The lack of studies for children and adolescents with type 2 diabetes has led to an absence of approval of new drugs for this patient population. This study reports findings of Liraglutide for youth.
Type 2 diabetes incidence in children and adolescents is on the rise and metformin is the drug of choice. Insulin is the only other drug that is approved for use in this patient population when metformin is not adequate. That is because of the lack of studies in youth for the approval of new drugs. A study published in April, 2019, “Liraglutide in Children and Adolescents with Type 2 Diabetes”, was conducted to determine whether Liraglutide for youth with type 2 diabetes, added to metformin (with or without basal insulin) is safe and effective.
The trial was a randomized, parallel-group, placebo-controlled trial with a 26-week double-blind period followed by a 26-week open-label period where 134 participants ages 10 to 17 at the time of randomization were enrolled. Participants in the study were eligible if they were within the age group, had type 2 diabetes, HA1C between 7% to 11% if they were treated with diet and exercise only, and between 6.5% to 11% if being treated with metformin with or without insulin, and BMI > 85th percentile. The participants eligible entered a run-in period where metformin dose was maximized and maintained at 2000mg per day, and patients that were already receiving higher doses of metformin continued to receive that dose. Participants treated with basal insulin had to be maintained at a stable dose for at least 8 weeks.
The participants enrolled were later randomized (double-blinded) to receive either subcutaneous Liraglutide (n=66) or placebo (n=68) for 26 weeks, with metformin +/- basal insulin and a diet and exercise program and after the 26-week visit, the treatment assignment was un-blinded and participants that have received Liraglutide continued to receive the treatment unchanged, and those that had received placebo discontinued placebo but continued to receive metformin +/- basal insulin, in an open-label period of 26-weeks. Liraglutide was initiated at a dose 0.6mg/day and increased in approximately 0.6mg increments every week for 2 to 3 weeks as tolerated to a maximum dose of 1.8mg/d. The primary efficacy endpoint of the study was the change from baseline in HbA1C at week 26. Secondary efficacy endpoints were the change in fasting plasma glucose levels from baseline, % of patients with HbA1C <7% and change from baseline in BMI z score at week 26.
The primary outcome results indicated the superiority of Liraglutide to placebo where the mean HbA1C change from baseline was reduced by 0.64% in the Liraglutide group and increased by 0.42% in the placebo group at week 26 (estimated treatment difference -1.06%; 95% [CI], -1.65 to -0.46; P<0.001). By week 52, superiority of Liraglutide was also shown as the estimated treatment difference increased to (-1.30%; 95% [CI], -1.89 to -0.70). The reduction of fasting plasma glucose levels was also higher in the Liraglutide group compared with placebo. In addition to that, 63.7% in the Liraglutide group vs 36.5% in the placebo group had achieved HbA1C <7% (P<0.001).
Superiority of Liraglutide in terms of lowering BMI z score was not shown and mean body weight decreased in both groups by week 26 but was maintained by Liraglutide only by week 52 (-1.91kg in Liraglutide vs 0.87kg in placebo group). No between group differences were seen in blood pressure. There was no difference between groups in adverse events occurring or increasing on the start of the study and 7 days after the last day. Rate of adverse events per 1 patient year exposure was higher with Liraglutide possibly due to gastrointestinal events (nausea), mostly mild in severity and have resolved and considered unrelated to Liraglutide or placebo per the investigators. No deaths were reported; however, a higher percentage of serious adverse events have occurred in the Liraglutide group compared with placebo. Hypoglycemia incidence was higher but no severe hypoglycemia episodes were reported with Liraglutide, while one severe hypoglycemia event has occurred in the placebo group in an insulin-treated participant.
- 63.7% of participants in the Liraglutide group achieved HbA1C <7% vs. 35% in the placebo group, i.e. almost twice as many.
- There was no difference in BMI z or body weight loss at week 26 between both groups, but the body weight loss was maintained only by Liraglutide by week 52.
- Liraglutide was superior to placebo in improving glycemic control and lowering fasting plasma glucose at weeks 26 and 52 in children and adolescents with type 2 diabetes with no adequate response to metformin +/- insulin. Liraglutide has shown to be safe in this patient population, however mild gastrointestinal adverse effects have been more commonly reported with Liraglutide.
Reference for Liraglutide for Youth with Type 2 Diabetes:
Tamborlane WV, Barrientos-Perez M, Fainberg U, et al. Liraglutide in Children and Adolescents with Type 2 Diabetes. N ENGL J MED. April, 2019. DOI: 10.1056/NEJMoa1903822
Marian Ayad, BSPharm, PharmD candidate, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences.
For more on diabetes in youth, see our Pediatrics section.