Diana Zuckerman, PhD and Christina Medina, BA
Updated June 2010, original article June 2007
Avandia has been a popular drug for diabetes, but is it safe? New research says that patients taking Avandia are more likely to die compared to diabetic patients taking other drugs, such as Actos.
Since 2007, the FDA required Avandia to include a black box warning for patients and doctors that it increases the risk of heart failure, which can be fatal. A block box around a warning about risks is the strongest warning the FDA requires, similar to the black box warning on cigarette packages, warning that smoking causes lung cancer, heart disease, and is dangerous for pregnant women.
Nearly 20 million Americans have type 2 diabetes, also known as adult-onset diabetes, a condition where a person’s body does not produce enough glucose (sugar) or respond well to the blood sugar that the body makes naturally. Diabetes can result in many very serious health problems, including kidney disease, blindness, limb amputation and, most notably, heart disease. It is these complications caused by the disease, not the diabetes itself, which cause serious long-term effects or death. Avandia is a prescription drug manufactured by GlaxoSmithKline that lowers the sugar levels in the blood. But, does it improve the health of diabetics?
Avandia was approved by the U.S. Food and Drug Administration (FDA) in March 1999 despite concerns from FDA scientists and other experts about the safety of the drug. As a condition of FDA approval, GlaxoSmithKline was required to continue to conduct clinical trials to assess the seriousness of heart complications related to the drug’s use.
On June 28, 2010, the Journal of the American Medical Association published two research studies that concluded that patients taking Avandia were more likely to die than patients taking other diabetes medication. The FDA will hold a public Advisory Committee meeting on July 13, 2010 to discuss what the FDA should do given the new research findings.
Why has it taken so long? On May 21, 2007, Dr. Steven Nissen and Kathy Wolski, MPH, published an article on the effects of Avandia and related drugs and cardiovascular risks in the New England Journal of Medicine based on a meta-analysis of 42 small studies. They concluded that Avandia increases the risk of heart attack by 40%, compared to placebo. The FDA and GlaxoSmithKline criticized the study, saying that the data were short-term (six months or less) and that the studies differed widely, so that combining them in a meta-analysis was questionable.
The new studies are harder to criticize. One of the June 2010 JAMA articles is also by Steve Nissen and Kathy Wolski, and is based on a meta analysis of 56 studies of more than 35,000 patients. The other is a 3-year comparison of Avandia and Actos, based on more than 220,000 patients and analyzed by FDA scientist Dr. David Graham and his colleagues.
On August 14, 2007, the FDA had announced “black box” warning labels for Avandia (also called rosiglitazone) but also for the other drugs in its class. The black box warnings now have to be changed for Actos, which the new research shows is much safer than Avandia. Other drugs in the same class as Avandia are called thiazolidinedione drugs. In addition to Actos (pioglitazone), they include Avandaryl (rosiglitazone and glimepiride), Avandamet (rosiglitazone and metformin), and Duetact (pioglitazone and glimepride). The warning explains that these drugs can cause or increase heart failure. If FDA takes Avandia off the market, they may need to take the combination drugs listed above that include Avandia off the market as well (Avandaryl and Avandamet).
In response to concerns that the risks of Avandia may outweigh the benefits, the FDA held a public meeting on July 30, 2007. At the meeting, FDA scientists pointed out that there are three studies indicating a significant increased risk of serious cardiovascular problems among patients taking Avandia compared to a placebo: the Nissen meta-analysis, an FDA meta-analysis, and an analysis by GlaxoSmithKline. Compared to diabetics taking insulin, the risk of serious heart complications more than doubled for diabetics taking Avandia in addition to insulin – a common treatment. Diabetics older than 65 and those taking nitrates also were at higher risk of heart disease if they took Avandia, compared to patients not taking Avandia.
As a result of media attention and the black box warning, many doctors and patients have decided during the last three that the risks are too high. Prescriptions for Avandia decreased dramatically, but it remained a very popular drug because questions remained about the safety of other diabetes drugs, some of which had not been scrutinized as carefully as Avandia.
Dr. Nissen points out that the purpose of diabetes drugs is to lessen the possible danger of diabetes, “not improvement in a laboratory measure of glycemic [blood sugar] control.” Since heart disease is the #1 cause of death among diabetics, it is reasonable to ask why a diabetes drug that possibly increases rather than decreases the risk of heart disease should remain on the market. Are warnings enough to keep patients safe? After looking at the study results, many experts are urging that patients and doctors consider whether older drugs for diabetes may be safer and more effective – as well as much less expensive. They are asking: should Avandia remain on the market?
The new research published in 2010 makes it clear that the risks outweigh the benefits of Avandia, even compared to Actos, which is another diabetes drugs in this class. There is therefore no apparent reason for a doctor to prescribe Avandia rather than Actos, or a patient to take it. In addition, the new research suggests that other, older diabetes drugs are likely to be safer than Avandia.