Avandia has been a popular drug for diabetes, but is it safe? A new black box warning requires the company making Avandia to warn patients and doctors that it increases the risk of heart failure, which can be fatal.

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. According to a Congressional hearing held in 2007, in the eight years since approval, the FDA has done little to make sure these studies were appropriately conducted. Rep. Henry Waxman (D-CA) has called the FDA’s negligent regulatory role “a major failure of our system”.

In 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.

On May 23, 2007 the FDA requested that manufacturers of Avandia and the similar drug, Actos, provide a warning on the label about the risk of congestive heart failure associated with the use of these drugs. However, this was not made public until a Congressional hearing on Avandia in June, 2007. Known as a “black box” warning for the black border that surrounds the text of the warning, this is placed on the package for prescription drugs.

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.

The Avandia controversy has received much media attention, and as a result more patients and doctors are reporting side effects, and many doctors and patients have decided that the risks are too high and the benefits too. However, questions remain about the safety of other diabetes drugs, some of which have not been scrutinized as carefully as Avandia.

ON August 14, 2007, the FDA announced that there are now "black box" warning labels for Avandia (also called rosiglitazone) but also for the other drugs in its class;   these thiazolidinedione drugs include Actos (pioglitazone), 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. 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.

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, Actos, and other drugs in this class remain on the market? If they are safe for some patients, we need new, better research to show which patients will benefit, and which will be harmed.