The glucagon-like peptide-1 (GLP-1) agonist semaglutide formulated for treating obesity (Wegovy) had a roaring takeoff a little more than a year ago, with surging patient demand after the US Food and Drug Administration (FDA) approved it in June 2021. But starting doses of the Wegovy form of semaglutide went missing in action starting late 2021 and continueto date, frustrating patients and their healthcare providers.
The arrival of Wegovy last year was hailed by obesity medicine specialists and others as a "game changer" for treating people with obesity because of semaglutide's proven safety and efficacy at the subcutaneous dose of 2.4 mg delivered once a week to produce at least 15% weight loss in half the people who received it, as documented last year in results from one of the drug's pivotal clinical trials.
But during the months following semaglutide's approval for treating obesity (it also received an FDA marketing nod in late 2017 as Ozempic for treating type 2 diabetes), a worldwide shortage of Wegovy, including in the United States, emerged.
A manufacturing glitch shut down the primary location for production of US-bound Wegovy injector pens for several months starting in late 2021, according to a December report from Novo Nordisk, the company that makes and markets the agent. (The Wegovy production issue appears to have had a very modest impact, especially in US pharmacies, on the supply of semaglutide formulated as Ozempic, also marketed by Novo Nordisk, although Wegovy supply and demand havedramatically limited Ozempic availability in Australia.)
"Unprecedented Demand" for Wegovy Derailed When Plant Went Off-Line
The supply side for Wegovy became so hopelessly broken that just months after US sales began and immediately skyrocketed, Novo Nordisk made the remarkable decision to pull starting doses of Wegovy from the market to make it much harder to initiate patients (semaglutide and other GLP-1 agonists require gradual dose ramp-up to avoid gastrointestinal side effects), and the company publicly implored clinicians to not start new patients on the agent, which is where the status remains as of early August 2022.
Novo Nordisk's financial report for the second quarter of 2022, released on August 3, said the company "expects to make all Wegovy dose strengths available in the US towards the end of 2022."
A Dear Health Care Provider letter that Novo Nordisk posted on its US Wegovy website last spring cited "unprecedented demand" that exceeded every prior product launch in the company's history. It forced Novo Nordisk to pull the plug on all US promotion of Wegovy and compelled the company to ask US clinicians to halt new patient starts.
"I stopped offering Wegovy to new patients" since about the beginning of 2022, says Lauren D. Oshman, MD, a family and obesity medicine specialist at the University of Michigan in Ann Arbor. "It's very frustrating to not have patients [with obesity] receive the optimal treatment available." Although she adds that she tries to match obesity treatments to each patient's clinical needs, and a GLP-1 agonist is not the first choice for every person with obesity.
"It was a disastrous roll-out," says Catherine W. Varney, DO, a family and obesity medicine specialist at the University of Virginia in Charlottesville. "It's frustrating to know that the treatment is therebut not being able to use it," she said in an interview.
"I had about 800 patients on Wegovy" when the supply dropped earlier this year, and "I couldn't handle the volume of messages that I got from patients," recalls Angela Fitch, MD, associate director of the Massachusetts General Hospital Weight Center in Boston. "It was painful," she said in an interview.
"Frustrating and chaotic," is the description from Ivania M. Rizo, MD, director of obesity medicine at Boston Medical Center.
The Liraglutide/Saxenda Workaround
The upshot is that people with obesity and their healthcare providers have been busy devising workarounds to try to meet the intense demand for this drug-assisted approach to appetite control and weight loss. Their tactics run a wide gamut based on the crazy-quilt diversity of health insurance coverage across America.
Because the bottleneck for starting Wegovy resulted from unavailable starting doses (dosing starts at 0.25 mg delivered subcutaneously once a week, eventually ramping up to a maximum of 2.4 mg weekly), one option was to start patients on a different GLP-1 agonist, such as liraglutide (Saxenda, approved for obesity).
Starting a patient on liraglutide involves the same sort of up-titration and acclimation to a GLP-1 agonist that semaglutide requires, and transition between these agents seems feasible for at least some. It also means daily injections of liraglutide rather than the weekly schedule for semaglutide, although some patients prefer maintaining a daily dosing schedule. Another limitation of liraglutide is that evidence shows it is not nearly as effective for weight loss as semaglutide.
Results from the head-to-head STEP 8 trial, published earlier this year, showed an average weight loss from baseline of about 16% with semaglutide and about 6% with liraglutide (and about 2% with placebo).
A "Reasonable" Evidence Base, but More Work
Changing from Saxenda to Wegovy, or from Wegovy to Saxenda, "would be reasonably evidence-based medicine," said Oshman in an interview. She has managed a Wegovy-to-Saxenda switch for a "handful" of patients to deal with Wegovy shortages, but she has not yet moved anyone to Wegovy after a Saxenda initiation.
"No prospective study has looked at this transition," but dose equivalence tables exist based on expert opinion, noted Oshman, as in this 2020 report.
Varney has several patients on the Saxenda-to-Wegovy track. She up-titrates patients on Saxenda to the maximum daily dose of 3.0 mg and then switches them to the 1.7 mg weekly dose of Wegovy, one of the "destination" Wegovy doses that has remained generally availableduring the shortage. But Varney's experience is that only half of her patients made the changeover smoothly, with the others having "severe gastrointestinal distress," including vomiting, she notes.
Fitch has also successfully used this Saxenda-to-Wegovy approach for some of her patients, but it hasn't been easy.
"It's more workand more prior authorizations. It's harder and adds a layer of stress," but, Fitch adds, "people are willing to work on it because the weight loss is worth it."
The liraglutide to semaglutide shuffle is "doable," says Rizo, "but I'm looking forward to not having to do it and being able to just start Wegovy."
The Tirzepatide Coupon Program Works "Off Label" for Obesity
Another workaround depends on the FDA approval in May for tirzepatide (Mounjaro) for type 2 diabetes. Tirzepatide is a related GLP-1 agonist that also adds a second incretin-like agonist activity that mimics the glucose-dependent insulinotropic polypeptide.
Soon after approval, Lilly, the company that markets tirzepatide, started a US coupon program geared exclusively to people with commercial insurance. Within certain refill and dollar limits, the program lets patients buy tirzepatide at pharmacies at an out-of-pocket cost of $25 for a 4-week supply (tirzepatide is also dosed by weekly subcutaneous injections). The program will extend into 2023.
Novo Nordisk offered US patients with commercial insurance a similar discount when Wegovy first hit the US market in 2021, but the program closed down once the supply shortage began.
"The coupons still work even when tirzepatide is used off-label," she notes. And while the drug's rollout is still only a couple of months old, so far, it's gone "beautifully" with no hints of supply issues, she says.
"We try to only prescribe agents that patients can continue to access," says Fitch, who has had some patients with commercial insurance start on Wegovy with coupon discounts only to later lose access.
Many commercial US insurers do not cover obesity treatments, a decision often driven by the employers who sponsor the coverage, she notes.
Study results have documented that when people with obesity stop taking a GLP-1 agonist their lost weight rebounds, as in a study published this year that tracked people who stopped taking semaglutide.
Fitch has had success prescribing tirzepatide to patients with obesity but without diabetes who have certain types of Medicare drug coverage policies, which often do not deny off-label drug coverage. That approach works until patients reach the "donut hole" in their drug coverage and are faced with a certain level of out-of-pocket costs that can balloon to several thousand dollars.
Even More Workarounds
Other approaches patients have used to acquire Wegovy include purchasing it in other countries, such as Canada or Brazil, says Fitch. But prices outside the United States, while substantially lower, can still be a barrier for many patients, notes Oshman.
Semaglutide in Canada goes for about $300 for a 4-week supply, roughly a quarter the US price, she says, but is "still too high for many of my patients."
Intense patient demand sometimes bordering on desperation has prompted some to seek semaglutide from private compounding pharmacies, a step clinicians regard as downright dangerous.
"Semaglutide from compounding pharmacies is not known to be safe. We feel strongly that it's not something that people should do," says Fitch.
"Compounding pharmacies have no FDA regulation. People don't know what they're getting. It's dangerous," agrees Varney. Physicians who refer people for privately compounded semaglutide "are taking advantage of desperate people," she adds.
Although it seems likely that Novo Nordisk will soon sort out the supply problems and Wegovy will once again become more widely available, some of the issues patients have had with access to theweight-loss medication stem from more systemic issues in the US health insurance landscape: an unwillingness by payers to cover the costs of weight loss medications, a shortcoming that also exists for Medicare and Medicaid.
"We need to make obesity treatment a standard benefit, and not something that can be carved out," says Fitch. People with obesity "deserve access to effective treatments for their disease," she declares.
Oshman, Varney, and Rizo have reported no relevant financial relationships. Fitch has reported being an advisor to Jenny Craig.
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The key to preventing drug shortages might be to find manufacturers of high-quality products and pay them enough for their drugs so that they make a reasonable profit and can invest in their facilities when they need to.
We expect to make all dose strengths of Wegovy® available in the US towards the end of the year. Commercial production at the contract manufacturing site was re-initiated and inventory building is ongoing. Novo Nordisk is also making plans for additional production capacity to come on-line in 2023.
Both Ozempic® and Wegovy® are the same medication: semaglutide. Wegovy®, however, is available in slightly higher doses: 0.25 mg, 0.5 mg, 1.0 mg, 1.7 mg, and 2.4 mg pens. Ozempic® is available in 0.25 mg, 0.5 mg, and 1.0 mg pens.
According to the Food and Drug Administration (FDA), typical causes of shortages include manufacturing quality problems, production delays, and product discontinuations.
Drug Shortages can occur for many reasons, including manufacturing and quality problems, delays, and discontinuations. Manufacturers provide FDA most drug shortage information, and the agency works closely with them to prevent or reduce the impact of shortages.
Between 1996 and 2002, the American Society of Health-System Pharmacists (ASHP) identified 224 drug shortages. But since 2006, there have been more drug shortages every year. In 2009, drug shortages began to reach crisis levels. This trend continued upward to 282 drug shortages by the middle of 2019.
- Reporting to FDA. Contact CDER Drug Shortages by email: email@example.com. Contact CDER Drug Shortages by phone: (240) 402-7770.
- Reporting to the American Society of Health-System Pharmacists (ASHP) Use the Society's Drug Product Shortages Report form (non-FDA site)
While Wegovy demand has been massive following the drug's approval last June, its rollout hasn't been without its hitches. Late last year, Novo revealed that the drug would run short after a contract manufacturer in charge of syringe filling halted deliveries because of manufacturing issues.
- bupropion and naltrexone (Contrave)
- liraglutide (Saxenda)
- orlistat (Alli, Xenical)
- phendimetrazine (Bontril PDM)
- phentermine (Adipex-P, Lomaira)
- phentermine and topiramate (Qsymia)
Indeed, weight gain after discontinuing the drugs is a concern; studies have found that two-thirds of patients gained the weight back after they stopped taking Wegovy. But obesity experts disagree about how long a patient should stay on the drugs.
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Sept. 16, 2022 – Adderall, the attention deficit hyperactivity disorder medication, is in short supply in some parts of the nation, pharmacy chains and Adderall users say. Half a dozen people told Bloomberg that pharmacies told them in August and September that the drug was out of stock.
Prescription drug abuse is the fastest growing drug problem in the United States. The increase in unintentional drug overdose death rates in recent years (Figure 1) has been driven by increased use of a class of prescription drugs called opioid analgesics.
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