Metformin Use and Risk of Total Joint Replacement in Patients with Type 2 Diabetes: A Population-Based Cohort Study

Background: Whether metformin use is associated with reduced risks of total knee replacement (TKR) and/or total hip replacement (THR) in patients with type 2 diabetes mellitus (DM) remains uncertain.Methods: We conducted a population-based cohort study using 2000-2013 Taiwan’s National Health Insurance Research Database. We selected participants over 45 years old when they were newly diagnosed with type 2 DM. Participants were classified into metformin users and non-users based on if metformin was ever used after diagnosis. The index date (defined as 3-month after first metformin prescription) of non-users was individually matched by age, sex and year of DM diagnosis using prescription time-distribution matching (PTDM). Additionally, propensity score matching (PSM) was used to balance co-variates including age, sex, urbanization, insurance type, adapted diabetes complication index (aDCSI), medications between two groups. The risks of TKR and/or THR in metformin users or non-users were assessed using Cox proportional hazard regression. Sensitivity analyses were performed by using inverse probability of treatment weighting (IPTW) and competing risk regression, and by using alternative outcomes (osteoarthritis-related TKR and/or THR, or the hospitalization due to knee or hip osteoarthritis). Daily dosages of metformin (0, <1.0 g/day and ≥1.0 g/day) from first prescription to 3-, 12- and 24-month landmark points were calculated to evaluate potential dose-response relationships.Findings: A total of 40694 participants (20347 non-metformin vs 20347 metformin) were included (mean [SD] age, 63 [11] years; 49.8% were women) after PTDM. Compared with the metformin non-users, participants who used metformin had lower risks of total knee or hip joint replacement [adjusted HR (aHR), 0.70; 95% CI, 0.60 to 0.81 for TKR or THR; aHR, 0.71; 95% CI, 0.61 to 0.84 for TKR; aHR, 0.61; 95% CI, 0.41 to 0.92 for THR] after adjustment for covariates. PSM analyses (10163 non-metformin vs 10163 metformin) and sensitivity analyses showed similar results. A high dose of metformin was associated with reduced cumulative incidence probabilities of TKR and/or THR.Interpretations: Metformin use in patients with type 2 DM was associated with a significantly reduced risk of total joint replacement largely due to osteoarthritis. Further randomized controlled clinical trials are warranted to determine if metformin is effective for the treatment of osteoarthritis.Funding: The present study was supported by the National Natural Science Foundation of China (32000925, 81974342), Guangzhou Municipal Science and Technology Project (CN) (202002030481), Basic and Applied Basic Research in Guangdong Province (2019A1515111169, 2019A1515110620) and Wu Jieping Medical Foundation Program (3206750.2020-03-12). Declaration of Interest: CD receives consulting fees from BioBone, and DJH receives consulting fees from Merck Serono, TLC Bio, Tissuegene, Lilly, and Pfizer for OA related scientific advisory roles. All other authors declare no competing interests.Ethical Approval: This study was approved by Institutional Review Board of Chung Shan MedicalUniversity Hospital (CS15134).