Impact of Japanese regulatory action on metformin-associated lactic acidosis in type II diabetes patients
- 373 Downloads
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.
KeywordsBoxed 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.
- 8.Qaseem A, Humphrey LL, Sweet DE, Starkey M, Shekelle P. Clinical Guidelines Committee of the American College of Physicians. Oral pharmacologic treatment of type 2 diabetes mellitus: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2012;156:218–31.CrossRefPubMedGoogle Scholar
- 14.Pharmaceuticals and Medical Devices Agency (PMDA). Pharmaceuticals and Medical Devices Safety Information No. 290. April 2012. http://www.pmda.go.jp/english/service/pdf/precautions/PMDSI-290.pdf. Accessed 3 Mar 2014.
- 17.Platt R, Carnahan RM, Brown JS, Chrischilles E, Curtis LH, Hennessy S, et al. The US food and drug administration’s mini-sentinel program: status and direction. Pharmacoepidemiol Drug Saf. 2012;21:Suppl 1:1–8.Google Scholar
- 19.Hanatani T, Sai K, Tohkin M, Segawa K, Antoku Y, Nakashima N, et al. Evaluation of two Japanese regulatory actions using medical information databases: a “Dear Doctor” letter to restrict oseltamivir use in teenagers, and label change caution against co-administration of omeprazole with clopidogrel. J Clin Pharm Ther. 2014;14(39):361–7.CrossRefGoogle Scholar
- 20.Hanatani T, Sai K, Tohkin M, Segawa K, Kimura M, Hori K, et al. A detection algorithm for drug-induced liver injury in medical information databases using the Japanese diagnostic scale and its comparison with the Council for International Organizations of Medical Sciences/the Roussel Uclaf Causality Assessment Method scale. Pharmacoepidemiol Drug Saf. 2014;23(9):984–8.CrossRefPubMedGoogle Scholar
- 23.Yang D, Dalton JE. A unified approach to measuring the effect size between two groups using SAS®. In: Proceedings of SAS Global Forum 2012, 22–25 April 2012, Orlando, Florida: Cary: SAS Institute, 2012.Google Scholar