FDA评价显示奥美沙坦不增加糖尿病患者心血管风险

美国食品药品管理局（FDA）6月24日报告称，对奥美沙坦安全性的评价没有发现糖尿病患者心血管风险增加与使用该药物相关的“确切证据”。不过，有关大剂量使用可能风险的一些担心仍然存在。

启动这项评价的原因是ROADMAP（奥美沙坦预防糖尿病微量白蛋白尿随机研究）试验意外发现，与安慰剂相比，奥美沙坦增加2型糖尿病患者心血管死亡风险。这项评价工作已经完成，FDA建议使用该血管紧张素受体阻断剂（ARB）的糖尿病患者应维持用药不变。

声明指出，FDA评价的一些研究资料，包括一项大规模联邦医疗保险（Medicare）患者观察性研究，将被列入Benicar、Benicar HCT、AZO、Tribenzor以及奥美沙坦通用名药品说明书中。

FDA声明称：“虽然ROADMAP试验和Medicare研究数据表明大剂量奥美沙坦可增加糖尿病患者心血管风险，但就所有试验和研究资料而言，上述结论并不确定。总体上，我们认为这些研究未能明确显示心血管风险增加。因此，目前可收集到的证据并不支持改变我们对奥美沙坦使用的推荐意见，也不支持有关糖尿病患者避免使用该药物的建议。”

不过，旨在评价奥美沙坦能否延缓2型糖尿病患者肾脏损害的ROADMAP研究显示，奥美沙坦治疗患者非致命性心梗风险较低（N. Engl. J. Med. 2011;364:907-17）。

在针对年龄≥65岁患者的 Medicare研究中，服用最大剂量奥美沙坦（40mg/d）>6个月的糖尿病患者死亡风险增加[风险比（HR），2.0]，但非糖尿病患者服用最大剂量奥美沙坦与死亡风险减少相关（HR，0.46）。FDA称，难以解释两组患者相互矛盾的结果，从而引发对两组患者结果可信性的怀疑。

纳入评价的其他研究还包括一项针对英国初级保健患者病历的研究。该研究比较了58,000余例接受大剂量奥美沙坦与其他APB治疗患者的结局。研究发现，总死亡和急性心梗风险增加与大剂量奥美沙坦使用相关，但不具有统计学意义（Pharmacoepidemiol. Drug Saf. 2014;23:340-7）。

FDA总结认为：“总体上，这些数据引发了有关糖尿病患者心血管风险增加可能与大剂量奥美沙坦使用相关的担心。”

FDA有关该问题的首篇安全性通讯于2010年6月发布，并于2011年4月进行了更新。

据FDA称，2013年约180万患者凭处方在美国门诊零售药房领取了奥美沙坦产品。

奥美沙坦治疗患者严重不良事件应通过800-332-1088或www.fda.gov/medwatch报告至FDA药物不良事件监测系统。

By: ELIZABETH MECHCATIE, Cardiology News Digital Network

Jun 25, 2014

The Food and Drug Administration’s review of the safety of olmesartan has found "no clear evidence" of increased cardiovascular risks associated with the use of the drug in people with diabetes, but some concern remains about the possible risk with high doses, the agency reported on June 24.

The review, prompted by the ROADMAP (Randomized Olmesartan and Diabetes Microalbuminuria Prevention) study of patients with type 2 diabetes – which unexpectedly found an increased risk of cardiovascular death among patients on olmesartan, compared with those on placebo – has been completed, and recommendations for the use of the angiotensin receptor blocker (ARB) in people with diabetes will remain unchanged, according to the FDA.

Information about some of the studies reviewed by the FDA, however, including a large observational study of Medicare patients, will be included in the labels of olmesartan products, which include Benicar, Benicar HCT, AZO, Tribenzor, and generic formulations, the statement said.

"While data from the ROADMAP trial and the Medicare study have suggested that high-dose olmesartan may increase CV risk in diabetic patients, when considering the data from all trials and studies, they are not conclusive," the FDA statement said, adding, "Overall, we determined these studies do not clearly show an increased cardiovascular risk. Thus, the collective evidence available at this time does not support changing our recommendations for olmesartan use and does not support recommending that its use be avoided in patients with diabetes."

The risk of nonfatal MI, however, was lower among those on olmesartan in the ROADMAP study, which was designed to determine whether olmesartan could delay kidney damage in patients with type 2 diabetes (N. Engl. J. Med. 2011;364:907-17).

In the Medicare study of patients aged 65 years and older, the risk of death was increased among patients with diabetes, who received the highest (40 mg/day) dose of olmesartan for more than 6 months (hazard ratio, 2.0). Among patients who did not have diabetes, however, the highest dose was associated with a reduced risk of death (HR, 0.46). The conflicting results in these two patient groups in the study "are difficult to reconcile and raise uncertainty about the credibility of the findings in either group," the FDA said.

Other studies reviewed include a U.K. study of primary care medical records that compared outcomes of patients receiving high-dose olmesartan with those treated with high doses of other ARBs in over 58,000 patients. The study found an increased risk of overall death and of acute myocardial infarction associated with the use of high-dose olmesartan, which was not statistically significant (Pharmacoepidemiol. Drug Saf. 2014;23:340-7).

"Overall, these data raise concern of possible increased cardiovascular risk associated with the use of high-dose olmesartan in diabetic patients," the FDA concluded.

The FDA’s first safety communication on this issue was posted in June 2010, followed by an update in April 2011.

In 2013, about 1.8 million people received a dispensed prescription for olmesartan products from U.S. outpatient retail pharmacies, according to the FDA.

Serious adverse events in patients treated with olmesartan products should be reported to the FDA’s MedWatch program at 800-332-1088 or www.fda.gov/medwatch.