Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes

Effect of Rosiglitazone on the Risk of Myocardial Infarction Steven E. Nissen, M.D., and Kathy Wolski, M.P.H.
Background
Rosiglitazone is widely used to treat patients with type 2 diabetes mellitus, but its From the Cleveland Clinic, Cleveland. Ad-
effect on cardiovascular morbidity and mortality has not been determined.
the Department of Cardiovascular Medi-cine, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, or at nissens@ccf.
org.
We conducted searches of the published literature, the Web site of the Food and Drug Administration, and a clinical-trials registry maintained by the drug manu- This article (10.1056/NEJMoa072761) was facturer (GlaxoSmithKline). Criteria for inclusion in our meta-analysis included a published at www.nejm.org on May 21, study duration of more than 24 weeks, the use of a randomized control group not receiving rosiglitazone, and the availability of outcome data for myocardial infarc- N Engl J Med 2007;356:2457-71.
tion and death from cardiovascular causes. Of 116 potentially relevant studies, 42 Copyright 2007 Massachusetts Medical Society. trials met the inclusion criteria. We tabulated all occurrences of myocardial infarc- tion 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 approximately 56 years, and the mean baseline glycated hemoglobin level was approximately 8.2%. In the rosiglitazone group, as compared with the control group, the odds ratio for myocardial infarction was 1.43 (95% confidence interval [CI], 1.03 to 1.98; P = 0.03), and the odds ratio for death from cardiovascular causes was 1.64 (95% CI, 0.98 to 2.74; P = 0.06).
Conclusions
Rosiglitazone was associated with a significant increase in the risk of myocardial
infarction and with an increase in the risk of death from cardiovascular causes that had borderline significance. Our study was limited by a lack of access to original source data, which would have enabled time-to-event analysis. Despite these limita- tions, patients and providers should consider the potential for serious adverse car- diovascular effects of treatment with rosiglitazone for type 2 diabetes.
n engl j med 356;24 www.nejm.org june 14, 2007 Downloaded from nejm.org on January 8, 2013. For personal use only. No other uses without permission. Copyright 2007 Massachusetts Medical Society. All rights reserved. T h e n e w e ng l a n d j o u r na l o f m e dic i n e Thiazolidinedione drugs are wide- any myocardial infarctions or deaths from cardio- ly used to lower blood glucose levels in pa- vascular causes and therefore were not included 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, duced: troglitazone, which was removed from the 38 reported at least one myocardial infarction, market because of hepatotoxicity, and two current- and 23 reported at least one death from cardio- ly available agents, rosiglitazone (Avandia, Glaxo- vascular causes. In these trials, 15,565 patients SmithKline) and pioglitazone (Actos, Takeda). The were randomly assigned to regimens that includ- thiazolidinediones are agonists for peroxisome- ed rosiglitazone, and 12,282 were assigned to proliferator–activated receptor γ (PPAR-γ). PPAR-γ 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 litazone within a single trial were pooled togeth- sensitivity in peripheral tissues.1,2 Rosiglitazone er, when applicable. The control group was de- was introduced in 1999 and is widely used as fined as patients receiving any drug regimen monotherapy or in fixed-dose combinations with other than rosiglitazone. The trials fall into three either metformin (Avandamet, GlaxoSmithKline) categories. 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 blood proval of rosiglitazone. Group-level data from glucose and glycated hemoglobin levels.3 Initial these five studies are available in publicly dis- studies were not adequately powered to deter- closed briefing documents archived on the FDA mine the effects of this agent on microvascular Web site.6 Data from these same trials are also or macrovascular complications of diabetes, in- reported in a summary fashion on a clinical- cluding cardiovascular morbidity and mortality.3 trial registry Web site maintained by the drug However, the effect of any antidiabetic therapy manufacturer, GlaxoSmithKline.5 Reports of four on cardiovascular outcomes is particularly im- of these five trials were also published in peer- portant, because more than 65% of deaths in reviewed journals.7-9 In these five trials, 1967 pa- patients with diabetes are from cardiovascular tients were randomly assigned to receive rosiglit- causes.4 Therefore, we performed a meta-analy- azone, and 793 patients were assigned to receive sis of trials comparing rosiglitazone with placebo various comparator drugs (Table 1).
or active comparators to assess the effect of this Other studies that we included in the meta- agent on cardiovascular outcomes. The source analysis were initially identified in the Glaxo- material for this analysis consisted of publicly SmithKline clinical-trial registry.5 As noted in available data from the original registration pack- Table 1, we included 35 studies in this category, age submitted to the Food and Drug Administra- 9 of which were published in peer-reviewed jour- tion (FDA), another series of trials performed by nals and 26 of which remain unpublished.10-18 the sponsor after approval, and two large, prospec- Whenever possible, the results obtained on the tive, randomized trials designed to study addition- 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 Analyzed Studies
were randomly assigned to receive rosiglitazone, Table 1 lists the 42 trials included in this meta- and 5960 patients were assigned to receive vari- analysis. We screened 116 phase 2, 3, and 4 trials ous comparator drugs.
for inclusion. Of these, 48 trials met the pre- A third data source consisted of two large, defined inclusion criteria of having a randomized recently published trials, the Diabetes Reduction 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) n engl j med 356;24 www.nejm.org june 14, 2007 Downloaded from nejm.org on January 8, 2013. For personal use only. No other uses without permission. Copyright 2007 Massachusetts Medical Society. All rights reserved. Rosiglitazone and Cardiovascular Outcomes (ClinicalTrials.gov number, NCT00279045).21 In ity across trials, allowing for the use of a fixed- the DREAM study, 2635 patients were randomly effects model. For additional analyses, the active assigned to receive rosiglitazone and 2634 patients comparator control groups were subgrouped into were assigned to receive placebo. The DREAM the following four classes for comparison with study was designed to determine whether rosigli- rosiglitazone: metformin, sulfonylurea, insulin, tazone could prevent the development of type 2 and placebo. Odds ratios and 95% confidence in- diabetes in patients at high risk for this disorder. tervals were calculated for each subgroup with the In the ADOPT trial, 1456 patients were random- use of methods similar to those used in the ly assigned to receive rosiglitazone and 2895 pa- pooled analyses. Data were analyzed with the use tients were assigned to receive either metformin of Comprehensive Meta-Analysis software, version or glyburide. The ADOPT study was designed to 2.2 (Biostat).
assess the durability of glycemic control with rosiglitazone therapy, as compared with therapy Baseline Characteristics
Outcome Measures
Table 2 reports the doses of rosiglitazone and We reviewed data summaries provided in the comparator drugs, baseline demographic charac- FDA review documents, the GlaxoSmithKline teristics, study periods, and glycated hemoglobin clinical-trial registry Web site, and published levels or fasting blood glucose levels for patients trial results and then abstracted from the ad- enrolled in the trials. The patients were relatively verse-event tabulations information on myocar- young, averaging less than 57 years of age for both dial infarction and death from cardiovascular the rosiglitazone group and the control group. causes. With the exception of the DREAM study, Overall, there was a moderate predominance of the included trials did not describe adjudication men. Diabetes control was relatively poor, with a of myocardial infarction or death from cardio- mean baseline glycated hemoglobin level of ap- vascular causes. Time-to-event data for cardio- proximately 8.2% for both study groups.
vascular events were not available in any of these trials, which precluded the calculation of hazard Myocardial Infarction and Death
ratios. Because only summary data were avail- Table 3 reports the myocardial infarction events able, it was not possible to discern whether the and deaths from cardiovascular causes that were same patient had both events. Therefore, an out- reported in the 42 clinical trials we reviewed. come measure based on the composite of death There were 86 myocardial infarctions in the rosig- or myocardial infarction could not be construct- litazone group and 72 in the control group. ed. Accordingly, these two outcomes are reported There were 39 deaths from cardiovascular causes in the rosiglitazone group and 22 in the control group. Table 4 lists the odds ratios, 95% confi- Statistical Analysis
dence intervals, and P values for myocardial in- Many trials had few cardiovascular events, so the farction and death from cardiovascular causes odds ratios and 95% confidence intervals were for the rosiglitazone group and the control group. calculated with the use of the Peto method.22-24 The summary odds ratio for myocardial infarc- Because all trials had similar durations of follow- tion was 1.43 in the rosiglitazone group (95% up for all treatment groups, the use of odds ra- confidence interval [CI], 1.03 to 1.98; P = 0.03). tios represents a valid approach to assessing the The odds ratio for death from cardiovascular risk associated with the use of rosiglitazone. Tri- causes in the rosiglitazone group, as compared als in which patients had no adverse cardiovas- with the control group, was 1.64 (95% CI, 0.98 to cular events in either group were excluded from 2.74; P = 0.06). Table 4 also lists odds ratios and analyses. All reported P values are two-sided. 95% confidence intervals for the pooled group of Statistical heterogeneity across the various trials trials that were smaller and of shorter duration; was tested with the use of Cochran’s Q statistic. results for the DREAM and ADOPT studies are A P value of more than the nominal level of 0.10 shown separately.
for the Q statistic indicated a lack of heterogene- Table 5 lists odds ratios for myocardial in- n engl j med 356;24 www.nejm.org june 14, 2007 Downloaded from nejm.org on January 8, 2013. For personal use only. No other uses without permission. Copyright 2007 Massachusetts Medical Society. All rights reserved. T h e n e w e ng l a n d j o u r na l o f m e dic i n e Rosiglitazone
Duration
Meta-Analysis.*
the
Registry
Rosiglitazone
original
Reference
included
Table 1. Clinical
Additional
n engl j med 356;24 www.nejm.org june 14, 2007 Downloaded from nejm.org on January 8, 2013. For personal use only. No other uses without permission. Copyright 2007 Massachusetts Medical Society. All rights reserved. Rosiglitazone and Cardiovascular Outcomes pro trials
randomized
published
spective,
administered administered administered type administered Recently
n engl j med 356;24 www.nejm.org june 14, 2007 Downloaded from nejm.org on January 8, 2013. For personal use only. No other uses without permission. Copyright 2007 Massachusetts Medical Society. All rights reserved. T h e n e w e ng l a n d j o u r na l o f m e dic i n e Glycated
Baseline Hemoglobin
Levels.*
Hemoglobin
Population
Glycated
Periods,
Characteristics,
Demographic
Baseline
Table 2. Doses,
n engl j med 356;24 www.nejm.org june 14, 2007 Downloaded from nejm.org on January 8, 2013. For personal use only. No other uses without permission. Copyright 2007 Massachusetts Medical Society. All rights reserved. Rosiglitazone and Cardiovascular Outcomes n engl j med 356;24 www.nejm.org june 14, 2007 Downloaded from nejm.org on January 8, 2013. For personal use only. No other uses without permission. Copyright 2007 Massachusetts Medical Society. All rights reserved. T h e n e w e ng l a n d j o u r na l o f m e dic i n e Glycated
Baseline Hemoglobin
Population
Table 2. (Continued.)
n engl j med 356;24 www.nejm.org june 14, 2007 Downloaded from nejm.org on January 8, 2013. For personal use only. No other uses without permission. Copyright 2007 Massachusetts Medical Society. All rights reserved. Rosiglitazone and Cardiovascular Outcomes n engl j med 356;24 www.nejm.org june 14, 2007 Downloaded from nejm.org on January 8, 2013. For personal use only. No other uses without permission. Copyright 2007 Massachusetts Medical Society. All rights reserved. T h e n e w e ng l a n d j o u r na l o f m e dic i n e Table 3. Myocardial Infarctions and Cardiovascular Deaths in Rosiglitazone Trials.
Rosiglitazone Group
Control Group
n engl j med 356;24 www.nejm.org june 14, 2007 Downloaded from nejm.org on January 8, 2013. For personal use only. No other uses without permission. Copyright 2007 Massachusetts Medical Society. All rights reserved. Rosiglitazone and Cardiovascular Outcomes Table 3. (Continued.)
Rosiglitazone Group
Control Group
farction and death from cardiovascular causes sure of such patients to rosiglitazone is wide- associated with rosiglitazone for subgroups de- spread, the public health impact of an increase in fined according to the comparator drug. Similar cardiovascular risk could be substantial if our results were obtained when the analysis exclud- data are borne out by further analysis and the ed trials with an active comparator group. The results of larger controlled trials.
heterogeneity P values were 0.53 for myocardial Although we did not have access to the source infarction and 0.68 for death from cardiovascu- data to construct a composite outcome that in- lar causes across subgroups. As compared with cluded myocardial infarction or death from car- placebo or other antidiabetic regimens, the esti- diovascular causes, the increase in the odds ratios mated odds ratios in all cases were greater than for both of these end points suggests that ob- 1.0, suggesting that observed adverse effects dur- served adverse effects associated with rosiglita- ing rosiglitazone treatment were not unique to zone were probably not due to chance alone. This meta-analysis included a group of trials that In an analysis that was not prespecified, we were of relatively short duration (24 to 52 weeks). also studied the effects of rosiglitazone on death The odds ratio for these shorter-term trials was from any cause. The odds ratio for death from any similar to the overall results of the meta-analy- cause was 1.18 (95% CI, 0.89 to 1.55; P = 0.24).
sis. Thus, in susceptible patients, rosiglitazone therapy may be capable of provoking myocardial infarction or death from cardiovascular causes after relatively short-term exposure. In contrast, Our data show that, as compared with placebo or long-term therapies that improve cardiovascular with other antidiabetic regimens, treatment with outcomes, such as statins and antihypertensive rosiglitazone was associated with a significant drugs, often take several years to provide benefits. increase in the risk of myocardial infarction and Notably, the estimates for the odds ratios for with an increase in the risk of death from cardio- myocardial infarction and death from cardiovas- vascular causes that was of borderline signifi- cular causes appear elevated for rosiglitazone in cance. The similar odds ratio for comparison comparison with placebo or other commonly pre- with placebo suggests that the increased risk as- scribed antidiabetic therapies (Table 5).
sociated with rosiglitazone was not a function of The mechanism for the apparent increase in the protective effects of active comparator drugs. myocardial infarction and death from cardiovas- However, these findings are based on limited ac- cular causes associated with rosiglitazone remains cess to trial results from publicly available sourc- uncertain. One potential contributing factor may es, not on patient-level source data. Furthermore, be the adverse effect of the drug on serum lipids. results are based on a relatively small number of The FDA-approved rosiglitazone product label events, resulting in odds ratios that could be af- reports a mean increase in low-density lipopro- fected by small changes in the classification of tein (LDL) cholesterol of 18.6% among patients events. Nonetheless, our findings are worrisome treated for 26 weeks with an 8-mg daily dose, as because of the high incidence of cardiovascular compared with placebo.25 In observational stud- events in patients with diabetes.4 Because expo- ies and lipid-lowering trials, elevated levels of n engl j med 356;24 www.nejm.org june 14, 2007 Downloaded from nejm.org on January 8, 2013. For personal use only. No other uses without permission. Copyright 2007 Massachusetts Medical Society. All rights reserved. T h e n e w e ng l a n d j o u r na l o f m e dic i n e Table 4. Rates of Myocardial Infarction and Death from Cardiovascular Causes.
Odds Ratio
Rosiglitazone Group
Control Group
Myocardial infarction
Death from cardiovascular causes
LDL cholesterol were associated with an increase farction, during phase 2 and 3 testing.28 After in adverse cardiovascular outcomes. Thus, an in- publication of an analysis of cardiovascular out- crease in LDL cholesterol of the magnitude ob- comes, muraglitazar was not approved by the served in the rosiglitazone group may have con- FDA, and further development was subsequently tributed to adverse cardiovascular outcomes, halted by the manufacturer. Development pro- although the rapidity and magnitude of the ap- grams for many other PPAR agonists have been parent hazard was not consistent with an effect terminated after evidence of toxicity emerged dur- ing preclinical studies or initial trials in humans. Several other properties of rosiglitazone may According to a former FDA official, more than contribute to adverse cardiovascular outcomes. 50 Investigational New Drug applications for Rosiglitazone and other thiazolidinediones are novel PPARs have been filed, but no additional known to precipitate congestive heart failure in drugs have successfully reached the market in susceptible patients.26 Congestive heart failure is more than 6 years.29 In some cases, these drugs a physiological state that is associated with an have failed because of evidence of direct myocar- increased intravascular volume. Volume overload dial toxicity in studies in animals,29 but few data increases stress on the left ventricular wall, a fac- on toxicity are available in the public domain be- tor that determines myocardial oxygen demand. cause of the common industry practice of not In susceptible patients, an increase in myocar- publishing safety findings for failed products.
dial oxygen demand could theoretically provoke PPAR agonists such as rosiglitazone have very ischemic events. The administration of thiazoli- complex biologic effects, resulting from the ac- dinediones, including rosiglitazone, also produc- tivation or suppression of dozens of genes.30 The es a modest reduction in the hemoglobin level.25 patterns of gene activation or suppression differ In susceptible patients, a reduced hemoglobin substantially among various PPAR agonists, even level may result in increased physiological stress, within closely related compounds. The biologic thereby provoking myocardial ischemia. A study effects of the protein targets for most of the of rosiglitazone that was conducted in rats report- genes influenced by PPAR agonists remain large- ed an increase in the rate of death after experi- ly unknown. Accordingly, many different and mentally induced myocardial infarction.27 seemingly unrelated toxic effects have emerged Rosiglitazone is not the first PPAR agonist that during development of other PPAR agents.29 has been reported to increase adverse cardiovas- Some drugs have provoked multispecies, multi– cular events. Muraglitazar, an investigational dual organ system cancers; others have resulted in PPAR-α and PPAR-γ agonist, increased adverse rhabdomyolysis or nephrotoxicity.29 Troglitazone cardiovascular events, including myocardial in- was withdrawn from the market for rare, but n engl j med 356;24 www.nejm.org june 14, 2007 Downloaded from nejm.org on January 8, 2013. For personal use only. No other uses without permission. Copyright 2007 Massachusetts Medical Society. All rights reserved. Rosiglitazone and Cardiovascular Outcomes sometimes fatal, liver toxicity. Accordingly, it must Table 5. Risk of Myocardial Infarction and Death from Cardiovascular Causes
be assumed that a variety of unexpected toxic for Patients Receiving Rosiglitazone versus Several Comparator Drugs.
effects are possible when PPAR agonists are ad- Odds Ratio
The question as to whether the observed risks Comparator Drug
of rosiglitazone represent a “class effect” of thia- Myocardial infarction
zolidinediones must also be considered. Pioglita- zone is a related agent also widely used to treat type 2 diabetes mellitus. However, unlike rosig- litazone, pioglitazone has been studied in a prospective, randomized trial of cardiovascular outcomes, called Prospective Pioglitazone Clini- cal Trial in Macrovascular Events (PROACTIVE).31 Death from cardiovascular causes
The primary end point, a broad composite that included coronary and peripheral vascular events, showed a trend toward benefit from pioglita- zone (hazard ratio, 0.90; P = 0.095). A secondary end point consisting of myocardial infarction, stroke, and death from any cause showed a sig- nificant effect favoring pioglitazone (hazard ra- tio, 0.84; P = 0.027). Notably, pioglitazone appears to have more favorable effects on lipids, particu- deaths. Accordingly, the confidence intervals for larly triglycerides, than does rosiglitazone.32 the odds ratios for myocardial infarction and These emerging findings raise an important death from cardiovascular causes are wide, re- question about the appropriateness of the cur- sulting in considerable uncertainty about the rent regulatory pathways for the development of magnitude of the observed hazard. Furthermore, drugs to treat diabetes. The FDA considers dem- we did not have access to original source data onstration of a sustained reduction in blood for any of these trials. Thus, we based the analysis glucose levels with an acceptable safety profile on available data from publicly disclosed sum- adequate for approval of antidiabetic agents. maries of events. The lack of availability of However, the ultimate value of antidiabetic ther- source data did not allow the use of more statis- apy is the reduction of the complications of dia- tically powerful time-to-event analysis. A meta- betes, not improvement in a laboratory measure analysis is always considered less convincing of glycemic control. Although reductions in blood than a large prospective trial designed to assess glucose levels have been shown to reliably reduce the outcome of interest. Although such a dedi- microvascular complications of diabetes, the ef- cated trial has not been completed for rosiglita- fect on macrovascular complications has proved zone, the ongoing Rosiglitazone Evaluated for to be unpredictable.33 After the failure of mura- Cardiac Outcomes and Regulation of Glycaemia glitazar and the apparent increase in adverse in Diabetes (RECORD) trial may provide useful cardiovascular outcomes with rosiglitazone, the insights.34 use of blood glucose measurements as a surro- Despite these limitations, our data point to gate end point in regulatory approval must be the urgent need for comprehensive evaluations to clarify the cardiovascular risks of rosiglitazone. Our study has important limitations. We The manufacturer’s public disclosure of sum- pooled the results of a group of trials that were mary results for rosiglitazone clinical trials is not originally intended to explore cardiovascular not sufficient to enable a robust assessment of outcomes. Most trials did not centrally adjudicate cardiovascular risks. The manufacturer has all cardiovascular outcomes, and the definitions of the source data for completed clinical trials and myocardial infarction were not available. Many should make these data available to an external of these trials were small and short-term, re- academic coordinating center for systematic anal- sulting in few adverse cardiovascular events or ysis. The FDA also has access to study reports n engl j med 356;24 www.nejm.org june 14, 2007 Downloaded from nejm.org on January 8, 2013. For personal use only. No other uses without permission. Copyright 2007 Massachusetts Medical Society. All rights reserved. T h e n e w e ng l a n d j o u r na l o f m e dic i n e and other clinical-trial data not within the pub- the potential risks of rosiglitazone in the treat- lic domain. Further analyses of data available to ment of type 2 diabetes.
the FDA and the manufacturer would enable a Dr. Nissen reports receiving research support to perform more robust assessment of the risks of this drug. clinical trials through the Cleveland Clinic Cardiovascular Coor- Our data suggest a cardiovascular risk associated dinating Center from Pfizer, AstraZeneca, Daiichi Sankyo, Roche, Takeda, Sanofi-Aventis, and Eli Lilly. Dr. Nissen consults with the use of rosiglitazone. Until more precise for many pharmaceutical companies but requires them to do- estimates of the cardiovascular risk of this treat- nate all honoraria or consulting fees directly to charity so that ment can be delineated in patients with diabetes, he receives neither income nor a tax deduction. No other poten- tial conflict of interest relevant to this article was reported.
patients and providers should carefully consider We thank Craig Balog for statistical programming support.
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