- The Washington Times - Friday, July 13, 2007

Reports to federal regulators of side effects to the blockbuster diabetes drug Avandia tripled in the month after a surprising analysis revealed possible heart risks.

The sudden spike is a sign that doctors probably were unaware of the drug’s possible role in their patients’ heart problems and therefore may not have reported many such cases in the past, several authorities said.

It also shows the flaws of the safety tracking system and suggests that a better one might have detected a potential problem before the drug had been on the market for eight years.

Avandia is used to control blood sugar, helping more than 6 million people worldwide manage Type 2 diabetes, the kind linked to obesity. These people are already at higher risk for heart attacks, so news that the drug might raise this risk by 43 percent was especially disturbing.

In the 35 days after May 21, when the New England Journal of Medicine published the analysis on the Internet, reports of heart attacks, deaths and hospitalizations leaped. The sharp rise in reports of heart problems appears in data obtained by the Associated Press through a Freedom of Information Act request to the federal Food and Drug Administration.

Only five heart attacks were reported in the 35 days before the study, compared with 90 in the same period afterward. Heart-related hospitalizations went from 11 to 126. The reports involve rosiglitazone, sold as Avandia and Avandamet.

Reporting a drug’s side effects is voluntary and only a crude indication, rather than a scientific measure, of how many problems patients are actually having. The FDA relies on this unenforced system once a drug is on the market. Critics say it leads to haphazard oversight in which problems can be missed because doctors don’t connect the dots between a drug and symptoms they see in a patient.

With Avandia, the published analysis likely led to more cases being reported, said Vanderbilt University diabetes specialist Dr. Alvin C. Powers.

“Now, patients and their doctors are much more aware of the possible link between Avandia and cardiovascular disease. This is good — this is going to help us going forward to determine whether or not this drug is safe,” he said.

The drug’s manufacturer, GlaxoSmithKline, insists the drug is safe and effective.

“This is a very well-known phenomenon,” by which news reports lead to increased reporting, said company spokeswoman Mary Anne Rhyne. “It’s good that there’s awareness of the reporting system, but drawing conclusions on such data is inappropriate.”

The FDA plans hearings on safety concerns about the drug on July 30. In the meantime, diabetes specialists advise users of the medication to talk to their doctors and not to immediately discontinue it.

The side effects reported range from symptoms as minor as a blister to as serious as sudden cardiac death. Most of the reports the AP reviewed seemed to involve serious side effects, and rosiglitazone is listed by the FDA as the “primary suspect” rather than other medicines the patient may have been taking.

There is a total of only 50 adverse event reports in January and 73 in February. From April 16 to May 21, when the study was published, 121 events were reported, including 11 deaths. In the 35 days after the study, 357 events were reported, including 38 deaths.

“You really can’t infer anything about incidence rates from that,” because the spike in reports is likely due to the “publicity effect” of the study, said Dr. David Graham, an FDA drug safety specialist.

Dr. David Nathan, chief of diabetes care at Massachusetts General Hospital, agreed, saying it was “not conceivable” that only five persons among the 1 million Americans taking Avandia had heart attacks in the month preceding the May 21 study, as the FDA reports suggest.

“It just heightens the concern about the poor reporting we have,” said Dr. Nathan, who has received speaker fees from Glaxo and other drug companies. Dr. Powers and Dr. Graham have no financial ties to any diabetes drug makers.

The issue has roiled the medical community and sparked congressional probes into whether the FDA is properly investigating safety issues. The FDA issued a “safety alert” about the drug only after the May 21 study came out, even though Glaxo informed the agency of its own analysis of heart risks nearly a year beforehand and possibly as early as 2005.

Avandia’s label warns about possible heart failure and other heart problems when taken with insulin. The drug also raises LDL, or so-called bad cholesterol, and can cause fluid retention and weight gain.

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