Background Rosiglitazone is widely used to treat patients withtype 2 diabetes mellitus, but its effect on cardiovascular morbidityand mortality has not been determined.
Methods We conducted searches of the published literature, theWeb site of the Food and Drug Administration, and a clinical-trialsregistry maintained by the drug manufacturer (GlaxoSmithKline).Criteria for inclusion in our meta-analysis included a studyduration of more than 24 weeks, the use of a randomized controlgroup not receiving rosiglitazone, and the availability of outcomedata for myocardial infarction and death from cardiovascularcauses. Of 116 potentially relevant studies, 42 trials met theinclusion criteria. We tabulated all occurrences of myocardialinfarction and death from cardiovascular causes.
Results Data were combined by means of a fixed-effects model.In the 42 trials, the mean age of the subjects was approximately56 years, and the mean baseline glycated hemoglobin level wasapproximately 8.2%. In the rosiglitazone group, as comparedwith the control group, the odds ratio for myocardial infarctionwas 1.43 (95% confidence interval [CI], 1.03 to 1.98; P=0.03),and the odds ratio for death from cardiovascular causes was1.64 (95% CI, 0.98 to 2.74; P=0.06).
Conclusions Rosiglitazone was associated with a significantincrease in the risk of myocardial infarction and with an increasein the risk of death from cardiovascular causes that had borderlinesignificance. Our study was limited by a lack of access to originalsource data, which would have enabled time-to-event analysis.Despite these limitations, patients and providers should considerthe potential for serious adverse cardiovascular effects oftreatment with rosiglitazone for type 2 diabetes.
Thiazolidinedione drugs are widely used to lower blood glucoselevels in patients with type 2 diabetes mellitus. In the UnitedStates, three such agents have been introduced: troglitazone,which was removed from the market because of hepatotoxicity,and two currently available agents, rosiglitazone (Avandia,GlaxoSmithKline) and pioglitazone (Actos, Takeda). The thiazolidinedionesare agonists for peroxisome-proliferator–activated receptor (PPAR-). PPAR- receptors are ligand-activated nuclear transcriptionfactors that modulate gene expression, lowering blood glucoseprimarily by increasing insulin sensitivity in peripheral tissues.1,2Rosiglitazone was introduced in 1999 and is widely used as monotherapyor in fixed-dose combinations with either metformin (Avandamet,GlaxoSmithKline) or glimepiride (Avandaryl, GlaxoSmithKline).
The original approval of rosiglitazone was based on the abilityof the drug to reduce blood glucose and glycated hemoglobinlevels.3 Initial studies were not adequately powered to determinethe effects of this agent on microvascular or macrovascularcomplications of diabetes, including cardiovascular morbidityand mortality.3 However, the effect of any antidiabetic therapyon cardiovascular outcomes is particularly important, becausemore than 65% of deaths in patients with diabetes are from cardiovascularcauses.4 Therefore, we performed a meta-analysis of trials comparingrosiglitazone with placebo or active comparators to assess theeffect of this agent on cardiovascular outcomes. The sourcematerial for this analysis consisted of publicly available datafrom the original registration package submitted to the Foodand Drug Administration (FDA), another series of trials performedby the sponsor after approval, and two large, prospective, randomizedtrials designed to study additional indications for the drug.
Methods
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 predefined inclusion criteria of having arandomized comparator group, a similar duration of treatmentin all groups, and more than 24 weeks of drug exposure. Sixof the 48 trials did not report any myocardial infarctions ordeaths from cardiovascular causes and therefore were not includedin the analysis because the effect measure could not be calculated.Of the remaining 42 studies, 38 reported at least one myocardialinfarction, and 23 reported at least one death from cardiovascularcauses. In these trials, 15,565 patients were randomly assignedto regimens that included rosiglitazone, and 12,282 were assignedto comparator groups with regimens that did not include rosiglitazone.
Table 1. Clinical Trials of Rosiglitazone in the Meta-Analysis.
Multiple groups of patients who received rosiglitazone withina single trial were pooled together, when applicable. The controlgroup was defined as patients receiving any drug regimen otherthan rosiglitazone. The trials fall into three categories. Onegroup includes five of the studies submitted to the FDA forthe March 22, 1999, advisory board hearing that recommendedapproval of rosiglitazone. Group-level data from these fivestudies are available in publicly disclosed briefing documentsarchived on the FDA Web site.6 Data from these same trials arealso reported in a summary fashion on a clinical-trial registryWeb site maintained by the drug manufacturer, GlaxoSmithKline.5Reports of four of these five trials were also published inpeer-reviewed journals.7,8,9 In these five trials, 1967 patientswere randomly assigned to receive rosiglitazone, and 793 patientswere assigned to receive various comparator drugs (Table 1).
Other studies that we included in the meta-analysis were initiallyidentified in the GlaxoSmithKline clinical-trial registry.5As noted in Table 1, we included 35 studies in this category,9 of which were published in peer-reviewed journals and 26 ofwhich remain unpublished.10,11,12,13,14,15,16,17,18 Wheneverpossible, the results obtained on the GlaxoSmithKline Web sitewere cross-checked with the publication. In cases of disagreementbetween published and unpublished data, data derived from themanufacturer'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 various comparatordrugs.
A third data source consisted of two large, recently publishedtrials, the Diabetes Reduction Assessment with Ramipiril andRosiglitazone Medication (DREAM) NCT00095654
[ClinicalTrials.gov]
trial20 and theA Diabetes Outcome Prevention Trial (ADOPT) (ClinicalTrials.govnumber, NCT00279045
[ClinicalTrials.gov]
).21 In the DREAM study, 2635 patients wererandomly assigned to receive rosiglitazone and 2634 patientswere assigned to receive placebo. The DREAM study was designedto determine whether rosiglitazone could prevent the developmentof type 2 diabetes in patients at high risk for this disorder.In the ADOPT trial, 1456 patients were randomly assigned toreceive rosiglitazone and 2895 patients were assigned to receiveeither metformin or glyburide. The ADOPT study was designedto assess the durability of glycemic control with rosiglitazonetherapy, as compared with therapy with metformin or glyburide.
Outcome Measures
We reviewed data summaries provided in the FDA review documents,the GlaxoSmithKline clinical-trial registry Web site, and publishedtrial results and then abstracted from the adverse-event tabulationsinformation on myocardial infarction and death from cardiovascularcauses. With the exception of the DREAM study, the includedtrials did not describe adjudication of myocardial infarctionor death from cardiovascular causes. Time-to-event data forcardiovascular events were not available in any of these trials,which precluded the calculation of hazard ratios. Because onlysummary data were available, it was not possible to discernwhether the same patient had both events. Therefore, an outcomemeasure based on the composite of death or myocardial infarctioncould not be constructed. Accordingly, these two outcomes arereported separately.
Statistical Analysis
Many trials had few cardiovascular events, so the odds ratiosand 95% confidence intervals were calculated with the use ofthe Peto method.22,23,24 Because all trials had similar durationsof follow-up for all treatment groups, the use of odds ratiosrepresents a valid approach to assessing the risk associatedwith the use of rosiglitazone. Trials in which patients hadno adverse cardiovascular events in either group were excludedfrom analyses. All reported P values are two-sided. Statisticalheterogeneity across the various trials was tested with theuse of Cochran's Q statistic. A P value of more than the nominallevel of 0.10 for the Q statistic indicated a lack of heterogeneityacross trials, allowing for the use of a fixed-effects model.For additional analyses, the active comparator control groupswere subgrouped into the following four classes for comparisonwith rosiglitazone: metformin, sulfonylurea, insulin, and placebo.Odds ratios and 95% confidence intervals were calculated foreach subgroup with the use of methods similar to those usedin the pooled analyses. Data were analyzed with the use of ComprehensiveMeta-Analysis software, version 2.2 (Biostat).
Results
Baseline Characteristics
Table 2 reports the doses of rosiglitazone and comparator drugs,baseline demographic characteristics, study periods, and glycatedhemoglobin levels or fasting blood glucose levels for patientsenrolled in the trials. The patients were relatively young,averaging less than 57 years of age for both the rosiglitazonegroup and the control group. Overall, there was a moderate predominanceof men. Diabetes control was relatively poor, with a mean baselineglycated hemoglobin level of approximately 8.2% for both studygroups.
Table 2. Doses, Baseline Demographic Characteristics, Study Periods, and Glycated Hemoglobin Levels.
Myocardial Infarction and Death
Table 3 reports the myocardial infarction events and deathsfrom cardiovascular causes that were reported in the 42 clinicaltrials we reviewed. There were 86 myocardial infarctions inthe rosiglitazone group and 72 in the control group. There were39 deaths from cardiovascular causes in the rosiglitazone groupand 22 in the control group. Table 4 lists the odds ratios,95% confidence intervals, and P values for myocardial infarctionand death from cardiovascular causes for the rosiglitazone groupand the control group. The summary odds ratio for myocardialinfarction was 1.43 in the rosiglitazone group (95% confidenceinterval [CI], 1.03 to 1.98; P=0.03). The odds ratio for deathfrom cardiovascular causes in the rosiglitazone group, as comparedwith the control group, was 1.64 (95% CI, 0.98 to 2.74; P=0.06).Table 4 also lists odds ratios and 95% confidence intervalsfor the pooled group of trials that were smaller and of shorterduration; results for the DREAM and ADOPT studies are shownseparately.
Table 4. Rates of Myocardial Infarction and Death from Cardiovascular Causes.
Table 5 lists odds ratios for myocardial infarction and deathfrom cardiovascular causes associated with rosiglitazone forsubgroups defined according to the comparator drug. Similarresults were obtained when the analysis excluded trials withan active comparator group. The heterogeneity P values were0.53 for myocardial infarction and 0.68 for death from cardiovascularcauses across subgroups. As compared with placebo or other antidiabeticregimens, the estimated odds ratios in all cases were greaterthan 1.0, suggesting that observed adverse effects during rosiglitazonetreatment were not unique to any specific comparator regimen.
Table 5. Risk of Myocardial Infarction and Death from Cardiovascular Causes for Patients Receiving Rosiglitazone versus Several Comparator Drugs.
In an analysis that was not prespecified, we also studied theeffects of rosiglitazone on death from any cause. The odds ratiofor death from any cause was 1.18 (95% CI, 0.89 to 1.55; P=0.24).
Discussion
Our data show that, as compared with placebo or with other antidiabeticregimens, treatment with rosiglitazone was associated with asignificant increase in the risk of myocardial infarction andwith an increase in the risk of death from cardiovascular causesthat was of borderline significance. The similar odds ratiofor comparison with placebo suggests that the increased riskassociated with rosiglitazone was not a function of the protectiveeffects of active comparator drugs. However, these findingsare based on limited access to trial results from publicly availablesources, not on patient-level source data. Furthermore, resultsare based on a relatively small number of events, resultingin odds ratios that could be affected by small changes in theclassification of events. Nonetheless, our findings are worrisomebecause of the high incidence of cardiovascular events in patientswith diabetes.4 Because exposure of such patients to rosiglitazoneis widespread, the public health impact of an increase in cardiovascularrisk could be substantial if our data are borne out by furtheranalysis and the results of larger controlled trials.
Although we did not have access to the source data to constructa composite outcome that included myocardial infarction or deathfrom cardiovascular causes, the increase in the odds ratiosfor both of these end points suggests that observed adverseeffects associated with rosiglitazone were probably not dueto chance alone. This meta-analysis included a group of trialsthat were of relatively short duration (24 to 52 weeks). Theodds ratio for these shorter-term trials was similar to theoverall results of the meta-analysis. Thus, in susceptible patients,rosiglitazone therapy may be capable of provoking myocardialinfarction or death from cardiovascular causes after relativelyshort-term exposure. In contrast, long-term therapies that improvecardiovascular outcomes, such as statins and antihypertensivedrugs, often take several years to provide benefits. Notably,the estimates for the odds ratios for myocardial infarctionand death from cardiovascular causes appear elevated for rosiglitazonein comparison with placebo or other commonly prescribed antidiabetictherapies (Table 5).
The mechanism for the apparent increase in myocardial infarctionand death from cardiovascular causes associated with rosiglitazoneremains uncertain. One potential contributing factor may bethe adverse effect of the drug on serum lipids. The FDA-approvedrosiglitazone product label reports a mean increase in low-densitylipoprotein (LDL) cholesterol of 18.6% among patients treatedfor 26 weeks with an 8-mg daily dose, as compared with placebo.25In observational studies and lipid-lowering trials, elevatedlevels of LDL cholesterol were associated with an increase inadverse cardiovascular outcomes. Thus, an increase in LDL cholesterolof the magnitude observed in the rosiglitazone group may havecontributed to adverse cardiovascular outcomes, although therapidity and magnitude of the apparent hazard was not consistentwith an effect produced by lipid changes alone.
Several other properties of rosiglitazone may contribute toadverse cardiovascular outcomes. Rosiglitazone and other thiazolidinedionesare known to precipitate congestive heart failure in susceptiblepatients.26 Congestive heart failure is a physiological statethat is associated with an increased intravascular volume. Volumeoverload increases stress on the left ventricular wall, a factorthat determines myocardial oxygen demand. In susceptible patients,an increase in myocardial oxygen demand could theoreticallyprovoke ischemic events. The administration of thiazolidinediones,including rosiglitazone, also produces a modest reduction inthe hemoglobin level.25 In susceptible patients, a reduced hemoglobinlevel may result in increased physiological stress, therebyprovoking myocardial ischemia. A study of rosiglitazone thatwas conducted in rats reported an increase in the rate of deathafter experimentally induced myocardial infarction.27
Rosiglitazone is not the first PPAR agonist that has been reportedto increase adverse cardiovascular events. Muraglitazar, aninvestigational dual PPAR- and PPAR- agonist, increased adversecardiovascular events, including myocardial infarction, duringphase 2 and 3 testing.28 After publication of an analysis ofcardiovascular outcomes, muraglitazar was not approved by theFDA, and further development was subsequently halted by themanufacturer. Development programs for many other PPAR agonistshave been terminated after evidence of toxicity emerged duringpreclinical studies or initial trials in humans. According toa former FDA official, more than 50 Investigational New Drugapplications for novel PPARs have been filed, but no additionaldrugs have successfully reached the market in more than 6 years.29In some cases, these drugs have failed because of evidence ofdirect myocardial toxicity in studies in animals,29 but fewdata on toxicity are available in the public domain becauseof the common industry practice of not publishing safety findingsfor failed products.
PPAR agonists such as rosiglitazone have very complex biologiceffects, resulting from the activation or suppression of dozensof genes.30 The patterns of gene activation or suppression differsubstantially among various PPAR agonists, even within closelyrelated compounds. The biologic effects of the protein targetsfor most of the genes influenced by PPAR agonists remain largelyunknown. Accordingly, many different and seemingly unrelatedtoxic effects have emerged during development of other PPARagents.29 Some drugs have provoked multispecies, multi–organsystem cancers; others have resulted in rhabdomyolysis or nephrotoxicity.29Troglitazone was withdrawn from the market for rare, but sometimesfatal, liver toxicity. Accordingly, it must be assumed thata variety of unexpected toxic effects are possible when PPARagonists are administered to patients.
The question as to whether the observed risks of rosiglitazonerepresent a "class effect" of thiazolidinediones must also beconsidered. Pioglitazone is a related agent also widely usedto treat type 2 diabetes mellitus. However, unlike rosiglitazone,pioglitazone has been studied in a prospective, randomized trialof cardiovascular outcomes, called Prospective PioglitazoneClinical Trial in Macrovascular Events (PROACTIVE).31 The primaryend point, a broad composite that included coronary and peripheralvascular events, showed a trend toward benefit from pioglitazone(hazard ratio, 0.90; P=0.095). A secondary end point consistingof myocardial infarction, stroke, and death from any cause showeda significant effect favoring pioglitazone (hazard ratio, 0.84;P=0.027). Notably, pioglitazone appears to have more favorableeffects on lipids, particularly triglycerides, than does rosiglitazone.32
These emerging findings raise an important question about theappropriateness of the current regulatory pathways for the developmentof drugs to treat diabetes. The FDA considers demonstrationof a sustained reduction in blood glucose levels with an acceptablesafety profile adequate for approval of antidiabetic agents.However, the ultimate value of antidiabetic therapy is the reductionof the complications of diabetes, not improvement in a laboratorymeasure of glycemic control. Although reductions in blood glucoselevels have been shown to reliably reduce microvascular complicationsof diabetes, the effect on macrovascular complications has provedto be unpredictable.33 After the failure of muraglitazar andthe apparent increase in adverse cardiovascular outcomes withrosiglitazone, the use of blood glucose measurements as a surrogateend point in regulatory approval must be carefully reexamined.
Our study has important limitations. We pooled the results ofa group of trials that were not originally intended to explorecardiovascular outcomes. Most trials did not centrally adjudicatecardiovascular outcomes, and the definitions of myocardial infarctionwere not available. Many of these trials were small and short-term,resulting in few adverse cardiovascular events or deaths. Accordingly,the confidence intervals for the odds ratios for myocardialinfarction and death from cardiovascular causes are wide, resultingin considerable uncertainty about the magnitude of the observedhazard. Furthermore, we did not have access to original sourcedata for any of these trials. Thus, we based the analysis onavailable data from publicly disclosed summaries of events.The lack of availability of source data did not allow the useof more statistically powerful time-to-event analysis. A meta-analysisis always considered less convincing than a large prospectivetrial designed to assess the outcome of interest. Although sucha dedicated trial has not been completed for rosiglitazone,the ongoing Rosiglitazone Evaluated for Cardiac Outcomes andRegulation of Glycaemia in Diabetes (RECORD) trial may provideuseful insights.34
Despite these limitations, our data point to the urgent needfor comprehensive evaluations to clarify the cardiovascularrisks of rosiglitazone. The manufacturer's public disclosureof summary results for rosiglitazone clinical trials is notsufficient to enable a robust assessment of cardiovascular risks.The manufacturer has all the source data for completed clinicaltrials and should make these data available to an external academiccoordinating center for systematic analysis. The FDA also hasaccess to study reports and other clinical-trial data not withinthe public domain. Further analyses of data available to theFDA and the manufacturer would enable a more robust assessmentof the risks of this drug. Our data suggest a cardiovascularrisk associated with the use of rosiglitazone. Until more preciseestimates of the cardiovascular risk of this treatment can bedelineated in patients with diabetes, patients and providersshould carefully consider the potential risks of rosiglitazonein the treatment of type 2 diabetes.
Dr. Nissen reports receiving research support to perform clinicaltrials through the Cleveland Clinic Cardiovascular CoordinatingCenter from Pfizer, AstraZeneca, Daiichi Sankyo, Roche, Takeda,Sanofi-Aventis, and Eli Lilly. Dr. Nissen consults for manypharmaceutical companies but requires them to donate all honorariaor consulting fees directly to charity so that he receives neitherincome nor a tax deduction. No other potential conflict of interestrelevant to this article was reported.
We thank Craig Balog for statistical programming support.
Source Information
From the Cleveland Clinic, Cleveland. This article (10.1056/NEJMoa072761) was published at www.nejm.org on May 21, 2007.
Address reprint requests to Dr. Nissen at the Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, or at nissens{at}ccf.org.
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Rosiglitazone and Cardiovascular Risk
Bracken M. B., Mannucci E., Monami M., Marchionni N., Diamond G. A., Kaul S., Brett A. S., Nissen S. E., Wolski K., Psaty B. M., Furberg C. D.
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A correction has been published: N Engl J Med 2007;357(1):100.
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