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20项研究的合并分析显示沙格列汀不会导致主要不良心血管事件增加
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20项研究的合并分析显示沙格列汀不会导致主要不良心血管事件增加


20-study analysis finds no MACE increase with saxagliptin


5月15日,在拉斯维加斯召开的美国临床内分泌医师学会(AACE)2014年年会上报告的一项对20项2型糖尿病研究的合并分析显示,沙格列汀治疗不会导致主要不良心血管事件(MACE)或心衰风险增加。


分析还发现,沙格列汀治疗与MACE终点各个成分之间也没有相关性,MACE是心血管(CV)死亡、心肌梗死(MI)和卒中组成的复合终点。


沙格列汀是一种口服二肽基肽酶-4(DPP-4)抑制剂,2009年经美国食品药品管理局(FDA)批准作为饮食和运动的辅助治疗用于改善2型糖尿病成年患者的血糖控制情况。


这项研究分析了20项随机对照试验中与沙格列汀相关的MACE裁决报告以及涉及心衰的研究者报告,这些研究评估的都是沙格列汀单药治疗或者添加治疗,共涉及9,156例2型糖尿病患者。与2013年发表的沙格列汀用于糖尿病患者的血管转归评估-心肌梗死溶栓53(SAVOR-TIMI 53研究)不同,该研究显示既往有CV病史或存在多个CV危险因素的患者因心衰住院的风险会增加,而在这20项研究中2型糖尿病患者出现CV事件的风险较低。

 


SAVOR-TIMI 53研究在16,000多例2型糖尿病合并心血管疾病或存在冠心病危险因素的患者中评估了沙格列汀的心血管安全性,结果显示在2年的中位随访期内沙格列汀治疗与出现缺血性主要复合终点(CV死亡、MI或缺血性卒中)的风险增加或减少均无关。但是沙格列汀治疗与因心衰住院的风险显著增加相关(危险比,1.27)(N. Engl. J. Med. 2013;369:1317-26)。FDA在2014年1月发出的安全警告中表示,鉴于该研究发现沙格列汀可能导致患者因心衰住院的风险增加,FDA已经要求沙格列汀的生产商评估使用该药与心衰之间“可能存在的相关性”。


这项纳入了20项研究的分析共涉及43份沙格列汀组的MACE报告和31份对照组的MACE报告。分析结果显示,沙格列汀组的MACE发生率(IR,定义为每100患者-年的事件数)为0.85/100患者-年,对照组为1.12/100患者-年。IR比值(定义为沙格列汀组患者的事件数除以对照组的事件数)为0.74。危险比为0.75,提示沙格列汀不会导致MACE风险增加。


有11项研究评估的是沙格列汀作为二甲双胍的添加治疗用于5,171例患者;针对这部分研究的亚组分析显示两组的MACE发生率也是相似的:沙格列汀组和对照组分别为0.79/100患者-年和0.85/100患者-年,IR比值为0.93。


在这20项研究中,从MACE终点的各个成分来看,沙格列汀组与对照组之间也没有统计学差异;沙格列汀组和对照组分别有21例和18例患者出现了心衰,IR比值为0.55。


与SAVOR-TIMI 53研究(在2型糖尿病合并心血管疾病或存在多个心血管危险因素的患者中分析MACE)一样,这项纳入了20项研究、以2型糖尿病一般人群为研究对象的合并分析也表明,沙格列汀与MACE或其单个成分或心衰风险增加均无关。


美国加州大学洛杉矶分校的医学教授Sanjay Kaul博士在接受采访时说,这项合并分析的结果“多少让人安心,提示了心血管事件风险较低的2型糖尿病患者使用沙格列汀不会导致MACE风险增加”,也没有达到FDA建议的抗糖尿病药物不可接受的风险阈值(危险比,1.3)。不过,他也补充道:“遗憾的是,即便是以风险较低的人群为研究对象,血糖控制情况改善也没能减少大血管事件。” 此外,该研究的“心衰事件数量还不足以可靠地判定该患者人群的心衰风险。” Kaul博士是去年评估罗格列酮(文迪雅)心血管安全性的FDA顾问小组会议的专家组成员,他没有参加此次年会。


5名作者中有3名是百时美-施贵宝公司的员工;另外2名是阿斯利康公司的员工。Kaul博士声明没有与沙格列汀相关的利益冲突;只是与其他公司生产的糖尿病治疗药物存在一些利益关系。


沙格列汀由阿斯利康公司生产销售,商品名为安立泽。




 




FROM AACE 2014


VITALS


Major finding: The incidence of MACE composite endpoint was similar among patients treated with saxagliptin (0.85/100 person-years) and controls (1.12/100 person-years) in 20 saxagliptin studies of patients with type 2 diabetes at a lower cardiovascular risk.


Data source: A pooled analysis of 20 randomized, controlled trials of saxagliptin as monotherapy or as add-on therapy in about 9,000 patients with type 2 diabetes compared the rates of the MACE endpoint and heart failure in patients on saxagliptin and controls.


Disclosures: Three of the five authors are employed by Bristol-Myers Squibb; two are employed by AstraZeneca.


Treatment with saxagliptin was not associated with an increased risk of major adverse cardiovascular events or heart failure in a pooled analysis of 20 studies of patients with type 2 diabetes.



The analysis also found no association with saxagliptin therapy and individual components of the major adverse cardiovascular events (MACE) endpoint, a composite of cardiovascular death, myocardial infarction, and stroke, according to a study being presented at the meeting. The results were released May 15 at the annual meeting of the American Association of Clinical Endocrinologists in Las Vegas.



Saxagliptin, a dipeptidyl peptidase–4 (DPP-4) inhibitor taken orally, was approved by the Food and Drug Administration in 2009 as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.


The study evaluated adjudicated reports of MACE and investigator reports of heart failure associated with saxagliptin in 20 studies of saxagliptin as monotherapy or as add-on therapy in 9,156 patients with type 2 diabetes. Unlike the SAVOR-TIMI 53 study (Saxagliptin Assessment of Vascular Outcomes Recorded in Patient With Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53) study, published in 2013, which found an increased risk of heart failure hospitalizations in patients with prior CV disease or multiple CV risk factors, the patients with type 2 diabetes enrolled in the 20 studies were at lower risk for CV events.



In the SAVOR-TIMI 53, which evaluated the drug’s cardiovascular safety in more than 16,000 patients with type 2 diabetes and established cardiovascular disease or risk factors for CHD, treatment with saxagliptin was not associated with an increased or reduced risk of ischemic risk for the composite of CV death, MI, or ischemic stroke, the primary endpoint, over a median of 2 years. But it was associated with a significantly greater risk of being hospitalized for heart failure (hazard ratio, 1.27) (N. Engl. J. Med. 2013;369:1317-26). In a January 2014 safety alert, the FDA said that the agency had requested the manufacturer of saxagliptin study “a possible association” between the use of the drug and heart failure, because of the increased risk of heart failure hospitalizations in that study.


In the 20-study analysis, based on 43 MACE reports in patients treated with saxagliptin and 31 MACE reports among controls, the MACE incidence rate (IR) – the number of events per 100 person-years – was 0.85/100 person-years for those on saxagliptin and 1.12/100 person-years for the controls. The IR ratio (the number of reports among saxagliptin-treated patients divided by the number of reports among the controls), was 0.74. The hazard ratio was 0.75, which suggests there is no increased risk of MACE associated with saxagliptin.


In a subset of 11 studies that evaluated saxagliptin as add-on therapy to metformin in 5,171 patients, the incidence rates were similar: 0.79/100 person-years for those on saxagliptin and 0.85/100 person-years for controls, with an IR ratio of 0.93.


In the 20 studies, the components of the MACE endpoint were also not statistically significantly different between those on saxagliptin and controls, and 21 patients on saxagliptin and 18 controls had heart failure, with an IR ratio of 0.55, he said.


Consistent with the SAVOR-TIMI 53 study, which analyzed MACE in patients with type 2 diabetes and cardiovascular disease or multiple cardiovascular risk factors, this 20-trial pooled analysis of patients from the general type 2 diabetes population found that saxagliptin was not associated with an increased risk of MACE or its components, or heart failure.


The pooled results “are somewhat reassuring in that the use of saxagliptin in patients with type 2 diabetes at lower risk for cardiovascular events is not associated with increased MACE risk,” and would have passed the FDA-recommended boundary for unacceptable risk for diabetes drugs (HR, 1.3), Dr. Sanjay Kaul said in an interview. However, he added, “it is disappointing that glycemic control did not translate into a macrovascular benefit, even though a lower risk population was evaluated.”


Moreover, the study “did not yield a sufficient number of heart failure events to reliably adjudicate the risk of heart failure in this patient population,” noted Dr. Kaul, professor of medicine, University of California, Los Angeles, who was not at the meeting. Dr. Kaul was a panelist at the FDA advisory panel meeting that reviewed the cardiovascular safety of rosiglitazone (Avandia) last year.


Three of the five authors are employed by Bristol-Myers Squibb; two are employed by AstraZeneca Dr. Kaul had no relevant disclosures related to saxagliptin; he has disclosures for diabetes agents manufactured by other companies.



Saxagliptin is marketed as Onglyza by AstraZeneca.