Pharma companies home in on GLP-2s and GLP-3s in race to innovate on obesity treatments

It’s hard to avoid GLP-1s. These popular diabetes and weight loss medications are all over commercials, the internet and prescription pads. Analysts are very bullish on their future earning potential, too: Overall, Morgan Stanley projects the GLP-1 market will be worth $190 billion by 2035, compared to the $79 billion in recorded 2025 total sales.

Pharma companies are looking to get a piece of that pie, in part, by GLP-one-upping each other. To do that, they’re developing novel GLP-based combination therapies.

Let’s break down two elements of that strategy: GLP-2s and GLP-3s.

What’s a GLP-2? GLP-2 is a molecular cousin of GLP-1. Both hormones are made from the same “parent” protein called proglucagon.

As a reminder: GLP-1 triggers the release of insulin, which is why drugs mimicking this hormone help treat diabetes. It also helps people feel full, which is why drug versions help with weight loss. Drugs like Ozempic and Wegovy (semaglutide) are GLP-1 receptor agonists, which means they turn up the natural effects GLP-1 has on the body.

GLP-2 helps keep the intestinal lining healthy by promoting gut growth and aiding in the absorption of nutrients, including fats. Because of this, the use of GLP-2 agonists for weight loss is a bit “counterintuitive,” David Cummings, a professor of medicine in the University of Washington’s Division of Metabolism, Endocrinology, and Nutrition, told Healthcare Brew.

Currently, the only FDA-approved GLP-2 is a drug called teduglutide, which is made by Takeda Pharmaceuticals. It hit the market in 2012. It’s used to treat short bowel syndrome, a rare condition in which the body is unable to absorb enough nutrients, either because part of the intestine is missing or damaged.

In March, Danish researchers published a small study funded by biotech Zealand Pharma exploring a combination GLP-1/GLP-2 therapy called dapiglutide. They found that the medicine helped participants lose some weight, but the loss wasn’t statistically significant. The authors concluded that “the findings support further investigation of higher doses in larger and longer studies to evaluate the weight-lowering potential of dapiglutide.”

In early June, the Indianapolis, Indiana-based pharma giant Eli Lilly bought a GLP-2 drug called sonefpeglutide from Korean drugmaker Hanmi Pharmaceutical for $75 million. Hanmi stands to gain an additional $1.2 billion if certain milestones are met, such as its drug gaining FDA approval.

Hanmi has studied the GLP-2 as a short bowel syndrome treatment. Lilly hasn’t disclosed its plans for sonefpeglutide, so it’s unclear whether the drugmaker is exploring its use in combination with a GLP-1 agonist. Lilly declined Healthcare Brew’s request for comment on the matter.

Already, Lilly has invested heavily in combination therapies. Zepbound and Mounjaro, which are FDA-approved for the treatment of obesity and diabetes, respectively, share the active ingredient tirzepatide. It activates receptors for GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). GIP is a hormone the small intestine releases to stimulate insulin secretion and regulate blood glucose.

A 2024 study published in the journal JAMA Internal Medicine found that patients on tirzepatide were more likely to lose weight than those taking semaglutide.

The addition of GIP agonists helps to further suppress appetite and increase satiety, Cummings said.

Now, on to GLP-3s. The term “GLP-3” does not actually refer to a specific peptide or hormone. Instead, it has become an informal term used to refer to triple-agonist medications.

Triple-agonist medications typically activate GLP-1 and GIP receptors, plus a third receptor that binds to the hormone glucagon. Like GLP-1 and GLP-2, glucagon comes from proglucagon—hence the name! (GLP stands for “glucagon-like peptide.”) Glucagon is a hormone that keeps blood sugar from dipping too low.

Retatrutide, one such investigational triple-agonist from Eli Lilly, is the “GLP-3” furthest along in development, currently in Phase 3 trials. Preliminary results show retatrutide can help patients on the highest dose lose an average of 28.3% of their body weight over 80 weeks.

“It’s about the same as a sleeve gastrectomy, the most common bariatric operation that’s performed,” Cummings said. “It’s not as much weight loss as you’d typically expect with a gastric bypass, so it’s not yet defeated metabolic bariatric surgery for weight loss, but it’s certainly knocking at the door.”