BMI standard deviation score reduced by GLP-1RA in obese adolescents
A Randomized, Controlled Trial of Liraglutide for Adolescents with Obesity
Introduction and methods
There is a need for effective, durable and safe interventions early in life for persons with obesity, as currently more than 70% of persons who have obesity before puberty will also have obesity during adulthood [1-3]. Liraglutide is a glucagon-like peptide 1 receptor agonist (GLP-1RA) that increases the postprandial insulin level in a glucose-dependent manner, reduces glucagon secretion and delays gastric emptying. It also reduces appetite and energy intake and thereby induces weight loss [4,5]. The FDA and EMA have approved liraglutide (3.0 mg) as an adjunct to lifestyle therapy in adults with obesity or overweight with ≥1 weight-related coexisting condition [6,7]. This study investigated the efficacy and safety of subcutaneous liraglutide (3.0 mg) as an adjunct to lifestyle therapy in pubertal adolescents with obesity.
This randomized, double-blind, placebo-controlled, phase 3 trial was conducted at 32 sites in 5 countries (Belgium, Mexico, Russia, Sweden and the United States). It was composed of a 12-week run-in period, a 56-week treatment period (with dose escalation over a period of 4 to 8 weeks) and a 26-week follow-up period without treatment. 251 Pubertal adolescents (12 to <18 years of age) with obesity were randomized to receive liraglutide (3.0 mg, n=125) or placebo (n=126) administered subcutaneously once daily. The starting dose of the liraglutide treatment was 0.6 mg daily for 1 week and the dose was increased weekly until the maximum tolerated dose or the 3.0 mg dose was reached. Obesity was defined as a BMI corresponding to an adult value of ≥30 and in the ≥95th percentile for age and sex. Participants were required to a have a stable (self-reported) body weight and poor response to lifestyle therapy alone. Persons with type 1 diabetes were excluded, but those with T2DM were eligible to participate.
The primary endpoint was change from baseline in the BMI standard-deviation score at week 56. This score is a measure of the number of standard deviations from the population mean BMI, matched for age and sex.
- Treatment with liraglutide led to a greater reduction in the BMI standard-deviation score at week 56 compared to placebo, with an estimated treatment difference of -0.22 (95%CI -0.37 to -0.08, P=0.002).
- Relative change in BMI was greater in the liraglutide group compared to the placebo group with an estimated treatment difference of -4.64 percentage points (95%CI -7.14 to -2.14).
- A reduction in BMI of ≥5% was observed in 43.3% of participants in the liraglutide group and in 18.7% of participants in the placebo group. A reduction in BMI of ≥10% was observed in 26.1 vs. 8.1%, respectively.
- A greater reduction was reported in the liraglutide group compared to the placebo group at week 56 in the following endpoints: BMI reported as a percentage of the 95th percentile (estimated treatment difference -6.24 percentage points, 95%CI -9.70 to -2.97), body weight (estimated treatment difference -4.50 kg [95%CI -7.17 to -1.84] for absolute change and -5.01 percentage points [95%CI-7.63 to -2.39] for relative changes) and waist circumference (-2.93 cm [95%CI -5.24 to -0.63]).
- 111 Participants (88.8%) in the liraglutide group and 107 participants (84.9%) in the placebo group reported adverse events. The most frequently reported adverse events in the liraglutide group were gastrointestinal events, including nausea, vomiting and diarrhea (occurring in 81 participants [64.8%] in the liraglutide group and in 46 participants [36.5%] in the placebo group, P<0.001). Gastrointestinal events occurred primarily during the liraglutide dose escalation period (4 to 8 weeks of the treatment period). Discontinuation of the treatment occurred in 13 participants in the liraglutide group, and in none in the placebo group (P<0.001). Discontinuation due to gastrointestinal events was reported in 10 participants. Serious adverse events occurred in 3 participants (3 events) in the liraglutide group and in 5 participants (6 events) in the placebo group.
- More hypoglycemic episodes occurred in the liraglutide group compared with the placebo group (26 vs. 18), but none of the episodes was considered severe according to the American Diabetes Association-International Society for Pediatric and Adolescent Diabetes classifications.
- No substantial difference was found between treatment groups in change in glycemic and cardiometabolic variables, overall weight-related quality of life, growth or pubertal development, and mean bone age.
Treatment with liraglutide plus lifestyle therapy led to a greater reduction in the BMI standard-deviation score compared to placebo plus lifestyle therapy in adolescents with obesity. Gastrointestinal adverse events, including nausea, vomiting and diarrhea, occurred more frequently in the liraglutide group compared to the placebo group, which suggests that treatment with liraglutide may not suitable for all patients.