New Triple Agonist Yields Major Weight Loss and Knee-pain reduction in Trials
A pair of phase 3 trials of of the investigational triple agonist retatrutide showed a mean weight loss of up to ~25% and clinically meaningful pain reduction versus placebo in people with obesity and osteoarthritis.
Compared to currently available GLP-1 (glucagon-like peptide-1) drugs like semaglutide or tirzepatide, which target one or two receptors and typically result in 10%-20% weight loss, retatrutide, a once-weekly injectable developed by Eli Lilly, targets three hormone receptors: , GIP (glucose-dependent insulinotropic polypeptide), and glucagon (GIP/GLP-1/glucagon).
The two trials, TRIUMPH-4 and TRIUMPH-1-OA, found that the highest doses produced average body-weight reductions of 20–25%. In a pooled analysis, roughly two-thirds of retatrutide recipients achieved ≥ 50% reduction in pain scores, compared with 38% on placebo. Additional benefits included lower blood pressure, improved lipids, and reduced systemic inflammation. The results were published in the New England Journal of Medicine.
Current knee-OA options (intra-articular corticosteroids, physiotherapy, topical agents, NSAIDs, opioids) offer only limited or short-term relief. Modest (5–10%) weight loss via diet and exercise can help but is hard to sustain, particularly when pain limits activity. Retatrutide’s three-receptor mechanism produced greater weight loss than dual or single agonists typically achieve.
Dr Thomas Schnitzer, corresponding author at Northwestern, said: “Participants had remarkable responses. Many of the people in this study lost considerable amounts of weight, with a few losing up to a hundred pounds or more.”
People who need a knee replacement were excluded from the trial. The biggest unknown from the study, Schnitzer said, is whether retatrutide slows the progression of knee OA enough to reduce the need for total joint replacement.
“That would be the goal here to say you can reduce people’s pain, and you can stop the progression of their osteoarthritis,” Schnitzer said.
The other area of this research that needs further investigation is whether the drug can reduce painful knee OA in people who are not overweight, as they were not included in the study.
“These drugs are believed to have significant anti-inflammatory activity, but the mechanism is not entirely known,” Schnitzer said. “Whether cutting down inflammation in the joint is also important in addition to reducing load needs more research, so this is still a first step, in my view. I’ve been working in the OA field for a long time, and I think this opens up opportunities to do a lot more studies to understand the condition better.”
Dr Philip Conaghan (University of Leeds) presented TRIUMPH-4 results at the American College of Rheumatology meeting.
Source: EurekAlert
