Does metformin protect against osteoarthritis? An electronic health record cohort study

Problem

Obesity is a major risk factor for osteoarthritis (OA) whilst there is some evidence that diabetes also increases risk. Statin treatment for primary or secondary prevention of vascular disease has been found to be associated with a reduction in some manifestations of clinical OA. Metformin is a common treatment for type 2 diabetes and has previously been investigated to determine whether it is associated with a reduction in the risk of cardiovascular events and all-cause mortality, but with conflicting findings. We hypothesised that patients with type 2 diabetes treated with metformin may show a reduced risk of OA compared to people with type 2 diabetes not so treated. To investigate this, we conducted a longitudinal analysis using routinely recorded electronic health record data.

Approach

This was a cohort study set within the Consultations in Primary Care Archive (CiPCA), a database of recorded primary care information in North Staffordshire. Patients at 13 general practices with recorded type 2 diabetes in the baseline period (2002-2003) and no record of osteoarthritis in the previous 2 years were identified. Exposure was defined as a prescription for metformin and outcome was an osteoarthritis diagnosis recorded during follow-up (maximum ten years). Cox’s proportional hazard models with Gamma frailty term were fitted, first using baseline exposure status only, and then allowing exposure to be time-dependent. Models were adjusted for age, gender, deprivation, and comorbidity defined by number of other prescription drugs.

Findings

There were 3217 participants with type 2 diabetes eligible for inclusion. In those prescribed metformin during the 2-year baseline period, the incidence of OA during follow-up was 301.3 per 10,000 person years compared to 314.6 for those not prescribed metformin. There was no association between OA and prescribed metformin treatment at baseline (adjusted HR: 1.02, 95% CI: 0.90, 1.14). A similar non-significant association was found when allowing exposure status of prescription of metformin to vary over time.Age (HR: 1.01 per year, 95% CI: 1.01, 1.02), female gender (HR: 1.28, 95% CI: 1.09, 1.52), and greater comorbidity (14+ drugs versus 0-5) (HR: 2.18, 95% CI: 1.71, 2.79) were associated with OA diagnosis during follow-up. There was significant heterogeneity between GP practices.

Consequences

There was no identified association between prescription of metformin and risk of OA in patients with type 2 diabetes though we were not able to adjust for obesity as a confounder. Consistent with previous literature we identified an increase in risk with increasing age and for females. We also identified a gradient of increasing hazard for OA against increasing numbers of drug types prescribed. Further research may assess the relationship of dosage and duration of metformin treatment with OA, and associations with site-specific OA.