Adding a Third Hormone to Tirzepatide Lifted Weight Loss to 23%

Eli Lilly reported that adding a third hormone-targeting peptide to tirzepatide pushed average weight loss past 23% in a mid-stage trial, well beyond what tirzepatide achieves by itself.

The data, presented at the European Association for the Study of Diabetes (EASD) annual meeting in Milan, come from a 48-week, randomized, double-blind, placebo-controlled phase 2b trial of 367 adults with obesity or overweight and type 2 diabetes, run at sites in the United States and Argentina. Participants started the trial at an average weight of about 232 pounds (105.4 kg) and an average A1C of 8.1%. At the highest dose combination tested — eloralintide 9 mg plus tirzepatide 15 mg — average weight loss reached 23.3% (54.1 lbs) and A1C fell 2.9 percentage points. Tirzepatide 15 mg alone produced 14.8% weight loss (34.4 lbs) and a 2.4-point A1C drop in the same trial; placebo produced 3.0% and 0.3 points, according to Lilly's announcement and the EASD meeting release.

Three hormones, one combination

Tirzepatide already works by activating two gut-hormone receptors at once: GIP and GLP-1. Both are released after eating and both feed into circuits that reduce appetite and improve insulin sensitivity, which is the basis for tirzepatide's existing approval for type 2 diabetes and obesity. The new element in this trial is eloralintide, a peptide Lilly designed to selectively activate the amylin receptor while largely avoiding the calcitonin receptor, a related target researchers have linked to some of the nausea seen with less-selective amylin drugs.

Amylin is a hormone the pancreas releases alongside insulin, and it signals fullness through a different part of the brainstem than GIP or GLP-1 do. Stacking a third, separately-acting appetite pathway on top of tirzepatide's existing two is the premise researchers are testing: that hormones working through different circuits can add up to more weight loss than pushing any single pathway harder. Novo Nordisk is pursuing a similar logic by pairing semaglutide with the amylin analog cagrilintide in CagriSema, and Boehringer Ingelheim's survodutide takes a different two-hormone route, activating a glucagon receptor instead — covered here in September. EloraTZP's trial is the first public data on what happens when a third hormone pathway is layered onto an already-approved two-hormone drug rather than designed in from the start.

What the trial showed, and what it didn't

All four EloraTZP dose combinations tested met the trial's primary and secondary endpoints, according to the EASD release, but the benefit was dose-dependent and not uniform. The lowest combination (eloralintide 3 mg plus tirzepatide 5 mg) produced 13.2% weight loss, matching the lowest dose of eloralintide alone and falling short of tirzepatide 15 mg by itself. Only the two higher-dose combinations clearly outperformed tirzepatide monotherapy. Eloralintide on its own, without tirzepatide, produced 8.2% to 12.3% weight loss depending on dose — meaningful, but well short of the combination arms.

This is conference-presented data only. HCPLive's writeup and Pharmacy Times' coverage both note the results have not yet appeared in a peer-reviewed journal, and the trial ran 48 weeks in a single population (adults with obesity and type 2 diabetes) — it says nothing yet about people with obesity but no diabetes, about durability beyond a year, or about harder outcomes like cardiovascular events. Lilly has said it plans to start phase 3 testing of an EloraTZP co-formulation by the end of 2026, which is the step that would normally generate that kind of longer, broader evidence.

The tradeoff: more weight loss, more dropouts

The combination arms came with a cost. Gastrointestinal side effects — the same nausea, vomiting and diarrhea that limit dose escalation on GLP-1 drugs generally — were more frequent in the combination arms than with either drug alone, and clustered during dose increases. Trial discontinuations for adverse events ranged from 10.8% to 27.0% in the combination arms, compared with 2.9% on tirzepatide alone and 0% to 10.8% on eloralintide alone (placebo discontinuation, for comparison, was 16.7%, a reminder that trial dropout isn't only a drug-side-effect story).

Liana Billings, the trial's lead investigator at Endeavor Health and the University of Chicago, told Pharmacy Times that gastrointestinal adverse event rates looked more like tirzepatide alone when the dosing was sequenced — tirzepatide started first, eloralintide layered in afterward — rather than escalated together. Lilly hasn't tested the reverse order, and sequencing is one of the open questions the planned phase 3 program is designed to answer, alongside whether a single co-formulated injection changes the tolerability picture at all. Three hormones outperformed two on the scale in this trial; the stomach still got the deciding vote on how many people stayed in it.

What this means for researchers

The headline number — 23.3% weight loss against tirzepatide's own 14.8% in the same trial — is the kind of result that normally only shows up by switching drug classes, not by adding a third hormone to an existing one. Billings described it during the EASD press briefing as being in the range typically associated with metabolic surgery, which is a notable claim for an injectable peptide combination this early in development, and one that still needs a larger, longer, peer-reviewed trial to hold up.

What isn't yet known matters as much as what was reported: whether the tolerability problem can be engineered away through sequencing or co-formulation, whether the effect generalizes beyond people who already have type 2 diabetes, and whether a three-hormone combination built from two separate injectables will ultimately compete with single-molecule triple agonists already in development elsewhere in the field. Phase 2b data presented at a conference is a reason to watch the phase 3 program closely, not a reason to treat the result as settled.

For now, EloraTZP is a research compound tested only inside a controlled trial, and the amylin-receptor selectivity that distinguishes eloralintide from older amylin drugs is itself a hypothesis the phase 3 data will have to confirm at scale.