A Randomized, Controlled Trial of Liraglutide for Adolescents with Obesity

Literature - Kelly AS, Auerbach P, Barrientos-Perez M et al., - N Engl J Med. 2020. doi: 10.1056/NEJMoa1916038.

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.

Main results

• 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.

Conclusion

References

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