TRIUMPH-4: Obesity with Knee Osteoarthritis (First Phase 3 Readout)

Study Overview

TRIUMPH-4 was the first Phase 3 trial in the retatrutide program to report results, announced by Eli Lilly in December 2025. It tested retatrutide in adults with obesity and knee osteoarthritis (OA), a group in whom excess weight directly adds to joint pain and disability. The results set a record: 28.7% mean weight loss at the 12 mg dose over 68 weeks, the largest weight reduction ever reported for any drug in a Phase 3 clinical trial.

Phase 3 Dose Escalation Protocol

The TRIUMPH Phase 3 program uses an updated escalation schedule compared with Phase 2. It adds a 6 mg step between 4 mg and 9 mg to improve gastrointestinal tolerability. All arms start at 2 mg and step up every 4 weeks.

A permanent dose reduction is allowed to manage gastrointestinal side effects. The Phase 2 escalation protocol did not have the 6 mg step.

Source: Giblin et al., Diabetes Obes Metab, January 2026.

Key Results

Weight Loss

TRIUMPH-4 showed weight loss beyond even the strong Phase 2 results:

The 12 mg result is 4.5 percentage points better than the Phase 2 result of -24.2% at 48 weeks, thanks to the longer treatment period (68 vs. 48 weeks) and the refined dose escalation.

Responder Analysis

Lilly’s topline release reported these thresholds; it did not give the share reaching 5%, 10%, 15% or 20%. With the treatment-regimen estimand (everyone randomized, whether or not they stayed on treatment), mean weight loss was 20.0% (9 mg) and 23.7% (12 mg) versus 4.6% on placebo.

Knee Osteoarthritis Outcomes

The co-primary endpoint, knee OA pain, improved dramatically:

• WOMAC pain score: down 4.5 points (75.8%) at 9 mg and 4.4 points at 12 mg, versus 2.4 points (40.3%) on placebo
• Free of knee pain at week 68 (post hoc analysis): 14.1% (9 mg) and 12.0% (12 mg) versus 4.2% on placebo
• Physical function (WOMAC): improved by 4.1 (9 mg) and 4.2 (12 mg) points versus 2.1 on placebo
• The pain reduction was larger than expected and may reflect both less mechanical load on the joint from weight loss and possible anti-inflammatory effects

New Safety Signal: Dysesthesia

TRIUMPH-4 found a new adverse event that had not stood out in Phase 2:

Dysesthesia (Abnormal Sensation)

• 12 mg group: 20.9% incidence
• 9 mg group: 8.8% incidence
• Placebo: 0.7% incidence
• Characterization: Described as tingling, numbness, or altered sensation, primarily in extremities
• Severity: Predominantly mild to moderate; rarely led to treatment discontinuation
• Onset: Typically during dose escalation phase
• Resolution: Often resolved or diminished with continued treatment

The later TRIUMPH trials reported lower dysesthesia rates at 12 mg (12.5% in TRIUMPH-1, 7.3% in TRIUMPH-2, 6.4% in TRIUMPH-3); the signal is still likely to be a focus of regulatory review. The cause is not fully understood and may relate to glucagon receptor effects on nerve cells or to rapid metabolic changes at higher doses.

Other Adverse Events

The wider gastrointestinal safety profile was typical of the incretin class:

Clinical Significance

Exceeding Phase 2 Benchmarks

TRIUMPH-4 confirmed that Phase 3 weight loss went beyond Phase 2, which does not always happen in drug development. The longer treatment period (68 weeks vs. 48 weeks) let weight loss continue further, and it may still not have fully leveled off.

Obesity-Osteoarthritis Nexus

This trial supported retatrutide in a specific high-burden group:

• Approximately 240 million adults globally have symptomatic knee OA
• Obesity is the strongest modifiable risk factor for knee OA progression
• Current weight loss therapies have not been specifically tested in OA populations at this scale
• Pain reductions of this size could, if they last, delay the need for knee replacement surgery; the trial did not test that

Competitive Positioning

With 28.7% weight loss, retatrutide now has the highest Phase 3 weight loss of any obesity drug in development or on the market, ahead of tirzepatide’s ~22% in SURMOUNT-1.

Publication

Topline results were announced in an Eli Lilly press release in December 2025. As of October 31, 2026 we have not found a peer-reviewed paper reporting TRIUMPH-4.