The TRIUMPH-4 Trial and Its Results

The Trial Structure

TRIUMPH-4 (NCT05931367) was a 68-week, Phase 3, randomized, double-blind, placebo-controlled study. It enrolled 445 adults with obesity or overweight (BMI ≥27 kg/m²) and radiologically confirmed knee osteoarthritis, excluding those with diabetes. The trial evaluated 9 mg and 12 mg target doses, with participants starting at 2 mg and escalating every four weeks.

Trial Endpoints

The primary objective of the study was to demonstrate that retatrutide is superior to placebo in meeting two primary endpoints:

• Endpoint 1: Reduction in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale score from baseline to Week 68.

• Endpoint 2: Reduction in body weight from baseline to Week 68.

Key secondary endpoints included:

• Percent change in body weight.

• Proportion of participants achieving 25% and 30% weight loss thresholds.

• Change in WOMAC physical function score.

Key Efficacy Results (12 mg Dose, Efficacy Estimated)

Retatrutide met all primary and key secondary endpoints:

• Primary Endpoint (Weight Loss): Participants lost an average of 28.7% of their body weight (~71.2 lbs).

• Primary Endpoint (Pain Reduction): Patients achieved an average 75.8% reduction in the WOMAC pain score.

• High-Threshold Responders: A significant portion of the cohort achieved exceptionally high levels of weight loss, with 39.4% losing ≥ 30 of their body weight, and 23.7% losing ≥ 35.

• Physical Function and Pain-Free Status: Physical function scores improved by 73.7%, and a post-hoc analysis revealed that 12.0% of patients on the 12 mg dose achieved complete freedom from knee pain at the end of the study.

Safety and Tolerability

Adverse events were consistent with other incretin therapies, primarily involving gastrointestinal effects such as nausea, diarrhea, constipation, and vomiting.

A specific sensory finding was noted: Dysesthesia occurred in 20.9% of the 12 mg group versus 0.7% on placebo. However, these events were generally mild and rarely led to discontinuation. Discontinuation rates due to adverse events, though higher in the retatrutide groups (18.2% at 12 mg) compared to placebo (4.0%), were often correlated with baseline BMI and included discontinuations for perceived excessive weight loss.

What This Means for Patients If Approved

If approved, TRIUMPH-4 data indicate that retatrutide may redefine the clinical management of obesity and its associated comorbidities.

• New Benchmark for Weight Loss: Achieving nearly 30% weight loss represents a therapeutic outcome previously attainable only through bariatric surgery. This reduction can significantly improve health and quality of life.

• Dual-Action Therapy: For millions living with obesity-related knee osteoarthritis, retatrutide provides a promise of a single injection that tackles both the underlying weight and the relentless pain, potentially sparing many from invasive joint surgeries.

• Reduced Metabolic Risk: Significant reductions in cardiovascular markers (systolic blood pressure, non-HDL cholesterol, triglycerides, hsCRP) indicate strong potential for preventing long-term cardiovascular and metabolic complications.

Conclusion

TRIUMPH-4 demonstrates retatrutide's promise as a powerful tool for cardiometabolic health. Its weight-loss and pain-relief results highlight its potential to advance obesity and osteoarthritis care, reflecting its innovative mechanism and its connection between obesity management and systemic health.

Future Directions

Lilly’s TRIUMPH Phase 3 program will continue through 2026, with seven additional studies planned. These trials will assess retatrutide’s effects in specific populations, aiming to address knowledge gaps and further define its long-term clinical relevance.

• Type 2 Diabetes and Obesity

• Moderate-to-Severe Obstructive Sleep Apnea

• Metabolic Dysfunctional-Associated Steatotic Liver Disease (MASLD)

• Cardiovascular and Renal Outcomes

Eli Lilly and Company. Lilly’s triple agonist retatrutide delivered weight loss of up to an average of 71.2 lb along with substantial relief from osteoarthritis pain in first successful Phase 3 trial. Published December 11, 2025. Accessed January 5, 2026. https://investor.lilly.com/news-releases/news-release-details/lillys-triple-agonist-retatrutide-delivered-weight-loss-average