The Food and Drug Administration's new indication for liraglutide (Saxenda) for weight loss in adolescents with obesity, announced on Dec. 4, received welcome as a milestone for advancing a field that's seen no new drug options since 2003 and boosted by 50% the list of agents indicated for weight loss in this age group.
But liraglutide's track record in adolescents in the key study published earlier in 2020 left some experts unconvinced that liraglutide's modest effects would have much impact on blunting the expanding cohort of teens who are obese.
"Until now, we've had phentermine and orlistat with FDA approval" for adolescents with obesity, and phentermine's label specifies only patients older than 16 years. "It's important that the FDA deemed liraglutide's benefits greater than its risks for adolescents," said Aaron S. Kelly, PhD, leader of the 82-week, multicenter, randomized study of liraglutide in 251 adolescents with obesity that directly led to the FDA's action.
"We have results from a strong, published randomized trial, and the green light from the FDA, and that should give clinicians reassurance and confidence to use liraglutide clinically," said Kelly, professor of pediatrics and codirector of the Center for Pediatric Obesity Medicine at the University of Minnesota in Minneapolis.
An "Unimpressive" Drop in BMI
Sonia Caprio, MD, had a more skeptical take on liraglutide's role with its new indication: "Approval of higher-dose liraglutide is an improvement that reflects a willingness to accept adolescent obesity as a disease that needs treatment with pharmacological agents. However, the study, published in New England Journal of Medicine, was not impressive in terms of weight loss, and more importantly liraglutide was not associated with any significant changes in metabolic markers" such as insulin resistance, high-sensitivity C-reactive protein, lipoproteins and triglycerides, and hemoglobin A1c.
The observed average 5% drop in body mass index seen after a year on liraglutide treatment, compared with baseline and relative to no average change from baseline in the placebo arm, was "totally insufficient, and will not diminish any of the metabolic complications in youth with obesity," commented Caprio, an endocrinologist and professor of pediatrics at Yale University in New Haven, Conn.
Results from the study led by Kelly also showed that liraglutide for 56 weeks cut BMI by 5% in 43% of patients, and by 10% in 26%, compared with respective rates of 19% and 8% among those in the placebo-control arm. He took a more expansive view of the potential benefits from weight loss of the caliber demonstrated by liraglutide in the study.
"In general, we wait too long with obesity in children; the earlier the intervention the better. A 3% or 4% reduction in BMI at 12 or 13 years old can pay big dividends down the road" when a typical adolescent trajectory of steadily rising weight can be flattened, he said in an interview.
Bariatric and metabolic surgery, although highly effective and usually safe, is seen by many clinicians, patients, and families as an "intervention of last resort," and its very low level of uptake in adolescents bears witness to that reputation. It also creates an important niche for safe and effective drugs to fill as an adjunct to lifestyle changes, which are often ineffective when used by themselves. Liraglutide's main mechanism for weight loss is depressing hunger, Kelly noted.
Existing Meds Have Limitations
The existing medical treatments, orlistat and phentermine, both have significant drawbacks that limit their use. Orlistat (Xenical, Alli), FDA approved for adolescents 12-16 years old since 2003, limits intestinal fat absorption and as a result often produces unwanted GI effects. Phentermine's approval for older adolescents dates from 1959 and has a weak evidence base, its label limits it to "short-term" use that's generally taken to mean a maximum of 12 weeks. And, as a stimulant, phentermine has often been regarded as potentially dangerous, although Kelly noted that stimulants are well-accepted treatments for other disorders in children and adolescents.
Liraglutide gives adolescents with obesity an edge in managing weight loss.
"The earlier we treat obesity in youth, the better, given that it tends to track into adulthood," agreed Caprio. "However, it remains to be seen whether weight reduction with a pharmacological agent is going to help prevent the intractable trajectories of weight and its complications. So far, it looks like surgery may be more efficacious," she said in an interview.
Another drawback for the near future with liraglutide will likely be its cost for many patients, more than $10,000/year at full retail prices for the weight-loss formulation, given that insurers have had a poor record of covering the drug for this indication in adults, both Caprio and Kelly noted.
Compliance with liraglutide is also important. Kelly's study followed patients for their first 26 weeks off treatment after 56 weeks on the drug, and showed that on average weights rebounded to virtually baseline levels by 6 months after treatment stopped.
Obesity Treatment Lasts a Lifetime
"Obesity is a chronic disease, that requires chronic treatment, just like hypertension," Kelly stressed, and cited the rebound seen in his study when liraglutide stopped as further proof of that concept. "All obesity treatment is lifelong," he maintained.
He highlighted the importance of clinicians discussing with adolescent patients and their families the prospect of potentially remaining on liraglutide treatment for years to maintain weight loss. His experience with the randomized study convinced him that many adolescents with obesity are amenable to daily subcutaneous injection using the pen device that liraglutide comes in, but he acknowledged that some teens find this off-putting.
For the near term, Kelly foresaw liraglutide treatment of adolescents as something that will mostly be administered to patients who seek care at centers that specialize in obesity management. "I'll think we'll eventually see it move to more primary care settings, but that will be down the road."
The study of liraglutide in adolescents was sponsored by Novo Nordisk, the company that markets liraglutide (Saxenda). Kelly has been a consultant to Novo Nordisk and also to Orexigen Therapeutics, Vivus, and WW, and he has received research funding from AstraZeneca. Caprio had no disclosures.
This article originally appeared on MDedge.com, part of the Medscape Professional Network.
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Cite this: FDA Approves Liraglutide for Adolescents With Obesity - Medscape - Dec 11, 2020.
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