Glucagon-like peptide 1 receptor agonist use and risk of arthroplasty for knee osteoarthritis: retrospective database analysis.
This retrospective cohort study used the TriNetX Global Research Network to examine whether GLP-1 receptor agonist (GLP-1 RA) use was associated with a reduced risk of total knee arthroplasty (TKA) in adults with knee osteoarthritis (OA) diagnosed between 2010 and 2024. Patients exposed to GLP-1 RAs (either any agent or newer agents—semaglutide or tirzepatide) were propensity score matched to unexposed controls, balancing for age, sex, race, musculoskeletal diagnoses, obesity-related conditions, BMI, and healthcare access proxies. Matched cohort sizes ranged from approximately 13,000 to 42,000 patients depending on the exposure class and treatment duration analyzed (1 or 3 years). The primary outcome was cumulative TKA incidence at 1, 3, 5, and 8 years, estimated via Kaplan-Meier curves and Cox proportional hazards models. The study found that GLP-1 RA use was associated with significantly lower TKA incidence across all subgroups, with larger reductions observed with longer treatment durations and with newer-generation agents. The authors suggest the findings are consistent with possible disease-modifying activity beyond weight loss, but acknowledge that as a retrospective observational design, causality cannot be established, and prospective randomized trials are needed.
Why this grade: Although the study is large and multicenter with propensity score matching, its retrospective observational design cannot establish causality, and residual confounding (e.g., by indication, lifestyle factors) cannot be excluded, limiting the strength of evidence to limited-human.
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 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.
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