Thr NEW ENGLAND JOURNAL Of MEDICINE and other clinical-trial data not within the pub. the potential risks of rosiglitazone in the treat ic domain further analyse s of data auiable to of type 2 diabe the eDa and the manufacturer would enable a t to rerfor more robust assessment of the risks of this drug ugh the Cl nd Our data suggest a cardiovascular risk associate with the us f rosiglitazone.Un re precis them to c estmates of th car dial her income nor a tax dedu kaootherpe 。 .Medica 11.We n P.Goldstein BI,Ros smtwithamprlandostgeaz ct a one oh ired gl Mo NB, N.h al dat May i8. a gowlcder foi M.ende cular fur nd e Is with rare events.stat med with of sparse data Srat Med 2004: ert P.Jo d R 02107 of the effe Bes2002.2.36 2107 in pat with htheadioa8 2001861659.20022 Endocrino and 17.1 ent from the American Heart As r 7.2003.Circulation 2003 AMd20030387-9 ter M.Van Gaal LE th Cole MA. of gl ling bu rdha Nisse SE.Wolski K.Top ion th apy in p g sul ular 1AMA2000284 etes 7 Ther 2003 3-d pr 2470 N ENGLJ MED 356:24 WWW.NEJM.ORG JUNE 14.2007 5.2016. ther uses without permissior ciety.All rights reserve
T h e n e w e ng l a nd j o u r na l o f m e dic i n e 2470 n engl j med 356;24 www.nejm.org june 14, 2007 and other clinical-trial data not within the public domain. Further analyses of data available to the FDA and the manufacturer would enable a more robust assessment of the risks of this drug. Our data suggest a cardiovascular risk associated with the use of rosiglitazone. Until more precise estimates of the cardiovascular risk of this treatment can be delineated in patients with diabetes, patients and providers should carefully consider the potential risks of rosiglitazone in the treatment of type 2 diabetes. Dr. Nissen reports receiving research support to perform clinical trials through the Cleveland Clinic Cardiovascular Coordinating Center from Pfizer, AstraZeneca, Daiichi Sankyo, Roche, Takeda, Sanofi-Aventis, and Eli Lilly. Dr. Nissen consults for many pharmaceutical companies but requires them to donate all honoraria or consulting fees directly to charity so that he receives neither income nor a tax deduction. No other potential conflict of interest relevant to this article was reported. We thank Craig Balog for statistical programming support. REFERENCES Vamecq J, Latruffe N. Medical significance of peroxisome proliferator-activated receptors. Lancet 1999;354:141-8. Campbell IW. The clinical significance of PPAR gamma agonism. Curr Mol Med 2005;5:349-63. Center for Drug Evaulation and Research. Approval package: Avandia (rosiglitazone maleate) tablets. Company: SmithKline Beecham Pharmaceuticals. Application no. 21-071. Approval date: 5/25/1999. (Accessed May 18, 2007, at http://www.fda.gov/cder/foi/nda/99/21071_ Avandia.htm.) American Diabetes Association. Complications of diabetes in the United States. (Accessed May 18, 2007, at http://www. diabetes.org/diabetes-statistics/ complications.jsp.) GlaxoSmithKline. Rosiglitazone studies. (Accessed May 18, 2007, at http://ctr. gsk.co.uk/Summary/rosiglitazone/ studylist.asp.) Center for Drug Evaluation and Research. Medical review(s). Application number: 021071. (Accessed May 18, 2007, at http://www.fda.gov/cder/foi/nda/99/ 21071_Avandia_medr.pdf.) Lebovitz HE, Dole JF, Patwardhan R, Rappaport EB, Freed MI. Rosiglitazone monotherapy is effective in patients with type 2 diabetes. J Clin Endocrinol Metab 2001;86:280-8. [Errata, J Clin Endocrinol Metab 2001;86:1659, 2002;2:iv.] Phillips LS, Grunberger G, Miller E, et al. Once- and twice-daily dosing with rosiglitazone improves glycemic control in patients with type 2 diabetes. Diabetes Care 2001;24:308-15. [Erratum, Diabetes 2001;24:973.] Jones TA, Sautter M, Van Gaal LF, Jones NP. Addition of rosiglitazone to metformin is most effective in obese, insulin-resistant patients with type 2 diabetes. Diabetes Obes Metab 2003;5:163-70. Fonseca V, Rosenstock J, Patwardhan R, Salzman A. Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial. JAMA 2000;283: 1695-702. [Erratum, JAMA 2000;284: 1384.] 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Weissman P, Goldstein BJ, Rosenstock J, et al. Effects of rosiglitazone added to submaximal doses of metformin compared with dose escalation of metformin in type 2 diabetes: the EMPIRE Study. Curr Med Res Opin 2005;21:2029-35. Wolffenbuttel BH, Gomis R, Squatrito S, Jones NP, Patwardhan RN. Addition of low-dose rosiglitazone to sulphonylurea therapy improves glycaemic control in Type 2 diabetic patients. Diabet Med 2000;17:40-7. St John Sutton M, Rendell M, Dandona P, et al. A comparison of the effects of rosiglitazone and glyburide on cardiovascular function and glycemic control in patients with type 2 diabetes. Diabetes Care 2002;25:2058-64. Raskin P, Rendell M, Riddle MC, et al. A randomized trial of rosiglitazone therapy in patients with inadequately controlled insulin-treated type 2 diabetes. Diabetes Care 2001;24:1226-32. Vongthavaravat V, Wajchenberg BL, Waitman JN, et al. An international study of the effects of rosiglitazone plus sulphonylurea in patients with type 2 diabetes. Curr Med Res Opin 2002;18:456-61. Baksi A, James RE, Zhou B, Nolan JJ. Comparison of uptitration of gliclazide with the addition of rosiglitazone to gliclazide in patients with type 2 diabetes inadequately controlled on half-maximal doses of a sulphonylurea. Acta Diabetol 2004;41:63-9. Barnett AH, Grant PJ, Hitman GA, et al. Rosiglitazone in Type 2 diabetes mellitus: an evaluation in British Indo-Asian patients. Diabet Med 2003;20:387-93. Kerenyi Z, Samer H, James R, Yan Y, Stewart M. Combination therapy with rosiglitazone and glibenclamide compared with upward titration of glibenclamide alone in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract 2004;63:213-23. Zhu XX, Pan CY, Li GW, et al. Addition of rosiglitazone to existing sulfonylurea treatment in Chinese patients with type 2 diabetes and exposure to hepatitis B or C. Diabetes Technol Ther 2003;5:33-42. The DREAM (Diabetes Reduction As- 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. sessment with ramipril and rosiglitazone Medication) Investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 2006;368:1096- 105. [Erratum, Lancet 2006;368:1770.] Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006;355:2427-43. [Erratum, N Engl J Med 2007;356:1387-8.] Bradburn MJ, Deeks JJ, Berlin JA, Localio AR. Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events. Stat Med 2007;26:53-77. Sweeting MJ, Sutton AJ, Lambert PC. What to add to nothing? Use and avoidance of continuity corrections in metaanalysis of sparse data. Stat Med 2004;23: 1351-75. [Erratum, Stat Med 2006;25:2700.] Sutton A, Cooper N, Lambert P, Jones D, Abrams K, Sweeting M. Meta-analysis of rare and adverse event data. Pharmacoeconomics Outcomes Res 2002;2:367. Avandia (rosiglitazone maleate) tablets: prescribing information. Research Triangle Park, NC: GlaxoSmithKline, 2007 (package insert). (Accessed May 18, 2007, at http://www.fda.gov/cder/foi/label/2007/ 021071s023lbl.pdf.) Nesto RW, Bell D, Bonow RO, et al. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association: October 7, 2003. Circulation 2003; 108:2941-8. Lygate CA, Hulbert K, Monfared M, Cole MA, Clarke K, Neubauer S. The PPARgamma-activator rosiglitazone does not alter remodeling but increases mortality in rats post-myocardial infarction. Cardiovasc Res 2003;58:632-7. Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA 2005; 294:2581-6. El-Hage J. Peroxisome proliferatoractivated receptor (PPAR) agonists: pre- 21. 22. 23. 24. 25. 26. 27. 28. 29. The New England Journal of Medicine Downloaded from nejm.org on February 5, 2016. For personal use only. No other uses without permission. Copyright © 2007 Massachusetts Medical Society. All rights reserved
ROSIGLITAZONE AND CARDIOVASCULAR OUTCOMES a rand rmandy IA.Charbonnel B.Eckland TICLES ON THD ds to log on tor elec 02g N ENCL J MED 3564 WWW.NEJM.ORG JUNE14.2007 2471
Rosiglitazone and Cardiovascular Outcomes n engl j med 356;24 www.nejm.org june 14, 2007 2471 clinical and clinical cardiac safety considerations. Rockville, MD: Center for Drug Evaluation and Research, 2006. (Accessed May 18, 2007, at http://www.fda.gov/cder/ present/DIA2006/El-Hage_CardiacSafety. ppt.) Lemay DG, Hwang DH. Genome-wide identification of peroxisome proliferator response elements using integrated computational genomics. J Lipid Res 2006; 47:1583-7. Dormandy JA, Charbonnel B, Eckland 30. 31. DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366:1279-89. Goldberg RB, Kendall DM, Deeg MA, et al. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care 2005;28:1547- 54. 32. Riveline JP, Danchin N, Ledru F, Varroud-Vial M, Charpentier G. Sulfonylureas and cardiovascular effects: from experimental data to clinical use: available data in humans and clinical applications. Diabetes Metab 2003;29:207-22. Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD): study design and protocol. Diabetologia 2005;48:1726-35. Copyright © 2007 Massachusetts Medical Society 33. 34. full text of all journal articles on the world wide web Access to the complete text of the Journal on the Internet is free to all subscribers. To use this Web site, subscribers should go to the Journal’s home page (www.nejm.org) and register by entering their names and subscriber numbers as they appear on their mailing labels. After this one-time registration, subscribers can use their passwords to log on for electronic access to the entire Journal from any computer that is connected to the Internet. Features include a library of all issues since January 1993 and abstracts since January 1975, a full-text search capacity, and a personal archive for saving articles and search results of interest. All articles can be printed in a format that is virtually identical to that of the typeset pages. Beginning 6 months after publication, the full text of all Original Articles and Special Articles is available free to nonsubscribers who have completed a brief registration. The New England Journal of Medicine Downloaded from nejm.org on February 5, 2016. For personal use only. No other uses without permission. Copyright © 2007 Massachusetts Medical Society. All rights reserved
罗格列酮大事记 罗格列酮是一种噻唑烷二酮类糖尿病药物。 1.2007年《新英格兰医学杂志》(NEM)上发表一篇荟萃分析，该研究报告 说文迪雅可能大幅增加心脏病风险引发世界关注。 2.自2010年起，罗格列酮的心血管风险争议引起各国药品管理部门的重视，欧 洲最早做出反应。2010年9月份，欧洲药品管理局(EMA)认为罗格列酮的 心血管风险超过其收益，EMA于2010年9月23日发表声明停止罗格列酮的临 床使用许可，暂停该药物的市场销售，在全欧洲范围内禁止罗格列酮，这意 味着罗格列酮药物从欧洲全面退市。 3.美国FDA同日发表声明，但没有暂停其市场销售，而是给予文迪雅“黑框” 警示，并要求葛兰素史克修改药物说明书，添加可能导致心血管风险的提示， 要求临床医生在使用该药时应进行适当的限制。要求重新审查个体病人的罗 格列酮心血管结果评价及RECORD研究。 4.2011年5月18日，FDA通过对含有罗格列酮的药物制定风险评估和管控策略 (REMS)程序，以确保没有其它治疗选择的患者能安全使用该药物。其程序 包括： (1)医务人员和患者必须加入文迪雅罗格列酮药物获取项目，方可开具处 方和获取药物： (2)医务人员和药师必须接受专门培训并取得相应资格： (3)仅通过认证的药商才能销售罗格列酮： (4)也只有既往一直服用罗格列酮的患者和不适合使用其他降糖药物的新 患者能继续接受罗格列酮治疗： (5)患者将不能在药店直接买到罗格列酮，必须通过邮购的形式。 同时，项目将就该药物的潜在风险及限制使用必要性开展教育。 5.在2013年6月召开的会议上，内分泌和代谢药物咨询委员会及风险管理咨询 委员会聚集在一起对RECORD的重新分析结果进行讨论。FDA专家小组再次 审查了Record研究及其后续分析结果。26名专家组成员中有13名投票支持罗 格列酮继续在市并建议解除对罗格列酮的相关限制
罗格列酮大事记 罗格列酮是一种噻唑烷二酮类糖尿病药物。 1. 2007年《新英格兰医学杂志》（NEJM）上发表一篇荟萃分析，该研究报告 说文迪雅可能大幅增加心脏病风险引发世界关注。 2. 自2010年起，罗格列酮的心血管风险争议引起各国药品管理部门的重视，欧 洲最早做出反应。2010年9月份，欧洲药品管理局（EMA）认为罗格列酮的 心血管风险超过其收益，EMA于2010年9月23日发表声明停止罗格列酮的临 床使用许可，暂停该药物的市场销售，在全欧洲范围内禁止罗格列酮，这意 味着罗格列酮药物从欧洲全面退市。 3. 美国FDA同日发表声明，但没有暂停其市场销售，而是给予文迪雅“黑框” 警示，并要求葛兰素史克修改药物说明书，添加可能导致心血管风险的提示， 要求临床医生在使用该药时应进行适当的限制。要求重新审查个体病人的罗 格列酮心血管结果评价及 RECORD 研究。 4. 2011年5月18日，FDA 通过对含有罗格列酮的药物制定风险评估和管控策略 (REMS)程序，以确保没有其它治疗选择的患者能安全使用该药物。其程序 包括： （1）医务人员和患者必须加入文迪雅-罗格列酮药物获取项目，方可开具处 方和获取药物； （2）医务人员和药师必须接受专门培训并取得相应资格； （3）仅通过认证的药商才能销售罗格列酮； （4）也只有既往一直服用罗格列酮的患者和不适合使用其他降糖药物的新 患者能继续接受罗格列酮治疗； （5）患者将不能在药店直接买到罗格列酮，必须通过邮购的形式。 同时，项目将就该药物的潜在风险及限制使用必要性开展教育。 5. 在2013年6月召开的会议上，内分泌和代谢药物咨询委员会及风险管理咨询 委员会聚集在一起对RECORD的重新分析结果进行讨论。FDA专家小组再次 审查了Record研究及其后续分析结果。26名专家组成员中有13名投票支持罗 格列酮继续在市并建议解除对罗格列酮的相关限制
6.2013年11月25日，美国食品与药品监督管理局(FDA)在其官方网站发布声 明，根据最新研究成果，将解除罗格列酮及其复方糖尿病药物的使用及处方 限制。 (1)FDA在声明中指出，尽管一些科学研究对罗格列酮的心血管安全性仍 存质疑，但最新发表的RECORD研究的结论显示，与糖尿病标准药物疗法相 比，文迪雅并未增加心脏病发作及死亡的风险)，这大大减少了我们对罗格 列酮的担忧和顾虑。 (2)FDA最终做出全面解除罗格列酮限制的决定，包括解除医务人员、患 者和药店均需注册特殊项目才能继续处方和接受含罗格列酮的药物的限制， 患者可以通过正规的零售药店和药商直接购买或邮购。含罗格列酮药物的生 产厂商需要告知医生目前对该药物心血管风险的认识。 (3)葛兰素史克发表声明说，该公司“欢迎FDA的决定并欣赏该机构对有关 文迪雅研究的认真审查，葛兰素史克始终坚持“只要使用得当，文迪雅是 款安全且有效的2型糖尿病治疗药物”，并表示将公司将与FDA合作更新文迪 雅的标签内容并实施FDA放宽限制的决定。 (4)另一方面，纽约西奈山糖尿病中心主任Robert Tamler博士表示，FDA 撤销限制的决定对临床实践是无关紧要的。患者从2007年开始就一直接收文 迪雅增加心血管风险的信息，即使FDA撤销对文迪雅的使用限制，患者对文 迪雅安全性的忧虑一时难以打消。 7.在中国，罗格列酮则一直没有退出市场。2000年10月上市后，一直到2013 年10月16日，中国国家食品药品监督局和卫生部联合发文，要求各级医疗机 构加强对于罗格列酮及其复方制剂的使用管理，同时要求生产企业在10月30 日之前按要求完成药品说明书的修改
6. 2013年11月25日，美国食品与药品监督管理局（FDA）在其官方网站发布声 明，根据最新研究成果，将解除罗格列酮及其复方糖尿病药物的使用及处方 限制。 （1）FDA在声明中指出，尽管一些科学研究对罗格列酮的心血管安全性仍 存质疑，但最新发表的RECORD研究的结论显示，与糖尿病标准药物疗法相 比，文迪雅并未增加心脏病发作及死亡的风险)，这大大减少了我们对罗格 列酮的担忧和顾虑。 （2）FDA最终做出全面解除罗格列酮限制的决定，包括解除医务人员、患 者和药店均需注册特殊项目才能继续处方和接受含罗格列酮的药物的限制， 患者可以通过正规的零售药店和药商直接购买或邮购。含罗格列酮药物的生 产厂商需要告知医生目前对该药物心血管风险的认识。 （3）葛兰素史克发表声明说，该公司“欢迎FDA的决定并欣赏该机构对有关 文迪雅研究的认真审查，葛兰素史克始终坚持“只要使用得当，文迪雅是一 款安全且有效的2型糖尿病治疗药物”，并表示将公司将与FDA合作更新文迪 雅的标签内容并实施FDA放宽限制的决定。 （4）另一方面，纽约西奈山糖尿病中心主任 Robert Tamler博士表示，FDA 撤销限制的决定对临床实践是无关紧要的。患者从2007年开始就一直接收文 迪雅增加心血管风险的信息，即使FDA撤销对文迪雅的使用限制，患者对文 迪雅安全性的忧虑一时难以打消。 7. 在中国，罗格列酮则一直没有退出市场。2000年10月上市后，一直到2013 年10月16日，中国国家食品药品监督局和卫生部联合发文，要求各级医疗机 构加强对于罗格列酮及其复方制剂的使用管理，同时要求生产企业在10月30 日之前按要求完成药品说明书的修改
1 What is Pharmacoepidemiology? Uaterdity of PUSA re inheo ficlds.The history of drug reguation will theb a0g,191 cuy and se ctively revi ed,focusing on the ting how cent decades.modern medicine has ory process for the with a pharmaceutical arm tarium what it had befor to place the use of phar re for our patients.itha Fina drug surveilla prope o do much greater contributions ofpha of product liabilty suits against pham eutica a w2 a political了 change in pharr ons.The harm that drug ge numbers o he fiel ha. eople.The term ag in book.More the field has ude issues other than ndeniandha指anwharnon The scope of ph this chapter will b cal pharmacology,and then to that of epide 614T an).Edited by Brian L Strom