MILAN — Combining the investigational amylin receptor agonist, eloralintide, with tirzepatide produced greater weight loss than either drug alone in adults with overweight/obesity and type 2 diabetes (T2D), results of a phase 2 trial showed.

Participants receiving the highest-dose combination (eloralintide 9 mg plus tirzepatide 15 mg), lost an average of 23.3% of their body weight, compared with 14.8% among those receiving tirzepatide 15 mg alone and 11.1% in those receiving eloralintide 9 mg alone. 

In addition, patients taking the combination saw accompanying improvements in blood glucose control. 

"Obesity and type 2 diabetes are interconnected, and we are seeing the potential benefit of targeting multiple hormonal pathways to address both," said lead study investigator Liana K. Billings, MD, director of clinical and genetics research in diabetes and cardiometabolic disease at Endeavor Health, Skokie, Illinois, in a press release. 

"We have really not seen this degree of weight loss in people with type 2 diabetes in previous studies," she noted during a press briefing here at the European Association for the Study of Diabetes (EASD) 2026 Annual Meeting where she presented the results. 

Weight Loss Approaches Levels Seen With Metabolic Surgery 

Eloralintide is a once-weekly selective amylin receptor agonist, and tirzepatide is a dual GIP/GLP-1 receptor agonist. Combining the agents therefore targets three nutrient-stimulated hormone pathways involved in regulating appetite and glycemia — amylin, GIP, and GLP-1. 

The 48-week, randomized, double-blind, placebo-controlled trial included 367 adults with obesity or overweight and T2D in the US and Argentina. Participants were randomized across 10 treatment groups to receive placebo, different doses of eloralintide alone, tirzepatide alone, combinations of the two drugs, or a sequential regimen in which eloralintide was added after tirzepatide escalation. 

At baseline, mean weight was 232.4 lb (105.4 kg), and mean A1c was 8.1%. The primary endpoint was percentage change in body weight at week 48 with the combination vs placebo; comparisons with tirzepatide and eloralintide monotherapy were secondary endpoints.

Weight loss increased across all four combination regimens. At week 48, mean reductions were 13.2% with eloralintide 3 mg plus tirzepatide 5 mg; 19.4% with eloralintide 6 mg plus tirzepatide 5 mg; 19.9% with eloralintide 6 mg plus tirzepatide 10 mg; and 23.3% with eloralintide 9 mg plus tirzepatide 15 mg.

In comparison, mean weight loss was 14.8% with tirzepatide 15 mg alone and ranged from 8.2% to 12.3% with eloralintide monotherapy. Participants receiving placebo lost 3.0%. In absolute terms, the highest-dose combination produced a mean loss of 54.1lb compared with 34.4lb with tirzepatide 15 mg alone. 

Billings highlighted how dramatically pharmacologic weight-loss targets have shifted recently. "We used to really try for 5% and 10%, and the fact that we're starting at 15% is pretty incredible," she said.

At the higher thresholds, 62% of participants receiving the add-in combination of tirzepatide 15 mg plus eloralintide 3/6 mg added-in achieved at least 20% weight loss, 36% achieved at least 25%, and 19% achieved at least 30% at week 48. Across the high-dose combination regimens, up to 25% of study participants achieved at least 30% weight loss.

Billings described this degree of weight loss as "very much in line with what we might expect with metabolic surgery."

Up to 77% Achieved Normoglycemia 

Glycemic control also improved substantially. Mean A1c reductions across the combination regimens ranged from 2.2 to 2.9 percentage points, compared with 2.4 percentage points with tirzepatide 15 mg alone, 1.1-1.4 percentage points with eloralintide alone, and 0.3 percentage points with placebo. 

Up to 77% of participants receiving combination therapy achieved an A1c below 5.7%, corresponding to normoglycemia.

And between 90% and 100% of participants receiving the combination regimens achieved an A1c below 7% at week 48, according to the presented data.

"This is our standard goal for blood sugar, and the fact that we can prescribe something and attain 100% of patients achieving that goal is quite remarkable," Billings said.

The efficacy analyses estimated treatment effects assuming that all randomized participants remained on their assigned intervention for 48 weeks, although dose interruptions or modifications were allowed. 

Could Sequential Dosing Improve Tolerability? 

The most common adverse events were gastrointestinal, including nausea, diarrhea, constipation, and vomiting, and were generally mild or moderate. Gastrointestinal events occurred more frequently with eloralintide-tirzepatide than with either drug alone. 

In the eloralintide 3/6/9 mg plus tirzepatide 15 mg group, nausea, diarrhea, and vomiting occurred in 48.6%, 29.7%, and 24.3% of participants, respectively, compared with 25.7%, 22.9%, and 11.4% with tirzepatide 15 mg alone. Fatigue was also higher in the higher-dose combination than with tirzepatide alone (24.3% vs 14.3%).

Billings explained that, "this would be expected because we're starting two medications at once and escalating them together."

The study also looked at a sequential strategy in which tirzepatide was escalated to 15 mg before eloralintide was added at week 24. 

"If we look at the cumulative incidence reports in the add-on, or the sequential [arm] … you see very similar adverse event incidence between nausea, fatigue, and vomiting," Billings noted. Rates of nausea, fatigue, and vomiting with sequential treatment were similar to those with tirzepatide alone: 27.8% vs 25.7%, 13.9% vs 14.3%, and 13.9% vs 11.4%, respectively.

Billings described the findings as "a really nice illustration" of how sequencing the drugs could help reduce side effects associated with using the two medications together.

Eloralintide monotherapy was also associated with low rates of vomiting and fatigue, which Billings described as comparable to placebo. One death occurred during the study, from a motor vehicle accident, and was not considered related to treatment.

Very Promising, but Larger Studies Needed 

Commenting on the findings, Anna Solini, MD, PhD, associate professor of internal medicine at the University of Pisa in Italy, described the results as "very promising," both in terms of efficacy and tolerability. 

She suggested, however, that tirzepatide was likely an important driver of the magnitude of weight loss achieved with the combination. "It's the driving force," she told Medscape Medical News.

Solini also urged caution in interpreting the findings, particularly when making indirect comparisons with other obesity trials. "We have to be very, very cautious," she said, noting that the combination treatment groups contained fewer than 100 participants each, whereas some comparator trials included several hundred participants. The findings now need confirmation in larger populations, she added.

Eloralintide and tirzepatide were administered as two separate injections in the phase 2 study. Lilly plans to initiate phase 3 studies of a co-formulated eloralintide and tirzepatide product by the end of 2026 using an optimized dose-escalation schedule. Eloralintide is already being evaluated as monotherapy in phase 3 obesity trials. 

Billings said the different doses and combinations could ultimately allow clinicians to tailor therapy according to patients' individual weight-loss and glycemic needs.

"We now have the opportunity with medications and combinations like this to be able to personalize our approach for our patients," she said.

The study was funded by Eli Lilly. Billings reported consulting honoraria from Novo Nordisk, Amgen, Lilly, Sanofi, Roche, and Bayer and research funding from Novo Nordisk, Amgen, Lilly, Endogenex, Sanofi, Pfizer, AstraZeneca, Roche, Genentech, and Kailera. Solini has no relevant disclosures. 

Becky McCall is a UK-based medical journalist and researcher who writes for Medscape Medical News and other medical and scientific publications. Her research at University College London focuses on antimicrobial resistance and the use of digital storytelling in health research.