Abstract
INTRODUCTION: Patients with type 2 diabetes (T2D) in Japan are prescribed a lower dose of metformin that their counterparts in Western countries due to concerns for the risk of lactic acidosis incidence. Here we report our study on the association between high-dose metformin administration and the incidence of lactic acidosis in Japanese patients with T2D. METHODS: A Japanese claims database (April 2008-November 2018) was analyzed. Factors associated with the incidence of lactic acidosis were first identified from the database records by conducting a case-control study, and these were then used as confounding factors in subsequent analyses. The association between high-dose metformin administration (≥ 1000 mg/day) and the incidence of lactic acidosis was compared with that between low-dose metformin (< 1000 mg/day) or no metformin administration and lactic acidosis incidence by using the following approaches: a logistic regression analysis hypothesizing that metformin-associated lactic acidosis is short term; a time-dependent proportional hazard model hypothesizing that the influence of metformin is cumulative; and a case-control study in which lactic acidosis incidence was the case and metformin administration within 3 months prior to the incidence of lactic acidosis (or corresponding date for the control) was the exposure. RESULTS: Prescriptions for biguanide and vitamin B complex and volume depletion were identified as factors associated with the incidence of lactic acidosis. The incidence rate was higher in patients prescribed metformin than in those not receiving metformin; however, it was not higher in those prescribed high-dose metformin compared to those prescribed low-dose metformin. The estimated regression coefficient for high-dose metformin administration was 0.816 (p < 0.001); this was not higher than those for low-dose metformin (1.047), vitamin B complex (2.725) and volume depletion (3.301). The time-dependent proportional hazard analysis did not indicate any effect of metformin prescription. CONCLUSION: The results suggest an association between metformin administration and the incidence of lactic acidosis, but an increase in the incidence rate of lactic acidosis was not observed in those patients receiving high-dose metformin compared to those receiving low-dose metformin.