Societies take stand against off-brand GLP-1s over safety concerns
A rise in the use of non-FDA-approved diabetes and obesity medications has spurred health care professionals and medical organizations to speak out about safety concerns.
In December, the FDA released a statement to health care professionals and patients warning against the use of compounded and counterfeit versions of diabetes and obesity drugs, including semaglutide (Ozempic/Wegovy, Novo Nordisk) and tirzepatide (Mounjaro/Zepbound, Eli Lilly). In its statement, the FDA emphasized that compounded and counterfeit drugs have not been reviewed for safety, effectiveness or quality.
Source: Abby Peterson, Washington State University. Printed with permission
The FDA began allowing the distribution of compounded semaglutide and tirzepatide when both drugs were initially placed on the agency’s drug shortage list in 2022. Section 503A of the Federal Food, Drug, and Cosmetic Act states a licensed pharmacist cannot compound “regularly or in inordinate amounts ... any drug products that are essentially copies of a commercially available drug product.” However, the FDA considers drugs that are on its drug shortage list as being not commercially available, allowing pharmacies to manufacture compounded forms of semaglutide and tirzepatide.
The narrative surrounding off-brand semaglutide and tirzepatide use is beginning to shift as tirzepatide was removed from the FDA’s drug shortage list in December and semaglutide was taken off the list in February. As a result, compounders can no longer distribute forms of tirzepatide, as of the time of publication, while distribution of compounded semaglutide must end for state-licensed 503A pharmacies after April 22 and for 503B outsourcing facilities after May 22.
Societies and others weigh in
Several medical societies and health care professionals have addressed concerns about safety of off-brand GLP-1s.
In January 2024, The Obesity Society, Obesity Action Coalition and Obesity Medicine Association released a joint statement against the use of compounded and counterfeit medications.
“To be clear, the only FDA-approved manufacturers of these medications are the companies that created the active pharmaceutical ingredients — Novo Nordisk and Eli Lilly,” the joint statement read. “These companies stated that they do not sell the active ingredient to compounding pharmacies, and substances made or distributed by compounding pharmacies or other health care practitioners that claim to be semaglutide or tirzepatide have not been reviewed by the FDA for safety, quality or efficacy.”
“[We want to] provide some guidance to people who don’t live in this space all the time,” Jamy Ard, MD, FTOS, professor in the department of epidemiology and prevention at the Wake Forest School of Medicine, past president of The Obesity Society and a Healio | Endocrine Today Editorial Board Member, said in an interview in February. “We think deeply about this, and we care a lot about it. It is our profession. We wanted to make sure people had a sense of how we are perceiving this.”
In November, the Endocrine Society hosted a virtual science writers’ conference to discuss differences between FDA-approved medications for obesity and non-approved forms of these drugs. One of the participants, Caroline M. Apovian, MD, co-director of the Center for Weight Management and Wellness in the division of endocrinology, diabetes and hypertension at Brigham and Women’s Hospital and a Healio | Endocrine Today Editorial Board Member, said much of the concern surrounding compounded medications revolves around the difference in how the FDA regulates them compared with agents from pharmaceutical companies.
“The FDA is there to protect Americans and does its due diligence every year,” Apovian told Healio | Endocrine Today. “Billions of dollars are spent by pharmaceutical companies to conduct studies with rigor and duration in order to meet FDA standards of quality, efficacy and safety.”
On Dec. 2, the American Diabetes Association released a statement centered on use of compounded and counterfeit semaglutide and tirzepatide. In the statement, the ADA advised health care professionals to avoid using compounded medications for the treatment of diabetes or obesity if possible and offered guidance for how to navigate medication shortages and other barriers patients may face with acquiring brand-name versions of the drugs.
“The ADA recommends against using non-FDA-approved compounded GLP-1 and dual GIP/GLP-1 receptor agonist products due to safety, quality and effectiveness concerns and uncertainty about their content,” Joshua J. Neumiller, PharmD, CDCES, FADCES, FASCP, vice chair and Allen I. White Distinguished Professor in the department of pharmacotherapy at Washington State University (WSU) College of Pharmacy and Pharmaceutical Sciences, and the ADA’s president of health care and education, and colleagues wrote in the ADA statement. “Compounded products are not FDA-approved and do not undergo FDA review for safety, quality or effectiveness standards. As a result, these products may present elevated risks to individuals.”
Neumiller told Healio | Endocrine Today that compounding pharmacies are an important resource overall in health care. However, the emergence of numerous online pharmacies and telemedicine companies selling off-brand drugs has made it difficult to determine which facilities are properly following safety regulations.
“When we think about compounded GLP-1s and dual agonists, there are some bad actors in the space,” Neumiller said. “People don’t know when they are seeing these advertisements if they are coming from a legitimate compounding pharmacy or if they will receive a lower-quality product.”
Despite the FDA’s recent removal of semaglutide and tirzepatide from its drug shortage list, concerns remain regarding counterfeit forms of both drugs. On Feb. 19, the National Association of Attorneys General submitted a letter to acting FDA commissioner Sara Brenner, MD, MPH, asking the agency to “take decisive action against bad actors unlawfully profiting off the high demand for FDA-approved weight loss and diabetes drugs.”
“While states play a role in protecting their own consumers, many organizations that sell unsafe, unregulated versions of GLP-1 operate outside the country,” the letter stated. “Concurrent federal action will provide the most robust protection against all the illegal and deceptive conduct.”
The statements issued by medical societies and government officials are important not just for health care professionals, but also for educating patients about how obesity management should be approached, according to Sangeeta Kashyap, MD, assistant chief of clinical affairs in the department of endocrinology, diabetes and metabolism at NewYork-Presbyterian/Weill Cornell Medical Center and a Healio | Endocrine Today Co-editor.
“Using compounded medications for the management of obesity is not standard of care,” Kashyap told Healio | Endocrine Today. “There are guidelines for obesity management, and none of these societies advocate for the use of compound drugs. These drugs have come about because of demand and lack of access.”
‘Multifaceted’ demand
The approval of semaglutide and tirzepatide for type 2 diabetes and later for obesity kickstarted a wave of patient demand, particularly due to the weight reduction effects of both drugs. After semaglutide and tirzepatide were placed on the FDA drug shortage list, Neumiller said many companies saw an opportunity to distribute off-brand forms of the drugs due to high demand.
“People are inundated with these advertisements online, through social media and the radio,” Neumiller said. “The awareness of the availability of these compounded products is high, in general, and we’ve seen a huge gravitation toward these medications.”
The demand for these medications is multifaceted. Apovian said some people using compounded or counterfeit medications do not have obesity and may be using the drugs strictly to lose a few pounds. However, many people diagnosed with obesity are using off-brand medications as well, according to Katherine H. Saunders, MD, DABOM, co-founder of FlyteHealth and an obesity physician at Weill Cornell Medicine. In some cases, Saunders said, patients find themselves facing numerous barriers with having access to the brand-name drug and will use a compounded medication instead.
“There have been humongous barriers to access to comprehensive, evidence-based, medical obesity care, including lack of coverage for all aspects of obesity treatment, high cost of obesity medications ... and too few clinicians trained in obesity medicine,” Saunders told Healio | Endocrine Today.
Apovian said she understands the dilemma some patients face, but emphasized how crucial safety is when prescribing a drug.
“When the FDA approves a product from a drug company, the drug company is backing the safety of that drug,” Apovian said. “With [compounded medications], you just do not have that.”
Safety concerns
Saunders said a common misconception many patients have about compounded medications is they are exactly the same as the brand-name drugs. However, she said off-brand forms of the drugs can vary based on the source.
“There are many different issues,” Saunders said. “No. 1, what is the product? No. 2, what pharmacy is it coming from and what’s the oversight there? No. 3, a lot of these products are combined with vitamins or other medications, or something else; these combinations haven’t been studied.”
Neumiller said the composition of off-brand drugs is one of the biggest safety issues. In a December report on its website, the FDA said some compounders were using salt forms of semaglutide in their agents, which are different from the ingredients used in Novo Nordisk’s FDA-approved versions of the drug.
Even if a compounding pharmacy follows the FDA’s regulations when manufacturing a medication, there are still questions regarding the use of the medication, Apovian said. Improper dosing of compounded drugs was identified as a concern for the FDA in an alert released in July. The FDA stated it received an unspecified number of adverse event reports linked to compounded semaglutide that were due to dosing errors. The FDA found some patients drew up a higher-than-prescribed dose, with some injecting a dose five to 20 times higher than what was prescribed.
Both Eli Lilly and Novo Nordisk have spoken out against the use of off-brand versions of tirzepatide and semaglutide, respectively. In an email to Healio | Endocrine Today, an Eli Lilly spokesperson cited the FDA’s warning letters to compounding pharmacies and published research showing impurities in some off-brand versions of GLP-1s.
“Compounders continue to put patients at risk by unlawfully mass-producing compounded products they claim contain tirzepatide,” an Eli Lilly spokesperson said. “These products are not FDA-approved, have not been reviewed by FDA for safety and effectiveness, and FDA cautions they can lead to ‘serious and potentially life-threatening adverse health consequences including infections and sepsis.’”
“Knock-off versions of ‘semaglutide’ pose significant threats to people’s health and safety,” a Novo Nordisk spokesperson said in an email to Healio | Endocrine Today. “Respected medical organizations and experts have raised serious concerns about these knock-offs, which abuse the original intent of compounding. Novo Nordisk shares these concerns and recognizes the danger of these knock-offs to patients. We have taken proactive steps to address the issue, including correcting misinformation, educating communities, and taking legal action when appropriate. Protecting people from knock-off versions of ‘semaglutide’ is part of our long-term commitment to people living with obesity and the health care professionals partnering on their care. Safe and effective FDA-approved treatments exist, and no one should have to compromise their health due to misinformation or lack of understanding.”
Compounded vs. counterfeit drugs
An organization representing compounding pharmacies said health care officials and pharmaceutical companies are mistakenly blaming compounders for safety issues with off-brand semaglutide and tirzepatide.
In an interview with Healio | Endocrine Today, Scott Brunner, CAE, CEO of the Alliance for Pharmacy Compounding, an organization that represents more than 600 compounding businesses across the U.S., said many of the safety concerns linked to improper ingredients are not coming from state-licensed compounding pharmacies. Instead, he cited illegal businesses, particularly online operations, that are selling counterfeit versions of the drugs.
“There are telehealth platforms that weren’t in this space 6 months ago, are opportunist and are making marketing claims that are questionable at best,” Brunner told Healio | Endocrine Today.
The sale of counterfeit medications is common among online pharmacies, according to a 2019 report from the National Association of Boards of Pharmacy. In the report, the association stated about 95% of websites that claim to be selling prescription-only drugs in the U.S. are doing so illegally. Brunner said the Alliance for Pharmacy Compounding provides a link on its website that allows patients to find a state-licensed pharmacy in the state they live in.
Counterfeit versions of semaglutide and tirzepatide have gotten the attention of both the FDA and researchers. In a research letter published in JAMA Network Open in August, the authors purchased off-brand forms of semaglutide from six online pharmacies. The researchers only received a product from three of the six pharmacies, and the products they did receive had much lower purity and 29% to 39% more semaglutide measured than what was on the label. The research letter followed an FDA warning in December 2023 about counterfeit Ozempic that was circulating in the U.S. drug supply chain.
“There have been reports to FDA and other sources about how the concentration of these products are not clearly listed or sold as [advertised],” Neumiller said. “There have also been reports of these products containing contaminants or other medications altogether. Unfortunately, in some cases people don’t know exactly what they are receiving when purchasing these products.”
Tenille Davis, PharmD, RPh, BCSCP, FAPC, chief advocacy officer for the Alliance for Pharmacy Compounding, said compounding pharmacies are beholden to regulations within their respective states. She said compounders can only obtain active pharmaceutical ingredients from FDA-registered manufacturers and must conduct multiple quality control and safety tests on the batches of compounded drugs they make.
“A lot of the ... distrust or fear that’s being portrayed in the media isn’t based on real state-licensed compounding pharmacy practice. It’s based on illegal online sellers of these peptide drugs that are research-grade,” Davis told Healio | Endocrine Today. “Those kind of counterfeit operations that are being conflated with legitimate compounding are hurting the image of compounding, even though we have all sorts of standards that we have to operate under.”
Brunner acknowledged the FDA’s concerns regarding overdosing of compounded semaglutide and tirzepatide but said that specific warning did not mention drug contamination. Brunner said overdosing also occurs with the brand-name versions of the drugs and is not limited to compounded medications.
“This was not about a contaminated drug,” Brunner said about the overdosing warning. “This was about prescribers not writing the prescription for the compounded drug to the proper specifications, and/or it was about patients who were sadly getting information from Reddit forums, TikTok and other places. They were often trying to game the system ... and injecting themselves with more of the drug than they should. That is a reasonable concern.”
Alternatives
Uncertainty surrounding the source of off-brand obesity medications has led many health care professionals to avoid drugs that are not FDA-approved.
“There are certainly some marketing strategies I’ve seen that are deceptive,” Ard said. “There have certainly been companies that have been sued because they’re ... passing it off like they’re selling the brand-name item, but they’re not. It certainly can be confusing at that level because of some of those marketing practices.”
Kashyap said one of the biggest concerns surrounding off-brand medications is the lack of a health assessment, particularly from many telehealth companies and online pharmacies.
“Some people come to see me after they’ve taken a compounded GLP-1,” Kashyap said. “They said they were provided it online with very little assessment of their health status and they didn’t feel comfortable. Where and how you get your weight-loss drugs at the end of the day is what it’s about. Going to a comprehensive weight management clinic where someone examines you, is thorough about your assessment and has a shared discussion about what your weight-loss goals should be is very important to me.”
Apovian discussed how obesity treatment may not involve pharmacotherapy for everyone. For adults with a BMI of 40 kg/m2 or higher or those with a BMI of 35 kg/m2 or higher with obstructive sleep apnea or prediabetes, Apovian recommends strongly considering bariatric surgery as a first-line therapy due to very low complication rates and robust and durable weight loss.
Saunders also said obesity medicine practices should conduct a full laboratory panel and health risk assessment to fully understand a patient’s condition.
“We want to understand what people have tried and failed already,” Saunders said. “Maybe they’ve been on a GLP-1 and they had side effects. Maybe they have never tried any medication, and we don’t need to jump straight to the most powerful weight medication. We can try more conservative options first. I collect all this information and then I use the information to educate them about why obesity is a disease.”
Kashyap said incretin-based medications are not the best answer for all people with obesity — older medications can still play a role in treatment.
“We can use metformin, phentermine/topiramate, bupropion/naltrexone,” Kashyap said. “Sometimes we don’t use GLP-1s. Sometimes people have digestive issues that have never been diagnosed and we don’t want to make their health worse. We want to help improve their health through weight loss.”
Shortages end, but concerns remain
Legal manufacturing of compounded semaglutide and tirzepatide is slated to end this spring. On Dec. 19, the FDA confirmed an earlier decision to remove tirzepatide from its drug shortage list. As part of its decision, the FDA permitted state-licensed 503A pharmacies to continue distributing compounded tirzepatide until Feb. 18 and 503B outsourcing facilities to continue dispensing compounded forms of the drug until March 19.
On Feb. 21, all doses of semaglutide were removed from the FDA drug shortage list. Similar to its tirzepatide decision, the FDA is allowing state-licensed 503A pharmacies to continue distributing compounded semaglutide until April 22 and 503B outsourcing facilities to continue dispensing compounded forms of the drug until May 22.
In an emailed statement, Brunner said compounding pharmacists have been preparing for the end of the semaglutide shortage and thanked the FDA for providing compounding facilities time to transition patients off the compounded medications. The organization also questioned whether the decision to end the shortages was too soon, as it noted “hundreds of thousands” of patients will have to transition to the brand-name medications in just a few months.
“All we can do now is watch what happens as patients hear this news and their providers and pharmacists work to get them a new prescription for the FDA-approved drug,” Brunner said in the statement. “There’s likely to be some sticker shock for many, and whether they’ll be able to continue to afford the therapy remains to be seen.”
Affordability and access remain concerns for some health care professionals. Ard said patients who used compounded drugs because they could not afford the brand-name drugs or did not have insurance coverage for them may either stockpile compounded medications or turn toward counterfeit versions of the drugs.
“I remain concerned that unscrupulous actors might continue selling unregulated versions to vulnerable patients,” Ard said in an email to Healio | Endocrine Today. “The FDA must remain vigilant and take robust measures to eliminate these practices.”
Counterfeit medications were the foremost concern of the National Association of Attorneys General in its Feb. 19 letter to the FDA. The organization stated counterfeit medications were entering the U.S. supply chain from foreign countries and could contain contaminants or dangerously high levels of active ingredients that may lead to serious side effects for patients. The organization asked the FDA to work with federal partners to stop the flow of counterfeit drugs entering the U.S.
On Dec. 17, the FDA issued warning letters to four companies that were selling multiple GLP-1 products for sale, including forms of drugs that have not yet been FDA approved such as retatrutide (Eli Lilly), CagriSema (Novo Nordisk) and survodutide (Boehringer Ingelheim/Zealand Pharma).
Apovian said she is hopeful that demand for non-FDA-approved obesity medication will dissipate as insurance coverage and access for therapies improves, and that recent findings on how incretin-based agents benefit cardiovascular and renal health will push stakeholders to make sure all people who need a drug will be able to access and afford it.
“Eventually, we will be winning the insurance battle,” Apovian said.
- References:
- Ashraf AR, et al. JAMA Netw Open. 2024;doi:10.1001/jamanetworkopen.2024.28280.
- Compounding when drugs are on FDA’s drug shortages list. https://www.fda.gov/drugs/human-drug-compounding/compounding-when-drugs-are-fdas-drug-shortages-list. Published Dec. 18, 2024. Accessed Feb. 3, 2025.
- FDA alerts health care providers, compounders and patients of dosing errors associated with compounded injectable semaglutide products. https://www.fda.gov/drugs/human-drug-compounding/fda-alerts-health-care-providers-compounders-and-patients-dosing-errors-associated-compounded. Published July 26, 2024. Accessed Feb. 3, 2025.
- FDA clarifies policies for compounders as national GLP-1 supply begins to stabilize. https://www.fda.gov/drugs/drug-safety-and-availability/fda-clarifies-policies-compounders-national-glp-1-supply-begins-stabilize. Published Dec. 19, 2024. Accessed Feb. 4, 2025.
- FDA concerns with unapproved GLP-1 drugs used for weight loss. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/fdas-concerns-unapproved-glp-1-drugs-used-weight-loss. Published Dec. 18, 2024. Accessed Feb. 4, 2025.
- FDA Roundup. https://www.fda.gov/news-events/press-announcements/fda-roundup-december-17-2024. Published Dec. 17, 2024. Accessed Feb. 4, 2025.
- FDA warns consumers not to use counterfeit Ozempic (semaglutide) found in U.S. drug supply chain. https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-consumers-not-use-counterfeit-ozempic-semaglutide-found-us-drug-supply-chain. Published Dec. 21, 2023. Accessed Feb. 5, 2025.
- Neumiller JJ, et al. Diabetes Care. 2025;doi:10.2337/dci24-0091.
- State and territory attorneys general urge FDA to take action against counterfeit and illegally sold GLP-1 drugs. https://www.naag.org/policy-letter/state-and-territory-attorneys-general-urge-fda-to-take-action-against-counterfeit-and-illegally-sold-glp-1-drugs. Published Feb. 19, 2025. Accessed Feb. 21, 2025.
- Statement of Alliance for Pharmacy Compounding CEO Scott Brunner on resolution of semaglutide injection shortage. https://join.a4pc.org/hubfs/APC-Statement-on-Semaglutide-Injection-Shortage-Resolution-Feb2025.pdf. Published Feb. 21, 2025. Accessed Feb. 24, 2025.
- 2019 Rogue Rx Activity Report. https://nabp.pharmacy/wp-content/uploads/2019/11/Rogue-Rx-Activity-Report-2019.pdf. Published November 2019. Accessed Feb. 24, 2025.
- For more information:
- Caroline M. Apovian, MD, can be reached at capovian@mgb.org; X (Twitter): @MarsApovian; LinkedIn: @drapovian.
- Jamy Ard, MD, FTOS, can be reached at jard@wakehealth.edu; X (Twitter): @drard; LinkedIn: @jamy_ard.
- Scott Brunner, CAE, can be reached at 100 Daingerfield Road, Suite 100, Alexandria, VA 22314.
- Tenille Davis, PharmD, RPh, BCSCP, FAPC, can be reached at 100 Daingerfield Road, Suite 100, Alexandria, VA 22314.
- Sangeeta Kashyap, MD, can be reached at srk4008@med.cornell.edu.
- Joshua J. Neumiller, PharmD, CDCES, FADCES, FASCP, can be reached at jneumiller@wsu.edu; X (Twitter): @JoshuaNeumiller.
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