Phase 2 Obesity Trial of Retatrutide (NCT04881706)

Study Overview

The Phase 2 obesity trial of retatrutide, registered as NCT04881706 on ClinicalTrials.gov, was a landmark study that produced the most striking weight loss results ever reported for a pharmacological agent in a randomized controlled trial. Published by Jastreboff et al. in the New England Journal of Medicine in June 2023, the trial demonstrated that retatrutide’s triple GIP/GLP-1/glucagon receptor agonism could produce weight reductions approaching those typically associated 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 to one of six arms:

1. Placebo (matched subcutaneous injection)
2. Retatrutide 1 mg (fixed dose)
3. Retatrutide 4 mg (escalating: 2 mg x4 weeks, then 4 mg)
4. Retatrutide 4 mg (fixed: 4 mg from start)
5. Retatrutide 8 mg (escalating: 2 mg x4 weeks, 4 mg x4 weeks, then 8 mg)
6. Retatrutide 12 mg (escalating: 2 mg x4 weeks, 4 mg x4 weeks, 8 mg x4 weeks, then 12 mg)

The escalating-dose design for higher dose groups was intended to improve gastrointestinal tolerability.

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

The weight loss results at 48 weeks were unprecedented:

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 achieving key weight loss thresholds at 48 weeks in the 12 mg group:

• ≥5% weight loss: ~100%
• ≥10% weight loss: ~93%
• ≥15% weight loss: ~83%
• ≥20% weight loss: ~73%
• ≥25% weight loss: ~50%

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 imaging substudy, participants with elevated baseline liver fat experienced dramatic, dose-dependent reductions. The 12 mg group showed an approximately 82% relative reduction from baseline, with a majority of participants achieving normalization of liver fat content below the 5% threshold.

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):

• Nausea: ~24%
• Diarrhea: ~22%
• Vomiting: ~13%
• Constipation: ~12%
• Decreased appetite: ~11%

GI events were predominantly mild to moderate and occurred most frequently during dose escalation. Treatment discontinuation due to adverse events was dose-dependent, ranging from ~0% (1 mg) to ~16% (12 mg). No unexpected safety signals were identified.

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 comparison between the 4 mg escalating and 4 mg fixed-dose groups provided direct evidence that gradual dose escalation improves both tolerability and efficacy, informing the design of the Phase 3 TRIUMPH program.

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