Liraglutide in Prader Willi–Syndrome: The Importance of Placebo-Controlled Studies

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Treatment of obesity and hyperphagia in pediatric patients with Prader–Willi syndrome (PWS) is among the most challenging experiences that an endocrinologist could face. PWS is a rare condition caused by the loss of expression of paternally inherited genes located at chromosome 15 q11-13. It occurs in 1 of 16 000 to 21 000 live births. It is characterized by an impaired hypothalamic development and function (1). Hypotonia, developmental delays, and behavioral deficits are part of the clinical picture. Short stature, hypogonadism, obesity, and hyperphagia are among the most common endocrine abnormalities. Pathophysiology of obesity and hyperphagia is partially known. Hyperphagia may be explained by overactivation of the limbic system and decreased cortical inhibition. In patients with PWS with obsessive eating behavior, the functional connectivity between ventral striatum, the hypothalamus, and the amygdala is decreased. Also, several orexigenic and anorexigenic hormones are involved. Higher concentrations of ghrelin (an orexigenic signal) and lower levels of adiponectin, leptin, and pancreatic polypeptide (anorexigenic signals) have been found. However, contradictory results are common in this field due to methodologic limitations (ie, small sample size) (2). Obesity prevention in children is the ideal scenario to avoid the long term complications. However, both, prevention and treatment of obesity are difficult to be accomplished. Scant physical activity, hyperphagia and behavioral deficits are major barriers to get long-term adherence to a healthy lifestyle. Family support is a critical component of therapy. However, it should be guided by a multidisciplinary team; food restrictions may precipitate anxiety outbursts and deterioration of the immediate support network. Evaluation of existing drug therapies in patients with PWS has been limited and complex. Some pharmacologic options (ie, metformin and naltrexone, alone or in combination with bupropion and glucagon-like peptide 1 [GLP1] agonists) have been assessed in a scant number of studies with several methodologic limitations. Among them are small sample size, open label study design, and biased selection criteria (ie, adults with diabetes or other metabolic comorbidities). The role of drug therapy in obesity prevention in PWS pediatric populations remains to be assessed.