Eli Lilly’s experimental drug retatrutide has demonstrated significant weight loss and pain reduction in a recent Phase III clinical trial, according to results released Thursday. The TRIUMPH-4 study showed that adults with obesity or overweight and knee osteoarthritis who received the highest dose of retatrutide lost an average of 28.7% of their body weight over 68 weeks. When adjusted for placebo, this equated to a 26.6% reduction.
The company also reported that participants experienced a 75% reduction in knee osteoarthritis pain. Additional benefits included improvements in physical function, reduced cardiovascular risk, and lower blood pressure.
BMO Capital Markets described the findings as “a true TRIUMPH,” noting, “These results help to solidify retatrutide’s profile as an even higher efficacy next generation GLP-1+ asset.” BMO had previously anticipated weight loss in the range of 20%-23% for retatrutide and a 50% pain reduction.
Retatrutide is designed to target three hormone receptors: GIP, GLP-1, and glucagon. This multi-target approach sets it apart from other drugs such as Novo Nordisk’s semaglutide, which achieved a 42% pain reduction in earlier studies.
Following the announcement, Eli Lilly’s stock price rose above $1,000 in pre-market trading on Thursday morning.
Despite these positive outcomes, new safety concerns have emerged. A side effect known as dysesthesia—an abnormal sensation causing discomfort or pain—was reported by 8.8% of patients taking the 9 mg dose and by 20.9% at the 12 mg dose. In comparison, only 0.7% of patients receiving placebo experienced this symptom. Dysesthesia was not observed in earlier trials of retatrutide.
BMO stated it would monitor future trial data closely for further information on this safety signal: “Discontinuation rates appear to highlight the speed and strength of weight loss was excessive for some patients with lower BMI.” The firm added that discontinuation rates were “overall acceptable,” especially among those with higher BMI.
Other common side effects included gastrointestinal symptoms such as nausea (43%), vomiting (21%), and diarrhea (33%). Discontinuation rates due to adverse events were higher among those taking retatrutide compared to placebo; some patients stopped treatment because they felt their weight loss was too rapid.
Lilly is positioning retatrutide as an option for people seeking greater weight loss than currently available GLP-1 therapies provide. The TRIUMPH-4 trial was not designed to determine maximum possible weight loss from the drug.
Retatrutide is part of Lilly’s broader effort to expand its obesity treatment portfolio alongside Mounjaro (tirzepatide), Zepbound, and orforglipron—a group Truist Securities projects could generate up to $101 billion in peak global sales.
In addition to TRIUMPH-4, Lilly has completed two other successful major trials this year involving its obesity pipeline drugs. The company plans further late-stage studies within its TRIUMPH program for retatrutide through at least the end of 2026; so far more than 5,800 people have been enrolled across various indications including obesity, obstructive sleep apnea, and knee osteoarthritis.
