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Review of: Kelly AS, Auerbach P, Barrientos-Perez M, et al. A randomised, controlled trial of liraglutide for adolescents with obesity. N Engl J Med 2020 May;382:2117–2128. DOI: 10.1056/nejmoa1916038.
Allocation: Central randomisation using a web-based response system. Randomisation was stratified according to pubertal status and glycaemic status.
Setting: 32 sites over five countries (Belgium, Mexico, Russia, Sweden and the USA).
Intervention: All participants received lifestyle therapy. 125 were assigned to liraglutide and 126 assigned to the placebo group, receiving a volume matched equivalent.
Patients: 251 participants, aged 12 to <18 years. All participants were obese (defined as body mass index (BMI) of 30 or more), stable body weight (self-reported change of less than 5 kg during the 90 days before screening) and poor response to lifestyle therapy alone.
Primary outcomes: Change in baseline BMI SD score.
Secondary: Reduction in BMI of at least 5% and 10% at week 56, change from baseline BMI, weight, waist circumference, blood pressure, waist:hip ratio, glucose metabolism, blood pressure and quality of life.
Follow-up: Outcome was measured over a 56-week treatment period. There was a 26-week follow-up period after ceasing treatment.
Main results
The patients who were given liraglutide had a much greater decrease in their BMI at week 56, but then demonstrated a larger increase in weight after the intervention was stopped (weeks 56 to 82).
Conclusion
The use of liraglutide led to a significantly greater reduction in the BMI SD score than placebo, but has no longer-term benefits.
Commentary
The recently published RCPCH State of Child Health report stated that there has been no improvement in childhood obesity, with over 34% of children 10–11 years old in England being overweight or obese in 2018/2019.1 In paediatrics, there is limited use of pharmacological treatments for childhood obesity with little evidence for each treatment option. Orlistat and metformin have been used in specialist clinics with varying success. A recombinant leptin has been used in the treatment of obesity but only for leptin deficiency, which is very rarely seen.
Liraglutide is a glucagon-like peptide-1 (GLP-1 receptor agonist). It works by suppressing appetite and delaying gastric emptying,2 both of which are responsible for causing weight loss. Liraglutide is administered as a once-daily subcutaneous injection and has a half-life of around 13 hours.3
The most important values to look at in this study are the BMI SD scores (SDS) as these numbers would account for the natural rise in BMI values seen throughout normal development, reflected in growth centile charts. This study has demonstrated a statistically significant improvement reducing BMI SDS with liraglutide during treatment phase, but with no longer-term benefits. Once liraglutide was stopped, the BMI SDS in the intervention group increased at a higher rate than the placebo group.
The available treatment options for obesity are associated with significant gastrointestinal side effects. Liraglutide, in particular, has been shown to be a poorly tolerated medication in clinical trials. It has a markedly higher rate of side effects than other pharmacological options. This has led to a large number of patients discontinuing treatment during trial periods, as seen within this study. In addition, these adverse effects can lead to a further deterioration of the child’s quality of life and self-confidence, which has often already been negatively impacted by their significant obesity.
With limited evidence for pharmacological treatments and increasing rates of obesity in childhood, there will be further demand for management options which produce a sustainable improvement in a child’s weight. From this study, liraglutide does not appear to be a suitable adjunctive therapy to use with non-pharmacological methods, such as lifestyle and behavioural management.
Footnotes
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; internally peer reviewed.