Key takeaways: Eli Lilly announced that a mid-stage trial in patients with obesity and type 2 diabetes showed its investigational combination therapy produced greater weight loss than high-dose tirzepatide, the company's flagship drug, used alone.

The data fueled market expectations that this drug could become a major backup therapy for patients who do not respond to existing GLP-1 products or whose weight loss falls short of expectations.

Lilly stated it plans to launch a Phase III trial of the combination therapy by the end of this year.

On Wednesday, Eli Lilly said that results from a Phase II trial in patients with obesity and type 2 diabetes showed its investigational combination therapy achieved greater weight loss than high-dose tirzepatide, the company's flagship drug, used alone.

The combination therapy met its primary endpoint in a patient population where weight loss is generally difficult to achieve. The results raised market hopes that it could become a major backup treatment option for patients who do not respond to existing GLP-1 drugs or whose weight loss falls short of expectations.

Lilly said it plans to initiate a Phase III trial of the therapy by year-end.

The combination pairs Lilly's investigational drug eloralintide, which targets amylin (a pancreatic hormone involved in regulating appetite and satiety), with low-dose tirzepatide. Tirzepatide is the active ingredient in the obesity injection Zepbound and the diabetes drug Mounjaro. Tirzepatide acts on two gut hormones: GLP-1 and GIP. Lilly believes that simultaneously activating three pathways, including amylin, can further suppress appetite and enhance weight loss; this was indeed confirmed in the 48-week Phase II trial.

Patients in the highest-dose group of the combination therapy achieved average weight loss of up to 23.3%, or approximately 54 pounds. The combination regimen was 9 mg of the amylin drug plus 15 mg of tirzepatide. In comparison, patients taking 15 mg of tirzepatide alone lost an average of 14.8%, or approximately 34.4 pounds; those taking eloralintide alone lost up to an average of 12.3%, or approximately 28.6 pounds.

Ken Custer, president of Lilly's cardiometabolic health division, said in an interview: "Some patients cannot achieve treatment goals with tirzepatide alone, and they also cannot with eloralintide alone. Combining the two to achieve stronger weight loss is undoubtedly one of the most intuitive advantages of this new therapy."

On September 21, 2026, in Houston, Texas, the Lilly logo was displayed at the groundbreaking ceremony for the Lilly pharmaceutical industrial park. The combination therapy also significantly reduced glycated hemoglobin (A1C, a core measure of blood sugar), with an average reduction of up to 2.9%; high-dose tirzepatide alone achieved an average reduction of up to 2.4%, and amylin monotherapy achieved an average reduction of up to 1.4%.

Investors and the medical community will likely focus next on patients' tolerability and persistence with this potent combination therapy. In the trial, the proportion of patients discontinuing the combination therapy due to adverse reactions ranged from 10.8% to 27% (varying by dose), significantly higher than the 2.9% in the tirzepatide monotherapy group. The eloralintide monotherapy group had a discontinuation rate due to adverse reactions of up to 10.8%, while the placebo group was 16.7%.

Lilly said the incidence of adverse reactions with the combination therapy was higher than with tirzepatide alone or eloralintide alone. The most common adverse reactions with the combination therapy were gastrointestinal, mostly mild to moderate, and occurred mostly during the dose-escalation phase of the trial.

However, Custer cautioned against overinterpreting the discontinuation rates from the Phase II trial. He noted that in a mid-stage trial in 2018, high-dose tirzepatide also had a relatively high discontinuation rate of about 25%. "This metric may not necessarily reflect the drug's final tolerability well," Custer said in an interview. "The purpose of Phase I and Phase II trials is to test the efficacy potential of the molecule itself; at the same time, we also learn about dosing regimens from the trials and then make adjustments. We do this with every new drug development."

Custer added that Lilly plans to adjust the dosing regimen of the combination therapy in Phase III trials. "We expect to ultimately achieve a good balance between efficacy and tolerability." Lilly also plans to develop the two drugs as a fixed-dose combination for Phase III, meaning patients would need only one injection to receive both tirzepatide and eloralintide.

Poised to Become a "Winning Regimen"

The trial data were presented at the Annual Meeting of the European Association for the Study of Diabetes (EASD) in Milan, Italy. Lilly announced on Wednesday that it plans to advance the combination product into Phase III research by the end of 2026. Before the Phase II data release, some analysts believed the combination therapy would directly compete with Novo Nordisk's next-generation obesity drug CagriSema (also an amylin plus GLP-1 targeted combination).

Custer said the combination therapy "has the potential to become a very successful regimen." "GLP-1, GIP, and amylin are all nutrient-stimulated hormones naturally secreted by the human body after eating that enhance satiety. This physiology-based combination approach may create a broadly applicable drug. It gently activates three hormone systems rather than forcibly stimulating a single pathway."

David Ricksinger, an analyst at Lirkin Partners, said before the data release that he was optimistic that Lilly's amylin-targeting eloralintide could become a "super blockbuster" drug; the drug is also undergoing monotherapy clinical trials. He told reporters that the drug's market potential "far exceeds current Wall Street expectations," with millions of patients who do not respond to existing GLP-1 drugs or cannot tolerate their side effects.

Ricksinger also mentioned that the combination therapy could serve as an alternative to Lilly's other next-generation weight-loss drug retatrutide. Retatrutide targets GLP-1, GIP, and glucagon, and has shown top-tier weight-loss data in clinical trials. The results announced on Wednesday further confirmed the positive performance of this amylin plus tirzepatide combination in Phase I trials. Phase I research showed that obese adult patients taking 5 mg of tirzepatide plus 3 mg of eloralintide lost 17% of their weight in 16 weeks, compared with 10% weight loss with the same dose of tirzepatide alone.