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Avandia and diabetes: Was revolution worth the risks?

By Caleb Hellerman, CNN
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STORY HIGHLIGHTS
  • Two new studies suggest Avandia may cause serious heart problems
  • Other research finds no increased risk from the diabetes drug
  • FDA to reveal data on Avandia before next week's advisory panel meeting
  • Avandia works to improve the body's ability to break down glucose in the blood

(CNN) -- A decade after critics first accused the Food and Drug Administration of downplaying side effects from Avandia, the agency says it will reveal on Friday the data it is reviewing ahead of an advisory panel meeting about the safety of the popular diabetes drug.

The meeting, scheduled for July 13 and 14, comes on the heels of two new studies suggesting that Avandia may cause serious or even life-threatening heart problems -- and a third study that seems to show just the opposite.

When the gavel comes down at the end, it could bring down the curtain on the troubled 11-year run of one of the pharmaceutical industry's biggest hits. Along the way, Avandia has left a trail of admirers who see it as revolutionizing diabetes care, along with critics who say the company oversold benefits while misleading patients and doctors about serious side effects.

After years of controversy, the FDA panel, along with doctors in both the pro- and anti-Avandia camps, finds itself weighing the same questions as it has all along: Does Avandia cause heart problems in healthy patients? Does it really work better than other drugs to treat diabetes? And for many diabetes specialists: Is concern about side effects trumped by a need to reassure alarmed patients who may stop taking medication altogether?

In type 2 diabetes, the body loses the capacity to metabolize glucose -- sugar -- in the blood. High blood sugar can lead to severe complications. Avandia was approved in 1999 after trials by GlaxoSmithKline (then known as SmithKline Beecham) showed that it could lower blood sugar, by improving the body's own ability to process glucose. It was an immediate success, with sales peaking at more than $3 billion in 2006.

Avandia's FDA timeline
Video: Alternatives for Avandia

The tide turned in June 2007, when Dr. Steven Nissen, a respected heart expert at the Cleveland Clinic, published a meta-analysis -- a paper looking at all the available research on Avandia -- and concluded that the drug not only failed to prevent heart disease in diabetics, but actually raised the risk of heart failure and increased the risk of heart attacks by 43 percent.

Confusion and controversy ensued, along with scrambling on the part of Glaxo. In a series of meetings, e-mails and public statements -- detailed in a Senate report released in February -- GlaxoSmithKline fought to clear the name of its popular drug. There were allegations of pressure, both public and private, on researchers. And there was the expedited publication of a major clinical trial known as the RECORD study, which compared Avandia with two older diabetes drugs -- metformin and sulfonylurea -- and found no link to heart problems. A more complete version of the results was made public last year.

RECORD, however, did not include enough patients -- or find enough heart problems -- to reach a definite conclusion. Critics, unmollified, accused Glaxo of putting business goals ahead of good science. The Senate report cited internal company documents and dismissed the RECORD study as a marketing tool "to limit competition from Actos," a competitor's drug.

A spokeswoman for GlaxoSmithKline says the company welcomes a full airing of the evidence. Dr. Murray Stewart, vice president of clinical development, said in a phone interview that the FDA will need to consider the "totality" of evidence, not just the meta-analyses. According to Stewart, "All the clinical trials show no increase in mortality" when Avandia is compared with other drugs.

I want the FDA to order the company to withdraw the drug. The evidence is there.
--Dr. Steven Nissen, Cleveland Clinic

A closer look reveals that concerns similar to those raised by Nissen date back to the 1990s. In 2000, the advocacy group Public Citizen successfully petitioned the FDA for a stronger warning label, based on studies in animals before the drug was approved.

Nissen said the FDA should have acted long ago. "There are no unique benefits for this drug that are not provided by other diabetes medications," he said in a phone interview last week. "I want the FDA to order the company to withdraw the drug. The evidence is there, and it's been there a long time. It's a matter of having the political will to do it."

The FDA would not comment prior to its document release, but such sweeping statements anger Dr. Alan Garber, a diabetes specialist at the Baylor College of Medicine in Houston. Garber has been an investigator on two major clinical trials of Avandia, with funding from GlaxoSmithKline, as well as from the National Institutes of Health and other sources. He says neither study found an increase in heart attacks, although he agrees that patients with heart failure should not take Avandia. Garber says those trials, along with the RECORD study, offer good evidence that Avandia is effective as well as safe for most patients.

"This drug offers the most durable glucose control of anything," he said. "The more you reduce glucose, the more you reduce the eye disease, the kidney disease and the neuropathic complications."

In clinical trials, patients on Avandia show a smaller rise in fasting glucose levels -- a standard measuring stick for diabetes -- than patients taking other drugs. In theory, as Garber points out, this should be good news for patients on Avandia. Critics, though, say there is no evidence of better long-term outcomes -- lower mortality or fewer complications.

Garber sits on the board of the American Association of Clinical Endocrinologists. He says the clinical trials -- which closely followed several thousand patients, under careful monitoring -- constitute a gold standard of evidence for the FDA, compared with broad but less detailed data used in studies such as Nissen's.

"If there is a [negative] effect, it's a small effect," says Garber. "Let's treat our patients instead of sensationalizing half-truths and conclusions that are not yet formed. Otherwise what happens is that patients stop taking their medicines. I've seen data, and a fair number of patients just stop taking medicine, and as a result their blood sugar rises. That convincingly demonstrates harm, whereas all these other things are all unproven."

Let's treat our patients instead of sensationalizing half-truths and conclusions that are not yet formed.
-- Dr. Alan Garber, Baylor College of Medicine
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Three studies made public in late June will add fuel to what was already shaping up as a potentially fiery debate at the FDA. In the Archives of Internal Medicine, Nissen and colleagues published an update of their 2007 paper, including additional studies, and reported a similar increased risk of heart attacks and heart failure. The Journal of the American Medical Association published an analysis by Dr. David Graham, the FDA scientist who first flagged deadly side effects of the painkiller Vioxx. Graham compared Avandia with Actos, and found patients on Avandia are more likely to suffer stroke, heart failure or premature death. At the same time, doctors who support Avandia got ammunition from a presentation at the scientific meeting of the American Diabetes Association. There, Dr. Richard Bach of Washington University presented data from the BARI-2D study, and said it shows patients on Avandia actually have a lower risk of heart attack or stroke.

Practicing physicians find themselves in a quandary. Since 2006, sales of Avandia have fallen by about two-thirds, with many physicians taking the tack of Dr. Barbara Onumah, a diabetes specialist at Washington Hospital Center in the nation's capital. After the first reports of trouble, she says, patients began coming into the office with news clippings and anxious questions. Since then she has switched all but one of her diabetes patients to different medications.

Onumah says she just wants some clarity. "I'm looking for a strong statement [from the FDA]. Because right now, there's a lot of information. But none of it is clear."

After Nissen's bombshell, the FDA pushed GlaxoSmithKline to launch a major effort to try to settle the safety issue once and for all. Known as the TIDE study, it's designed to recruit more than 15,000 patients and be completed by 2015. However, barely a thousand patients have been willing to sign up -- a shortfall that seems likely to continue in the wake of ongoing doubt and negative reports. An FDA spokeswoman says the fate of the TIDE study will be on the agenda of next week's meeting.

CNN's Saundra Young contributed to this report.

 
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