The United States, like much of the developed world, is facing increasing rates of childhood obesity and related health concerns. Despite years of research and various efforts, addressing this public health issue remains a complex challenge.
This article reviews the potential mechanisms, benefits, and considerations for using GLP-1 agonists in children based on the current scientific understanding. While early research is promising, the application of these treatments in children requires careful consideration and should always be done in consultation with a healthcare provider.
As a pediatrician, I recognize that while the science behind these treatments is evolving, it's important to remember that individual responses to treatments can vary. For children, every approach needs to be carefully weighed, considering their unique developmental needs.
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Why Has the Fight Against Obesity Been So Challenging?
Several factors contribute to the struggle against obesity, including:
- Widespread availability of inexpensive, high-calorie, ultra-processed foods
- Reduced physical activity due to modern lifestyles, increased screen use, and limited access to safe exercise spaces
- Chronic exposure to obesogenic chemicals in air, water, and food
- Pervasive mental stress in society
- Shifts in the intestinal microbiome influenced by these factors, along with antibiotic and medication use
- Inadequate allocation of medical and nutritional resources
While governments and healthcare providers have focused on education to address these challenges, it has not been effective for many. Structural issues, such as high-calorie school meals and food deserts, highlight the limitations of current strategies.
Recently, GLP-1 agonists have gained attention in treating type 2 diabetes and obesity in adults, due to their ability to help regulate blood sugar and support weight management. As their use among adults has grown, there is increasing interest in exploring their potential for managing obesity and type 2 diabetes in children.
Why is Childhood Obesity Such a Concern?
Childhood obesity is a pressing public health issue with significant long-term health implications. It is linked to various health risks, including type 2 diabetes, cardiovascular conditions, certain cancers, and psychosocial challenges. These concerns make addressing obesity in children critical for supporting their future well-being.
Traditional interventions, such as lifestyle changes and behavioral therapies, often yield limited success, underscoring the need for more effective strategies. While addressing the root causes of obesity, such as diet and activity, is important, broader systemic changes have not gained widespread momentum. Therefore, it’s essential for parents and healthcare providers to explore the available options for supporting healthy growth and weight management in children.
What is GLP-1?
GLP-1 is an incretin peptide hormone produced in the gut by the enteroendocrine L cells in the distal small intestine and colon, primarily in response to macronutrient ingestion. (1)
When it’s released into the bloodstream and the gut, it triggers several actions: it increases insulin secretion from the pancreas in response to glucose, reduces the release of glucagon (a hormone that raises blood sugar), shifts the immune system towards an anti-inflammatory state, slows down how quickly the stomach empties, and signals the brain to promote feelings of fullness through the vagus nerve.
These effects are mediated through the GLP-1 receptor, a G-protein coupled receptor expressed in various tissues, including the pancreas, brain, and gastrointestinal tract. (7)
What the Research Shows About GLP-1 Agonists for Adults
GLP-1 agonists, such as exenatide, liraglutide, semaglutide, and others, mimic the action of the endogenous GLP-1 peptide by binding to the GLP-1 receptor, thereby potentiating the physiological effects.
The data to date have shown that these medicines lead to improved glycemic control, reduced inflammation, reduced cardiovascular disease, weight loss, and appetite suppression in studies and clinical experience in adult populations. (11)
The use of GLP-1 agonists in adults has shown substantial benefits, prompting investigations into their efficacy and safety in children.
What the Research Shows About GLP-1 Agonists for Pediatric Obesity
Let us look at the pivotal studies that have explored the potential of GLP-1 agonists in treating pediatric obesity and diabetes, which are the backbone of the current recommendations for use in children.
Liraglutide for Adolescents with Obesity
The first randomized controlled trial assessed the efficacy of liraglutide in 251 adolescents with obesity. The trial demonstrated significant reductions in body mass index (BMI) and improved metabolic parameters compared to placebo over 56 weeks in children aged 12 to 18 years old.
These findings suggest that GLP-1 agonists can be a valuable adjunct to lifestyle interventions in managing pediatric obesity. Weight loss was roughly double in the treatment arm with a 10% BMI improvement compared to 5% for placebo.
Side effects were also double in the treatment arm. They included nausea, vomiting, diarrhea, pancreatitis and hypoglycemia. Roughly 10% of the trial patients in the liraglutide treatment arm dropped out due to side effects. The other take home point is the weight gain returned rapidly with cessation of drug use. (5)
Semaglutide for Adolescents with Obesity
Study number two looked at a total of 201 participants with obesity taking semaglutide versus placebo. The mean change in BMI by the end of the trial was a reduction by 16.1% with semaglutide and 0.6% with placebo. 73% of active participants in the treatment arm lost 5% weight, as compared with 18% in the placebo arm.
All cause side effects were significantly greater in the semaglutide group with five participants experiencing cholelithiasis. Serious adverse events were reported in 11% of the participants in the treatment arm. Mild pancreatic enzyme elevations were noted in few treated patients, not rising to pancreatitis diagnosis. (11)
Liraglutide for Adolescents with Type 2 Diabetes
Tamborlane and colleagues looked at 135 type 2 diabetic adolescents treated with liraglutide for 26 weeks, noting a 0.6% drop in hemoglobin A1C as the primary endpoint. (8)
A commonly cited study by Klein et al. in 2014 was too underpowered to gain any guidance. (6)
In the study by Kelly et al., the secondary endpoints looking at lipids and hemoglobin A1C were trending but not statistically significant. (5)
Exenatide for Pre-Teens and Teens
A 2022 study by Tamborlane noted a 0.36% drop in Hgb A1C over 26 weeks in pre-teens and teens treated with exenatide. Their ability to enhance insulin secretion, suppress glucagon release, and improve beta-cell function can help achieve better glycemic control.
These results underscore the early potential of GLP-1 agonists to address both hyperglycemia and obesity in this population. (9)
Common Side Effects of GLP-1 Agonists
If the above studies note significant benefits while on treatment, does this finding outweigh the safety and tolerability of GLP-1 agonists in children?
These are the most critical considerations for providers and parents. While adult studies provide a robust safety profile, pediatric populations may exhibit different responses due to developmental and physiological differences.
Common side effects of GLP-1 agonists include gastrointestinal symptoms such as nausea, vomiting, and diarrhea. These effects are generally transient and diminish over time.
However, the impact on growth and development needs careful monitoring. Long-term studies are required to assess the potential effects on pubertal development and bone health.
Effects of GLP-1 Agonists on Body Composition
Losing fat mass is beneficial, whereas losing lean mass is absolutely not. This effect would actually cannibalize the metabolic pathways over time.
What the data says is this: If you, your child or loved one have excessive fat mass, but also do not have normal volumes of lean mass, these medicines may be detrimental to overall health and thus your health span. This is also to say that even the healthy lean mass but the obese fat mass group may not like these medicines as they still reduce the overall lean mass volume.
In Wildnig's adult study, the lean mass loss was massive at close to 40%. Serious side effects were 3x higher in the treatment arm, with 164 events in 1306 patients treated or 12.6%. There is also some concern around resting heart rate increases leading to a net negative metabolic effect over time. (12)
Lean muscle mass, resting heart rate, and other key health metrics raise questions about the long-term use of these medications, especially in children. It's important to carefully weigh the risks and benefits. Current evidence suggests that, under medical supervision, GLP-1 agonists may support metabolic health and help manage obesity-related issues in the appropriate population.
Practical Considerations for GLP-1 Agonists for Pediatric Patients
When considering GLP-1 agonists for pediatric patients, key factors like dosing, administration, and adherence must be carefully addressed. Dosing should be adjusted for body weight and developmental stage, with lower dosing that gradualyl titrates up to help minimize side effects and improve tolerability.
The promising results from the few initial pediatric studies indicate a need for further research to establish the long-term efficacy and safety of GLP-1 agonists in pediatric populations. Key areas for future investigation include:
- Long-term Outcomes: Assessing the sustained effects of GLP-1 agonists on weight management, glycemic control, and comorbidities over extended periods is crucial. Especially, if and when the medications are discontinued. The adult data is not reassuring here.
- Developmental Impact: Evaluating the potential effects of GLP-1 agonists on growth, pubertal development, and bone health to ensure they do not adversely affect normal developmental processes will take years to ferret out.
- Combination Therapies: Exploring the synergistic effects of GLP-1 agonists with other pharmacological or behavioral interventions to enhance treatment outcomes.
- Psychosocial Factors: Understanding the psychological and social impacts of GLP-1 agonist therapy in children, including quality of life and adherence challenges.
Are There Natural Approaches That May Support GLP-1 Production?
Could natural GLP-1 production, supported by the microbiome and nutrition, be another approach? Research suggests that certain gut bacteria, such as Akkermansia muciniphila, may help release short-chain fatty acids, which can promote GLP-1 production. Akkermansia is an important part of gut diversity, making up 8-10% of the human microbiome.
In a study by Zhao and colleagues, they noted that fiber acts as a key source of nutrition for microbial growth, which may play a role in reducing blood sugar levels. Dr. Cutcliffe and colleagues compared a placebo group to participants who took WBF-011, a supplement containing inulin and several beneficial bacteria such as Akkermansia muciniphila, Clostridium beijerinckii, Clostridium butyricum, Bifidobacterium infantis, and Anaerobutyricum hallii.
The research showed significant improvements in their primary outcome: a reduction in total glucose levels over time. Secondary outcomes also improved, including a 0.6% decrease in glycated hemoglobin (A1c) and a reduction in incremental glucose levels over a three-month period. The supplement demonstrated a favorable safety profile, contributing to a high level of comfort for its use.
The key takeaway is that natural approaches may be preferable for some individuals, as they might reduce the potential risk of rare side effects associated with GLP-1 agonists. These medications have not been extensively studied in children over the long term, and long-term use may be necessary, as stopping the medication could lead to a return of weight-related concerns.
When considering options for addressing diabetes and obesity in children, it may be worth exploring nutritional and probiotic approaches as a first step.
Labs to Monitor Metabolic Health in Children
The following labs from BostonHeart Diagnostics can help detect metabolic issues:
- Insulin
- Hemoglobin A1c (HbA1c)
- High Sensitivity C-Reactive Protein (hs-CRP)
- Triglycerides (TG)
- Uric Acid (UA)
- Alanine Aminotransferase (ALT)
In addition to the blood labs listed above, the GI Effects® Comprehensive Profile - 3 day by Genova Diagnostics is another recommended test because it can detect levels of Akkermansia muciniphila in the gut.
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Summary
The use of GLP-1 agonists in children represents a possible but cautious avenue for managing obesity and type 2 diabetes, conditions that have become increasingly prevalent and challenging to treat in pediatric populations.
The mechanisms of action of GLP-1 agonists—enhancing insulin secretion, suppressing glucagon release, and promoting weight loss—address key pathophysiological aspects of these conditions.
While the preliminary data on efficacy and safety are encouraging, further research is needed to establish comprehensive guidelines for their use in children. By integrating GLP-1 agonists into a holistic treatment plan that includes lifestyle modifications and behavioral support, healthcare providers can offer a more effective approach to managing pediatric obesity and type 2 diabetes, ultimately improving long-term health outcomes for affected children.
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