Abstract
Background
Sitagliptin, the first of a new class of dipeptidyl peptidase-4 (DPP-4)-inhibitory oral antihyperglycaemic drugs (OHDs), was introduced in Japan in December 2009. In April 2010 a safety alert was issued regarding the risk of serious hypoglycaemic events, and prescribers were recommended to reduce the dose of sulfonylurea (i.e. glimepiride, glibenclamide [glyburide] or gliclazide) in patients receiving a combination of sulfonylurea and sitagliptin.
Objective
A propensity score-matched cohort study was performed using Japanese pharmacy prescription receipt data for OHDs in order to confirm reported changes in OHD prescription behaviour for patients receiving sitagliptin before and after the safety alert.
Methods
Prescription data from about 6,500 medical institutions throughout Japan during December 2009 to 31 December 2010 were randomly collected from 300 pharmacies, covering 82,064 patients with 629,955 prescriptions for OHDs. Patients who had received a sulfonylurea and sitagliptin (1,788 patients/3,576 prescriptions) before the safety alert were designated as the DPP-4 group. Patients who had received a sulfonylurea but not sitagliptin (30,963 patients/61,926 prescriptions) before the alert were designated as the non-DPP-4 group. Propensity score matching was employed to match baseline characteristics, such as age, sex, type of OHD, metformin use, type of prescribers period for measuring baseline period and type of prescribers’ institutions, for 1,783 patients from each group. In the matched cohort, logistic regression analysis was conducted to compare prescription trends before and after the alert. The primary outcome measure of this study was dose of glimepiride, glibenclamide or gliclazide prescribed for DPP-4 and non-DPP-4 patients.
Results
In the propensity score-matched cohort, the proportion of glimepiride dose >2 mg of DPP-4 patients was reduced from 45.8 % in Period 1 (before the alert) to 37.5 % in Period 2 (after the alert) (odds ratio [OR] 0.71; 95 % CI 0.579–0.870), whereas in the case of non-DPP-4 patients the proportion was changed from 28.9 % to 29.5 % in the matched cohort (OR 1.03; 95 % CI 0.868–1.215). The mean prescribed glimepiride dose in DPP-4 patients was also reduced from 2.79 ± 1.81 mg in Period 1 (before the alert) to 2.38 ± 1.71 mg in Period 2 (after the alert) [p < 0.0001], whereas the corresponding change in the case of non-DPP-4 patients was from 2.01 ± 1.56 mg to 2.01 ± 1.54 mg (p = 0.94). The difference between the mean prescribed doses in the two groups was statistically significant in both periods. Similar trends of prescription pattern changes were seen for glibenclamide and gliclazide. The reduction of prescribed sulfonylurea dose in DPP-4 patients following the safety alert coincided with a decrease of adverse event reports.
Conclusion
Our results indicate that propensity score matching to control for baseline characteristics of individual patients and prescribers is a useful approach to avoid selection bias and confounding effects in evaluating the influence of an event on prescription behaviour. This case-matched study indicated that sulfonylurea prescription behaviour changed significantly after the sitagliptin safety alert. There was a significant reduction in sulfonylurea dose after the alert in DPP-4 patients, but not in non-DPP-4 patients. Our findings should be helpful for assessing and improving the effectiveness of other regulatory safety alerts.
References
Iwamoto Y, et al. Dose-ranging efficacy of sitagliptin, a dipeptidyl peptidase-4 inhibitor, in Japanese patients with type 2 diabetes mellitus. Endocr J. 2010;57(5):383–94.
Iwamoto Y, et al. Efficacy and safety of sitagliptin monotherapy compared with voglibose in Japanese patients with type 2 diabetes: a randomized, double-blind trial. Diabetes Obes Metab. 2010;12(7):613–22.
Hermansen K, Kipnes M, Luo E, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab. 2007;9:733–45.
Karagiannis T, et al. Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis. BMJ. 2012;344:e1369.
Committee on proper use of incretin and SUs (Japan Diabetes Society): recommendation. 2010. Available from URL: http://www.jds.or.jp/uploads/photos/595.pdf. Accessed 20 Dec 2012.
Pharmaceutical and Food Safety Bureau, MHLW. Safety division notification no. 427001. 2010. Available from URL: http://www.info.pmda.go.jp/kaitei/kaitei20100427.html. Accessed 20 Dec 2012.
Ministry of Health, Labour and Welfare (MHLW). Pharmaceuticals and Medical Devices Safety information no. 269. May 2010. Available from URL: http://www1.mhlw.go.jp/kinkyu/iyaku_j/iyaku_j/anzenseijyouhou/269.pdf. Accessed 20 Dec 2012.
Sato D, et al. Impact of the sitagliptin alert on prescription of oral antihyperglycemic drugs in Japan. Int J Clin Pharm. 2012;34(6):917–24.
Arai K, et al. Present status of insulin therapy for type 2 diabetes treated by general practitioners and diabetes specialists in Japan: third report of a cross-sectional survey of 15,652 patients. J Diabetes Invest. 2012;3(4):396–401.
Austin PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res. 2011;46(3):399–424.
Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika. 1983;70(1):41–55.
D’Agostino RB Jr. Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med. 1998;17:2265–81.
Parsons LS. Reducing bias in a propensity score matched-pair sample using Greedy matching techniques. In: Proceedings of the Twenty-Sixth Annual SAS Users Group International Conference, Long Beach, California; 2001 Apr 22–25. Cary: SAS Institute; 2001.
The Diabetes Strategic Research Group, Health Science Research Fund (MHLW), Japan. Diabetes standard treatment manual. 2011. Available from URL: http://www.ncgm-dmic.jp/doc/diabetes_treatment_manual.pdf. Accessed 26 Jul 2012.
Fukushima M, et al. Insulin secretion capacity in the development from normal glucose tolerance to type 2 diabetes. Diabetes Res Clin Pract. 2004;66(Suppl. 1):S37–43.
Nathan DM, et al. Relationship between glycated haemoglobin levels and mean glucose levels over time. Diabetologia. 2007;50:2239–44.
Kaneko T, et al. Clinical study on glimepiride (HOE 409) on non-insulin dependent diabetes mellitus patients. J Clin Ther Med. 1993;9(4):809–25.
Cabana MD et al. Why don’t physicians follow clinical practice guidelines? A framework for improvement. JAMA 1999;282:1458–65.
Acknowledgements
The authors thank the Japan Medical Information Research Institute Inc. for data collection and Dr. Hirotsugu Suwanai, Diabetes and Metabolic Medicine, Faculty of Medicine, University of Tokyo, for medical advice.
Funding
No sources of funding were used to conduct this study or prepare this manuscript.
Conflicts of interest
Dr. Kimura and Dr. Masuda are employed by the University of Tokyo, with endowment funding from several companies, including Daiichi Sankyo Co., Ltd. and Chugai Pharmaceutical Co., Ltd. Dr. D. Sato and Dr. Y. Sato declare no conflicts of interest.
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Sato, D., Sato, Y., Masuda, S. et al. Effects of a Sitagliptin Safety Alert on Prescription Behaviour for Oral Antihyperglycaemic Drugs: A Propensity Score-Matched Cohort Study of Prescription Receipt Data in Japan. Drug Saf 36, 605–615 (2013). https://doi.org/10.1007/s40264-013-0068-0
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DOI: https://doi.org/10.1007/s40264-013-0068-0