Complete overview of retatrutide's clinical trial program: Phase 2 NEJM data, the TRIUMPH Phase 3 program, FDA approval timeline, and what the evidence means for researchers.
Research Disclaimer: This page summarizes published clinical trial data for educational purposes. Retatrutide is not FDA-approved for human use as of 2026. All data cited is from peer-reviewed publications or ClinicalTrials.gov registrations.
Retatrutide (LY3437943) is an investigational triple receptor agonist developed by Eli Lilly. It simultaneously activates GLP-1 (glucagon-like peptide-1), GIP (glucose-dependent insulinotropic polypeptide), and glucagon receptors — a mechanism that distinguishes it from all currently approved weight-loss medications.
The addition of glucagon receptor agonism is the key differentiator. While semaglutide and tirzepatide reduce caloric intake primarily through appetite suppression, retatrutide also increases energy expenditure through thermogenesis and direct hepatic lipolysis — effectively burning more calories at rest in addition to reducing intake.
Phase 2 results published in the New England Journal of Medicine in June 2023 showed retatrutide produced the highest weight loss ever recorded in a pharmaceutical trial at that time — 24.2% average body weight reduction at 48 weeks with the 12 mg/week dose.
First-in-human safety and pharmacokinetics study. Established tolerability and dose-ranging data for weekly subcutaneous administration.
338 adults with obesity (BMI ≥30 or ≥27 with comorbidity). Primary endpoint: % change in body weight at 24 weeks. Extended to 48 weeks. Published in NEJM June 2023.
Obesity without type 2 diabetes. Larger population, longer duration. Primary endpoint: ≥5% body weight reduction at 72 weeks. Estimated completion 2025–2026.
Type 2 diabetes with obesity. Evaluating HbA1c reduction and weight loss co-primary endpoints. Comparing against tirzepatide as active comparator.
Cardiovascular outcomes trial. Evaluating MACE (major adverse cardiovascular events) in high-risk patients. Mirrors the SELECT trial design used for semaglutide.
Eli Lilly has not announced a submission date. Analysts project NDA submission in late 2026 pending Phase 3 readout, with potential approval in 2027.
Retatrutide Phase 2 weight loss by dose group (NEJM 2023, NCT04881760). 48-week data. For research purposes only.
Source: Jastreboff AM et al. N Engl J Med 2023;389:514–526. NCT04881760. 48-week data, n=338.
| Dose | Avg Weight Loss | ≥30% Weight Loss | HbA1c Change | Notes |
|---|---|---|---|---|
| Placebo | 2.1% | 0% | −0.1% | Control group |
| 1 mg/week | 8.7% | 2% | −0.8% | Lowest active dose |
| 4 mg/week | 17.3% | 9% | −1.4% | Mid-range dose |
| 8 mg/week | 22.8% | 19% | −1.8% | High dose |
| 12 mg/week | 24.2% | 26% | −2.2% | Maximum studied dose |
Average body weight reduction at 48 weeks (12 mg group)
Participants who lost more than 30% of body weight
HbA1c reduction in the 12 mg group
No plateau observed — weight loss continued throughout
Of weight lost was fat mass (vs ~60% for semaglutide)
Reduction in liver fat (PDFF) in participants with NAFLD
Note: Cross-trial comparisons are indicative only — different populations, durations, and endpoints make direct comparison difficult.
| Compound | Mechanism | Weight Loss | Duration | Phase | Lean Mass |
|---|---|---|---|---|---|
| Retatrutide 12 mg | GLP-1 + GIP + Glucagon | 24.2% | 48 weeks | Phase 2 | ~70% fat |
| Tirzepatide 15 mg | GLP-1 + GIP | 22.5% | 72 weeks | Phase 3 | ~67% fat |
| Semaglutide 2.4 mg | GLP-1 | 14.9% | 68 weeks | Phase 3 | ~60% fat |
| Liraglutide 3 mg | GLP-1 | 8.0% | 56 weeks | Phase 3 | ~58% fat |
Eli Lilly's TRIUMPH program is the Phase 3 clinical development plan for retatrutide. It mirrors the structure used for tirzepatide's SURPASS and SURMOUNT programs, with multiple parallel trials evaluating different patient populations and endpoints.
TRIUMPH-1 is the pivotal obesity trial — the equivalent of SURMOUNT-1 for tirzepatide. It enrolls adults with BMI ≥30 (or ≥27 with weight-related comorbidity) without type 2 diabetes. The primary endpoint is ≥5% body weight reduction at 72 weeks, with key secondary endpoints including ≥10%, ≥15%, and ≥20% weight reduction thresholds.
TRIUMPH-2 evaluates retatrutide in adults with type 2 diabetes and obesity, with co-primary endpoints of HbA1c reduction and body weight reduction. This trial includes tirzepatide as an active comparator — making it the first head-to-head trial between the two compounds.
TRIUMPH-CV is a cardiovascular outcomes trial designed to demonstrate MACE reduction, which will be required for broad insurance coverage. This mirrors the SELECT trial that established semaglutide's cardiovascular benefit and was critical for its commercial success.
As of early 2026, Eli Lilly has not announced a specific NDA (New Drug Application) submission date for retatrutide. Phase 3 TRIUMPH trials are ongoing, with estimated completion dates of 2025–2026 for the primary endpoints.
Based on typical FDA review timelines (12 months for standard review, 6 months for priority review), analysts project potential FDA approval in late 2026 or 2027 — assuming Phase 3 results replicate Phase 2 efficacy and the cardiovascular safety profile is acceptable.
This page will be updated as TRIUMPH trial results are published and FDA submission timelines are announced.
The Phase 2 safety data was generally consistent with the GLP-1 receptor agonist class. The most common adverse events were gastrointestinal, occurring primarily during dose escalation and resolving with continued treatment.
| Adverse Event | Retatrutide 12 mg | Placebo |
|---|---|---|
| Nausea | 45% | 16% |
| Vomiting | 23% | 5% |
| Diarrhea | 18% | 9% |
| Constipation | 14% | 7% |
| Decreased appetite | 12% | 3% |
| Serious adverse events | 9% | 7% |
| Discontinuation due to AEs | 16% | 2% |
The 16% discontinuation rate due to adverse events in the 12 mg group is higher than tirzepatide (7% in SURMOUNT-1) and semaglutide (7% in STEP-1), largely driven by GI events during the aggressive titration schedule used in Phase 2. Phase 3 protocols use a slower titration to address this.
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As of 2026, retatrutide has completed Phase 2 trials and is in Phase 3 trials under the TRIUMPH program. Phase 2 results published in the New England Journal of Medicine showed 24.2% average body weight reduction at 48 weeks with the 12 mg dose.
The Phase 2 trial (NCT04881760) enrolled 338 adults with obesity. At 48 weeks, the 12 mg/week dose group achieved 24.2% average body weight reduction. 26% of participants lost more than 30% of their body weight. The placebo group lost 2.1%.
TRIUMPH is Eli Lilly's Phase 3 clinical trial program for retatrutide. It includes multiple trials evaluating retatrutide for obesity, type 2 diabetes, cardiovascular outcomes, and NASH/MAFLD. TRIUMPH-1 focuses on obesity without diabetes; TRIUMPH-2 focuses on type 2 diabetes.
Retatrutide's Phase 2 data showed 24.2% weight loss vs tirzepatide's Phase 3 SURMOUNT-1 data of 22.5%. However, these are different trial designs and populations, making direct comparison difficult. Retatrutide's additional glucagon receptor agonism appears to provide incremental fat loss beyond dual GLP-1/GIP agonism.
In Phase 2 trials, the most common side effects were gastrointestinal: nausea (45%), vomiting (23%), diarrhea (18%), and constipation (14%). Most GI events were mild-to-moderate and occurred during dose escalation. Serious adverse events occurred in 9% of the 12 mg group vs 7% placebo.
Eli Lilly has not announced a specific FDA submission date as of early 2026. Phase 3 trials are ongoing. Based on typical timelines, FDA approval could come in late 2026 or 2027 if Phase 3 results replicate Phase 2 efficacy and the safety profile remains acceptable.
Phase 2 data showed retatrutide preserved lean mass better than historical semaglutide data. Approximately 70% of weight lost was fat mass vs 30% lean mass — comparable to tirzepatide and better than semaglutide's approximately 60/40 fat-to-lean ratio. This is attributed to the GIP receptor component.
Retatrutide is a triple agonist targeting GLP-1, GIP, and glucagon receptors simultaneously. GLP-1 agonism reduces appetite and slows gastric emptying. GIP agonism improves insulin sensitivity and enhances fat metabolism. Glucagon receptor agonism increases hepatic glucose output, thermogenesis, and direct lipolysis — adding a metabolic burn component absent from dual agonists.
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