May 21, 2007 (Cleveland, OH) - A new meta-analysis has suggested that the diabetes drug rosiglitazone (Avandia, GlaxoSmithKline) may increase the risk of MI and cardiovascular death [1].
The analysis, published online today in the New England Journal of Medicine, shows a significant increase in the risk of MI and an increase in cardiovascular death of borderline significance with rosiglitazone.
The authors, led by Dr Steven Nissen (Cleveland Clinic, OH), say these new findings are "worrisome" because of the high incidence of cardiovascular events in patients with diabetes. "Because exposure of such patients to rosiglitazone is widespread, the public-health impact of an increase in cardiovascular risk could be substantial if our data are borne out by further analysis and the results of larger controlled trials," they write.
Nissen commented to heartwire: "The FDA must now evaluate all the data they have, and they have more data than we had access to. I was working with one arm tied behind my back, as we did not have original source data. In my view, the risks we saw are correct, but the FDA will have to make a decision on this. In the meantime, individual physicians should look at our data and make up their own minds about whether to continue using this drug."
Editorial: "Rationale for rosiglitazone now unclear"
In an accompanying editorial, Drs Bruce Psaty (University of Washington, Seattle) and Curt Furberg (Wake Forest University, Winston-Salem, NC) share Nissen’s concerns [2]. "In view of the potential cardiovascular risks and in the absence of evidence of other health advantages, except for laboratory measures of glycemic control, the rationale for prescribing rosiglitazone at this time is unclear. Unless new data provide a different picture of the risk/benefit profile, regulatory action by the FDA is now warranted," they say.
Nissen and his coauthor, Kathy Wolski, note that rosiglitazone was approved based on its ability to lower blood glucose levels, and studies so far conducted have not been large enough to assess its impact on long-term events. Noting that the effect of any diabetes therapy on cardiovascular outcomes is particularly important given that 65% of deaths in diabetic patients are from cardiovascular causes, they performed a meta-analysis of trials comparing rosiglitazone with placebo or an active comparator to assess its effect on cardiovascular outcomes.
The source material for this analysis consisted of publicly available data submitted to the FDA as part of the approval package, another series of trials performed by the sponsor after approval, and two large prospective randomized trials designed to study additional indications for the drug (DREAM and ADOPT). In all, 42 trials met the inclusion criteria of a follow-up period of at least 24 weeks, the use of a randomized control group, and the availability of outcome data on MI and cardiovascular death. In these trials, 15 560 patients were assigned to rosiglitazone and 12 283 received placebo or an active comparator.
Results showed that rosiglitazone-treated patients had an odds ratio of 1.43 for MI and 1.64 for cardiovascular death compared with the control group. Odds ratio for MI and CV death for rosiglitazone vs control
Outcome
Odds ratio
95% CI
p
MI
1.43
1.03–1.98
0.03
Cardiovascular death
1.64
0.98–2.74
0.06
Nissen and Wolski note that the increased risk associated with rosiglitazone is the same when compared with placebo or with an active comparator, suggesting that this observation was not due to a protective effect of comparator drugs.
They point out that this meta-analysis is limited by a lack of access to original source data, which would have enabled time-to-event analysis, and on a relatively small number of events (there were 86 MIs and 39 cardiovascular deaths in the rosiglitazone patients vs 72 MIs and 22 cardiovascular deaths in control patients). But they say that despite these limitations, patients and providers should consider the potential for serious adverse cardiac effects of treatment with rosiglitazone.
Nissen explained to heartwire that he requested the original data from these trials from the manufacturer but they were unable to reach agreement over the terms.
Nissen and Wolski say the mechanism for the increased risk remains uncertain and could be due to several factors, including an adverse effect on lipid levels, precipitation of heart failure, and a reduction in hemoglobin levels.
What about other drugs in this class?
Rosiglitazone belongs to a class of drugs known as peroxisome proliferator-activated receptor (PPAR) agonists. Nissen and Wolski point out that it is not the first of this drug class to be associated with cardiovascular events, as the investigational agent muraglitazar was dropped from late-stage development because of adverse cardiovascular events, and development of many other PPAR agonists has also been stopped after early evidence of toxicity.
To heartwire, Nissen commented: "These drugs are very complex, and every one is different in that they all turn on or off different genes, so you can’t really talk about a class effect. They all have to be evaluated separately." He noted that the other major drug in this class--pioglitazone--has shown a reassuring effect on cardiovascular outcomes in a large-scale trial (PROACTIVE). "The PROACTIVE data went in the right direction, so I would say pioglitazone was probably safe," he said.
Nissen noted that such a large-scale trial has not been conducted with rosiglitazone, but that one is under way--the RECORD study. ‘However, the RECORD results are not due out until 2009, and even then this trial may not be adequately powered," he added.
Another failure of the regulatory process?
In their paper, Nissen and Wolski call for more stringent evaluation of diabetes drugs preapproval. "The FDA considers demonstration of a sustained reduction in blood glucose levels with an acceptable safety profile adequate for approval of antidiabetic agents. However, the ultimate value of antidiabetic therapy is the reduction of the complications of diabetes, not improvement in a laboratory measure of glycemic control. . . . After the failure of muraglitazar and the apparent increase in adverse cardiovascular outcomes with rosiglitazone, the use of blood glucose measurements as a surrogate end point in regulatory approval must be carefully reexamined," they write.
This view is shared by Psaty and Furberg, who write: "Ongoing trials using rosiglitazone may provide important new data, but for a drug approved in 1999, the delay in obtaining information about health outcomes has already been considerable." They add that tens of millions of prescriptions for rosiglitazone have been written, and if the current findings represent a valid estimate of the risk of cardiovascular events, rosiglitazone represents a "major failure of the drug-use and drug-approval process in the United States."
FDA: No action recommended at this time
In a statement released at the same time as this paper, the US FDA notes that it is aware of this meta-analysis but that other published and unpublished data from long-term clinical trials of rosiglitazone, including an interim analysis of data from the RECORD trial and unpublished reanalyses of data from DREAM, provide contradictory evidence about the risks in patients treated with Avandia.
The agency advises patients taking rosiglitazone, especially those who are known to have underlying heart disease or who are at high risk of heart attack, to talk to their doctor about this new information.
The FDA says its analyses of all available data are ongoing, and it has not confirmed the clinical significance of the reported increased risk in the context of other studies. Noting that there is inherent risk associated with switching patients with diabetes from one treatment to another, the agency says it is not asking GlaxoSmithKline to take any specific action at this time.
“FDA is carefully weighing several complex sources of data, some of which show conflicting results, related to the risk of heart attack and heart-related deaths in patients treated with Avandia," said Steven Galson, director of the FDA's Center for Drug Evaluation and Research. "We will complete our analyses and make the results available as soon as possible. FDA will take the issue of cardiovascular risk associated with Avandia and other drugs in this class to an advisory committee as soon as one can be convened," he added.
The statement notes that since rosiglitazone was approved, the FDA has been monitoring several heart-related adverse events (fluid retention, edema, and congestive heart failure) based on signals seen in previous controlled clinical trials and from postmarketing reports. The most recent labeling change for Avandia also included a new warning about a potential increase in heart attacks and heart-related chest pain in some individuals using Avandia, which was based on the result of a controlled clinical trial in patients with existing congestive heart failure.
GSK disagrees with Nissen’s conclusions
GlaxoSmithKline also issued a statement strongly disagreeing with the conclusions reached in the article, which it says are based on “incomplete evidence and a methodology that the author admits has significant limitations.”
The company notes that the totality of its data show that Avandia has a comparable cardiovascular profile to other oral antidiabetic medicines, adding that “GSK stands firmly behind the safety of Avandia when used appropriately, and we believe its significant benefits continue to outweigh any treatment risks.”
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