International Journal of Clinical Pharmacy

, Volume 37, Issue 3, pp 537–545 | Cite as

Impact of Japanese regulatory action on metformin-associated lactic acidosis in type II diabetes patients

  • Tadaaki Hanatani
  • Kimie Sai
  • Masahiro Tohkin
  • Katsunori Segawa
  • Yoshiro Saito
Research Article


Background The March 2012 regulatory action issued by the Japanese government signalled the rare but serious complication of lactic acidosis that can occur during metformin treatment, especially with the high dose formulation, h-metformin, and in those above 75 years old. Objective To assess quantitatively the impact of this regulatory action on patient management using a medical information database (MID). Setting Eight hospitals in Japan. Method Using a commercial MID, we collected data on adult outpatients treated with metformin, including h-metformin, during a 2-year study period between April 1, 2011 and March 31, 2013. The 2-year study period spanned 1 year before and after the regulatory action. The frequencies of lactate measurement in all metformin users, h-metformin users, and new users (started on metformin during the study period) were compared between the periods before and after the regulatory action, using generalized estimating equations. Trends in metformin prescription for elderly patients were analysed month-wise by regression analysis using an interrupted time series design. Main outcome measure The rate ratios (RR) of lactate testing before and after the regulatory action. Results Of 4347 metformin users, 784 patients were >75 years old. A significant increase in lactate measurement was observed after the regulatory action than before in the overall study population, with an adjusted RR of 2.14 (95 % confidence interval 1.24–3.68). No significant change was found in h-metformin users and new users because lactate measurements were being performed as frequently in these subgroups before the regulatory action. There were no meaningful changes in the proportion of elderly metformin users in the overall population. Conclusion The regulatory action led to increased lactate measurement in the overall metformin users, but did not affect metformin prescription rate in the elderly patients. Our findings probably reflect the doctors’ judgement that the benefits of metformin use outweigh the risk of lactic acidosis if lactate testing is performed regularly.


Boxed warning Drug safety Japan Lactic acidosis Medical information Metformin Regulatory action 



The authors would like to thank Ms. Kaori Ota and Mr. Masaki Nakamura from Medical Data Vision Co., Ltd., Tokyo, Japan, for their technical support.


The study was supported in part by the Health and Labour Sciences Research grants from the Ministry of Health, Labour and Welfare, Japan (H23-iyaku-shitei-025, H26-iyakuB-ippan-007, H26-chikyukiboB-ippan-002).

Conflicts of interest

All authors have no conflict of interest relevant to this study.


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Copyright information

© Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie 2015

Authors and Affiliations

  • Tadaaki Hanatani
    • 1
    • 2
  • Kimie Sai
    • 1
  • Masahiro Tohkin
    • 2
  • Katsunori Segawa
    • 1
  • Yoshiro Saito
    • 1
  1. 1.Division of Medicinal Safety ScienceNational Institute of Health SciencesTokyoJapan
  2. 2.Department of Regulatory Science, Graduate School of Pharmaceutical SciencesNagoya City UniversityNagoyaJapan

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