Protective Effect of Metformin Against Thyroid Cancer Development: A Population-Based Study in Korea

Background: Metformin, the most widely used drug for type 2 diabetes, has recently attracted attention with regard to its antitumor activity. However, clinical studies have yielded conflicting results regarding the association between metformin and thyroid cancer development, despite its antitumor effect in preclinical studies. Methods: This is a retrospective cohort study using the Korean National Health Insurance claim database. Matched populations of 128,453 metformin users and 128,453 non-users were analyzed for thyroid cancer incidence. Metformin users were categorized into lowest, middle, and highest tertiles according to cumulative dose or duration of metformin therapy. Results: Thyroid cancer developed in 340 (0.26%) metformin users and 487 (0.38%) non-users during a mean follow-up of 7.2 years (hazard ratio = 0.69 [confidence interval 0.60-0.79]; p < 0.001). The incidence of thyroid cancer per 10 ⁵ person-years was 51.6 in metformin non-users. For metformin users, the incidence was 84.5 for <529,000 mg, 20.6 for 529,000-1,007,799 mg, and 6.3 for >1,007,799 mg; 86.3 for <1085 days, 20.3 for 1085-2094 days, and 4.7 for >2094 days for duration of therapy. The hazard ratio for thyroid cancer decreased significantly in metformin users as a function of dose and duration of metformin therapy. Conclusions: Metformin appears to be associated with a preventive effect on thyroid cancer development in a nationwide population-based study, but is not effective in the early phase of treatment. Considering the increasing prevalence of obesity and the role of insulin resistance in the development of cancer, metformin might be the preferred treatment for its dual anti-diabetic and antitumor effects.