Results of two large rosiglitazone analyses – despite showing increased cardiovascular risk with rosiglitazone, compared with pioglitazone and control therapy – are not likely to have much of an impact on the outcome of an upcoming U.S. Food and Drug Administration meeting on the drug’s cardiovascular safety, according to experts.

One study, an update to the 2007 meta-analysis that spurred the ongoing controversy over rosiglitazone’s heart risks, revealed an increased risk of acute myocardial infarction, but not mortality, with rosiglitazone, compared with control therapy. The other, an analysis of a Medicare database that compared rosiglitazone with pioglitazone, conversely showed an increased risk of stroke, heart failure, and death, but not acute MI. (Medicare is a federally administered system of health insurance in the United States that is available to persons aged 65 and over.)

The studies were published online June 28 in the JAMA and the Archives of Internal Medicine in advance of the FDA’s July 13 meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and its Drug Safety and Risk Management Advisory Committee.

The revised meta-analysis was conducted by the same team – Dr. Steven E. Nissen and Kathy Wolski – who authored the 2007 meta-analysis (N. Engl. J. Med. 2007;356:2457-71) and includes 14 studies not in the 2007 report, but the conclusions have not changed substantially.

Rosiglitazone was significantly associated with higher risk of MI but not cardiovascular death in both meta-analyses; however, the odds ratio for MI, 1.43 in the earlier study, was shaved to 1.28, mostly owing to the data from the 4,447-patient Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) trial, which showed no increased risk of MI or mortality. Excluding RECORD from the analysis yielded an odds ratio of 1.39. Rosiglitazone was not significantly linked to cardiovascular or all-cause mortality in either analysis.

The revised meta-analysis included 56 trials, comprising 35,531 patients, of whom 19,509 received rosiglitazone and 16,022 received control therapy. To calculate odds ratios and confidence intervals, Dr. Nissen and Ms. Wolski used the Peto method, which excludes trials with no adverse outcomes and produces a fixed-effect analysis (Arch. Intern. Med. June 28, 2010 [doi:10.1001/archinternmed.2010.207]).

The results “suggest an unfavorable benefit to risk ratio for rosiglitazone,” wrote Dr. Nissen, chair of cardiovascular medicine at the Cleveland Clinic, and Ms. Wolski, also of the Clinic. “Because no unique benefits of rosiglitazone use have been identified, administration of this agent solely to lower blood glucose levels is difficult to justify.”

In the Medicare study, Dr. David J. Graham of the FDA’s Office of Surveillance and Epidemiology in Silver Spring, Maryland, and colleagues conducted a retrospective observational study of more than 225,000 Medicare patients (mean age 74 years) who initiated treatment with rosiglitazone or pioglitazone through a Medicare Part D prescription drug plan from July 2006 to June 2009 were followed for up to 3 years (JAMA 2010;304[doi:10.1001/jama.2010.920]).

Medicare’s database on its prescription benefit, initiated in 2006 as Part D, provided an opportunity to investigate whether rosiglitazone has increased cardiovascular risks, compared with pioglitazone, in a national sample of patients over age 65, the authors explained. Using a Cox proportional hazard model stratified by prior history of a cardiovascular end point and cancer, they adjusted for baseline characteristics such as cardiovascular disease, diabetes-related diseases, associated medications, and other variables.

Patients taking rosiglitazone, compared with those on pioglitazone, had significantly higher risk of stroke (hazard ratio 1.27), heart failure (1.25), and death (1.14), but not of acute MI (1.06). The risk for the composite end point of all these outcomes combined was significantly higher in the rosiglitazone patients (HR 1.18), compared with pioglitazone patients. The attributable risk for this composite end point was 1.68 excess events per 100 person-years of treatment with rosiglitazone, compared with pioglitazone. Pioglitazone and rosiglitazone are both in the thiazolidinedione drug class.

The investigators also performed post-hoc analyses comprising the subjects who entered the study before and after May 21, 2007, when Dr. Nissen’s first meta-analysis was published. The results of both were “nearly identical” to the main study results, they reported.

The study was limited by its observational nature, which is subject to bias because of confounding, Dr. Graham and colleagues said. This potential was mitigated, however, by the “wide array” of variables they collected and adjusted for, they said, because the two cohorts “were virtually indistinguishable with respect to these numerous baseline characteristics.”

In an editorial comment (JAMA 2010;304[doi:10.1001/jama.2010.954), Dr. David N. Juurlink wrote “[w]hile the overall findings are not novel, this study is large, rigorously conducted, and exceptionally timely,” referring to the upcoming FDA hearing.

The July FDA hearing will be the second in three years to examine rosiglitazone’s cardiovascular safety. The first, in July 2007, was in response to the Nissen meta-analysis. The panel voted 22-1 to keep rosiglitazone on the market, and the agency added a boxed warning to the drug’s label and asked manufacturer GlaxoSmithKline to conduct a cardiovascular safety trial, which is now enrolling patients (Thiazolidinedione Intervention With Vitamin D Evaluation, or TIDE).

The FDA convened the meeting partly in response to a February 2010 letter from the U.S. Senate Finance Committee that accused the agency of endangering patients by allowing them to enroll in a trial, referring to TIDE, that is likely to harm them, and withholding its own conclusions about rosiglitazone’s dangers.

The committee released a letter to FDA Commissioner Margaret A. Hamburg, citing an FDA document saying “there was no evidence that rosiglitazone confers any unique health benefits over pioglitazone while there is strong evidence that rosiglitazone confers an increased risk of [acute myocardial infarction] and heart failure compared to pioglitazone.”

Furthermore, the FDA’s document acknowledges that, in reference to the TIDE study, “any proposed head-to-head trial of rosiglitazone vs. pioglitazone would be unethical and exploitative.”

Asked about this report, FDA spokeswoman Karen Riley noted at the time that Dr. Janet Woodcock, director of the agency’s Center for Drug Evaluation and Research, requested in December 2009 that “all appropriate offices within the center rapidly evaluate new data on Avandia [rosiglitazone] with the aim of presenting it to an FDA advisory committee in the summer of 2010.”

Dr. Juurlink in his editorial predicted that the FDA will have two options: One, recommend that rosiglitazone be removed from the U.S. market and that TIDE be terminated, and two, do nothing and await the TIDE results. With the second scenario, “the desire for certainty trumps safety, patients may lose, and an ethically questionable trial will continue to seek participants who, it seems, may not fully appreciate the potential risks of participation,” he wrote.

Experts disagreed that the new studies would have an impact on the FDA’s meeting. “My comment on these studies is that we don’t need new epidemiologic studies piling on to what we already know about rosiglitazone,” said Dr. John Buse, professor of medicine and chief of the division of endocrinology at the University of North Carolina, Chapel Hill. He said in an interview that we know all we can know about rosiglitazone in comparison with pioglitazone and with control therapies. So we need to either wait for a randomized, controlled trial to provide definitive answers or stop prescribing the drug, he said. Indeed, he said, the most important message for clinicians from the three articles is from Dr. Juurlink’s editorial.

Dr. Prakash Deedwania agreed that there are no new findings that will assist the FDA in its deliberating. Indeed, the reduced odds ratio for MI in the Nissen meta-analysis may dilute the agency’s legal standing to withdraw rosiglitazone, Dr. Deedwania, professor of medicine and chief of cardiology at the University of California, San Francisco, Fresno, said in an interview.

Regarding the Medicare study, Dr. Robert M. Califf of the Duke Translational Medicine Institute in Durham, North Carolina, noted in an interview that the showing of increased myocardial infarction is inconsistent with findings of randomized controlled trials, “and I trust RCTs more than an observational study.”

Dr. Nissen has received research support from AstraZeneca, AtheroGenics, Eli Lilly, Novartis, Pfizer, Resverlogix, Takeda, Daiichi Sankyo, and Sanofi-Aventis. He has consulted for a many pharmaceutical companies without financial compensation. All payments from any for-profit entity are paid directly to charity. Dr. Graham and colleagues did not report disclosures, nor did Dr. Juurlink.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

有专家表示，两项大规模罗格列酮研究分析的结果（尽管显示罗格列酮相比吡格列酮和对照治疗可增加心血管风险）不可能对美国食品药品管理局(FDA)即将举行的审评该药心血管安全性的听证会结果产生较大的影响。

 

其中一项分析是对2007年那项引发人们对罗格列酮心脏风险争议不断的Meta分析的更新。该分析显示，与对照治疗相比，罗格列酮可增加急性心肌梗死(MI)风险，但不增加死亡风险。相反，另一项使用Medicare 数据库来比较罗格列酮和吡格列酮的分析则显示，罗格列酮可增加卒中、心力衰竭和死亡风险，但不增加急性MI风险(Medicare是美国联邦政府管理的医疗保险系统，其面向65岁及以上的人群)。

 

这两项分析已于6月28日在线发表于《美国医学会杂志》(JAMA)和《内科学纪要》(Archives of Internal Medicine)，先于FDA即将在7月13日举行的内分泌和代谢药物咨询委员会与药品安全和风险管理咨询委员会联合会议。

 

该修订后的Meta分析的作者 Steven E. Nissen博士和Kathy Wolski同时也是2007 年Meta分析(N. Engl. J. Med. 2007;356:2457-71) 的作者。与2007年的分析相比，该修订后的分析新增了14项研究，但结论并无实质性改变。

 

 

这两项Meta分析均显示，罗格列酮与MI风险增加显著相关，但与心血管死亡风险增加无关；然而，修订分析中的MI比值比(OR)为1.28，相比2007年分析中的1.43略有下降，这主要是由RECORD(罗格列酮治疗糖尿病的心血管转归和血糖调节评价研究)的 4,447例患者的数据所引起，后者显示罗格列酮不增加MI或死亡风险。从分析中排除RECORD 研究后，所得OR为1.39。两项分析均显示，罗格列酮与心血管或全因死亡无显著关联。

 

该修订后的Meta分析包括56项试验，共35,531例患者，其中19,509例接受罗格列酮治疗，16,022例接受对照治疗。为了计算OR和可信区间，Nissen博士和Wolski 女士采用了Peto 法进行固定效应分析，该方法可排除无不良转归的试验 (Arch. Intern. Med. June 28, 2010 [doi:10.1001/archinternmed.2010.207])。

 

克利夫兰诊所心血管科主任Nissen博士与同样来自该诊所的Wolski女士写道，结果“表明罗格列酮的效益风险比不佳。由于未观察到罗格列酮治疗所带来的任何独特益处，因此难以为单用该药来降低血糖提供合理依据。”

 

FDA监测与流行病学办公室的 David J. Graham博士及其同事在一项回顾性观察性研究中对225,000余例Medicare患者(平均年龄74岁)进行了3年随访(JAMA 2010;304[doi:10.1001/jama.2010.920])。这些患者在2006年7月至2009年6月间通过Medicare Part D 处方药计划开始接受罗格列酮或吡格列酮治疗。

 

 

作者指出，2006年启动的Medicare Part D 处方药计划使他们能够在年龄65岁以上的全国患者样本中探讨罗格列酮与吡格列酮相比是否增加心血管风险。他们采用经既往心血管终点和癌症病史分层的Cox比例风险模型，对心血管疾病、糖尿病相关疾病、相关药物和其他变量等基线特征进行校正。

 

罗格列酮治疗患者的卒中[危险比(HR) 1.27]、心力衰竭(HR 1.25)和死亡(HR 1.14)风险显著高于吡格列酮治疗患者，但急性MI风险(HR 1.06)不显著高于后者。罗格列酮治疗患者的复合终点(包括上述所有这些结局指标)风险(HR 1.18)显著高于吡格列酮治疗患者，并且罗格列酮治疗患者该复合终点的归因风险比吡格列酮治疗患者高1.68件事件/100人·年。 吡格列酮和罗格列酮均属于噻唑烷二酮类药物。

 

Medicare 研究的研究者还对在2007年5月21日前后入组的患者进行了事后分析(正好为Nissen博士的第一项Meta分析发表时)。他们指出，两者在主要研究方面的分析结果“几乎相同”。

 

Graham博士及其同事表示，Medicare 研究的局限性在于使用观察设计，这一设计可因混杂因素而导致偏倚。但他们表示，他们所采集和校正的“大量”变量减少了产生偏倚的可能性，因为两个队列“在这些大量基线特征方面几乎相同”。

 

David N. Juurlink 博士在随刊编者按 (JAMA 2010;304[doi:10.1001/jama.2010.954)中写道：“尽管这项经严格实施的大规模研究的整体结果并不新颖，但在FDA听证会即将举行的这个节骨眼上，该研究来得非常及时。”

 

7月份的FDA听证会是3年内举行的第2次审查罗格列酮心血管安全性的听证会。2007年7月举行的第1次听证会是为了回应Nissen博士的Meta分析而举行的。专家组以22:1的投票比例保住罗格列酮不被撤市，并且FDA要求生产商葛兰素史克在该药标签上增加黑框警告以及进行心血管安全性试验。该试验名为维生素D干预的噻唑烷二酮药物评估(TIDE)试验，目前正在招募患者。

 

FDA举行听证会的目的部分在于回应美国参议院财政委员会2010年2月份向其发出的谴责信。该信谴责FDA允许TIDE试验招募患者的做法有可能会对患者造成伤害，并谴责其隐瞒了关于罗格列酮危险性的结论。

 

该委员会向FDA专员 Margaret A. Hamburg发出了信件，信中援引FDA文件称“没有证据表明罗格列酮具有任何优于吡格列酮的独特健康益处，但有确凿证据表明罗格列酮与吡格列酮相比可增加急性MI和心力衰竭的风险。”

 

此外，FDA的文件在谈到TIDE研究时承认，“任何建议直接比较罗格列酮与吡格列酮的试验都是不符合伦理学原则的，且具有利用(患者的)性质。”

 

FDA发言人 Karen Riley 女士在被问及该文件时指出，FDA药品审评和研究中心主任Janet Woodcock博士在2009年12月时要求“本中心的所有相应办公室迅速对有关文迪雅(罗格列酮)的最新数据进行评价，并争取在2010年夏天将审评结果上报至FDA顾问委员会。”

 

Juurlink博士在随刊编者按中预测FDA将提出两个观点：一是建议罗格列酮从美国市场上退出并终止TIDE研究；二是什么也不做，就等着TIDE研究结果的出炉。就第2种情况而言，他写道：“对确定性的期望胜于安全性，患者可能会有所损失，并且此项在伦理学上遭受质疑的试验将会继续招募那些不是完全了解参与研究的潜在风险的受试者。”

 

专家们均认为，这些最新研究不会对FDA听证会产生影响。北卡罗来纳大学查普尔山分校内分泌学系主任兼医学教授John Buse博士说：“我对这些研究的评论是，我们不需要新的流行病学研究来增加我们对罗格列酮的既有认识。” 他在接受采访时表示，我们已经掌握了我们所能掌握的有关罗格列酮与吡格列酮和对照治疗相比的资料。 因此，我们要做的是要么等待随机对照试验为我们提供明确的答案，要么就停止开具该药。他表示，Juurlink博士的随刊编者按为这3篇论文提供了对临床医生来说最重要的信息。

 

Prakash Deedwania博士也认为，没有新的有助于FDA审议的研究结果。弗雷斯诺加州大学旧金山分校心脏病科主任兼医学教授的Deedwania博士在接受采访时表示，在Nissen博士的Meta分析中，MI比值比降低，这确实可能会动摇FDA撤回罗格列酮的法律立场。

 

北卡罗来纳州达勒姆市杜克大学转化医学研究所的Robert M. Califf博士在接受采访时指出，Medicare研究中有关MI风险增加的结果与随机对照试验的结果不一致，而且“相较观察性研究，我更相信随机对照试验的结果。”

 

Nissen博士从阿斯利康、AtheroGenics、礼来、诺华、辉瑞、Resverlogix、武田、第一三共株式会社和赛诺菲-安万特公司获得研究支持。他还是多家制药公司的免费顾问。从任何营利实体获得的所有款项均直接支付给慈善机构。Graham博士及其同事以及Juurlink博士均未作经济利益冲突声明。

 

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