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Retatrutide-Obesity
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What are the preliminary results with retatrutide from TRIUMPH-4 in participants with obesity or overweight and osteoarthritis?
In TRIUMPH-4, retatrutide met the co-primary endpoints and lowered weight by up to an average of 28.7%, and reduced pain by up to an average of 4.5 points using the WOMAC pain score. The overall safety of retatrutide was consistent with other incretins.
TRIUMPH-4 Phase 3 Study Design of Retatrutide in Adults with Obesity or Overweight and Osteoarthritis
Retatrutide is a novel, synthetic molecule with potent agonist action at the
- glucose-dependent insulinotropic polypeptide (GIP)
- glucagon-like peptide-1 (GLP-1), and
- glucagon receptors.1
TRIUMPH-4 is a phase 3, multicenter, randomized, double-blind study evaluating the efficacy and safety of retatrutide compared to placebo in adults with obesity or overweight and knee osteoarthritis (OA).2
Participants were randomized to receive once-weekly subcutaneous injections of
- retatrutide escalated to 9 mg
- retatrutide escalated to 12 mg, or
- placebo.2
Participants initiated treatment at a 2 mg dose, which was titrated in 4-week intervals to the randomized target dose; this dose was subsequently maintained throughout the 68-week treatment period (see TRIUMPH-4 Study Design more details).2
Figure Description: TRIUMPH-4 is a phase 3, 68-week trial with a 4-week safety follow-up. All participants receive adjunct lifestyle counseling focused on a healthy diet and physical activity. Participants are randomized 1:1:1 to retatrutide escalated to 9 mg or 12 mg maximum dose or placebo, in addition to healthy diet and physical activity.
Abbreviations: PBO = placebo; QW = once weekly.
Dose escalation is fixed, and dose reductions are permitted for gastrointestinal adverse events or for participants who reached a body mass index (BMI) ≤22 kg/m2 or perceived excessive weight loss.2
All participants receive individualized lifestyle counseling focusing on
- a healthy diet rather than caloric restriction, and
- at least 150 minutes of moderate-intensity physical activity per week that includes a strength-training component.2
Inclusion and Exclusion Criteria
TRIUMPH-4 Key Inclusion and Exclusion Criteria presents the key inclusion and exclusion criteria for Triumph-4.
Key Inclusion Criteria |
Key Exclusion Criteria |
|
|
Abbreviations: BMI = body mass index
Co-Primary Endpoints
The TRIUMPH-4 co-primary endpoints are change from baseline to week 68 in
- % body weight, and
- Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) pain subscale score.2
WOMAC is a 24-question instrument administered at screening, baseline, and throughout the study including week 68. Participants recorded their responses using a 0–10 Numeric Rating Score for each question in the subscales of
- pain (5 questions)
- stiffness (2 questions), and
- physical function (17 questions).2
Each subscale score is calculated by summing the scores of the individual items and converting to a 0–10 scale by dividing it by the number of items in the subscale.2
Preliminary Efficacy Outcomes
In TRIUMPH-4, retatrutide 9 mg and 12 mg met the co-primary and key secondary endpoints as presented in TRIUMPH-4 Weight and Pain Co-Primary and Key Secondary Endpoints: Efficacy Estimand Results. 4
Two statistical estimands, efficacy or treatment-regimen, were used to evaluate efficacy data from TRIUMPH-4 of retatrutide:
- Efficacy estimand evaluates the treatment effect prior to discontinuation of the study drug or other intercurrent event
- Treatment-regimen estimand evaluates the treatment effect irrespective of adherence to the study drug or other intercurrent event. 5
Endpoint |
Retatrutide 9 mg |
Retatrutide 12 mg |
Placebo |
Co-Primary Endpoints |
|||
Change in body weight, % (kg; lbs)a |
-26.4 |
-28.7 |
-2.1 |
Change in WOMAC pain subscale score, points (%)b |
-4.5 |
-4.4 |
-2.4 |
Secondary Endpoints |
|||
Achieved ≥25% weight loss, % |
47.7 |
58.6 |
1.3 |
Achieved ≥30% weight loss, % |
30.5 |
39.4 |
0.8 |
Achieved ≥35% weight loss, % |
18.2 |
23.7 |
0.0 |
Change in WOMAC physical function subscale score, points (%)d |
-4.1 |
-4.2 |
-2.1 |
Achieved ≥70% reduction in WOMAC pain subscale score, %e |
73.0 |
67.7 |
26.2 |
aBaseline average = 112.7 kg (248.5 lbs; 40.4 kg/m2 BMI)
bBaseline average WOMAC score = 6.0 points
cPercent change in the WOMAC pain subscale score and percent change in the WOMAC physical function subscale score were not pre-specified and were estimated from a post-hoc analysis.
dBaseline physical function subscale score = 5.8 points
eNot controlled for multiplicity.
In an additional post-hoc analysis, the percentage of participants completely free of knee pain at 68 weeks based on observed efficacy estimand data was
- 14.1% on retatrutide 9 mg
- 12.0% on retatrutide 12 mg, and
- 4.2% on placebo.4
For the treatment regimen estimand data, both retatrutide 9 mg and retatrutide 12 mg met the co-primary endpoints. 4
The percent change in body weight was
- -20.0% (-22.9 kg; -50.5 lbs) for retatrutide 9 mg
- -23.7% (-27.2 kg; -60.0 lbs) for retatrutide 12 mg, and
- -4.6% (-5.3 kg; -11.7 lbs) for placebo.4
The change in WOMAC pain subscale score was
- -4.0 points (-67.2%) for retatrutide 9 mg
- -3.7 points (-62.6 %) for retatrutide 12 mg, and
- -2.1 points (-35.1%) for placebo.4
Preliminary Safety Outcomes
The overall safety profile of retatrutide in TRIUMPH-4 was consistent with observations in other incretin clinical trials. The most common adverse events are presented in Common Adverse Events in TRIUMPH-4. 4
Adverse Event, (%) |
Retatrutide 9 mg |
Retatrutide 12 mg |
Placebo |
Nausea |
38.1 |
43.2 |
10.7 |
Diarrhea |
34.7 |
33.1 |
13.4 |
Constipation |
21.8 |
25.0 |
8.7 |
Vomiting |
20.4 |
20.9 |
0 |
Decreased appetite |
19.0 |
18.2 |
9.4 |
Dysesthesiaa |
8.8 |
20.9 |
0.7 |
aDysesthesia events were generally mild and rarely led to treatment discontinuation.
Discontinuation rates due to adverse events were
- 12.2% in retatrutide 9 mg
- 18.2% in retatrutide 12 mg, and
- 4.0% in placebo.4
In TRIUMPH-4, 84.0% of participants had a baseline BMI ≥35. Discontinuation rates in these participants due to adverse events were
- 8.8% in retatrutide 9 mg
- 12.1% in retatrutide 12 mg doses, and
- 4.8% in placebo.4
Future TRIUMPH Results
Detailed TRIUMPH-4 results will be presented in future medical meetings and published in peer-reviewed journals. Additional TRIUMPH program results are expected in 2026.4
References
1Jastreboff AM, Kaplan LM, Frías JP, et al; Retatrutide Phase 2 Obesity Trial Investigators. Triple–hormone-receptor agonist retatrutide for obesity — a phase 2 trial. N Engl J Med. 2023;389(6):514-526. https://doi.org/10.1056/nejmoa2301972
2Giblin K, Kaplan LM, Somers VK, et al. Retatrutide for the treatment of obesity, obstructive sleep apnea, and knee osteoarthritis: Rationale and design of the TRIUMPH registrational clinical trials. Diabetes Obes Metab. Published online October 15, 2025. https://doi.org/10.1111/dom.70209
3A study of retatrutide (LY3437943) once weekly in participants who have obesity or overweight and osteoarthritis of the knee (TRIUMPH-4). Clinicaltrials.gov identifier: NCT05931367. Updated April 22, 2025. Accessed December 5, 2025. https://clinicaltrials.gov/study/NCT05931367
4Lilly’s triple agonist, retatrutide, delivered weight loss of up to an average of 71.2 lbs along with substantial relief from osteoarthritis in first successful Phase 3 trial. Press release. Eli Lilly and Company; Dec 11, 2025. Accessed Dec 11, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-triple-agonist-retatrutide-delivered-weight-loss-average
5Data on file, Eli Lilly and Company and/or one of its subsidiaries.
Date of Last Review: December 09, 2025