Eloralintide and tirzepatide combination beats tirzepatide alone in phase 2b obesity and diabetes trial

A pairing of eloralintide and tirzepatide produced more weight loss than tirzepatide alone in a phase 2b trial in adults with obesity and type 2 diabetes, Eli Lilly said. The top tested combination averaged 23.3% weight loss at 48 weeks, against 14.8% for tirzepatide alone. The results were presented at the annual meeting of the European Association for the Study of Diabetes in Milan. Lilly plans phase 3 studies of a single co-formulated product. Stomach side effects pushed more people out of the combination arms.

What the phase 2b trial tested

The study enrolled 367 adults in the United States and Argentina who had obesity or overweight together with type 2 diabetes, according to a Lilly release. It ran for 48 weeks and was double blind and placebo controlled. Participants were assigned to placebo, to eloralintide on its own, to tirzepatide on its own, or to one of four combinations of the two drugs. The primary endpoint was the percent change in body weight compared with placebo. The change in A1C, a marker of average blood sugar over roughly three months, was a secondary endpoint. At the start, participants weighed 105.4 kilograms on average and had an average A1C of 8.1%. The trial is listed in the ClinicalTrials.gov study record as NCT06603571.

Eloralintide is an investigational amylin receptor agonist. Amylin is a hormone released from the pancreas together with insulin; it slows the emptying of the stomach and signals fullness to the brain. Tirzepatide, sold as Mounjaro and Zepbound, acts on the GIP and GLP 1 receptors. The logic of pairing eloralintide and tirzepatide is that two separate hormone systems may add up to more weight loss than either one alone. Eloralintide has no approval anywhere and is already in phase 3 testing as a single drug for obesity, Lilly said. The combination arms used several strength pairings reached by gradual escalation, and this report does not give the individual amounts used for the unapproved compound.

Weight loss and A1C results at 48 weeks

On the efficacy estimand, which estimates the effect if people had stayed on treatment, the top combination arm lost 23.3% of body weight on average at 48 weeks, Lilly reported. Tirzepatide alone at its highest strength produced 14.8%, and placebo produced 3.0%. The lowest combination lost 13.2%, while the two middle combinations landed close together at 19.4% and 19.9%. Eloralintide alone produced between 8.2% and 12.3% across its three strengths, and its highest strength did not beat the middle one. All combination arms met the primary and secondary endpoints, the company said. The figures come from a company release and a conference presentation; the release did not cite a peer reviewed paper.

On the efficacy estimand, which estimates the effect if people had stayed on treatment, the top combination arm lost 23.3% of body weight on average at 48 weeks, Lilly reported.

Blood sugar moved in the same direction. The top combination of eloralintide and tirzepatide lowered A1C by 2.9 points from the 8.1% starting average, against 2.4 points for tirzepatide alone and 0.3 points for placebo. Lead author Liana K. Billings of Endeavor Health said participants "had substantial weight loss alongside meaningful reductions in A1C." The gap over tirzepatide alone was larger for weight than for A1C, which already fell steeply on the single drug. Readers comparing these numbers with other studies should check which estimand a headline uses, because results that count everyone randomised are usually lower. The table sets out each arm as Lilly reported it.

Tolerability and dropouts in the combination arms

Gastrointestinal events were the most common side effects, Lilly said, and they were mostly mild to moderate and clustered in the period when doses were being raised. They were more frequent in the combination arms than with either drug alone. Discontinuation because of adverse events ranged from 10.8% to 27.0% across the combination arms. The comparable figure was 2.9% for tirzepatide alone and up to 10.8% for eloralintide alone. The placebo group stood at 16.7%, an unusually high figure for people on an inactive injection, and the release did not explain it. The release also did not list specific events by arm, so readers cannot yet see how often nausea, vomiting or diarrhea occurred in each group.

Dropouts shape how far the headline number travels. A weight loss figure built on the efficacy estimand describes people who kept taking the drug, and in the busiest combination arm more than one in four stopped because of side effects. That does not erase the result, but it means the benefit depends on people getting through the first months. Lilly said its phase 3 programme will use an optimised dose escalation schedule, which suggests the company sees a slower build up as the main lever for tolerability. Whether that works will only be clear once the larger studies report. The trial also enrolled only people with type 2 diabetes, who usually lose less weight on these drugs than people without diabetes.

Amylin combinations and the road to phase 3

Lilly plans to begin phase 3 studies of a co-formulated EloraTZP product by the end of 2026, meaning both peptides in a single injection rather than two separate shots. Kenneth Custer, who leads the company's cardiometabolic health unit, called EloraTZP "our next frontier, pairing a selective amylin receptor agonist with tirzepatide." The company has not given a timeline for a regulatory filing. Nothing in this phase 2b result changes what doctors can prescribe today. Tirzepatide remains approved on its own label, and eloralintide remains an experimental compound that is available only inside clinical trials. Any use of either peptide outside a trial or a prescription carries the counterfeit and sterility risks this site has reported on.

Lilly is not alone in pairing amylin with an incretin drug. Novo Nordisk combined cagrilintide with semaglutide in CagriSema, which produced large weight loss but fell short of its own target in the REDEFINE 1 trial. Roche agreed to co-develop Zealand Pharma's long acting amylin analogue petrelintide, a bet that amylin can either stand alone or join a combination. The EloraTZP data add a third approach: a separate amylin peptide stacked on an already approved dual agonist. The open questions are whether the extra weight loss holds in larger and longer trials, and whether tolerability improves enough to keep people on treatment.

Conclusion

The phase 2b readout shows that adding eloralintide to tirzepatide pushed average weight loss well past tirzepatide alone in adults with type 2 diabetes, with a smaller extra gain in A1C. It also shows a tolerability cost, with dropouts for side effects reaching 27% in one combination arm. The data so far come from a company release and a conference talk. Phase 3 trials of a co-formulated eloralintide and tirzepatide product will decide whether the gain holds and whether a slower dose escalation keeps people on treatment.