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On November 24, 2008, researchers in the United States stated that older diabetics taking GlaxoSmithKline’s Avandia to control their blood sugar had a higher risk of death and heart failure while on the drug than those who took Takeda Pharmaceutical’s Actos, a drug in the same class. Researchers said the head-to-head comparison confirms prior analyses finding Avandia carries greater risks than Actos, particularly in older diabetics.

Surprisingly, the study found no difference in heart attack and stroke risks. But since 75% of diabetics die from heart-related causes, the researchers think heart attacks and strokes likely contributed to the overall increased deaths in the Avandia group.

“We hypothesize that many of the deaths were due to myocardial infarction (heart attack) and stroke,” Dr. Wolfgang Winkelmayer of Brigham and Women’s Hospital in Boston and colleagues wrote in the Archives of Internal Medicine.

New analyses of clinical studies found Avandia raised the risk of heart attacks, which has sent sales of the drug plummeting. An analysis of studies on Actos, meanwhile, suggested it reduced the risk of heart attacks and strokes.

Both Avandia, known generically as rosiglitazone, and Actos, known generically as pioglitazone, raise the risks of heart failure and carry strong warnings on their labels.

“Altogether, the picture people got was it looks like rosiglitazone might be associated with badness and pioglitazone is neutral and even beneficial,” Winkelmayer said in a telephone interview.

“For me, that left an important question open. What if you happen to directly compare those two treatments together.”

He and colleagues studied Medicare claims data from 28,361 U.S. patients older than 65 years who began taking either rosiglitazone or pioglitazone between 2000 and 2005.

They checked for overall risk of death while taking the drug, as well as heart attacks and heart failure and other side effects in this population of older diabetics.

Of those studied, 14,260 began treatment with pioglitazone and 14,101 with rosiglitazone.

“Those who started with rosiglitazone had a 15% increased risk of dying from any cause compared with pioglitazone,” Winkelmayer said. They also found patients on rosiglitazone had a 13% great risk of heart failure compared with those on pioglitazone.

“The interesting part is that we didn’t find any difference for the risk of stroke or heart attack,” he said.

Winkelmayer thinks this may be because older diabetics are less likely to survive a heart attack or stroke.

“This hypothesis we cannot test because we don’t have any cause of death data for these patients. It remains speculation.”

Glaxo disputed the findings. “This new study is inconsistent with evidence from randomized clinical trials and has significant limitations,” said company spokesman Jeff McLaughlin in an e-mail. He said the company’s long-term data suggest no increased risk of death for people taking the drug.

Safety issues raised by the study could be because of differences in the study populations, McLaughlin said, and a randomized clinical trial was the best way to settle safety questions.

Winkelmayer said the study was not a randomized clinical trial, which is the most reliable type of study, but he said the characteristics in both study populations were surprisingly similar, making the comparison quite strong.

“I think it’s one more piece of the puzzle,” he said. “It will contribute to a more compelling picture that will inform policymakers with regard to how to move forward.”

Last month, two major medical groups dropped Avandia from the list of recommended treatments for people with type II diabetes, the most common form of the disease.

Approximately 23.6 million U.S. children and adults have diabetes, according to the American Diabetes Association. Type II diabetes is closely linked to obesity.

A November 20, 2008, Philadelphia Inquirer article discusses how a Maryland doctor said she felt “threatened and disappointed” after GlaxoSmithKline P.L.C. urged her to stop discussing her concerns that the company’s diabetes drug, Avandia, caused heart problems.

The doctor’s claim marks the second time that GlaxoSmithKline has been accused of trying to intimidate a researcher who pointed out problems associated with Avandia, which before its side effects became well-known was the top-selling diabetes drug. In 2007, University of North Carolina researcher John Buse testified before Congress that GlaxoSmithKline had called him a liar and suggested it might sue him if his comments about Avandia’s potential safety problems caused the company’s stock to drop.

On November 19, 2008, GlaxoSmithKline, a London company that has large operations in the Philadelphia area, said it had taken appropriate action when Mary Money, an internist in Hagerstown, Md., told the company of repeated instances of congestive heart failure and dangerous fluid retention in patients taking Avandia.

“GSK did not dispute the occurrence of adverse events observed by this physician. In fact, GSK promptly shared the information with the Food and Drug Administration and conducted its own scientific analyses,” the company said in a statement.

The company also said its label at the time Money had raised her concerns included warnings about the risk of congestive heart failure. Those warnings were strengthened in later years as more evidence emerged about heart problems. The drug’s label now includes a black-box warning, the FDA’s strongest.

The new assertions were first reported in the November 19, 2008, Wall Street Journal.

Money and Stephen Lippman, a doctor she worked with who also was head of the diabetes program at the local hospital, Washington County Hospital, said in interviews that the company had failed to take their concerns seriously.

Money said her concerns began in the fall of 1999, after a patient she had put on Avandia developed congestive heart failure and “massive fluid retention. I was just barely able to keep her out of the hospital.”

The patient’s problems disappeared when Money took her off Avandia. Soon, more patients developed the same problems after they started taking Avandia.

She took her concerns to Lippman, who found additional patients with the same side effects after starting Avandia. Together, they collected data on 85 patients, about half of whom had significant edema, or fluid retention and swelling. Edema can indicate heart problems.

In April 2000, Money and Lippman met with GlaxoSmithKline representatives. She said a GlaxoSmithKline physician she identified as Daniel Everitt, who now works for Centocor Inc., of Horsham, attended in person. A Centocor spokesman said yesterday that Everitt declined to comment.

Money also said Martin St. John Sutton, a cardiologist at the University of Pennsylvania, had participated in the meeting by phone. Sutton did not return a call seeking comment.

After the meeting, GlaxoSmithKline asked the hospital’s chief of staff, in a letter, to make sure his doctors did not disseminate “unsubstantiated” information about Avandia.

Money said she expected to hear back directly from GlaxoSmithKline after the meeting, but did not until the hospital’s chief of staff told her about the letter from the company.

Mary Anne Rhyne, a spokeswoman for GlaxoSmithKline, said in a statement that the letter was necessary. “When GSK learns about statements by physicians that are inconsistent with the scientific data on its medicines, we have the responsibility to do what we can to correct these inaccuracies for the benefit of physicians, patients and scientific discourse,” the statement said.

“After first discussing these issues in great detail with Dr. Money, GSK wrote a letter to Washington County Hospital because Dr. Money’s unsubstantiated theory had been shared with all of the departments and medical staff at the hospital.”

Money said she interpreted the letter as an effort to silence her and Lippman.

“I guess I was quite naive,” she said. “I thought that the drug company would want to know that their drug was at risk of harming patients.”

She said she felt vindicated last year when Steven Nissen of the Cleveland Clinic published research in the New England Journal of Medicine saying that Avandia could increase the risk of heart attack 43%.

Nissen said that GlaxoSmithKline had always treated him respectfully, even when it disagreed with him. Nissen has consulted for several drug companies, including GlaxoSmithKline.

Lippman said the meeting with GlaxoSmithKline representatives and subsequent letter had disturbed him.

“The problem with [the] drug system is that if people on the front line feel that they’re going to get humiliated for bringing up questions, they’re not going to report things and they are not going to be the canary in the coal mine,” Lippman said. “The issue is that whatever the 800-pound gorilla thought they were doing, it was intimidating.”

Sen. Charles Grassley (R., Iowa) is expected in the next few weeks to release results of an investigation into GlaxoSmithKline’s handling of Avandia.

Avandia has attracted many critics, including the consumer group Public Citizen, which has asked the FDA to take the drug off the market. This week, John Jenkins, director of the FDA’s Office of New Drugs, told Reuters that his agency was looking more carefully at the rise of heart risks related to drugs, including Avandia, that treat chronic conditions.

Some doctors say they believe Avandia helps some patients and should remain on the market.

Zachary T. Bloomgarden, an endocrinologist at Mount Sinai Medical Center in New York, said Avandia could help reduce serious health problems in diabetic patients who do not respond as well to other treatments. He also has received grants and fees from many drug companies, including GlaxoSmithKline.

On October 30, 2008, the consumer group Public Citizen asked the FDA to ban GlaxoSmithKline PLC’s problematic diabetes drug Avandia over safety concerns. The move follows updated practice guidelines released last week by the American Diabetes Association and the European Association for the Study of Diabetes that recommend doctors not use the drug.

Avandia’s safety record has been gloomy since an analysis of studies released last year suggested it was linked to an increase in heart attacks. In November the FDA strengthened a black-box warning on Avandia telling doctors the product was linked to a potential increase in heart attack risk.

The agency said the drug would remain on the market while a safety assessment continues. FDA officials have said there’s been a split within the agency about whether to pull Avandia off the market or allow it to stay on the market with stronger warnings.

In a petition filed with the FDA, Public Citizen said that in addition to the heart risks it identified 14 cases of Avandia-induced liver failure, including 12 deaths after a review of adverse-event reports filed with FDA. In a statement, GlaxoSmithKline said it had not yet looked at the petition but said that “we do not believe there is a connection between liver toxicity and this medicine.” The company said Avandia was safe and effective when used appropriately.

The FDA didn’t immediately return a request for comment on the petition.

Sales of Avandia have fallen sharply since the safety questions surfaced last year, but Public Citizen said about 10,000 prescriptions are still being filled a day for Avandia.

An estimated 20 million Americans have Type-2 diabetes, a disease characterized by high blood-glucose levels that result from the body’s inability to use insulin. Insulin, produced by the pancreas, is needed to take sugar from blood into cells.

Drugs such as Avandia, and a similar drug Actos by Takeda Pharmaceutical Co., are designed to make the body more sensitive to insulin in order to help lower blood sugar. Other drugs used to treat diabetes include sulfonylurea drugs, which work to stimulate the pancreas to release insulin, and metformin, which works on the liver to reduce blood sugar. Diabetes itself increases the risk for cardiovascular disease, kidney disease, blindness and amputations.

The FDA approved Avandia for use in treating Type-2 diabetes in 1999. Although Actos is similar to Avandia it has not been linked to a possible increase in heart attacks. Both drugs carry a warning about increased risk of heart failure or the inability of the heart to properly pump blood.