Mutations in the IGF-IR gene that lead to abnormalities in the function or number of IGF-I receptors may also retard intrauterine and subsequent growth in humans.
Objective To evaluate the effects of exenatide on body mass index (BMI) and cardiometabolic risk factors in adolescents with severe obesity. Design Three-month, randomized, double-blind, placebo-controlled, multicenter clinical trial followed by a three-month open label extension. Setting An academic medical center and an outpatient pediatric endocrinology clinic. Patients Twenty-six adolescents (age 12–19 years) with severe obesity (BMI ≥ 1.2 times the 95th percentile or ≥ 35 kg/m2). Intervention All patients received lifestyle modification counseling and were equally randomized to exenatide or placebo injection, twice per day. Main Outcome Measures The primary endpoint was the mean percent change in BMI measured at baseline and three-months. Secondary endpoints included absolute change in BMI, body weight, body fat, blood pressure, hemoglobin A1c, fasting glucose, fasting insulin, and lipids at three-months. Results Twenty-two patients completed the trial. Exenatide elicited a greater reduction in percent change in BMI compared to placebo (−2.70%, 95% CI (−5.02, −0.37), P = 0.025). Similar findings were observed for absolute change in BMI (−1.13 kg/m2, 95% CI (−2.03, −0.24), P = 0.015) and body weight (−3.26 kg, 95% CI (−5.87, −0.66), P = 0.017). Although not reaching the level of statistical significance, reduction in systolic blood pressure was observed with exenatide. During the open label extension, BMI was further reduced in those initially randomized to exenatide (cumulative BMI reduction of 4%). Conclusions These results provide preliminary evidence supporting the feasibility, safety, and efficacy of glucagon-like peptide-1 receptor agonist therapy for the treatment of severe obesity in adolescents. Trial Registration This study is registered on the www.clinicaltrials.gov website (ClinicalTrials.gov identifier: NCT01237197).
The objective of this pilot study was to evaluate the effects of exenatide on body mass index (BMI) (primary endpoint) and cardiometabolic risk factors in non-diabetic youth with extreme obesity. Twelve children and adolescents (age 9–16 years old) with extreme obesity (BMI ≥1.2 times the 95th percentile or BMI ≥35 kg/m2) were enrolled in a 6-month, randomized, open-label, crossover, clinical trial consisting of two, 3-month phases: 1) a control phase of lifestyle modification and 2) a drug phase of lifestyle modification plus exenatide. Participants were equally randomized to phase-order (i.e., starting with control or drug therapy) then crossed-over to the other treatment. BMI, body fat percentage, blood pressure, lipids, oral glucose tolerance (OGTT), adipokines, plasma biomarkers of endothelial activation, and endothelial function were assessed at baseline, 3-, and 6-months. The mean change over each 3-month phase was compared between treatments. Compared to control, exenatide significantly reduced BMI (−1.7 kg/m2, 95% CI (−3.0, −0.4), P = 0.01), body weight (−3.9 kg, 95% CI (−7.11, −0.69), P = 0.02), and fasting insulin (−7.5 mU/L, 95% CI (−13.71, −1.37), P = 0.02). Significant improvements were observed for OGTT-derived insulin sensitivity (P = 0.02) and beta cell function (P = 0.03). Compliance with the injection regimen was excellent (≥94%) and exenatide was generally well-tolerated (the most common adverse event was mild nausea in 36%). These preliminary data suggest that exenatide should be evaluated in larger, well-controlled trials for its ability to reduce BMI and improve cardiometabolic risk factors in youth with extreme obesity.
Aims There are no treatments for the extreme hyperphagia and obesity in Prader-Willi syndrome (PWS). The bestPWS trial assessed the efficacy, safety, and tolerability of the methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib. Materials and Methods Participants with PWS (12–65 years) were randomly assigned (1:1:1) to biweekly placebo, 1.8 mg beloranib, or 2.4 mg beloranib injection for 26 weeks at 15 US sites. Coprimary endpoints were the changes in hyperphagia (measured by Hyperphagia Questionnaire for Clinical Trials [HQ-CT]; possible score 0–36) and weight by intention-to-treat. ClinicalTrials.gov registration: NCT02179151. Results 107 were included in the intention-to-treat analysis: placebo (n=34), 1.8 mg beloranib (n=36), or 2.4 mg beloranib (n=37). Improvement (reduction) in HQ-CT total score was greater in the 1.8 mg (mean difference −6.3, 95% CI −9.6 to −3.0; p=0.0003) and 2.4 mg beloranib groups (−7.0, 95% CI −10.5 to −3.6; p=0.0001) vs placebo. Compared to placebo, weight change was greater with 1.8 mg (mean difference −8.2%, 95% CI −10.8 to −5.6; p<0.0001) and 2.4 mg beloranib (−9.5%, 95% CI −12.1 to −6.8; p<0.0001). Injection site bruising was the most frequent adverse event with beloranib. Dosing was stopped early due to an imbalance in venous thrombotic events in beloranib-treated participants (two fatal events of pulmonary embolism and two events of deep vein thrombosis) compared to placebo. Conclusions MetAP2 inhibition with beloranib produced statistically significant and clinically meaningful improvements in hyperphagia-related behaviors and weight loss in participants with PWS. Although investigation of beloranib has ceased, inhibition of MetAP2 is a novel mechanism for treating hyperphagia and obesity.
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