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Diabetes Drugs Boost Heart Failure But Not Death

THURSDAY Sept. 27, 2007 -- The widely used diabetes drugs Avandia and Actos increase the risk for heart failure for patients with type 2 diabetes, but they do not raise the risk for cardiovascular death, U.S. researchers report.

The findings add to the controversy around these medications, which belong to a class of blood sugar-lowering drugs called thiazolidinediones (TZDs).

The higher danger of heart failure linked to Avandia and Actos resulted in the U.S. Food and Drug Administration (FDA) requiring the makers of these drugs place a "black box" warning on the labels of these medications.

In July, an FDA panel mulled removing Avandia from the market but then recommended against such a move. At the time, the panel said that the evidence linking Avandia to an increased risk for heart attack was not conclusive.

"There has been a lot of controversy and confusion about the use of these two drugs," noted the lead researcher of the new study, Dr. Richard Nesto, chair of the department of cardiovascular medicine at the Lahey Clinic Medical Center, in Burlington, Mass.

In their study, published in the Sept. 29 issue of The Lancet, Nesto's group collected data on more than 20,000 patients who had participated in seven clinical trials and received Avandia or Actos.

Nesto's team found a 72 percent increase risk of congestive heart failure among a wide range of patient types -- for example, those with so-called "pre-diabetes" or full-blown type 2 diabetes but without cardiovascular disease, those with type 2 diabetes and cardiovascular disease, and patients with type 2 diabetes and an already documented history of congestive heart failure.

However, the risk of cardiovascular death for these patients was not increased with either of the two drugs, Nesto's group found.

"That's an important observation," Nesto said. "What it means is that, even despite the risk of heart failure in some patients and despite analysis that showed there might be an increased risk of heart attack, we did not find an increased risk of death from cardiac causes. So, this should be somewhat reassuring," he said.

GlaxoSmithKline, the maker of Avandia, said the finding that Avandia does not boost users' cardiovascular death risk is not surprising.

"The findings are consistent with the results of several long-term outcomes trials with TZDs," the company noted in a statement released Thursday.

According to the drug maker, congestive heart failure is linked to fluid retention (edema), and "it is also well known that TZDs can cause some fluid retention, which can lead to, or worsen, congestive heart failure. If congestive heart failure signs and symptoms develop, and heart failure is confirmed, heart failure can be appropriately managed by a physician."

But Nesto believes that doctors should avoid prescribing these drugs to any patient with heart failure. "There are [therapeutic] alternatives where there are not these risks of heart failure," he said.

One expert agreed that the findings were familiar.

"These findings are similar to what we found in our studies," said Dr. Sonal Singh, an assistant professor of internal medicine at Wake Forest University School of Medicine in Winston-Salem, N.C. "This means that the black box warning is not enough," he said. "These drugs should be avoided in any patient at risk for heart failure," he said. "It's the nail in the coffin for using TZDs in people at risk for cardiovascular disease."

Dr. Steven Nissen, the chairman of the department of cardiovascular medicine at the Cleveland Clinic, was responsible for finding the association between Avandia and heart attack risk. He said the Lahey study failed to deal with the problem of specific risks linked to the use of these drugs.

"This new analysis does not answer the question whether the observed increase in heart failure leads to other serious complications, including death," Nissen said. "The authors did not examine the risk of cardiac death in patients who developed congestive heart failure while taking a TZD drug. Instead, they looked at overall cardiovascular mortality. This finding neither confirms, nor refutes, the hypothesis that TZDs lead to major complications of heart failure, including death," he said.

And concentrating on the risks, rather than the benefits, of these drugs misses the point, another expert said. The real question, according to Dr. Victor Montori, is whether these drugs are of any benefit at all to patients.

Right now, it's a matter of faith that lowering blood sugar really prevents the complications of type 2 diabetes, said Montori, an associate professor of medicine at the Mayo Clinic in Rochester, Minn., and co-author of an accompanying journal editorial.

There haven't yet been any large, extended clinical trials that measure the outcomes that really matter to diabetic patients, Montori said. Those outcomes include feeling better and living longer, he said. "Therefore, clinicians and patients cannot have a discussion with confidence about the potential benefits and downsides of currently available diabetes medications," he said.

Montori believes that, right now, it's not clear that the blood sugar reductions seen with these drugs actually prevent diabetes complications such as heart disease. The proof that reducing blood sugar prevents the complications of diabetes is based on evidence from patients with the much rarer, inherited type 1 diabetes which is usually treated with insulin, he said.

"That same proof is much shakier in patients with type 2 diabetes." Montori said. "And it seems that it matters with which drug you lower blood sugar in patients with type 2 diabetes."

Montori believes clinical trials could help determine whether these drugs are effective at all in terms of patients' quality of life.

The counter-argument is that if long trials were required, there would be fewer drugs on the market, and patient's choices would be limited.

"The current approach increases choice, but patients do not have the information they need to make the necessary choices," Montori said. "We cannot be confident that the options we have are associated with more good than harm,"

More information

For more on diabetes drugs, visit the U.S. Food and Drug Administration.

Posted: September 2007


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