Retatrutide Phase 2 Obesity Trial: -24.2% Weight Loss

Study Overview

The Phase 2 obesity trial of retatrutide, registered as NCT04881760 on ClinicalTrials.gov, produced the most striking weight loss results ever reported for a drug in a randomized controlled trial. Published by Jastreboff et al. in the New England Journal of Medicine in June 2023, the trial showed that retatrutide’s triple GIP/GLP-1/glucagon receptor agonism could produce weight loss approaching what is usually seen with bariatric surgery.

Study Design

Design

Randomized, double-blind, placebo-controlled, dose-ranging, parallel-group study.

Duration

48 weeks of treatment, with a primary endpoint assessment at 24 weeks and key secondary endpoint at 48 weeks.

Population

Adults aged 18-75 years with:

• Obesity (BMI ≥30 kg/m2), or
• Overweight (BMI ≥27 kg/m2) with at least one weight-related comorbidity (hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease)

Exclusion criteria included type 1 or type 2 diabetes, recent weight change (>5 kg in 3 months), prior bariatric surgery, and significant renal or hepatic impairment.

Treatment Arms

Participants were randomized in a 2:1:1:1:1:2:2 ratio to seven groups:

1. Retatrutide 1 mg
2. Retatrutide 4 mg, starting at 2 mg
3. Retatrutide 4 mg, starting at 4 mg
4. Retatrutide 8 mg, starting at 2 mg
5. Retatrutide 8 mg, starting at 4 mg
6. Retatrutide 12 mg, starting at 2 mg
7. Placebo (matched subcutaneous injection)

Where a dose was raised, it went up every 4 weeks. There was no group that stayed on a fixed 4 mg dose for a lower-dose comparison: both 4 mg sub-arms ended on 4 mg, and they differed only in the starting dose. The published results pool the two 4 mg sub-arms and the two 8 mg sub-arms.

Endpoints

Primary endpoint: Percent change in body weight from baseline at 24 weeks.

Key secondary endpoints:

• Percent change in body weight from baseline at 48 weeks
• Proportion of participants achieving ≥5%, ≥10%, ≥15% weight loss at 48 weeks
• Change in waist circumference
• Change in cardiometabolic parameters (blood pressure, lipids)
• Liver fat content change (MRI-PDFF substudy)

Results

Weight Loss

Mean weight change at 24 weeks (primary endpoint) and 48 weeks:

All active treatment arms demonstrated statistically significant weight loss versus placebo (p<0.001 for all comparisons at 48 weeks).

Responder Analysis

The proportion of participants reaching weight loss thresholds at 48 weeks:

Weight Trajectory

Weight loss was progressive throughout the 48-week treatment period. In the higher-dose groups, the trajectory had not fully plateaued by week 48, indicating that longer treatment could yield additional weight reduction.

Liver Fat

In the MRI-PDFF substudy of 98 participants with MASLD and at least 10% liver fat, liver fat fell in a dose-dependent way. At 24 weeks the mean relative change was -81.4% at 8 mg and -82.4% at 12 mg, against +0.3% on placebo, and 79% and 86% of participants in those groups had normal liver fat (below 5%). At 48 weeks the 12 mg change was -86.0% (Sanyal et al., Nature Medicine, 2024).

Cardiometabolic Parameters

Improvements were observed across multiple cardiometabolic markers:

• Systolic blood pressure: -4 to -8 mmHg reductions
• Triglycerides: ~25-40% reductions
• Waist circumference: ~10-15 cm reductions
• HDL cholesterol: modest increases

Safety

The adverse event profile was consistent with the incretin-based therapy class:

Most common adverse events (12 mg group, n=62, over 48 weeks; placebo in brackets):

• Nausea: 45% (11%)
• Decreased appetite: 29% (9%)
• Vomiting: 19% (1%)
• Constipation: 16% (3%)
• Diarrhea: 15% (11%)

GI events were predominantly mild to moderate, occurred most frequently during dose escalation, and were less common with a 2 mg than a 4 mg starting dose (nausea 17% vs 60% in the two 8 mg groups). Treatment discontinuation due to adverse events was 6% to 16% across the retatrutide groups (7% at 1 mg, 16% at 12 mg) and 0% on placebo. Heart rate rose with dose, peaked at 24 weeks and then declined. Serious adverse events occurred in 4% of both the retatrutide and placebo groups. Source: Jastreboff et al., NEJM 2023, Table 3.

Significance

Record-Setting Weight Loss

The 24.2% mean weight loss in the 12 mg group exceeded any previously reported pharmacological intervention:

• Semaglutide 2.4 mg achieved ~15-17% in the STEP trials
• Tirzepatide 15 mg achieved ~20-22% in SURMOUNT-1
• The retatrutide result approaches the 25-35% range typical of bariatric surgery

Dose-Escalation Validation

The trial tested two starting doses (2 mg and 4 mg) for the 4 mg and 8 mg targets, with dose increases every 4 weeks. The Phase 3 TRIUMPH trials start every participant at 2 mg and raise the dose every 4 weeks.

Liver Fat Discovery

The liver fat data emerged as one of the most impactful secondary findings, generating interest in retatrutide for MASLD/MASH and contributing to the mechanistic understanding of glucagon receptor agonism’s hepatic effects.

Publication

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

Limitations

• Relatively small sample size (338 participants) limits ability to detect uncommon adverse events
• 48-week treatment duration may not capture maximum weight loss or long-term safety
• Study population was predominantly White and conducted at U.S. sites
• No active comparator arm (only placebo control)
• Weight loss trajectory was ongoing at week 48, making the ultimate magnitude of effect uncertain