Semaglutide: Weighing the Pros and Cons for Use in Pediatrics
With news headlines like CNBC’s “Miracle Drug Could Remake the Weight Loss Industry,” The Week Magazine’s “A ‘Game Changer’ for Weight Loss,” Rolling Stone’s “Who Deserves the New ‘Miracle’ Weight Loss Drugs?” and various social media posts from countless influencers raving about their weight loss, it appears semaglutide may be the miracle weight loss drug the world’s been waiting for.
Semaglutide is an injectable, antidiabetic medication used for treating Type 2 diabetes and for assisting with long-term weight management. The use of semaglutide products Ozempic and Wegovy has increased at a staggering rate despite the recent concern around its shortage this past fall. In fact, between February 2022 and 2023, there has been a 46% increase in sales — equating to about a $2.8 billion increase ($1.5 billion of that earned within the past three months). Barclays predicts that at its peak, Wegovy’s sales will reach $14.5 billion — no doubt furthered by the brand drug’s recent label expansion into adolescent obesity treatment alongside new guidance from the American Academy of Pediatrics (AAP).
The AAP 2023 comprehensive guidelines regarding the evaluation and treatment of children and adolescents are a paradigm shift from previous guidance, which recommended watchful waiting as the method for managing youth obesity. These updated guidelines view childhood obesity as a chronic disease state that requires early intensive therapy, including lifestyle, pharmacological and surgical interventions. Several pharmacological interventions are recommended within the guidelines, including GLP-1 agonists – the class of medications used in treating Type 2 diabetes and obesity to which semaglutide belongs.
But the question remains — should the healthcare community be so eager to adopt semaglutide use in pediatrics based on what is known and unknown about long term use of GLP-1 agonists?
Semaglutide’s success weighed, measured and found … wanting?
With the prevalence of childhood and adolescent obesity at an all-time high of 19.7% in the U.S., it is conceivable that the use of GLP-1 agonists may become routine in childhood obesity management given the AAP’s endorsement and the rapid uptake of GLP-1 agonists in adults.
Although liraglutide (Saxenda) was the first GLP-1 agonist approved for use in pediatric patients aged 12 years and older for chronic weight management, its modest weight loss effect and daily administration schedule makes it likely that once-weekly semaglutide — approved in December 2022 for pediatric patients aged 12 years and older with an initial body mass index (BMI) at the 95th percentile or greater for age and sex — will become the preferred GLP-1 agonist for managing pediatric obesity. Approval of semaglutide was based on the impressive weight loss results from the STEP TEENS trial, which assessed the use of 2.4 mg semaglutide (or a placebo) once weekly with lifestyle intervention in 201 randomized adolescents aged 12-18 years across a 68-week period. In this highly adherent cohort of adolescents, semaglutide reduced BMI by 16.1%, and 73% of semaglutide-treated patients achieved at least a 5% reduction in body weight during the 68 weeks. This significant weight loss was accompanied by reductions in waist circumference, glycated hemoglobin level, total cholesterol, low-density lipoprotein cholesterol, and very-low-density lipoprotein cholesterol, triglycerides and alanine transaminase (ALT) levels.
Despite these game-changing results, the trial leaves many unanswered questions that could affect a patient’s treatment journey in a rush to anoint pharmacotherapy as a panacea for obesity.
Most trial participants were female (62%) despite obesity occurring relatively equally across sexes. This underrepresentation of males may be impactful — in adult semaglutide trials, females experienced greater weight loss than males. Additionally, the mean age of participating adolescents was 15.4 years, with 62% of adolescents reaching the end of puberty at the start of the trial. While most persons who have obesity before puberty will also have obesity as adults, there is still a sizeable minority whose prepubescence obesity is likely to be overmedicalized based on these trial results.
In the STEP TEENS trial, very few participants had comorbidities at baseline with only 13% reporting hypertension and 4% reporting Type 2 diabetes. This, in addition to the short 68-week follow-up time, does not answer if weight loss alone without other sustained lifestyle changes in diet, activity and socioeconomic determinants alters the risk of cardiometabolic diseases (such as hypertension, hypercholesterolemia or Type 2 diabetes) in the long term. Is the weight loss gained from semaglutide — while notable in trials — enough without additional changes to curb development of another clinically significant disease? In the trial, patients weighed, on average, 236.5 pounds and lost 33 pounds while reducing their BMI from 37 kg/m2 to 31 kg/m2. While the significant weight loss with semaglutide should not be minimized, adolescents remained obese even after 68 weeks of treatment.
Sustained semaglutide use could be a tall order
Studies show that when GLP-1 agonists are stopped, weight loss is reversed and cardiometabolic variables revert to baseline. So, this begs the question: Will semaglutide be a lifelong medication solution if started during childhood or adolescence?
In adult semaglutide trials, participants regained two-thirds of prior weight loss one year after withdrawal of treatment, a trend also noted in the STEP TEENS trial during a seven-week off-treatment period. This lack of weight loss persistence and the need for long-term pharmacological maintenance raises other questions: What is the mental impact for a pediatric patient if they stop therapy and weight is regained? Where does the weight loss come from — is it lean body mass or fat mass?
Adult trials suggest that lean mass — muscle and bone — account for roughly 39% of the total semaglutide weight loss. Is this amount of lean weight loss impactful for pediatric patients, and are there long-term adverse events with extended semaglutide use if started during adolescence and continued for 10, 20 or even 30 years? In the short term, semaglutide was associated with an elevated risk for gallbladder disease (4% vs. 0% for placebo), elevations in amylase and lipase levels, and a small increase in heart rate in adolescents. Significant hair loss — anecdotally reported on social media — was not assessed in the STEP TEENS trial but has been reported in other GLP-1 agonist trials.
Lastly, with an average cash price of $15,000 per year, the affordability of long-term treatment is a concern. If socioeconomic issues contribute to obesity because of limited access to nutritious food and resources, then the same socioeconomic issues will likely contribute to semaglutide, making it challenging for adults and adolescents to gain consistent access to the medication. Likewise, should they be able to gain access to semaglutide via a patient assistance program, there would still be the question of whether they could afford the lifestyle changes recommended by the AAP.
While semaglutide is an advancement in obesity management and fills an unmet need in practice, there are still questions about its long-term effects in pediatrics. It is important for providers to fully inform patients about these uncertainties and to temper the anecdotal social media reports with data to discourage evidence-free indication creep (i.e., use in overweight adolescents). Semaglutide is an important addition to our treatment options, but America’s childhood obesity problem will not be fixed with medication alone, even if it is a “miracle” or a “game changer.”