BALTIMORE — Liraglutide (Victoza) added to metformin, with or without basal insulin, significantly improved glycemic control in adolescents with type 2 diabetes versus placebo, according to results from the Ellipse trial.
In a sample of 134 children (ages 10-17 years), liraglutide plus metformin demonstrated a 0.64 percentage point decrease in mean glycated hemoglobin levels at 26 weeks versus 0.42 percentage points for placebo (difference -1.06, 95% CI -1.65 to -0.46, P<0.001), reported William Tamborlane, MD, of Yale University in New Haven, Connecticut, and colleagues.
Fasting plasma glucose levels also decreased at 26 weeks and 52 weeks versus placebo, and more patients in the liraglutide group versus placebo attained glycated hemoglobin levels <7% (63.7% vs 36.5%, respectively), they wrote in the New England Journal of Medicine. The results were simultaneously presented at the Pediatric Academic Societies annual meeting.
However, “This efficacy came at the cost of an increased frequency of gastrointestinal adverse events,” the authors noted.
“The one and only drug formally tested in children with type 2 diabetes was metformin, and that study ended in 1999…the paper that was published with the results was in 2002,” Tamborlane told MedPage Today. “When you turn on the TV, there are advertisements for Invokana [canagliflozin] and Victoza, and all these drugs for type 2 diabetes, but none of them have been successfully tested in children.”
The American Diabetes Association recommends asymptomatic children with type 2 diabetes who have HbA1c levels <8.5% receive metformin as a first-line treatment. If patients have a blood glucose >250 mg/dL or HbA1c levels ≥8.5% and suffer from weight loss, the guidelines recommend additional insulin. But if these two pharmacologic agents fail, there are few options available.
Unlike insulin, which can cause weight gain, liraglutide can also help with weight loss, said Mary Ellen Vajravelu, MD, of the Children’s Hospital of Philadelphia, who was not involved in this study. She added that it would be interesting to see if a once-weekly GLP-1 receptor agonist could achieve a similar efficacy and safety profile in this population.
“Metformin has some problems with tolerability sometimes, and there are also GI side effects associated with that medicine, so having an additional option out there is going to be really helpful,” Vajravelu told MedPage Today.
A similar number of patients in Ellipsis experienced adverse events (AEs) between groups, although the rate of AEs per 1 patient-year of exposure was higher in the liraglutide group versus placebo (7.1 vs 5.4, relative risk 1.05, 95% CI 0.90-1.22), the authors reported.
These were mainly GI in nature, with patients receiving liraglutide most commonly experiencing vomiting (25.8%), nausea (28.8%), diarrhea (22.7%), and headache (21.2%).
An “unexpected finding” was that no difference was observed in BMI z score between the liraglutide and placebo groups (difference -0.05, 95% CI -0.15 to 0.06, P=0.39), although “the fact that some children were probably still growing may explain the findings,” the authors reported.
In the trial, 66 patients in the active arm initiated liraglutide at a dose of 0.6 mg per day, which was increased in increments of 0.6 mg per week across a 3-week dose-escalation period to a maximum 1.8 mg per day. However, patients with a fasting plasma glucose ≤110 mg/dL in the 3 consecutive days before returning for another dose did not increase their dose.
If patients received basal insulin, it was reduced by 20% when patients initiated the trial, but could be returned to its baseline level after the dose-escalation period.
Children with a BMI >85th percentile who were being treated with diet and exercise alone were included if their hemoglobin levels were between 7%-11%. Children taking metformin were included if their levels were between 6.5%-11%, regardless of whether they were also on insulin. They were excluded if they had a fasting C-peptide level <0.6 ng/mL, type 1 diabetes, or a family history of medullary thyroid cancer or multiple endocrine neoplasia 2, the authors noted.
Adolescents involved in the trial were also required to have a fasting plasma glucose level between 126 mg and 220 mg/dL in addition to a stable metformin dose between 1,000 and 2,000 mg per day for at least 8 weeks, they added.
For the total patient population, the mean age was 14.6 years and the average BMI was 33.9. About 62% of the sample was female, 65% were white, and the majority of participants resided in North America (47%) and Europe (34%), although children from 25 countries were included, the authors reported.
Patients were unblinded at 26 weeks and the trial continued as an off-label study, in which about 81% of the liraglutide group and 77% of the placebo group completed treatment to 52 weeks. Here, the efficacy of liraglutide persisted, with a difference of -1.30 percentage points (95% CI -1.89 to -0.70) by 52 weeks observed between groups, they added.
At the time of study conclusion, about 50% of patients received the maximum liraglutide dose, which potentially limited the findings, and may indicate that the dose-escalation schedule was too rapid, Tamborlane’s group noted. Additional study limitations included the long recruitment period and the “somewhat limited” diversity amongst participants.
The study was supported by Novo Nordisk, the U.K. Medical Research Council, the National Institutes of Health Research (NIHR) Translational Research Collaboration for Rare Diseases, and the NIHR Wellcome Clinical Research Facility.
Tamborlane disclosed support from Novo Nordisk, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Eisai, and Takeda. Co-authors disclosed support from Nova Nordisk, AstraZeneca, Servier, Bristol Myers Squib, Merck, Sharpe and Dohme, the Nestle Nutrition Institute, Abbott Nutrition, the NIH, Daiichi Sankyo WELKid, the Pediatric Diabetes Consortium, Boehringer Ingelheim, DiabetOmics Inc, and the European Union.