Tripling down on GLP-1: The new triple receptor agonist drug as a weight-loss treatment.

The two pharmaceutical leaders in weight-loss drug race; Eli Lilly and Novo Nordisk developed and have been testing their triple receptor agonist drugs during clinical trials for weight loss. This new triple receptor agonist consists of glucagon peptide-1 receptor agonist (GLP-1 RA), glucose-dependent insulinotropic polypeptide (GIP), and glucagon.  

Eli Lilly is currently testing Retatrutide, an experimental triple receptor agonist drug for patients with obesity (without diabetes, whereas Novo Nordisk, with collaboration with another partner, The United Bio-Technology Co. is testing UBT251 in patients with type 2 diabetes (T2D). The weight loss results from each drug have been impressive, and each drug seems to cause greater weight loss than the previous GLP-1 receptor agonists that were available on the market. Here is a quick review of what’s been happening in clinical trials run by each company testing its triple receptor agonist weight loss drug.

Eli Lilly

During TRIUMPH-1 phase 3 clinical trial, the highest dose (12mg) of retatrutide resulted in 28.3% weight loss over 80 weeks with 45.3% of participants achieving greater or equal to 30% weight loss. Lowest dose (4mg) resulted in 19.0% weight loss in 80 weeks. (done in patients with BMI greater than or equal to 35 without diabetes). In patients with type 2 diabetes, TRANSCEND-T2D-1, a phase 3 clinical trial for treatment of T2D with retatrutide, the highest dose 12 mg, achieved 16.8% weight loss over 40 weeks, and lowered A1C by an average of 1.7% to 2% across doses at 40 weeks in TRANSCEND-T2D-1 phase 3 clinical trial.

Novo Nordisk and The United Bio-Technology Co., Ltd.

During phase 2 clinical trial, Novo Nordisk-partnered drug achieved 19.7% weight loss in China. UBT251 also lowered A1C levels up to 2.16% after 24 weeks.

How do these triple receptor agonist drugs work?

First, the mechanism and the effects of GLP-1 receptor agonist is well known. The agonist binds to its receptor to suppress appetite, slow down digestion, and decrease blood sugar levels. GIP, when combined with GLP-1 receptor agonist, amplifies the all of these effects induced by GLP-1 receptor agonist.

Then, how does glucagon, the third component of the triple receptor agonist drug help with weight loss?

1. Glucagon increases energy expenditure by stimulating thermogenesis (heat production), causing the body to burn more calories throughout the day. This helps counteract the decrease in metabolic rate that typically occurs during weight loss.

2. Glucagon promotes lipolysis, which means it signals the liver and fatty tissues to break down stored fat into usable energy.

Question: I thought glucagon raises blood sugar by signaling the liver to release stored sugar, so how does this help patients with type 2 diabetes?

Glucagon in retatrutide or UBT251 activates glucagon receptor only subtly, which allows stimulation of fat burning without significantly increasing bloodstream with stored sugar. Also, the GLP-1 and GIP receptor agonists of this drug stimulates insulin secretion and slows gastric emptying, which in combination can neutralize any potential blood sugar-raising effect by glucagon. This is why retatrutide or UBT251 administration results in net decrease in blood sugar and HbA1c during weight loss.

Side effects of retatrutide and UBT251

Safety and tolerability profile of retatrutide is like UBT251. The side effects of the triple receptor agonists like retatrutide and UBT251 showed occurrences of vomiting, nausea, headache, diarrhea, constipation, abdominal pain, which are similar to those shown from patients treated with GLP-1 receptor agonists (Zepbound or Wegovy) and dual agonist tirzepatide.

Who is winning the “race?”

So far, Elli Lilly is hitting stride with their triple receptor agonist, retatrutide as an experimental drug that has been shown up to 30% weight loss for people who participated in the clinical trial, which is greater weight loss than any other GLP-1 receptor agonist drugs in the market. The side effects of these triple agonist drugs still present, and the side effects are like those of other GLP-1 receptor agonist drugs available: nausea, diarrhea, vomiting, and more.

We will see what’s in the future for weight loss drugs in terms of their side effects. Whether it’s single, dual, or triple receptor agonis, the side effects are still present in all the GLP-1 receptor agonist-containing drug.

Pharmaceutical companies are already investing in developing weight loss drugs that minimizes these side effects. It’s unclear whether this effort will result in development of supplementary drug or a completely new drug to cause weight loss while minimizing the side effects. Who knows? Perhaps, we will soon see a quadruple receptor agonist.

References

1.       Al‑Haddad M, Al‑Haddad M, Al‑Haddad M, et al. Association Between Vitamin D Deficiency and Severity of COVID‑19 Infection: A Systematic Review. Cureus. 2024;16(7):e66731. Published July 10, 2024. doi:10.7759/cureus.66731

2.      Novo Nordisk. Novo Nordisk announces positive results for amycretin in obesity treatment. Published January 5, 2025. Accessed June 8, 2026. https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=916519

3.      Clinical Trials Arena. Novo Nordisk‑partnered drug shows 19.7% weight loss in Phase II trial. Published January 6, 2025. Accessed June 8, 2026. https://www.clinicaltrialsarena.com/news/novo-nordisk-partnered-drug-shows-19-7-weight-loss-in-phase-ii-trial/

4.      Eli Lilly and Company. Lilly’s triple agonist retatrutide delivered powerful weight loss in clinical study. Published June 26, 2023. Accessed June 8, 2026. https://investor.lilly.com/news-releases/news-release-details/lillys-triple-agonist-retatrutide-delivered-powerful-weight-loss

Eli Lilly and Company. Lilly’s triple agonist retatrutide demonstrated significant weight loss in Phase II trial. Published June 26, 2023. Accessed June 8, 2026.

Assessed and Endorsed by the MedReport Medical Review Board