Diabetes Drugs and Heart Risk
New Studies Link Avandia, but Not Actos, to Heart Attacks
Actos, Avandia: New Drug Class, New Side Effects continued...
The drugs activate an important chemical-signaling pathway that controls
some of the body's most basic functions. That pathway has several signal boxes,
called PPAR receptors. Nobody yet knows all of the things that happen when
drugs activate PPAR receptors. But two things happen that are good for people
with diabetes: The cells of the body become more sensitive to insulin, and
blood sugar levels go down.
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
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
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."