Glaxo's Avandia May Raise Heart-Attack, Death Risks
May 21, 2007
By Michelle Fay Cortez

GlaxoSmithKline Plc's drug Avandia, the world's top-selling oral diabetes treatment, may raise a patient's chance of having a heart attack, researchers said. Glaxo shares fell the most in five years.

Patients getting Avandia were 43 percent more likely to have a heart attack, according to an analysis released today of previous studies. Researchers also found a trend toward high death rates. Glaxo executives said more rigorous research showed no increase in danger, and U.S. regulators said they don't yet have enough information to determine any risks.

The new findings, released by the New England Journal of Medicine, cast doubt on the future of a drug that is taken by 1 million Americans and generated sales of $3 billion last year. Questions about Avandia's safety may benefit Takeda Pharmaceutical Co.'s Actos, a similar product that doesn't have a heart risk, or new treatments such as Eli Lilly & Co.'s Byetta and Merck & Co.'s Janumet.

``The whole reason we try to lower blood sugar is to prevent complications of diabetes, the most important of which is heart disease,'' said Steven Nissen, chair of cardiology at the Cleveland Clinic in Ohio, who led the study. ``Obviously when you have a drug that lowers blood sugar but increases the risk of heart disease, it has major public health consequences.''

Shares Fall

Glaxo's American depositary receipts, each representing two ordinary shares, fell $4.53, or 7.9 percent, to $53.18 at 4:12 p.m. in New York Stock Exchange composite trading. The decline in the ADRs was the biggest since May 2002. Shares of London-based Glaxo fell 74 pence, or 5 percent, to 1,390 pence at 4:35 p.m. in London.

Heightened attention to Avandia's safety is likely to cut into sales, said Tim Anderson, an analyst at Prudential Equity Group.

``Patients should not stop taking any prescribed medications without first discussing the issue with their health care provider,'' the American Diabetes Association, the American College of Cardiology and the American Heart Association said today in a joint statement. ``Further research will be needed in this area to provide conclusive evidence.''

Almost 21 million people in the U.S. have diabetes, a disease in which the body doesn't properly make or use the hormone insulin to convert blood sugar to energy, according the American Diabetes Association. Avandia lowers blood sugar levels, which can cause complications including kidney and eye damage, by increasing the body's sensitivity to insulin.

Nissen's Track Record

Nissen has a track record of calling attention to safety risks involving widely used drugs. He and his former boss, cardiologist Eric Topol, were the first to question the safety of Merck's now withdrawn pain pill Vioxx. They also uncovered risks of heart attacks and strokes in patients taking Bristol-Myers Squibb Co.'s experimental diabetes pill Pargluva.

Avandia is Glaxo's second-best-selling drug after the asthma treatment Advair, marketed in some countries as Seretide. The drug was approved by the U.S. Food and Drug Administration in 1999.

A similar analysis conducted by Glaxo and submitted in preliminary form to regulators in 2005 suggested a 30 percent increased risk of cardiovascular complications. The data didn't provide a clear picture of the drug's risks and benefits, according to Glaxo.

The best measure of Avandia's side effects comes from long- term trials, not the compilation of shorter-term studies captured in the New England Journal article, Glaxo executives said today.

`Many, Many Trials'

``We've done many, many of these trials,'' said Lawson Macartney, senior vice president of the company's cardiovascular and metabolic medicine development center, on a conference call with reporters. ``Throughout this body of evidence in these long- term trials, we are not seeing anything like the changes observed'' in the results reported today.

In the new study, Nissen and Kathy Wolski analyzed data from 42 studies involving 15,560 patients who took the drug and 12,283 patients who were given other medications or a placebo. Patients getting Avandia were 64 percent more likely to die from cardiovascular causes, though those findings could have resulted from chance, the researchers said.

There were 158 heart attacks and 61 deaths from cardiovascular causes among the patients in the studies, which generally lasted from six months to a year.

`Reassuring' Information

FDA officials said they haven't confirmed that Avandia raises the risks of heart attacks or that competing medicines for diabetes have fewer risks. A preliminary review provided ``reassuring'' information, said Robert Meyer, a supervisory medical officer in the agency's drug-evaluation office, on a conference call today.

``We don't have a clear regulatory or clinical advice message as of today,'' he said. Meyer didn't rule out action by the FDA after the agency completes its review. Regulators could change the prescribing information for Avandia to restrict its use, require Glaxo to conduct more studies or pull the product off the market entirely.

U.S. Representatives John Dingell and Bart Stupak, both Michigan Democrats, said they will investigate the ``failure'' of Glaxo and the FDA to warn consumers of the increased heart risks seen in the company's own analysis.

The House Oversight Committee will review on June 6 the action the agency has taken thus far, according to a statement released today by Chairman Henry Waxman, a California Democrat.

Rationale `Unclear'

Considering the potential heart risks and in the absence of other advantages, the rationale for prescribing Avandia ``at this time is unclear,'' wrote drug safety experts Bruce M. Psaty, of the University of Washington's cardiovascular health research unit, and Curt D. Furberg, of Wake Forest University's division of public health sciences, in an editorial that accompanied the study in the New England Journal.

Insofar as the new findings ``represent a valid estimate of the risk of cardiovascular events, rosiglitazone represents a major failure of the drug-use and drug-approval process in the United States,'' they wrote.

The study's findings aren't definitive. The researchers compiled data from existing studies of Avandia, known chemically as rosiglitazone, that were submitted to U.S. regulators to support the drug's approval and others that were conducted subsequently, in part to expand the drug's label.

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