Glucagon-like peptide 1 (GLP-1) agonists were on everybody’s mind at the recent JPM healthcare conference in the U.S. as it was one of the major highlights at the event. But all the hype around this class of drugs, which took off when Ozempic was given the go-ahead by the U.S. Food and Drug Administration (FDA) in 2017, was renewed when rival Zepbound was approved mere months ago.
What makes these drugs so special in the first place?
The mechanism behind GLP-1 agonists
GLP-1 is a hormone that is produced by the proglucagon gene in the L cells of the small intestine. L cells are present along the gastrointestinal epithelium, and express hormones like GLP-1 and peptide YY (PYY), both linked to appetite.
The hormone binds to its receptor, which is expressed in various cells including in the pancreas, kidneys, heart and skin. This hormone boosts insulin production in the body. But in people with type 2 diabetes, the insulin response is impaired to GLP-1.
That’s where GLP-1 agonists come into play. These drugs mimic the hormone to stimulate insulin production in the body. As a result, when blood sugar levels increase, say, after a meal, these drugs can lower the blood sugar by causing the body to generate insulin, thereby controlling type 2 diabetes. This is also pretty much how Novo Nordisk’s Ozempic works.
Ozempic vs. Wegovy
The drug, which contains semaglutide, has a dosage of 0.25 mg, which is injected subcutaneously once a week for four weeks. Afterwards, the dosage is increased to 0.5 mg, once a week.
After the FDA and European Medicines Agency approved it in 2017 and 2018, the ‘Ozempic craze’ came to being. As it gained the attention from celebrities and social media influencers as an ‘obesity drug,’ it turned into a fad that sent the wrong public health message.
Firstly, the drug was not prescribed to treat obesity. However, as GLP-1 agonists can target areas of the brain that regulate appetite, people began to take it to treat obesity. While the drug helped people with weight loss, those who continued with a sedentary, high-cholesterol lifestyle, would still be at the risk of developing cardiovascular diseases.
Then, the Danish market leader came out with Wegovy, which, like Ozempic, contained the active ingredient semaglutide but at a different dosage, to treat obesity. Wegovy is of a higher dose, with dosage beginning at 0.25 mg, and steadily rising up to 2.4 mg, once a week.
This raised the sales of Novo Nordisk’s GLP-1 agonists from 113 billion Danish kroner ($16.51 billion) in 2022 to 154 billion kroner ($195.39 million) in 2023. The drugs were so much in demand that, to grapple with the shortage of the drugs, regulators had mulled over a potential ban on Ozempic export in November.
The drugs are now rivaled by Eli Lilly’s Zepbound, which was greenlit by the FDA in November to treat obesity, and is branded as Mounjaro for diabetes. Unlike Novo’s GLP-1 agonists, these are dual agonists, as they activate GLP-1 as well as the hormone glucose-dependent insulinotropic polypeptide (GIP), which plays a role in lipid metabolism and the development of obesity. Zepbound contains the active ingredient tirzepatide.
Plus, there are other GLP-1 agonists in the market, like exenatide, sold under the brand name Byetta and Bydureon, among others, which was the first of its kind to get approval as an anti-diabetic from the FDA, in 2005.
GLP-1 agonist side effects: a concern?
Now, almost two decades later, these drugs remain a hit. But that’s not to say the drugs are without side effects. Typically, they can cause nausea, diarrhea, stomach aches, constipation, low appetite and blood sugar, headaches and sometimes adverse reactions to the injection on the skin, according to the U.K. National Health Service (NHS).
But the most concerning side effects are probably depression and suicidal ideation. A review by Reuters back in October, found 265 reports of patients on GLP-1 agonists since 2010 experiencing suicidal thoughts, out of which, 36% of these reports describe a death by suicide or suspected suicide.
As millions of patients are pushed to get on these drugs to aid in weight loss, there is cause for some worry, according to the report. Wegovy’s U.S. prescribing label explains that patients who participated in clinical trials, did experience depression and suicidal thoughts. So, it is recommended for patients to be monitored when on the drug, and for those who have a history of depression and suicide attempts, to avoid taking it.
But a research paper published in Nature Medicine, discovered that obesity and anti-diabetic drugs that contain semaglutide have a lower risk of suicidal ideation than non-GLP-1 agonists. In fact, it was found that GLP-1 agonists have a 49% to 73% lower risk of first-time or recurring suicidal ideation compared to other obesity and type 2 diabetes drugs, according to a release by the National Institutes of Health in the U.S.
Then, last week, another Reuters report quashed claims linking the class of drugs to these dangerous side effects. However, the report maintains that a small risk cannot be ruled out especially since there is a lack of adequate data to prove otherwise.
Why are GLP-1 agonists so expensive?
Despite evidence suggesting that obesity may often be caused by insulin resistance and hormonal issues, in the U.S., Wegovy is priced at nearly $1,350 a month. It is no longer covered by insurance, with some saying that this is partly because of the stigmatization of obesity. The cost in the U.S. is more than four times higher than Germany’s $328 price tag.
While these drugs are costly out-of-pocket, Novo is set to ramp up production after it performed controlled launches in the U.K. and Germany last year, to pace the demand. The company plans to test different dosages as well as alternate methods of drug delivery, compared to the current injectable option. And, with regards to a broader GLP-1 agonists perspective, GLP-1 production is poised to double this year, according to J.P. Morgan Research.
What GLP-1 means for the biotech industry
At one point last year, these drugs sparked a buying spree, to the extent that Novo Nordisk became Europe’s biggest company by stock market value, briefly dethroning French luxury group LVMH. The Danish company’s stock market value surpassed Denmark’s entire economic output, back in September. Now, the obesity drug market is set to reach $100 billion by 2030, according to BMO Capital Markets analyst Evan David Seigerman.
Moreover, investors have caught wind of the fact that these drugs might be on their way to cure cardiovascular diseases as well. While concrete evidence is yet to prove this, some studies have shown that GLP-1 agonists – Wegovy, in particular – have cut the risk of cardiac-related death in patients with obesity and cardiovascular diseases by 15%, and lowered major adverse cardiovascular events (MACEs) by 20%.
At present, American company Altimmune’s GLP1/glucagon dual receptor pemvidutide is being evaluated in the clinic to treat obesity and non-alcoholic steatohepatitis (NASH). An interim readout of the phase 2 trial showed that the drug led to lower amounts of serum lipids including total cholesterol and low-density lipoprotein (LDL-C), improved blood pressure and contributed to weight loss.
And, as it looks to go head-to-head with Wegovy and Zepbound once it enters the market, Pfizer’s danuglipron is also being developed in the clinic. Although a phase 2b trial of the drug under a twice-daily formulation was canned for mass discontinuations last month, a once-daily dosage study will begin soon.
Whether these drugs will be effective in treating cardiovascular illnesses, we are a long way ahead of finding out, but the industry can hope to see a spike in sales, and further advances in GLP-1 research in the near future.