Evelyn Pringle September 15, 2007
A recent poll by MedPage Today found that only 9% of the doctors who responded said they would continue to prescribe the diabetes drug rosiglitazone, sold as Avandia and Avandamet by GlaxoSmithKline, without reservation since an FDA advisory panel acknowledged that the drug increases heart risks for patients with Type II diabetes.
The results published on August 6, 2007, reported that 36% of the responding doctors said they would continue to prescribe the drug for select patients, but 55% said they will no longer prescribe it and 23% said the drug should be taken off the market.
On July 30, 2007, the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee of the FDA met to discuss the risks associated with Avandia and concluded that the use of the drug was associated with a greater risk of myocardial infarction, angina, or sudden death than placebo, or other diabetes drugs such as metformin or sulfonylureas.
In the end, the panel recommended that Avandia should remain on the market but said stronger warnings should be added to the label and that extensive educational efforts should begin immediately.
However a new study in the September 11, 2007 Journal of American Medicine that found Avandia increased the risk of heart attack by 42% and doubled the risk of heart failure has researchers at Wake Forest University in North Carolina, led by Dr Sonal Singh, an assistant professor of internal medicine, once again calling for the removal of the drug from the market.
“These data suggest a reversal of the benefit-to-harm balance for Avandia present at the time of approval,” the study authors wrote. “Regulatory agencies ought to reevaluate whether Avandia should be allowed to remain on the market,” they state.
They researchers also warn that health plans and doctors should not wait for regulatory action. “They should avoid using Avandia in patients with diabetes who are at risk of cardiovascular events, especially since safer treatment alternatives are available,” the authors conclude.
A second study published in the same issue of JAMA, conducted at the Cleveland Clinic, analyzed data from clinical trials on patients taking Actos (pioglitazone), a drug in the same class as Avandia, and found it to be more beneficial to diabetics.
To reach their conclusion, the lead author, Dr A Michael Lincoff, vice chairman for research in the department of cardiovascular medicine at Cleveland Clinic, and co-author, Dr Steven Nissen, one of the world’s leading cardiologists, analyzed data from 19 trials on more than 16,000 patients and found Actos actually reduces heart attacks, strokes and deaths by 18%, although it does increase the risk of heart failure.
In the month after May 21, 2007, when the New England Journal of Medicine first published a previous analysis of Avandia studies by Dr Nissen online, that revealed an increased risk of heart attack and cardiovascular death associated with the drug, reports of side effects tripled, according to a July 12, 2007 review of FDA data on adverse events reports obtained by the Associated Press with a FOIA request.
Only five heart attacks were reported in the 35 days before the study appeared online on May 21, 2007, compared with 90 in the same period afterward, and heart-related hospitalizations increased from 11 to 126, the AP found.
From April 16 to May 21, FDA data showed a total of 121 adverse events reported, including 11 deaths. But in the 35 days after the study, 357 events were reported, including 38 deaths.
Avandia was approved on May 25, 1999, and the FDA's primary medical reviewer recommended approval because clinical trials showed it to be effective at reducing blood sugar. But the reviewer also noticed that the data raised questions about Avandia's long-term effect on the heart. An excerpt from the reviewer's findings states:
"Whether [Avandia] favorably affects the natural history of type 2 diabetes is open to question. Long term improvement in HbAl c [a measure of blood sugar] should decrease the risk of retinopathy [eye problems], nephropathy [kidney problems] and neuropathy [nerve problems]."
"However, the increase in body weight and undesirable effects on serum lipids [cholesterol] is cause for concern. Heart disease due to atherosclerosis is a major cause of morbidity and mortality in patients with type 2 diabetes, and it cannot be assumed that treatment with [Avandia] will decrease the risk."
Because of concerns over the possibility for "deleterious long term effects on the heart," the reviewer recommended that "a postmarketing study to address these concerns needs to be a condition of approval."
Since that recommendation was made in 1999, experts estimate that tens of thousands of patients have been harmed by Avandia, and they blame the FDA for not requiring Glaxo to conduct a thorough post-market study on the drug's heart risks.
Critics say the agency had many warnings. In March 2000, Dr John Buse wrote the FDA to request "cardiovascular safety trials in high-risk populations." In February 2003, the World Health Organization issued a warning about cardiac risks associated with TZD's, the class of drugs that include Avandia. A review in the NEJM a year later stated that, "data about the effects of TZDs on cardiovascular disease are urgently needed."
In August 2006, Glaxo provided the FDA and the European Medicine Agency with the results of several studies, including an analysis with findings similar to those published in the NEJM, and by October 2006, the product labels in Europe included a new warning. However, American Avandia users knew nothing of the risks until May 2007.
"Rosiglitazone represents a major failure of the drug-use and drug-approval processes in the United States," leading public health experts Dr Bruce Psaty and Dr Curt Furberg wrote in a NEJM editorial published on June 14, 2007, in comparing the Avandia situation to the Vioxx debacle in 2004.
"In view of the potential cardiovascular risks and in the absence of evidence of other health advantages, except for laboratory measures of glycemic control, the rationale for prescribing rosiglitazone at this time is unclear," they stated in the editorial.
On July 24, 2007, Senators Chuck Grassley and Max Baucus, of the Senate Finance Committee, issued a press release to say they were investigating reports that FDA management had once again "muzzled" not one, but two senior safety reviewers who reported problems with Avandia.
"Based on our ongoing investigation," the Senators wrote, "it appears that FDA staff who voiced safety concerns about Avandia were removed from the very jobs that are supposed to protect the American public."
"Hardworking and knowledgeable employees at the FDA," Senator Baucus said, "strive to keep Americans and their health care providers informed about drug safety, but under Commissioner von Eschenbach's leadership it seems that drug manufacturers' interests may be allowed to trump science."
"The FDA undermines public safety every time it works to muzzle one of its own scientists," Senator Grassley stated. "It's time to stop this dangerous and repetitive practice where the FDA tries to shoot the messenger when it doesn't want to hear the message."
"The FDA must make decisions that are based on science and aim to protect the health of the American public," the press release states.
Experts say the rising number of risks found to be associated with Avandia outweigh any benefits of its use. A study in the July 17, 2007 Annals of Internal Medicine found that older and cheaper oral drugs for Type II diabetes were just as effective at controlling glycemia and improving lipid profiles as the newer medications.
The federal Agency for Healthcare Research and Quality commissioned the analysis in 2005. Dr Shari Bolen and colleagues of John Hopkins University reviewed data on 10 drugs from more than 216 published studies and systematic reviews for their report and found that second-generation sulfonylureas and metformin controlled blood glucose and other cardiovascular risk factors well.
The study found metformin to have the best risk-benefit profile. "Each oral diabetes agent is associated with adverse events that counterbalance its benefits," the authors wrote. "Overall, metformin seemed to have the best profile of benefit to risk."
"Large, long-term comparative studies on major clinical end points, such as myocardial infarction, chronic kidney disease, and cardiovascular mortality, are needed to determine definitively the comparative effects of the oral diabetes agents, especially in light of recent controversy regarding rosiglitazone," the authors concluded.
Another study by German researchers, first posted online on July 18, 2007, by The Cochrane Collaboration, reviewed the data from 18 published trials with 8,432 patients and also found that glycemic control was no better in patients taking Avandia than those given other oral anti-diabetic drugs.
The researchers found that Avandia might worsen complications of diabetes such as weight gain, swelling, bone fractures and heart disease. Dr Bernd Richter, of Duesseldorf's Heinrich-Heine University, who led the study, questioned whether it was even ethical to conduct any more clinical trials on Avandia.
"I see a bundle of adverse effects, and I don't see really good positive effects," Dr Richter told Reuters on July 18, 2007. "On a global scale," he said, "tiny risks can translate into big effects, because millions of people are taking this drug."
All of the published studies reviewed evaluated Avandia's ability to lower blood sugar levels, the authors said, and the drug produced about the same reductions as other oral drugs. But when they looked at "patient-oriented" results such as side effects, diabetic complications or death, they found patients on Avandia gained up to 11 pounds and had double the risk of developing edema (swelling).
The largest trial reviewed involved over 4,000 patients and revealed evidence of an increased cardiovascular risk, as well as an increased number of broken bones in women.
"We didn't find any benefits of rosiglitazone over other drugs for type 2 diabetes, but the drug is clearly associated with increased risks of edema, fractures, and weight gain," Dr Richter told HeartWire on July 17, 2007.
"These adverse effects, together with the suggestion of an increased cardiovascular risk," he said, "lead us to conclude that doctors should think twice about using rosiglitazone, as we have good alternatives."
Although bone fractures in women were previously identified, a new study in the June 2007 issue of Diabetes Care, from the VA Medical Center and Louisiana State University in Shreveport, found that men taking Avandia and other thiazolidinediones for an average of 16 months also had lower bone density in the hips and spine.
"This suggests that thiazolidinedione treatment is a risk factor and can contribute to excess incidence of fractures in diabetes," the researchers wrote in the study.
Another new study published in the June 21, 2007 issue of BMC Medicine by Dr Maria Ramos-Nino and colleagues reports that patients who take thiazolidinediones may have an increased risk of developing cancer.
The researchers investigated the association of thiazolidinediones and cancer prevalence among nearly 9,000 diabetic patients and randomly selected 1,003 patients to interview about personal and clinical characteristics, including any history of malignancy. After factoring in the potential effects of other risk factors, the investigators found that the use of any thiazolidinedione was associated with a 59% increased risk of cancer, but there was an 89% increased risk associated with Avandia.
In addition, the report indicates that the use of sulfonylureas by women was associated with a 51% lower risk of cancer. The researchers found that women taking thiazolidinediones were more than 2 times as likely to have cancer as women not taking the drugs, but said the association was not statistically significant in men.
A new Consumer Best Buy Drug report advises people with Type II diabetes to avoid the newer, heavily-advertised Avandia and Actos because the older drugs are cheaper, just as effective and as safe, if not safer. According to Consumer the generic version of metformin costs between $38 to $60 per month, compared to $142 to $262 for Actos and Avandia, depending on the dose.
The report advises diabetics to talk to their doctors about taking metformin, saying the drug not only controls blood sugar as effectively as the other medications but also reduces the level of "bad" LDL cholesterol, does not cause weight gain and is less likely to cause hypoglycemia, a dangerously low blood sugar level.
Consumer also rates Amaryl (glipizide) and Glucotrol (glimepiride) as good buys.
Avandia was the top-selling oral diabetes drug in the US in 2006, with $2.2 billion in sales, according to IMS Health, a medical information tracking firm. It was Glaxo's second best-selling drug worldwide with sales of $3.3 billion.
However, according to a July 25, 2007 press release announcing Glaxo's second quarter earnings, sales of the Avandia product group fell 22% worldwide and 31% in the US, following the publication of the May analysis in the NEJM.
Glaxo is already facing litigation by shareholders, angered over the drastic decline in sales, who blame the company for withholding information about the Avandia risks.
In a June 11, 2007 press release, the New York law firm of Kaplan Fox & Kilsheimer announced the filing of a shareholder's lawsuit alleging the company misled investors about the safety of Avandia and failed to disclose an analysis of clinical trials which found that Avandia patients were at an increased risk of heart attacks and "engaged in a scheme to deceive the market" with conduct that "artificially inflated GSK's stock price" and "as a result plaintiff and other members of the class suffered economic loss."
A month later, Charles H Johnson & Associates issued a July 13, 2007 press release to announce that a class action had been filed in the US District Court for the Southern District of New York on behalf of purchasers of Glaxo publicly-traded securities during the class period October 27, 2005 through May 21, 2007, with similar allegations.
Glaxo's July 25, 2007 press release also reports the filing of more lawsuits. "Following publication of the NEJM article,” it states, “the Group has been named in product liability lawsuits on behalf of individuals and purported class action cases asserting consumer fraud and/or personal injury claims on behalf of purchasers and users of Avandia."
"All these actions are pending in federal district courts in the USA and all are at early stages," Glaxo noted in the press release.
(This article is part of the Avandia Update series sponsored by Baum Hedlund)
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