Retatrutide Clinical Trial Results Explained (2023–2026)
Retatrutide went from an early-stage compound to one of the most closely watched obesity drugs in the world in about three years. This explainer walks through every major trial published or announced through October 2026, with the numbers that matter and the caveats that are often left out of headlines.
Key facts
- Retatrutide (LY3437943) is an investigational once-weekly injection from Eli Lilly that activates three hormone receptors: GIP, GLP-1 and glucagon.
- In the pivotal phase 3 TRIUMPH-1 trial, the 12 mg dose produced an average 28.3% weight loss at 80 weeks (efficacy estimand), or 25.0% when every randomized participant is counted.
- Gastrointestinal side effects were common, and up to 18.2% of participants on the highest dose stopped treatment because of adverse events in one phase 3 trial.
- Retatrutide is not FDA-approved. Lilly plans to submit it for U.S. approval in the first quarter of 2027.
What is retatrutide?
Retatrutide is a single peptide engineered to act on three receptors at once. Approved drugs such as semaglutide (Wegovy, Ozempic) target only the GLP-1 receptor, and tirzepatide (Zepbound, Mounjaro) targets GLP-1 and GIP. Retatrutide adds the glucagon receptor, which is thought to increase energy expenditure and help clear fat from the liver. That is why it is often called a “triple agonist.”
In clinical trials it is given as a once-weekly subcutaneous injection. In phase 3, participants started at 2 mg and the dose was raised every four weeks until they reached their assigned maintenance dose of 4 mg, 9 mg or 12 mg — all under medical supervision.
Phase 2: the 24% result that started the buzz (NEJM, 2023)
The first large obesity study was published in The New England Journal of Medicine in June 2023 (Jastreboff et al.). It enrolled 338 adults with obesity, or overweight plus a weight-related condition, and ran for 48 weeks.
| Dose | Weight change at 24 weeks | Weight change at 48 weeks |
|---|---|---|
| 1 mg | −7.2% | −8.7% |
| 4 mg | −12.9% | −17.1% |
| 8 mg | −17.3% | −22.8% |
| 12 mg | −17.5% | −24.2% |
| Placebo | −1.6% | −2.1% |
At 48 weeks, every participant on 8 mg or 12 mg lost at least 5% of body weight, and 83% of the 12 mg group lost at least 15%, compared with 2% on placebo. Side effects were mostly gastrointestinal, dose-related and mild to moderate; heart rate rose in a dose-dependent way, peaking at 24 weeks.
Phase 2 in type 2 diabetes and fatty liver
A companion trial in The Lancet (Rosenstock et al., 2023) tested retatrutide in 281 adults with type 2 diabetes at 42 U.S. sites. At 24 weeks, the 12 mg dose lowered HbA1c by 2.02 percentage points, versus 1.41 points for the approved GLP-1 drug dulaglutide and 0.01 points for placebo. Body weight fell by 16.9% at 36 weeks.
A liver substudy published in Nature Medicine in 2024 (Sanyal et al.) followed 98 participants with metabolic dysfunction-associated steatotic liver disease (MASLD). After 24 weeks on 12 mg, liver fat fell by 82.4% on average, and 86% of participants reached normal liver-fat levels (under 5%). Nobody on placebo did.
The phase 3 program at a glance
Lilly’s phase 3 work is split into the TRIUMPH trials (obesity and its complications) and TRANSCEND-T2D (type 2 diabetes). The main registrational trials are:
| Trial | Population | Participants | ClinicalTrials.gov |
|---|---|---|---|
| TRIUMPH-1 | Obesity/overweight without diabetes (with knee-OA and sleep-apnea substudies) | ~2,339 | NCT05929066 |
| TRIUMPH-2 | Obesity plus type 2 diabetes | 1,152 | NCT05929079 |
| TRIUMPH-3 | BMI ≥35 plus established cardiovascular disease | ~1,949 | NCT05882045 |
| TRIUMPH-4 | Obesity plus knee osteoarthritis | 445 | NCT05931367 |
| TRIUMPH-5 | Head-to-head vs tirzepatide | 800 | NCT06662383 |
| TRANSCEND-T2D-1 | Type 2 diabetes, monotherapy | 537 | NCT06354660 |
Enrollment counts differ slightly between Lilly’s releases and the registry; the table uses the figures reported by each source.
TRIUMPH-4: weight loss and knee pain relief (December 2025)
TRIUMPH-4 was the first phase 3 readout. Over 68 weeks, adults with obesity and knee osteoarthritis lost 26.4% (9 mg) and 28.7% (12 mg) of their body weight, versus 2.1% on placebo (efficacy estimand). Knee pain on the WOMAC scale fell by about 75% on the active doses compared with about 40% on placebo.
The trial also exposed the trade-off of very potent weight loss. Nausea affected 43.2% of the 12 mg group, vomiting 20.9%, and dysesthesia — an abnormal or unpleasant skin sensation — 20.9%, versus 0.7% on placebo. 18.2% of the 12 mg group discontinued because of adverse events. Lilly said discontinuations were more common in people with a lower starting BMI and included some for “perceived excessive weight loss.”
TRIUMPH-1: 28.3% at 80 weeks (May 2026, now in NEJM)
TRIUMPH-1 is the pivotal obesity trial. About 2,339 adults with a mean starting weight of 248.5 lb were randomized to 4 mg, 9 mg, 12 mg or placebo for 80 weeks. The peer-reviewed results appear in the TRIUMPH-1 paper in The New England Journal of Medicine.
| Dose | Efficacy estimand | Treatment-regimen estimand |
|---|---|---|
| 4 mg | −19.0% | −17.6% |
| 9 mg | −25.9% | −23.7% |
| 12 mg | −28.3% (about 70 lb) | −25.0% |
| Placebo | −2.2% | −3.9% |
Why two numbers? The efficacy estimand estimates the effect in people who kept taking the drug as intended. The treatment-regimen (intention-to-treat) estimand counts everyone who was randomized, including people who stopped early. The second number is lower but better reflects real-world use.
On 12 mg, 45.3% of participants lost at least 30% of their body weight and 65.3% ended the trial with a BMI under 30. In the sleep-apnea substudy, the apnea-hypopnea index fell by roughly 32–34 events per hour on the higher doses, versus 9.6 on placebo.
You may see a figure of 30.3% online. That comes from a pre-specified 104-week extension in 532 participants with a BMI of 35 or higher — not from the main 80-week result.
Diabetes and heart-disease populations
- TRANSCEND-T2D-1 (The Lancet, June 2026): in 537 adults with early type 2 diabetes, 12 mg lowered HbA1c by 1.94 points and weight by 15.3% at 40 weeks.
- TRIUMPH-2 (obesity plus type 2 diabetes): weight fell by up to 20.8% (efficacy estimand) and HbA1c by about 1.5 points. The Lancet publication reports 18.8% on 12 mg using the treatment-regimen estimand.
- TRIUMPH-3 (BMI ≥35 with heart disease): weight fell by 22.6% on 12 mg, with triglycerides down 37% and the inflammation marker hsCRP down 51%. The trial was not designed to show whether heart attacks or strokes are prevented — that is the job of the 10,000-person TRIUMPH-Outcomes study.
As expected, people with type 2 diabetes lost less weight than people without it, a pattern also seen with semaglutide and tirzepatide.
Side effects seen in trials
Across the program, the most common side effects were nausea, diarrhea, vomiting and constipation, mostly during dose escalation. Two signals stand out compared with older drugs:
- Dysesthesia (skin sensitivity or tingling): 12.5% on 12 mg in TRIUMPH-1 and 20.9% in TRIUMPH-4, versus about 1% on placebo.
- Discontinuation due to adverse events: 11.3% on 12 mg in TRIUMPH-1, 13.5% in TRIUMPH-3 and 18.2% in TRIUMPH-4.
These rates were observed in carefully monitored trials with gradual dose escalation.
When could retatrutide be approved?
Lilly has said it is preparing a U.S. submission for the first quarter of 2027, covering obesity, knee osteoarthritis pain and obstructive sleep apnea. One complication: the FDA classified retatrutide as a drug rather than a biologic in 2024. Lilly challenged that decision in court; a federal court largely sided with the FDA in September 2025, and Lilly has appealed. Head-to-head results against tirzepatide (TRIUMPH-5) and semaglutide (TRANSCEND-T2D-2) are still pending.
Why “research peptide” retatrutide is not the same thing
Until approval, the only legal way to receive retatrutide as a treatment in the U.S. is through a clinical trial or Lilly’s physician-requested expanded-access program, which opened in August 2026 for patients who meet strict criteria.
Retatrutide sold online is sold as a research chemical. The FDA states that retatrutide cannot be compounded and has sent warning letters to sellers who label it “for research use only” while marketing it for human use. In August 2026, Lilly filed six lawsuits against sellers, warning that black-market products “could be fake, impure or mis-dosed.” CBS News reported in October 2026 on two unverified FDA adverse-event reports describing deaths in people who had used black-market retatrutide, and U.S. poison centers logged a sharp rise in retatrutide exposures during 2026.
That is why, when we rate retatrutide vendors, independent third-party testing carries the largest weight in our methodology: a certificate of analysis from a named lab is the minimum evidence that a vial contains what the label says. For how retatrutide compares with semaglutide and tirzepatide, read our explainer on GLP-1 vs dual vs triple agonists.
Sources: Jastreboff et al., NEJM 2023; Rosenstock et al., Lancet 2023; Sanyal et al., Nature Medicine 2024; Eli Lilly press releases of December 11, 2025, May 21, 2026 and July 23, 2026; ClinicalTrials.gov; FDA; BioPharma Dive; CBS News.