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Retatrutide-Obesity

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What is the impact of retatrutide in patients with obesity or overweight and osteoarthritis of the knee?

Retatrutide met the co-primary body weight and WOMAC pain endpoints in TRIUMPH-4 and the primary WOMAC pain endpoint in the TRIUMPH-1 knee OA basket study. Most common AEs were GI related and generally mild to moderate in severity.

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Content Overview

Which retatrutide clinical trials evaluated adults with obesity or overweight and knee osteoarthritis?
What was the TRIUMPH-4 phase 3 study design in adults with obesity or overweight and knee osteoarthritis?
- TRIUMPH-4 Inclusion and Exclusion Criteria
- TRIUMPH-4 Coprimary Endpoints
What were the preliminary efficacy outcomes with retatrutide in TRIUMPH-4?
What were the preliminary safety outcomes with retatrutide in TRIUMPH-4?
What was the TRIUMPH-1 knee osteoarthritis basket study design in adults with obesity or overweight?
What were the efficacy and safety outcomes in the TRIUMPH-1 knee osteoarthritis basket study?
- TRIUMPH-1 Knee Osteoarthritis Basket Safety Outcomes
What additional retatrutide results are expected from the TRIUMPH program?
References

Which retatrutide clinical trials evaluated adults with obesity or overweight and knee osteoarthritis?

Retatrutide is a novel, synthetic molecule with agonist action at the

glucose-dependent insulinotropic polypeptide (GIP)
glucagon-like peptide-1 (GLP-1), and
glucagon receptors.¹

Retatrutide is an investigational agent and has not received marketing authorization from any regulatory authority.

The safety and efficacy of retatrutide in adults with obesity or overweight and osteoarthritis (OA) of the knee were evaluated in 2 phase 3, randomized, double-blind, placebo-controlled clinical trials including

TRIUMPH-4, a trial dedicated to participants with obesity or overweight and OA of the knee, and
TRIUMPH-1, a master protocol obesity trial that included a nested knee OA basket study.²

A basket study is an independent, statistically rigorous trial within a master protocol that provides indication-specific information. In a basket study, a predefined subgroup of participants who met additional disease-specific eligibility criteria was enrolled within a larger master protocol and evaluated against its own primary endpoint using indication-specific assessment scales.²

Additional details on each trial are provided below.

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What was the TRIUMPH-4 phase 3 study design in adults with obesity or overweight and knee osteoarthritis?

TRIUMPH-4 was a phase 3, multicenter, randomized, double-blind study that evaluated the efficacy and safety of retatrutide compared with placebo in adults with obesity or overweight and knee OA.²

A total of 445 participants were randomized 1:1:1 to receive once-weekly subcutaneous injections of

retatrutide escalated to 9 mg
retatrutide escalated to 12 mg, or
placebo.²^,⁴

Participants initiated treatment at a 2 mg dose, which was escalated in 4-week intervals to the randomized target dose; this dose was subsequently maintained throughout the 68-week treatment period (see Figure 1 for more details).²

Figure 1. TRIUMPH-4 Study Design²

Figure 1 description: TRIUMPH-4 was a phase 3, 68-week trial with a 4-week safety follow-up. All participants received adjunct lifestyle counseling focused on a healthy diet and physical activity. Participants were 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 was fixed, and dose reductions were permitted only during the dose escalation phase 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 received 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

TRIUMPH-4 Inclusion and Exclusion Criteria

Table 1 presents the key inclusion and exclusion criteria for TRIUMPH-4.

**Table 1.** TRIUMPH-4 Key Inclusion and Exclusion Criteria^2,3
Key Inclusion Criteria	Key Exclusion Criteria
Adults aged ≥18 years with a history of ≥1 unsuccessful dietary effort to reduce body weight BMI ≥27 kg/m² Index knee pain >12 weeks before screening and presence of index knee pain for >15 days in the month prior to screening Knee X-ray with moderate radiographic changes (Kellgren-Lawrence grade 2 or 3) at screening At least 1 of the following: >50 years of age morning stiffness in index knee <30 minutes in duration crepitus in index knee	Type 1 or Type 2 diabetes Weight change >5 kg within 90 days of screening Chronic systemic glucocorticoid therapy Steroid joint injections within 90 days of screening Other joint injections and procedures within 6 months of screening Joint disease other than osteoarthritis Taking weight loss drugs, including over-the-counter medications within 90 days prior to screening prior or planned surgical treatment for obesity

Abbreviations: BMI = body mass index.

TRIUMPH-4 Coprimary Endpoints

The TRIUMPH-4 coprimary endpoints were change from baseline to week 68 in

% body weight, and
Western Ontario and McMaster 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 Scale version 3.1 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 by the number of items in the subscale.²

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What were the preliminary efficacy outcomes with retatrutide in TRIUMPH-4?

In TRIUMPH-4, retatrutide 9 mg and 12 mg met the coprimary endpoints for both the treatment-regimen estimand and the efficacy estimand, as well as the key secondary endpoints, as presented in Table 2.⁴

Efficacy data from TRIUMPH-4 were evaluated using 2 statistical estimands

the treatment-regimen estimand, which evaluates the treatment effect irrespective of adherence to the study drug or other intercurrent event, and
the efficacy estimand, which evaluates the treatment effect prior to discontinuation of the study drug or other intercurrent event.⁵

**Table 2.** TRIUMPH-4 Weight and Pain Coprimary and Secondary Endpoint Results by Estimand⁴
Endpoint	Retatrutide 9 mg	Retatrutide 12 mg	Placebo
Treatment-regimen estimand
Coprimary endpoints
Change in body weight, % (kg; lbs)^a	-20.0 (-22.9; -50.5)	-23.7 (-27.2; -60.0)	-4.6 (-5.3; -11.7)
Change in WOMAC pain subscale score, points (%)^b	-4.0 (-67.2)^c	-3.7 (-62.6)^c	-2.1 (-35.1)^c
Efficacy estimand
Coprimary endpoints
Change in body weight, % (kg; lbs)^a	-26.4 (-29.1; -64.2)	-28.7 (-32.3; -71.2)	-2.1 (-2.1; -4.6)
Change in WOMAC pain subscale score, points (%)^b	-4.5 (-75.8)^c	-4.4 (-74.3)^c	-2.4 (-40.3)^c
Secondary endpoints
≥25% weight loss, %	47.7	58.6	1.3
≥30% weight loss, %	30.5	39.4	0.8
≥35% weight loss, %	18.2	23.7	0.0
Change in WOMAC physical function subscale score, points (%)^d	-4.1 (-71.8)^c	-4.2 (-73.7)^c	-2.1 (-35.6)^c
≥70% reduction in WOMAC pain subscale score, %^e	73.0	67.7	26.2

Abbreviations: BMI = body mass index; WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index.

^aBaseline average = 112.7 kg (248.5 lbs; 40.4 kg/m²BMI)

^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

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What were the preliminary safety outcomes with retatrutide in TRIUMPH-4?

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 Table 3.⁴

**Table 3.** Common Adverse Events in TRIUMPH-4⁴
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
Dysesthesia^a	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 kg/m². 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

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What was the TRIUMPH-1 knee osteoarthritis basket study design in adults with obesity or overweight?

TRIUMPH-1 (NCT05929066) was a phase 3, randomized, double-blind clinical trial that evaluated the efficacy and safety of retatrutide compared with placebo in adults without type 2 diabetes who had

obesity, or
overweight and at least 1 weight-related comorbidity.²

The TRIUMPH-1 master protocol included a nested basket study in a subset population of participants with OA of the knee.²

The study randomized 2339 participants, including 574 participants with knee OA, in a 1:1:1:1 ratio to receive retatrutide 4 mg, 9 mg, 12 mg, or placebo.²^,⁵

Participants initiated treatment at a 2 mg dose, which was escalated in 4-week intervals to the randomized target dose; this dose was subsequently maintained throughout the 80-week treatment period.²

TRIUMPH-1 Knee Osteoarthritis Basket Inclusion and Exclusion Criteria

Table 4 presents the key inclusion and exclusion criteria for the TRIUMPH-1 knee osteoarthritis basket study.

**Table 4. TRIUMPH-1 Knee Osteoarthritis Basket Inclusion and Exclusion Criteria**²^,⁵
Key Inclusion Criteria	Key Exclusion Criteria
TRIUMPH-1 master protocol criteria (applied to all participants): Adults aged ≥18 years with a history of ≥1 unsuccessful dietary effort to reduce body weight BMI ≥30 kg/m², or ≥27 kg/m² with at least 1 of the following comorbidities: dyslipidemia, OSA, HTN, or CVD Additional knee OA basket criteria: Index knee pain >12 weeks before screening and presence of index knee pain for >15 days in the month prior to screening Knee X-ray with moderate radiographic changes (Kellgren-Lawrence grade 2 or 3) at screening At least 1 of the following: >50 years of age morning stiffness in index knee <30 minutes in duration crepitus in index knee	TRIUMPH-1 master protocol criteria (applied to all participants): Type 1 or Type 2 diabetes Weight change >5 kg within 90 days of screening Chronic systemic glucocorticoid therapy Taking weight loss drugs, including over-the-counter medications within 90 days prior to screening Prior or planned surgical treatment for obesity Additional knee OA basket criteria: Steroid joint injections within 90 days of screening Other joint injections and procedures within 6 months of screening Joint disease other than osteoarthritis

Abbreviations: BMI = body mass index; CVD = cardiovascular disease; HTN = hypertension; OA = osteoarthritis; OSA = obstructive sleep apnea.

TRIUMPH-1 Knee Osteoarthritis Basket Baseline Characteristics

Baseline characteristics for participants in the TRIUMPH-1 knee OA basket study are presented in Table 5.⁵

**Table 5. TRIUMPH-1 Knee Osteoarthritis Basket Baseline Characteristics**⁵
Characteristic	Knee OA Basket (n=574)
Age, years, mean (SD)	56.1 (9.1)
Female, n (%)	435 (75.8)
BMI, kg/m², mean (SD)	40.8 (6.9)
WOMAC pain subscale score (0-10), mean (SD)	6.0 (1.3)

Abbreviations: BMI = body mass index; OA = osteoarthritis; WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index.

Data are mean (SD) or n (%).

Randomization within the knee OA basket: placebo, n=144; retatrutide 4 mg, n=143; retatrutide 9 mg, n=143; retatrutide 12 mg, n=144.

WOMAC pain subscale score was assessed using the 5-item WOMAC instrument (Numeric Rating Scale version 3.1) and converted to a 0-10 scale, with pain severity classified as mild (<4), moderate (4 to <7), or severe (≥7).

TRIUMPH-1 Knee Osteoarthritis Basket Primary Endpoint

The primary endpoint in the TRIUMPH-1 knee OA basket study was change from baseline in WOMAC pain subscale score (5-item WOMAC Numeric Rating Scale version 3.1, converted to a 0-10 scale) at week 80 for

retatrutide 9 mg vs placebo, and
retatrutide 12 mg vs placebo.⁵

Comparisons of retatrutide 4 mg vs placebo for WOMAC pain subscale score were prespecified key secondary endpoints controlled for type 1 error.⁵

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What were the efficacy and safety outcomes in the TRIUMPH-1 knee osteoarthritis basket study?

In the TRIUMPH-1 knee osteoarthritis basket study, retatrutide 9 mg and 12 mg met the primary endpoint, as presented in Table 6.⁵

WOMAC pain outcomes were evaluated using the same 2 estimands described for TRIUMPH-4. In the knee osteoarthritis basket, the intercurrent events were treatment discontinuation, initiation of prohibited weight-management treatments, prohibited knee surgery or procedures, and use of excessive pain medications.⁵

Retatrutide reduced WOMAC pain subscale score from baseline by up to 61.6% for the treatment-regimen estimand and by greater than 70% for the efficacy estimand.⁵

**Table 6. Change From Baseline in WOMAC Pain Subscale Score at Week 80 in the TRIUMPH-1 Knee Osteoarthritis Basket Study**⁵
Endpoint	Placebo n=144	Retatrutide 4 mg n=143	Retatrutide 9 mg n=143	Retatrutide 12 mg n=144
Treatment-regimen estimand
Change in WOMAC pain score, points (95% CI)	−1.9 (−2.3 to −1.4)	−3.2 (−3.6 to −2.8)^a	−3.5 (−3.9 to −3.1)	−3.6 (−4.0 to −3.3)
Difference vs placebo (95% CI)	NA	−1.3 (−1.9 to −0.8)^a,b	−1.6 (−2.2 to −1.0)^b	−1.8 (−2.3 to −1.2)^b
Efficacy estimand
Change in WOMAC pain score, points (95% CI)	−2.2 (−2.7 to −1.8)	−3.7 (−3.9 to −3.4)^a	−4.2 (−4.5 to −3.9)	−4.3 (−4.6 to −4.0)
Difference vs placebo (95% CI)	NA	−1.4 (−2.0 to −0.9)^a,b	−2.0 (−2.5 to −1.4)^b	−2.1 (−2.6 to −1.5)^b

Abbreviations: NA = not available, not applicable, or not analyzed; WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index.

Data are model-based estimates and 95% CIs. Confidence intervals were not adjusted for multiplicity and should not be used for hypothesis testing.

^a Retatrutide 4 mg WOMAC pain endpoints were prespecified key secondary endpoints controlled for type 1 error; retatrutide 9 mg and 12 mg WOMAC pain endpoints were the primary endpoints for the knee osteoarthritis basket.

^b p<.001 for all comparisons with placebo.

The treatment-regimen estimand estimates the average treatment effect regardless of treatment discontinuation or initiation of prohibited weight-management treatments; continuous outcomes were analyzed by analysis of covariance. The efficacy estimand estimates the treatment effect assuming all participants remained on their assigned treatment for 80 weeks and did not initiate prohibited weight-management treatments, prohibited knee surgery or procedures, or excessive pain medications; continuous outcomes were analyzed by a mixed model for repeated measures.

WOMAC pain subscale score was assessed using the 5-item WOMAC instrument (Numeric Rating Scale version 3.1) and converted to a 0-10 scale, with pain severity classified as mild (<4), moderate (4 to <7), or severe (≥7).

TRIUMPH-1 Knee Osteoarthritis Basket Safety Outcomes

The safety of retatrutide in TRIUMPH-1 (including the knee OA basket study population) was generally consistent with phase 2 results, and generally similar to those seen with incretin-based therapies.⁵ The most common AEs were gastrointestinal, were generally mild to moderate in severity, occurred mostly during dose escalation, and were more common at higher doses.⁵

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What additional retatrutide results are expected from the TRIUMPH program?

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

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References

The published references below are available by contacting 1-800-LillyRx (1-800-545-5979).

Jastreboff 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
Giblin 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. 2026;28(1):83-93. https://doi.org/10.1111/dom.70209
A 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
Lilly’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
Jastreboff AM, Kaplan LM, Davies MJ, et al. Retatrutide, a triple hormone receptor agonist for treatment of obesity. N Engl J Med. Published online September 29, 2026. https://doi.org/10.1056/NEJMoa2604169

Date of Last Review: August 31, 2026

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