Diabetes Drugs and Heart Risk
New Studies Link Avandia, but Not Actos, to Heart Attacks
Actos, Avandia: New Drug Class, New Side Effects continued...
Bad things can happen, too. Rezulin, the first FDA-approved glitazone, was taken off the market after three years when it was linked to liver failure. Two similar drugs (called glitazars because they activate two different PPAR receptors) didn't make it through the testing process. Muraglitazar increased heart complications, and tesaglitazar harmed the kidneys.
"This PPAR system is pretty complicated. At this point we don't fully understand it," Solomon says. "I think that whenever a drug is on the market without a well-documented mechanism of action, unanticipated events occur."
Actos and Avandia both increase a patient's risk of heart failure.
In addition to these side effects, Singh notes that patients taking the drugs have an increased risk of bone fractures and increased risk of macular edema leading to blindness.
Takeda's Spanheimer does not dispute that these new adverse events are beginning to appear. He says the company is working hard to understand why they are occurring, when, and in which patients.
"What we are learning about macular edema and bone fractures is it has taken quite awhile -- over 8 million patients -- to see these side effects come out," he says. "You have to be concerned about long-term safety. Some of these side effects, when they appear, are not very strong signals of a drug effect, and it takes a long time for them to be manifest. With any new drug class, you have to look at it two ways -- and one way is we are starting to define the safety profile of this drug."
Lincoff says that from a cardiologist's perspective, the heart benefits of Actos outweigh the heart-failure hazard.
"In general, the heart failure related to these two drugs seems to be reversible -- it seems to be due not to damaging the heart, but to retaining fluid," he says. "But death, heart attack, and stroke are all irreversible. So the benefit of Actos outweighs all these risks from fluid retention."
Singh takes a less rosy view of both drugs.
"What should we tell patients? We look at diabetes control, and either switch them to diabetes drugs that do not have these risks, or switch them to insulin," he says. "I do not switch them from Avandia to Actos. Yes, Actos does not have this increased risk of heart attack. But it does increase risk of heart failure -- true, without increases in mortality -- but heart failure has consequences to patients."