What Are the Safety Concerns Regarding Compounded GLP-1 Receptor Agonists?

Background
Obesity is a chronic and complex condition marked by excessive fat accumulation that poses serious risks to physical health and overall quality of life.¹ It increases the likelihood of developing noncommunicable diseases such as type 2 diabetes, cardiovascular disease, certain cancers, and musculoskeletal disorders. The causes are multifactorial, often involving imbalances in diet and physical activity, but also influenced by environmental, socioeconomic, and genetic factors.

Despite being largely preventable, obesity continues to rise globally.¹ As of 2022, more than 2.5 billion adults worldwide were classified as overweight, with nearly 900 million meeting the criteria for obesity. This surge reflects a stark upward trend, with adult obesity rates more than doubling and adolescent obesity rates quadrupling since 1990. Even among children the burden is rising, with an estimated 35 million children classified as overweight in 2024.

Guideline Recommended Pharmacologic Treatments

Multiple adult clinical guidelines endorse the use of glucagon-like peptide 1 (GLP-1) receptor agonists as effective pharmacologic treatments for obesity in individuals with a body mass index (BMI) of 30 kg/m² or higher, or ≥27 kg/m² in the presence of weight-related comorbidities.^2-4 Notable among these are the 2022 guidelines from the American Gastroenterological Association (AGA), the 2025 Standards of Care from the American Diabetes Association (ADA), and the 2015 guideline from the Endocrine Society. These guideline recommendations highlight GLP-1 receptor agonists as valuable tools for both weight reduction and improvement of associated metabolic conditions.

The AGA’s 2022 guidance supports the use of semaglutide 2.4 mg administered subcutaneously once weekly in adults with obesity or those who are overweight with related complications, in combination with lifestyle interventions.² Due to its substantial overall benefit, semaglutide is prioritized over other anti-obesity agents for long-term management. Liraglutide 3.0 mg administered daily is also recommended conditionally, though it tends to cause more gastrointestinal side effects and has a higher rate of treatment discontinuation compared to semaglutide. Similarly, the 2025 ADA Standards recommend GLP-1 receptor agonists (specifically semaglutide, liraglutide, or tirzepatide) for individuals with type 2 diabetes mellitus (T2DM) and obesity, recognizing their dual benefit in supporting glycemic control and achieving sustained weight loss.³ The ADA emphasizes that these agents should be continued even after initial weight goals are met to help prevent weight regain and maintain cardiometabolic improvements.

The 2015 Endocrine Society guideline also supports the use of GLP-1 receptor agonists, including liraglutide and exenatide, particularly in patients with obesity and T2DM.⁴ These agents are recommended as adjuncts to lifestyle modification and metformin, with a treatment continuation threshold based on achieving at least 5% weight loss within the first three months. Collectively, these guidelines underscore GLP-1 receptor agonists as central agents in obesity pharmacotherapy, given their effectiveness in delivering clinically meaningful weight loss and improving comorbid conditions.

In pediatric populations, both the 2023 American Academy of Pediatrics (AAP) guideline and the 2025 ADA Standards provide direction on the use of weight-loss medications.^5,6 The AAP recommends considering pharmacologic therapy in children aged 8 to 11 years with obesity, when used alongside intensive health behavior and lifestyle interventions, and strongly encourages this approach in adolescents aged 12 years and older.⁵ The ADA advises considering GLP-1 receptor agonists in children aged 10 and older with T2DM and obesity who fail to meet glycemic goals on metformin alone.⁶ Neither the AAP nor the ADA specifies a preferred GLP-1 receptor agonist, reflecting the broader support for this class of medications in managing pediatric obesity, particularly when comorbid conditions like T2DM are present.^5,6

Compounded GLP-1 Receptor Agonists
Glucagon-like peptide-1 receptor agonists have revolutionized the management of T2DM and obesity by improving glycemic control and promoting weight loss. Their growing popularity has, however, led to increased interest in alternative formulations from compounding pharmacies because most GLP-1 receptor agonists used for weight loss (e.g., semaglutide and tirzepatide) are only available as brand-name products.⁷ A compounded medication may be considered suitable when a patient’s medical needs cannot be addressed with an FDA-approved product, or if the approved medication is unavailable on the market.⁸ However, because compounded drugs are not FDA-approved, they do not undergo the agency’s evaluation for safety, efficacy, or quality prior to being distributed.

Despite FDA warnings against using non-approved compounded versions when FDA-approved medications are available, the market for these knockoff products has surged, with many active pharmaceutical ingredients (APIs) arriving from unregistered, foreign manufacturers.⁷ Poorly regulated compounding practices and unvetted foreign APIs are creating real and immediate dangers for American consumers seeking weight loss therapies.

FDA Safety Communications

The FDA has issued multiple safety communications addressing significant concerns about the use of compounded GLP-1 receptor agonists, particularly semaglutide and tirzepatide, for weight management.⁸ Compounded GLP-1 receptor agonist products can differ from FDA-approved versions in several ways that may increase the risk of medication errors. For example, the FDA has noted that compounders may provide semaglutide in a range of packaging formats, such as multi-dose vials or prefilled syringes. Additionally, the concentration of the drug can vary between compounders, and even a single compounder may produce multiple strength variations of compounded GLP-1 receptor agonists. In some cases, the dosing instructions provided with compounded formulations have directed patients to measure their injections in “units,” a volume that can vary based on the product’s concentration, rather than using standard measurements like milligrams or milliliters.⁹

As of April 30, 2025, the FDA had received 520 adverse event reports related to compounded semaglutide and 480 reports concerning compounded tirzepatide, though the true number is likely higher due to underreporting from state-licensed pharmacies not required to submit such data.⁸ Many patients mistakenly administered 5 to 20 times their intended dose, often because they were unfamiliar with measuring small volumes using insulin syringes or received unclear instructions.⁹ Reported side effects included gastrointestinal issues, fainting, dehydration, and more serious conditions like pancreatitis and gallstones leading to hospitalization. Additionally, healthcare providers themselves have made dosing miscalculations when converting from milligrams to units or milliliters, resulting in patients receiving significantly higher doses than prescribed.

Further complicating safety, some compounded versions use unapproved salt forms of semaglutide, such as semaglutide sodium or acetate, which are different from the active pharmaceutical ingredient found in FDA-approved products.⁸ The FDA has stated there is no evidence that these salt forms are chemically or pharmacologically equivalent and no legal basis supports their use in human compounding.

The FDA has also been combatting the growing presence of counterfeit and illegally marketed GLP-1 drugs.⁸ Counterfeit semaglutide has been identified in the U.S. supply chain, and these unauthorized products may contain incorrect or harmful ingredients, or inconsistent dosages. Online sales of unapproved semaglutide and tirzepatide have prompted multiple FDA warning letters to stop the distribution of these risky medications. The agency strongly advises consumers to purchase medications only from state-licensed pharmacies. Additionally, FDA enforcement actions have targeted products falsely marketed as “for research purposes” or “not for human consumption,” which are being sold directly to patients for injection. These products often lack quality assurances and pose significant health risks.

In response to the increased use of compounded GLP-1 products during supply shortages of approved medications, the FDA temporarily exercised enforcement discretion to allow compounding of these drugs under specific conditions.¹⁰ However, with the resolution of the national semaglutide shortage as of February 2025, the FDA clarified that this enforcement discretion period had ended for state-licensed pharmacies as of April 22, 2025, and for outsourcing facilities as of May 22, 2025.

Conclusion
Compounded GLP-1 receptor agonists have gained attention as substitutes for branded weight-loss products during times of high demand or limited availability, but their use is accompanied by significant clinical and regulatory risks. The FDA has highlighted multiple safety concerns, including dosing inconsistencies, formulation variability, and serious adverse events. Given these concerns, healthcare professionals should emphasize the use of FDA-approved therapies whenever feasible and take extra precautions when compounded versions are used. Comprehensive patient counseling, verification of pharmacy practices, standardized dosing tools, and regulatory awareness are all essential components of safe prescribing.

References

1. World Health Organization. Obesity and overweight. Updated May 7, 2025. Accessed July 23, 2025. https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight.
2. Grunvald E, Shah R, Hernaez R, et al. AGA clinical practice guideline on pharmacological interventions for adults with obesity. Gastroenterology. 2022;163(5):1198-1225. doi:10.1053/j.gastro.2022.08.045.
3. American Diabetes Association Professional Practice Committee. 8. Obesity and weight management for the prevention and treatment of type 2 diabetes: standards of care in diabetes-2025. Diabetes Care. 2025;48(1 Suppl 1):S167-S180. doi:10.2337/dc25-S008
4. Apovian CM, Aronne LJ, Bessesen DH, et al. Pharmacological management of obesity: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015;100(2):342-362. doi:10.1210/jc.2014-3415.
5. Hampl SE, Hassink SG, Skinner AC, et al. Clinical practice guideline for the evaluation and treatment of children and adolescents with obesity. Pediatrics. 2023;151(2):e2022060640. doi:10.1542/peds.2022-060640
6. American Diabetes Association Professional Practice Committee. 14. Children and adolescents: standards of care in diabetes-2025. Diabetes Care. 2025;48(1 Suppl 1):S283-S305. doi:10.2337/dc25-S014
7. Partnership for Safe Medicines. New report reveals illegal ingredients for knockoff weight loss drugs flooding into U.S. from foreign sources, endangering patient safety. Published February 20, 2025. Accessed July 23, 2025. https://www.safemedicines.org/2025/02/new-report-reveals-illegal-ingredients-for-knockoff-weight-loss-drugs-flooding-into-u-s-from-foreign-sources-endangering-patient-safety.html
8. U.S. Food and Drug Administration. FDA’s concerns with unapproved GLP-1 drugs used for weight loss. U.S. Food and Drug Administration. Published May 30, 2025. Accessed July 24, 2025. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/fdas-concerns-unapproved-glp-1-drugs-used-weight-loss knockoff-weight-loss-drugs- flooding-into-u-s-from-foreign-sources-endangering-patient-safety.html.
9. U.S. Food and Drug Administration. FDA alerts health care providers, compounders of dosing errors. U.S. Food and Drug Administration. Published July 26, 2024. Accessed July 25, 2025. https://www.fda.gov/drugs/human-drug-compounding/fda-alerts-health-care-providers-compounders-and-patients-dosing-errors-associated-compounded
10. U.S. Food and Drug Administration. FDA clarifies policies for compounders as national GLP-1 supply begins to stabilize. U.S. Food and Drug Administration. Published April 28, 2025. Accessed July 25, 2025. https://www.fda.gov/drugs/drug-safety-and-availability/fda-clarifies-policies-compounders-national-glp-1-supply-begins-stabilize

Prepared by:
Faria Munir, PharmD, MS, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago Retzky College of Pharmacy

August 2025

The information presented is current as of July 25, 2025. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.