JAMA study also says Avandia causes heart attack

Results mirror May 2007 results

On December 11, 2007, a study published in the Journal of the American Medical Association concluded that older patients treated with Avandia had a significantly increased risk of suffering from a heart attack or dying. The findings mirror earlier studies, which also linked Avandia and cardiac risks.

The new study found Avandia patients had a 60 percent increased risk of heart failure, a 40 percent increased risk of heart attacks, and a 30 percent increased risk of death. This research also suggests that for every 100 people taking Avandia over a four-year period, there would be five additional deaths, four additional heart attacks, and three additional episodes of heart failure.

“Our study suggests that, at least in this high-risk population, the harms of the drug may outweigh the benefits,” said Dr. Lorraine L. Lipscombe, lead author of the study.

In May 2007, Dr. Steven E. Nissen from the Cleveland Clinic published a study suggesting Avandia patients had a 42 percent increased risk of heart attack. After reviewing Nissen’s study, the Food and Drug Administration (FDA) said in November 2007 that the evidence was inconclusive, and allowed Avandia to remain on the market with a “black box” warning on the label.

“As you accumulate more and more evidence that Avandia has this problem and it involves a very serious consequence, namely heart attack and death, it puts a lot of pressure on the FDA to do more,” Nissen said.

The FDA, however, is standing by its earlier decision.

“This new study we have just seen today does not change the FDA’s recommendations,” read a statement from the agency, adding that the data is inconclusive.

Source: “Study adds to Avandia doubts,” News and Observer, December 12, 2007.

Report Shows Avandia and Actos Increase Heart Failure Risk

Nissen says study doesn’t confirm or deny heart attack risk

On Thursday, September 27, 2007, U.S. researchers released a report revealing that the popular diabetes drugs Avandia and Actos increase heart failure risk but do not increase the risk for cardiovascular death in patients with type 2 diabetes.

The already controversial Avandia and Actos medications, which belong to a class of sugar-lowering drugs called thiazoilidinediones (TZDs), prompted the United States Food and Drug Administration (FDA) to require makers to place a “black box” warning on the labels after the risk of heart failure was linked to the medications.

The FDA decided not to remove the drugs from the market in July 2007, reasoning that evidence linking Avandia to heart failure was inconclusive.

Dr. Robert Nesto is the chair of the department of cardiovascular medicine at the Lahey Clinic Medical Center, in Burlington, Massachusetts, and the lead researcher of the September 27th study of Avandia and Actos. This study examined the results of seven clinical trials involving 20,000 patients administered Avandia or Actos.

Nesto’s team discovered a 72 percent increase of congestive heart failure among diabetes patients with different medical backgrounds and congestive heart failure histories. The risk of cardiovascular death was not increased in the patients, however, according to the study.

GlaxoSmithKline, maker of Avandia, suggests that congestive heart failure and fluid retention are linked, and “it is well known that TZDs can cause some fluid retention, which can lead to, or worsen, congestive heart failure. If congestive heart failure signs and symptoms develop, and heart failure is confirmed, heart failure can be appropriately managed by a physician.”

Dr. Nesto however, believes that doctors should avoid prescribing Avandia and Actos to patients with heart failure.

Dr. Steven Nissen, chairman of the department of cardiovascular medicine at the Cleveland Clinic, was the original researcher who linked Avandia to heart attack risk. He lightly criticizes Nesto’s study for not dealing with specific risks of using the drugs.

“The new analysis does not answer the question whether the observed increase in heart failure leads to other serious complications, including death,” according to Nissen. “The authors did not examining the risk of cardiac death in patients who developed congestive heart failure while taking a TZD drug. Instead they looked at overall cardiovascular mortality. This finding neither confirms, no refutes, the hypothesis that TZDs lead to major complications of heart failure.”

Source: “Diabetes Drugs Boost Heart Failure But Not Death,” Forbes.Com, September 28, 2007.

German doctors say Avandia is more dangerous than alternatives

Trials suggest Avandia increases heart attack risks by 43 percent

GlaxoSmithKline’s embattled diabetes drug Avandia suffered a major blow July 17, 2007, when German researchers said the drug may complicate the disease and questioned whether it was ethical to continue researching Avandia when safer alternatives were available.

Known generically as rosiglitazone, Avandia is in the middle of an investigation by the U.S. Food and Drug Administration, which is scheduled to review the drug July 30. One American researcher, Dr. Steven Nissen, published a report indicating Avandia increased the risk of a heart attack by 43 percent.

The ongoing controversy over Avandia has financial analysts humming about the drug’s sales. Even if the FDA allows the drug to remain on the market, analysts are forecasting Avandia’s sales to be down 35 percent in four years.

“Avandia itself is going to struggle whatever happens,” Mike Ward, an analyst at Nomura Code Securities in London, said. “Whether it ever bounces back, even if the [FDA] advisory committee is relatively kind, it’s going to take time.”

Sources: Ben Hirschler, “New study slams safety of Glaxo’s Avandia drug,” Reuters, July 18, 2007; Michelle Fay Cortez and Lisa Rapaport, “Glaxo’s Avandia Pill Faces FDA Warning, Doctor Revolt (Update 4),” Bloomberg, July 19, 2007.

U.S. Congress rethinking drug-approval policy

Washington Post likens Congress’ suggestion to “chasing the horses after they are out of the barn”

A July 5, 2007 article in the Washington Post asked questions about the long-term effects of the Prescription Drug User Fee Act of 1992, a piece of legislation originally aimed at getting innovative and highly beneficial drugs to market more rapidly. Fifteen years later, the result may be drugs raced through clinical trials and into the market, where consumers are now suffering. The Post cited three drugs in particular: Vioxx, Ketek and Avandia.

In the decade after 1993, the average approval time for standard drugs went from 22 months to 14, and “priority” drugs decreased from 13 months to six. But now, in the middle of 2007, the U.S. Congress is rethinking the 1992 act. Among the options facing the legislature is increasing the fees and devoting them to “post-market surveillance.”

The Post equated post-market surveillance to someone trying to chase horses once they leave the barn.

“I am deeply disappointed in the way things are headed,” Jerry Avorn, a Harvard Medical School physician, said. “This is our last chance to get it right before five more years go by.”

Source: David Brown, “Congress Seeks to Balance Drug Safety, Quick Approval,” Washington Post, July 5, 2007.

FDA receives triple Avandia reports after study

90 heart attacks, 126 hospitalizations and 38 deaths reported since analysis of drug

In the wake of published research possibly linking diabetes drug Avandia to heart risks, federal regulators said reports of the drug’s side effects tripled in a single month, according to an Associated Press report released July 13, 2007. The Associated Press obtained the information from the FDA through a Freedom of Information Act request.

In the 35 days prior to the New England Journal of Medicine’s published analysis, the FDA received reports of five heart attacks and 11 heart-related hospitalizations concerning rosiglitazone, the drug in Avandia and Avandamet. However, 35 days after the report, the FDA received reports of 90 heart attacks and 126 heart-related hospitalizations involving the same drug. The FDA received reports of 11 deaths in the 35 days prior to the study, compared to 38 in the same time after.

Dr. David Graham, a drug-safety expert with the FDA, said consumers “can’t infer anything about incidence rates” from the increased reports because the increase is likely due to the study’s “publicity effect.”

Dr. David Nathan, the head of diabetes care at Massachusetts General Hospital, echoed Dr. Graham when he said it was “not conceivable” that only five in one million Americans taking Avandia had heart attacks in the month preceding the study.

Source: Marilynn Marchione, “Diabetes Drug Side Effect Reports Triple,” Associated Press, July 13, 2007.

Study associates new risks with Avandia

Popular diabetes drug may lower bone density

In the midst of links to serious heart ailments, new studies are pointing to additional increased health risks associated with GlaxoSmithKline’s drug Avandia. With tests already demonstrating the drug weakened bones in women, a June 2007 article in Diabetes Care found men on the product had lower bone mineral density in the spine and hips.

“This suggests that thiazolidinedione treatment Avandia is a risk factor and can contribute to excess incidence of fractures in diabetes,” researchers from the Virginia Medical Center and Louisiana State University in Shreveport, Louisiana wrote in the study.

The new study could lead to a warning label on the drug. The FDA is scheduled to discuss Avandia at a meeting on July 30, 2007.

Source: Kari Lundgren and Andrea Gerlin, “Glaxo’s Avandia May Get Bone Warning, Analyst Says,” Bloomberg, July 4, 2007.

FDA reprimands its own scientist for Avandia warning

Employee and her staff said Avandia was not safe

On June 12, 2007, USA Today reported on a scientist from the U.S. Food and Drug Administration (FDA) who said her directors reprimanded her for recommending that Avandia get a “black box” warning about congestive heart failure.

Rosemary Johann-Liang, the former deputy director of the Division of Drug Risk Evaluation, said she recommended the Avandia warning on the suggestion of her staff. The FDA is investigating the validity of Johann-Liang’s claims.

In the meantime, the Senate Finance Committee is asking the FDA to make sure no scientist is reprimanded for raising safety questions.

“Those FDA employees dedicated to post-marketing surveillance…should be able to express their opinions in writing and independently without fear of retaliation, or reprimand or reprisal,” Sen. Chuck Grassley wrote in a letter dated June 4, 2007.

Johann-Liang said she wanted to be an advocate for drug safety, but oftentimes, her bosses did not want to hear about it.

“A lot of times the agency doesn’t want to hear that there are problems,” she said. “I think, in general, there is a culture of ‘The drug is always innocent.’”

Specifically Johann-Liang is warning people about Avandia, which she feels is a dangerous drug.

“People are continuing to be hurt,” she said. “Congestive heart failure is a very, very clear adverse reaction syndrome with Avandia.”

Source: Rita Rubin, USA Today, “FDA scientist says she was reprimanded for warning.” June 12, 2007.

Professor testifies GSK trials of Avandia about marketing, not safety

Bruce Psaty says there’s a ‘crisis in confidence’ about safety of U.S. medicines

On June 6, 2007, University of Washington medicine and epidemiology professor Bruce Psaty testified that GlaxoSmithKline (GSK) did not address safety questions in Avandia trials. Instead, he said, the trials focused on marketing questions.

Psaty wrote editorials accompanying Dr. Steve Nissen’s recent meta-analysis of Avandia published in the New England Journal of Medicine.

“GSK did not make a serious effort to verify the presumed health benefits of Avandia in a timely fashion,” Psaty testified at a congressional hearing of Avandia. “The…trials focused largely on marketing questions and failed to address directly questions of heart-attack risk or benefits.”

He also said the U.S. Food and Drug Administration (FDA) lacks the leadership and authority to require pharmaceutical companies to conduct high-quality trials.

“If sponsors do not voluntarily initiate large long-term trials of public health importance, then the FDA needs the authority to insist that they do so in a timely fashion,” he said.

GSK has conducted a trial, called RECORD; but Psaty said it is limited and, even if the study is finished, it will not be complete.

“GSK’s RECORD study has several major limitations in design and conduct, and even if it continues to its planned conclusion, information about heart attack risk from the RECORD trial is likely to be incomplete,” Psaty said.

With Avandia, he claims, the FDA failed in warning and informing consumers of the risks associated with the drug. He added that the U.S. product label for Avandia still does not identify heart attack as a potential reaction in diabetics.

Psaty says there is a crisis in confidence about the safety of medicines in America that began with the withdrawal of rofecoxib (Vioxx), a drug developed to treat osteoarthritis. Vioxx was recalled in September 2004 because it was found to increase heart attack and strokes. Vioxx was one of the most widely used medications to ever be withdrawn from the market.

The FDA has still not announced an Avandia, recall.

Sources: “Testimony of Bruce M. Psaty, M.D., Ph.D.,” before the House Committee on Oversight and Government Reform, June 6, 2007; “Rofecoxib,” Wikipedia, June 8, 2007.

Patients start to file cases against Avandia

Shareholders lawsuit seeks class-action status

At least two cases have been filed against GlaxoSmithKline PLC (GSK) about the company’s diabetes drug Avandia. The lawsuits allege that GSK caused patients to suffer heart attacks

Shareholders in GSK. also filed a lawsuit, claiming the company misled investors about the safety of the drug. The lawsuit seeks class-action status and alleges the company failed to acknowledge a link between Avandia and higher risk of heart attacks.

On May 29, 2007, Sharon Ann Dabon filed a suit against GSK claiming Avandia caused her to suffer injuries like heart injury and liver failure. Another case, filed June 1, 2007 by Benjamin Sarconi, claims Avandia caused a heart attack and congestive heart failure.

Some attorneys said the personal injury lawyers for those filing Avandia lawsuits may have difficulty proving the drug caused heart problems because diabetes itself increases a person’s risk for heart attacks.

Source: “Jeanne Whalen,” Shareholders sue Glaxo over Avandia disclosure,” Wall Street Journal, June 13, 2007.

UNC doctor says GlaxoSmithKline threatened to sue him over Avandia criticism

Buse says Avandia may increase risk by 50 percent

When Dr. John B. Buse testified at a U.S. Congressional hearing on June 6, 2007, he explained how a top executive at pharmaceutical giant GlaxoSmithKline (GSK) threatened him with a lawsuit because the doctor warned the public about Glaxo’s drug, Avandia.

Buse’s confrontation with GSK began in 1999, he said, when he told the U.S. Food and Drug Administration that Avandia raised the risk of chest pain and heart attacks by 50 percent. He said he was given 25 minutes to present two hours worth of research at that hearing.

After that hearing, Buse said “an executive,” later tabbed as Dr. Tadataka Yamada, the then-chief of research and development at SmithKline Beecham, called him a “liar” and a “scoundrel” for his research on Avandia.

According to Buse, the company went as far as suggesting to his boss that the doctor wanted to be paid off. Buse wrote in a letter to Yamada in 1999, in which he said “I was not upset when my chairman called me into his office to tell me that some in your company perceive me as being ‘for sale,’ as he knows me well enough to doubt it.”

In addition, GSK suggested Buse might be sued for lost profits. “The market capitalisation of the company had declined by $4 billion and there were people in the company who felt I might be liable for that,” he stated.

Representative John Yarmuth, Democrat from Kentucky, said in the June 6 hearing, “We cannot have a post-regulatory environment where manufacturers intimidate scientists.”

Sources: Stephanie Saul, “Doctor Says He Was Assailed for Challenging Drug’s Safety,” New York Times, June 7, 2007.