Children and adolescents with Type 2 diabetes, already taking metformin (with or without insulin) showed improvement in blood sugar control with the addition of liraglutide compared to similar patients who did not receive the treatment, according to a new phase 3 trial.
William V. Tamborlane, MD, with the Department of Pediatrics, Yale University, New Haven, CT, and colleagues reported their findings in the August 15, 2019 issue of The New England Journal of Medicine.
Metformin, a biguanide antihyperglycemic is first-line therapy for pediatric Type 2 diabetes. Several studies have shown that patients experience continued worsening in β-cell function and glycemic control, eventually requiring additional treatment. The only approved drug class for add-on therapy in the pediatric population is insulin, which is used in over half of patients within a few years of starting metformin. While many drug classes are available for adults, trials specifically proving safety and efficacy in the pediatric population are required for approval.
The glucagon-like peptide-1 (GLP-1) receptor agonists have been used in the treatment of adult Type 2 diabetes for over ten years. Liraglutide, one such GLP-1 receptor agonist, was studied in a pediatric phase 2 trial and demonstrated the safety and tolerability of the adult dose range. It is unclear, however, if liraglutide is safe and effective in a pediatric Type 2 diabetes population already taking metformin.
This study, called Ellipse (Evaluation of Liraglutide in Pediatrics with Diabetes), is a phase 3, randomized, placebo-controlled trial. Patients were between 10 and 17 years of age, had a body-mass index (BMI) greater than the 85th percentile, and had glycated hemoglobin levels between 7.0 and 11.0% if they were treated with diet and exercise alone, or between 6.5 and 11.0% if they were treated with metformin (with or without insulin). 135 patients were randomized (134 of whom received at least one dose of study drug or placebo) to receive subcutaneous liraglutide, at standard dose adjustments, or placebo for 26 weeks. The trial was continued for another 26-week open-label period in which the liraglutide group continued treatment, and the placebo group discontinued the placebo. 90.9% of patients in the liraglutide group and 84.1% in the placebo group completed 26 weeks of treatment, and 84.8% of patients in the liraglutide group and 76.8% in the placebo group completed 52 weeks. After the third week of the trial (dose escalation period), 55.6% of the liraglutide group and 72.7% of the placebo group reached the maximum dose of 1.8 mg. The mean changes in glycated hemoglobin were compared between groups.
Measured at week 26, the mean glycated hemoglobin level decreased by 0.64 percentage points in the liraglutide group and increased by 0.42 percentage points in the placebo group (between-group difference -1.06 percentage points; 95% confidence interval [CI], -1.65 to -0.46; P<0.001). At week 52, the difference in mean glycated hemoglobin levels was increased (-1.30 percentage points; 95% [CI], -1.89 to -0.70). Secondary outcomes showed liraglutide is superior to placebo in reducing fasting plasma glucose levels, and in the number of patients reaching a glycated hemoglobin level of less than 7.0%. Unexpectedly, no difference was observed between groups in body weight or BMI score at week 26 (differences have been observed in adult trials of liraglutide).
The rate of adverse events was higher in the liraglutide group, mainly due to gastrointestinal complaints. Nausea and vomiting were the most frequently reported, however, all adverse events were reportedly mild. Hypoglycemia was also observed more frequently in the liraglutide group, but no episodes were reported as severe. One severe hypoglycemic episode did occur in the placebo group, in a patient taking insulin.
The study authors note that although the trial showed the safety and efficacy of liraglutide, a few aspects of the trial may be somewhat limiting. The relatively small number of patients in the trial may help explain the lack of difference in body weight and BMI between groups at week 26. The dosing schedule used may explain why only about one-half of the study patients received the highest dose of liraglutide. Also, the lack of diversity in the trial population may make the results difficult to generalize to other populations. Further studies will be required to help clarify these issues.
The study was funded by Novo Nordisk.
Tamborlane, WV, et al. Liraglutide in children and adolescents with type 2 diabetes. N Engl J Med. 2019; 381:637-46.