The Phase 2 randomized clinical trial of retatrutide was published in the New England Journal of Medicine on June 26, 2023. Led by Dr. Ania Jastreboff (Yale University) and colleagues, the trial provided the first rigorous efficacy data for the triple-agonist approach to weight loss.
Study design
Population: 338 adults with obesity (BMI ≥30) or overweight (BMI ≥27) with at least one weight-related comorbidity. Excluded: type 2 diabetes.
Duration: 48 weeks of treatment
Arms: Retatrutide at 1 mg, 4 mg, 8 mg, 12 mg, or placebo — all once-weekly subcutaneous injection
Primary endpoint: Percent change in body weight from baseline at 24 weeks
Key secondary: Percent change at 48 weeks
Key results at 48 weeks
The weight loss was dose-dependent, meaning higher doses produced greater effects:
| Dose | Mean weight loss | ≥5% loss | ≥10% loss | ≥15% loss | ≥20% loss |
|---|---|---|---|---|---|
| Placebo | ~2.1% | 31% | 11% | 3% | 0% |
| 1 mg | ~8.7% | 75% | 39% | 21% | 8% |
| 4 mg | ~17.1% | 91% | 78% | 60% | 30% |
| 8 mg | ~22.8% | 92% | 87% | 77% | 55% |
| 12 mg | ~24.2% | 100% | 93% | 83% | 63% |
At the 12 mg dose, every participant lost at least 5% of body weight, and nearly two-thirds lost more than 20%. The weight loss trajectory had not plateaued at 48 weeks, suggesting further reductions might be possible with longer treatment.
Side effects
Gastrointestinal events — nausea, diarrhea, vomiting, constipation — were the most common and were dose-dependent. Most were mild to moderate and improved over time. Discontinuation due to adverse events was higher in the treatment groups (up to ~16% at 12 mg) compared to placebo (~4%).
Heart rate increases of 2–7 beats per minute were observed, consistent with other incretin-based therapies. No unexpected safety signals emerged in this 338-person trial, but the authors cautioned that larger and longer studies were needed.
Why this paper mattered
Before this publication, the concept of a triple agonist (GIP + GLP-1 + glucagon) was largely theoretical. The Phase 2 data proved:
- Triple agonism is viable — hitting all three receptors produced greater weight loss than targeting one or two alone
- The dose-response is clean — more receptor activation meant more weight loss, supporting the mechanism
- Safety was manageable — the profile resembled existing incretin drugs, with no “new” class of side effects from glucagon activation
These results directly led to the design and launch of the five-trial TRIUMPH Phase 3 program.
Source
- Jastreboff AM, 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 | PMID: 37366315 - ClinicalTrials.gov — NCT04881760
This article summarizes published scientific research. It does not constitute medical advice.