Metformin use and associated risk of total joint replacement in patients with type 2 diabetes: a population-based matched cohort study

Abstract

Background: It is uncertain whether metformin use is associated with reduced risk of joint replacement in patients with type 2 diabetes mellitus. We aimed to establish whether metformin use was associated with a reduced risk of total knee replacement (TKR) or total hip replacement (THR) among these patients.

Methods: We selected patients with type 2 diabetes mellitus that was diagnosed between 2000 and 2012 from the Taiwan National Health Insurance Research Database. We used prescription time-distribution matching and propensity-score matching to balance potential confounders between metformin users and nonusers. We assessed the risks of TKR or THR using Cox proportional hazards regression.

Results: We included 20 347 participants who were not treated with metformin and 20 347 who were treated with metformin, for a total of 40 694 participants (mean age 63 yr, standard deviation 11 yr; 49.8% were women) after prescription time-distribution matching. Compared with participants who did not use metformin, those who used metformin had lower risks of TKR or THR (adjusted hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.60-0.81 for TKR or THR; adjusted HR 0.71, 95% CI 0.61-0.84 for TKR; adjusted HR 0.61, 95% CI 0.41-0.92 for THR) after adjustment for covariates. Propensity-score matching analyses (10 163 participants not treated with metformin v. 10 163 treated with metformin) and sensitivity analyses using inverse probability of treatment weighting and competing risk regression showed similar results.

Interpretation: Metformin use in patients with type 2 diabetes mellitus was associated with a significantly reduced risk of total joint replacement. Randomized controlled clinical trials in patients with osteoarthritis are warranted to determine whether metformin is effective in decreasing the need for joint replacement.

Figure 1:

Study flowchart. Note: DM = diabetes mellitus, LHID = the Longitudinal Health Insurance Database, OA = osteoarthritis, PSM = propensity-score matching, PTDM = prescription time-distribution matching, THR = total hip replacement, TKR = total knee replacement. *Index date for metformin users was 3 months after first prescription of metformin. †Participants who did not use metformin were individually matched with those who did use metformin by PTDM.

Figure 2:

Cumulative probability of (A) total hip or knee replacement, (B) total knee replacement and (C) total hip replacement in a prescription time-distribution matched (PTDM) cohort of participants who did or did not use metformin, and of (D) total hip or knee replacement, (E) total knee replacement and (F) total hip replacement in a propensity-score matched (PSM) cohort of participants who did or did not use metformin. We conducted log-rank tests to compare the distributions of cumulative incidence curves, estimated by the Kaplan–Meier method, between the 2 groups (metformin nonusers v. metformin users).