Retatrutide Once Weekly in Adults with Knee Osteoarthritis Pain and Obesity

Background: The efficacy and safety of retatrutide, an investigational triple agonist of glucosedependent insulinotropic polypeptide, glucagon-like peptide 1, and glucagon receptors for painful knee osteoarthritis (OA) in people with obesity are unknown.Methods: Two phase 3 trials enrolled adults with painful knee OA and BMI ≥27 kg/m 2 without diabetes.Participants were randomly assigned to once-weekly subcutaneous retatrutide (TRIUMPH-4, N=445: 9-mg, 12-mg; TRIUMPH-1-OA, N=574: 4-mg, 9-mg, 12-mg) or placebo.TRIUMPH-4 co-primary endpoints were change in WOMAC pain score (range, 0-10, higher=more pain) and percent change in bodyweight at week 68; TRIUMPH-1-OA primary endpoint was change in WOMAC pain score at week 80.For non-pain-related endpoints, intercurrent events were handled by a treatment policy strategy (treatment-regimen estimand [TRE]).For pain-related outcomes, a hybrid-treatment estimand was applied with a hypothetical strategy for participants with intercurrent events suggesting treatment failure and treatment policy strategy elsewhere.We also report an intention-to-treat estimand that applied a treatment policy strategy for all intercurrent events (hereafter ITT).Results: In TRIUMPH-4 (68 weeks), mean change in WOMAC pain (hybrid-treatment estimand) was -3.96 (9-mg), -3.74 (12-mg) and -2.12 (placebo) (difference vs. placebo [95% CI] -1.83 [-2.37,-1.30],-1.61 [-2.16,-1.07],respectively); differences by ITT estimand: -1.70 [-2.19,-1.22];-1.38 [-1.91,-0.85])(P <0.001).Mean percent change in bodyweight was -20.0%(9-mg), -23.7% (12-mg) and -4.6% (placebo) (differences: -15.4 [-18.7,-12.1];-19.2 [-22.4,-15.9])(P <0.001).In TRIUMPH-1-OA (80 weeks), mean change in WOMAC pain (hybrid-treatment estimand) was -3.22 (4-mg), -3.48 (9-mg), -3.64 (12-mg) and -1.87 (placebo) (differences: -1.35 [-1.92,-0.78];-1.61 [-2.20,-1.02];-1.77 [-2.34,-1.20]);and differences by ITT estimand: -0.96 [-1.61,-0.30];-1.41 [-2.07,-0.75];-1.64 [-2.26,-1.02])(P≤0.005).In both trials, serious adverse events (AEs) were more common with retatrutide than placebo, and gastrointestinal AEs were most common.Conclusions: In participants with painful knee OA and obesity, retatrutide treatment resulted in significant reductions in both WOMAC pain scores and bodyweight.(Funded by Eli Lilly and Company; TRIUMPH-4 ClinicalTrials.gov:NCT05931367; TRIUMPH-1 ClinicalTrials.gov:NCT05929066) Osteoarthritis (OA), a progressive joint disease, often includes pain that limits quality of life and confers substantial socioeconomic burdens on patients, healthcare systems, and society.[1][2][3] Obesity is a risk factor in both OA onset and progression.[1][2][3] Excess bodyweight increases mechanical loading on weight-bearing joints; further, increased joint stress accelerates cartilage degeneration and possible malalignment.1,3,4 Excess adiposity may also contribute to a systemic, low-grade inflammatory state.5 Weight reduction is considered an important component of knee OA management; each pound of bodyweight lost is associated with an approximately 4-fold load reduction across the knee.6 Biomechanical and clinical benefits increase with weight loss; progressively greater weight reduction is associated with lower maximum knee compressive forces and greater symptom improvements.7 Clinical guidelines include weight reduction alongside exercise, pharmacologic therapies such as nonsteroidal anti-inflammatory agents, intra-articular injections, and surgical interventions.8,9 Current pharmacologic therapies may provide modest efficacy but limited tolerability and safety.A study of semaglutide suggested improved knee OA pain, 10 highlighting the possibility that additional obesity therapeutics might address both excess bodyweight and knee OA symptoms.Retatrutide is an investigational triple-receptor agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1 (GLP-1), and glucagon receptors.In phase 2 clinical trials in patients with obesity, retatrutide demonstrated average weight reductions from 8.7%-24.2%,versus 2.1% with placebo (percentage point difference: -6.6 to -22.1), at 48 weeks.11 The two trials presented here, one published in part previously, 12 evaluated the efficacy, tolerability, and safety of once-weekly injectable retatrutide in adults with painful knee OA and obesity.