Abstract Body

The increasing number of young patients with obesity worldwide is a major challenge for health care systems in many countries.

The gold standard for the treatment of obesity remains a multimodal conservative treatment regime to improve physical activity & reduce caloric intake.

Unfortunately, with this conservative treatment regime, the impact on body weight is overall modest and the majority of patients regain weight. This is the reason why there is an urgent need to establish new treatment strategies for children and adolescents with obesity in order to reduce the risk for the development of comorbidities, and increased mortality later in life.

The leptin-melanocortin pathway and the incretin system are deeply involved in a complex regulation of food intake. One of the incretins is the glucagon like peptide-1 (GLP-1). Like human GLP-1, liraglutide (Saxenda®) is a glucagon- like peptide 1 receptor (GLP-1R) agonist that works on glucose metabolism and body weight due to various mechanisms: promoting insulin secretion from pancreatic β-cells; reducing glucagon secretion from pancreatic α-cells; improving insulin sensitivity; reducing gastric emptying; and improving central appetite regulation.

A large randomized, double-blind placebo- controlled trial, published by Kelly et al., which consisted of a 56-week treatment period and a 26-week follow-up period evaluated the efficacy and safety of liraglutide (3.0 mg) or placebo subcutaneously once daily, in addition to lifestyle therapy among adolescents 12-18 years of age with obesity and a poor response to lifestyle therapy. The results of the study showed that liraglutide was superior to placebo with regard to the change from baseline in the BMI standard-deviation score at week 56, with a significant higher percentage of patients that achieved a reduction of at least 5% in the BMI in the liraglutide group compared with the placebo group. Major side effects included gastrointestinal symptoms.

After this publication, the Saxenda® has been approved by the FDA in 2021 as an anti-obesity drug in addition to lifestyle therapy in adolescents. Further data from real- life setting are needed to assess the use of the medication in larger number of pediatric patients with obesity, in order to evaluate its efficacy and safety in the long-term and the possibility of prevention of obesity related comorbidities.

Abstract Body

Genetic obesity disorders are severe and disabling disorders with a variety of accompanying symptoms or features. These disorders are rare to extremely rare and can be difficult to diagnose. Genetic obesity disorders are more often diagnosed in children than in adult patient groups. Genetic obesity reflects a heterogeneous group of conditions. They are classically divided into non-syndromic and syndromic obesity. Non-syndromic genetic obesity disorders are often caused by a single gene defect leading to defective leptin-melanocortin pathway. Severe obesity classically presents in the first years of life. Syndromic genetic obesity differs from non-syndromic, as they have additional symptoms, apart from obesity, like neurodevelopmental disorders and/or polymalformative syndrome.

Children with rare genetic obesity disorders present with insatiable behavior (hyperphagia) and early-onset obesity. The cause is a genetic defect disrupting the signaling through the melanocortin-4 receptor (MC4R) pathway, in the hypothalamus.

Traditional lifestyle interventions are an important basis of treatment but patients are often treatment resistant. In addition to supportive lifestyle interventions, novel pharmacotherapeutic treatment options have become available. Case series have been described using dextroamphetamine or GLP1 agonist. After EMA approval based on clinical trials, patients with specific genetic obesity disorder can now be treated with the MC4R agonist from the age of 6.

In conclusion drugs targeting central brain pathways of weight regulation and energy expenditure provide new and promising treatment options for patients with genetic obesity disorders.

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