Case report: Long-term efficacy and safety of semaglutide in the treatment of syndromic obesity in Prader Willi syndrome - case series and literature review.

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Prader Willi syndrome (PWS) is a genetic condition caused by loss of the paternal copy of a region of imprinted genes on chromosome 15. There is severe muscular hypotonia in...

The mainstay management of hyperphagia and obesity in Prader-Willi syndrome (PWS) relies on dietary restrictions, strict supervision and behavioural modifications, which can be stressful for the patient and caregiver. There is no established pharmacological strategy to manage this aspect of PWS. Theoretically, glucagon-like peptide-1 (GLP-1) receptor agonists (GLP1-RA) used in patients with obesity and type 2 diabetes mellitus (T2DM) may be efficacious in weight and glycaemic control of PWS patients. We conducted a systematic review of the literature to summarize the evidence on the use of GLP1-RA in PWS patients. Primary studies were searched in major databases using key concepts 'Prader-Willi syndrome' and 'GLP1 receptor agonist' and outcomes, 'weight control OR glycaemic control OR appetite regulation'. Ten studies included, summarizing GLP1-RA use in 23 PWS patients (age, 13-37 years), who had used either exenatide (n = 14) or liraglutide (n = 9) over a duration of 14 weeks to 4 years. Sixteen (70%) of these patients had T2DM. Ten patients experienced improvement in body mass index, ranging from 1.5 to 16.0 kg/m2 , while improvement in HbA1c was seen in 19 of 23 cases, ranging between 0.3% and 7.5%. All five studies reporting appetite or satiety showed improvement in satiety levels. There were no reported serious side effects. GLP1-RA appears safe in PWS patients and may have potential benefits for weight, glycaemic and appetite control. Nonetheless, we also highlight a significant gap in the literature on the lack of well-designed studies in this area, which limits the recommendation of GLP1-RA use in PWS patients at present.

Prader-Willi syndrome (PWS) is associated with hyperphagia and hyperghrelinemia with major morbidity because of obesity without effective medical treatment targeting hyperphagia. Exenatide (Byetta [synthetic Exendin-4]; AstraZeneca, Wilmington DE) is a GLP-1 receptor agonist which reduces appetite and weight and may be an effective treatment in PWS. The objective of this study is to determine the effect of a 6-month trial of exenatide on appetite, weight and gut hormones in youth with PWS. Ten overweight and obese subjects with PWS (13-25 years) were recruited for a 6-month open-label, non-randomized, longitudinal study conducted at Children's Hospital Los Angeles. Exenatide was given using standard diabetes dosing without dietary modifications. Weight, body mass index (BMI), truncal fat, appetite and plasma acylated ghrelin were measured over 6 months. Mixed meal tolerance tests were performed at 0 and 6 months. Appetite scores significantly decreased from baseline (32.2 ± 8.7) after 1, 3 and 6 moths of treatment (27.5 ± 8.8, 25.4 ± 9.3, and 25.4 ± 7.2 respectively; p = 0.004). Hemoglobin A1c decreased significantly after treatment, but weight, BMI z-score and adiposity did not. There was no significant change in ghrelin. This is the first longitudinal investigation of the effects of exenatide in subjects with PWS. It was effective in decreasing appetite, without change in weight or BMI in the short term. Larger, controlled, longer-term trials in patients with PWS are needed to confirm the efficacy and safety of exenatide and to evaluate whether its use might induce weight loss when given in conjunction with behavioural modification.

INTRODUCTION Obesity is a chronic disease associated with significant metabolic and cardiovascular complications. Bariatric surgery remains the most effective treatment for severe obesity, achieving substantial and sustained weight loss while improving glycemic control and reducing cardiovascular risk. Glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as a pharmacological alternative, offering weight reduction and metabolic benefits with a lower risk of immediate complications. However, differences in long-term efficacy, safety, and adherence raise questions about their potential to replace metabolic surgery. OBJETIVE This study aims to compare the effectiveness, safety, and long-term outcomes of GLP-1 receptor agonists and bariatric surgery in obesity management. The analysis includes weight loss results, metabolic improvements, treatment adherence, complication rates, and cost-effectiveness. Additionally, the study explores whether a combined approach could enhance obesity treatment outcomes. METHODS A narrative review was conducted using articles published in the last five years from PubMed, Cochrane, Medline, Embase, and SciELO databases. The descriptors used included “Obesity treatment” OR “Bariatric surgery” OR “GLP-1 receptor agonists” OR “Pharmacological weight loss” OR “Metabolic surgery.” Studies comparing pharmacological and surgical interventions in terms of weight loss, metabolic effects, cardiovascular outcomes, and patient adherence were analyzed. RESULTS AND DISCUSSION Bariatric surgery resulted in greater long-term weight loss and higher rates of type 2 diabetes remission compared to GLP-1 receptor agonists. While pharmacotherapy provided significant metabolic improvements, its efficacy depended on continuous use, with weight regain frequently occurring after discontinuation. GLP-1 receptor agonists demonstrated cardiovascular benefits, but adherence was limited due to gastrointestinal side effects and financial burden. In contrast, surgery carried higher initial risks but produced sustained metabolic benefits and reduced long-term medication dependence. CONCLUSION Bariatric surgery remains the superior intervention for obesity management, particularly in patients with severe obesity and metabolic syndrome. GLP-1 receptor agonists offer a viable non-surgical alternative but require continuous therapy for sustained effects. A personalized approach, integrating pharmacological and surgical strategies, may optimize outcomes in select patients. Future research should focus on refining combined treatment models to maximize long-term success.

Prader–Willi syndrome (PWS) is a complex genetic disorder characterized by muscular hypotonia, hypogonadism, short stature, hyperphagia, obesity, cognitive disabilities and behavioral problems. Body composition is abnormal and growth hormone (GH) secretion is insufficient with more body fat than lean body mass. In children with PWS treatment with GH improves height, head size, body composition and psychomotor functioning. In adults with PWS treatment with GH improves body composition, physical activity and quality of life. However, restricted diet and regular physical exercise are cornerstone treatments in PWS also during GH treatment. GH treatment should be considered in PWS patients with a genetically confirmed diagnosis. Cognitive disabilities and scoliosis are not contraindications to GH treatment. Adverse effects to GH treatment in PWS are few, but glucose metabolism and changes in respiration must be monitored carefully, especially in individuals with predispositions. GH treatment should be continued as long as benefits outweigh the risks.

We describe the National Institutes of Health rare disease consortium for Prader-Willi syndrome (PWS) developed to address concerns regarding medical care, diagnosis, growth and development, awareness, and natural history. PWS results from errors in genomic imprinting leading to loss of paternally expressed genes due to 15q11-q13 deletion, maternal disomy 15 or imprinting defects. The 8 year study was conducted at four national sites on individuals with genetically confirmed PWS and early-onset morbid obesity (EMO) with data accumulated to gain a better understanding of the natural history, cause and treatment of PWS. Enrollment of 355 subjects with PWS and 36 subjects with EMO began in September 2006 with study completion in July 2014. Clinical, genetic, cognitive, behavior, and natural history data were systematically collected along with PWS genetic subtypes, pregnancy and birth history, mortality, obesity, and cognitive status with study details as important endpoints in both subject groups. Of the 355 individuals with PWS, 217 (61%) had the 15q11-q13 deletion, 127 (36%) had maternal disomy 15, and 11 (3%) had imprinting defects. Six deaths were reported in our PWS cohort with 598 cumulative years of study exposure and one death in the EMO group with 42 years of exposure. To our knowledge, this description of a longitudinal study in PWS represents the largest and most comprehensive cohort useful for investigators in planning comparable studies in other rare disorders. Ongoing studies utilizing this database should have a direct impact on care and services, diagnosis, treatment, genotype-phenotype correlations, and clinical outcomes in PWS.

We analyzed international consensuses of experts and clinical recommendations on diagnosis and treatment of Prader-Willi syndrome (PWS): PWS consensus diagnostic criteria (1993); US PWS Association (PWSA-USA) consensus statements on evaluating of breathing abnormalities (2007), osteoporosis (2008), growth hormone treatment in PWS (2000 and 2009); Endocrine society clinical practice guideline on Prevention and treatment of pediatric obesity (2008); the Second Expert Meeting of the Comprehensive Care of Patients with PWS Consensus published as Recommendations for the diagnosis and management of PWS (2008). Historical analysis and comparison of recommendations are presented in this review article. Absence of Russian clinical practice guidelines on PWS patients management makes necessary the detailed study of listed documents.

Introduction: Prader-Willi syndrome (PWS) is a neurometabolic genetic disorder with chromosomal 15q11-q13 deletions or uniparental disomy with absence of paternally expressed genes affecting 1/12,000 – 1/15,000 newborns. The syndrome is characterized by hypotonia, intellectual disability, behavioral problems, psychiatric phenotypes, short stature, central hypocorticism, pubertal insufficiency and hypogonadism leading to osteoporosis. The most life-threatening characteristic is excessive appetite, which leads to morbid obesity and diabetes and its related complications.Areas covered: In this paper, the authors review evidence-based papers that present the management of patients with PWS, involving aspects of reduced GH secretion, hypogonadotropic hypogonadism, abnormal appetite control and high pain threshold, all suggesting hypothalamic-pituitary dysfunction. The treatment of these homeostatic alterations is presented, and the consideration of a multidisciplinary approach and future perspectives are discussed. Finally, the authors briefly review the current status of treatment and perspectives specific for PWS.Expert opinion: Despite the detailed knowledge about obesity mechanisms regulated at the hypothalamic level, the pharmacological intervention is limited currently to substitution of proven endocrine deficiencies (growth hormone, thyroxine, sex steroids, glucocorticoids), prevention and treatment of metabolic complications (the most severe being diabetes) and osteoporosis. Treatment of mental disturbances and skin-picking, severe obesity and altered body composition often requires a team including a pediatrician, an endocrinologist, a psychiatrist, a bariatric surgeon and strong support from the family and caregivers.

Prader–Willi Syndrome (PWS), first described in 1956, is a unique genetic condition with a prevalence of 1 in 10,000 – 25,000. Features include severe lifelong hypotonia, insatiable appetite, short stature, obsessive-compulsive behaviour, morbid obesity, hypogonadism, kyphosis, scoliosis and osteoporosis. Studies beginning in the 1970s demonstrated that PWS is associated with a deficiency in growth hormone. Growth hormone treatment in children with PWS improves linear growth and more importantly leads to an increased muscle mass, bone mineral density and physical performance. In mid-2000, growth hormone became the first pharmaceutical approved in the US and Europe for the treatment of childhood PWS. It is now considered an essential part of comprehensive care for this condition. Ongoing studies address issues of growth hormone dosage, long-term efficacy, effects on neonatal and childhood growth and development and effects in adults with PWS.

Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are a class of antidiabetic drugs developed over the past 15 years. GLP-1, a gastrointestinal peptide hormone that contributes to the postprandial incretin effect, stimulates glucose-dependent insulin secretion. The incretin effect is greatly diminished in type 2 diabetes, but can be restored by GLP-1RAs. These drugs also exert other GLP-1 effects, including reducing glucagon secretion, delaying gastric emptying, reducing food intake, improving cardiac ventricular function, and lowering blood pressure. Short-acting GLP-1RAs are administered once daily (lixisenatide) or twice daily (exenatide); long-acting GLP 1RAs are administered once daily (liraglutide) or once weekly (slow-release exenatide, dulaglutide, albiglutide). All GLP-1RAs significantly reduce glycated hemoglobin (HbA1c) in patients with type 2 diabetes whose glycemic control is inadequate with oral antidiabetic drugs. Compared with other antidiabetic medications, GLP-1RAs provide better glycemic control with the additional benefit of weight loss. Within this class, long-acting GLP-1RAs are more efficacious than short-acting GLP-1RAs, with similar or lower risk of hypoglycemia and lower incidence of gastrointestinal adverse effects. Head-to-head trials and a network meta-analysis suggest that once daily liraglutide is the most effective GLP-1RA in reducing HbA1c. Dulaglutide is the only once-weekly GLP 1RA demonstrated to be noninferior to liraglutide. The once-weekly GLP-1RAs offer additional advantages to patients, including fewer injections and easy-to-use, single-dose pen devices. Despite the relatively recent development of GLP-1RAs, international diabetes guidelines recognize the benefits of this class of drugs and recommend them as a treatment option for patients with type 2 diabetes.

Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are a class of antidiabetic drugs developed over the past 15 years. GLP-1, a gastrointestinal peptide hormone that contributes to the postprandial “incretin effect”, stimulates glucose-dependent insulin secretion. The incretin effect is greatly diminished in type 2 diabetes, but can be restored by GLP-1RAs. These drugs also exert other GLP-1 effects, including reducing glucagon secretion, delaying gastric emptying, reducing food intake, improving cardiac ventricular function, and lowering blood pressure. Short-acting GLP-1RAs are administered once daily (lixisenatide) or twice daily (exenatide); long-acting GLP 1RAs are administered once daily (liraglutide) or once weekly (slow-release exenatide, dulaglutide, albiglutide). All GLP-1RAs significantly reduce glycated hemoglobin (HbA1c) in patients with type 2 diabetes whose glycemic control is inadequate with oral antidiabetic drugs. Compared with other antidiabetic medications, GLP-1RAs provide better glycemic control with the additional benefit of weight loss. Within this class, long-acting GLP-1RAs are more efficacious than short-acting GLP-1RAs, with similar or lower risk of hypoglycemia and lower incidence of gastrointestinal adverse effects. Head-to-head trials and a network meta-analysis suggest that once daily liraglutide is the most effective GLP-1RA in reducing HbA1c. Dulaglutide is the only once-weekly GLP 1RA demonstrated to be noninferior to liraglutide. The once-weekly GLP-1RAs offer additional advantages to patients, including fewer injections and easy-to-use, single-dose pen devices. Despite the relatively recent development of GLP-1RAs, international diabetes guidelines recognize the benefits of this class of drugs and recommend them as a treatment option for patients with type 2 diabetes.

Introduction: Prader-Willi syndrome (PWS) is the most well-known condition of genetic obesity. Over the past 20 years, advances have been achieved in the diagnosis and treatment of PWS with a significant improvement in prognosis. Areas covered: This review focuses on the benefits of multidisciplinary approach in children and adolescents with PWS. In particular, the neonatologist and geneticist play a key role in early diagnosis and the clinical follow-up of the PWS patient must be guaranteed by a team including pediatric endocrinologist, psychologist, nutritionist/dietician, neurologist/neuropsychiatrist, sleep specialist, ears, nose and throat specialist (ENT), lung specialist, dentist, orthopedist and ophthalmologist and, eventually, gastroenterologist. We searched PubMed and critically summarized what has been reported in the last 10 years on PWS. Expert opinion: The multidisciplinary care in association with an early diagnosis and GH treatment postpones overweight development and decreases prevalence of obesity in individuals with PWS. Further prognostic improvements are expected through the selection of teams particularly experienced in the management of individuals with PWS and the discovery of new drugs.

Debate remains as to how to balance the use of recombinant human growth hormone (rhGH) as an important treatment in Prader-Willi syndrome (PWS) with its potential role in obstructive sleep apnea. This single-center, retrospective study assessed differences in overnight polysomnography results between children with and without PWS and changes in respiratory parameters before and after the initiation of rhGH treatment in those with PWS. Compared with age-, sex-, and body-mass-index-matched controls (n = 87), children with PWS (n = 29) had longer total sleep time (434 ± 72 vs. 365 ± 116 min; p < 0.01), higher sleep efficiency (86 ± 7 vs. 78 ± 15%; p < 0.05), and lower arousal events (8.1 ± 4.5 vs. 13.0 ± 8.9 events/h; p < 0.05). Mean oxygen saturation was lower in PWS children (94.3 ± 6.0 vs. 96.0 ± 2.0%; p < 0.05), with no other differences in respiratory parameters between groups. Eleven children with PWS (38%) met the criteria for further analyses of the impact of rhGH; polysomnography parameters did not change with treatment. Compared with other children undergoing polysomnography, children with PWS had more favorable markers of sleep continuity and lower oxygen saturation for the same level of respiratory disturbance. rhGH administration was not associated with changes in respiratory parameters in PWS.

Disclosure: A. Leong: None. S. Chen: None. M. Alimussina: None. J. Bryce: None. M. Chen: None. A. Fu: None. E.F. Gevers: None. C. Hoybye: None. M. Hughes: None. V. Iotova: None. M.Y. Jalaludin: None. G.F. Kerkhof: None. F. Luo: None. J. Miller: None. O. Nyunt: None. E.F. Roche: None. M.G. Shaikh: None. T. Strong: None. M. Tauber: None. L.S. Tyszler: None. S.F. Ahmed: None.Introduction: Recombinant Human Growth Hormone (GH) was approved in the US (2000) and Europe (2001) for children with Prader-Willi Syndrome (PWS) to improve growth and body composition, with reported benefits in cognition, motor skills and behaviour. However, longer term safety and efficacy data of GH in PWS are still lacking and may be difficult to interpret due to lack of consistency in data collection among studies. This study aimed to identify the minimum dataset (MDS) that could be measured in a routine clinical setting across the world, to minimise burden on clinician data entry and improve quality of data collection to facilitate future studies on long term outcomes. Methods: The study was undertaken by the PWS Expert Working Group in GloBE-Reg, an international registry platform which supports studies on long-term safety and effectiveness of drugs. Twelve clinical experts on PWS from 10 countries and two patient representatives collaborated to develop this recommendation, based on previously published methodology (Chen et al. Horm Res Pediatr 2023). Data fields that achieved 70% consensus in terms of importance qualified for the MDS, provided <50% deemed the item difficult to collect. Several anomalies to the MDS rule were discussed to formulate the final MDS recommendation. Results: In total, 294 items were compiled from routine clinical practice with 33 redundant items removed and 261 items subjected to the grading system. 151/261 items achieved consensus as important data to collect when monitoring children with PWS on GH treatment, while 218/261 items were deemed easy to collect. Combining both the criteria for importance and ease of collection, 126 items fulfilled the MDS requirement. Four items were designated as core data, two were computed fields, five reassigned as non-MDS, 13 removed as unrelated to safety and effectiveness and 65 were merged into 18 fields. Several anomalies which did not fulfill MDS criteria were also extensively discussed to determine its validity within the MDS, in particular family history of Type 2 diabetes, change of GH therapy (if applicable) and adherence, to produce the final MDS recommendations of 58 items; of which 24 are only to be completed once. Conclusion: This exercise has identified by consensus the minimum dataset considered necessary, which can be collected through real-world data, to provide consistency and comparability in global studies for monitoring the safety and effectiveness of GH in children with PWS, applicable to the current daily preparations and potential newer long-acting GH.Presentation: Saturday, July 12, 2025