Retatrutide significantly reduced knee pain and body weight in a phase 3 trial, raising the prospect of another treatment option for patients with obesity-related osteoarthritis.
Experimental obesity drug retatrutide cut knee osteoarthritis pain by more than 60% in patients with obesity, according to phase 3 trial results published in the New England Journal of Medicine.
The once-weekly injectable also delivered average weight loss of up to 25% over 80 weeks, with researchers reporting significant improvements in physical function and cardiometabolic health.
The findings come from the Eli Lilly-funded TRIUMPH-1 trial, which enrolled 2339 adults with obesity but without diabetes across 131 sites in 11 countries.
Participants were randomly assigned to receive retatrutide at doses of 4mg, 9mg, or 12mg, or placebo, for 80 weeks.
Retatrutide is a triple hormone receptor agonist targeting glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon receptors. It is currently not approved for use or sale anywhere in the world.
Of the trial participants, 574 had moderate to severe knee osteoarthritis, with both pain and radiographic evidence of disease. In this subgroup, retatrutide produced substantial improvements in pain scores measured using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC).
At 80 weeks, patients receiving 9mg and 12mg retatrutide experienced mean reductions of 3.5 and 3.6 points respectively on the 10-point WOMAC pain scale, compared with a 1.9-point reduction in the placebo group.
The between-group differences were 1.6 and 1.8 points respectively, with both comparisons reaching statistical significance. The 4mg dose also improved pain scores, producing a mean reduction of 3.2 points.
The researchers said the findings represented a reduction in knee pain of more than 60% among participants receiving retatrutide, based on the trial’s hybrid-treatment estimand.
An intention-to-treat analysis also demonstrated significant improvements, with pain scores falling by 3.9 and 4.1 points in the 9mg and 12mg groups respectively, compared with 2.5 points in the placebo group.
Weight loss was substantial across all treatment groups.
At 80 weeks, mean body weight had fallen by 17.6% with retatrutide 4mg, 23.7% with 9mg, and 25.0% with 12mg, compared with 3.9% in the placebo group. More than one-third of participants receiving the highest dose lost at least 30% of their baseline body weight, while 21.1% lost at least 35%.
The researchers said the magnitude of weight loss suggested that treatment targeting multiple hormone pathways could offer benefits beyond those achieved with existing obesity medications.
The drug also significantly reduced obstructive sleep apnoea severity in a separate subgroup of 243 participants.
Among patients receiving 9mg and 12mg retatrutide, the mean number of apnoea-hypopnoea events per hour fell by 34.3 and 31.7 respectively, compared with 9.9 in the placebo group.
Improvements were also observed in physical functioning and quality of life scores, waist circumference, systolic blood pressure, triglycerides, fasting insulin, high-sensitivity C-reactive protein.
At the highest dose, high-sensitivity C-reactive protein levels fell by 62.6%, compared with 24.9% in the placebo group.
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However, treatment was associated with adverse events, predominantly gastrointestinal symptoms including nausea, diarrhoea, and constipation.
These were generally mild to moderate and occurred most frequently during dose escalation. Treatment discontinuation because of adverse events occurred in 4.1%, 6.5%, and 11.1% of patients receiving the 4mg, 9mg, and 12mg doses respectively, compared with 4.6% of placebo recipients.
Serious adverse events were reported in 7.7% to 10.5% of retatrutide-treated participants, compared with 5.5% of those receiving placebo.
The researchers acknowledged that the trial’s duration limited conclusions about long-term safety and the durability of treatment benefits.
For rheumatologists, the findings add to growing evidence that pharmacological weight management could improve symptoms in patients with obesity-associated knee osteoarthritis.
However, the trial did not establish whether the improvement in knee pain was attributable entirely to weight loss or whether other mechanisms contributed. It also did not establish an effect on structural disease progression.
The researchers said the results supported the potential role of retatrutide in treating obesity and its associated complications, although longer-term research will be needed to establish its safety and sustained clinical benefits.
“It has been hypothesised that treating obesity with therapies that target multiple nutrient-stimulated hormone pathways may facilitate greater weight reduction and broader health improvement,” they wrote.
“Therapies that target these pathways have transformed the treatment of obesity, with average weight reductions of 12 to 22%.
“Weight reductions of 30 to 35% or greater have previously been attainable with bariatric surgery or combination pharmacotherapy.
“In this trial, weight loss of at least 35% was reported in nearly a quarter of the participants (21% with the treatment-regimen estimand and 27% with the efficacy estimand).
“Given the degree of weight reduction in response to retatrutide, these data support the possibility of treating to a defined target as is done for other diseases (e.g., a glycated haemoglobin target of <6.5% for type 2 diabetes), rather than to a relative percent change in weight.”
