Phase 2 Results Published in NEJM: Retatrutide Achieves 24% Weight Loss at 48 Weeks
The landmark Phase 2 trial of retatrutide published in the New England Journal of Medicine showed dose-dependent weight loss up to ~24% — results that set the stage for the Phase 3 TRIUMPH program.
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:
1. **Triple agonism is viable** — hitting all three receptors produced greater weight loss than targeting one or two alone
2. **The dose-response is clean** — more receptor activation meant more weight loss, supporting the mechanism
3. **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](https://www.nejm.org/doi/full/10.1056/NEJMoa2301972) | PMID: 37366315
- [ClinicalTrials.gov — NCT04881760](https://clinicaltrials.gov/study/NCT04881760)
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*This article summarizes published scientific research. It does not constitute medical advice.*