Avandia: What’s Known and Not Known

Avandia was a popular drug for diabetes, but is it safe? There is research evidence that patients taking Avandia are more likely to die compared to diabetic patients taking other drugs.  The FDA defends the use of Avandia, but many concerns remain.

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) orrespond 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.

Previously, Dr. Steven Nissen and Kathy Wolski, MPH, published an article on the effects of Avandia and related drugs and cardiovascularrisks 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 2010 studies are harder to criticize.  One of them 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.

The “black box” warning labels for Avandia (also called rosiglitazone) are also required for the other drugs in its class.  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).

As a result of media attention and the black box warning, many doctors and patients have decided that the risks are too high. Prescriptions for Avandia decreased dramatically, but 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?

Starting in 2010, the FDA began requiring special certification for healthcare providers who prescribed Avandia.  Only specially certified pharmacies could dispense it, and only patients who were already taking it before the restrictions or new patients who could not use any other glucose-lowering medications were eligible to take it.

However, the company insisted that Avandia was safe and challenged the studies indicating it was not.  Dr. Nissen and other critics of the company’s research pointed out the flaws in the research design.  Despite the unanswered questions and continuing concerns of many experts, in November 2013, the FDA announced its conclusion that Avandia does not pose a greaterrisk of heart disease than the most commonly used Type 2 diabetes drugs and withdrew the stronger label warnings and otherrestrictions. Rather than proceeding with caution, the FDA told GlaxoSmithKline that they no longer need to conduct a previously required study comparing Avandia to Actos and other diabetes drugs.

The FDA’s decision leaves physicians and patients with limited information about which diabetes drugs are safer, and for which patients.  However, the law suits against Avandia have continued and the safety questions still concern many physicians and patients.

In January 2014, the FDA approved a new diabetes drug, Farxiga, that seems to be less effective than Avandia, Actos, and several other diabetes drugs; increases the risk of genital fungal infections and bladder infections, and may increase the risk of bladder cancer and breast cancer. Read here for more on Farxiga.

All articles are reviewed and approved by Dr. Diana Zuckerman and other senior senior staff.