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Finding of Increased Heart Attack, Death in Diabetes Patients from Avandia(rosiglitazone) Sparks FDA Alert

FDA issues immediate alert on the drug marketed as Avandia.

May 21, 2007 – Rosiglitazone, a drug widely used to treat type 2 diabetes, was found to significantly increase the risk of heart attacks and death from cardiovascular causes in a study of a wide range of data and clinical trials. The Food and Drug Administration immediately issued an alert on the drug marketed as Avandia. The study's authors also question the approval process used by the FDA for the approval of drugs to treat diabetes.

The New England Journal of Medicine published the study online today, ahead of its print publication on June 14, along with an editorial calling for changes in the current bill being shaped in Congress to make changes in the practices of the FDA.

"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," write the study authors, Steven E. Nissen, M.D., Department of Cardiovascular Medicine, Cleveland Clinic, and Kathy Wolski, M.P.H.

The authors do note, "Our study was limited by a lack of access to original source data, which would have enabled time-to-event analysis.

"Despite these limitations, patients and providers should consider the potential for serious adverse cardiovascular effects of treatment with rosiglitazone for type 2 diabetes."

The study included searches of the published literature, the Website of the FDA and clinical-trials registry maintained by the drug manufacturer (GlaxoSmithKline). Of 116 potentially relevant studies, 42 trials met the inclusion criteria. Mean age of subjects in the 42 trials was 56.

There were 86 myocardial infarctions in the rosiglitazone group and 72 in the control group. There were 39 deaths from cardiovascular cause in the rosiglitazone group and 22 in the control group.

In the rosiglitazone group, as compared to control group, the odds ratio for myocardial infarction was 1.43 (43%) and the odds ratio for deaths from cardiovascular causes was 1.64 (65%).

"These emerging findings raise an important question about the appropriateness of the current regulatory pathways for the development of drugs to treat diabetes," the authors write.

"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 the laboratory measure of glycemic control."

The editorial, Rosiglitazone and Cardiovascular Risk, is by Bruce M. Psaty, M.D., Ph.D., and Curt D. Furberg, M.D., Ph.D.

They focus on the Food and Drug Administration Revitalization Act, which was passed by the Senate on May 10 and is now in the House.

"It has many strengths," the say but none of its provisions would necessarily have identified the cardiovascular risks of rosiglitazone "in a timely fashion."

They suggest "a true life-cycle approach, as advocated by the Institute of Medicine, would continue the evaluation of both efficacy and safety after approval convert surrogate end points into clinically meaningful outcomes, integrate new information about health benefits and risks, and communicate those findings effectively to patients and physicians.

The conclude by saying "The health of the public would benefit from additional revisions to the drug-safety legislation as in moves through the House of Representatives."

Source: Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes by Steven E. Nissen, M.D., and Kathy Wolski, M.P.H., New England Journal of Medicine.

>> New England Journal of Medicine Online

FDA Issues Safety Alert on Avandia

The U.S. Food and Drug Administration (FDA) is aware of a potential safety issue related to Avandia (rosiglitazone), a drug approved to treat type 2 diabetes. Safety data from controlled clinical trials have shown that there is a potentially significant increase in the risk of heart attack and heart-related deaths in patients taking Avandia.

However, other published and unpublished data from long-term clinical trials of Avandia, including an interim analysis of data from the RECORD trial (a large, ongoing, randomized open label trial) and unpublished reanalyses of data from DREAM (a previously conducted placebo-controlled, randomized trial) provide contradictory evidence about the risks in patients treated with Avandia.

Patients who are taking Avandia, especially those who are known to have underlying heart disease or who are at high risk of heart attack should talk to their doctor about this new information as they evaluate the available treatment options for their type 2 diabetes.

FDA's analyses of all available data are ongoing. FDA has not confirmed the clinical significance of the reported increased risk in the context of other studies. Pending questions include whether the other approved treatment from the same class of drugs, pioglitazone, has less, the same or greater risks.

Furthermore, there is inherent risk associated with switching patients with diabetes from one treatment to another even in the absence of specific risks associated with particular treatments. For these reasons, FDA is not asking GlaxoSmithKline, the drug's sponsor, to take any specific action at this time. FDA is providing this emerging information to prescribers so that they, and their patients, can make individualized treatment decisions.

"FDA remains committed to assuring that doctors and patients have the latest information available to make treatment and medication use decisions. In this case, 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, M.D., M.P.H., director of 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."

Avandia was approved in 1999 for treatment of type 2 diabetes, a serious and life threatening disease that affects about 18 to 20 million Americans. Diabetes is a leading cause of coronary heart disease, blindness, kidney failure and limb amputation. Since the drug was approved, FDA has been monitoring several heart-related adverse events (e.g., fluid retention, edema and congestive heart failure) based on signals seen in previous controlled clinical trials of Avandia alone and in combination with other drugs, and from postmarketing reports.

FDA has updated the product's labeling on several occasions to reflect these new data, most recently in 2006. 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. This new warning was based on the result of a controlled clinical trial in patients with existing congestive heart failure.

Recently, the manufacturer of Avandia provided FDA with a pooled analysis (meta analysis) of 42 randomized, controlled clinical trials in which Avandia was compared to either placebo or other anti-diabetic therapies in patients with type 2 diabetes.

The pooled analysis suggested that patients receiving short-term (most studies were 6-months duration) treatment with Avandia may have a 30-40 percent greater risk of heart attack and other heart-related adverse events than patients treated with placebo or other anti-diabetic therapy. These data, if confirmed, would be of significant concern since patients with diabetes are already at an increased risk of heart disease.

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Major Heart, Diabetes Groups Urge Caution in Wake of Avandia Warning

Study raises concerns; Groups advise patients with diabetes to talk to their doctor

May 22, 2007 – The risk of heart attack and death for type 2 diabetes patients taking the drug Avandia “appears to be small”, but “must be considered carefully,” says a statement issued Monday by the American College of Cardiology, American Diabetes Association and American Heart Association. They advise patients using this drug should talk to their health care provider to determine the most appropriate course of action.

Avandia Drug Maker Disagrees with Study Saying the Diabetes Drug Increases Heart Attacks, Deaths

GlaxoSmithKline says it's “highly effective” treatment for type 2 diabetes

May 22, 2007 – The maker of the diabetes drug Avandia, GlaxoSmithKline, responded quickly to an online study published Tuesday by the New England Journal of Medicine indicating the drug, highly popular for treating type 2 diabetes, significantly increased the risk of heart attack and death.

Senate Committee Wants Answers About Avandia, Company Defends Record

Committee leaders send letters to FDA and GlaxoSmithKline

May 22, 2007 – The Senate Finance Committee leadership obviously had their guns loaded when the New England Journal of Medicine published a study yesterday showing the type 2 diabetes drug Avandia (rosiglitazone) significantly increases the risk of heart attack and death. And, the drug-maker quickly responded to the senators.