Eloralintide paired with tirzepatide produces added weight loss in type 2 diabetes

Key takeaways:

• Adults with type 2 diabetes lost more weight with eloralintide plus tirzepatide than with tirzepatide alone.
• HbA1c fell by at least 2.2 percentage points across all combination treatment groups.

In a phase 2 trial, an investigational amylin receptor agonist used together with tirzepatide led to weight loss of as much as 23.3% in adults with type 2 diabetes and obesity.

Earlier findings had shown that eloralintide (Eli Lilly), a once-weekly injectable medication, produced weight loss of up to 19.9% in adults with overweight or obesity without diabetes. New results presented at the European Association for the Study of Diabetes annual meeting suggest that pairing eloralintide with the GLP-1/glucose-dependent insulinotropic polypeptide (GIP) dual agonist tirzepatide (Mounjaro/Zepbound, Lilly) may offer additional benefits for people with obesity and type 2 diabetes.

“We now have the opportunity with medications and combinations like this to be able to personalize our approach for our patients and be able to make sure we are addressing their weight-loss needs as well as their glucose needs by different levels and combinations of these medications,” Liana K. Billings, MD, MMSc, vice chair of research at Endeavor Health and director of clinical and genetics research in diabetes and cardiometabolic disease and clinical associate professor in medicine at University of Chicago Pritzker School of Medicine, said in a press conference.

The phase 2 study enrolled 367 adults with type 2 diabetes and overweight or obesity. It included 10 groups: three received eloralintide alone at 3 mg, 6 mg or 9 mg; four received combination therapy with eloralintide 3 mg plus tirzepatide 5 mg, eloralintide 6 mg plus tirzepatide 5 mg, eloralintide 6 mg plus tirzepatide 10 mg, or eloralintide 9 mg plus tirzepatide 15 mg; one received tirzepatide 15 mg alone; one received tirzepatide 15 mg alone for 24 weeks with eloralintide 3 mg or 6 mg added during the remaining 24 weeks; and one received placebo. The trial lasted 48 weeks.

Study outcomes

By the efficacy estimand, the largest reduction in body weight at 48 weeks was 23.3% with eloralintide 9 mg plus tirzepatide 15 mg. The eloralintide 6 mg plus tirzepatide 10 mg group lost 19.9% of body weight, and the eloralintide 6 mg plus tirzepatide 5 mg group lost 19.4%. Participants who started tirzepatide 15 mg alone for 24 weeks and then added eloralintide later also had a 19.9% weight reduction at 48 weeks. Every eloralintide-tirzepatide combination outperformed placebo, which was associated with a 3% reduction at 48 weeks (P < .001 for all). Adults given tirzepatide 15 mg alone lost 14.8% at 48 weeks.

“Tirzepatide 15 mg is our current, effective GLP-1 therapy for type 2 diabetes in weight,” Billings said. “We have not seen these degrees of weight loss in people with type 2 diabetes in previous studies.”

The share of adults who lost at least 20% of body weight at 48 weeks was 49% with eloralintide 6 mg plus tirzepatide 10 mg, 63% with eloralintide 9 mg plus tirzepatide 15 mg and 62% with tirzepatide 15 mg plus add-on eloralintide. In addition, 25% of participants receiving eloralintide 9 mg plus tirzepatide 15 mg lost at least 30% of body weight.

According to a Lilly press release, at 48 weeks HbA1c fell by 2.9 percentage points in the eloralintide 9 mg plus tirzepatide 15 mg group, by 2.6 percentage points in the eloralintide 6 mg plus tirzepatide 10 mg group, by 2.7 percentage points in the eloralintide 6 mg plus tirzepatide 5 mg group, and by 2.2 percentage points in the eloralintide 3 mg plus tirzepatide 5 mg group, compared with a 0.3 percentage point decline with placebo.

Among all combination therapy groups, at least 90% of patients reached an HbA1c below 7% at 48 weeks. The proportion of adults who achieved an HbA1c below 5.7% was 77% with eloralintide 3 mg plus tirzepatide 5 mg, 69% with eloralintide 6 mg plus tirzepatide 10 mg, 77% with eloralintide 9 mg plus tirzepatide 15 mg, and 69% with tirzepatide 15 mg plus add-on eloralintide.

Safety data

The rate of treatment-emergent adverse events was similar across all trial arms. Gastrointestinal events were the most common and included nausea, diarrhea, constipation, fatigue and reduced appetite. Rates of vomiting and fatigue with eloralintide alone were similar to those seen with placebo. Billings said nausea, fatigue and vomiting were reported more often with eloralintide 9 mg plus tirzepatide 15 mg than with tirzepatide alone.

“This would be expected because we are starting two medications at once and escalating them together,” Billings said. “But then, if we look at the cumulative incidence reports in the add-on [arm], we see very similar adverse event incidence for nausea, fatigue and vomiting.”

Overall, 6.5% of study participants reported at least one serious adverse event. Fewer than 10% of adults in any group stopped the trial because of adverse events.

Phase 3 trial coming

In the phase 2 study, participants receiving the two drugs in combination were given separate injections. However, Rachel L. Batterham, OBE, MBBS, PhD, FRCP, senior vice president of medical innovation and external engagement for Lilly, told Healio that the company plans to co-formulate the drugs into a single injection for its upcoming phase 3 trial.

“GLP-1, GIP and glucagon are all incretins, and they all work through a similar mechanism of action, whereas amylin works through a completely different mechanism of action,” Batterham told Healio. “When you bring tirzepatide and amylin together, then you are having an additive effect of these different mechanisms. That’s why we’re seeing, in particular, the reduction in HbA1c of 2.9 percentage points and also the additive effect on weight loss.”

Batterham said Lilly is also studying eloralintide on its own in other ongoing phase 3 trials.

For more information:

Rachel L. Batterham, OBE, MBBS, PhD, FRCP, can be reached at endocrinology@healio.com.

Sources/Disclosures

Source:

Billings L. Session S21. Presented at: European Association for the Study of Diabetes Annual Meeting; Milan.

Reference:

• Lilly's EloraTZP (combination of eloralintide and tirzepatide) delivered greater weight loss and A1C reduction vs. tirzepatide 15 mg in adults with obesity and type 2 diabetes. https://investor.lilly.com/news-releases/news-release-details/lillys-eloratzp-combination-eloralintide-and-tirzepatide. Published Sept. 30, 2026. Accessed Sept. 30, 2026.

Disclosures: Billings reports consulting for Amgen, Bayer, Lilly, Novo Nordisk, Roche and Sanofi; and receiving research funding from Amgen, AstraZeneca, Endogenex, Genentech, Kailera, Lilly, Novo, Pfizer, Roche and Sanofi. Batterham reports being an employee of Lilly. The trial was funded by Lilly.

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