BALTIMORE — Liraglutide (Victoza, Novo Nordisk) added to metformin (with or without insulin) significantly reduced HbA1c levels in obese 10- to 16-year-old children and adolescents with type 2 diabetes in a phase 3 study.
Among these young patients who all received metformin, those who also received liraglutide had better glycemic control at 1 year versus placebo, although liraglutide-treated patients had more gastrointestinal adverse events and surprisingly, did not lose more weight.
William V. Tamborlane, MD, Yale University, New Haven, Connecticut, presented the findings from the ELLIPSE trial in a poster here at the Pediatric Academic Societies (PAS) 2019 Meeting. The study was simultaneously published online in the New England Journal of Medicine.
ELLIPSE is the first completed phase 3 trial in children and adolescents with type 2 diabetes in more than a decade, Todd Hobbs, MD, vice president and chief medical officer for Novo Nordisk in North America, told Medscape Medical News in an email.
The drug may fill "a growing unmet medical need," he added, since the number of children and adolescents with type 2 diabetes is increasing, driven by rising rates of childhood obesity, but treatment options are limited to metformin and insulin in contrast with "the wide range of oral and injectable treatments that are currently approved for adults."
This is a "practice-changing" study, noted Tamborlane in an email to Medscape Medical News, since "metformin fails quickly as monotherapy in type 2 diabetes kids and insulin is the only second-line drug approved for kids with type 2 diabetes."
"The benefits are great, and the adverse events were generally minor" with liraglutide, he summarized.
"The results of the ELLIPSE trial," Hobbs said, "have been submitted to the US Food and Drug Administration [FDA] and European Medicines Agency [EMA] for evaluation as a potential treatment option for children 10 years and above with type 2 diabetes."
Invited to comment, Silva Arslanian, MD, University of Pittsburgh, Pennsylvania, who was lead author of a recent position statement from the American Diabetes Association (ADA) on the evaluation and management of youth-onset type 2 diabetes, said: "The positive results observed with liraglutide with respect to lowering HbA1c and plasma glucose make it a new and effective therapeutic option for youth with [type 2 diabetes]."
"Once it gets FDA and EMA approval, it will change clinical practice as an added agent to metformin with or without insulin," she predicted.
In the meantime, she said, "I cannot endorse off-label use, but I suspect some healthcare providers" will use the drug off-label in certain patients.
"A Growing Unmet Medical Need"
Regulatory agencies require that new drugs that have been approved to treat type 2 diabetes in adults undergo safety and efficacy trials in youth, the authors write.
Previously, a phase 2 trial showed that the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide was effective in children with type 2 diabetes at the same doses approved in adults.
The current phase 3 trial in 25 countries extends this work
From 2012 to 2018, the trial enrolled and randomized 135 patients who were 10 to < 17 years old and obese (> 85th percentile for their peers of the same age and gender) with HbA1c levels of 7.0% to 11.0%, maintained on diet and exercise alone, or 6.5% to 11.0% on added metformin or basal insulin monotherapy or combined therapy.
Patients were randomized to receive daily subcutaneous injections of liraglutide or placebo, along with 1000 to 2000 mg/day of metformin.
The dose of liraglutide was escalated from 0.6 mg to 1.2 mg to 1.8 mg, or maximum tolerated dose, during a 3-week dose-escalation phase, and then maintained at a stable dose.
Patients who were initially on basal insulin continued to receive it in the liraglutide or placebo groups, with dose adjustment.
All patients also received diet and exercise counseling according to local standards.
At 26 weeks, patients were unblinded.
For the next 26 weeks, patients in the placebo group no longer received placebo, but those in the liraglutide group continued to receive liraglutide and all patients also received metformin with or without basal insulin. The patients were allowed prespecified rescue treatment with insulin, if needed.
Patients in the liraglutide and placebo groups had similar baseline characteristics.
On average, they were 14.6 years old and 62% were female. Close to half were enrolled in North America (47%), and the rest were enrolled in Europe (34%), Asia (9%), or elsewhere (10%).
About two thirds were white (65%) and the rest were Asian (13%), black (12%), or American Indian or Alaskan native (2.2%).
They had a mean body mass index (BMI) of 33.9 kg/m2 and a BMI z score of 2.94 (where a BMI z score of > +2 standard deviations is equivalent to an adult BMI > 30 kg/m2 and indicates obesity).
No Weight Loss With Liraglutide in Adolescents
The primary endpoint was mean HbA1c at 26 weeks, which decreased by 0.64% in the liraglutide group but increased by 0.42% in the placebo group (P < .001).
At that time, more patients in the liraglutide than the placebo group had an HbA1c < 7% (64% vs 38%; P < .001).
Similarly, at 52 weeks, mean HbA1c decreased by 0.50% in the liraglutide group but increased by 0.80% in the placebo group (P < .001).
At both times, fasting plasma glucose decreased more in the liraglutide group than in the placebo group.
"An unexpected finding of this trial," Tamborlane and colleagues write, "was the lack of difference between the groups in BMI z score or body weight at week 26, a finding that differs from the results of trials in adults."
The BMI z score at week 26 decreased by 0.25% in the liraglutide group and by 0.21% in the placebo group (P = .39).
This may be because only about half of the patients in the liraglutide group received the full 1.8 mg/day dose, the researchers speculate, and also, the trial included a relatively small number of patients and the children were still growing.
"The lack of superiority of liraglutide in lowering BMI and weight is disappointing and contrary to adult data," Arslanian also noted.
"I remain curious about this, and I wonder if more patients had received the higher dose if this may have been different."
Over the 52 weeks, adverse events occurred in more patients in the liraglutide group than in the placebo group (85% vs 81%).
The most common adverse events in the liraglutide group, occurring in 10% or more of patients, were nausea (29%), vomiting (26%), diarrhea (23%), headache (21%), abdominal pain (18%), nasopharyngitis (17%), dizziness (12%), and gastroenteritis (11%).
And more than 5% of patients in the liraglutide group had upper respiratory infection, dyspepsia, rash, pyrexia, decreased appetite, and constipation.
The most common adverse events in the placebo group were nasopharyngitis (28%), headache (19%), diarrhea (16%), nausea (13%), and upper abdominal pain (12%).
"Similar to adult type 2 diabetes studies," Hobbs said, "mild gastrointestinal complaints were the main cause of increased adverse event rates with liraglutide, and most adverse events resolved with few adverse consequences."
Minor hypoglycemia occurred in 24% of patients in the liraglutide group (and 10% in the placebo group). No patients in the liraglutide group and one in the placebo group had severe hypoglycemia.
The study was funded by Novo Nordisk. Tamborlane has reported receiving grants from Novo Nordisk, and outside this study, consulting fees from AstraZeneca, Eli Lilly, and Eisai, and grants from AstraZeneca, Boehringer Ingelheim, and Takeda. Disclosures of the other authors are listed with the article. Arslanian has served on a data monitoring committee for AstraZeneca, a data safety monitoring board for Boehringer Ingelheim, and advisory boards for Eli Lilly, Novo Nordisk, and sanofi aventis, and has received research grants from Eli Lilly and Novo Nordisk through her institution.
N Engl J Med. Published online April 28, 2019. Article
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Cite this: ELLIPSE: Liraglutide Effective for Diabetes in Adolescents - Medscape - Apr 28, 2019.
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