GlaxoSmithKline has responded quickly to refute an article in the New England Journal of Medicine which suggests that the firm’s blockbuster diabetes treatment Avandia might significantly increase the risk of heart attacks.
Nevertheless, the impact of the article has been considerable and led to a 5% decline in GSK’s stock price as well as a safety alert from the US Food and Drug Administration. In the meta-analysis, authored by Steven Nissen, one of the first doctors to raise questions about the cardiovascular safety of Merck & Co’s Vioxx (rofecoxib), and Kathy Wolski, researchers looked at 42 studies of Avandia (rosiglitazone) involving 15,560 patients who received the drug and 12,283 who were treated with placebos or other medicines.
The study in the NEJM concluded that patients on Avandia were 64% more likely to die from cardiovascular causes, and raised the likelihood of suffering a heart attack by 43%. There were a total of 158 heart attacks and 61 deaths from cardiovascular causes in patients involved in the studies but the number of rosiglitazone-associated events was small – 86 myocardial infarctions in Avandia patients versus 72 in the controls and 39 cardiovascular deaths versus 22.
Weaknesses in data used in meta-analysis
The authors acknowledged that there were possible weaknesses in the data used in the meta-analysis and its findings could have resulted from chance, but the NEJM’s editor, Jeffrey Drazen, said: “We view this as the best publicly available data on a very important question. It shows what we regard as a preliminary, but worrisome, signal about cardiovascular toxicity of this drug.”
An editorial accompanying the article, written by Bruce Psaty and Curt Furberg, also acknowledged that the study had a number of serious limitations and "the possibility that the findings were due to chance cannot be excluded," regulatory action by the FDA is warranted. “In view of the potential cardiovascular risks,” the editorial said, “and in the absence of evidence of other related advantages, except for laboratory measures of glycaemic control, the rationale for prescribing rosiglitazone at this time is unclear.”
Drs Psaty and Furberg also tore a strip off the FDA, saying that “insofar as the findings of Nissen and Wolski represent a valid estimate of the risk of cardiovascular events, rosiglitazone represents a major failure of the drug-use and drug-approval processes in the USA.
GSK came out fighting and said that it “strongly disagrees with the conclusions reached in the NEJM article, which are based on incomplete evidence and a methodology that the author admits has significant limitations”. The firm added that “in contrast to a meta-analysis, the most scientifically rigorous way to examine the safety and benefits of a medicine is to conduct large scale, long-term clinical trials in patients with the disease. Several trials of this type have been ongoing for many years.”
In particular, GSK pointed to its long-term, landmark ADOPT study which compared both the safety and effectiveness of Avandia with other oral anti-diabetic medicines in over 4,300 patients studied for up to six years. This showed that the overall risk of serious, cardiovascular events for patients on Avandia was comparable to metformin and sulfonylurea (glyburide), two of the most commonly used medicines to treat type 2 diabetes. In another long-term study, DREAM – which followed over 5,200 patients at high risk of developing of type 2 diabetes for a period of three to five years - Avandia monotherapy showed no increase in cardiovascular risk when compared to placebo.
In its safety alert, the FDA said that while it is aware of "a potential safety issue" associated with Avandia, it is not asking GSK to take any action as yet. This is because other published and unpublished data of the compound, including an interim analysis of data from the ongoing RECORD trial and unpublished reanalyses of data from DREAM “provide contradictory evidence about the risks in patients treated with Avandia”. The agency added that 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 FDA did confirm, however, that it is reviewing the safety of Avandia
Avandia has been on the market since 1999 and had first-quarter sales of $384 million, up 24%, making it GSK’s second best-seller. However the NEJM could contribute to a dent in that figure as patients are likely to flock to their physicians and look to switch treatments. That is the sort of response US consumer group Public Citizen would like to see and Sidney Wolfe, director of its Health Research Group, claimed that “despite prior knowledge of serious cardiac problems,” the FDA has failed to require GSK to adequately warn about the dangers of this drug “that should be, at best, a last-choice treatment for type 2 diabetes. Dr Wolfe concluded by saying that “we strongly urge patients - as we have for almost two and a half years - not to use this drug”.