Eli Lilly and Company announced positive results from its Phase III trial study TRIUMPH-4 showing that retatrutide produced substantial weight loss and showed reductions in knee pain for adults with obesity or overweight and knee osteoarthritis.

Retatrutide is a once-weekly investigational molecule that activates receptors for GIP, GLP-1, and glucagon.

TRIUMPH-4, a global, randomized study, evaluated retatrutide’s two highest doses, 9 mg and 12 mg, over a 68 week period.¹ In the trial, where most participants had a body mass index (BMI) of at least 23.5 lbs/ft² at baseline, both doses met all primary and key secondary endpoints, with patients receiving the 12 mg dose losing an average of 28.7% of their body weight, more than 70 pounds on average, while those on 9 mg lost 26.4%. ¹ Placebo-treated participants reported aloss of just 2.1%.

"People with obesity and knee osteoarthritis often live with pain and restricted mobility, and may eventually require total joint replacement," said Kenneth Custer, Ph.D., executive vice president and president, Lilly Cardiometabolic Health. "We are encouraged by the results of TRIUMPH-4, which highlight the powerful effect of retatrutide, a first-in-class triple agonist, on body weight, pain and physical function. With seven additional Phase III readouts expected in 2026, we believe retatrutide could become an important option for patients with significant weight loss needs and certain complications, including knee osteoarthritis."

What were the results from the TRIUMPH-4 Phase III trial?

In the Phase III trial study, pain reduction was similarly notable using the WOMAC pain scale. Retatrutide reportedly lowered pain scores by upwards of four and a half points from a baseline of six, representing roughly a 76% improvement.¹

Measures of physical function improved as well, and in a post-hoc analysis, with more than one in eight patients treated with retatrutide reporting a complete freedom from knee pain at week 68, compared with 4.2% on placebo.

Beyond weight and pain outcomes, the investigational agent also reduced several cardiovascular risk markers, including non-HDL cholesterol, triglycerides, hsCRP, and systolic blood pressure at the highest dose.¹

Secondary endpoints showed a high proportion of participants achieving ≥25%, ≥30%, and ≥35% weight loss, levels rarely observed in previous obesity trials.¹

Retatrutide was also associated with gastrointestinal side effects typical of incretin-based therapies, such as nausea, diarrhea, constipation, vomiting, and decreased appetite as the most common events, occurring more frequently than with placebo.

Dysesthesia was reported in up to 20.9% of participants at the 12 mg dose and was generally mild and infrequently lead to discontinuation. Overall discontinuation rates were similar across study arms, though discontinuations related to adverse events were higher in participants with lower baseline BMIs.

The TRIUMPH-4 trial results are a part of Lilly’s broader TRIUMPH program, which includes multiple ongoing Phase III trials evaluating retatrutide for the following indications:

• Obesity
• Overweight with comorbidities
• Type 2 diabetes
• Obstructive sleep apnea
• Knee osteoarthritis
• Other metabolic conditions

Seven additional Phase III readouts are expected in 2026, including studies evaluating maintenance dosing strategies.

Sources

1. Lilly's triple agonist, retatrutide, delivered weight loss of up to an average of 71.2 lbs along with substantial relief from osteoarthritis pain in first successful Phase 3 trial Eli Lilly and Company December 11, 2025 https://www.prnewswire.com/news-releases/lillys-triple-agonist-retatrutide-delivered-weight-loss-of-up-to-an-average-of-71-2-lbs-along-with-substantial-relief-from-osteoarthritis-pain-in-first-successful-phase-3-trial-302638804.html