Retatrutide Phase 2 Trial: Understanding the NEJM Study

Explore the design, weight outcomes, adverse events, and limitations of the 48-week Phase 2 retatrutide obesity trial published in NEJM.

8/5/20266 min read

Retatrutide Phase 2 Trial: Understanding the NEJM Study

In 2023, The New England Journal of Medicine published results from a Phase 2 clinical trial investigating retatrutide in adults with obesity or overweight who did not have type 2 diabetes.

The 48-week study evaluated several retatrutide doses and dose-escalation schedules. Researchers reported dose-dependent reductions in average body weight, with the largest average reduction occurring in the highest-dose group. Gastrointestinal adverse events were common and also generally increased with dose.

This article provides an independent educational summary of that specific Phase 2 study. It does not provide treatment recommendations or instructions for using retatrutide.

What is retatrutide?

Retatrutide, also identified by the research code LY3437943, is a single investigational molecule designed to activate three hormone receptors:

  • Glucose-dependent insulinotropic polypeptide, or GIP, receptor

  • Glucagon-like peptide-1, or GLP-1, receptor

  • Glucagon receptor

For that reason, it is described as a triple hormone receptor agonist. The simultaneous activation of these three pathways distinguishes retatrutide from single-receptor and dual-receptor incretin therapies.

As of August 2026, retatrutide has not been approved by any regulatory authority and is not available for routine public use. Lilly states that it remains investigational and is legally available for human use only through authorised Lilly clinical trials.

What question did the Phase 2 trial investigate?

The researchers sought to evaluate the efficacy, tolerability, and safety of different retatrutide doses in adults with obesity or overweight.

The trial’s primary endpoint was the percentage change in body weight from the beginning of the study to week 24. Weight change at week 48 was evaluated as a secondary endpoint.

The study was intended to help researchers identify suitable doses and escalation strategies for later, larger Phase 3 trials.

How was the study designed?

The study was a:

  • Phase 2 trial

  • Randomised trial

  • Double-blind trial

  • Placebo-controlled trial

  • 48-week study

A total of 338 adults were enrolled in the United States. Participants had obesity or were overweight with at least one weight-related health condition, but they did not have type 2 diabetes.

Participants were randomly assigned to one of seven groups:

  • Retatrutide 1 mg

  • Retatrutide 4 mg, beginning at 2 mg

  • Retatrutide 4 mg, beginning at 4 mg

  • Retatrutide 8 mg, beginning at 2 mg

  • Retatrutide 8 mg, beginning at 4 mg

  • Retatrutide 12 mg, beginning at 2 mg

  • Placebo

The assigned treatment was administered once weekly for 48 weeks. The different starting-dose groups allowed researchers to examine whether a more gradual escalation affected tolerability.

What happened at 24 weeks?

At week 24, the reported least-squares mean changes in body weight were:

Study groupAverage body-weight changeRetatrutide 1 mg−7.2%Combined retatrutide 4 mg groups−12.9%Combined retatrutide 8 mg groups−17.3%Retatrutide 12 mg−17.5%Placebo−1.6%

The study therefore demonstrated a dose-response pattern at the primary 24-week endpoint. Participants assigned to higher retatrutide doses experienced larger average reductions in body weight than participants assigned to the lower dose or placebo.

These figures describe group averages within a controlled clinical trial. They do not predict the response of an individual person.

What happened at 48 weeks?

At week 48, the reported average changes in body weight were:

Study groupAverage body-weight changeRetatrutide 1 mg−8.7%Combined retatrutide 4 mg groups−17.1%Combined retatrutide 8 mg groups−22.8%Retatrutide 12 mg−24.2%Placebo−2.1%

The largest average reduction occurred in the 12 mg group. Weight reduction in the higher-dose groups appeared to be continuing at the end of the 48-week study rather than reaching a clear plateau.

The results should not be interpreted as evidence that a higher dose is appropriate for every person. Dose selection in clinical research also depends on tolerability, adverse events, participant characteristics, and the overall benefit-risk assessment.

How many participants reached major weight-reduction thresholds?

At 48 weeks, the study also evaluated the percentages of participants who achieved reductions of at least 5%, 10%, and 15% of their starting body weight.

Among participants assigned to 12 mg retatrutide:

  • 100% achieved at least 5% weight reduction.

  • 93% achieved at least 10% weight reduction.

  • 83% achieved at least 15% weight reduction.

Among participants assigned to placebo:

  • 27% achieved at least 5% weight reduction.

  • 9% achieved at least 10% weight reduction.

  • 2% achieved at least 15% weight reduction.

These results apply to participants included in the trial analysis and should be interpreted within the study’s selection criteria and controlled conditions.

Were changes in other metabolic measurements observed?

The researchers also assessed exploratory cardiometabolic measurements.

Lilly reported changes in areas including:

  • Systolic and diastolic blood pressure

  • Triglycerides

  • LDL cholesterol

  • Total cholesterol

  • HbA1c

  • Fasting glucose

  • Fasting insulin

These measurements were exploratory outcomes rather than the study’s primary endpoint. The findings may support additional research, but they do not independently establish a long-term cardiovascular or metabolic benefit.

What adverse events were reported?

The most common adverse events were gastrointestinal. These included symptoms such as:

  • Nausea

  • Diarrhoea

  • Vomiting

  • Constipation

The gastrointestinal events were generally described as mild to moderate. They occurred most frequently during dose escalation and were more common with higher doses. A lower starting dose appeared to reduce some gastrointestinal effects compared with beginning treatment at a higher dose.

Dose-dependent increases in heart rate were also observed. These increases reached their highest levels around week 24 and subsequently declined.

These findings demonstrate why average weight outcomes should not be assessed separately from safety and tolerability.

Did everyone complete the trial?

Not every participant completed the full treatment period.

Some participants discontinued treatment because of adverse events, withdrawal, loss to follow-up, or other reasons. Discontinuation can affect the interpretation of clinical-trial results, particularly when side effects occur more frequently at higher doses.

The published estimates used defined statistical methods to account for missing data and treatment discontinuation. This means the reported percentages should not be treated as a simple average of only the participants who completed every dose.

What are the study’s main strengths?

The study had several important strengths:

Randomised and placebo-controlled design

Random assignment and the use of a placebo group reduced the likelihood that differences in outcomes were caused only by baseline differences between participants.

Double-blinding

Participants and study personnel were blinded to treatment assignment, helping reduce expectation and observation bias.

Multiple doses and escalation schedules

The study evaluated four target doses and different starting-dose approaches. This allowed researchers to examine both dose-dependent efficacy and tolerability.

Forty-eight weeks of follow-up

The study was longer than many early-phase dose-finding trials and allowed researchers to observe how weight changed beyond the 24-week primary endpoint.

What are the study’s limitations?

The findings should also be interpreted with several limitations in mind.

It was a Phase 2 trial

Phase 2 trials are generally designed to explore efficacy, dose selection, and initial safety. They are not large enough to fully characterise uncommon adverse events or establish long-term safety.

The trial included 338 participants

Although adequate for a mid-stage trial, this population was considerably smaller than later Phase 3 obesity trials involving thousands of participants.

Treatment lasted 48 weeks

The study could not determine what happens after several years of exposure or what happens to body weight after treatment is discontinued.

Participants did not have type 2 diabetes

The findings from this study should not automatically be generalised to adults with type 2 diabetes or to populations that would not have met the study’s eligibility requirements.

The study was funded by Lilly

Eli Lilly developed retatrutide and funded the trial. Several study authors were affiliated with the company. Sponsor involvement does not invalidate the research, but it is a relevant potential conflict of interest and supports the importance of independent review and replication.

The study did not establish regulatory approval

Positive Phase 2 findings do not establish that an investigational molecule is safe and effective for general public use. Larger and longer Phase 3 studies and regulatory review are required.

How does this study relate to newer retatrutide research?

This NEJM paper reports the original 48-week Phase 2 obesity trial published in 2023.

Since then, Lilly has announced topline results from several larger Phase 3 trials. Those later announcements should be assessed separately because they involve different study populations, durations, endpoints, and statistical analyses. As of August 2026, detailed peer-reviewed reports for some newer Phase 3 findings are still pending.

The results of newer studies do not change the design or findings of this Phase 2 paper. They contribute additional evidence to the developing research programme.

Conclusion

The Phase 2 trial found that retatrutide was associated with dose-dependent average reductions in body weight over 24 and 48 weeks in adults with obesity or overweight who did not have type 2 diabetes.

At 48 weeks, the reported average reduction ranged from 8.7% in the 1 mg group to 24.2% in the 12 mg group, compared with 2.1% in the placebo group. Gastrointestinal adverse events were common, particularly during dose escalation, and tolerability varied across the dosing strategies.

The findings supported progression to larger Phase 3 trials. However, this study alone did not establish long-term safety, suitability for an individual, or regulatory approval.

Original publication

Jastreboff AM, Kaplan LM, Frías JP, et al.
“Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial.”
The New England Journal of Medicine. 2023;389:514–526.
DOI: 10.1056/NEJMoa2301972.

Clinical trial registration: NCT04881760.

Research and educational disclaimer

This article is an independent educational summary of published scientific research. It does not reproduce or replace the original paper and does not constitute medical advice, prescribing information, a treatment recommendation, or instructions for personal use.

Retatrutide remains investigational and has not been approved by any regulatory authority. Lilly states that products claiming to be retatrutide outside its authorised clinical trials may contain incorrect ingredients, unknown contaminants, or inaccurate quantities.