Liraglutide effects in a paediatric (7-11 y) population with obesity: A randomized, double-blind, placebo-controlled, short-term trial to assess safety, tolerability, pharmacokinetics, and pharmacodynamics

Abstract

Background: Childhood obesity is a major public health concern with limited treatment options.

Objective: The aim of this study was to assess safety, tolerability, pharmacokinetics, and pharmacodynamics during short-term treatment with liraglutide in children (7-11 y) with obesity.

Methods: In this randomized, double-blind, placebo-controlled trial, 24 children received at least one dose of once-daily subcutaneous liraglutide (n = 16) or placebo (n = 8) starting at 0.3 mg with weekly dose escalations up to 3.0 mg or maximum tolerated dose, and 20 children completed the trial (14 in the liraglutide group and six in the placebo group). The primary endpoint was the number of adverse events.

Results: Baseline characteristics (mean ± standard deviation) included the following: age 9.9 ± 1.1 years, weight 71.5 ± 15.4 kg, and 62.5% male. Thirty-seven adverse events were reported in nine liraglutide-treated participants (56.3%) versus 12 events in five placebo-treated participants (62.5%). Most adverse events were mild in severity, three were of moderate severity, and none were severe. Gastrointestinal disorders were the most frequently reported events occurring in 37.5% of liraglutide-treated participants compared with placebo (12.5%). Six asymptomatic hypoglycaemic episodes occurred in five participants of whom four were liraglutide treated. Liraglutide exposure was consistent with dose proportionality. Body weight was the only covariate to significantly impact exposure. A significant reduction in body mass index (BMI) Z score from baseline to end of treatment (estimated treatment difference: -0.28; P = 0.0062) was observed.

Conclusion: Short-term treatment with liraglutide in children with obesity revealed a safety and tolerability profile similar to trials in adults and adolescents with obesity, with no new safety issues.

Keywords: Clinical trial; GLP-1; liraglutide; paediatric.

Figure 1

Timing and duration of selected gastrointestinal (GI) adverse events (AEs) with liraglutide. The doses shown are those at the start of the event. Individual square boxes indicate the day of AE onset and could have ranged from <1 min to 24 h. There were no AEs of nausea, vomiting, or upper abdominal pain reported in participants treated with placebo. Numbers on the y axis designate individual participants. Two participants (participants 3 and 4) each used one optional week and were treated with liraglutide 0.9 mg d⁻¹ for 2 wk before further dose escalation. One participant (participant 6) reached a maximum dose of liraglutide 2.4 mg d⁻¹ using one optional week and remained at this dose for 3 wk. All GI AEs were mild in severity with the exception of vomiting of moderate severity in participant 6. No participants were treated beyond 8 wk

Figure 2

Dose‐normalized average concentrations in children, adolescents, and adults (A) before and (B) after adjustment for differences in body weight. Individual data points are represented by shaded rectangles. Squares indicate geometric mean model–based estimates of the average concentration in steady state with 95% CI for each trial assuming full compliance to liraglutide 3.0 mg treatment. Data in (B) are adjusted on the basis of individual body weights. Mean body weights are shown. Data are from the current trial in children and previous clinical pharmacology trials in adolescents21 and adults.22 BW, body weight; C _avg, estimated average plasma liraglutide concentration in a dosing interval at steady state; CI, confidence interval; N, number of participants analysed