GLP-1 Receptor Agonist Use Significantly Reduces Total Knee Arthroplasty Risk in Knee Osteoarthritis Patients
Background
Knee osteoarthritis (OA) is a pervasive chronic condition causing significant pain and disability, yet effective disease-modifying therapies remain elusive. Current treatments primarily focus on symptom management, often culminating in total knee arthroplasty (TKA) for advanced cases. While glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are well-established for their cardiometabolic benefits and have shown promise in reducing OA-related pain, it has been unclear whether these agents could actually slow disease progression sufficiently to reduce the need for surgical intervention like TKA. This study addresses that critical gap, exploring the long-term impact of GLP-1 RA use on TKA incidence.
Study Design
Researchers conducted a retrospective cohort study using the TriNetX Global Research Network, identifying adults diagnosed with knee OA between January 1, 2010, and December 31, 2024. Patients were stratified by GLP-1 RA exposure: either any GLP-1 RA or new generation agents (semaglutide or tirzepatide). Exposure durations of 1 year or 3 years were analyzed. These groups were then propensity score matched to non-exposed cohorts, balancing for age, sex, race, musculoskeletal diagnoses, obesity-related conditions, body mass index, and healthcare access proxies. The primary endpoint was the cumulative incidence of TKA at 1, 3, 5, and 8 years, with hazard ratios (HRs) estimated via Cox proportional hazards models and absolute risk differences from Kaplan-Meier curves.
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 consistently associated with a significantly lower cumulative TKA incidence across all exposure classes, durations, and follow-up intervals, with all results achieving p<0.001. The protective effect was evident even with shorter exposure: > With 1 year of 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). This indicates a 10% reduction in TKA risk. Risk reductions were more pronounced with newer agents and longer treatment durations. For instance, 3 years of exposure to semaglutide or tirzepatide resulted in an absolute risk difference of -4.71 percentage points at 8 years (HR 0.72, 95% CI 0.67 to 0.78), representing a substantial 28% reduction in TKA risk.
Key Findings
- GLP-1 RA use significantly lowered cumulative total knee arthroplasty (TKA) incidence across all durations and follow-up intervals (all p<0.001).
- One year of any GLP-1 RA exposure reduced TKA risk by 2.80 percentage points at 8 years (HR 0.90, 95% CI 0.83 to 0.98).
- Newer generation GLP-1 RAs (semaglutide/tirzepatide) showed greater risk reductions.
- Three years of semaglutide or tirzepatide exposure reduced TKA risk by 4.71 percentage points at 8 years (HR 0.72, 95% CI 0.67 to 0.78).
Why It Matters
This study provides compelling real-world evidence that GLP-1 RAs may offer a disease-modifying benefit for knee osteoarthritis, extending beyond mere pain reduction to potentially delay or prevent the need for total knee arthroplasty. For individuals with knee OA, particularly those with obesity or metabolic comorbidities, this suggests a significant non-surgical intervention that could improve long-term joint health and quality of life. The finding that newer generation GLP-1 RAs like semaglutide and tirzepatide, and longer treatment durations, yield greater reductions in TKA risk is crucial. This could inform future clinical guidelines, potentially integrating GLP-1 RA therapy earlier in the management of OA to alter disease trajectory and reduce the burden of surgical interventions. Consideration of GLP-1 RAs for OA patients, especially those with obesity, could become a standard part of care.
glp-1-ra
semaglutide
tirzepatide
knee-osteoarthritis
osteoarthritis
arthroplasty