Could Liraglutide Stall the Onset of Type 2 Diabetes in Kids?

Doug Brunk

December 16, 2019

LOS ANGELES — Until the recent approval of liraglutide for the treatment of children and adolescents with type 2 diabetes, investigators like Sonia Caprio, MD, were at their wits' end watching the beta-cell function of their patients decline on metformin treatment.

"The kids were not doing well. It was like they were being treated with water," Dr. Caprio, a pediatric endocrinologist at Yale University, New Haven, Conn., said at the annual World Congress on Insulin Resistance, Diabetes and Cardiovascular Disease.

For example, in the NIH-funded TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study that began enrollment in 2004, 699 patients aged between 10 and 17 years and with type 2 diabetes were treated with metformin (1,000 mg, twice daily) to attain a glycated hemoglobin level of less than 8% and were then randomly assigned to continued treatment with metformin alone or to metformin combined with rosiglitazone (4 mg, twice a day) or a lifestyle-intervention program that focused on weight loss through modifying eating and activity behaviors (N Engl J Med.  2012;366:2247-56).

Over the course of 11 months, the researchers found that 46% of the children were failing treatment. "The worst arm was the metformin arm," said Dr. Caprio, who was involved with the study. "Kids were not responding to the drug at all. About 52% of children failed to do better using metformin – a classic drug that we all start kids on when we diagnose them with type 2 diabetes."

Findings from a follow-up study, TODAY2, showed that these young patients were prone to serious diabetes-related events, such as heart attacks, chronic kidney disease, retinal disease, neuropathy, and complications in the offspring of pregnancies.

In addition, results from the RISE (Restoring Insulin Secretion) Pediatric Medication Study found that, in youth with impaired glucose tolerance or recently diagnosed type 2 diabetes, neither 3 months of insulin glargine followed by 9 months of metformin nor 12 months of metformin alone halted the progressive deterioration of beta-cell function (Diabetes Care. 2018;41:1717-25).

"The uniqueness of RISE is that we employed very sophisticated techniques to measure insulin secretion and sensitivity while they were being treated with these usual drugs," said Dr. Caprio, who was one of the study investigators. "The beta cell is unresponsive to metformin and other treatments. The question is, why?"

Despite these findings, 2018 consensus guidelines from the American Diabetes Association on the evaluation and management of youth-onset diabetes (Diabetes Care. 2018;41:2648-68) call for the administration of metformin twice daily in youth with new-onset diabetes who have a hemoglobin A1c (HbA1c) level of less than 8.5%. "I argue that is not the way. We need better ways to treat [these patients] because they are moving fast to having complications," she said.

Enter the Ellipse Trial, a pivotal multicenter, randomized study that evaluated the effect of the glucagonlike peptide-1 receptor agonist liraglutide in children and adolescents with type 2 diabetes (N Engl J Med. 2019;381:637-46).

Researchers, led by William V. Tamborlane, MD, chief of Yale Medicine Pediatric Endocrinology, also in New Haven, randomized 135 patients to one of two arms: 66 to subcutaneous liraglutide (up to 1.8 mg/day) and 69 to placebo for a 26-week, double-blind period, followed by a 26-week open-label extension period. All patients received metformin during the trial. More than half of the study participants (62%) were female, the mean age was 15 years, 65% were white, the mean body mass index was 33.9 kg/m2, their mean fasting glucose was 8.4 mmol/L, and their mean HbA1c was 7.8%.

At 26 weeks, the mean glycated hemoglobin level had decreased by 0.64 percentage points with liraglutide and increased by 0.42 percentage points with placebo, for an estimated treatment difference of −1.06 percentage points (P less than .001). By 52 weeks, the difference increased to −1.30 percentage points.

"There was also a significant drop in BMI z score in patients treated with liraglutide, which is important," Dr. Caprio said. "This medication is having an impact on weight, which is a key driver of the onset of type 2 diabetes in youth. This is a remarkable achievement because weight loss is hard to achieve in obese adolescents, as we showed in the TODAY study."

The number of adverse events reported by patients was similar in the treatment and placebo groups (85% and 81%, respectively), but the overall rates of adverse events and gastrointestinal adverse events were higher with liraglutide.

"I use liraglutide just for weight reduction because I mainly see a lot of kids with obesity. Many kids are not responding because of the GI effects of this drug. I think the weight loss could have been better had the investigators moved to a dose of 1.8 mg, which we use in adults."

A fasting plasma glucose of 6.1 mmol/L was the primary reason for participants remaining on a lower dose of liraglutide, she said. At the same time, liraglutide concentration data indicated a high rate of noncompliance, which was expected in this population. "That's a big problem we face with children," Dr. Caprio said. "Some of them are not constantly taking the medication. They skip doses a lot. But that happens with patients in this age group."

"Finally, we have something else to help children and teenagers to delay the complications we are seeing," Dr. Caprio said. "To me, I think this is a new era. I have hope. It will be interesting to see whether liraglutide and perhaps SGLT2 [sodium-glucose transporter 2] inhibitors can delay the onset of type 2 diabetes in children. In my view, we will be doing this with drugs. I don't think the weight loss [concerns are] going to go away without medication, unfortunately."

Dr. Caprio reported having no financial disclosures.

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