Janet McCaskill, a 58-year-old grandmother residing in Knightdale, North Carolina, has sampled a plethora of diets throughout her life. "I've dabbled in Weight Watchers, experimented with the ketogenic diet, and even sought the advice of a nutritionist," she recounted. Despite initial successes, she found that these diets eventually fell short of her expectations. In late 2022, with a weight of approximately 212 pounds and growing concerns over her health following the loss of her brother and both parents to heart disease, McCaskill embarked on an off-label weight loss journey using the diabetes medication Mounjaro. This drug belongs to the GLP-1 receptor agonist class, which also includes Ozempic, Wegovy, and Zepbound. "It has been a lifesaver," she expressed. However, the high cost was a barrier, and after switching to a more affordable compounding pharmacy version last year, she now fears losing access to her medication. This concern arises from the FDA's recent determination that the shortage of the brand-name drug has been resolved, thereby mandating the cessation of compounding.

A law permitting compounding pharmacies to fill gaps during drug shortages has enabled thousands, if not millions, of individuals to access expensive GLP-1 medications at a reduced cost—a practice that some physicians warn could pose safety risks due to the lack of FDA approval for compounded drugs. For individuals like McCaskill, however, it has been a vital resource. As pharmaceutical companies significantly increase their production, access to these medications is rapidly changing. "I'm utterly devastated," she confessed. In just over a year, McCaskill reported losing nearly 100 pounds and has since maintained her current weight of around 117 pounds. Her blood pressure has decreased, and her A1C levels, a measure of blood sugar, along with her triglyceride levels, have significantly improved. She has made substantial changes to her dietary habits and increased her physical activity. McCaskill's four granddaughters, aged between 6 and nearly 12, were her primary motivation for starting the medication. "They cheer me on, and I'm as involved with them as I've ever been," she said. As an office manager for an auto restoration and repair business, McCaskill noted that her insurance never covered Mounjaro. The drug, which uses the active ingredient tirzepatide, was approved by the FDA in May 2022 for type 2 diabetes; although McCaskill's blood sugar was slightly elevated, she did not have diabetes, and many plans do not cover GLP-1 drugs for weight loss purposes. She opted to pay out-of-pocket, utilizing a coupon from manufacturer Eli Lilly that reduced the cost by half, but it still amounted to approximately $500 per month. When Lilly's coupon program ended in the summer of 2023, McCaskill's healthcare provider suggested an alternative: compounded tirzepatide, a version of the drug not approved by the FDA but legally available through a local pharmacy. It cost less than $250 for a month's supply. McCaskill switched and continued to experience benefits; she and her husband have been using this version since. Now, however, she is worried they will both have to discontinue its use.

Last week, the FDA updated its drug shortage database to remove tirzepatide, which had been on the list—alongside related semaglutide-based drugs Ozempic and Wegovy—since 2022 due to unprecedented demand. This action signifies that the compounding of tirzepatide, as done by McCaskill's local pharmacy, must come to an end. While it indicates that branded versions of tirzepatide-based drugs—Mounjaro for diabetes and Zepbound, approved at the end of 2023 for weight loss—are more widely available, it has caused panic among individuals like McCaskill. "I was working until almost 10 o'clock last night responding to patients' inquiries," said Michele Kessler, a physician assistant at Durham Women's Clinic in North Carolina and McCaskill's provider. "I have numerous patients who are doing very well, and they are going to be abruptly discontinued without any warning." The FDA allows the compounding of medicines that are "essentially copies of a commercially available drug" during a shortage, but once the shortage is resolved, it is only permitted if not done "regularly or in excessive amounts." Compounding can often occur if patients require a modification to a medication, perhaps due to an allergy to one of the original ingredients or a need for a liquid formulation instead of a pill. "It's like you walk into a bakery, and you want chocolate cupcakes with white icing, we make those; if you want vanilla cupcakes with blue icing, we can accommodate that," said Jennifer Burch, pharmacist and owner of Central Compounding Center in Durham, where Kessler refers her patients for compounded tirzepatide. "We can customize it to your preferences." Her pharmacy even creates medication for pets and can adjust the flavor based on the animals' preferences: fish, chicken, or, in one instance, bubble gum. "I'm curious, how did you figure out the cat likes bubble gum?" Burch mused.

However, recently, her staff has been working tirelessly to compound tirzepatide and semaglutide, she said. Over the past six weeks, Burch reported filling approximately 900 prescriptions for compounded tirzepatide and 500 for compounded semaglutide, utilizing active ingredients purchased from chemical suppliers that she claims validate their products through compendial testing to ensure they meet quality standards. For compounded tirzepatide, Burch's pharmacy charges between $200 and $400 per month, depending on the dosage. Without insurance, Mounjaro costs $1,069 per month, and Zepbound is $1,060, according to Lilly. The company also offers a savings card for Zepbound, making it available for about $650 per month for certain patients with commercial insurance that does not cover the drug. In August, Lilly introduced more affordable versions of its lower doses of Zepbound in single-dose vials; patients must draw up the medication and inject it using a needle and syringe. The regular forms of the drug come in autoinjector pens. The vials are available for self-pay through a Lilly program called LillyDirect, which facilitates access to doctors and shipping of medicines to patients. They cost $399 for the lowest dose for a four-week supply or $549 for the next higher dose— the one McCaskill is on. "Many of us won't be able to continue affording these prices," McCaskill said.

It is unclear how many people are using compounded tirzepatide and semaglutide, as prescriptions are not tracked through conventional channels, according to Evan Seigerman, an analyst with financial firm BMO Capital Markets who closely monitors Lilly and Novo Nordisk, the manufacturer of semaglutide-based drugs Ozempic and Wegovy. He mentioned that some estimates place prescriptions for compounded versions as high as 20% of all prescriptions for these drugs. Scott Brunner, chief executive officer of the Alliance for Pharmacy Compounding, estimated that millions of people could be using compounded versions—and many may not be able to transition. "Price is not a justification for dispensing a compounded medication, but the reality is, many patients could afford the compounded versions of tirzepatide, and they likely won't be able to afford the FDA-approved drug," Brunner said. His organization requested the FDA to provide a buffer of at least 60 days before compounding must cease to "ensure continuity of patient care." He reported hearing from over a dozen member pharmacies that branded tirzepatide products were still not available through their ordering systems despite the shortage ending. The FDA acknowledged in its statement about the end of the tirzepatide shortage that "patients and prescribers may still encounter intermittent localized supply disruptions as the products move through the supply chain from the manufacturer and distributor to local pharmacies." In response to an inquiry about the request for a 60-day buffer, the FDA stated it does not discuss interactions between the agency and companies. Although compounding has facilitated access for individuals who might otherwise struggle to find or afford the genuine medications, the practice can entail risks since it is not regulated by the FDA in the same manner as branded and generic pharmaceuticals. "Doctors often ask me... 'How can I be sure the compounded version my patients are receiving is safe and effective?' And I respond, 'You can't,'" said Dr. Angela Fitch, chief medical officer of care provider Knownwell and past president of the Obesity Medicine Association. "This has always been the issue with it." The FDA has warned that it has received reports of dosing errors with compounded semaglutide products, some of which led to hospitalization, and that some products sold by compounders used salt forms of semaglutide, which are "different active ingredients than those used in the approved drugs." It has also cautioned about counterfeit versions of drugs and medications sold under false labels such as "for research purposes" or "not for human consumption," which the agency stated could be harmful. Additionally, Lilly and Novo Nordisk have taken legal action against some med spas, weight loss clinics, pharmacies, and others selling compounded products that they claim pose "significant risks to patients."

This week, Novo Nordisk published a study it conducted in the journal Pharmaceutical Research, asserting that it found impurities and lower concentrations of active ingredients in some compounded versions of its drugs. However, the end of the shortages seems unlikely to signify the complete end of compounding these medicines. For now, semaglutide remains on the FDA's shortages list in the lowest dose of Wegovy, the version approved for weight loss. Novo Nordisk says it continues to invest in increasing its manufacturing capacity but did not specify when the shortage would be fully resolved. Even when it is, companies that have built business models around compounding, such as telehealth provider Hims & Hers, may find ways to continue providing compounded versions by offering different doses than what's FDA-approved. The company informed analysts on its quarterly earnings conference call in August that it saw a path "beyond the shortage dynamic" in part through offering "personalized GLP-1 doses, which enhance the commercially available dosages for patients." McCaskill expressed hope that Lilly might consider further reducing the price of its medicines to make them more accessible to those who have been relying on compounded tirzepatide. And Fitch criticized the lack of insurance coverage for obesity care. Data from trials indicates that most individuals who discontinue GLP-1 medications regain a significant amount of the weight they lost, and McCaskill does not wish to revert the health improvements she has been experiencing. "I've heard some people are attempting to split their doses, but I'm hesitant to do that," she said. "I simply don't want to tamper with anything when it's working 100% for me."