New Obesity Drug Targets Four Hormones for Superior Weight Loss

The New Drug Blockbusters

Since its effects on weight loss became well known, the diabetes drug semaglutide, commercialized by Novo Nordisk (NVO -1%) under the brand name Wegovy, has taken the pharmaceutical industry by storm.

Since semaglutide was found to help with heart diseases and cardiovascular risks, irrespective of whether the patient is already suffering from it or not, and whether the patient is diabetic or not.

Still, semaglutide is far from perfect, with side effects like nausea leading many patients to quit using it, despite the weight loss benefits.

This has opened the way for a new stream of anti-obesity drugs, dealing with this disease by regulating hormones controlling blood sugar, appetite, and the body’s metabolism.

Obesity is a significant public health issue, with the lives of hundreds of millions at stake due to the risks associated with obesity.

“Obesity is linked to over 180 different disease conditions, including cancer, cardiovascular disease, osteoarthritis, liver disease, and type 2 diabetes, and affects over 650 million people worldwide.”

Krishna Kumar – Professor of Chemistry at TUFT

With a potential $150B market to grab, this should be of prime interest to investors, a topic we discussed in our article “Top Companies in Obesity Treatments”.

Hormonal Drugs For Treating Obesity

Semaglutide & GLP-1

Semaglutide mimics a weight-related hormone called GLP-1 (glucagon-like peptide-1). It is a rather complex molecule, and its production process is not trivial, leading to Novo Nordisk struggling to keep up with the exploding demand throughout 2023 and 2024.

Source: News Medical

The way it works is by regulating a wide array of digestion and metabolic mechanisms, impacting insulin production in the pancreas, regulating blood sugar levels, slowing digestion, and reducing appetite.

(If you want more details, you can read a compilation of scientific publications about semaglutide in Science Direct.)

Unfortunately, the drug also comes with some common side effects.

“The biggest problem with GLP-1 drugs is that they have to be injected once a week, and they can induce a very strong feeling of nausea. As much as 40% of people using these drugs give up after the first month.”

Krishna Kumar – Professor of Chemistry at TUFTS

Glucose-Dependent Insulinotropic Peptide (GIP)

GIP is another hormone released after eating, which makes us feel full after a meal. GIP is rather similar to GLP-1, and so a drug displaying the chemical structure and effects of both was developed, tirzepatide. Commercialized under the brand names Mounjaro (for diabetes) and Zepbound (for obesity), it is produced by Ely Lilly (LLY -0.06%). Together, Mounjaro and Zepbound sold for a total revenue of $16.5B in 2024.

This drug has the advantage of reduced nausea and might, as a result, be a serious competitor to Wegovy.

Glucagon

This trend of adding more functions from other hormones to the semaglutide chemical structure is a durable one.

Another product, retatrudide, is currently undergoing clinical trials and has just done that. Not only does it have GLP-1 and GIP functions, but it also acts like glucagon, another closely related hormone. As each of these hormones has its own receptors in human cells, the combined effect can be better tolerated and more powerful.

This is also being developed by Eli Lilly, confirming the solid position of the company in the sector.

The early clinical trial indicates that it might have an even greater achievable weight loss (up to 24%) compared to the original GLP-1 drugs (6-15%).

Why Four Hormones Might Be Better Than One

Not As Good As Surgery

Still, the ultimate standard to which obesity drugs need to be compared is bariatric surgery. This surgery reduces the size of the stomach or sometimes bypasses the stomach to reduce the amount of food digested.

Source: Gleneagles Hospital

While highly invasive, bariatric surgery can achieve a long-lasting weight loss of up to 30%, which is associated with radical improvement on countless health indicators, and overall reduced mortality.

If the combination of another and then two additional metabolic hormones to GLP-1 effects provides better results, why not try four?

Peptide YY (PYY)

PYY is a molecule secreted by the gut after we have eaten a meal. Its main role is to reduce appetite and slow the food-emptying process out of the stomach.

More interestingly, these effects are mediated by an entirely different mechanism than either GLP-1 or GIP.

It might even have an additional effect of “burning off fat, which is of course one of the most desired final effects of any anti-obesity drug.”

Because PYY is part of a completely different class of hormones from GLP-1, GIP, and glucagon, it has more potential for synergy with these hormones than adding another glucagon-like hormone to the mix.

This direction of anti-obesity drug development is the one that a team of researchers has taken, with their results recently published in the Journal of the American Chemical Society¹, under the title “Molecular Design of Unimolecular Tetra-Receptor Agonists”.

Building A Tetra-Receptor Agonist

Because the PYY receptor belongs to an entirely different class of protein, so far no progress has been made to leverage it to regulate appetite and fight obesity.

This is not true anymore, as the researchers published chimeric peptides able to contain the sequences of GLP-11, GIP, glucagon, and PYY all at once, while preserving their structural integrity.

It was done by joining two peptide segments end-to-end, creating a new ‘tetra-functional’ clinical candidate.

Source: Journal of the American Chemical Society

Impact On Future Therapies

One important element is that this approach could lead to an obesity treatment using drugs that take into account that different people have different metabolic and genetic profiles.

“One of the limitations of the current drugs is that individual variation, possibly including how people express target receptors or respond to their corresponding hormones, can lead to lesser than desired weight loss outcomes in many patients,”

Martin Beinborn – Professor of Chemistry at TUFTS

For example, if a patient has a different profile on the GLP-1 gene or protein presence in its cells in particular, Wegovy might have widely varying effects compared to another patient.

But if 4 different mechanisms are activated, along 2 completely different classes of proteins and receptors, the effects might be both more consistent and more powerful.

“By hitting four different hormone receptors at the same time, we hope to improve the chances of averaging out such variation toward the goal of achieving greater and more consistent overall effectiveness.”

Martin Beinborn – Professor of Chemistry at TUFTS

Another question about obesity drugs is the nature of body weight being lost. Losing fat is desirable, but losing muscle mass is not.

This can be compounded by the tendency of patients to regain weight when interrupting the treatment, with a seesawing effect of losing both fat and muscles when losing weight, but regaining only fat during the rebound.

“This two-pronged approach will not only support reaching and keeping one’s target weight, but may also help preserve bone and muscle mass.”

Martin Beinborn – Professor of Chemistry at TUFTS

Investing in BioTech

Eli Lilly and Company

After the astounding success of Novo Nordisk with Wegovy, its competitors worked hard to catch up and propose an even better alternative.

One of them is Eli Lilly, another prominent player in the diabetes drug market, with extensive experience working with incretin analogs, the class of molecules including GLP-1, glucagon, and GIP.

Eli Lilly is now the market leader in incretin analogs in the USA, with 53.3% of the market share of total prescriptions. This resulted in the company seeing a revenue growth of 45% year-to-year for its key products, which also include non-diabetes, non-obesity related drugs.

Source: Eli Lilly

As mentioned above, Mounjaro/Zepbound is only a step on the way, with the additional effect of glucagon to be added to a new product in the future, if the clinical trials go well.

Another potentially new important obesity drug is orforglipron, an oral version of GLP-1, which would be easier to take than the current ones, based on injections.

To answer the associated demand with these strong sales, the company is planning to drastically expand its US manufacturing capacities, with a total of $50B of investments planned. Eli Lilly is also planning to increase its R&D spending by 8%.

It should be noted that Eli Lilly is a more diversified company than Novo Nordisk, with notably a pipeline on Alzheimer’s, Parkinson’s, cancer, autoimmune diseases (Crohn’s, Rheumatoid Arthritis, Multiple Sclerosis), etc.

Source: Eli Lilly

So while obesity drugs and diabetes are becoming the core of the company’s revenues, these segments should also be considered by potential investors.

Latest Eli Lilly (LLY) Stock News and Developments

Study Referenced

^{1. Tristan C. Dinsmore, Jacob E. Cortigiano, Siyuan Xiang, Marina V. Spenciner, Alexandra R. Dobbins, Richard L. Zhao, Brett M. Waldman, Martin Beinborn, and Krishna Kumar. Molecular Design of Unimolecular Tetra-Receptor Agonists. Journal of the American Chemical Society 2025 147 (24), 20819-20832. https://doi.org/10.1021/jacs.5c04095}