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Glaxo's Avandia Risks Prompt Doctors to Switch Drugs

By John Lauerman and Elizabeth Lopatto

May 23, 2007 - (Bloomberg) -- Boston doctor Annaswamy Raji says she was so alarmed by a study linking GlaxoSmithKline Plc's drug Avandia to heart disease that she immediately advised a diabetes patient to stop taking the medicine.

Research released May 21 by the New England Journal of Medicine provided evidence that Avandia raises the chance of a heart attack by as much as 43 percent. London-based Glaxo shares dropped for a third day, bringing the week's decline to 8.4 percent. The data caused U.S. lawmakers to question the government's drug-safety monitoring.

Some doctors say the risks uncovered in the study are outweighed by the drug's benefits. Patients should continue taking Avandia, the world's top-selling oral diabetes treatment with $3 billion in revenue last year, until Glaxo or U.S. regulators provide more guidance, they say. Meanwhile, some doctors, insurance companies and hospitals say they are reconsidering the use of Avandia.

Raji took an 83-year-old man off the drug because he ``is at a higher risk for heart disease and heart attack,'' said the Boston physician, an endocrinologist at Harvard Medical School and Brigham and Women's Hospital, in a telephone interview yesterday. "Given the new information and until more data is available, I recommended that he stop this medication.''

Raji said her hospital is reviewing its use of Avandia. Other doctors said they were getting questions about its safety from patients.

Patient Panic

"We figured we had about 30 calls from last night until this morning,'' said Farida Khan, chief of endocrinology at New York Methodist Hospital, who works in a practice with two other specialists. "There are more messages in our offices that we haven't picked up yet.''

Glaxo shares fell 27 pence, or 2 percent, to 1,344 pence in London. They may reach their worst week since January 2003. The stock is little changed this year, trailing the 600 member Dow Jones Stoxx Index, which has risen 8.2 percent.

While the study findings raise some concern and indicate the need for more clear data, there is no need for alarm, according to an editorial released today by the Lancet, a prominent medical journal that published one of the largest studies on Avandia.

Doctors, patients and regulators can safely wait for the results of a pivotal trial, dubbed Record, that is specifically looking at heart risks among patients taking Avandia, known chemically as rosiglitazone, the editors said.

"To avoid unnecessary panic among patients, a calmer and more considered approach to the safety of rosiglitazone is needed,'' they wrote. "It would be premature to over interpret a meta-analysis that the authors and NEJM editorialists all acknowledge contains important weaknesses.''

Of the 21 million people in the U.S. who have diabetes, two-thirds will die from either heart disease or a stroke, according to the American Diabetes Association. Doctors are trying to determine what to do about the 1 million who take Avandia after the study became public this week.

Talking to Doctors

"Our immediate concern is that patients aren't unduly alarmed by the reporting of the data,'' said Philip Thomson, a Glaxo spokesman, in a telephone interview. ``We are making every effort to communicate with physicians and patients our strong belief that Avandia is a highly effective treatment for type 2 diabetes.''

The findings raise concerns similar to those faced by Merck & Co. after the 2004 withdrawal of the painkiller Vioxx, responsible for $2.5 billion in annual sales. Results from a cancer study linked the drug to heart disease. The studies included in the analysis of Avandia similarly weren't intended to establish the product's effects on the heart.

Cleveland Clinic cardiologist Steven Nissen 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. John Buse, a diabetes specialist at the University of North Carolina School of Medicine in Chapel Hill, said he needs more information before switching patients to other drugs.

"It's an extremely well-done version of this kind of study,'' Buse said. "It's possible that it's wrong.''

Takeda's Actos

Glaxo has declined to release more data on Avandia that might clarify its effects on the heart, Buse said. In the meantime, most patients can probably continue taking Avandia for at least three months, or until a clearer picture emerges.

The European Medicines Agency advised patients today that they should continue taking the medicine and speak with their physicians at their next regular visit. Product information on the risk of cardiac events related to the drug was updated last year, the regulator said.

Other research indicates Actos, sold by Japan's Takeda Pharmaceutical Co., lowers blood sugar in the same way as Avandia and cuts levels of blood fats such as cholesterol that raise the risk of heart disease.

If the findings of this week's New England Journal report turn out to be related to fluid retention or weight gain, it may have consequences for rival treatments of the same type as Avandia. Those drugs are known as thiazolidinediones, or TZDs.

Class Problem?

"We know TZDs cause fluid retention,'' Steve Kahn, co- author of an earlier trial called ADOPT, said in an interview in December.

Other types of drugs offer diabetes patients possible options, such as metformin, which slows the absorption of sugar; injections of the hormone insulin; and sulfonylureas, which stimulate the pancreas to make more insulin.

"Given the data that are available, the conservative approach would be to change to another class of drugs,'' or switch to Actos, said David Nathan, director of the diabetes center at Massachusetts General Hospital in Boston. "In the absence of other balancing data, doctors need to take this seriously.''

U.S. medical experts are already urging lawmakers to require companies to conduct longer studies of new drugs, even after they are approved, and to make the results public to identify risks as quickly as possible. The Avandia findings stemmed from a lawsuit Glaxo settled with New York that required it to make the results of its studies public. Not all companies are similarly obligated.

"The health of the public would benefit from additional revisions to the drug-safety legislation,'' particularly as lawmakers work on a Food and Drug Administration revitalization bill that would give the agency additional powers, said Bruce Psaty, a cardiologist and drug safety expert from the University of Washington, in an editorial that accompanied the study.

Medco, Massachusetts General

Medco Health Solutions Inc., the biggest U.S. manager of drug benefits, based in Franklin Lakes, New Jersey, is considering whether to add information on Avandia's possible heart-attack risk to an alert system of potential side effects that it sends to doctors.

Nathan said doctors at Massachusetts General will meet to determine whether to make new recommendations for the drug. Blue Cross and Blue Shield of Massachusetts will also review whether the study warrants any action, said Chris Murphy, a spokesman.

Other drugs to treat diabetes have side effects, North Carolina's Buse said. High doses of insulin can drive blood sugar to a low level, called hypoglycemia, which can lead to unconsciousness and accidents. Sulfonylureas have also been associated with heart disease in studies that haven't been confirmed. About 1 in 20 patients can't take metformin because of diarrhea, bloating and other side effects.

"The message we've asked our staff to give patients is to stay on Avandia,'' Buse said. ""If they're nervous, they can come in to discuss their options. The only bad decision they can make is to stop Avandia without talking to us.''

To contact the reporter on this story: John Lauerman in Boston at jlauerman@bloomberg.net ; Elizabeth Lopatto in New York at elopatto@bloomberg.net .