Two published meta-analyses have added significant weight to the suggestion that treating type 2 diabetes using rosiglitazone (GlaxoSmithKline’s Avandia®) can significantly increase a patient’s risk of suffering a heart attack, stroke, or indeed dying from any cause.
One of the studies, completed in advance of FDA’s meeting to review the safety of the GSK drug, suggested that rosiglitazone was associated with a 28–39% increased risk of myocardial infarction. These results are published in the Archives of Internal Medicine in a paper titled “An Updated Meta-analysis of Risk for Myocardial Infarction and Cardiovascular Mortality."
The other study, which evaluated patients aged 65 years and over, found that in comparison with pioglitazone (Takeda’s Actos®), rosiglitazone was associated with a 1.25-fold increase in the risk of heart failure, a 1.27-fold increase in the risk of stroke, and a 1.14-fold increase in the risk of death. The data is published online today in JAMA in a paper titled “Risk of Acute Myocardial Infarction, Stroke, Heart Failure, and Death in Elderly Medicare Patients Treated With Rosiglitazone or Pioglitazone.”
The study appearing in Archives of Internal Medicine was carried out by Steven E. Nissen, M.D., and Kathy Wolski at the Cleveland Clinic Foundation. They conducted a meta-analysis of 56 trials including GSK studies and those available on Medline. The combined studies included some 35,500 patients, 19,509 of whom received rosiglitazone and 16,022 of whom received control medications. Back in May 2007, Drs. Nissen and Wolski published a paper in The New England of Journal Medicine that kicked off the concerns about rosiglitazone's cardiovascular safety.
In their latest study, the authors conclude that their analyses “suggest an unfavorable benefit to risk ratio for rosiglitazone use.” They further point out that even a modest increase in the risk of myocardial infarction in a diabetic population would have serious consequences. Given that here are now 12 classes of drugs approved to lower blood glucose levels, the researchers say that, “because no unique benefits of rosiglitazone use have been identified, administration of this agent solely to lower blood glucose levels is difficult to justify.”
In the JAMA paper, the Center for Drug Evaluation and Research's David J. Graham, M.D., and colleagues pulled data from studies that together included 227,571 patients aged 65 years or older who were treated for type 2 diabetes using either rosiglitazone or pioglitazone. The researchers also point out that the cardiovascular risks of rosiglitazone and pioglitazone have been compared in several other observational studies.
Seven trials highlighted an increased risk of acute myocardial infarction associated with rosiglitazone therapy, and in three of these studies the risk was found to be statistically significant. The risk of stroke associated with rosiglitazone was also found to be higher, although nonsignificantly, in two studies comparing rosiglitazone with pioglitazone. Heart failure risk was statistically significantly increased in three comparative trials and nonsignificantly raised in another comparative trial. Two studies suggested that in comparison with pioglitazone, rosiglitazone increases the risk of all-cause mortality by a statistically significantly amount.
The papers are published just a couple of weeks after it was widely reported that Germany's Federal Joint Committee of doctors and health insurers, which recommends on drug reimbursement in the country, concluded that rosiglitazone and pioglitazone, which is also a thiazolidinedione drug, should not be reimbursed due to health concerns. The committee's chairman, Rainer Hess is reported to have said, "There are other pharmaceuticals that have no such side effects and long-term risks. We believe that patients should be protected against useless and, more importantly, harmful therapies."
GSK, meanwhile, has responded to both publications by claiming that results from the meta-analyses remain at odds with those from six controlled clinical trials. “Taken together, these trials show that rosilglitazone does not increase the overall risk of heart attack, stroke, or death,” the firm states.
Rosiglitazone was first approved in 1999 as a treatment for hyperglycemia. Concerns about the cardiovascular safety of the drug have been the subject of ongoing debate since the Nissen/Wolski paper in 2007. Although a risk evaluation review by EMEA did uphold the positive benefit-risk ratio of the drug in 2008, GSK was made to revise its European label for Avandia to state that available data indicates that rosiglitazone may be associated with an increased risk of myocardial infarction. The U.S.-marketed version of the drug has also undergone three label revisions pointing out potential cardiovascular risks associated with treatment. The firm has consistently refuted the suggestion that the drug may be associated with serious health issues.
Rosiglitazone and pioglitazone are the only thiazolidinediones currently approved in the U.S. for the treatment of type 2 diabetes. Takeda’s pioglitazone achieved global sales of ¥384.7 billion (about $4.3 billion) in fiscal year 2009. Worldwide sales of GSK’s Avandia have been dipping since the health scares were first raised in 2007. In calendar year 2009, sales of the drug declined another 16% to £771 million (roughly $1.16 billion). In the U.S., specifically, sales of Avandia dropped 22% during 2009.