[Image courtesy of Adobe Stock]
Global shortages of GLP-1 agonists like semaglutide (Ozempic/Wegovy) and tirzepatide (Mounjaro/Zepbound) could last until at least mid-2024 as a result of manufacturing snags and high demand, as BMJ and others have noted.
Supply chain scramble
Eli Lilly, whose Mounjaro and Zepbound are tirzepatide formulations for diabetes and weight management, respectively, is struggling to produce enough of the therapy even as it expects to ramp up production volume 50% in the first half of 2024 compared to the same period in 2023. The company is also potentially eyeing regulatory approval for Mounjaro in additional therapeutic areas such as moderate-to-severe obstructive sleep apnea following promising trial outcomes. With Mounjaro’s sales reaching $1.8 billion globally — and $1.5 billion in the U.S. alone during the first quarter of 2024 — the demand continues to surge.
Dr. Christine Ren-Fielding
The situation is leading to frustration and delays in treatment. “Just five minutes ago, a patient asked me to prescribe Wegovy instead of Ozempic, [the blockbuster GLP-1 agonist from Novo Nordisk], because their pharmacy was out of stock,” said Dr. Christine Ren-Fielding, who runs the weight management program at NYU Langone. After locating a pharmacy purporting to have the medication, she sent the prescription over only to hear that it was out of stock. That pharmacy said “they were out of stock for that patient, so I had to ask my office to contact them again,” Ren-Fielding said.
Bureaucratic hurdles frustrate doctors and patients
Ren-Fielding describes a tactical hurdle where prescribers must navigate pre-authorization processes, limited pharmacy stock, and escalating dosage protocols. But then there’s the pre-authorization process, which involves justifying the medical necessity of the treatment to insurance companies. The process is “a heavy workload where we have to answer questions, be on call with the insurance company to prove they should cover it,” Ren-Fielding noted.
“It’s not a clinically friendly environment – very time-consuming and expensive for the patient and insurance companies,” Ren-Fielding added. On top of that is the matter of escalating dosages where patients start low and increase incrementally to limit side effects. “The low 2.5mg dose of one medication may only be at certain pharmacies,” she added. “Then for the next dose, we have to find a different pharmacy carrying that dose.”
Mounjaro (tirzepatide) is the first GIP and GLP-1 receptor agonist approved by FDA. [Image courtesy of Eli Lilly]
Patients face an equally challenging situation. If they can’t access their next dose, they must either stay on a suboptimal lower dose or restart the process from the beginning. “My office keeps a weekly list of what pharmacies have which doses, but most patients don’t have that access. It’s very tedious and unfair that only some can find their needed dose by knowing the right people,” Ren-Fielding laments.
The high cost of weight loss: Payers push back
Payers are also grappling with the high costs and long-term implications of GLP-1 therapy. Many are either blocking or limiting coverage, limiting access to patients unable to pay out of pocket for the therapies. “But if patients’ BMI qualifies for bariatric surgery, it may be easier to get surgery coverage since it’s less expensive long-term for reliable weight loss,” Ren-Fielding said.
While there is little precedent for the level of attention GLP-1 agonists have garnered, data suggests that sustainable weight loss with the drug class requires durable use. As Ren-Fielding explains, “GLP-1 agonists are not a cure, they purely control appetite and improve satiety. If you stop them, the weight comes back.” Thus, the drug class may ultimately play a role similar to statins for high cholesterol or antihypertensive medications for blood pressure. To keep on working, patients may need to keep taking them indefinitely.
A concerted effort to address the obesity epidemic
Addressing the obesity epidemic will require a concerted effort from healthcare providers, payers, and policymakers alike. “Having an effective medication has been really great for treating this chronic obesity condition. But as you mentioned, there are problems with supply chain issues, access due to expense, and whether public health systems can sustain the cost. It’s becoming a fascinating public health issue that the government must look at very seriously,” Ren-Fielding emphasizes. Collaborative efforts to improve access, affordability, and long-term sustainability will be critical in harnessing the full potential of GLP-1 agonists to combat obesity on a societal scale.
The long search for safe and effective obesity medications
For decades, the search for a safe and effective obesity medication seemed like a pipe dream. There have, however, been drugs that offer promise. In the 1990s, fen-phen, a combination of fenfluramine and phentermine, became a mega-seller with prescriptions topping 18 million in 1996. But the drug was tied to valvular heart disease and pulled from the market. Similarly, rimonabant, which was approved in 2006 in Europe as an anti-obesity drug, initially seemed to offer promise by blocking the endocannabinoid system in the brain to promote weight loss. But over risks of serious psychiatric side effects like depression, anxiety, and suicidal thoughts, the drug was yanked from the market in 2008. Similarly, lorcaserin was a weight loss pill that worked by regulating appetite that was initially approved by the FDA in 2012. But after a clinical trial found an increased risk of cancer in patients taking the drug long-term, it was withdrawn from the U.S. market in 2020.
“Several medications made it close to approval in phase 3 trials, like Belviq which was eventually approved then taken off the market. But many others were dropped due to an unacceptably high potential suicide risk when targeting the urge to eat and reward centers in the brain,” notes Ren-Fielding.
Targeting physiology, not just appetite
The breakthrough in developing weight loss drugs came through research into GLP-1 (glucagon-like peptide-1) agonists, which were originally developed for treating diabetes. The discovery of GLP-1 agonists as potential weight loss drugs has its origins in research on the Gila monster, a venomous lizard native to the southwestern United States and northwestern Mexico. The Gila monster’s venom contains a hormone called exendin-4, which is similar in structure to human GLP-1 but has a longer half-life. Exendin-4 was found to mimic the effects of GLP-1, stimulating insulin secretion and suppressing appetite. This led to the development of exenatide, a synthetic version of exendin-4, as the first GLP-1 agonist approved for treating type 2 diabetes in 2005. By modifying the structure of human GLP-1 to create longer-acting GLP-1 agonists like liraglutide and semaglutide (Ozempic/Wegovy), pharmaceutical companies developed an entirely new class of drugs that not only help control blood sugar in diabetes but also induce significant weight loss.
The result of this breakthrough opened up a new physiological pathway to target for weight management, moving away from the focus on central nervous systems to the gut.
The rise of GLP-1 agonists has the potential to significantly shift attitudes and reduce stigma around obesity treatment. “Now, with the GLP-1 agonist medications, it’s almost like a gateway to validating the real trouble and challenge of weight control,” Ren-Fielding explains. “It validates the whole condition and the chronicity of obesity – that people’s bodies are defending against weight loss.” By demonstrating that obesity is a chronic disease rather than a personal failing, these drugs could help to reframe societal perceptions.
Filed Under: Metabolic disease/endicrinology
