Search Retatrutide - Obesity (type in keywords)

Search Medical Information

If you wish to report an adverse event or product complaint, please call 1-800-LILLYRX (1-800-545-5979)

Retatrutide-Obesity

This information is provided in response to your request. Resources may contain information about doses, uses, formulations and populations different from product labeling.

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

In patients with obesity and knee OA, retatrutide met the coprimary body weight and WOMAC pain endpoints in TRIUMPH-4 and the primary WOMAC pain endpoint in TRIUMPH-1 knee OA basket study. Most common AEs were GI related and mild to moderate in severity.

prepped

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?
What were the efficacy outcomes with retatrutide in TRIUMPH-4?
- TRIUMPH-4 and TRIUMPH-1 Knee Osteoarthritis Basket Pooled Results
What was the TRIUMPH-1 knee osteoarthritis basket study design in adults with obesity or overweight?
What were the efficacy outcomes in the TRIUMPH-1 knee osteoarthritis basket study?
What were the safety outcomes with retatrutide in TRIUMPH-4 and the TRIUMPH-1 knee osteoarthritis basket study?
References

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

Molecule Description

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 yet received approval from any regulatory authority.

Retatrutide Trials in Obesity and Osteoarthritis of the Knee

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 osteoarthritis 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.

Statistical Estimands in TRIUMPH-4 and the TRIUMPH-1 Knee Osteoarthritis Basket Study

Efficacy data from TRIUMPH-4 and the TRIUMPH-1 knee osteoarthritis basket study were evaluated using statistical estimands that differed by endpoint type. The estimands used in both trials were

the treatment-regimen estimand (weight-related endpoints), which evaluates the treatment effect irrespective of adherence to the study drug or other intercurrent events,
the hybrid-treatment estimand (pain-related endpoints), which uses a hypothetical strategy for intercurrent events that indicate treatment failure (starting a prohibited weight management treatment, prohibited knee surgery or procedures, or excessive pain medication use) and a treatment-policy strategy for all other intercurrent events, and
the efficacy estimand (weight- and pain-related endpoints), which estimates the treatment effect assuming participants adhered to their assigned retatrutide or placebo regimen and had no intercurrent events.⁵

In the TRIUMPH-1 knee osteoarthritis basket study, continuous outcomes were analyzed by analysis of covariance for the hybrid-treatment estimand and by a mixed model for repeated measures for the efficacy estimand.⁵

The hybrid-treatment estimand reflects the average treatment effect among all participants who started treatment, without crediting retatrutide for improvement that resulted from prohibited weight management medication, knee surgery or procedures, or excessive pain medication use.⁵

Back to Content Overview

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

In the TRIUMPH-4 clinical trial, 445 adults with obesity or overweight and knee OA 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^,⁵

Participants in the retatrutide arms 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^,⁵

Figure 1. TRIUMPH-4 Study Design⁵

Study design: retatrutide 9 or 12 mg or placebo once weekly, dose escalation to week 16, primary endpoint week 68, 4-week follow-up.

Figure 1 description: Participants with a body mass index of 27.0 kg/m² or greater and osteoarthritis were screened for up to 35 days and then randomized 1:1:1 at week 0 to once-weekly retatrutide 9 mg, once-weekly retatrutide 12 mg, or once-weekly placebo. Retatrutide was started at 2 mg and increased every 4 weeks through 4 mg, 6 mg, and 9 mg; the 12 mg group reached 12 mg at week 16. Visits continued every 4 weeks. The primary endpoint and end of treatment were at week 68, followed by 4 weeks of post-treatment follow-up.

Abbreviations: BMI = body mass index; OA = osteoarthritis; PBO = placebo; Q4W = every 4 weeks; QW = once weekly; RETA = retatrutide.

Retatrutide dose could be reduced to manage gastrointestinal adverse events during the first 20 weeks or inadequate oral intake, or when excessive weight loss occurred or body mass index (BMI) fell to ≤22 kg/m².⁵

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^,⁵
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 WOMAC pain subscale score (0-10 Numeric Rating Scale) ≥4 and ≤9 in the index knee at screening and randomization 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 for >14 days or receipt of such therapy within 90 days of screening (visit 1) 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; WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index.

TRIUMPH-4 Coprimary Endpoints

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

percentage 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 to 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 to 10 scale by dividing by the number of items in the subscale.² For all WOMAC subscales, scores range from 0 to 10, with higher scores indicating worse outcomes (ie, more pain, more stiffness, or greater limitation in physical function) and lower scores indicating better outcomes.

Although not specific to the WOMAC pain subscale, previous analysis using the 0 to 10 Pain Intensity Numeric Rating Scale (PI-NRS) noted a

reduction of approximately 2 points (or 30%) corresponded to a patient global impression of change rating of "much improved," and
reduction of approximately 4 points (or 50%) corresponded to "very much improved."⁶

TRIUMPH-4 Baseline Characteristics

Baseline characteristics for participants in TRIUMPH-4 are presented in Table 2.⁵

**Table 2. TRIUMPH-4 Baseline Characteristics**⁵
Characteristic	Retatrutide 9 mg (N=148)	Retatrutide 12 mg (N=148)	Placebo (N=149)
Age, years, mean (SD)	55.1 (9.6)	54.8 (9.9)	55.6 (9.8)
Female sex, n (%)	94 (63.5)	94 (63.5)	94 (63.1)
Race, n (%)
White	97 (65.5)	101 (68.2)	97 (65.1)
American Indian or Alaska Native	36 (24.3)	31 (20.9)	33 (22.1)
Black or African American	11 (7.4)	8 (5.4)	9 (6.0)
Multiple	0	3 (2.0)	0
Asian	0	1 (0.7)	1 (0.7)
Native Hawaiian or other Pacific Islander	0	1 (0.7)	1 (0.7)
Not reported	4 (2.7)	3 (2.0)	8 (5.4)
Hispanic or Latino ethnicity, n (%)	61 (41.2)	45 (30.4)	55 (36.9)
Weight, kg, mean (SD)	112.4 (22.7)	113.5 (22.4)	112.2 (23.1)
BMI, kg/m², mean (SD)	40.5 (7.2)	40.3 (7.0)	40.5 (6.8)
BMI ≥35 kg/m², n (%)	125 (84.5)	124 (83.8)	125 (83.9)
WOMAC pain subscale score (0-10), mean (SD)	6.02 (1.29)	5.88 (1.25)	5.94 (1.24)
WOMAC physical function subscale score (0-10), mean (SD)	5.99 (1.47)	5.72 (1.56)	5.56 (1.60)
Kellgren-Lawrence grade, n (%)
Grade 2	55 (37.2)	50 (33.8)	55 (36.9)
Grade 3	93 (62.8)	96 (64.9)	94 (63.1)
Grade 4	0	2 (1.4)	0

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

Data are mean (SD) or n (%), unless noted. Sex, race, and ethnicity were reported by the participants. WOMAC scores are based on a Numeric Rating Scale of 0 to 10, with higher scores indicating more pain or greater limitation in physical function.

Kellgren-Lawrence grade is a radiographic measure of osteoarthritis severity assessed on knee X-ray, with a scale range from 0 (no radiographic evidence of osteoarthritis) to 4 (large osteophytes and marked narrowing of joint space).

Back to Content Overview

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

In TRIUMPH-4, retatrutide 9 mg and 12 mg met the coprimary endpoints and the key secondary endpoints (p<.001 for all comparisons with placebo), as presented in Table 3.⁵

Estimand definitions are provided in Statistical Estimands in TRIUMPH-4 and the TRIUMPH-1 Knee Osteoarthritis Basket Study.

**Table 3. TRIUMPH-4 Weight and Pain Coprimary and Secondary Endpoint Results by Estimand**⁵
Endpoint	Retatrutide 9 mg (N=148)	Retatrutide 12 mg (N=148)	Placebo (N=149)
Treatment-regimen estimand (weight-related endpoints)
Coprimary endpoint
Change in body weight, %^a	-20.0^b	-23.7^b	-4.6
Key secondary endpoints
≥5% weight loss, %	89.9^b	95.0^b	41.9
≥10% weight loss, %	81.5^b	83.9^b	22.5
≥15% weight loss, %	63.7^b	75.6^b	15.2
≥20% weight loss, %	48.5^b	65.9^b	9.9
≥25% weight loss, %	33.7^b	45.1^b	3.1
Hybrid-treatment estimand (pain-related endpoints)
Coprimary endpoint
Change in WOMAC pain subscale score, points^c	-3.96^b	-3.74^b	-2.12
Key secondary endpoint
Change in WOMAC physical function subscale score, points^d	-3.64^b	-3.57^b	-1.80
Change in WOMAC pain subscale score at week 36, points	-3.57^b	-3.24^b	-1.93
≥50% reduction in WOMAC pain, %	76.9	66.1	42.3
≥50% reduction in WOMAC physical function,%	73.3	67.1	39.4
Efficacy estimand (weight- and pain-related endpoints)
Coprimary endpoints
Change in body weight, %^a	-26.4^b	-28.7^b	-2.1
Change in WOMAC pain subscale score, points^c	-4.48^b	-4.41^b	-2.43
Secondary endpoints
≥5% weight loss, %	96.3^b	97.3^b	33.4
≥10% weight loss, %	91.9^b	92.7^b	12.0
≥15% weight loss, %	75.5^b	86.8^b	6.3
≥20% weight loss, %	62.8^b	77.1^b	3.7
≥25% weight loss, %	47.7^b	58.6^b	1.3
Change in WOMAC physical function subscale score, points^d	-4.14^b	-4.20^b	-2.06
Change in WOMAC pain subscale score at week 36, points	-3.92^b	-3.71^b	-2.26
≥50% reduction in WOMAC pain, %	85.8	78.1	45.6
≥50% reduction in WOMAC physical function, %	81.9	79.8	42.3
Participants with baseline BMI ≥35 kg/m² (key secondary endpoints)
Hybrid-treatment estimand
Change in WOMAC pain subscale score, points	-4.12^b	-3.91^b	-2.12
Treatment-regimen estimand
Change in body weight, %	-21.6^b	-25.6^b	-3.4
≥5% weight loss, %	93.6^b	96.4^b	42.3
≥10% weight loss, %	85.5^b	88.4^b	21.2
≥15% weight loss, %	68.1^b	81.3^b	14.6
≥20% weight loss, %	53.3^b	70.9^b	9.5
≥25% weight loss, %	38.9^b	52.3^b	3.0
Efficacy estimand
Change in WOMAC pain subscale score, points	-4.45^b	-4.43^b	-2.44
Change in body weight, %	-25.7^b	-29.0^b	-2.3
≥5% weight loss, %	98.0^b	99.5^b	35.5
≥10% weight loss, %	93.7^b	94.4^b	11.7
≥15% weight loss, %	77.5^b	88.3^b	6.3
≥20% weight loss, %	63.9^b	78.7^b	3.4
≥25% weight loss, %	49.0^b	62.7^b	1.6

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

Data are model-based estimates. Outcomes are at week 68 unless specified. WOMAC is based on a Numeric Rating Scale of 0 to 10 (higher scores indicate more pain). P values were not reported for the ≥50% responder rows in TRIUMPH-4 alone.

^aBaseline average = 112.7 kg (40.4 kg/m²BMI).

^bp<.001 vs placebo.

^cBaseline average WOMAC score = 5.95 points.

^dBaseline physical function subscale score = 5.75 points.

TRIUMPH-4 and TRIUMPH-1 Knee Osteoarthritis Basket Pooled Results

Achievement of a ≥50% reduction in WOMAC pain and physical function scores at week 68 (hybrid-treatment estimand) was a pooled key secondary endpoint across TRIUMPH-4 and the TRIUMPH-1 knee osteoarthritis basket study. In the pooled analysis, the percentages of participants receiving retatrutide 9 mg, retatrutide 12 mg, and placebo, respectively, with a ≥50% reduction in the

WOMAC pain subscale score were 69.6%, 63.2%, and 37.8%, and
WOMAC physical function subscale score were 64.6%, 63.5%, and 33.1%.⁵

Both retatrutide doses differed from placebo (p<.001 for each comparison).⁵ Results for TRIUMPH-4 alone are presented in Table 3.

Back to Content Overview

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

TRIUMPH-1 enrolled adults without diabetes who had

obesity, or
overweight and at least 1 weight-related comorbidity.²^,⁵

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^,⁴^,⁵

Participants in the retatrutide arms 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^,⁵

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**^2,⁴
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 WOMAC pain subscale score (0-10 Numeric Rating Scale) ≥4 and ≤9 in the index knee at screening and randomization 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 for >14 days or receipt of such therapy within 90 days of screening (visit 1) 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 OA

Abbreviations: BMI = body mass index; CVD = cardiovascular disease; HTN = hypertension; OA = osteoarthritis; OSA = obstructive sleep apnea; WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index.

TRIUMPH-1 Knee Osteoarthritis Basket Primary Endpoint

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

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

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

TRIUMPH-1 Knee Osteoarthritis Basket Baseline Characteristics

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

**Table 5. TRIUMPH-1 Knee Osteoarthritis Basket Baseline Characteristics**⁵
Characteristic	Knee OA Basket (n=574)	Retatrutide 4 mg (N=143)	Retatrutide 9 mg (N=143)	Retatrutide 12 mg (N=144)	Placebo (N=144)
Age, years, mean (SD)	56.1 (9.1)	56.3 (9.4)	56.4 (9.3)	55.7 (9.2)	56.0 (8.7)
Female sex, n (%)	435 (75.8)	108 (75.5)	108 (75.5)	109 (75.7)	110 (76.4)
Race, n (%)
White	421 (73.3)	105 (73.4)	104 (72.7)	105 (72.9)	107 (74.3)
American Indian or Alaska Native	71 (12.4)	18 (12.6)	16 (11.2)	17 (11.8)	20 (13.9)
Black or African American	55 (9.6)	16 (11.2)	12 (8.4)	15 (10.4)	12 (8.3)
Multiple	2 (0.3)	1 (0.7)	0	1 (0.7)	0
Asian	7 (1.2)	0	4 (2.8)	1 (0.7)	2 (1.4)
Native Hawaiian or other Pacific Islander	3 (0.5)	0	2 (1.4)	1 (0.7)	0
Not reported	15 (2.6)	3 (2.1)	5 (3.5)	4 (2.8)	3 (2.1)
Hispanic or Latino ethnicity, n (%)	130 (22.6)	32 (22.4)	35 (24.5)	31 (21.5)	32 (22.2)
Weight, kg, mean (SD)	112.5 (23.5)	111.9 (22.5)	111.0 (21.1)	114.3 (26.3)	112.8 (23.7)
BMI, kg/m², mean (SD)	40.8 (6.9)	40.9 (6.6)	40.5 (6.6)	41.0 (7.5)	40.7 (6.9)
BMI ≥35 kg/m², n (%)	475 (82.8)	119 (83.2)	117 (81.8)	116 (80.6)	123 (85.4)
WOMAC pain subscale score (0-10), mean (SD)	5.97 (1.25)	6.1 (1.22)	5.93 (1.11)	6.04 (1.31)	5.83 (1.33)
WOMAC physical function subscale score (0-10), mean (SD)	5.83 (1.58)	5.86 (1.67)	5.86 (1.31)	5.96 (1.56)	5.64 (1.73)
Kellgren-Lawrence grade, n (%)
Grade 0	1 (0.2)	0	0	1 (0.7)	0
Grade 1	1 (0.2)	0	0	0	1 (0.7)
Grade 2	212 (36.9)	48 (33.6)	55 (38.5)	56 (38.9)	53 (36.8)
Grade 3	360 (62.7)	95 (66.4)	88 (61.5)	87 (60.4)	90 (62.5)
Grade 4	0	0	0	0	0

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

Data are mean (SD) or n (%), unless noted. Sex, race, and ethnicity were reported by the participants.

WOMAC pain and physical function subscale scores were assessed using the Numeric Rating Scale (version 3.1, 0-10 scale), with higher scores indicating more pain or greater limitation in physical function.

Back to Content Overview

What were the efficacy 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 and retatrutide 4 mg met the key secondary endpoint (p<.001 for each comparison with placebo for the hybrid-treatment estimand), as presented in Table 6.⁵

WOMAC pain outcomes were evaluated using the hybrid-treatment and efficacy estimands described in Statistical Estimands in TRIUMPH-4 and the TRIUMPH-1 Knee Osteoarthritis Basket Study.⁵

Retatrutide also reduced WOMAC pain at weeks 36 and 68, improved WOMAC physical function, and reduced body weight; outcomes in participants with a baseline BMI ≥35 kg/m² were consistent with those in the overall knee osteoarthritis basket population (Table 6).⁵

**Table 6.** **Efficacy Outcomes in the TRIUMPH-1 Knee Osteoarthritis Basket Study**^4,5
Endpoint	Retatrutide 4 mg N=143	Retatrutide 9 mg N=143	Retatrutide 12 mg N=144	Placebo N=144
Hybrid-treatment estimand (pain-related endpoints)
Primary endpoint
Change in WOMAC pain subscale score at week 80, points	−3.22^a,b	−3.48^b	−3.64^b	−1.87
Key secondary endpoints
Change in WOMAC pain subscale score at week 68, points	−3.11^b	−3.18^b	−3.17^b	−1.72
Change in WOMAC pain subscale score at week 36, points	−3.15^b	−2.88^b	−2.90^b	−1.87
Change in WOMAC physical function subscale score at week 80, points	−3.21^b	−3.42^b	−3.48^b	−1.53
Treatment-regimen estimand (weight-related endpoints)
Key secondary endpoint
Change in body weight at week 80, %	−17.5^b	−22.9^b	−24.8^b	−4.3
Efficacy estimand (weight- and pain-related endpoints)
Primary endpoint
Change in WOMAC pain subscale score at week 80, points	−3.66^a,b	−4.19^b	−4.30^b	−2.24
Key secondary endpoint
Change in body weight at week 80, %	−18.6^b	−25.4^b	−28.7^b	−1.5
Participants with baseline BMI ≥35 kg/m² (key secondary endpoints)
Hybrid-treatment estimand
Change in WOMAC pain subscale score at week 80, points	−3.18^b	−3.46^b	−3.65^b	−1.95
Treatment-regimen estimand
Change in body weight at week 80, %	−16.3^b	−22.6^b	−24.8^b	−3.4

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

Data are model-based estimates, shown as mean change. WOMAC pain and physical function are based on a Numeric Rating Scale of 0 to 10, with higher scores indicating more pain or greater limitation in physical function.

^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 vs placebo.

Back to Content Overview

What were the safety outcomes with retatrutide in TRIUMPH-4 and the TRIUMPH-1 knee osteoarthritis basket study?

The overall safety profile of retatrutide in TRIUMPH-4 and the TRIUMPH-1 knee osteoarthritis basket study was generally consistent with phase 2 results and generally similar to that of other incretin-based therapies (GLP-1 and GIP/GLP-1 receptor agonists).^4,5

Across both trials, nausea, diarrhea, and constipation were the most frequent adverse events with retatrutide. Most gastrointestinal events were mild to moderate in severity, occurred mostly during dose escalation, and were more common at higher doses.^4,5

Safety outcomes for both trials are presented in Table 7 and Table 8.

**Table 7. Safety Outcomes in TRIUMPH-4 and the TRIUMPH-1 Knee Osteoarthritis Basket Study**^4,5
Parameter	TRIUMPH-4			TRIUMPH-1 OA
Parameter	Retatrutide 9 mg N=147	Retatrutide 12 mg N=148	Placebo N=149	Retatrutide 4 mg n=143	Retatrutide 9 mg n=143	Retatrutide 12 mg n=144	Placebo n=144
Any adverse event emerging during treatment, n (%)	125 (85.0)	127 (85.8)	110 (73.8)	130 (90.9)	132 (92.3)	136 (94.4)	125 (86.8)
Nausea, %	38.1	43.2	10.7	28.7	39.9	43.8	16.7
Diarrhea, %	34.7	33.1	13.4	24.5	37.1	34.7	21.5
Constipation, %	21.8	25.0	8.7	26.6	28.0	36.1	12.5
Vomiting, %	20.4	20.9	0	8.4	17.5	25.7	7.6
Decreased appetite, %	19.0	18.2	9.4	14.0	16.1	22.2	10.4
Discontinuation due to an adverse event, n (%)^a	19 (12.9)	27 (18.2)	6 (4.0)	4 (2.8)	12 (8.4)	22 (15.3)	9 (6.2)
Discontinuation due to a gastrointestinal adverse event, n (%)	9 (6.1)	12 (8.1)	2 (1.3)	2 (1.4)	6 (4.2)	8 (5.6)	0
Serious adverse event, n (%)	14 (9.5)	16 (10.8)	3 (2.0)	6 (4.2)	14 (9.8)	21 (14.6)	10 (6.9)
Death, n^b	1	1	0	0	0	0	0

Abbreviations: MedDRA = Medical Dictionary for Regulatory Activities; OA = osteoarthritis.

Safety population: all participants who were randomly assigned a study intervention and received ≥1 dose of double-blind study intervention. Adverse events were coded using MedDRA version 28.1. TRIUMPH-4 did not include a retatrutide 4 mg treatment group.

^aApproximately one-half of the discontinuations due to adverse events in TRIUMPH-4 were considered due to gastrointestinal events and one-third in TRIUMPH-1-OA.

^bBoth deaths in TRIUMPH-4 were assessed by the investigators as unrelated to study treatment. No deaths occurred in the TRIUMPH-1 knee osteoarthritis basket study.

**Table 8. Treatment-Emergent Adverse Events of Special Interest in TRIUMPH-4 and the TRIUMPH-1 Knee Osteoarthritis Basket Study**⁵
Treatment-emergent adverse event	TRIUMPH-4			TRIUMPH-1 OA
Treatment-emergent adverse event	Retatrutide 9 mg N=147	Retatrutide 12 mg N=148	Placebo N=149	Retatrutide 4 mg n=143	Retatrutide 9 mg n=143	Retatrutide 12 mg n=144	Placebo n=144
Dysesthesia^a	13 (8.8)	31 (20.9)	1 (0.7)	9 (6.3)	24 (16.8)	22 (15.3)	1 (0.7)
Injection site reactions	13 (8.8)	9 (6.1)	4 (2.7)	11 (7.7)	17 (11.9)	20 (13.9)	8 (5.6)
Severe gastrointestinal disorders	5 (3.4)	4 (2.7)	1 (0.7)	0	13 (9.1)	5 (3.5)	1 (0.7)
Malignancies	7 (4.8)	2 (1.4)	1 (0.7)	2 (1.4)	3 (2.1)	6 (4.2)	3 (2.1)
Severe cardiac disorders and arrhythmias	3 (2.0)	2 (1.4)	0	0	0	2 (1.4)	2 (1.4)
Severe gallbladder and biliary tract disorders	1 (0.7)	1 (0.7)	0	1 (0.7)	1 (0.7)	0	2 (1.4)
Adjudication-confirmed MACE	2 (1.4)	1 (0.7)	0	0	0	1 (0.7)	0
Severe malnutrition	1 (0.7)	1 (0.7)	0	1 (0.7)	1 (0.7)	0	0
Severe renal events	0	1 (0.7)	0	1 (0.7)	0	1 (0.7)	0
Adjudication-confirmed pancreatitis	0	0	0	0	2 (1.4)	0	0
Severe hepatic disorders	0	0	0	0	0	1 (0.7)	0
Severe hypersensitivity reactions	0	0	0	0	1 (0.7)	0	0
Thyroid malignancies and C-cell hyperplasia	0	0	0	0	0	1 (0.7)	0
Depression, suicidal ideation, and behavior	0	1 (0.7)	0	0	0	0	0
Severe ketoacidosis^b	0	0	0	0	0	0	0

Abbreviations: MACE = major adverse cardiovascular event; MedDRA = Medical Dictionary for Regulatory Activities.

Data are n (%). Safety population: all participants who were randomly assigned a study intervention and received ≥1 dose of double-blind study intervention. Adverse events were coded using MedDRA version 28.1. TRIUMPH-4 did not include a retatrutide 4 mg treatment group.

^aDysesthesia events were generally mild and rarely led to treatment discontinuation.

^bDue to inadequate nutritional intake and other types of metabolic acidosis and ketosis.

Back to Content Overview

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 January 21, 2026. Accessed October 27, 2026. https://clinicaltrials.gov/study/NCT05931367
Jastreboff AM, Kaplan LM, Davies MJ, et al; TRIUMPH-1 Investigators. 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
Schnitzer TJ, Hunter DJ, Conaghan PG, et al. Retatrutide once weekly in adults with knee osteoarthritis pain and obesity. N Engl J Med. Published online November 8, 2026. https://www.nejm.org/doi/full/10.1056/NEJMoa2610676
Farrar JT, Young JP Jr, LaMoreaux L, Werth JL, Poole RM. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain. 2001;94(2):149-158. https://doi.org/10.1016/S0304-3959(01)00349-9

Date of Last Review: October 17, 2026

Are you satisfied with this content?