Striking Weight Loss Seen With Combo Drug In Diabetes Trial

Adults with type 2 diabetes who received the highest tested dose of investigational eloralintide plus tirzepatide lost an average of 23.3% of their body weight over 48 weeks, compared with 14.8% among participants receiving tirzepatide alone, according to a phase IIb trial presented at the European Association for the Study of Diabetes annual meeting in Milan. The greater weight loss came with more adverse events and a higher rate of stopping treatment because of them, making tolerability a key issue as the combination moves toward larger trials.

The double-blind, parallel-group study randomized 367 adults with overweight or obesity and type 2 diabetes in the United States and Argentina among 10 treatment groups. These included placebo, eloralintide alone at three doses, tirzepatide alone, four combination-dose groups, and a group that began tirzepatide and added eloralintide at week 24. The reported weight-loss result for the highest-dose combination used the study’s efficacy estimand; the source report does not provide further detail here on how that analysis handled participants who discontinued treatment.

In that highest-dose group, one quarter of participants lost at least 30% of their body weight, compared with 12% in the tirzepatide-alone group. The study also reported that 96% of participants in both the highest-dose combination group and the tirzepatide-alone group reached an HbA1c below 7%. A lower HbA1c threshold of 5.7% was reached by 77% in the combination group and 66% with tirzepatide alone.

Tolerability results were less favorable for the combination. Treatment-emergent adverse events were reported in 84% of participants on the highest combination dose, compared with 71.4% taking tirzepatide alone. Discontinuation due to adverse events occurred in 27% of the highest-dose combination group and 2.9% of the tirzepatide-alone group. One participant in the lowest-dose combination group died; investigators judged the death unrelated to the study drug, according to the report.

Greater Weight Loss, More Treatment Stops

The result suggests that combining medications acting on different hormonal pathways could produce additional weight loss for some people with type 2 diabetes. The trial’s reported 23.3% average loss exceeded the 14.8% observed with tirzepatide alone in this study, while the glucose-control results were similar on the measure of HbA1c below 7%. These findings are early evidence from a mid-stage trial, not proof that the combination will deliver the same outcomes in routine care or in a larger population.

The discontinuation figures are just as relevant to patients and clinicians as the weight-loss result. A treatment that causes more participants to stop because of adverse events may not be suitable for everyone, even if weight reduction is greater among those analyzed. Phase III testing will need to clarify the balance between benefit and tolerability, alongside the safety profile over longer periods. The study does not establish that the combination is approved or available for treatment.

How the Two Medicines Work

Eloralintide is an investigational selective amylin receptor agonist, while tirzepatide, sold as Mounjaro for diabetes and Zepbound for weight management, acts at GIP and GLP-1 receptors. The combination is designed to activate three hormone pathways involved in appetite and blood-sugar regulation. During this trial, the medicines were given as two separate injections; presenter Liana Billings said a single-injection formulation is being planned.

Billings, an endocrinologist at Endeavor Health in Evanston, Illinois, told the meeting that people with type 2 diabetes have historically lost less weight on GLP-1-based medicines than people without diabetes. She said the 23.3% result was also above the 20.9% weight loss reported with tirzepatide in non-diabetic populations. Those are comparisons across different study populations and trials, rather than a direct comparison within this phase IIb study.

Eloralintide is also being tested as a single medicine in phase III obesity trials, according to the report. Eli Lilly, which is developing the drugs, plans to advance the combination into phase III by the end of the year.

“These substances are released naturally by the body after eating, with each acting through its own distinct receptor to help regulate hunger and blood sugar.”

— Eli Lilly, the developer, in a statement

Questions Before Phase III Results

The trial was a phase IIb study with 367 participants, and the available report does not give detailed results for every dose group or the full range of adverse events. It is not yet clear how the weight-loss and discontinuation rates would compare across a larger, longer study, or whether the benefits and tolerability differ among patient groups. The report also does not specify the individual adverse events that most often led participants to stop treatment.

The 23.3% figure was reported using an efficacy estimand. The source material does not explain the analysis method in enough detail to determine how it accounts for missing data or treatment discontinuation, so the estimate should not be treated as a straightforward outcome for every person who started treatment. The trial also cannot establish long-term safety, effects on diabetes complications, or whether a single-injection formulation would perform the same way as two separate injections.

Lilly Plans Larger Combination Trials

Eli Lilly plans to begin phase III development of eloralintide plus tirzepatide by the end of the year, according to the report. Those studies are expected to test the combination in larger groups and provide more information on sustained weight loss, blood-sugar control, adverse events, and treatment discontinuation. Details such as trial size, duration, and dosing were not included in the source material.

For now, the combination remains investigational. The next meaningful evidence will be whether later trials reproduce the phase IIb weight-loss result while reducing uncertainty about who can tolerate treatment and how its risks compare with its benefits.

Key Questions

How much weight did participants lose on the combination?

Participants in the highest-dose eloralintide-tirzepatide group lost an average of 23.3% of body weight over 48 weeks in the reported efficacy estimand. The tirzepatide-alone group lost 14.8% over the same period.

Did the combination improve blood sugar more than tirzepatide alone?

On the reported HbA1c threshold below 7%, 96% in each group reached the target. At the below-5.7% threshold, the figures were 77% with the highest-dose combination and 66% with tirzepatide alone. These trial results do not establish whether the difference at the lower threshold is meaningful in broader patient populations.

What safety or tolerability concerns were reported?

Treatment-emergent adverse events occurred in 84% of the highest-dose combination group, compared with 71.4% of the tirzepatide-alone group. Twenty-seven percent of the combination group stopped treatment because of adverse events, versus 2.9% on tirzepatide alone. Investigators judged one death in a lower-dose combination group unrelated to the study drug.

Is eloralintide plus tirzepatide available as a treatment?

No. The combination is investigational and was studied in a phase IIb trial. Eli Lilly plans to move it into phase III development by the end of the year, according to the report.

Were the two medicines given as one injection?

No. Participants received the drugs as two separate injections during the trial. Billings said a single-injection formulation is being planned, but the source report does not provide a timeline or clinical results for that formulation.

Source: rss