Impact Sibutramine Therapy in Children with Hypothalamic Obesity or Obesity with Aggravating Syndromes

Department of Pediatrics and the National Childhood Obesity Centre, B57, Karolinska University Hospital, Huddinge, S-141 86 Stockholm, Sweden.
Journal of Clinical Endocrinology & Metabolism (Impact Factor: 6.21). 11/2007; 92(11):4101-6. DOI: 10.1210/jc.2007-0826
Source: PubMed


Behavioral treatment of children suffering from hypothalamic obesity or uncomplicated obesity in combination with syndromes that aggravate this condition has proven to be ineffective. The combination of comorbidities and severe obesity lower the quality of these children's lives drastically. The present goal was to determine whether treatment with sibutramine has a beneficial effect on such children.
A double-blind, placebo-controlled, cross-over study (20 + 20 wk), followed by a 6-month open phase, was performed. The primary indicator of efficacy was the body mass index (BMI) sd score (SDS) value, which was analyzed using an ANOVA repeated-measures design [intention to treat (ITT)]. The 50 children (7-20 yr of age) involved included 22 with hypothalamic obesity and 28 with uncomplicated obesity plus aggravating syndromes. Forty-five patients completed the first phase, and 42 participated in the entire study.
The group that initially received the placebo demonstrated an insignificant decrease (-0.06) in BMI SDS during this treatment but a significant decrease (-0.68; P < 0.001) when treated with sibutramine. The other group demonstrated a reduction in their BMI SDS of -0.72 during administration of sibutramine and a rebound of +0.43 when placed on the placebo (P < 0.001 in both cases). The response of children with hypothalamic obesity was also significant but was less pronounced than that of children with nonhypothalamic obesity. During the open phase, a continuous reduction in weight was observed. The treatment was tolerated well.
The clinically and statistically significant weight reduction caused by sibutramine in this short-term study indicates that treatment of hypothalamic and syndromal obesity with this drug may be beneficial.

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Available from: Annika Janson, May 23, 2015
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    • "Sibutramine is a nonspecific inhibitor of the presynaptic reuptake of serotonin and norepinephrine. A double-blind, placebo-controlled trial of 21 subjects showed significant weight reduction through the administration of sibutraimine52). However, sibutramine has been withdrawn from the market due to its adverse cardiovascular effects. "
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    ABSTRACT: The hypothalamus plays a key role in the regulation of body weight by balancing the intake of food, energy expenditure, and body fat stores, as evidenced by the fact that most monogenic syndromes of morbid obesity result from mutations in genes expressed in the hypothalamus. Hypothalamic obesity is a result of impairment in the hypothalamic regulatory centers of body weight and energy expenditure, and is caused by structural damage to the hypothalamus, radiotherapy, Prader-Willi syndrome, and mutations in the LEP, LEPR, POMC, MC4R and CART genes. The pathophysiology includes loss of sensitivity to afferent peripheral humoral signals, such as leptin, dysregulated insulin secretion, and impaired activity of the sympathetic nervous system. Dysregulation of 11β-hydroxysteroid dehydrogenase 1 activity and melatonin may also have a role in the development of hypothalamic obesity. Intervention of this complex entity requires simultaneous targeting of several mechanisms that are deranged in patients with hypothalamic obesity. Despite a great deal of theoretical understanding, effective treatment for hypothalamic obesity has not yet been developed. Therefore, understanding the mechanisms that control food intake and energy homeostasis and pathophysiology of hypothalamic obesity can be the cornerstone of the development of new treatments options. Early identification of patients at-risk can relieve the severity of weight gain by the provision of dietary and behavioral modification, and antiobesity medication. This review summarizes recent advances of the pathophysiology, endocrine characteristics, and treatment strategies of hypothalamic obesity.
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    • "Even more distressing, attempts at weight loss through caloric restriction and exercise are largely unsuccessful (Lustig et al., 2003; Eyal et al., 2006). Pharmacological treatment of HO and hyperphagia has shown success in a few clinical studies and case reports (Mason et al., 2002; Lustig et al., 2003; Danielsson et al., 2007; Hamilton et al., 2011) though weaker weight reductions were observed compared to uncomplicated obesity (Danielsson et al., 2007). A recent study of both normal weight and obese CP patients showed that insulin resistance and altered gut hormone secretion are not exclusively a result of obesity but hypothalamic disruption caused by the tumor and/or its treatment (Roth et al., 2011b). "
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    • "As discussed earlier, additional therapies to target HO have been studied. Their mechanisms of action include increasing sympathetic tone (Mason et al., 2002; Ismail et al., 2006; Danielsson et al., 2007; Schultes et al., 2009), reducing insulin secretion, and improving sensitivity (Lustig et al., 1999, 2003a; Inge et al., 2007; Hamilton et al., 2011). Patients have experienced a decrease in weight gain or weight stabilization but without dramatic weight reduction. "
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