GLP-1 Drugs: The Science and the Scarcity

How breakthroughs in GLP-1 science are creating new challenges.

Ozempic, Wegovy, Zepbound, and Mounjaro are dominating the pharmaceutical landscape. It’s predicted that Novo Nordisk’s Ozempic will be the second top-selling drug of 2024, with projected sales exceeding $16 billion US dollars.

Read about the projected top-selling drugs for 2024 here:

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This surge has sparked a weight management drug frenzy with many major pharmaceutical companies evaluating obesity management drugs in clinical trials. What exactly are semaglutides, tirzepatides, and GLP-1s? And what is the role of compounding pharmacies in face of widespread GLP-1 drug shortages?

What are GLP-1 receptor agonists?

GLP-1 stands for glucagon-like peptide-1. GLP-1 receptor agonists are drugs that mimic the hormone GLP-1 by binding to its receptors in the body. Examples of GLP-1 drugs include semaglutide (found in Ozempic and Wegovy), tirzepatide (found in Mounjaro and Zepbound) or liraglutide (Saxenda and Victoza). These drugs differ in their dosing schedules and specific medical uses.

Our bodies naturally produce GLP-1 in the small intestine in response to food intake. This hormone then plays a crucial role in regulating blood glucose levels by enhancing insulin production from the pancreas. One advantage of synthetic GLP-1 drugs like Ozempic or Wegovy is their prolonged presence in the body compared to naturally occurring GLP-1.

Mechanism of action: How GLP-1s work in the body

This graph provides a high level overview of the roles of naturally occurring GLP-1 in the body:

(1) When food is consumed, it begins to break down in the stomach and small intestine.
(2) The breakdown of food, particularly carbs, leads to an increase in blood glucose levels.
(3) Cells in the small intestine respond by secreting the hormone GLP-1.
(4) GLP-1 travels through the bloodstream and binds to GLP-1 receptors on the pancreas, which causes pancreas to produce insulin. Insulin then lowers blood glucose.
(5) Insulin promotes the uptake of glucose by tissues, especially muscle and fat cells, for energy use or storage. In the liver, insulin promotes the conversion of glucose into glycogen for storage. All of this leads to a decrease in blood glucose levels.

Since the development of the first GLP-1 medication, Byetta, by Amylin Pharmaceuticals in 2005 and its commercialization by AstraZeneca, these drugs have been widely used for managing type 2 diabetes. Patients and scientists noticed Byetta’s weight loss benefits early on, but it wasn’t until around 2020 that these drugs became significantly popular. Despite its initial success, Byetta, derived from Gila monster venom, was less convenient and offered more modest weight loss compared to today’s GLP-1 drugs. Nonetheless, it paved the way for further research into GLP-1.

Beyond their primary role in glucose control, GLP-1 drugs offer additional benefits, including appetite suppression and subsequent weight loss. These benefits have significantly contributed to the growing interest in GLP-1 medications for both diabetes management and weight reduction.

GLP-1s interact with receptors in the brain to promote satiety and reduce appetite, making individuals feel fuller for longer periods and helping to manage weight. They also slow down gastric emptying, which moderates the rise in blood glucose levels after meals by delaying the entry of food into the small intestine. This not only helps in blood sugar control but also enhances the feeling of fullness. Additionally, GLP-1 medications have been shown to have beneficial effects on cardiovascular health, further contributing to their appeal in treating type 2 diabetes and beyond.

Potential side effects of GLP-1 medications

Some people are concerned about the short- and long-term side effects of taking GLP-1 medications. Overall the risks are small and for many probably don’t outweigh the benefits.

More common side effects include nausea and vomiting. Less common, but more severe side effects that have been reported include gallbladder and pancreas problems.

The majority of people have also reported muscle mass loss because the weight loss is so rapid. A monoclonal antibody called bimagrumab is currently in Phase 2 clinical trials at Eli Lilly. Bimagrumab leads to increased muscle mass and muscle function, and may also further help with weight loss. It will likely be administered along with GLP-1 medication to enhance the overall treatment efficacy by promoting muscle growth while continuing to control glucose levels and aid in weight reduction.

Read about the weight loss drugs currently in clinical trials at Eli Lilly and Novo Nordisk here:

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GLP-1 drugs also include a warning about the risks of thyroid cancer that have been observed in animal studies. However, recent reports suggest no significant risk in humans. Despite this, the FDA advises people with a history of thyroid cancer or a family history of this cancer to avoid GLP-1 drugs.

As mentioned above, GLP-1 drugs also act on the brain, mainly the hypothalamus. Hypothalamus receives signals from different parts of the brain and releases hormones that target other organs and influence many bodily functions, including appetite, fluid balance, heart rate, mood, and sleep. More studies are needed to evaluate the long-term effects of GLP-1 drugs on the hypothalamus.

Additionally, there have been case reports and anecdotal evidence suggesting that GLP-1 drugs can negatively impact mood. Most people experience rebound weight gain when they stop taking the drugs, and repeated yo yo effect can leave people feeling depressed.

Lastly, you may have heard of Ozempic babies, a phenomenon that has gained attention through social media reports of women becoming pregnant while using these drugs, sometimes after previous struggles with infertility or despite using oral contraceptives.

The increased fertility may be attributed to weight loss improving metabolic health and restoring regular ovulation. Additionally, GLP-1 drugs can interfere with the absorption of oral contraceptives due to slow gastric emptying, potentially reducing their effectiveness.

The rise of weight loss drug copycats

The KFF Health Tracking Poll from May 2024 provides significant insights into the public’s use and perceptions of GLP-1 drugs. About 1 in 8 adults surveyed reported having ever taken a GLP-1 drug with 1 in 16 currently taking one. This high demand is behind nationwide shortages that have been happening since 2022 and are expected to last throughout 2024.

KFF survey also reported that about half of adults who have taken GLP-1s say it was difficult to afford the cost of these drugs that come with a hefty price tag of about $1000 U.S. dollar per dose without insurance.

This is where compounding pharmacies come in. Compounding pharmacies in the U.S. operate in a unique niche within the market for weight loss drugs. Regulated by state boards, these pharmacies are authorized to produce customized versions of medications tailored to individual patient needs. This customization can include altering or omitting ingredients to prevent allergic reactions or improving the taste of a medication. They’re also allowed to make compounded drugs during drug shortages.

The Federal Food, Drug, and Cosmetic Act (FD&C Act) mandates that drugs be proven safe and effective for their intended use before marketing. However, once approved, physicians can legally prescribe drugs for off-label uses, as seen with Ozempic and other GLP-1 receptor agonists for weight loss. While this practice is legal, it raises several concerns, mainly regarding safety and efficacy. These concerns have prompted the FDA to issue a warning specifically about compounded semaglutide.

The FDA warned that some compounders may be using salt forms of semaglutide, which are different from the base form used in approved drugs. These salt forms have not been shown to be safe and effective.

The FDA has also found illegally marketed semaglutide products online and is investigating reports of counterfeit Ozempic in the U.S.

While the FD&C Act provides the framework for drug approval and regulation in the U.S., the current trend of using Ozempic for weight loss demonstrates how consumer behavior can sometimes outpace regulatory intent.

Future of GLP-1 medications

Pharma companies are developing new formulations, combinations and delivery methods to enhance efficacy and patient convenience. For instance, Eli Lilly is working on a once-weekly oral GLP-1 receptor agonist, potentially revolutionizing the administration of these drugs. Many companies aside from Lilly and Novo Nordisk are also jumping on the train, testing their own GLP-1s in clinical trials, which could help with shortages in the future.

The GLP-1 landscape is also evolving in terms of treatment guidelines, with organizations like the American Diabetes Association increasingly recommending these drugs as early interventions for type 2 diabetes management. As regulatory agencies continue to monitor the safety and efficacy of these medications, the GLP-1 market is expected to grow significantly, potentially reaching $50 billion annually by 2030.

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Thanks for reading!

DISCLAIMER: This content is for informational purposes only. It should not be taken as medical, legal, investment, financial, or other advice. The views expressed here are my own and do not reflect the opinions of any company or institution.

DISCLOSURE: I have no business relationships with any company mentioned in this article.

Graphs were created using BioRender.com.