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

Study Overview

TRIUMPH-4 was the first Phase 3 trial in the retatrutide development program to report results, announced by Eli Lilly in December 2025. The trial evaluated retatrutide in adults with obesity and knee osteoarthritis (OA), a population where excess body weight directly contributes to joint pain and disability. The results were historic: 28.7% mean weight loss at the 12 mg dose over 68 weeks — the largest weight reduction ever reported for any pharmaceutical agent in a Phase 3 clinical trial.

Key Results

Weight Loss

TRIUMPH-4 demonstrated weight loss that exceeded even the impressive Phase 2 results:

The 12 mg result represents a 4.5 percentage point improvement over the Phase 2 result of -24.2% at 48 weeks, driven by the longer treatment duration (68 vs. 48 weeks) and optimized dose escalation.

Responder Analysis

Knee Osteoarthritis Outcomes

The co-primary endpoint of knee OA pain showed dramatic improvement:

• WOMAC pain score: 75% reduction from baseline at 12 mg
• Physical function: Significant improvement in stair climbing, walking, and daily activities
• Stiffness: Marked reduction in morning stiffness
• The magnitude of pain reduction exceeded expectations and may reflect both weight-related mechanical offloading and potential anti-inflammatory effects

New Safety Signal: Dysesthesia

TRIUMPH-4 identified a new adverse event that was not prominent in Phase 2:

Dysesthesia (Abnormal Sensation)

• 12 mg group: 20.9% incidence
• 8 mg group: 12.3% 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

This safety signal will require careful monitoring in subsequent TRIUMPH trials and will be a focus of regulatory review. The mechanism is not fully understood but may relate to rapid metabolic changes or direct neuronal GLP-1 receptor effects at higher doses.

Other Adverse Events

The broader safety profile was consistent with Phase 2:

• Nausea: ~22% (12 mg)
• Diarrhea: ~18%
• Vomiting: ~12%
• Constipation: ~10%
• Treatment discontinuation due to AEs: ~10% (12 mg)

Clinical Significance

Exceeding Phase 2 Benchmarks

The TRIUMPH-4 results confirmed that Phase 3 weight loss exceeded Phase 2, a pattern not always seen in drug development. The longer treatment duration (68 weeks vs. 48 weeks) allowed the weight loss trajectory to progress further, though it may still not have fully plateaued.

Obesity-Osteoarthritis Nexus

This trial validated retatrutide for a specific high-burden population:

• 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
• The 75% pain reduction may delay or prevent the need for knee replacement surgery

Competitive Positioning

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

Publication

Results presented at a major medical conference in December 2025, with full publication expected in the New England Journal of Medicine in 2025-2026.