Retatrutide: Phase 3 Results and What Is Still Unknown

Retatrutide is not approved anywhere. It is the most discussed of the next generation of these medicines because it adds a third target, the glucagon receptor, and because its first phase 3 results arrived in 2026. This is what has been published and announced so far, and what is still missing.

A third receptor

Semaglutide acts on one receptor, the one for GLP-1. Tirzepatide acts on two, adding the receptor for GIP. Retatrutide, developed by Eli Lilly under the code LY3437943, acts on both of those and on a third: the receptor for glucagon, the hormone the pancreas releases to raise blood glucose between meals.

The phase 2 trial

The phase 2 trial, published in 2023, enrolled 338 adults with obesity, or with overweight and at least one weight-related condition. Just over half, 51.8 percent, were men. They were randomised to one of several retatrutide dose levels or to placebo for 48 weeks. Some groups began at a lower starting dose than others, which showed whether starting lower changed the side effects.

The main question was the change in body weight at 24 weeks, with 48 weeks as a secondary measure. At 48 weeks, average body weight was 8.7 percent lower in the lowest dose group, 17.1 and 22.8 percent lower in the two middle dose groups, and 24.2 percent lower in the highest dose group, against 2.1 percent lower on placebo.

In the highest dose group, every participant reached a reduction of at least 5 percent, 93 percent reached at least 10 percent and 83 percent reached at least 15 percent. On placebo the same figures were 27, 9 and 2 percent.

Gastrointestinal events were the most common adverse events. They became more frequent with higher doses, were mostly mild to moderate, and were partly reduced by starting at the lower dose. Heart rate rose in a dose-dependent way, peaked at 24 weeks and declined afterwards. A phase 2 trial of 338 people is designed to choose the doses for phase 3, not to settle questions of safety.

TRIUMPH-1: the first phase 3 results

On 21 May 2026, Eli Lilly announced the top-line results of TRIUMPH-1, an 80-week, double-blind, placebo-controlled trial in 2,339 adults with obesity, or with overweight and at least one weight-related condition, and without diabetes. An extension continued for another 24 weeks, to 104 weeks, in 532 participants with a BMI of 35 or more.

According to the company, average body weight at 80 weeks was 19.0, 25.9 and 28.3 percent lower on the three retatrutide dose levels, against 2.2 percent lower on placebo. In the highest dose group, 45.3 percent of participants reached a reduction of at least 30 percent. In the extension, the highest dose group averaged 30.3 percent at 104 weeks.

The same announcement reports the adverse events for the highest dose level against placebo. Nausea affected 42.4 percent against 14.8 percent, diarrhoea 32.0 against 13.5 percent, and vomiting 25.3 against 4.8 percent. Dysaesthesia, an abnormal or unpleasant sensation in the skin, was reported by 12.5 percent against 0.9 percent. Adverse events led 11.3 percent of the highest dose group to stop treatment, against 4.9 percent on placebo.

TRIUMPH-2 and TRIUMPH-3

On 23 July 2026 the company reported two more 80-week trials. TRIUMPH-2 enrolled 1,152 adults with type 2 diabetes and obesity or overweight. Average body weight was 12.7, 19.1 and 20.8 percent lower on the three dose levels, against 4.0 percent on placebo, and HbA1c fell by 1.4, 1.6 and 1.5 percentage points, against 0.2 on placebo.

Smaller reductions in people with diabetes are a familiar pattern with these medicines. In the two tirzepatide trials behind the 2023 US approval of Zepbound, the highest dose level produced an average reduction 18 percent greater than placebo in people without diabetes, and 12 percent greater in people with type 2 diabetes.

TRIUMPH-3 enrolled 1,949 adults with a BMI of 35 or more and established cardiovascular disease, with or without diabetes. Average body weight was 21.6 and 22.6 percent lower on the two dose levels tested, against 3.2 percent on placebo.

The most common adverse events in both trials were diarrhoea, nausea, constipation and decreased appetite, with vomiting also common in TRIUMPH-2. In TRIUMPH-2, adverse events led 3.8, 11.6 and 7.7 percent of the retatrutide groups to stop treatment, against 4.9 percent on placebo. In TRIUMPH-3 the figures were 9.8 and 13.5 percent, against 4.8 percent.

Why an announcement is not yet a paper

Every TRIUMPH figure in this article comes from company announcements. Top-line results are real data, but they are a summary that the sponsor selects. A full paper adds the methods, every pre-specified outcome, confidence intervals and the complete list of adverse events, and it goes through peer review. Regulators go further still and examine the full dataset.

Questions such as how the dysaesthesia cases developed and resolved, and how heart rate behaved over 80 weeks, need the full publications. The company has said it plans to submit an application for US approval in the first quarter of 2027.

Safety: what is still unknown

• Long-term safety. The longest data run to 104 weeks. Effects that appear after years of use cannot yet be seen.
• The dysaesthesia signal. One in eight people at the highest dose level in TRIUMPH-1 reported it. Its cause and course had not been described in a peer-reviewed paper when this article was checked.
• Heart outcomes. Whether retatrutide changes heart attacks, strokes or deaths needs an outcome trial of the kind SELECT was for semaglutide and SURPASS-CVOT for tirzepatide.
• Stopping treatment. For tirzepatide, SURMOUNT-4 showed substantial regain after withdrawal. Retatrutide has no published equivalent yet.
• The regulators' view. No regulator has yet weighed the full evidence.

Retatrutide outside the trials

Because it is not approved anywhere, no retatrutide medicine exists. Trial participants received investigational product made to the sponsor's specifications and were monitored by the trial doctors, and every result above describes that setting only.

The FDA has named retatrutide among the compounds in warning letters to companies selling products labelled "for research purposes" or "not for human consumption" while giving instructions for personal use. None of the results in this article describe those products.