New Drug Combo With Zepbound Leads to Massive Weight Loss

Zepbound is already one of the most powerful weight-loss drugs available. Now researchers have found that combining it with an experimental drug targeting a different appetite hormone may help people shed nearly a quarter of their body weight.

“It’s a pretty astonishing degree of weight loss,” David Preiss, a professor of metabolic medicine and clinical trials at the University of Oxford who was not involved in the research, told New Scientist.

The experimental combination, called EloraTZP, pairs tirzepatide — the active ingredient in Zepbound and the diabetes drug Mounjaro — with eloralintide, a new drug being developed by Eli Lilly.

Tirzepatide mimics two naturally occurring hormones, GLP-1 and GIP, which help regulate appetite and blood sugar. Eloralintide targets a third pathway involving amylin, a hormone released after eating that helps promote feelings of fullness.

“Adding a drug acting like amylin [alongside tirzepatide] effectively brings a third appetite-regulating pathway into play, which may explain why the combination appears to deliver substantially greater weight loss,” Lora Heisler, a professor at the University of Aberdeen who was not involved in the study, told New Scientist.

The 48-week Phase 2b trial included 367 adults in the U.S. and Argentina who had Type 2 diabetes and either obesity or overweight. Participants received different doses of eloralintide, tirzepatide, the two drugs together, or placebo.

People taking the highest-dose combination — 9 milligrams of eloralintide plus 15 milligrams of tirzepatide — lost an average 23.3% of their body weight, or about 54 pounds, among those who adhered to treatment.

By comparison, those taking the maximum 15-milligram dose of tirzepatide alone lost an average 14.8%, or about 34 pounds. The placebo group lost 3%. The findings were presented at the annual meeting of the European Association for the Study of Diabetes in Milan.

The combination also produced substantial improvements in blood sugar. A1C, a measure of average blood sugar over the previous two to three months, fell by as much as 2.9 percentage points with the combination, compared with 2.4 points with tirzepatide alone.

“These are massive reductions,” said Preiss. “You would imagine that this [and the weight loss] would reduce the risk of cardiovascular complications, high blood pressure,” although he cautions that further studies are needed.

Side Effects a Concern

The extra weight loss came with a trade-off.

Gastrointestinal problems, including nausea, vomiting and diarrhea, were more common among people receiving the combination. Depending on the dose, 10.8% to 27% of participants taking EloraTZP discontinued treatment because of adverse events, compared with 2.9% of those taking tirzepatide alone. Most gastrointestinal side effects were mild to moderate and occurred as doses were being increased.

“They might find the combination more difficult to tolerate,” said Heisler. “If the patient’s already doing well on a drug like tirzepatide, then additional benefit may not outweigh the added treatment burden or side effects.”

The findings also don’t mean everyone taking Zepbound should add another drug. Eloralintide remains experimental, and the combination has not been approved by the Food and Drug Administration.

Another limitation is that all participants had Type 2 diabetes. Weight-loss medications often produce greater weight reductions in people with obesity who don’t have diabetes, but researchers don’t yet know whether EloraTZP will follow the same pattern.

Lilly plans to begin Phase 3 trials of EloraTZP by the end of 2026, using a single injection containing both drugs rather than the two separate weekly injections used in this trial.

Eloralintide is also undergoing Phase 3 testing on its own for obesity.

If larger trials confirm the results, combining drugs that target several of the body’s appetite-regulating pathways could usher in an even more potent generation of obesity treatments.

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