Retatrutide Once Weekly in Adults with Knee Osteoarthritis Pain and Obesity
- Design
- Randomized trial · 1019 participants · Intermediate outcome
- Match to healthy normal-weight adults aged 55–75
- Different populationINDIRECT: all participants had obesity (BMI ≥27 with an obesity-related complication; arm mean BMI 40.3 to 41.0, about 80% above 35) and painful knee osteoarthritis. Diabetes was excluded and mean age (55.2 and 56.1) sits at the lower edge of the target range, but no normal-weight people were enrolled.
- Could weight loss explain it?
- LikelyWeight fell by 20.0% and 23.7% on retatrutide against 4.6% on placebo at 68 weeks, and knee pain is an outcome weight loss is known to improve; the authors name reduced knee loading as a leading candidate mechanism and call the mechanisms incompletely understood. No mediation analysis, weight-matched comparison or pre-weight-loss measurement was reported (pain was first assessed at week 16), so the pain benefit cannot be separated from weight loss.
- Study tier
- Study tier 2MODERATE: two randomized, double-blind, placebo-controlled phase 3 trials of moderate size (445 and 574 randomized) that replicate each other, with an intermediate primary outcome (a validated symptom scale); the risk of unblinding from gastrointestinal effects on a self-reported pain score and sponsor involvement in the analysis keep it below HIGH.
- Assessment
- Version 3 · Two reviewers differed; settled by a recorded ruling · Nov 11, 2026
Study facts come from the paper. Population match, weight-loss explanation and study tier are our judgments, made against the reference group of healthy normal-weight adults aged 55–75.
Two phase 3 trials randomly assigned adults with painful knee osteoarthritis, a BMI of at least 27 and no diabetes (445 in TRIUMPH-4, 574 in TRIUMPH-1-OA) to weekly injections of retatrutide, an investigational drug acting on GLP-1, GIP and glucagon receptors, or placebo for 68 or 80 weeks. Knee pain on a 0 to 10 scale improved more with retatrutide at every dose (for example a difference of -1.83 points with 9 mg at 68 weeks), and body weight fell 20.0% and 23.7% against 4.6% with placebo. Serious adverse events were more common with retatrutide in both trials, and stomach and bowel side effects were the most frequent. Everyone enrolled had obesity, so the trials do not show what the drug would do in people of normal weight, much of the pain relief may come from the weight loss itself, and the trials were funded by Eli Lilly, the drug's maker.
01Findings
What the study reported
- Drugs
- Retatrutide
- Dose
- 9 or 12 mg once weekly (TRIUMPH-4); 4, 9, or 12 mg once weekly (TRIUMPH-1-OA); started at 2 mg and escalated every 4 weeks
- Route
- subcutaneous
- Comparator
- placebo
- Treatment duration
- 68 weeks (TRIUMPH-4); 80 weeks (TRIUMPH-1-OA)
- Primary outcome
- change in WOMAC knee pain score (0 to 10) in both trials, with percent change in body weight as a co-primary end point in TRIUMPH-4; at week 68 (TRIUMPH-4) and week 80 (TRIUMPH-1-OA)
- Effect
- WOMAC pain difference vs placebo (hybrid estimand): TRIUMPH-4 -1.83 (9 mg) and -1.61 (12 mg) at 68 weeks; TRIUMPH-1-OA -1.35 (4 mg), -1.61 (9 mg), -1.77 (12 mg) at 80 weeks; ITT differences -1.70 and -1.38 (TRIUMPH-4) and -0.96, -1.41, -1.64 (TRIUMPH-1-OA). Body weight -20.0% (9 mg) and -23.7% (12 mg) vs -4.6% with placebo in TRIUMPH-4 (differences -15.4 and -19.2 percentage points). Serious adverse events more common with retatrutide in both trials.
- 95% confidence interval
- TRIUMPH-4 pain: 95% CI -2.37 to -1.30 (9 mg) and -2.16 to -1.07 (12 mg); TRIUMPH-1-OA pain: 95% CI -1.92 to -0.78, -2.20 to -1.02, -2.34 to -1.20; TRIUMPH-4 weight: 95% CI -18.7 to -12.1 and -22.4 to -15.9
- P value
- P<0.001 for all TRIUMPH-4 comparisons (pain and weight); P≤0.005 for all TRIUMPH-1-OA comparisons (ITT pain)
- Follow-up
- 68 weeks (TRIUMPH-4); 80 weeks (TRIUMPH-1-OA)
- Adverse events
- Serious adverse events were more common with retatrutide (TRIUMPH-4: 9.5% and 10.8% vs 2.0% with placebo; TRIUMPH-1-OA: 4.2% (4 mg), 9.8% (9 mg) and 14.6% (12 mg) vs 6.9%); gastrointestinal events (nausea, diarrhoea, constipation) were the most common, mostly mild to moderate and during dose escalation; discontinuation for adverse events 2.8%–18.2% with retatrutide vs 4.0%–6.2% with placebo; dysesthesia 6.3%–20.9% vs 0.7%; one death in each TRIUMPH-4 retatrutide group, judged unrelated, and none in TRIUMPH-1-OA.
- Limitations
- The authors note pain was first assessed at week 16, hsCRP only at start and end, enrolment was limited to people with overweight or obesity and knee OA, and the trials did not assess OA progression or joint replacement. A self-reported pain outcome alongside frequent gastrointestinal effects risks unblinding, and the sponsor took part in design, analysis and writing, with sponsor employees among the authors.
Who was studied
- Mean age
- 55.2 (SD 9.7) in TRIUMPH-4 and 56.1 (SD 9.1) in TRIUMPH-1-OA (Table 1 totals)
- Age min
- 18
- Sex distribution
- 63.4% women (TRIUMPH-4); 75.8% women (TRIUMPH-1-OA)
- Bmi mean
- 40.3 to 41.0 across arms and trial totals (Table 1)
- Bmi min
- 27
- Obesity status
- required (BMI ≥27 kg/m2 with at least one obesity-related complication; about 80% had BMI >35)
- Diabetes status
- excluded
- Baseline condition
- painful knee osteoarthritis with obesity
- Sample size
- 1019
- Inclusion exclusion
- adults ≥18 with radiographic knee OA and WOMAC pain 4 to 9 in the index knee, BMI ≥27 with an obesity-related complication, at least one failed diet attempt; excluded diabetes and weight change >5 kg in the prior 90 days
Study quality details
- Study design
- Randomized controlled trial
- Sample size
- 1019
- Randomization
- yes
- Blinding
- double-blind
- Comparator
- placebo
- Follow up duration
- 68 weeks (TRIUMPH-4); 80 weeks (TRIUMPH-1-OA)
- Outcome type
- intermediate
- Replication
- not assessed
- Consistency with other evidence
- not assessed
- Population applicability
- INDIRECT
- Statistical precision
- CI reported: TRIUMPH-4 pain: 95% CI -2.37 to -1.30 (9 mg) and -2.16 to -1.07 (12 mg); TRIUMPH-1-OA pain: 95% CI -1.92 to -0.78, -2.20 to -1.02, -2.34 to -1.20; TRIUMPH-4 weight: 95% CI -18.7 to -12.1 and -22.4 to -15.9
- Risk of bias
- not assessed
- Peer review status
- yes
02Funding
Funding and conflicts
- Funding
- Eli Lilly and Company
- Industry funded
- Yes
- Manufacturer
- Eli Lilly and Company
- Sponsor role
- Lilly was involved in study design and conduct, data collection, management, analysis and interpretation, manuscript preparation, review or approval, and the decision to submit; it had no right to veto publication; final decisions rested with the authors, who included Lilly employees.
- Author conflicts
- not reported
- Independent replication
- unknown
Funding is shown on every study and never used to score it.
04Source
The source, as retrieved
Abstract
[BACKGROUND] Retatrutide, an investigational triple agonist of GIP, GLP-1, and glucagon receptors, may be useful for the treatment of painful knee osteoarthritis in persons with obesity. [METHODS] In two phase 3 trials, adults without diabetes who had painful knee osteoarthritis and a body-mass index of at least 27 were randomly assigned to receive once-weekly subcutaneous retatrutide (9 or 12 mg in TRIUMPH-4 and 4, 9, or 12 mg in TRIUMPH-1-OA) or placebo. In TRIUMPH-4, the primary end points were the change in the WOMAC pain score (range, 0 to 10, with higher scores indicating worse pain) and the percent change in body weight at week 68. In TRIUMPH-1-OA, the primary end point was the change in the WOMAC pain score at week 80. For non-pain-related end points, intercurrent events were handled with a treatment-policy strategy. For pain-related end points, a hybrid-treatment estimand was applied, with a hypothetical strategy for intercurrent events that suggested treatment failure and a treatment-policy strategy elsewhere. We also report results for an intention-to-treat (ITT) estimand. [RESULTS] A total of 445 participants underwent randomization in TRIUMPH-4 and 574 in TRIUMPH-1-OA. At 68 weeks, the mean changes in the WOMAC pain score (hybrid-treatment estimand) with retatrutide in TRIUMPH-4 were -3.96 (9 mg) and -3.74 (12 mg), versus -2.12 with placebo (difference vs. placebo, -1.83 [95% confidence interval {CI}, -2.37 to -1.30] and -1.61 [95% CI, -2.16 to -1.07], respectively). For the ITT estimand, the corresponding differences from placebo were -1.70 (95% CI, -2.19 to -1.22) and -1.38 (95% CI, -1.91 to -0.85) (P<0.001 for all comparisons). The mean percent changes in body weight with retatrutide were -20.0% (9 mg) and -23.7% (12 mg), versus -4.6% with placebo (difference vs. placebo, -15.4 percentage points [95% CI, -18.7 to -12.1] and -19.2 percentage points [95% CI, -22.4 to -15.9]; P<0.001 for both comparisons). At 80 weeks, the mean changes in the WOMAC pain score (hybrid-treatment estimand) with retatrutide in TRIUMPH-1-OA were -3.22 (4 mg), -3.48 (9 mg), and -3.64 (12 mg), versus -1.87 with placebo (difference vs. placebo, -1.35 [95% CI, -1.92 to -0.78], -1.61 [95% CI, -2.20 to -1.02], and -1.77 [95% CI, -2.34 to -1.20], respectively). For the ITT estimand, the corresponding differences from placebo were -0.96 (95% CI, -1.61 to -0.30), -1.41 (95% CI, -2.07 to -0.75), and -1.64 (95% CI, -2.26 to -1.02) (P≤0.005 for all comparisons). In both trials, serious adverse events were more common with retatrutide than with placebo, and the most common adverse events were gastrointestinal. [CONCLUSIONS] In participants with painful knee osteoarthritis and obesity, treatment with retatrutide resulted in significantly greater reductions in both the WOMAC pain score and body weight than placebo. (Funded by Eli Lilly; TRIUMPH-4 and -1 ClinicalTrials.gov numbers, NCT05931367 and NCT05929066.).
Where this record came from
| Source | Retrieved | Identifier |
|---|---|---|
| pubmed | Nov 11, 2026 | 43001755 first ingestion |