medwireNews: The Ellipse investigators report improved glycemic control at the price of early and mostly mild gastrointestinal events in children and adolescents with type 2 diabetes.
During 26 weeks of treatment, glycated hemoglobin (HbA1c) levels fell by 0.64 percentage points from a baseline of 7.87% (63 mmol/mol) in the 66 children, aged 10 to 16 years, who were randomly assigned to receive the glucagon-like peptide-1 receptor agonist.
By contrast, average HbA1c in the 68 children receiving placebo injections increased by 0.42 percentage points from a baseline of 7.69% (61 mmol/mol), giving an estimated treatment difference of 1.06 percentage points in favor of liraglutide.
Speaking to medwireNews, study author William Tamborlane (Yale University, New Haven, Connecticut, USA) described the trial as “transformational.”
He stressed that the only medication currently approved by the regulatory agencies as an add-on therapy after metformin is insulin, “and insulin does not do well in this population.”
He said: “That’s why this is such an important study: it’s the first successful trial that is required for the regulatory agencies to approve an additional new drug for treatment of kids with type 2 – this is the first one since metformin.”
As reported in The New England Journal of Medicine, the trial participants had been diagnosed with type 2 diabetes an average of 1.9 years prior to enrollment. All were using metformin, titrated to the maximum tolerated dose during an 11- to 12-week run-in period, and 18.7% were using insulin.
Liraglutide also significantly reduced fasting glucose levels relative to placebo, and significantly more participants achieved their HbA1c target of 7.0% (53 mmol/mol) or lower, at 63.7% versus 36.5%. The treatment difference in HbA1c levels in favor of liraglutide increased further during an additional 26 weeks of open-label treatment, to 1.30 percentage points.
The average baseline BMI standard deviation score (SDS) was 3.03 in the liraglutide group and 2.86 in the placebo group. During the blinded phase of the trial this decreased in both groups, by a respective 0.25 and 0.21, but the difference between the two did not attain statistical significance, despite the known weight-reducing effects of liraglutide in adults with diabetes.
Tamborlane believes that slow liraglutide dose titration might explain this finding. All participants in the liraglutide group started on a dose of 0.6 mg/day, increasing to 1.2 mg/day and then 1.8 mg/day (the adult dose) if needed, but only 53.6% were on the highest dose by week 48, with 28.6% achieving glucose control on the lowest dose. Weight loss with liraglutide is dose-dependent; the approved dose specifically for weight loss in adults is 3.0 mg/day.
“So it may have been that for caution dealing with kids they didn’t push on to the highest dose, which is the standard in adults, and that may explain why they did not have as much weight loss,” said Tamborlane.
The only adverse effects to occur significantly more often in the liraglutide than placebo groups were gastrointestinal events, specifically nausea and vomiting (28.8 vs 13.2 and 25.8 vs 8.8%, respectively), but Tamborlane described these as “relatively early and relatively mild, and very similar to what you would see when we start someone on metformin.”
Hypoglycemia was also significantly more frequent with liraglutide than placebo (45.5 vs 25.0%), but there were no severe episodes.
Findings from research such as the TODAY and RISE studies have suggested a more aggressive disease course when type 2 diabetes is diagnosed in youth or young adults. Although Tamborlane agrees that the condition does “move along from one stage to the next more quickly” in these young people, he disputes the notion that it represents a different process, saying that, fundamentally, “it is still severe insulin resistance and aggressive beta-cell failure.”
And he said: “I think that one of the problems with getting new drugs approved for pediatrics is actually us pediatricians, by trying to emphasize that the disease is so different from adults in type 2.”
This in turn, he believes “has limited the ability of the regulatory agencies to extrapolate efficacy for all these drugs that have been used in adults,” meaning that the options for children with type 2 diabetes remain extremely restricted, not helped by heightened concerns around testing medications in children.
Tamborlane added: “My own personal view is that the regulatory agencies are very picky, almost nit-picky, on different subtle aspects of the trial; meanwhile, there’s kids who are sitting here with an A1c of 14, not getting the opportunity to see if they would benefit from these newer drugs.”
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