Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have taken the type 2 diabetes and obesity market by storm. Outside of the pharmaceutical industry, Wegovy and Zepbound are becoming household names with the products becoming popular with influencers on social media.

As the hype around them intensifies, the candidates are being investigated in other indications beyond metabolic disorders, with trials underway in cardiovascular, neurodegenerative, and respiratory disease. As more indications emerge that respond to these drugs, the question is where will the market end?

Market leaders for GLP-1RAs NovoNordisk and Eli Lilly are now the two biggest pharmaceutical companies in the world, with NovoNordisk holding the position of the biggest company in Europe. NovoNordisk has a market cap of $426.5bn while Eli Lilly’s market cap is $730.6bn.

Novo Nordisk is the market leader in the GLP-1RA space, with a value market share of 65.2%.

Despite their significant influence in the market, neither NovoNordisk nor Eli Lilly were the first to market a GLP1ra drugs. Amylin Pharmaceuticals and AstraZeneca were the first companies to market, releasing exenatide in 2005.

NovoNordisk’s candidate semaglutide is marketed as Ozempic for type 2 diabetes and Wegovy for obesity. GlobalData predicts a global sales forecast of semaglutide of $44bn in 2029.

Eli Lilly’s candidate tirzepatide is marketed as Mounjaro for type 2 diabetes and Zepbound for obesity. GlobalData predicts a global sales forecast of tirzepatide of $33.4bn in 2029.

GlobalData is the parent company of the Clinical Trials Arena.

How new indications were discovered

Currently, most indications being investigated are co-morbidities after investigators saw signals in type 2 diabetes and obesity trials that this drug may be effective elsewhere. Sydney Wilbon, a PhD student at the University of Texas, who wrote a paper on GLP-1RAs effects beyond obesity and diabetes, says: “They saw decreases in cardiovascular events, strokes, decrease in renal progression and that has prompted this new research interest in these other indications for the drugs.”

The number of trials being conducted in these drugs beyond obesity and diabetes peaked in 2023, with the numbers of trials initiating yearly nearly tripling since with 2013.

Dr. Sulagna Misra who runs Misra Wellness in Los Angeles says that as an obesity specialist, she witnesses first-hand the benefits they provide patients with comorbidities of their disease.

“When we treat obesity, we treat things that are related to the condition, so it's easy for us to say that these will likely help in cardiovascular related syndromes or metabolic related because we're addressing hormones and we're addressing the weight,” Misra says.

Gastrointestinal, cardiovascular and CNS leading the way

According to GlobalData’s Pharmaceutical Intelligence Centre, the majority of trials for GLP1-RAs are still in metabolic disorders, even when excluding diabetes and obesity. The next largest therapy areas overall are gastrointestinal, cardiovascular, and the central nervous system.

Some of the main indications which GLP-1RAs are being investigated in are liver diseases (6.2%), non-viral hepatitis (4.1%), steatohepatitis (4.1%), metabolic dysfunction-associated steatohepatitis (MASH) (4.1%), cardiovascular disease (3.9%), fatty liver disease (2.8%) and neurology (2.7%).

Wilbon especially has high hopes for their treatment in cardiovascular diseases. “The cardiovascular system has a higher level of expression of these receptors and cardiovascular disease is one of the major comorbidities in people with diabetes, it is in fact the number one cause of death in this population,” says Wilbon.

Other indications include polycystic ovarian syndrome, myocardial infarction, kidney disease, psychiatric disorders, Alzheimer’s disease, Parkinson’s disease, and addictive disorders.

It is not just the heart and pancreas where GLP1 is expressed Wilbon says. “There's also a very high expression of the GLP1 receptor in the brain as well and that is what actually mediates the reduced appetite that a lot of patients experience,” says Wilbon.

Anand Parikh, CEO at Faeth Therapeutics, which is developing its own metabolic candidate that targets the phosphoinositide 3-kinase pathway in oncological indications, says he has hopes that GLP-1RAs will be assistive in a number of diseases associated with obesity and type 2 diabetes including sleep apnoea, cardiometabolic disease and potentially even some rare diseases. He has some reservations however about neurological and neurodegenerative diseases at this point.

“There's this old joke that neurology is 30 years behind oncology and in some ways, neurology is getting to where oncology was in the 1990s where everything is genetic. In the same way that oncology over rotated towards genetics, I think that is going to happen in neurology but as there becomes a more metabolic understanding of neurology I think GLP-1RAs could play a role,” Parikh explains.

While Professor Mikhail Kolonin, director of the Center for Metabolic and Degenerative Diseases, says they can work in some capacity but that there will be a limit. “For patients who have developed symptoms of Alzheimer's or Parkinson's, they're not going to help. As far as being drugs to cure diseases, I don’t know - time will tell but there will be a limit,” he says.

Although there are very few trials at this stage, GLP-1RAs are also being investigated in some oncological indications, but Parikh says that researchers must be cautious as they could worsen the disease of some cancers.

“For cancers that have high rates of cachexia like a pancreatic cancer, you will not want to use a GLP-1RAs or you would have to be very careful about dosing,” Parikh explains. “These are patients who already struggle to eat and are losing lean body mass so the GLP-1RAs could have an antagonistic effect on what is already a poor side effect of the disease.”

Sponsor or institution led?

As in diabetes and obesity, NovoNordisk is leading the way in alternative indications, running 17% of trials, with Eli Lilly holding the second spot, running 9% of these trials. Other big names are trying to make their mark with Pfizer, AstraZeneca, and Merck all in the top 10 sponsors.

Misra says she is not surprised that sponsors like NovoNordisk and Eli Lilly are leading the way, adding she would be more surprised if the companies were not on top.

“I would be surprised if they didn't pour money into this space. It would be idiotic to not get indications for all things that are obesity related when they are already approved for obesity. It's the easier pathway which is why they're doing these investigations and there's money there,” says Misra.

Commercial sponsors are leading the way in a variety of therapy areas beyond metabolic disorders including gastrointestinal and musculoskeletal disorders. Meanwhile, institutional sponsors are conducting the majority of trials in central nervous system, cardiovascular and respiratory.

Misra says that it is not surprising that institutional sponsors are leading the way here. “Cardiologists don't want patients dying on the table. Everyone wants improved cardiovascular outcomes and we know these drugs improve cardiovascular outcomes in conjunction with other cardiovascular drugs, so they need to be involved,” Misra explains. For the same reasons, Misra adds she is not surprised that institutional sponsors are leading the way in respiratory trials.

“Large sponsor large trials are designed for an approval while investigator-initiated trials are to find the information which cardiologists and pulmonologists want to convince them that this isn't just a way for patients to lose weight,” Parikh adds.

How will GLP-1RAs fit in the treatment paradigm?

With the candidates being investigated in so many indications, if efficacious, the next question is whether they will be approved and if they will become first line therapies.

According to Wilbon, for indications such as certain neurodegenerative diseases, they could become a first line therapy but only in lieu of anything better.

“For patients with many comorbidities, because these drugs hit so many targets at the same time, you can reduce the number of pills a patient's taking, which makes it a very attractive first line therapy option,” Wilbon adds.

Kolonin has concerns if these were to become commonly used drugs. “My worry would be that patients will develop resistance to them. I anticipate we will be hearing about that.”

Another question is if the candidates are efficacious in many indications will they be classified as ‘wonder drugs’?

Wilbon says the term wonder drug should be used with caution. “All drugs have side effects and those have to be very much considered. Also, the indications for these drugs haven't been proven outside of diabetes and obese populations, which I think limits the ability to call them a wonder drug.”

However, Kolonin disagrees to an extent. “I think they could be considered a wonder supplement. I think a lot of people would be willing to start taking them routinely like we take vitamins because they're safe, they're made by the body and they do good things,” he explains.

Parikh also has reservations, saying that in his opinion metabolic drugs like GLP-1RAs are unlikely be effective enough as monotherapies for some indications, but believes there is real promise as combination therapies.  “The concept of metabolic synthetic lethalities, where you hit the genetics of whatever disease you're looking at, but then you use metabolism to block the resistance pathways or the escape pathways,” says Parikh.

“This is going to be a really interesting ticket that I think has applicability, way beyond cancer, rare disease, or inborn errors of metabolism or even cardiometabolic disease,” Parikh concludes.