While the findings may be conflicting, the hint of cardiovascular safety issues is enough to worry some. "Any [diabetes] drug that is worth anything needs to decrease the risk of cardiovascular disease," says Sidney Wolfe, editor of worstpills.org and director of the health research group at the consumer advocacy organization Public Citizen. "When a drug increases the risk of cardiovascular disease, it should be off the market," he says. "It's a huge failure that the FDA has not taken it off the market." The FDA says that it is requiring GlaxoSmithKline to conduct a cardiovascular outcome trial on Avandia to provide a definitive answer to whether Avandia poses an unacceptable risk of cardiovascular disease.
Concern about how Avandia affects the heart led Public Citizen to call for a ban on the drug. The nonprofit watchdog group sent a petition to the FDA in October 2008 but so far has not received a response, Wolfe says. FDA spokesperson Karen Riley says that the agency tries to respond to citizen petitions within a 90-day time frame and that the Public Citizen petition is under active review.
"Patients with diabetes have a two-to-four-times greater risk of heart disease than their nondiabetic counterparts, and none of the currently approved antidiabetic therapies has been convincingly proven to reduce that risk," says Riley. Responding to questions raised about Avandia, the FDA in December 2008 instituted tougher standards for approval of diabetes drugs. It now asks drug companies applying for approval of a new diabetes medication to "provide better evidence that the therapy will not increase the risk of such cardiovascular events as a heart attack," Riley says. A medication called alogliptin, which drugmaker Takeda Pharmaceutical Co. had hoped to win approval for this year, will most likely be delayed until 2012 because the FDA has asked the company to conduct a cardiovascular safety clinical trial. Another new diabetes drug, Victoza (liraglutide), has been approved in Europe but not in the United States.
Public Citizen says that Glucophage (metformin) and Glucotrol (glipizide) are safer diabetes treatment options; it does not recommend Actos because the group believes Actos shares some of Avandia's safety problems, except for risk of heart attack. Robert Spanheimer, vice president of medical and scientific affairs at Takeda—which also makes Actos—says that the company acknowledges the drug's possible link to heart failure. He said that people who develop signs of heart failure should seek prompt treatment. Heart failure "is recognizable, [and] it is treatable," he says. "If patients understand the risk and understand the early symptoms, they can go to their doctor and be treated."
GlaxoSmithKline says it stands behind the safety of Avandia. "We think that it's been shown to be a safe and effective treatment for type 2 diabetes for the appropriate patient," says Mary Anne Rhyne, a GlaxoSmithKline spokesperson. The RECORD study "addresses some of the [previous] concern, and we feel like it reinforces its safety for long-term glucose control for diabetes patients."
Eye risks. People taking medications in a class of drugs called thiazolidinediones, also known as glitazones—comprising Avandia and Actos—appear to be at higher risk for macular edema, according to a study published in April in the American Journal of Ophthalmology. (Macular edema occurs when the macula—the portion of the retina responsible for sharp central vision—swells as a result of leaking fluid.) While the authors said that more research is needed, they noted that eye doctors should consider the role of glitazones when treating patients who have macular edema. The labels for Avandia and Actos warn that anyone taking the medication who experiences vision problems should promptly see an ophthalmologist. (In a bit of good news, a separate study found that Avandia may help to slow certain types of eye disease.)
Fractures. Both Avandia and Actos appear to increase the risk of bone fractures in women—but not in men, according to a meta-analysis published in December 2008 in the Canadian Medical Association Journal. Researchers looked at 10 clinical trials involving more than 13,000 diabetics who were taking Avandia, Actos, or neither medication. The medications seemed to reduce bone density in the hips and spine of the women taking them—which researchers estimated could double the fracture risk in these women.