Across the past two years, GLP-1 agonists—a class of drugs that treat type 2 diabetes (T2D) and obesity—have not only become a major source of industry discourse, but a household name. These medications, which mimic the functions of the naturally occurring hormone GLP-1 (glucagon-like peptide-1), have been lauded for their efficacy in not only controlling blood sugar levels but also promoting weight loss.
As of mid-2024, a full 6% of US adults are actively taking GLP-1 agonists, but the huge potential addressable market for these drugs, combined with an ongoing shortage, means that these medications have plenty of additional potential running room. These levels of demand—and the pervasiveness of these drugs in the public domain—are virtually unprecedented, meaning that all healthcare professionals and industry generalists must stay on top of developments in this space.
In today's post, we'll break down what we do—and don't—know about these medications as of August 2024.
What are GLP-1 agonists, and why is everyone talking about them?
GLP-1 is glucagon-like peptide, a hormone that the body produces on its own. The hormone is produced by the small intestine and plays a variety of roles, including regulating appetite, facilitating digestion, and helping to normalize/lower blood sugar levels. Glucagon-like peptide receptor agonists (GLP-1 RAs or GLP-1 agonists for short) are drugs manufactured to bind to GLP-1 receptors, essentially mimicking and magnifying the effects of these hormones.
Why are GLP-1 agonists so groundbreaking?
Evidence so far demonstrates that GLP-1 agonists can produce unprecedented results for people trying to achieve weight loss, in some cases enabling patients to lose 15-20% of their body weight—two to three times the amount achieved with previous medications.
We are also finding out that the impacts of GLP-1 agonists go beyond weight loss, manifesting in sometimes surprising ways. Studies have shown that GLP-1 agonists can trigger effects in the brain, the heart, the liver, the pancreas, the stomach, and the muscles—meaning that they could have implications for conditions other than type 2 diabetes and obesity, such as heart disease, kidney disease, liver disease, and even neurological conditions such as Alzheimer's disease.
Why are we talking about GLP-1 agonists now?
GLP-1 agonists are not exactly new, although this is a common misconception. The first GLP-1 agonists—intended to treat T2D—came onto the market almost two decades ago. And the first GLP-1 agonist for obesity/weight loss was approved a full decade ago.
Neither of these medications gained much traction. Byvetta, the first to be approved, faced lawsuits and gained a FDA warning after being associated with several severe cases of pancreatitis. Saxenda, the second to be approved, only achieved middling weight-management results for a large share of those who took it, and physicians were reticent to prescribe weight-loss medications after the disastrous effects of drugs such as fen-phen were revealed in the late 90s.
The current surge in demand began in 2017, when Novo Nordisk released Ozempic to the market. Ozempic initially had a stable but relatively small user base, comprised primarily patients with T2D who could not take or weren’t responding to the existing first line treatment metformin.
In 2021, the FDA approved Novo Nordisk's Wegovy, a slight reformulation of Ozempic designed specifically for weight loss, which drove a huge spike in public awareness of GLP-1 agonists. The medications were further popularized due to their supposed use by various celebrities for cosmetic weight loss purposes.
What is the potential user base for GLP-1 agonists?
Popularity spiked dramatically following Wegovy's approval, with prescriptions doubling in 2022 and again in 2023. Early data for 2024 suggests that the number of new prescriptions will rival last year's numbers, if not exceed it.
But even with hundreds of thousands of new prescriptions every year, the widespread incidence of both diabetes and obesity means there is a lot more room to run. As noted earlier, about 6% of Americans are currently taking GLP-1s—but 10% of U.S. adults have type 2 diabetes and over 40% have obesity.
Drugmakers are actively working to secure FDA approval for other clinical indications as well. In March of this year, Wegovy was approved for overweight or obese patients with cardiovascular disease.
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What are the risks or concerns associated with GLP-1 agonists?
#1: Compounded semaglutide and counterfeit drugs
By all accounts, there continues to be a sizable supply shortage for GLP-1 agonists. That gap in supply has given a boost to compounding pharmacies (who are allowed to produce customized versions of drugs, OR identical versions of drugs that are in short supply i) and online prescribing platforms. It has also given rise to concerns about counterfeit drugs that may be circulating on the market, as well as the safety and efficacy of the compounded semaglutide produced by compounding pharmacies.
In January of this year, the FDA noted that it had "received adverse event reports after patients used compounded semaglutide" and that "patients should not use a compounded drug if an approved drug is available to treat a patient." In July, the agency followed up with a notice that it had "received reports of adverse events, some requiring hospitalization, that may be related to overdoses due to dosing errors associated with compounded semaglutide injectable products." And in August, Eli Lilly, the maker of Zepbound and Mounjaro, sent a series of cease-and-desist letters to providers urging them to stop prescribing compounded versions of those drugs.
#2: Adverse effects and long-term efficacy
There have been quite a few studies measuring adherence among different groups and with different formulations, so the exact numbers vary. But the overall takeaway is that it is challenging to stay on these medications, even in clinical trial conditions.
Recent data from insurance claims indicates that 30% of patients stop treatment within a month, well before any clinically meaningful results could be achieved. And over half stop within the first three months, which might be enough to achieve some mostly cosmetic weight loss, but little more. Within two years, the vast majority of patients have stopped taking their GLP-1 agonists. Because these drugs essentially act as hormones (which, once metabolized, lose their efficacy), this drop in adherence may not bode well for maintaining the effects of these drugs in the long term.
It’s not hard to understand why sticking with this regime is challenging—a large minority of patients report unpleasant side effects such as nausea and vomiting, and some experience additional side effects such as injection-site reactions, infections, heart burn, and headaches. The FDA is also tracking some adverse event reports that starting GLP-1 treatment caused or exacerbated serious psychiatric conditions associated with depression and suicidality.
Even among those that don't report significant clinical side effects, the financial burden of these drugs, as well as the injectable nature of the most popular versions (which much be administered via subcutaneous injection), are major deterrents for many patients.
And a not-insignificant minority of patients point to a lack of efficacy—either insufficient weight reduction or lack of significant decrease in blood glucose levels.
There is work being done now to help address some of these shortfalls.
Manufacturers are in the process of making new GLP-1s that are easier to produce, store, and administer. These take the form of orally-administered pills or injectables that can be taken at a lower frequency, both of which have the potential to bring down costs and increase the appeal for patients who dislike self-injection.
There are also new formulations that act on other receptors in addition to GLP-1 receptors to significantly increase the medication's effectiveness, in some cases doubling the weight reduction patients experience.
Both of these innovations are on the market already. The oral GLP-1 RA Rybelsus is available now. And while not quite as effective as injectables, it is more accessible for some. Mounjaro and Zepbound are Lilly’s dual agonists that seem to surpass Novo Nordisk’s Ozempic and Wegovy in weight loss power.
The last category of innovations, which is targeted at reducing the negative side effects, is more experimental. Clinical trials are being run on combination therapies that can help preserve muscle mass—a big issue for GLP-1 users—and maybe even cut back on GI symptoms.
#3: Spending impact
Of course, a final area of concern centers around the cost of these drugs. The price of these medications (roughly $1,000 per month before insurance) is not particularly high on a unit basis compared to many other drugs on the market. But the fact that patients must take these drugs into perpetuity to maintain their effects makes the potential cost base quite large, especially given the large size of the total addressable market.
A major open question at this point is how the spending impact of these drugs might compare to the avoided cost of alternative treatments. Perhaps nowhere is this tension more apparent than in the case of chronic kidney disease (CKD)—a condition that is currently difficult to treat, typically leading to dialysis, transplant, or even death. CKD is a major cost driver for Medicare, accounting for nearly $90B in spending a year. Studies from Novo Nordisk show an almost 25% reduction in adverse kidney outcomes for diabetes patients with CKD, and the company is trying to get Wegovy’s indications expanded to include CKD before year’s end.
Want more on GLP-1 agonists?
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