ORLANDO (EGMN) —Rosiglitazone did not increase the risk of death, heart attack, or stroke in patients with diabetes and cardiovascular risk factors, according to a new post-hoc analysis of the landmark BARI 2D study.
In fact, the analysis suggested that rosiglitazone may actually provide some protection against cardiovascular events, Dr. Richard Bach said at the annual meeting of the American Diabetes Association. Patients taking the drug were 28% less likely to have a heart attack or stroke, or to die from a cardiovascular event, than those who were not taking a thiazolidinedione, Dr. Bach said during a press briefing.
The findings should bring a bit of perspective to the 3-year debate over rosiglitazone’s safety profile, he said, and help the U. S. Food and Drug Administration evaluate the matter at its July 13th meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and its Drug Safety and Risk Management Advisory Committee. Although carrying all the possible confounders of a post-hoc analysis, BARI 2D (N. Engl. J. Med. 2009; 360:2503-2515) did provide an excellent vehicle for examining the drug’s safety profile, he said in an interview.
“It was a trial designed specifically to look at cardiovascular outcomes in a high-risk population, so I believe the information it gives us is quite reliable,” said Dr. Bach of Washington University in St. Louis. “This should provide some reassurance to patients [taking the drug]. I would suggest that these data do not show a degree of harm that would put a vulnerable population at risk.”
In an attempt to shed more light on the question, Dr. Bach and his colleagues embarked on a post-hoc analysis of the BARI 2D trial. BARI compared the effects of insulin replacement and insulin sensitization therapies in 2,368 patients with both type 2 diabetes and stable coronary heart disease. A second comparison was prompt revascularization vs. delayed or no revascularization.
Patients were not randomized to rosiglitazone; treatment with a thiazolidinedione was left up to the discretion of the treating physicians. Rosiglitazone was used in 992 patients; considering that BARI 2D patients had an average 5 year follow-up, more than 3,000 patient/years of rosiglitazone exposure were available for analysis, said BARI co-investigator Maria Brooks, Ph.D., of the University of Pittsburgh. Because they were judged to be in need of additional diabetes medications, patients who received rosiglitazone had higher baseline hemoglobin A1c levels, a longer duration of diabetes, and more albuminuria than those who did not receive the drug.
Nearly 1,200 patients had no thiazolidinedione exposure, yielding more than 7,000 patient/years of follow-up data.
In a regression analysis that was adjusted for differences in baseline characteristics and use of other antidiabetes agents, rosiglitazone was associated with a significant 28% reduction in the composite outcome of cardiovascular death, heart attack, and stroke. The rate of stroke was also significantly lower with rosiglitazone (64% reduction). While the rate of heart attack and cardiovascular death was lower with rosiglitazone, the differences were not statistically significant.
Rosiglitazone was also associated with a significantly increased risk of fracture (62%), compared with no thiazolidinedione exposure. “This is something we have seen in other trials and was not a surprise,” Dr. Bach said.
He added that this single look at the rosiglitazone data won’t be enough to completely reconcile the debate. “The term ‘safe’ is always going to be a difficult term to use with any medication. A definitive answer to the question of ‘safe,’ as well as ‘unsafe’ probably has to wait more with respect to information about rosiglitazone.”
The U.S. Food and Drug Administration is scheduled to review rosiglitazone’s safety profile on July 13. Dr. Brooks will present the BARI 2 data during the meeting.
Rosiglitazone has been the topic of heated debate since 2007, when Dr. Steven E. Nissen, chair of cardiovascular medicine at the Cleveland Clinic, published the results of his 42-trial rosiglitazone meta-analysis. The analysis included 15,565 patients assigned to treatment protocols using rosiglitazone and 12,282 assigned to protocols using placebo. He examined all occurrences of heart attack and death from cardiovascular disease, and concluded that rosiglitazone conferred a significant 43% increased risk of heart attack and a nonsignificant 64% increased risk of cardiovascular death.
There were 86 heart attacks and 39 cardiovascular deaths – a number Dr. Nissen noted in his paper as relatively small. “Nonetheless, our findings are worrisome because of the high incidence of cardiovascular events in patients with diabetes,” he wrote. “Because exposure of such patients to rosiglitazone is widespread, the public health impact of an increase in cardiovascular risk could be substantial if our data are borne out by further analysis and the results of larger controlled trials.” analysis determined that treatment with (N. Engl. J. Med. 2007; 356:2457-71).
The meta-analysis provoked a storm of comment, ultimately contributing to an FDA review of rosiglitazone’s safety data. In November 2007, the FDA added a warning label to the drug about potential cardiac risks.
Since then, large trials have provided some reassurance regarding rosiglitazone use. In 2009, results of 4,447-patient Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) trial showed no increased risk of MI or mortality.
The BARI 2D trial was sponsored by GlaxoSmithKline, Astrellas Pharma US, Merck, Abbott Laboratories, and Pfizer Inc. Dr. Bach reported financial relationships with all those companies. Dr. Brooks had no conflicts to declare.
Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.
奥兰多(EGMN)——据对BARI 2D研究所做的一项最新的事后分析显示，有糖尿病和心血管危险因素的患者服用罗格列酮后，其死亡、心脏病发作或卒中的风险并未增加。
Richard Bach博士在美国糖尿病学会年会上说，这项分析表明，罗格列酮可能事实上还会产生针对心血管事件的保护作用。在一次新闻发布会上，他指出，与未服用噻唑烷二酮类药物的患者相比，服用罗格列酮者心脏病发作或卒中的风险，或死于心血管事件的可能性降低28%。
他说，上述结果应使人们对3年的有关罗格列酮安全谱的争论形成一定的认识，并有助于美国食品药品管理局(FDA)在7月13日召开的内分泌和代谢药物咨询委员会与药物安全和风险管理咨询委员会联合会议上对该药进行评价。他在一次受访中说道，尽管事后分析会有各种可能的干扰因素，但BARI 2D (N. Engl. J. Med. 2009; 360:2503-2515)研究确实为审查该药物的安全谱提供了一个极佳的途径。
圣路易斯华盛顿大学的Bach博士说：“该试验旨在观察高危群体中的心血管结局，因此我认为它所提供给我们的信息非常可靠。这应该使服用此药的患者略感宽慰。我认为，这些数据并未显示可能会使易感人群有风险的危害程度。”
为更好地阐释此问题，Bach博士及其同事开始对BARI 2D试验进行事后分析。BARI研究比较了胰岛素替代治疗与胰岛素增敏治疗的效果，其受试者为2,368例患有2型糖尿病合并稳定性冠心病的患者。另一项比较为即刻血运重建与延迟或无血运重建的比较。
患者未被随机分配接受罗格列酮治疗；噻唑烷二酮类药物治疗的实施由主治医生决定。992例患者服用了罗格列酮；鉴于BARI 2D试验的患者平均随访5年，故罗格列酮治疗组有逾3,000患者·年用于分析，BARI合作研究者、匹兹堡大学的Maria Brooks博士说。由于这些患者被判定需要服用其他抗糖尿病药，故接受罗格列酮治疗的患者相对于未接受该药治疗的患者而言，基线HbA1c水平较高，糖尿病病程较长且蛋白尿发生率较高。
近1,200例患者未服用噻唑烷二酮类药物，使随访数据超过7,000患者·年。
在回归分析中，对基线特征和其他抗糖尿病药物应用情况方面的差异进行调整后发现，罗格列酮与心血管死亡、心脏病发作及卒中构成的复合结局显著减少达28%有关。尽管罗格列酮治疗组心脏病发作率和心血管死亡率较低，但差异未达到统计学意义。
服用罗格列酮者骨折风险(62%)相对于未服用噻唑烷二酮类药物者显著增加。Bach博士说：“这种情况我们在其他试验中也曾观察到，并不感到意外。”
他补充说，单凭罗格列酮的这些数据还不足以完全平息这场争论。“‘安全’这一数据很难用于任何一种药物。在有关罗格列酮的信息方面，不得不继续等待针对“安全”以及“不安全”问题的明确答案。”
美国食品药品管理局计划于6月13日对罗格列酮的安全谱进行审核。Brooks博士将在会议期间公布BARI 2研究的数据。
2007年，克利夫兰诊所心血管药物主席Steven E. Nissen博士发表了他对42项罗格列酮相关的试验所做的荟萃分析的结果。从那时以来，罗格列酮一直备受争议。这项荟萃分析包括15,565例接受罗格列酮治疗的患者和12,282例接受安慰剂处置方案的患者。Steven博士检查了所有的心脏病发作和心血管死亡事件的发生情况，并断定罗格列酮导致心脏病发作风险显著增加43%，而心血管死亡风险增加64%(无意义)。
Nissen博士在他的论文中发现有86例心脏病发作和39例心血管死亡，该数字相对较小。他写道：“然而，由于糖尿病患者中心血管事件发生率很高，故我们的结果令人担忧。因为这类患者服用罗格列酮很普遍，若我们的数据通过进一步分析和较大型对照试验的结果得到证实，那么心血管风险增加将会产生极大的公共卫生影响”(N. Engl. J. Med. 2007; 356:2457-71)。
这项荟萃分析掀起了争论狂潮，最终导致FDA对罗格列酮安全性数据进行审查。2007年12月，FDA在该药的产品说明书中增加了一个有关潜在心脏风险的黑框警告。
自此以来，在罗格列酮使用方面的大型研究提供了一些“定心丸”。在2009年，包括4,447例患者的RECORD(评价罗格列酮对糖尿病患者心血管结局和血糖调节的影响)试验表明，服用罗格列酮未增加MI或死亡风险。
BARI 2D试验得到葛兰素史克、安斯泰来制药(美国)有限责任公司、默克、阿伯特实验室以及辉瑞公司的赞助。Bach博士报告称与上述所有公司均有经济关系。Brooks博士无利益冲突的声明。
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