GlaxoSmithKline Plc's best-selling diabetes pill Avandia has heart risks that will require restricting the drug's use, U.S. regulators said.
Avandia increased the chances of heart attacks when combined with insulin, according to a report by U.S. Food and Drug Administration staff members. The analysis, released on the FDA's Web Site in preparation for an advisory panel hearing July 30, also found Avandia's effect on the heart was no greater than competing drugs in other studies lasting longer than one year.
The FDA advisers will be asked whether Avandia should remain on the market or carry heightened warnings. A report in May tied Avandia to a 43 percent increased risk of heart attacks. Even before that, in February, drug-safety scientists at the FDA concluded from their own analysis that Avandia shouldn't be used with insulin or in heart disease patients.
"Current available information points to an increased risk of cardiovascular adverse effects," including heart failure, heart attacks and death from heart complications, Kate Gelperin and Lanh Green, drug safety scientists at the agency, wrote in a July 6 memo included in today's FDA documents.
"A critical question to be resolved in determining appropriate regulatory action is whether the anticipated therapeutic benefit" of Avandia outweighs its demonstrated heart risks, they wrote.
Shares of Glaxo, the world's largest drugmaker after Pfizer Inc., fell 28 pence, or 2.2 percent, to 1,247 pence in London. The stock has lost almost 15 percent of its value since the May report on Avandia, making the company the fourth-worst performer this year of the 13 companies in the Bloomberg Europe Pharmaceutical Index.
Last August, Glaxo itself recommended adding information to the drug's prescribing label saying the risks caused by reduced blood flow to the heart were greater with Avandia in a review of earlier trials. It also wanted to include data from health insurance records that showed no increased risk with the drug. The information is given with the drug in Europe now.
Lawyers for Avandia users contend that the company rushed the diabetes drug to market without proper testing and hid its health risks.
"This confirms our worst fears that GSK has put patients at risk in an effort to increase profits," David Ratner, a New York lawyer who is preparing to file product-liability suits on behalf of more than 100 former Avandia users. "We hope the FDA has the courage to require GSK to pull the drug from the market."
The FDA didn't act on the Glaxo request because the findings from the two studies were conflicting and required the agency to do its own analysis, said Susan Cruzan, an agency spokeswoman. That work was only recently completed, the staff members said in documents today.
Neither study showed the drug protected the heart or reduced complications, a serious blow to the goal of diabetes treatment that should be highlighted on the drug's label with a black box, they said. A black box warning on prescribing information for doctors is the strongest caution the FDA can make and often results in reduced drug sales.
The FDA's failure to act last year on data from the company may lead the agency to go lightly on Glaxo at the panel hearing tomorrow, analysts said.
The recommendations for warnings and restrictions on the drug lessen the chance it will be pulled from the market, a step analysts and investors say is unlikely. Whether the drug will ever recover its lost sales remains in doubt, they said.
"There are now alternatives that weren't there when Avandia was approved," said Nick Turner, an analyst at Mirabaud Securities in London. "My own feeling is they will put a black box warning on Avandia, they will restrict its use for patients whose blood glucose is not maintained at goal and whose diabetes is worsening."
Avandia was the world's best-selling diabetes pill and London-based Glaxo's second biggest drug last year, generating revenue of $3.3 billion worldwide. Sales fell 22 percent after the Cleveland Clinic reported the heart risks in the New England Journal of Medicine on May 21, Glaxo said yesterday.
The company submitted hundreds of pages of documents, including two additional studies involving more than 400,000 patients, to the FDA that support Avandia's safety and effectiveness, said Anne Phillips, vice president of clinical development of metabolic drugs, in a telephone interview.
The review of earlier trials called a meta analysis, conducted by Steven Nissen, head of cardiology at the Cleveland Clinic in Ohio, raised the question of whether Avandia could cause heart problems, Phillips said. Data collected by the company and others on the drug, including large and long-term studies, resolves the issue, she said.
"We know the answer," Phillips said. "When we look at all of the data, and this is the best studied oral anti-diabetic agent that there is, we do not see an increase in cardiovascular death, we actually see fewer strokes, we see no differences in heart attack risks between Avandia and the most commonly prescribed oral anti-diabetic agents."
The FDA panel, a joint meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee, will consider whether Avandia is safe and whether any changes should be made about which patients should receive it. The group may also recommend new warnings about the drug's risks and benefits.
The agency isn't obligated to follow the committee's recommendations, though it typically does.
Almost 21 million Americans and 170 million people worldwide have diabetes, according to the National Institutes of Health. There is an epidemic of type 2 diabetes underway, fueled by rising obesity rates, age and sedentary lifestyles, public health officials said.
The cells of those patients don't properly use insulin, a hormone that turns blood sugar into energy. Persistent high blood sugar eventually damages the nerves and blood vessels, leading to blindness, kidney failure and death.
A study of health insurance claims for 402,000 patients enrolled in 80 U.S. plans found no differences in hospital stays for heart complications among those taking Avandia or drugs, including Actos from Osaka-based Takeda Pharmaceutical Co.
Avandia and Actos belong to a family of medicines known as thiazolidinediones, or TZDs. They work by making diabetics more sensitive to the hormone insulin and have been taken by more than 15 million patients since they became available in 1999.
A second study of 200 high-risk patients with heart disease found those getting Avandia had fewer complications, including heart attacks, strokes and deaths, than those on placebo.
"We are continuing to look at this, others are continuing to look at this and there is a huge amount of data on the table that supports the safety of Avandia," she said.