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In this large real-world, propensity score–matched cohort study, 1 glucagon-like peptide-1 (GLP-1) receptor agonist use was associated with a significantly lower cumulative risk of total knee arthroplasty (TKA) in patients with knee osteoarthritis across all time points. Importantly, the benefit was duration-dependent and agent-dependent, with longer exposure (3 years) and newer-generation agents (semaglutide, tirzepatide) demonstrating the greatest reductions in risk of progression to TKA, reaching an absolute risk reduction of up to 4.71% at 8 years. These findings suggest that sustained GLP-1 therapy may modify disease progression beyond weight loss alone, potentially through anti-inflammatory and analgesic mechanisms. From a population perspective, this translates to a meaningful clinical impact, with estimates suggesting approximately 14 000 fewer TKAs annually in the USA among eligible patients. While promising, these results remain observational and require confirmation in prospective trials before routine adoption into clinical management of knee osteoarthritis.