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.
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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)
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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-
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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
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Rosiglitazone and Cardiovascular Outcomes
pro trials randomized published spective,
administered administered administered type administered
Recently
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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,
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Rosiglitazone and Cardiovascular Outcomes
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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.)
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Rosiglitazone and Cardiovascular Outcomes
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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
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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
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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
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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
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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
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