FDA重申：罗格列酮并不增加心血管事件风险

有关罗格列酮对心血管事件的事情由来以久，有些研究认为它能明显增加心血管事件的风险，而有些研究则持相反观点。最新FDA再次声明，罗格列酮并不增加心血管事件的风险。

有关罗格列酮增加心血管事件的不龙去脉，MedSci这里全面回顾一下：

罗格列酮显著增加心血管事件发生--2007年

2007年New england journal of Medicine发表了一篇重量级文献Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes（2型糖尿病治疗药物罗格列酮（商品名：Avandia）致心肌梗死与心血管疾病死亡的风险），作者是克利弗兰的Nissen SE 和Wolski K(http://content.nejm.org/cgi/content/full/NEJMoa072761)。研究发现Avandia增加心血管相关疾病死亡几率达64%和心肌梗死发生率达43%。该药物生产商为GlaxoSmithKline。文章才刊发一天，已经引起了相当大的反响。

BARI 2D研究事后分析：

　　罗格列酮不增加心梗和卒中风险

　　在6月29日的2010年美国糖尿病学会（ADA）年会上，对2型糖尿病冠脉旁路血运重建研究（BARI 2D）的事后分析显示，在4.5年随访期间，与非噻唑烷二酮类药物治疗相比，罗格列酮显著增加了骨折风险，但与MI和卒中发生风险增加无关。罗格列酮使死亡、MI或卒中风险降低了28%，使卒中风险降低了64%。

　　研究者称，罗格列酮用于2型糖尿病和稳定冠心病患者，并无显著心血管风险，甚至对缺血性心血管事件还可能有潜在保护性作用。

　　该研究的终点事件采用前瞻性收集的方法，并经过独立判定。受试人群包括了心血管事件很高危的患者，在此类患者中得出的结论与总体研究结果一致。然而，该研究存在一定局限性，很多受试者接受了多种降糖药物治疗，因此不易分析单独任一降糖药物的作用。

    中华医学会糖尿病学分会主任委员纪立农教授研究认为2型糖尿病患者使用罗格列酮控制血糖，不会增加心脏病发作或心血管死亡风险。成果在第70届美国糖尿病学会年会发表的2型糖尿病旁路血管成形术血运重建研究得出的结果。

RECORD研究证明罗格列酮并不增加心血管事件
　　背景
　　最近公布的一项荟萃分析结果，使人担心用罗格列酮治疗2型糖尿病，可能与心肌梗死和心血管原因死亡的危险增加有关。
　　方法
　　我们对一项随机、多中心、开放标签、非劣效性临床试验进行计划外中期分析，该试验纳入4447例接受二甲双胍或磺脲类药物治疗时血糖控制不充分的2型糖尿病患者，其中2220例患者被分配接受额外添加罗格列酮治疗（罗格列酮组），2227例患者被分配接受二甲双胍加磺脲类药物联合治疗（对照组）。主要终点是心血管原因导致的住院或死亡。
　　结果
　　因为平均随访时间只有3.75年，所以我们的中期分析检出治疗差异的统计学把握度有限。罗格列酮组的217例患者和对照组的202例患者发生经过裁定的主要终点[风险比为1.08，95%可信区间（CI）为0.89～1.31]。纳入待裁定的终点后，风险比为1.11（95%CI为0.93～1.32）。罗格列酮组和对照组在心肌梗死和心血管原因或任何原因造成的死亡方面，无统计学显著差异。罗格列酮组的心衰患者比对照组多（风险比为2.15，95%CI为1.30～3.57）。
　　结论
　　我们对这项正在进行中的研究所做的中期分析结果，在罗格列酮对心血管原因造成的住院或死亡的总体危险的影响方面，无最终结论。没有死亡增加的证据，无论是心血管原因导致的死亡还是全因性死亡。罗格列酮与心衰危险增加有关。这些数据不足以确定该药是否与心梗危险增加相关。

　　图2　主要终点（心血管原因导致的住院或死亡）的Kaplan-Meier分析
　　此图显示研究中发生的已裁定事件（A幅）和已裁定事件加研究截止时正在等待裁定的事件（B幅）。

　　■ 最新荟萃分析与回顾性研究：

　　罗格列酮增加心血管事件风险

　　6月28日在线发表于《内科学文献》（Arch Intern Med）的一项荟萃分析显示，罗格列酮使MI风险增加28%~39%。该研究由著名学者史蒂芬・尼森（Steven Nissen）等完成。研究者对2010年2月份之前的检索数据进行了分析，共纳入56项研究35531例患者。结果显示，罗格列酮显著增加了MI风险（OR=1.28），但并未显著增加心血管死亡率（OR=1.03）。

　　无独有偶，同日在线发表于《美国医学会杂志》（JAMA）的一项回顾性观察研究，比较了227571例65岁以上受试者接受罗格列酮或吡格列酮的预后。随访至3年结果显示，与吡格列酮相比，罗格列酮与卒中、心衰和全因死亡风险增加相关。

　　鉴于迄今缺乏一致性研究结论，AHA和美国心脏病学会（ACC）呼吁更多相关临床对照研究，而ADA和欧洲糖尿病研究学会（EASD）则在2008年重申，罗格列酮应作为生活方式干预和二甲双胍治疗基础上的2型糖尿病二线用药。

　　7月中旬，FDA委员会将召开听证会，对罗格列酮安全性以及是否需要将该药撤市展开进一步讨论。此外，噻唑烷二酮及维生素D干预疗效的评价（TIDE）研究预计将于2015年完成。

　　■ 专家观点：解析最新证据 期待更多研究 继续关注罗格列酮心血管安全性

　　中国人民解放军总医院 陆菊明教授

　　2007年尼森发表的荟萃分析对罗格列酮的心血管安全性提出了质疑，自此这一话题成为糖尿病学界的关注焦点，相关研究未取得一致意见。

　　6月28日，随着《美国医学会杂志》与《内科学文献》发表有关罗格列酮心血管安全性新的荟萃分析与观察性研究结果，使这一稍显沉寂的话题再次引发热议。

　　同样值得关注的是，在ADA年会上，一项关于罗格列酮安全性研究的事后分析为罗格列酮的心血管安全性带来了正面的结果。

　　结果表明，合并冠心病的2型糖尿病患者服用罗格列酮后，包括死亡和MI相对风险的缺血性心血管事件和充血性心力衰竭风险无显著升高。

　　服用罗格列酮患者的卒中（相对风险为0.40，95%可信区间为0.18~0.87）和死亡、MI和卒中复合事件发生率（相对风险为0.80，95%可信区间为0.63~1.03）有所降低。

　　该研究主要研究者理查德・贝曲（Richard Bach）教授认为，上述数据非常重要，提示2型糖尿病合并冠心病患者服用罗格列酮并不存在严重的心血管风险。

　　上述3项研究结果无疑为罗格列酮的心血管安全性提供了更多证据，但各研究本身存在缺陷，值得重视。随机对照临床研究仍然是评价医学问题的金标准。

　　自2007年FDA联合顾问委员会审核罗格列酮的心血管安全性问题以来，已有6项临床对照研究（RECORD、APPROACH、VICTOR、VADT、ACCORD 和BARI 2D）结果公布。上述试验结果表明，罗格列酮并未升高心脏病发作、卒中或死亡的总体风险。

　　正在进行的TIDE研究拟入选1.6万例有心血管疾病史或有心血管疾病高危因素的2型糖尿病患者，旨在头对头比较罗格列酮与吡格列酮对心血管事件（心血管死亡、MI或卒中）的影响，我们期待这一随机对照临床研究结果为医学工作者了解罗格列酮的心血管安全性提供更具说服力的证据。

拓展阅读：

NEJM：二甲双胍加用罗格列酮改善年轻2型糖尿病患者血糖控制（TODAY研究）

FDA限制罗格列酮使用新规

英文报道：

Silver Spring, MD - An extensive analysis by the US Food and Drug Administration (FDA) concludes that the much-discussed diabetes drug rosiglitazone (Avandia, GlaxoSmithKline) does not increase the risk for adverse cardiovascular outcomes.

The data were discussed on the first day of a two-day joint meeting of the FDA's Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee, being held to determine the future of rosiglitazone in the US [1], and supports the findings of a recent readjudication of the Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes (RECORD) trial.

The data were discussed on the first day of a two-day joint meeting of the FDA's Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee, being held to determine the future of rosiglitazone in the US [1].

Since September 2010, rosiglitazone's use there has been severely restricted due to cardiovascular safety concerns. At the time it imposed the restrictions, the FDA also called for an independent readjudication of GlaxoSmithKline's RECORD study, the only randomized trial of the drug to specifically examine CV outcomes.

Presentations yesterday were broadly supportive of the readjudication finding, although several concerns remain, many pertaining to the initial trial design. Today the two advisory committees will vote on what to do next with rosiglitazone.

The multicenter, open-label RECORD trial randomized 4447 patients with type 2 diabetes who were poorly controlled (HbA_1c 7.9%), despite treatment with metformin or a sulfonylurea, to either rosiglitazone or a combination of metformin plus a sulfonylurea. The study met its primary end point, to show noninferiority with regard to composite end points of CV death and CV hospitalizations (hazard ratio 0.99, 95% CI 0.85-1.16) [2].

Presentations on the first day of the new hearing were given by the FDA, GlaxoSmithKline, and by the Duke Clinical Research Institute (DCRI), which conducted the RECORD readjudication with data provided by GlaxoSmithKline.

In the morning, Dr Thomas A Marciniak (FDA Division of Cardiovascular and Renal Products) delivered a personal critique of the RECORD readjudication, in which he stated that the DCRI's review was not independent because the institution was paid by GlaxoSmithKline. He also accused the DCRI of "extreme mishandling" of the data and cited methodological flaws of the original trial.

Marciniak, who had delivered a similar assessment of RECORD at a July 2010 FDA advisory committee hearing on the safety of rosiglitazone, when he was among the reviewers, was this time speaking only for himself and not on behalf of the FDA.

Subsequent presenters yesterday included Dr Kenneth W Mahaffey, the DCRI's associate director, and Dr Robert Bigelow (DCRI), who summarized the readjudication, which involved 22 reviewers at eight organizations.

Readjudication of a total 2223 events revealed no significant event risks for the rosiglitazone group (2220 patients) compared with those receiving sulfonylureas and/or metformin (2227). The hazard ratios were 0.95 for the composite end point of CV death, MI, or stroke; 0.90 for CV death; 1.13 for MI; 0.79 for stroke; and 0.86 for all-cause death. None of those were statistically significant.

Numerous sensitivity analyses to account for missing data did not change the conclusion, that the results "were consistent with originally published RECORD results," said Mahaffey.

A series of detailed FDA presentations essentially backed up the DCRI's conclusion, despite numerous discrepancies between the original trial analysis and the readjudication in the attribution of causes of death.

"Irrespective of the specific analysis selected, the hazard ratio is in the favorable to neutral range, which seems reassuring," said Dr Ellis F Unger, director of the FDA's Office of Drug Evaluation 1.

However, several presenters and panel members expressed concern about one major limitation of RECORD that the readjudication could not address: it was an open-label trial, which introduces the potential for bias.

This was done out of necessity, because the "rescue medication," insulin, is contraindicated for use with rosiglitazone in Europe. It would have been impractical to blind the study subjects with multiple daily sham injections, noted Dr Karen Murry Mahoney (FDA Division of Metabolism and Endocrinology Products).

Another concern, raised by two panel members, related to the possible treatment effect of statins, which were used more often in the rosiglitazone patients. That topic will be discussed further today.

Rosiglitazone was pulled from the European market in 2010 at the same time the US imposed restrictions. In the US, it is available only under a risk evaluation and mitigation strategy (REMS), which limits its use to patients who were already taking it or to new patients for whom no other glucose-lowering agents are acceptable.

Since the REMS was imposed, the number of patients using rosiglitazone has dropped dramatically from 117 349 in 2009 to 3405 during 2011-2013.

Today, the two advisory panels will be asked to vote on whether to keep the current REMS program as is, modify it, remove it and allow freer use of rosiglitazone, or remove rosiglitazone from the US market.