Retatrutide Phase 2 NEJM Trial Results: What the 48-Week Data Showed

Important: investigational medicine notice. Retatrutide is an investigational medication. It has not received marketing authorisation from the Medicines and Healthcare products Regulatory Agency (MHRA) or any other regulator, and it cannot be legally prescribed, dispensed or sold in the UK outside of an authorised clinical trial. This article is for information only. It is not medical advice and is not a recommendation to seek, request or use retatrutide. If you are considering weight-management medication, speak to your GP or a regulated UK prescriber about MHRA-approved options.

In June 2023, the New England Journal of Medicine published the results of a Phase 2 clinical trial of retatrutide — a then-novel investigational triple hormone receptor agonist developed by Eli Lilly. The trial, led by Ania Jastreboff and colleagues, was the first peer-reviewed study to report what retatrutide could do for body weight in adults with obesity. The headline number — a mean weight reduction of 24.2% at 48 weeks on the highest dose — drew significant attention from clinicians and researchers and, in time, from the broader public.

This article walks through what the trial actually measured, what it found, and what its limitations are. It is intended for a motivated reader rather than a specialist, but it does not over-simplify. The key data points are cited to the published paper directly so you can verify them at source.

What kind of trial was this?

The Phase 2 trial published by Jastreboff and colleagues was a double-blind, randomised, placebo-controlled trial. In plain English, that means:

Double-blind: neither the participants nor the researchers giving out the medication knew who was receiving retatrutide and who was receiving placebo (an inactive injection). Blinding helps prevent expectations from biasing what people report.
Randomised: participants were allocated to retatrutide or placebo by a randomisation process, not by choice. This makes it more likely that the groups are comparable at the start.
Placebo-controlled: the comparator arm received placebo, so any effect of retatrutide can be measured against the natural variation that occurs without treatment.

These design features make Phase 2 trials of this kind a reliable way to assess whether a medicine has a real effect, and how big that effect appears to be. They are not, on their own, sufficient for regulatory approval — that requires the larger Phase 3 trials that the TRIUMPH programme is currently running.

Who was included in the trial?

The trial enrolled adults with a body-mass index (BMI) of 30 or higher (the clinical definition of obesity), or a BMI of 27 to less than 30 (the overweight range) plus at least one weight-related health condition. Participants with type 2 diabetes were not eligible for this particular trial — a separate trial of retatrutide in type 2 diabetes was run in parallel and reported separately.

This is the same broad enrolment criterion used in Phase 3 trials of other weight-management medicines such as semaglutide (STEP 1) and tirzepatide (SURMOUNT-1), which makes cross-trial comparisons of the headline weight-reduction numbers at least roughly meaningful — though, as discussed below, those comparisons carry caveats.

What doses were tested?

Participants on retatrutide were assigned to one of several dose groups: 1 mg, 4 mg, 8 mg, or 12 mg, each given as a once-weekly subcutaneous injection. The higher doses used a gradual titration schedule — starting low and increasing over several weeks — to reduce the gastrointestinal side effects that tend to appear when these medicines are introduced too quickly. The placebo group received weekly injections of inactive solution on the same schedule.

The trial ran for 48 weeks of treatment. This is shorter than the 68 or 72 weeks used in the Phase 3 trials of semaglutide and tirzepatide, which is worth noting when comparing numbers across studies. Weight reduction in trials of this class of medicine has generally continued to accumulate over time rather than plateauing early, so a longer trial would, all else being equal, be expected to produce a larger total reduction.

What did the trial find?

The primary efficacy measure was percentage change in body weight from baseline. The published results, as reported in the New England Journal of Medicine, were as follows.

At 24 weeks, the least-squares mean percentage change in body weight in the retatrutide groups was:

−7.2% in the 1 mg group
−12.9% in the combined 4 mg group
−17.3% in the combined 8 mg group
−17.5% in the 12 mg group

By comparison, the placebo group showed only a small change at the same time point.

At 48 weeks — the full trial duration — the figures had increased further:

The 12 mg group showed a mean weight reduction of approximately 24.2%
The 8 mg group showed approximately 22.8%
The 4 mg group showed approximately 17.1%
The 1 mg group showed approximately 8.7%
The placebo group showed approximately 2.1%

The trial also reported the proportion of participants who achieved categorical weight-reduction thresholds at 48 weeks. In the 8 mg group, 100% of participants achieved a weight reduction of 5% or more, 91% achieved 10% or more, and 75% achieved 15% or more. In the 12 mg group, the same thresholds were reached by 100%, 93% and 83% of participants respectively. In the placebo group, those thresholds were reached by 27%, 9% and 2% of participants respectively.

These are striking numbers in the context of obesity pharmacotherapy. The 12 mg group achieved at 48 weeks a reduction greater than any other weight-management medicine had reported at that point in its development. The published paper attributed this to the combination of GLP-1, GIP and glucagon receptor activation acting together — an explanation discussed in more detail in the previous article in this series, How Retatrutide Works.

What else did the trial measure?

Beyond body weight, the trial reported improvements in a range of cardiometabolic markers in the retatrutide groups compared with placebo. These included:

Waist circumference
Systolic and diastolic blood pressure
Glycated haemoglobin (HbA1c) — a marker of average blood sugar over the previous 2 to 3 months
Fasting glucose
Fasting insulin
Triglycerides and total cholesterol (with the exception of HDL cholesterol)

Of particular note: among participants who had prediabetes at baseline, 72% reverted to normoglycaemia (normal blood-sugar range) with retatrutide treatment.

What were the side effects?

The most common adverse events in the retatrutide groups were gastrointestinal: nausea, diarrhoea, constipation and vomiting. The paper reported these were dose-related — more common at higher doses — and mostly mild to moderate in severity. Starting at a lower dose (2 mg instead of 4 mg) and titrating upwards more gradually partially mitigated these effects.

The trial also reported a dose-dependent increase in heart rate, which peaked at 24 weeks and declined thereafter. Both glucagon and GLP-1 can have effects on heart rate (chronotropic effects), so this is not unexpected for a medicine that activates these receptors — but it is a finding that will be examined more closely in larger Phase 3 trials. A more detailed discussion of the side-effect profile is covered in a separate article in this series, Retatrutide Side Effects and Safety Profile.

What are the limitations of this trial?

Several limitations are worth keeping in mind when interpreting the headline numbers:

Phase 2, not Phase 3. Phase 2 trials are smaller and shorter than the registration trials required for regulatory approval. They establish whether a medicine is worth taking forward into Phase 3, and they identify a likely dose range — but they are not the basis on which regulators license a medicine. The TRIUMPH Phase 3 programme is currently producing the larger trial data that the MHRA and FDA would review.

No active comparator. The trial compared retatrutide with placebo, not with currently approved medicines like Wegovy or Mounjaro. Without a direct head-to-head trial against an active comparator, cross-trial comparisons (retatrutide's 24.2% vs semaglutide's ~14.9% vs tirzepatide's ~22.5%) must be read with caution: the trials had different durations, enrolment criteria and statistical methods.

Treatment duration was 48 weeks. Longer trials, including the TRIUMPH Phase 3 programme, are required to understand how weight reduction evolves over time, whether plateaus occur, and what happens if and when the medicine is discontinued.

Heterogeneous sex distribution. The paper notes that the trial enrolled approximately equal proportions of men and women, which may have dampened the efficacy results compared with trials that have enrolled higher proportions of women (67% to 78% in some comparable studies).

What this trial established

The Phase 2 NEJM trial established three things that have shaped the development of retatrutide since:

The triple-agonist hypothesis works in humans. Activating GLP-1, GIP and glucagon receptors together produced larger weight reduction than dual or single-agonist medicines have reported.
A useful dose range exists. The 8 mg and 12 mg doses showed the largest effects and were carried forward into Phase 3, alongside lower doses that may be relevant for tolerability or maintenance.
The safety signal is broadly consistent with the GLP-1 class. Gastrointestinal effects dominate, dose-related, mostly mild to moderate. The heart-rate signal is being watched.

What it did not establish is the long-term efficacy, the cardiovascular outcomes, the picture in type 2 diabetes, or the safety profile across the much larger populations the Phase 3 programme is studying. Those questions are the subject of the TRIUMPH trials — covered in the next article in this series.

The bottom line

The Phase 2 NEJM trial of retatrutide reported mean body-weight reductions of up to 24.2% at 48 weeks, accompanied by improvements in blood pressure, lipids and glucose markers, with a side-effect profile broadly typical of the GLP-1 medicine class. These results were striking and informed the design of the ongoing Phase 3 programme — but they are Phase 2 results, and Phase 2 results do not licence a medicine. Retatrutide remains investigational, is not approved in the UK, and cannot be legally prescribed or supplied here outside an authorised clinical trial.

If you are considering weight-management medication, the place to begin is a conversation with your GP or a regulated UK prescriber about the MHRA-approved options available in the UK today.

Sources and further reading

Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. New England Journal of Medicine. 2023;389(6):514–526. DOI: 10.1056/NEJMoa2301972.
Eli Lilly press release, 26 June 2023: Lilly's phase 2 retatrutide results published in The New England Journal of Medicine show the investigational molecule achieved up to 17.5% mean weight reduction at 24 weeks in adults with obesity and overweight.
Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. New England Journal of Medicine. 2021;384(11):989–1002 (STEP 1 trial).
Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. New England Journal of Medicine. 2022;387(3):205–216 (SURMOUNT-1 trial).
UK Government / MHRA: GLP-1 medicines for weight loss and diabetes: what you need to know (GOV.UK publication).