CHICAGO — For people with painful knee osteoarthritis (OA) who are overweight or have obesity, everyday activities such as walking, climbing stairs and standing up from a chair can be difficult.
In two Northwestern University-led phase 3 clinical trials involving more than 1,000 participants combined, those taking the highest dose of retatrutide, a new experimental weight-loss injectable drug, lost about one-quarter of their body weight on average. A pooled analysis of the studies found that about two-thirds of participants receiving retatrutide experienced at least a 50% reduction in knee pain, compared with 38% of those receiving placebo.
In addition to weight loss and pain relief, participants experienced other significant benefits, including reduced blood pressure, lower lipid levels and less systemic inflammation.
The findings from both trials will be published Nov. 8 in the New England Journal of Medicine.
"The findings are really saying for people who are overweight and have OA, if you lose a significant amount of weight with this treatment, there is a good chance that you're going to get a meaningful reduction in your knee pain," said corresponding author Dr. Thomas Schnitzer , professor of physical medicine and rehabilitation, anesthesiology and medicine (rheumatology) at Northwestern University Feinberg School of Medicine. "A major factor is that you're loading your knees less and therefore, there's less pain and it allows you to increase your function."
Study co-author Philip Conaghan , professor of musculoskeletal medicine at the University of Leeds in the United Kingdom, will present the findings from one trial, called TRIUMPH-4, at 11:15 a.m. (E.T.) Sunday, Nov. 8, at the American College of Rheumatology annual meeting in Orlando, Florida. The results of the second study, called TRIUMPH-1-OA, will be presented the same day in a separate poster session.
Drug could become a treatment for 5% of Americans
Approximately 5% of the U.S. population (15 million people) have painful knee OA. Current treatments include corticosteroid injections, which only provide short-term benefit, physical therapy, topical treatments, opioids and non-steroidal oral drugs like ibuprofen and Voltaren. Previous research has found losing 5%-10% of a person's body weight through diet and exercise can reduce their knee OA symptoms. However, Schnitzer said it is difficult to lose more than 10% through those means alone, and it is difficult to exercise with existing knee pain.
Compared to currently available GLP-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, activates receptors for three distinct natural hormones and resulted in 20%-25% weight loss in study participants. Scientists from Eli Lilly are study co-authors.
"Participants had remarkable responses," Schnitzer said. "Many of the people in this study lost considerable amounts of weight, with a few losing up to a hundred pounds or more."
Diet and exercise remain the foundation of care
Schnitzer noted the first step patients who are overweight and have painful knee OA should take is diet, exercise and lifestyle modifications, which can help and are less expensive. They also are not associated with known GLP-1 side effects such as gastrointestinal problems and loss of muscle mass, which is important for people with knee OA as muscle helps stabilize the knee. However, if patients are unable to lose weight and are still limited by their knee pain, this would be a good option if it is approved by the U.S. Food and Drug Administration.
Key questions remain
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."
The researchers measured participants' pain using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) Pain index, in which participants at a visit would rate their pain on a scale of 0 to 10. Additionally, participants would log their daily pain rating with an app.
The study is titled, "Retatrutide Once Weekly in Adults with Knee Osteoarthritis Pain and Obesity."
