Sequel for Vioxx Critic: Attack on Avandia (part 1)

[JohnMack]

Source: WSJ

MEDICAL DETECTIVE
Sequel for Vioxx Critic: Attack on Diabetes Pill
Glaxo Shares Plunge As Dr. Nissen Sees Risk To Heart From Avandia
By ANNA WILDE MATHEWS
May 22, 2007; Page A1

An analysis linking the widely used diabetes drug Avandia to higher risk of heart attacks represents a serious blow to GlaxoSmithKline PLC and underscores how outside critics have been empowered to challenge big-selling drugs after the outcry over the withdrawn painkiller Vioxx.

Glaxo rang up more than $3 billion in world-wide sales of Avandia last year. Its share price fell more than 7% after the New England Journal of Medicine released the analysis by prominent cardiologist Steven Nissen of the Cleveland Clinic, who helped raise early safety concerns about Vioxx. The analysis suggested that people on Avandia have a 43% higher chance of suffering a heart attack.

Glaxo said it "strongly disagrees" with his conclusions, which come from a "meta-analysis" in which results from many trials are combined. Glaxo said data sources it considers more reliable suggest that Avandia is no riskier for the heart than other diabetes medications. (See related article.1)

Dr. Nissen started his quest to gather data about Avandia's risks last year, after he spotted what he thought were hints of trouble in published studies. Along the way, he set congressional investigations into motion, and, last month, hit pay dirt with a Google search that pointed him to a trove of study data. Brushing aside the arguments of Glaxo executives who rushed to Cleveland, he pushed his concerns into one of the world's top medical journals in just a few weeks.

One issue coming under congressional scrutiny is whether the Food and Drug Administration should have acted faster to alert the public about possible risk from Avandia. Glaxo performed its own meta-analysis, which also showed a potential danger. It shared an early version of it with the FDA in September 2005 and a more complete one in August 2006. The findings weren't reflected on the U.S. label, which is supposed to give a comprehensive review of the drug's risks.

NEW PRESCRIPTION

• The Issue: Vioxx critic Steven Nissen of the Cleveland Clinic turned his focus to diabetes drug Avandia, and found link to heart-attack risk.

• Whom It Affects: About one million Americans currently are taking Avandia, which had world-wide sales above $3 billion last year.

• The Response: Drug maker GlaxoSmithKline says the data are flawed. The FDA says the data raise concern but are inconclusive, and that it is conducting its own analysis.


Robert Meyer, head of the FDA office that oversees diabetes drugs, said the agency is still working on its analysis. "We have other data that suggests we can't make a definitive conclusion at this point," said Dr. Meyer, although he called the meta-analyses "a signal of concern."

The news sent doctors and patients taking Avandia scurrying to re-evaluate their options. Alternatives include a similar drug, Actos, made by Takeda Pharmaceutical Co., which didn't show a link to heart attacks or strokes in a trial published in the Lancet in 2005. Diabetes treatments that work in different ways, such as Merck & Co.'s Januvia, and older drugs like metformin could also gain sales.

"Cardiovascular disease is far and away the leading cause of death in diabetes. If you find a diabetes drug increases the risk of heart attacks, the consequences are so grave that it warrants urgent action," said Dr. Nissen, the 58-year-old chairman of cardiovascular medicine at the Cleveland Clinic, in an interview.

Dr. Nissen has consulted for drug companies including Glaxo. He is leading a small clinical trial of Actos funded by Takeda. He gives his drug-industry payments to charity and said his work for Takeda doesn't affect his view of competing drugs.

Cindy Roth, a diabetes patient in Whitewater, Kan., said the news about Avandia is a "little bit of a scare," in particular because heart problems run in her family. "I thought, 'Great, just one more thing,'" she said. Ms. Roth said she would follow her doctor's advice on whether to stop taking the drug.

Outside specialists are in a more powerful position these days to challenge marketed drugs. After the 2004 withdrawal of Merck's arthritis drug Vioxx and other well-publicized safety issues, the FDA is under pressure to respond more aggressively to signals of possible danger.

Prodded by lawmakers and medical journals, companies have put large databases of once-secret information about clinical trials online. The FDA's Web site also contains significant data on approved drugs. Dr. Nissen's Googling turned up a public database that GlaxoSmithKline created after it was sued over its antidepressant Paxil. The company had been accused of burying information about Paxil, including possible links to suicidal thinking in adolescents.

Dr. Nissen's analysis of Avandia combined 42 studies. In addition to showing higher heart-attack risk, it showed a 64% elevated risk of death from cardiovascular causes such as heart attack and stroke, although the latter result didn't meet a standard statistical test for significance.

The absolute risk of heart attacks and death was still low. Among people in Dr. Nissen's analysis who took Avandia, the rate of heart attack was between 0.43% and 1.85%, while the cardiovascular-death rate was between 0.14% and 0.51%.

About seven million people world-wide have taken Avandia, and about one million Americans are currently using it, GlaxoSmithKline said. Avandia is the London-based company's second-biggest seller after the asthma medication Advair, and last year various forms of the drug represented 37% of the U.S. market for oral diabetes treatments, according to the company. Glaxo has been studying Avandia as a possible treatment for people with early signs of diabetes and Alzheimer's patients.

Democratic Rep. Henry Waxman of California said he will hold a hearing in early June and summon FDA Commissioner Andrew von Eschenbach, Glaxo Chief Executive Jean-Pierre Garnier and Dr. Nissen.

A sharply worded editorial in the New England Journal of Medicine accompanying Dr. Nissen's study said "regulatory action by the Food and Drug Administration is now warranted." The editorial questioned the measure of effectiveness the FDA typically uses to approve diabetes drugs. The agency mostly examines how well the drugs reduce blood sugar, which is supposed to be a surrogate for improving more important outcomes, like heart disease. The FDA said yesterday it has strong evidence to suggest that reducing blood sugar translates into real-world benefit for patients.

Diabetes specialists were divided yesterday over whether patients taking Avandia should stop. "Patients and physicians need to take this seriously, in the absence of other data," said David Nathan, a professor at Harvard University. While calling the Nissen analysis "imperfectly done," he said: "Since heart disease is the major killer of people with diabetes, it's hard to imagine why you would use a drug that might increase the risk of heart disease."

John Buse, president-elect of the American Diabetes Association and a professor at the University of North Carolina, said he's "not sure the data are strong enough to encourage wholesale switching" from Avandia. "I doubt [Avandia] would be associated with a 40% increase in risk when the studies are done," he said.

Dr. Nissen has long been one of the nation's most prominent cardiologists. In the past few years, he has increasingly focused on drug safety. He was co-author of a 2001 analysis that flagged a possible heart risk with Vioxx and a similar painkiller, Celebrex. Merck initially dismissed the concerns, but pulled Vioxx three years later when its own study confirmed the risk.

In 2005, Dr. Nissen published an article in the Journal of the American Medical Association raising concerns about the cardiovascular risks associated with Pargluva, a diabetes drug that an FDA advisory panel had voted in favor of. The FDA declined to approve the drug and the companies hoping to market it, Merck and Bristol-Myers Squibb Co., abandoned the effort.

Dr. Nissen said that after his article about Pargluva appeared, he received an email from a leading diabetes expert who suggested that Avandia raised similar concerns.

See part 2 in "Reply"

[JohnMack]

See part 1

Although their mode of action isn't identical, both Pargluva and Avandia work by affecting what are known as peroxisome proliferator-activated receptors, or PPARs. These are receptors in a cell's nucleus that affect a broad range of human genes. Because of their wide effect, many experimental PPAR drugs have been derailed by safety problems including possible hazards to the heart, kidney and muscles as well as tumors in animals.

Nonetheless, more than 50 PPAR drugs are being studied by pharmaceutical companies because the potential benefits are big too, according Pharmaprojects, a unit of Informa Healthcare Ltd. In Type 2 diabetes, patients don't produce enough insulin, a hormone needed to convert sugar and other food into energy, or their cells ignore the insulin that is being produced. Avandia and Actos, another PPAR drug, increase the sensitivity of cells to insulin, lowering blood sugar.

After their introduction in 1999, Avandia and Actos both soon became multibillion-dollar-a-year sellers. The labels on the two drugs have warned that they can cause fluid retention leading to congestive heart failure, a chronic condition in which the heart has trouble pumping blood. But regulators generally saw that as a manageable side effect. Signs of heart failure can be spotted early and treated with drugs, whereas in a heart attack, blood is choked off from the heart and immediate death can result.

Dr. Nissen said that even before the 2005 email, he had favored Actos. He had been nervous about Avandia because its label shows it is tied to an increase in LDL, or "bad" cholesterol, though company salespeople reassured him that HDL or "good" cholesterol also rose.

Dr. Nissen began following Avandia closely and was struck last year by the results of two major trials of the drug, published in the New England Journal of Medicine and the Lancet. The two studies showed the drug was effective in controlling blood sugar, but Dr. Nissen thought they held signs of cardiovascular problems.

He asked Kathy Wolski, a Cleveland Clinic statistician, to do a rough analysis combining studies published about the drug. The numbers, when added together, hinted at problems but didn't prove anything. "I honestly thought we weren't going to go any further with it," Ms. Wolski said. "He did not let it go. He was like a dog with a bone."

Dr. Nissen wrote to GlaxoSmithKline in early January, asking for more data. The company offered to collaborate with him, but said it wanted to crunch the numbers itself. Dr. Nissen countered that the Cleveland Clinic needed full access to all the raw information and the right to publish as it pleased. Talks over the matter were inconclusive.

The cardiologist also shared his early results with congressional staffers, hoping they would use their authority to get the FDA to share trial results filed by the company. Aides to Democratic Rep. John Dingell of Michigan and Mr. Waxman called FDA officials in on March 16 to discuss their handling of Avandia.

In the end, it turned out humble Internet searches were all Dr. Nissen needed. In mid-April, he found online the 1999 FDA document detailing the agency's original review of the drug. Then, in a Google search, Dr. Nissen found the online database of Glaxo study results. Many of the trial summaries included heart-attack data.

Dr. Nissen made another discovery in scrolling through the Web site. The company itself had done a meta-analysis similar to the one he was attempting, and quietly posted the result. The analysis, which didn't appear to include the two big trials published last year, tied the drug to a 31% higher risk of events involving an obstruction of blood flow, such as heart attacks. The rate for people taking Avandia was 1.99%, compared with 1.51% for other patients.

Glaxo's summary said that "no definitive conclusion can be drawn." It noted that a separate study using a large database kept by a health insurer hadn't shown evidence of risk. "We are confident about the safety profile of Avandia," said Ronald Krall, Glaxo's chief medical officer, yesterday. Glaxo said ongoing trials haven't shown signs of a risk.

The Web site was a "gold mine," Dr. Nissen said. On May 1, he and Ms. Wolski sent the New England Journal of Medicine a manuscript tying Avandia to a statistically significant heart risk.

Glaxo learned of the submission and dispatched four executives to Cleveland. Dr. Krall argued that the data didn't clearly show a risk. Glaxo said yesterday that the meta-analysis technique isn't the most rigorous way to reach conclusions about safety issues because it combines studies that are designed differently and the data collected in the studies may not be comparable.

Dr. Nissen said the meeting was "very collegial and respectful," but the Glaxo team didn't change his mind about the safety concerns.

The New England Journal sharply accelerated its usual review process. "We felt it was our responsibility not to take eight, nine, 10 weeks to get this out," said Jeffrey Drazen, editor in chief.

With the data now public, the battle may shift to Capitol Hill. In a letter to the FDA dated April 30, the House Democrats plus Republican Sen. Charles Grassley expressed concern that "tens of thousands of excess heart attacks may have occurred" since the FDA began reviewing data from Glaxo's internal meta-analysis.

Yesterday, the Senate Finance Committee chairman, Montana Democrat Max Baucus, and Sen. Grassley sent a letter to Glaxo mentioning "reports that GSK employees silenced one or more medical professionals who attempted to speak out about the potential for cardiovascular problems with Avandia." In a statement, the company called the suggestion "absolutely false."

-- Jeanne Whalen and

Sarah Rubenstein

contributed to this article.

Write to Anna Wilde Mathews at anna.mathews@wsj.com10