Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Drug Saf. 2013 Aug;36(8):605-15. doi: 10.1007/s40264-013-0068-0.
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.
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.
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.
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.
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.
西他列汀是首个二肽基肽酶-4（DPP-4）抑制剂类的新型抗高血糖药物（OHD），于 2009 年 12 月在日本上市。2010 年 4 月，发布了关于严重低血糖事件风险的安全性警示，建议在同时接受磺酰脲类药物和西他列汀治疗的患者中，减少磺酰脲类药物（即格列美脲、格列本脲[glyburide]或格列齐特）的剂量。
使用日本药房处方收据数据进行倾向评分匹配队列研究，以确认在安全性警示发布前后，接受西他列汀治疗的患者的 OHD 处方行为是否发生了报告的变化。
从 300 家药店随机抽取了 2009 年 12 月至 2010 年 12 月期间日本约 6500 家医疗机构的处方数据，涵盖了 82064 名接受 OHD 治疗的患者，共 629955 张处方。在安全性警示前，同时接受磺酰脲类药物和西他列汀治疗的患者（1788 名患者/3576 张处方）被指定为 DPP-4 组。在警示前，仅接受磺酰脲类药物而未接受西他列汀治疗的患者（30963 名患者/61926 张处方）被指定为非 DPP-4 组。采用倾向评分匹配，将年龄、性别、OHD 类型、二甲双胍使用情况、测量基线期的开方者类型和开方者机构类型等基线特征进行匹配，为每个组匹配 1783 名患者。在匹配队列中，进行逻辑回归分析以比较警示前后的处方趋势。本研究的主要结局测量指标是为 DPP-4 和非 DPP-4 患者开的格列美脲、格列本脲或格列齐特的剂量。
在倾向评分匹配队列中，DPP-4 患者中格列美脲剂量>2mg 的比例从第 1 期（警示前）的 45.8%降至第 2 期（警示后）的 37.5%（比值比[OR]0.71；95%置信区间[CI]0.579-0.870），而非 DPP-4 患者在匹配队列中的比例从 28.9%变为 29.5%（OR 1.03；95%CI 0.868-1.215）。DPP-4 患者的格列美脲平均处方剂量也从第 1 期（警示前）的 2.79±1.81mg 降至第 2 期（警示后）的 2.38±1.71mg（p<0.0001），而非 DPP-4 患者的相应变化从 2.01±1.56mg 变为 2.01±1.54mg（p=0.94）。两组之间的平均处方剂量差异在两个时期均具有统计学意义。格列本脲和格列齐特的处方模式变化趋势也相似。安全性警示后，DPP-4 患者的磺酰脲类药物剂量减少与不良事件报告的减少相吻合。
我们的结果表明，采用倾向评分匹配来控制个体患者和开方者的基线特征是一种有用的方法，可以避免选择偏差和混杂效应，从而评估事件对处方行为的影响。本病例匹配研究表明，磺酰脲类药物的处方行为在西他列汀安全性警示后发生了显著变化。在 DPP-4 患者中，磺酰脲类药物的剂量在警示后显著减少，但在非 DPP-4 患者中没有减少。我们的发现应该有助于评估和改善其他监管安全警示的有效性。
