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BALTIMORE – Liraglutide (Victoza, Novo Nordisk) added to metformin (with or without insulin) significantly reduced HbA level1 C levels in obese children and adolescents with type 2 diabetes aged 10 to 16 in a phase III study.
Of these young patients who all received metformin, those who also received liraglutide had better glycemic control at 1 year compared with placebo, although patients treated with liraglutide had more gastrointestinal adverse events than those treated with liraglutide. intestinal and, surprisingly, they did not lose more weight.
William V. Tamborlane, MD, Yale University, New Haven, Connecticut, presented the results of the ELLIPSE trial on a poster presented here at the 2019 meeting of Pediatric Academic Societies (PAS). The study was published simultaneously online in the journal New England Journal of Medicine.
ELLIPSE is the first phase 3 trial completed on children and adolescents with type 2 diabetes for more than 10 years, said Todd Hobbs, MD, vice president and chief medical officer of Novo Nordisk in North America. Medscape Medical News in an email.
The drug could meet "a growing and dissatisfied medical need," he added, as the number of children and adolescents with type 2 diabetes is increasing, because of the increasing rate Obesity in children, but treatment options are limited to metformin and insulin "the wide range of oral and injectable treatments currently approved for adults."
It's a study that "changes the practice," noted Tamborlane in an email to Medscape Medical News, since "metformin quickly fails as monotherapy in children with type 2 diabetes and that insulin is the only second-line drug approved for children with type 2 diabetes."
"The benefits are enormous and the side effects have been generally minor," he summed up with liraglutide.
"The results of the ELLIPSE trial," said Hobbs, "were submitted to the US Food and Drug Administration. [FDA] and European Medicines Agency [EMA] to be evaluated as a potential treatment for children 10 years and older with type 2 diabetes. "
Guest to comment, Silva Arslanian, MD, University of Pittsburgh, Pennsylvania, lead author of a recent position statement from the American Diabetes Association (ADA) on the badessment and management of diabetes mellitus. type 2 in young people, said: "The results observed with liraglutide with regard to the reduction of HbA level1 C and plasma glucose make it a new and effective therapeutic option for young people [type 2 diabetes]. "
"Once this has been approved by the FDA and the EMA, it will change clinical practice as an agent added to metformin with or without insulin," she predicted.
In the meantime, she said: "I can not approve the use not indicated on the labels, but I suspect that some health care providers" will use the drug not indicated on the label some patients.
"A growing and unmet medical need"
The authors write that regulators require that new drugs approved to treat type 2 diabetes in adults be tested for safety and effectiveness in young people.
Previously, a phase 2 trial had shown that liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1), was effective in children with type 2 diabetes at the same doses as those approved in the US. ;adult.
The ongoing phase 3 trial in 25 countries extends this work
From 2012 to 2018, the trial included and randomized 135 patients aged 10 to 10 years. < 17 years old and obese (> 85th percentile for same-age and same-bad peers) with HbA1 C levels from 7.0% to 11.0%, maintained on a diet alone and exercise, or from 6.5% to 11.0% with the addition of metformin or basal insulin monotherapy or in combination.
Patients were randomized to receive daily subcutaneous injections of liraglutide or placebo, as well as 1,000 to 2,000 mg / day of metformin.
The dose of liraglutide was increased from 0.6 mg to 1.2 mg to 1.8 mg, or maximum tolerated dose, during a phase of dose increase for 3 weeks, and then maintained. at a stable dose.
Patients who initially took basal insulin continued to receive it in the liraglutide or placebo groups, with dose adjustment.
All patients also received diet and exercise counseling in accordance with local standards.
At 26 weeks, the patients were non-blind.
Over the next 26 weeks, placebo patients did not receive placebo, but those in the liraglutide group continued to receive liraglutide and all patients also received metformin with or without basal insulin. Patients were allowed to prescribe insulin rescue therapy, if necessary.
Patients in the liraglutide and placebo groups had similar initial characteristics.
On average, they were 14.6 years old and 62% were women. Nearly half of them were registered in North America (47%) and the rest in Europe (34%), Asia (9%) or elsewhere (10%).
About two-thirds were white (65%) and the other Asian (13%), black (12%), Native American or Alaska native (2.2%).
They had an average body mbad index (BMI) of 33.9 kg / m2 and a BMI score of 2.94 (where a BMI score of> +2 standard deviations equates to an adult BMI> 30 kg / m2 and indicates obesity).
No weight loss with liraglutide in adolescents
The main endpoint was the average HbA1 C at 26 weeks, decreasing by 0.64% in the liraglutide group but increasing by 0.42% in the placebo group (P <0.001).
At that time, more patients in the liraglutide group had HbA1 C <7% (64% vs 38%); P <0.001).
Similarly, at 52 weeks, the average HbA1 C decrease of 0.50% in the liraglutide group but increase of 0.80% in the placebo group (P <0.001).
At these two times, fasting plasma glucose levels decreased more in the liraglutide group than in the placebo group.
"An unexpected discovery of this trial," write Tamborlane and colleagues, "was the lack of difference between z score groups or body weight at BMI at week 26, finding that differs from the results trials in adults. "
The z score of BMI at week 26 decreased by 0.25% in the liraglutide group and by 0.21% in the placebo group (P = 0.39).
This may be due to the fact that only about half of the patients in the liraglutide group received the full dose of 1.8 mg / day, according to the researchers, and that the trial included a relatively small number of patients. and that the children were still growing.
"The lack of superiority of liraglutide on lowering BMI and weight is disappointing and contrary to data in adults," Arslanian also said.
"I remain curious about this and wonder if more patients have received the higher dose if it may have been different."
In the 52 weeks, more patients in the liraglutide group experienced side effects than those 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%) and abdominal pain (18%). nasopharyngitis (17%), vertigo (12%) and gastroenteritis (11%).
And more than 5% of patients in the liraglutide group had upper respiratory tract infection, dyspepsia, rash, pyrexia, loss of 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 studies of type 2 diabetes in adults," said Hobbs, "mild gastrointestinal disorders are the leading cause of increased rates of adverse events with the liraglutide, and most adverse events have been resolved with few adverse consequences. "
Minor hypoglycemia occurred in 24% of patients in the liraglutide group (and 10% in the placebo group). Severe hypoglycaemia was not observed in any liraglutide and one placebo group patients.
The study was funded by Novo Nordisk. Tamborlane reported receiving grants from Novo Nordisk and, aside from this study, consulting fees from AstraZeneca, Eli Lilly and Eisai, as well as grants from AstraZeneca, Boehringer Ingelheim and Takeda. The disclosures of other authors are listed with the article. Arslanian has served on a Data Monitoring Committee for AstraZeneca, a Data Security Oversight Committee for Boehringer Ingelheim, and on advisory committees for Eli Lilly, Novo Nordisk and sanofi aventis, and has received research grants from this group. company, Eli Lilly and Novo Nordisk.
N Engl J Med. Posted online 28 April 2019. Article
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