MRI scanner is composed of a long tube surrounded by a coil that forms a powerful magnetic field. Participants will be placed on an examination table in the centre of the tube in a supine position. By changing gradients in the magnetic field and transmitting radio waves, resonance of the atomic nuclei of the brain can be induced. During the scan we will acquire both structural and functional information about the brain. The structural MRI sequences will provide a high-resolution anatomical image of the brain. A functional MRI (fMRI) scan provides the opportunity to track changes in e.g., blood oxygenation, which serve as an index for neural activation in different parts of the brain while the participants are at rest. This protocol includes morphological neuroimaging and resting-state fMRI. The MRI scanning session will last approximately one hour.

7. To explore the genetic risk scores correlated to treatment response:

All participants are chip genotyped to define polygenic risk scores. From blood samples, we will extract DNA material. We will use the Infinium Global Screening Array, and analyse our array with Illumina Genome Studio before the bioinformatic removal of SNPs containing genes mentioned in the "American College Medical Genetics and Genomics" List.

8. To explore the effect on the microbiota:

We will analyze the microbiome in fecal and saliva samples of participants. Furthermore, fecal and saliva samples were collected from the same individuals when they were children with obesity, allowing us to compare potential differences already evident as children that may indicate later treatment response to lifestyle change and GLP-1RA treatment.

9. To explore the effect on metabolomics in urine:

Urine samples are collected at the two test days and will be stored frozen for later analyses for potential changes in the metabolomic profile.

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