Striking Weight Loss Seen With Combo Drug in Diabetes Trial

Adults with type 2 diabetes achieved impressive weight loss with an investigational combination agent of eloralintide plus tirzepatide (Mounjaro, Zepbound), according to a phase IIb study.

In the 10-arm trial, participants on the highest tested dose of eloralintide plus tirzepatide lost 23.3% of their body weight over 48 weeks in the efficacy estimand compared with a loss of 14.8% with tirzepatide alone.

Based on these trends, “we would hopefully see continued weight loss,” said Liana Billings, MD, MMSc, of Endeavor Health in Evanston, Illinois, at the European Association for the Study of Diabetes (EASD) annual meeting in Milan.

For context, “tirzepatide at 15 mg is our current very effective GLP-1 therapy for type 2 diabetes and weight [management]. We have really not seen these degrees of weight loss in people with type 2 diabetes in previous studies,” she explained.

The weight loss reported in this study surpassed even that seen with tirzepatide in non-diabetic populations (20.9%). Historically, people with type 2 diabetes achieve less weight loss on GLP-1-based agents than those without diabetes.

A quarter of participants in the highest-dose eloralintide-tirzepatide arm lost at least 30% of their body weight, a benchmark that is comparable to metabolic surgery, Billings noted, compared with 12% with tirzepatide alone.

Eloralintide is a selective amylin receptor agonist, while tirzepatide is a dual GIP/GLP-1 receptor agonist. The combination agent was engineered to simultaneously activate three complementary nutrient-stimulated hormones — GIP, GLP-1, and amylin — with minimal activity at the calcitonin receptor.

“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,” developer Eli Lilly explained in a statement.

Billings said that clinicians “now have the opportunity with medications and combinations like this to personalize our approach for patients, ensuring we address both their weight loss and glucose needs through different doses and combinations.”

“Obesity and type 2 diabetes are interconnected, and we are seeing the potential benefit of targeting multiple hormonal pathways to address both,” she added.

Notably, nearly all participants in the highest-dose combination group achieved an HbA1c level below 7% (96%), which Billings described as “hugely clinically impactful.” For participants receiving tirzepatide alone, the same proportion also reached this mark.

“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.

Additionally, 77% of participants in the highest-dose combination group reached an HbA1c level below 5.7%, the threshold for normoglycemia, versus 66% of those on tirzepatide alone.

Despite impressive weight loss and glycemic control, tolerability was less favorable.

About 84% of participants in the highest-dose combination group experienced treatment-emergent adverse events compared with 71.4% in the tirzepatide-alone group. Nearly 10 times as many participants in the highest-dose combination arm discontinued treatment due to adverse events as those on tirzepatide alone (27% vs 2.9%).

The double-blind, parallel-group trial randomized 367 adults with obesity or overweight and type 2 diabetes across the U.S. and Argentina into 10 equal groups: one placebo group, three eloralintide monotherapy groups, one tirzepatide monotherapy group, four combination eloralintide-tirzepatide groups, and one group that initiated tirzepatide and added eloralintide at week 24.

The combination therapy was administered as two separate injections during the trial, though plans are underway to formulate both drugs into a single shot, Billings noted.

One death occurred in the lowest-dose combination group, but the investigators deemed it unrelated to the study drug.

Eloralintide is already being evaluated as a single agent in phase III trials for obesity. Eli Lilly plans to advance the eloralintide-tirzepatide combination into phase III development by the end of the year.