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Wednesday, August 6, 2008

Diabetes Drug, Byetta, Shows a Life-Extending Promise

The New York Times reports that patients with diabetes who took Byetta, an injectable drug that lowers blood sugar, had a much lower chance of dying that those who took any other drug.  Alex Berenson writes,

Byetta2Can Byetta, an injectable drug that lowers blood sugar, really help people with diabetes to live longer?

Possibly, according to the results of a major clinical trial presented at the American Diabetes Association annual conference. In the trial, called Accord, patients with Type 2 diabetes were prescribed Byetta or any of several other diabetes medicines. Patients who took Byetta had a much lower chance of dying, about 75 percent lower, than those who took any other drug.

The finding, presented in June, has generated a stir among diabetes researchers, although so far it has attracted little public notice. Neither Eli Lilly or Amylin, the companies that jointly market Byetta, is publicizing the findings, in part because no one is sure whether the reduction in the death rate is real or a chance finding. Only about 825 patients in the 10,000-patient Accord trial took Byetta, and those who did were likelier to be healthier than other patients.

“We don’t know whether it’s the drug or the healthy participant,” said Dr. Michael Miller, professor of biostatistics at Wake Forest University and the lead statistician on the Accord trial.

The trial’s finding came as a surprise even to Lilly and Amylin, said Dr. James Malone, the global medical director of Byetta for Lilly.

“We were not aware of the results before they were presented at A.D.A., and I was sitting in the audience and my jaw just dropped,” Dr. Malone said. The trials that Lilly and Amylin have conducted on Byetta, have not shown a reduction in mortality in patients taking the medicine, but they were not intended to do so.

Although Byetta has been a moderate success in the market, with sales expected to reach about $700 million this year, prescriptions are short of what analysts had forecast when the medicine was introduced in 2005.

For the Accord finding to be proved, it must be tested in a large trial that would compare the cardiac health and overall death rates of thousands of patients, half receiving Byetta and half receiving a placebo. So far, Lilly and Amylin have not committed to undertaking such a trial, which would take years and cost tens of millions of dollars.

Further complicating the issue is that the two companies are working a reformulated version of Byetta, which could be injected once weekly instead of twice daily, and they may prefer to run the trial on the new medicine, which has not yet been approved by the Food and Drug Administration.

Dr. Malone said the two companies hoped to make a decision on holding a large mortality trial by the end of the year.

Even so, the finding adds to an emerging body of evidence that Byetta — the first in a new class of diabetes medicines called incretin mimetics — may work better than other diabetes medicines, at least for people who can tolerate its side effects, which can include severe nausea.

Byetta is less likely than other diabetes medicines to cause hypoglycemia, or dangerously low blood sugar. In addition, while most diabetes medicines cause patients to gain weight, patients on Byetta typically lose several pounds each year on the medicine. Weight gain is associated with cardiovascular problems, the most common causes of death for people with diabetes.

“My suspicion is that when you look at the determinants of mortality, which were weight gain and hypoglycemia in that study, Byetta would be the antimortality drug, because it’s associated with weight loss and less hypoglycemia,” said Dr. Alan Garber, an endocrinologist and professor of medicine at Baylor.

In addition, animal trials offer some evidence that Byetta may directly benefit the heart, Dr. Malone said.

Byetta, generically called exenatide, is a synthetic version of a protein originally discovered in the venom of a lizard, the Gila monster. It encourages digestion and the production of insulin. Byetta is currently approved for use alongside other diabetes drugs, and Lilly and Amylin have asked the F.D.A. to approve it as a monotherapy as well.

When Byetta was introduced in 2005, prescriptions for it grew rapidly. But for the last year, Byetta prescriptions have been roughly flat at about 250,000 a month.

Doctors say that some patients cannot tolerate the nausea that Byetta can cause and others do not like injecting the medicine twice daily. Concerns about pancreatitis, an inflammation of the pancreas that can be fatal in rare cases, have also hurt the drug, although Byetta has not been proved to cause pancreatitis.

Dr. Joel Zonszein, an endocrinologist at Montefiore Medical Center in the Bronx, said some primary care doctors do not like to prescribe Byetta because they must teach patients how to give injections, a time-consuming process. “It is a drug that is difficult to prescribe,” Dr. Zonszein said.

Meanwhile, prescriptions for Januvia, a medicine in pill form from Merck that works in a somewhat similar way as Byetta, have taken off since Merck introduced it in October 2006. More than 500,000 patients a month are being given prescriptions for Januvia or Janumet, which combines Januvia with a second diabetes medicine in a single pill.

“Januvia has been effectively marketed in the primary care community,” said Dr. John Buse, vice chairman for the Accord study and professor of medicine at the University of North Carolina, Chapel Hill. “I think there is some misunderstanding about the relationship between Januvia and Byetta among primary care providers.”

Dr. Buse said that the data from Accord was intriguing but not enough to persuade him that Byetta could reduce deaths in diabetes patients.

“The number of patients in Accord that were treated with exenatide was a very small proportion of the total patients in Accord, and they got exenatide relatively late in the trial,” he said. He said he hoped Lilly and Amylin would decide to invest in the trial necessary to test Byetta’s effect on mortality.

“They need to do it,” he said.

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