Layton Deborah, Coughtrie Abigail L, Qayum Naseer, Shakir Saad A W
Drug Safety Research Unit, Bursledon Hall, Blundell Lane, Southampton, SO31 1AA, UK.
Associate Department of the School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK.
Drug Saf. 2016 Nov;39(11):1093-1104. doi: 10.1007/s40264-016-0451-8.
Clinical trials have identified peripheral oedema (PO) as an adverse event of vildagliptin (an oral anti-diabetic drug [OAD]). A post-marketing study (PMS) was conducted to advance the understanding of vildagliptin use and particular safety concerns identified within the risk-management plan. PMS objectives included comparing the hazards between vildagliptin monotherapy and combination therapy for selected a priori identified risks, including PO.
This study was a per-protocol supplementary analysis to investigate the pattern of onset and effect of vildagliptin combination therapy on PO risk.
The PMS used an observational cohort design. OAD exposure, selected risk factors and outcome data were collected from general practitioners in England regarding vildagliptin users for the 6-month period after starting treatment. Data analysis comprised univariate case/non-case analysis, time-to-onset analysis and Cox proportional hazard models to estimate hazard ratios (HR) of PO adjusting for selected patients' baseline characteristics.
The study cohort included 4828 patients (median age 63 years; interquartile range [IQR] 54-71), 2692 of whom were male (55.8 %). The crude cumulative hazard of PO was 19.09 cases (95 % confidence interval [CI] 13.54-26.10) per 1000 person-years; 50 % of cases occurred during the first 34 days of treatment. A significantly faster time to PO onset was observed in patients prescribed concomitant sulfonylureas versus other treatment combinations (log rank test [LRT] p = 0.0365); in patients with a prior history of PO (LRT p < 0.001), arrhythmia (LRT p = 0.0003) or hypertension (LRT p = 0.0125); and in patients aged ≥60 years (LRT p = 0.0047). Similarly, the case/non-case univariate analysis indicated that patients with PO were older; had a higher prevalence of a history of either arrhythmia, hypertension or PO; and frequently used a sulfonylurea in combination. In the hazard function analysis, only sex and prior PO history had a profound effect on risk of PO after starting vildagliptin. Furthermore, effect modification was observed between sex and prior PO history; in male patients of average age (62 years), the HR was 12.84 (95 % CI 4.96-33.23); in females, it was 1.44 (95 % CI 0.32-6.40).
In this planned supplementary analysis, the findings suggest that PO occurred most frequently within 1 month after starting treatment with vildagliptin, and previous PO history and male sex in elderly patients were important predictors of this risk. The observation that concomitant use of a sulfonylurea may also increase PO risk early after starting treatment should be taken into consideration if prescribing OADs in combination with vildagliptin.
临床试验已确定外周水肿（PO）是维格列汀（一种口服抗糖尿病药物[OAD]）的不良事件。开展了一项上市后研究（PMS），以加深对维格列汀使用情况以及风险管理计划中确定的特定安全问题的理解。PMS的目标包括比较维格列汀单药治疗与联合治疗在选定的预先确定风险（包括PO）方面的危害。
本研究是一项按方案补充分析，旨在调查维格列汀联合治疗对PO风险的发病模式和影响。
PMS采用观察性队列设计。从英国全科医生处收集了开始治疗后6个月内维格列汀使用者的OAD暴露情况、选定的风险因素和结局数据。数据分析包括单变量病例/非病例分析、发病时间分析和Cox比例风险模型，以估计在调整选定患者基线特征后PO的风险比（HR）。
研究队列包括4828名患者（中位年龄63岁；四分位间距[IQR]54 - 71），其中2692名男性（55.8%）。PO的粗累积发病率为每1000人年19.09例（95%置信区间[CI]13.54 - 26.10）；50%的病例发生在治疗的前34天内。与其他治疗组合相比，联用磺脲类药物的患者PO发病时间明显更快（对数秩检验[LRT]p = 0.0365）；有PO既往史的患者（LRT p < 0.001）、心律失常患者（LRT p = 0.0003）或高血压患者（LRT p = 0.0125）；以及年龄≥60岁的患者（LRT p = 0.0047）。同样，病例/非病例单变量分析表明，PO患者年龄更大；心律失常、高血压或PO既往史的患病率更高；并且经常联用磺脲类药物。在风险函数分析中，开始使用维格列汀后，只有性别和既往PO史对PO风险有显著影响。此外，观察到性别与既往PO史之间存在效应修正；在平均年龄（62岁）的男性患者中，HR为12.84（95%CI 4.96 - 33.23）；在女性患者中，HR为1.44（95%CI 0.32 - 6.40）。
在这项计划的补充分析中，研究结果表明，PO最常发生在开始使用维格列汀治疗后的1个月内，既往PO史和老年男性是该风险的重要预测因素。如果联用OAD与维格列汀，应考虑到联用磺脲类药物也可能在开始治疗后早期增加PO风险这一观察结果。
