Results from a phase 3 trial, Evaluation of Liraglutide in Pediatrics with Diabetes (Ellipse), investigating liraglutide use in youth.
With the rise of the incidence of type 2 diabetes in children and adolescents, often driven by childhood obesity, it is essential to investigate treatment options for these groups. Metformin is the most common treatment for youth, but when there is a rapid decline in beta-cell function as well as severe insulin resistance metformin alone may not be enough. The only other drug class approved in this population is insulin, mainly due to a lack of trials in youth. Now with regulatory agencies mandating new drugs for type 2 diabetes also undergo efficacy and safety trials for youth, liraglutide, a glucagon-like peptide-1 analog, phase 3 trial results are reported.
The Evaluation of Liraglutide in Pediatrics with Diabetes (Ellipse) was a phase 3 trial of liraglutide that was launched in 2012 and completed in 2018. The trial aimed to confirm the superiority of liraglutide to placebo in controlling blood sugar in children and adolescents when added to treatment with metformin with or without insulin. The trial design was a randomized, parallel-group, placebo-controlled trial with a 26-week double-blind period followed by a 26-week open-label extension period. Patients were 10-17 years old, had type 2 diabetes, glycated hemoglobin levels between 7.0%-1.0% if they were being treated with diet and exercise alone, or between 6.5%-11.0% if being treated with metformin (with or without insulin), and had a BMI higher than the 85th percentile. Patients were either already taking metformin or were titrated to the maximum tolerated dose (1000mg to 2000mg/day for most patients), and patients who were being treated with insulin had to have been on a stable dose for at least eight weeks. Patients were then randomly assigned (1:1) to receive subcutaneous liraglutide or placebo for 26 weeks, in combination with metformin, with or without basal insulin, and on a diet and exercise regimen. The liraglutide dose started at 0.6mg/day and was titrated as tolerated for three weeks. After 26 weeks, the treatment assignment was unblinded and the trial continued for 26 more weeks. During this open-label period, patients assigned to liraglutide continued this treatment and the patients assigned to placebo discontinued the placebo injection but continued metformin (with or without basal insulin). The primary efficacy endpoint was the change from baseline in HbA1C at week 26. Secondary efficacy endpoints were the change in fasting plasma glucose from baseline, the percentage of patients who reached HbA1C of less than 7.0%, the change from baseline in the BMI z score, change in body weight, fasting lipid levels, systolic & diastolic blood pressure. The study required 47 patients in each group to achieve 80% power. The pattern-mixture model was utilized in the primary statistical analysis. Post hoc analyses of the primary endpoint and two of the confirmatory secondary endpoints were performed, and logistic regression was used to analyze the proportion of patients attaining specified glycated hemoglobin levels.
The study included 134 patients who received at least one dose of liraglutide (66 patients) or placebo (68 patients). 87.4% in the treatment group, and 84.1% in the placebo group, completed the 26 weeks of treatment. The mean glycated hemoglobin levels at week 26 were reduced by 0.64 from baseline in the treatment group vs. being raised by 0.42 in the placebo group (estimated treatment difference, −1.06 percentage points; 95% confidence interval [CI], −1.65 to −0.46; P<0.001), yielding that liraglutide is superior to placebo. The findings were consistent at week 52 (−1.30 percentage points; 95% CI, −1.89 to −0.70). All sensitivity analyses were consistent with the primary analysis. Liraglutide was also superior in reducing plasma glucose levels at weeks 26 and 52. The treatment group also had a more significant percentage of patients achieving a glycated hemoglobin level of less than 7.0% (63.7% vs. 36.5% p<0.001). Change in BMI z score, SBP/DBP, and change in VLDL levels did not show a significant difference between the groups. The rate of adverse events was higher in the treatment group, nausea being the most common.
Results from this trial show that liraglutide is a useful option in lowering HbA1C, as well as fasting blood glucose levels. The fact that this study did not show a difference in BMI z scores, as liraglutide has with adults, was unexpected. This could be due to patients being unable to achieve the target dose of 1.8mg and the smaller sample size. The results of this study can help aid health care professionals in the treatment of type 2 diabetes in children and adolescents.
- Patients in the Treatment group were unable to achieve the target dose of 1.8mg, which could be responsible for not seeing a reduction in BMI.
- Mean glycated hemoglobin levels at week 26 were reduced by 0.64 from baseline in the treatment group vs. being raised by 0.42 in the placebo group.
- Results from this trial show that liraglutide is a useful option in lowering HbA1C.
Reference for “Liraglutide Use in Youth with Type 2 Diabetes “:
Tamborlane WV, Barrientos-Pérez M, Fainberg U, Frimer-Larsen H, Hafez M, Hale PM, Jalaludin MY, Kovarenko M, Libman I, Lynch JL, Rao P, Shehadeh N, Turan S, Weghuber D, Barrett T; Ellipse Trial Investigators. Liraglutide in Children and Adolescents with Type 2 Diabetes. N Engl J Med. 2019 Aug 15;381(7):637-646. doi: 10.1056/NEJMoa1903822.
Alessa Grieff, PharmD Candidate, University of South Florida College of Pharmacy