Liraglutide's Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics in Pediatric Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Trial

Abstract

Background: The prevalence of type 2 diabetes (T2D) in youth is increasing. Treatment options beyond metformin and insulin are needed. The safety, tolerability, pharmacokinetics, and pharmacodynamics of liraglutide once daily in youth (10-17 years old) with T2D were investigated in a randomized, double-blind, placebo-controlled trial. Subjects and Methods: Youth treated with diet/exercise alone or with metformin and having a hemoglobin A 1c (HbA 1c ) level of 6.5-11% were randomized to liraglutide (n = 14) or placebo (n = 7). Starting at 0.3 mg/day, doses were escalated weekly to 0.6, 0.9, 1.2, and 1.8 mg/day (or placebo equivalent) for 5 weeks. Results: Nineteen participants completed the trial. Baseline characteristics were similar between groups, with mean (SD) values for age of 14.8 (2.2) years, weight of 113.2 (35.6) kg (range, 57-214 kg), diabetes duration of 1.7 (1.4) years, and HbA 1c level of 8.1% (1.2%). No serious adverse events (AEs), including severe hypoglycemia, occurred. Transient gastrointestinal AEs were most common at lower liraglutide doses during dose escalation. No significant changes in safety and tolerability parameters occurred. There was no evidence of pancreatitis or lipase elevations above three times the upper normal limit; calcitonin levels remained within the normal range. For liraglutide 1.8 mg, mean half-life was 12 h, and clearance was 1.7 L/h. After 5 weeks, the decline in HbA 1c level was greater with liraglutide versus placebo (-0.86 vs. 0.04%, P = 0.0007), whereas mean body weight remained stable ( -0.50 vs. -0.54 kg, P = 0.9703). Conclusions: Liraglutide was well tolerated in youth with T2D, with safety, tolerability, and pharmacokinetic profiles similar to profiles in adults.

Liraglutide: A Review of Its Use in Adult Patients with Type 2 Diabetes Mellitus

“…The pharmacokinetic profile of liraglutide (0.6-1.8 mg/day) in paediatric patients (aged 10-17 years) with type 2 diabetes was similar to historical data in adults with type 2 diabetes [19]. In a single-dose study in patients with varying degrees of hepatic impairment, exposure to liraglutide was slightly lower in those with mild or moderate hepatic impairment compared with healthy volunteers, but significantly lower (&43 %) in those with severe hepatic impairment (Child-Pugh score [9) [12,13].…”

ISPAD Clinical Practice Consensus Guidelines 2018: Type 2 diabetes mellitus in youth

“…The side effects generally decrease over time. Besides a single publication of the pharmacodynamics and the pharmacokinetics of liraglutide in adolescents with T2DM, there are no published studies of efficacy and safety of incretin mimetics in youth T2D, but several are currently underway.…”

Clinical Pharmacokinetics and Pharmacodynamics of Antihyperglycemic Medications in Children and Adolescents with Type 2 Diabetes Mellitus

“…A long-acting Glucagon-like peptide-1 (GLP-1) receptor agonist is used off-label in T2DM youth [45] In a publication by Klein et al, liraglutide administration was compared to placebo in T2DM adolescents, aged 10–17 years, who were treated with diet/exercise alone or with metformin [46] . No serious adverse effects were observed, including severe hypoglycemia.…”

“…No serious adverse effects were observed, including severe hypoglycemia. Mild gastrointestinal side effects were more common in the liraglutide group [47] although unlike adult, no weight loss was observed in this population [45] . A subsequent efficacy and safety trial of liraglutide compared to metformin is currently recruiting participants within the pediatric population (clinicaltrials.gov: NCT01541215).…”

“…Liraglutide pharmacokinetics in youth were comparable to the adult and showed linear dose-concentration relationship. For a 1.8 mg dose, liraglutide tmax was 8 hour, half-life was 12 hour and apparent clearance was 1.7 L/h [47] . Population pharmacokinetics analysis was used to compare liraglutide pharmacokinetics obtained from one pediatric trial with two adult trials [77] .…”