Monogenic Obesity
Conditions
Keywords
Monogenic obesity, Semaglutide, WEGOVY
Brief summary
Rare genetic forms of obesity, so called monogenic obesity are linked to alteration in energy balance involving hypothalamic pathways. More than 60 genes encoding for proteins located in the hypothalamic leptin/melanocortin pathway have been described in the French National Protocol for Diagnostic and Care (PNDS). While pathogenic and likely pathogenic variants in these genes are well-established causes of monogenic obesity, current evidence supports a broader genetic architecture of obesity, better understood as a continuum ranging from rare high-impact variants to polygenic susceptibility. Variants of uncertain significance (VUS) as well as variants currently classified as benign or likely benign are frequently identified in clinical practice, and their classification may evolve over time as genomic databases expand and functional data accumulate In addition, polygenic background may interact with rare variants and contribute to the severity of the phenotype, disease progression, and therapeutic response. The natural history of monogenic obesity is characterized by an early onset in childhood, with a major increase in weight in adolescence and young adulthood. The worsening of obesity exposes these patients to severe complications. Severe obesity and eating disorders have a major impact on the quality of life of the person but also of the family and caregivers. Clinical management is complex and requires comprehensive, specialized and multidisciplinary management. The usual lifestyle approaches have so far shown disappointing results, similarly to bariatric surgery which leads to a more frequent weight regain in the situation of monogenic obesity, justifying new approaches. In this context, evaluating the response to treatment in the particular condition of monogenic obesity is crucial to propose therapeutic options as early as possible to limit weight evolution and its complications. GLP-1 (glucagon-like peptide 1) based innovative therapies have recently emerged as a promising option for treatment of obesity and its complications. This is the case for Semaglutide marketed as OZEMPIC® and WEGOVY®, developed by Novo Nordisk. However, there is a lack of data to confirm that semaglutide could be also effective in monogenic obesity. The aim of the ObGeSema project is to set up a cohort composed of patients (1) having already initiated a treatment and (2) newly treated by Semaglutide in 21 pediatric and adult Specialized Obesity Centres (CSOs) and describe their evolution over a 4 years follow-up.
Detailed description
Rare genetic forms of obesity, so called monogenic obesity are linked to alteration in energy balance involving hypothalamic pathways. More than 60 genes encoding for proteins located in the hypothalamic leptin/melanocortin pathway have been described in the French National Protocol for Diagnostic and Care (PNDS) https://www.has-sante.fr/jcms/p\_3280217/fr/generique-obesites-de-causes-rares). While pathogenic and likely pathogenic variants in these genes are well-established causes of monogenic obesity, current evidence supports a broader genetic architecture of obesity, better understood as a continuum ranging from rare high-impact variants to polygenic susceptibility. Variants of uncertain significance (VUS) as well as variants currently classified as benign or likely benign are frequently identified in clinical practice, and their classification may evolve over time as genomic databases expand and functional data accumulate In addition, polygenic background may interact with rare variants and contribute to the severity of the phenotype, disease progression, and therapeutic response. The natural history of monogenic obesity is characterized by an early onset in childhood, with a major increase in weight in adolescence and young adulthood. The worsening of obesity exposes these patients to severe complications. Severe obesity and eating disorders have a major impact on the quality of life of the person but also of the family and caregivers. Clinical management is complex and requires comprehensive, specialized and multidisciplinary management. The usual lifestyle approaches have so far shown disappointing results, similarly to bariatric surgery which leads to a more frequent weight regain in the situation of monogenic obesity, justifying new approaches. In this context, evaluating the response to treatment in the particular condition of monogenic obesity is crucial to propose therapeutic options as early as possible to limit weight evolution and its complications. GLP-1 based innovative therapies have recently emerged as a promising option for treatment of obesity and its complications. This is the case for Semaglutide marketed as OZEMPIC® and WEGOVY®, developed by Novo Nordisk. However, there is a lack of data to confirm that semaglutide could be also effective in monogenic obesity, particularly across the full spectrum of genetic variants involved in the leptin-melanocortin pathway. In France, semaglutide is currently accessible through several regulatory frameworks: OZEMPIC® (up to 2 mg/week) is reimbursed by the French Social Security for the treatment of type 2 diabetes in adult patients. WEGOVY® (up to 2.4 mg/week) was available through an Early Access Programme from May 2022 to September 2024 for adults with BMI \>40 kg/m² and at least one comorbidity. Treatment initiated in this framework can be continued until December 2025. Since November 2024, WEGOVY® (up to 2.4 mg/week) has had marketing authorization for the treatment of adolescents and adults ≥12 years with BMI ≥30 kg/m². However, the drug is not yet reimbursed, except in rare cases through individual exceptional reimbursement for rare and complex diseases. Given this evolving regulatory landscape, it is essential to assess the real-life efficacy and safety of semaglutide in individuals with including both adolescents and adults carrying variants across the continuum of genetic susceptibility. The aim of the ObGeSema project is to set up a cohort composed of patients (1) having already initiated a treatment and (2) newly treated by Semaglutide in 21 pediatric and adult Specialized Obesity Centres (CSOs) and describe their evolution over a 4 years follow-up.
Interventions
None listed
Sponsors
Assistance Publique - Hôpitaux de Paris
Study design
Observational model
COHORT
Time perspective
OTHER
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients (≥12 years) having already initiated a treatment with SEMAGLUTIDE (regardless of the context: early access, routine care, self-financing, or exceptional reimbursement) or with a physician's decision to initiate treatment in the standard care. All patients having initiated treatment will be proposed to participate, including those having already stopped the treatment at the time of study initiation. * Confirmation of monogenic obesity, as practiced in clinical routine, regardless of current classification (i.e., pathogenic, likely pathogenic, variant of uncertain significance \[VUS\], or benign) in a gene with leptin-melanocortin pathway described in PNDS (https://www.has-sante.fr/jcms/p\_3280217/fr/generique-obesites-de-causes-rares). ) For patients with VUS or benign variants, inclusion is conditional on the availability of a polygenic risk score (PRS) * Patients duly informed and not objecting to participate in the study. For patients ≥12 years \<18 years Parents duly informed and not objecting that their child taking part in the study * Patients affiliated to a social security scheme or State Medical Assistance (AME).
Exclusion criteria
* Pregnant and breastfeeding women
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in weight and Body Mass Index (BMI) | From baseline (T0) to T12 | Percentage of subjects with a change in weight and Body Mass Index (BMI).Weight will be measured at initiation and at 12 months of the Semaglutide treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in weight and Body Mass Index (BMI) | From baseline (T0) to 6 and/or 24 and/or 36 and/or 48 and/or 60 months | Percentage of subjects with a change in weight and Body Mass Index (BMI). Weight will be measured at initiation of the Semaglutide treatment and at each visit |
| Reduction of body weight equal to or above 5% | From baseline (T0) to 6 and/or 12 and/or 24 and/or 36 and/or 48 and/or 60 months | Percentage of subjects achieving a reduction of body weight equal to or above 5%(number of subjects with a % of body weight changes \> -5%)X100/ number of the total subject |
| Change in Hunger score | From baseline (T0) to 12 and/or 24 and/or 36 and/or 48 and/or 60 months | Number and percentage of subjects with change in Hunger score |
| Change in eating behaviour measured by Food Craving questionnaire | From baseline (T0) to 12 months | Number and percentage of subjects with change in Food Craving scale |
| Change in eating behaviour measured by the Binge Eating Scale (BES) | From baseline (T0) to 12 months | Number and percentage of subjects with change in Binge Eating Scale (BES) |
| Change in eating behaviour measured by the Dutch Eating Behaviour Questionnaire (DEBQ) | From baseline (T0) to 12 months | Number and percentage of subjects with change in Dutch Eating Behaviour Questionnaire (DEBQ) |
| Change in eating behaviour measured by the Dykens questionnaire for ≥18 years patients | From baseline (T0) to 12 months | Number and percentage of subjects with change in Hyperphagia score with the Dykens questionnaire for intellectual disability |
| Change in eating behaviour measured by the Child Eating Behaviour Questionnaire (CEBQ) | From baseline (T0) to 12 months | Number and percentage of subjects with change in the Child Eating Behaviour Questionnaire (CEBQ) for intellectual disability for ≥18 years patients |
| Change in the International physical activity questionnaire (IPAQ - short form) for ≥18 years patients | From baseline (T0) to 12 months | Number and percentage of subjects with change of the International physical activity |
| Change in Digestive disorders (GIQLI ) for ≥18 years patients | From baseline (T0) to 12 and/or 24 and/or 36 and/or 48 and/or 60 months | Number and percentage of subjects with change in Digestive disorders (GIQLI ). Digestive disorders are measured by the Gastrointestinal Quality of Life Index (GIQLI) |
| Change in score of quality of life scores (patient and parents) for ≥18 years patients | From baseline (T0) to 12 months | Number and percentage of subjects with change in score of quality of life scores .Quality of life is measured with the Impact of Weight on Quality of Life-Lite scale (IWQOL-Lite) |
| Change in sleep disorder (MCTQ score) for ≥18 years patients | From baseline (T0) to 12 months | Number and percentage of subjects with Change in sleep disorder. Sleep disorder is measured with the Micro Munich Chronotype Questionnaire (MCTQ) |
| Change in anxiety and depression score for ≥18 years patients | From baseline (T0) to 12 and/or 24 and/or 36 and/or 48 and/or 60 months | Number and percent of subjects with change in anxiety and depression score. Anxiety and depression is measured with the Hospital Anxiety and Depression scale (HAD) |
| ● Change in Body Mass Index : BMI Z-score for 12 to <18 years | From baseline (T0) to 6 and/or 12 and/or 24 and/or 36 and/or 48 and/or 60 months | Weight will be measured at initiation of the Semaglutide treatment and at each visit |
| Change in eating behaviour scores CEBQ ( Child Eating Behaviour Questionnaire) or Hyperphagia score with the Dykens questionnaire and for intellectual disability. For 12 to <18 years patients | From baseline (T0) to 12 months | Number and percentage of subjects with change |
| Change in score of IWQOL Impact of Weight on Quality of Life (patient and parents). For 12 to <18 years patients | From baseline (T0) to 12 months | Number and percentage of subjects with change in score Impact of Weight on Quality of Life |
| Change in Digestive disorders GIQLI score (Gastrointestinal Quality of Life Index). For 12 to <18 years patients | From baseline (T0) to 12 and/or 24 and/or 36 and/or 48 and/or 60 months | Number and percentage of subjects with change |
| Treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) | From baseline (T0) to 6 and/or 12 and/or 24 and/or 36 and/or 48 and/or 60 months | Number of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) |
Countries
France
Contacts
CONTACTChristine POITOU-BERNERT, MD,PhD
CONTACTSarra POCHON
PRINCIPAL_INVESTIGATORChristine POITOU-BERNERT, MD,PhD
Assistance Publique - Hôpitaux de Paris
STUDY_DIRECTORBéatrice DUBERN, MD,PhD
Assistance Publique - Hôpitaux de Paris
Outcome results
None listed