The NEW ENGLAND JOURNAL f MEDICINE AHIAZOLIDINEDIONE DRUGS ARE WIDE any mvocardial infarctions or deaths from cardic ly used to lower hlood glucose levels in na and therefo tients with type 2 diabetes mellitus.In the in the analysis because the effect measure could United States,three such agents have been intro- not be calculated.Of the remaining 42 studies, 38 reported at least one myocardi: and 23 reported at le st one ed e ra comparator groups with regimens that did not receptors are ligand-activated nuclear transcrip- include rosiglitazone. tion factors that modulate gene expression,lower Multiple groups of patients who received rosig ing blood glucose primarily by increasing insulin when appli cable.The control g roup wa wide used as pa rec ing any d falt reg ries.One group includes five of the stud. or glimepiride (Avandaryl,GlaxoSmithKline). ies submitted to the FDA for the March 22,1999. The original approval of rosiglitazone was advisory board hearing that recommended ap- based on the ability of the drug to reduce blo proval of rosiglitazone.Group-level data from glucose and glycat d hem oglobin levels s are availab stu cd ve stud cun ite s D rom the rted in fashime trials cluding cardiovascular morbidity and mortality. However,the effect of any antidiabetic therapy on cardiovascular outcomes is particularly im- of these five trials were also published in peer reviewed journals.In these e trials,1967 es are tients we or active com rators to ass sess the effect of this Other studies that meta agent on cardiovascular outcomes.The sourc analysis were initially identified in the glaxo material for this analysis consisted of publicly SmithKline clinical-trial registry.As noted in available data from the original registration pack Table 1,we included 35 studies in this category age submitted to the F od and Drug Administr tion (FDA),a er serie of trial 26 ssible.the d on al indications for the drug. cthhepebicionnsoFantheake between published and unpublished data,data METHODS derived from the manufacturer's web site were used.In this group of 35 trials,9507 7 patients sts the 42 trials d11 48 trials me defined inclusion criteria of having a randomized comparator group,a similar duration of treat Assessment with Ramipiril and Rosiglitazone ment in all groups,and more than 24 weeks of Medication (DREAM)NCT00095654 trial20 and drug exposure.Six of the 48 trials did not report the A Diabetes Outcome Prevention Trial (ADOPT) 2458 N ENGLJ MED 356:24 WWW.NEJM.ORG JUNE 14.2007T h e n e w e ng l a nd j o u r na l o f m e dic i n e 2458 n engl j med 356;24 www.nejm.org june 14, 2007 Thiazolidinedione drugs are wide￾ly used to lower blood glucose levels in pa￾tients with type 2 diabetes mellitus. In the United States, three such agents have been intro￾duced: troglitazone, which was removed from the market because of hepatotoxicity, and two current￾ly available agents, rosiglitazone (Avandia, Glaxo￾SmithKline) and pioglitazone (Actos, Takeda). The thiazolidinediones are agonists for peroxisome￾proliferator–activated receptor γ (PPAR-γ). PPAR-γ receptors are ligand-activated nuclear transcrip￾tion factors that modulate gene expression, lower￾ing blood glucose primarily by increasing insulin sensitivity in peripheral tissues.1,2 Rosiglitazone was introduced in 1999 and is widely used as monotherapy or in fixed-dose combinations with either metformin (Avandamet, GlaxoSmithKline) or glimepiride (Avandaryl, GlaxoSmithKline). The original approval of rosiglitazone was based on the ability of the drug to reduce blood glucose and glycated hemoglobin levels.3 Initial studies were not adequately powered to deter￾mine the effects of this agent on microvascular or macrovascular complications of diabetes, in￾cluding cardiovascular morbidity and mortality.3 However, the effect of any antidiabetic therapy on cardiovascular outcomes is particularly im￾portant, because more than 65% of deaths in patients with diabetes are from cardiovascular causes.4 Therefore, we performed a meta-analy￾sis of trials comparing rosiglitazone with placebo or active comparators to assess the effect of this agent on cardiovascular outcomes. The source material for this analysis consisted of publicly available data from the original registration pack￾age submitted to the Food and Drug Administra￾tion (FDA), another series of trials performed by the sponsor after approval, and two large, prospec￾tive, randomized trials designed to study addition￾al indications for the drug. Me thods Analyzed Studies Table 1 lists the 42 trials included in this meta￾analysis. We screened 116 phase 2, 3, and 4 trials for inclusion. Of these, 48 trials met the pre￾defined inclusion criteria of having a randomized comparator group, a similar duration of treat￾ment in all groups, and more than 24 weeks of drug exposure. Six of the 48 trials did not report any myocardial infarctions or deaths from cardio￾vascular causes and therefore were not included in the analysis because the effect measure could not be calculated. Of the remaining 42 studies, 38 reported at least one myocardial infarction, and 23 reported at least one death from cardio￾vascular causes. In these trials, 15,565 patients were randomly assigned to regimens that includ￾ed rosiglitazone, and 12,282 were assigned to comparator groups with regimens that did not include rosiglitazone. Multiple groups of patients who received rosig￾litazone within a single trial were pooled togeth￾er, when applicable. The control group was de￾fined as patients receiving any drug regimen other than rosiglitazone. The trials fall into three categories. One group includes five of the stud￾ies submitted to the FDA for the March 22, 1999, advisory board hearing that recommended ap￾proval of rosiglitazone. Group-level data from these five studies are available in publicly dis￾closed briefing documents archived on the FDA Web site.6 Data from these same trials are also reported in a summary fashion on a clinical￾trial registry Web site maintained by the drug manufacturer, GlaxoSmithKline.5 Reports of four of these five trials were also published in peer￾reviewed journals.7-9 In these five trials, 1967 pa￾tients were randomly assigned to receive rosiglit￾azone, and 793 patients were assigned to receive various comparator drugs (Table 1). Other studies that we included in the meta￾analysis were initially identified in the Glaxo￾SmithKline clinical-trial registry.5 As noted in Table 1, we included 35 studies in this category, 9 of which were published in peer-reviewed jour￾nals and 26 of which remain unpublished.10-18 Whenever possible, the results obtained on the Glaxo­SmithKline Web site were cross-checked with the publication. In cases of disagreement between published and unpublished data, data derived from the manufacturer’s Web site were used. In this group of 35 trials, 9507 patients were randomly assigned to receive rosiglitazone, and 5960 patients were assigned to receive vari￾ous comparator drugs. A third data source consisted of two large, recently published trials, the Diabetes Reduction Assessment with Ramipiril and Rosiglitazone Medication (DREAM) NCT00095654 trial20 and the A Diabetes Outcome Prevention Trial (ADOPT) 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