A Systematic Assessment of Cardiovascular Outcomes in the Saxagliptin Drug Development Program for Type 2 Diabetes
A Systematic Assessment of Cardiovascular Outcomes in the Saxagliptin Drug Development Program for Type 2 Diabetes
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DOI：
10.3810/pgm.2010.05.2138
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发表时间：
2010-05-01
影响因子：
4.2
通讯作者：
Mahaffey, Kenneth W.
中科院分区：
文献类型：
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作者：
Frederich, Robert;Alexander, John H.;Mahaffey, Kenneth W.
目的：本研究的目的是评估所有8个评价萨格列汀治疗2型糖尿病患者的随机2/3期试验中心血管事件的相对风险(RR)。方法：研究人员通过标准的不良事件报告程序报告心血管事件(死亡、心肌梗死、中风、血管重建术和心脏缺血)，并进行系统识别。使用由独立临床事件委员会(CEC)预先指定的终点定义，对所有死亡、失误和中风进行特殊后盲判定。结果：共纳入4607例患者(萨格列汀[2.5-100 mg/d]治疗3356例，对照组1251例，安慰剂656例，二甲双胍328例，格列本脲治疗267例)。中位年龄分别为54岁(萨格列汀)和55岁(四分位数范围，各47-61岁)；51%为女性，73%为白人，52%为高血压，44%有高胆固醇血症，39%有吸烟史，20%有一级家族成员有早发冠心病，12%有心血管疾病既往病史。61名患者发生了心血管事件(38例[1.1%]，萨格列汀；23例[1.8%]，对照组)，研究人员报告了41名患者的心血管死亡/心肌梗死/中风事件：23例(0.7%)，萨格列汀；18例(1.4%)，对照组(相对风险，95%可信区间[CI]，0.44[0.24-0.82])。CEC回顾了147名有潜在心血管事件的患者，共确定了40名心血管死亡/心肌梗死/中风患者：22名(0.7%)，萨格列汀；18名(1.4%)，对照(RR，0.43[0.23-0.80])。心血管死亡、心肌梗死和卒中的构成比(萨格列汀与对照组)分别为7(0.2%)比10(0.8%)，8(0.2%)比8(0.6%)，11(0.3%)比5(0.4%)。结论：在广泛的药物开发计划中，随机分配萨格列汀的患者没有观察到心血管死亡/心肌梗死/中风的风险增加。尽管这一系统性综述具有固有的和重要的局限性，但数据支持使用saxagliptin可能减少心血管事件。萨格列汀具有心血管保护作用的假设将在一项大型随机临床结果试验中进行检验，该试验评估萨格列汀与标准治疗相比，对心血管事件风险增加的2型糖尿病患者的疗效。
Objective: The objective was to assess the relative risk (RR) for cardiovascular (CV) events across all 8 randomized phase 2/3 trials evaluating saxagliptin in patients with type 2 diabetes mellitus. Methods: Cardiovascular events (death, myocardial infarction [MI], stroke, revascularization procedures, and cardiac ischemia) were reported by investigators through standard adverse event reporting procedures and were systematically identified. Post hoc blinded adjudication of all deaths, MIs, and strokes was performed using prespecified endpoint definitions by an independent clinical events committee (CEC). Results: A total of 4607 randomized and treated patients (n = 3356 treated with saxagliptin [2.5-100 mg/d]; n = 1251, comparator [n = 656, placebo; n = 328, metformin; n = 267, uptitrated glyburide]) were included. The median ages were 54 years (saxagliptin) and 55 years (comparator) (interquartile range, 47-61 each); 51% were female, 73% were white, 52% were hypertensive, 44% had hypercholesterolemia, 39% had a smoking history, 20% had a first-degree family member with premature coronary heart disease, and 12% had prior CV disease. Cardiovascular events were experienced by 61 patients (38 [1.1%], saxagliptin; 23 [1.8%], comparator), and CV death/MI/stroke events were reported by investigators in 41 patients: 23 (0.7%), saxagliptin; 18 (1.4%), comparator (relative risk, 95% confidence interval [CI], 0.44 [0.24-0.82]). The CEC reviewed 147 patients with potential CV events and identified a total of 40 patients with CV death/MI/stroke: 22 (0.7%), saxagliptin; 18 (1.4%), comparator (RR, 0.43 [0.23-0.80]). Component proportions for CV death, MI, and stroke were (saxagliptin vs comparator): 7 (0.2%) vs 10 (0.8%), 8 (0.2%) vs 8 (0.6%), and 11 (0.3%) vs 5 (0.4%), respectively. Conclusion: No increased risk of CV death/MI/stroke was observed in patients randomly assigned saxagliptin across a broad drug development program. Although this systematic overview has inherent and important limitations, the data support a potential reduction in CV events with saxagliptin. The hypothesis of CV protection with saxagliptin will be tested prospectively in a large randomized clinical outcome trial evaluating saxagliptin compared with standard of care in patients with type 2 diabetes at increased risk for CV events.