Glucagon-like peptide 1 receptor agonist use and risk of arthroplasty for knee osteoarthritis: retrospective database analysis.

“Glucagon-like peptide 1 receptor agonist use and risk of arthroplasty for knee osteoarthritis: retrospective database analysis. Carter V(1)(2), Desverreaux E(1)(2), Amin I(1), Fogarty AE(3), Hussain N(4), D'Souza R(5), Karri J(6)(2). Author information: (1)Department of Orthopaedic Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA. (2)Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, Maryland, USA. (3)Department of Physical Medicine and Rehabilitation, University of Utah School of Medicine, Salt Lake City, Utah, USA. (4)Department of Anesthesiology, Ohio State University Wexner Medical Center, Columbus, Ohio, USA. (5)Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota, USA. (6)Department of Orthopaedic Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA jkarri@som.umaryland.edu. BACKGROUND: Knee osteoarthritis (OA) is a leading cause of chronic pain and disability, with limited disease modifying therapies. While glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have established cardiometabolic benefits and have been associated with reductions in knee OA related pain, it is unclear whether they can reduce progression to total knee arthroplasty (TKA). METHODS: We conducted a retrospective cohort study using the TriNetX Global Research Network, identifying adults with knee OA diagnosed between January 1, 2010, and December 31, 2024. Patients were stratified by GLP-1 RA exposure class (any GLP-1 RA or new generation agents, semaglutide or tirzepatide) and treatment duration (1 or 3 years), and then compared with propensity score matched non-exposed cohorts balanced for age, sex, race, musculoskeletal diagnoses, obesity related conditions, body mass index, and proxies for healthcare access. The primary outcome was cumulative incidence of TKA at 1, 3, 5, and 8 years. Hazard ratios (HRs) were estimated by Cox proportional hazards models and absolute risk differences from Kaplan-Meier curves, expressed as exposed minus non-exposed. RESULTS: After propensity score matching, cohort sizes ranged from 13 351 (new generation GLP-1 RA, 3 year exposure) to 42 062 patients (any GLP-1 RA, 1 year exposure). GLP-1 RA use was associated with significantly lower cumulative TKA incidence across all exposure classes, durations, and follow-up intervals (all p<0.001). With 1 year exposure to any GLP-1 RA, the absolute risk difference at 8 years was -2.80 percentage points (HR 0.90, 95% CI 0.83 to 0.98). Risk reductions were greater with new generation agents and longer duration: 3 year exposure to semaglutide or tirzepatide gave an absolute risk difference of -4.71 percentage points at 8 years (HR 0.72, 95% CI 0.67 to 0.78). CONCLUSIONS: In this large, multicenter, real world cohort study, GLP-1 RA use was associated with a significantly reduced long term risk of TKA in patients with knee OA, with effects that were greater with longer treatment duration and newer generation agents. These duration and agent dependent associations are consistent with potential disease modifying activity beyond weight loss alone, although prospective trials are needed to establish causality and define optimal treatment targets. © American Society of Regional Anesthesia & Pain Medicine 2026. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ Group. Conflict of interest statement: Competing interests: RDS is a member of the editorial board of Regional Anesthesia and Pain Medicine. RDS was not involved in the peer review or editorial decision making process for this manuscript.”