沙格列汀、阿格列汀心血管安全性获证实

《新英格兰医学杂志》9月2日在线发表、同时在欧洲心脏病学会(ESC)年会上公布的两项随机双盲安慰剂对照研究显示，沙格列汀和阿格列汀既不增加也不降低2型糖尿病高危患者的主要不良心血管事件发生率。

这两种药物均为近期获批的抗糖尿病药物，属于选择性二肽基肽酶-4(DDP-4)抑制剂。

SAVOR-TIMI 53

SAVOR-TIMI 53由布里格姆妇女医院和哈佛医学院的Benjamin M. Scirica医生及其同事进行，纳入16,492例具有明确心血管疾病史或多个血管疾病危险因素的2型糖尿病患者。613例患者被随机分入沙格列汀组(剂量范围：2.5~5 mg/d)，609例被分入安慰剂组。

主要终点是心血管死亡、心肌梗死或缺血性卒中的复合终点事件。中位随访2.1年发现，沙格列汀组和安慰剂组这一主要终点事件的发生率相似，分别为7.3%和7.2%(N. Engl. J. Med. 2013 Sept. 2 [doi: 10.1056/NEJMoa1307684])。

重要的次要终点是心血管死亡、心肌梗死、卒中、因不稳定型心绞痛、冠状动脉血运重建或心力衰竭住院的复合终点事件。治疗组和安慰剂组这一次要终点事件的发生率也相似，分别为12.8%和12.4%。

然而，治疗组因心力衰竭住院的患者比例高于安慰剂组(3.5% vs. 2.8%)，研究者指出这是超出预期的发现，有待进一步研究。

上述结果表明，在中位随访2年内，沙格列汀DPP-4抑制治疗既不增加也不降低缺血性事件发生率，但更长期的治疗可能会产生不同结果。

研究者总结认为，该研究与目前正在进行的探讨其他DPP-4抑制剂和新型抗高血糖药的研究为指导未来对糖尿病患者的治疗提供了强有力的证据。

EXAMINE

EXAMINE非劣效性研究由康涅狄格大学医学院的William B. White医生及其同事进行，纳入近期发生急性心肌梗死或需住院的不稳定型心绞痛的2型糖尿病患者，患者在整个研究期间接受针对糖尿病和心血管危险因素的标准治疗。2,679例患者被随机分入阿格列汀组（剂量范围：6.25~25 mg/d，基于患者基线时的估计肾小球滤过率），2,701例被分入安慰剂组。


William B. White医生

主要终点为心血管源性死亡、非致死性心肌梗死或非致死性卒中的复合终点事件。中位随访18个月时，阿格列汀组和安慰剂组主要终点事件的发生率相似，分别为11.3%和11.8%。阿格列汀组和安慰剂组的严重不良事件发生率无显著差异，分别为33.6%和35.5% (N. Engl. J. Med. 2013 Sept. 2 [doi: 10.1056/NEJMoa1305889])。

研究者指出，在中位随访18个月内，在这组心血管事件风险非常高的患者中，阿格列汀既不增加也不降低心血管发病率和死亡率；研究结果未排除这些心血管终点存在远期风险的可能性。

研究者总结认为，这些数据可用于指导临床医生从现有的多种抗糖尿病药物中选择适当药物治疗心血管风险非常高的2型糖尿病患者。

SAVOR-TIMI 53研究获阿斯利康和百时美施贵宝公司支持。EXAMINE研究获武田美洲开发中心支持。两项研究的多位研究者声明存在经济利益冲突。详情见NEJM.org的全文。

随刊述评：锁定标准心血管危险因素

科罗拉多大学的William R. Hiatt医生、洛杉矶Cedars-Sinai医疗中心的Sanjay Kaul医生和布朗大学的Robert J. Smith医生表示，SAVOR-TIMI 53和EXAMINE研究结果表明，沙格列汀和阿格列汀在心血管风险方面相对安全，但令人失望的是，采取强化血糖控制和使用这些糖尿病药物均未产生任何心血管获益迹象。

这两项研究结果不支持使用糖化血红蛋白作为评估心血管风险或糖尿病治疗获益的有效替代指标。降低糖尿病患者心血管风险的最佳方法，应当是将重点放在积极管理标准心血管危险因素上，而非放在强化血糖控制上。

3位述评作者均声明存在经济利益冲突。Hiatt医生是审查罗格列酮的FDA咨询委员会的成员。详情见NEJM.org上的随刊述评全文(N. Engl. J. Med. 2013 Sept. 2 [doi: 10.1056/NEJMp1309610])。

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By: SHARON WORCESTER, Cardiology News Digital Network

Neither saxagliptin nor alogliptin was associated with increased – or decreased – rates of major adverse cardiovascular events in high-risk patients with type 2 diabetes mellitus in separate randomized, double-blind, placebo-controlled trials.

The findings with respect to these recently approved antidiabetic therapies – members of the same class of selective dipeptidyl peptidase–4 (DDP-4) inhibitors – provide clinicians with important information to help guide treatment decision-making for patients with type 2 diabetes and cardiovascular risk, the authors concluded.
 
Both studies were mandated by the Food and Drug Administration, which in 2008 began requiring all diabetes therapies to demonstrate cardiovascular safety after concerns were raised in 2007 about a link between rosiglitazone (Avandia) and an increased risk of myocardial infarction. The results were reported at the annual congress of the European Society of Cardiology, and were simultaneously published online Sept. 2 in the New England Journal of Medicine.

SAVOR-TIMI 53

SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53) randomized 16,492 patients with type 2 diabetes and a history of established cardiovascular disease or multiple risk factors for vascular disease to either saxagliptin, doses ranging from 2.5 to 5 mg daily, or placebo.

The primary endpoint – a composite of cardiovascular death, myocardial infarction, or ischemic stroke – occurred at similar rates in 613 patients randomized to receive saxagliptin treatment and 609 patients randomized to receive placebo (7.3% and 7.2%, respectively) at a median follow-up of 2.1 years, Dr. Benjamin M. Scirica of Brigham and Women’s Hospital and Harvard Medical School, Boston, and his colleagues reported on behalf of the SAVOR-TIMI 53 Steering Committee and Investigators.

A major secondary endpoint – a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization, or heart failure – also occurred at similar rates in the treatment and placebo groups (12.8% and 12.4%, respectively), they reported (N. Engl. J. Med. 2013 Sept. 2 [doi: 10.1056/NEJMoa1307684]).

However, more patients in the treatment group than in the placebo group were hospitalized for heart failure (3.5% vs. 2.8%), they noted, adding that this was an unexpected finding that merits further study.

The findings demonstrate that DPP-4 inhibition with saxagliptin neither increases nor decreases the rate of ischemic events over a median 2-year period, although longer duration of treatment may have different effects.

"Together with ongoing trials of other DPP-4 inhibitors and novel antihyperglycemic agents, these data will provide a more rigorous and robust evidence base than is currently available to guide the future care of patients with diabetes," they concluded.

EXAMINE

Similarly, the EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care) trial showed that the primary endpoint – a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke – did not occur significantly more often at a median follow-up of 18 months in 2,679 patients randomized to receive treatment, compared with 2,701 patients randomized to receive placebo (11.3% vs. 11.8%, respectively), Dr. William B. White of the University of Connecticut School of Medicine, Farmington, and his colleagues reported on behalf of the EXAMINE investigators.

Patients included in this noninferiority study had type 2 diabetes and a recent acute myocardial infarction or unstable angina requiring hospitalization, who received standard-of-care treatment for diabetes and cardiovascular risk factors throughout the study period. Alogliptin doses ranged from 6.25 to 25 mg daily on the basis of the patients’ estimated glomerular filtration rate at baseline.

"The alogliptin and placebo groups did not differ significantly with respect to the incidence of serious adverse events (33.6% and 35.5%, respectively)," the investigators wrote (N. Engl. J. Med. 2013 Sept. 2 [doi: 10.1056/NEJMoa1305889]).

In this group of patients at very high cardiovascular event risk, alogliptin did not increase or decrease cardiovascular morbidity or mortality over a median 18-month period; the findings do not rule out longer-term risks with respect to cardiovascular endpoints, they noted.

"These data can be used to help guide clinicians in choosing among the many available antidiabetic agents when treating patients with type 2 diabetes and very high cardiovascular risk," they concluded.

The SAVOR-TIMI 53 trial was supported by AstraZeneca and Bristol-Myers Squibb. The EXAMINE trial was supported by Takeda Development Center Americas. Multiple authors for both studies reported disclosures. Details are provided with the full text of each article at NEJM.org.

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Target standard cardiovascular risk factors

The findings of the SAVOR-TIMI 53 and EXAMINE trials show the relative safety of saxagliptin and alogliptin in terms of cardiovascular risk, but it is disappointing that neither the use of intensive glycemic control nor the use of these diabetes medications is associated with any suggestion of cardiovascular benefit.

These studies were required by the Food and Drug Administration to assess cardiovascular safety – a requirement for all new diabetes drugs that came in the wake of recently debunked concerns raised in 2007 regarding the safety of rosiglitazone. Perhaps the recent experience with rosiglitazone will allow the FDA to become more targeted in its adjudication of the cardiovascular safety of new diabetes drugs, focusing the considerable resources needed to rule out a cardiovascular concern only on drugs with clinical or preclinical justification for the expenditure.

Regardless, based on the SAVOR-TIMI 53 and EXAMINE findings, the use of glycated hemoglobin as a valid surrogate for assessing cardiovascular risk or benefit of diabetes therapy is not supported.

The optimal approach to the reduction of cardiovascular risk in diabetes should focus on aggressive management of the standard cardiovascular risk factors rather than on intensive glycemic control.

Dr. William R. Hiatt of the University of Colorado in Aurora, Dr. Sanjay Kaul of Cedars-Sinai Medical Center in Los Angeles, and Dr. Robert J. Smith of Brown University in Providence, R.I., made these comments in an editorial that accompanied the published versions of the SAVOR and EXAMINE reports (N. Engl. J. Med. 2013 Sept. 2 [doi: 10.1056/NEJMp1309610]). All reported having disclosures, and Dr. Hiatt served on the FDA advisory committee that reviewed rosiglitazone. Details are available with the full text of the editorial at NEJM.org.