According to the FDA’s announcement, the “FDA previously communicated to the public about the possible association between rosiglitazone and increased cardiovascular risk in a 2007 safety alert. The agency also sought advice from external experts at the July 30, 2007, joint meeting of the FDA Endocrinologic and Metabolic Drugs and Drug Safety and Risk Management Advisory Committees. The RECORD study data represent the only new information from a completed randomized, controlled clinical trial of rosiglitazone received by FDA since the 2007 announcements.”

The RECORD study, which stands for Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes, was designed to evaluate the cardiovascular safety of rosiglitazone. This practice is consistent with the FDA’s December 2008 Guidance for Industry that recommends that manufacturers of new treatments for diabetes carefully design their clinical trials to include an evaluation of cardiovascular safety.

Once the FDA has completed its review of rosiglitazone, the agency will present its findings at a joint public meeting of the Endocrinologic and Metabolic Drugs and Drug Safety and Risk Management Advisory Committees in July 2010.

Rosiglitazone, a treatment for Type 2 diabetes, is sold as a single-ingredient product under the brand name Avandia, and is available in combination with other diabetes medications, such as metformin, under the brand name Avandament, or glimepride, under the brand name Avandaryl. The FDA advises that patients who are currently taking any form of rosiglitazone should not stop taking their medication without first talking to their healthcare professional. Any side effects with this or any other medication should be reported to the FDA MedWatch Adverse Event Reporting program at www.fda.gov/medwatch.

SOURCE: Avandia Recall › FDA announces it will review studies linking Avandia to heart attacks

Researchers announced the results of the RECORD trial at the American Diabetes Association meeting in New Orleans. The study monitored 2,220 patients who received Avandia (rosiglitazone) as a supplement to metformin, normally the first-line drug in diabetes 2 treatment, or sulphonylurea. 2,227 other patients received a combination of metformin and sulphonylurea without Avandia.

GlaxoSmithKline said the findings confirmed that “cardiovascular hospitalization and cardiovascular death was not statistically different between the two groups after an average of 5.5 years of therapy.”

Philip Home, a professor at Newcastle University in Newcastle Upon Tyne in the UK and chairman of the RECORD trial, said the data “leads us to conclude that rosiglitaone carries no increased risk of overall cardiovascular death or hospitalization compared to the most commonly used diabetes medicines…which have been used for decades.”

However, an editorial by Toronto doctors Ravi Retnakaran and Bernard Zimman in the medical journal The Lancet, in which the RECORD results were published, raised doubts about the study’s accuracy. The doctors wrote that “definitive conclusions about the relation between rosiglitazone and cardiovascular disease remain elusive, owing to study limitations.”

The overall rate of cardiovascular problems in the RECORD patients was unusually low, and ten percent more of the Avandia patients were taking statins – cholesterol fighting drugs that effectively reduce the risk of heart attack.

Moreover, 45 percent of the RECORD participants dropped out of the study at some point, yet Glaxo maintains that the high dropout rate did not influence the results. Doctors Retnakaran and Zimman believe that dropout rate alone compromises the trial’s conclusions.

Steven E. Nissen, M.D. of the Cleveland Clinic said that “it is impossible to assess the safety of a drug when patients are not actually taking it.”

SOURCE: Avandia Recall › Doctors and critics doubt the accuracy of Avandia study

The group enumerated its concerns in a full petition, citing both safety and efficacy issues. Adverse events linked to Avandia and listed in the petition include liver failure, myocardial ischemia (increased risk of heart attack), congestive heart failure, macular edema (vision loss), anemia, and bone fractures.

One new analysis of the FDA’s Adverse Event Reporting System (AERS) data revealed that of 14 Avandia users who experienced kidney failure, 12 died.

“The evidence for this unique combination of toxicities is compounded by the accompanying lack of evidence of any clinical benefit, compared to other approved drugs for diabetes,” the petition states.

The petition also refers to statements released earlier by both the American Diabetes Association and the European Association for the Study of Diabetes advising against the use of Avandia given the availability of better options.

To support its claim, Public Citizen also included a graph highlighting the dwindling sales of Avandia from the first quarter of 2006 to the second quarter of 2008. 13.3 million Avandia prescriptions were written in 2006, yet only 4.6 million were written in the last year. Avandia prescriptions have declined steadily since late 2006.

“The FDA is in possession of clear, unequivocal evidence that (Avandia) causes a wide variety of toxicities,” Public Citizen said in its petition to the FDA.

Drugmaker GlaxoSmithKline issued a response to the petition on Friday, standing by Avandia.

“The safety of patients using our medicine is very important to us. On a continual basis, an external Hepatic Safety Board reviews any adverse event report received by GSK of liver failure, liver-related deaths and liver transplants for possible relationship to AVANDIA. As recently as July 2008, this panel of experts continued to endorse a favorable hepatic safety profile for AVANDIA,” the statement said.

Public Citizen is a nonprofit consumer advocacy organization representing more than 80,000 consumers in the U.S. It was founded in 1971 to “represent consumer interests to Congress, the executive branch, and the courts.”

SOURCE: Avandia Recall › Consumer watchdog urges immediate Avandia ban

For years, GlaxoSmithKline, the manufacturer of Avandia, enjoyed stellar sales of the diabetes drug. Avandia was GSK’s second-best seller until the results of some studies surfaced that indicated the drug poses serious risks for its users.

In February of 2007, a press release issues by GSK announced a link between female users and increased risk of bone fractures, especially of the upper arms, hands, and feet.

In June of last year, an article in The New England Journal of Medicine reported that Avandia significantly increased the likelihood of heart attacks by 43% and death by cardiovascular diseases by as much as 64% in users.

The news dealt a devastating blow to Avandia. Estimates indicate that annual Avandia profits dropped by a billion pounds (nearly $1.8 billion U.S.). A growing number of lawsuits against GSK and competition from cheaper generics also threaten GSK’s numbers. It could be argued that while additional job cuts save the company some money, those cuts are only necessary to make the company’s numbers more attractive to investors.

According to the Hertfordshire Mercury, a GSK spokeswoman explained the cuts as “part of GSK’s longer-term strategy to ensure that we invest in key areas of future growth and evolve our business to compete effectively in what is a rapidly changing and challenging environment for pharmaceutical companies.”

Translated from CEO-speak, the statement seemingly alludes to all the problems pharmaceutical companies face these days — that they must appear extra-profitable to investors while sustaining aggressive ad campaigns amidst litigation and declining sales.

SOURCE: Avandia Recall › Avandia sales drop hurting GlaxoSmithKline

The maker of the drug, GlaxoSmithKline (GSK), disputes the osteoporosis finding. The company said in a statement today that their ADOPT studies showed no increase in spine or hip fractures which are associated with osteoporosis.

The company says they will be looking further into the subject.There are other possibly safer alternative treatments for diabetes, according to Paul Brandt, an associate professor of neuroscience and experimental therapeutics at Texas A&M Health Science Center College of Medicine. “Anyone who is already at risk for osteoporotic fractures should consider an alternative anti-diabetic drug.”

Amanda Gardner of HealthDay News reports that Avandia affects a key cellular protein called the peroxisome proliferator-activated receptor (PPAR-gamma). The mice studies by the Salk Institute for Biological Studies in La Jolla California found that activating this receptor stimulates the production of osteoclasts. These osteoclasts degrade bone.

Avandia recently received some bad press concerning the relation of the drug with heart problems. Avandia, along with four other drugs in the same class, were given blackbox warnings by the Food and Drug Administration (FDA). These warnings are the strictest advisories offered by the FDA for products that they have approved. The drug was linked to heart failure in some patients.

SOURCE: Avandia Recall › Type 2 diabetes drug Avandia linked to osteoporosis and bone loss

Details of this strange turn of events were about to be published in the journal Nature before US Senator Charles Grassley broke its embargo and issued a letter written to GSK asking the firm what action it had taken on receiving the article from Steven Haffner of the University of Texas Health Science Center in San Antonio. The NEJM piece linked Avandia (rosiglitazone) to a 43% increased risk in heart attacks and strokes and observers were struck by the speed and detail of GSK’s rebuttal. There would now appear to be an explanation, however.

The Nature article notes that Dr Haffner faxed his copy of the article 17 days before publication in the NEJM to Alexander Cobitz, a GSK employee he knew. “Why I sent it is a mystery,” Dr Haffner is quoted as saying. “I don’t really understand it. I wasn’t feeling well. It was bad judgement.” He notes that he has worked with the UK-based drugs giant many times, principally on the Avandia ADOPT study, but refutes the notion that his motivastion for the leak was cash. “I’ve got a considerable amount of money,” he said. “I didn’t do it to raise my income or anything like that.”

GSK spokeswoman Nancy Pekarek told Nature that she was not aware of anyone at the firm informing the journal of the confidentiality breach. She added that Dr Haffner had expressed concerns regarding the methodology of the analysis, and sent the article, written by Steven Nissen of the Cleveland Clinic, for advice.

Dr Nissen has expressed his disappointment over the confidentiality breach, as has Sen Grassley, a fierce critic of the relationship of the pharmaceutical industry with doctors and regulators. He said that “the most troubling aspect of this situation is that the integrity of another aspect of the scientific process is called into question – scientific peer review”.

January 31st, 2008 by Kevin Grogan with Pharma Times

SOURCE: Avandia Recall › GSK Sent Avandia meta analysis before publication

For four years, the study followed patients over age 65, who have the highest rate of type 2 diabetes but aren’t well represented in clinical trials, says lead author Lorraine Lipscombe, a Toronto endocrinologist and researcher at the Institute for Clinical Evaluative Science, funded by the Ontario government.

Lipscombe’s team looked at how patients fared on Avandia or Actos, the only two drugs in their class, compared with those on other diabetes pills.

Since August, the U.S. labels for Avandia and Actos have carried a “black box” warning against their use in patients with advanced congestive heart failure. But the new study found Avandia raised heart failure risk even in patients with no history of the condition, suggesting the heart failure warning doesn’t go far enough, Lipscome’s team writes in The Journal of the American Medical Association.

About 8 percent of patients went to a hospital for congestive heart failure or a heart attack during the study. Compared with patients on other diabetes pills, those on only Avandia or Actos had a 60 percent higher risk of congestive heart failure and a 40 percent higher heart attack risk. They also had a 29 percent higher risk of death.

For reasons not yet clear, the increased heart risks seen in the Avandia/Actos group were predominantly in those on Avandia. That doesn’t mean Actos is safer, Lipscombe says. Her study might have had too few Actos patients – half the number on Avandia – to detect a higher risk, she says.

In observational studies such as this, factors other than the drugs in question might skew results, so clinical trials that randomly assign patients to treatments are considered the gold standard.

“The problems with the study become obvious with regard to the CHF (congestive heart failure) findings,” Nancy Pekarek, spokeswoman for Avandia maker Glaxo-SmithKline, said in an e-mail. “We know (Avandia and Actos) have well-documented and similar CHF events, yet this study somehow finds an increase in these events with Avandia versus Actos.”

But Steven Nissen, the Cleveland Clinic’s chief of cardiovascular surgery, says Lipscombe’s study “has a lot of appeal. It’s independent, it’s not funded by industry, and it’s huge.” And, “it’s real-life data.”

Nissen reported in The New England Journal of Medicine in May the pooled results of 42 short-term clinical trials showed Avandia patients were 43 percent more likely to have a heart attack or be hospitalized for blocked coronary arteries than others in the trials.

Based on Nissen’s study and others, the Food and Drug Administration last month added information to Avandia’s black box about a potential increased heart attack risk. The FDA has asked Glaxo to compare Avandia’s heart attack risk with those of other diabetes pills. That clinical trial is not expected to be done until March 2014.

January 8th, 2008 by RITA RUBIN with APP.com

SOURCE: Avandia Recall › Avandia study shows increased heart risks or death

Grant started taking Avandia two years ago after he was diagnosed with type 2 diabetes. Prior to taking Avandia, he had no history of heart problems. “Grant had never had any problems in the past,” Mark says. “He had a clean bill of health in terms of his heart prior to that. There was no history of heart disease in our family.”

Within a year of being on Avandia, Grant was diagnosed with high blood pressure. Within two years, Grant was diagnosed with 80 percent blockage of his arteries. He required a quadruple bypass surgery. Grant went in for the surgery on a Monday, but experienced some complications and came out of the surgery with a heart fibrillation.
Only three days after the surgery, Grant suffered a massive stroke, which left him paralyzed on his left side and unable to speak. “We don’t know what caused the stroke, but we assume it had something to do with his requiring the operation to begin with,” Mark says.

Furthermore, Grant’s kidneys shut down and he developed swelling on his brain. Luckily, after two days of dialysis, Grant’s kidneys began to function again and he regained his ability to speak three weeks later. However, damage to his brain was about 25 percent.

“The surgeon and the doctor controlling Grant’s diabetes were surprised he was there with blocked arteries, considering his health prior to this,” Mark says. “They couldn’t believe that a 45-year-old had the problems Grant had.”

Some people might think that Grant’s stroke and other problems were caused by complications from the surgery and that Avandia had nothing to do with it. However, would Grant have required the surgery if he had not been on Avandia? Even if Avandia did not directly cause the stroke, it may have been an indirect cause because it pushed Grant’s blood pressure up and started a chain of events that culminated in his stroke.

“Grant will probably never be 100 percent,” Mark says. “He had 25 percent of his brain affected by the stroke. He was an amazing musician, so that’s rough for him. He’s lost a lot of quality of life. Having said that, he’s got a sense of humor and he’s working hard.

“In Grant’s room, a room of eight people, there were four other patients that had open-heart surgery that had also been on Avandia. Something must be going on-some doctors must have an idea of what is going on.

“It’s starting to sound a lot like Vioxx, where statements are made that the risks outweigh the benefits.

“I just want some justice done here for my brother.”

December 22nd, 2007 by Heidi Turner with LawyersandSettlements.com

SOURCE: Avandia Recall › Avandia starting to sound a lot like Vioxx

Avandia’s heart attack link came to light when an analysis of 42 clinical trails published by the Cleveland Clinic in May showed that patients taking the drug had a 43% higher risk of having a heart attack. Just last month, the Food & Drug Administration (FDA) announced the addition of a long-awaited black box warning for Avandia’s increased risk of heart attacks. However, many patient advocates and FDA critics thought the black box warning was a weak response to Avandia’s safety issues, and have called on GlaxoSmithKline, the maker of Avandia, and the FDA to pull the drug from the market.

Now, it seems that Avandia side effects have reached the general public. That is made clear in a study conducted by scientists at the Institute for Clinical Evaluative Sciences in Toronto, Canada. Researchers there analyzed data for 159,026 older adults who were treated with at least one oral diabetes drug between 2002 and 2005 and were entered in an Ontario healthcare database.

The subjects were followed through March 2006. During an average follow-up period of 3.8 years, 7.9 percent of the patients were hospitalized for congestive heart failure, 7.9 percent were hospitalized for a heart attack, and 19 percent died, according to the researchers’ report in Journal of the American Medical Association. Further analysis revealed that the risks were largely confined to patients who were using Avandia, known generically as rosiglitazone.

The Canadian researchers wrote that their findings “provide evidence from a real-world setting and support data from clinical trials that the harms of thiazolidinediones may outweigh their benefits, even in patients without obvious…cardiovascular disease”.

This latest research does not bode well for Avandia. Earlier this month, pharmacy benefit managers HealthTrans and Prime Therapeutics announced that they would be dropping the controversial diabetes drug from their value-based prescription drug formularies as of January 1, 2008 because of safety concerns.

In October, the Department of Veterans Affairs (VA) announced that it was removing Avandia from its prescription drug formulary because of its heart attack risks. The VA said that it would still make Avandia available for patients who were already taking it and wanted to continue. But the decision means that patients not currently prescribed Avandia will not be able to get it through the VA in the future. Prior to its announcement, the VA accounted for about 8 percent of Avandia sales.

Avandia was once GlaxoSmithKline’s second-biggest selling drug, with worldwide revenue of $3.2 billion in 2006, but sales have plunged since May, with US sales down 48 percent in the third quarter from a year ago.

December 17th, 2007 by Staff with NewsInferno.com

SOURCE: Avandia Recall › Avandia heart attacks seen in general patient population

Compared with other diabetes pills, Avandia’s use was associated with a 60 percent higher risk of heart failure, 40 percent higher risk of heart attack and 30 percent higher risk of death in patients 65 and older, the researchers found.

“The risks associated with these drugs may outweigh the benefits, at least for older populations,” said Dr. Lorraine L. Lipscombe, the lead author of the study and a researcher at a health research agency funded by the Ontario government.

The findings, published in the influential Journal of the American Medical Association, will probably intensify pressure on the government to restrict sales of the oral diabetes medicine.

“It should come off the market,” said Dr. Sidney M. Wolfe, director of health research at Public Citizen, a liberal interest group preparing to petition the Food and Drug Administration to pull the drug.

Sales of Avandia have plummeted since Dr. Steven Nissen, a prominent cardiologist, reported in May that it raised the risk of heart attack. His report prompted congressional hearings and demands to stop sales.

The FDA decided against that last month, instead adding a label warning that urges users to consult a doctor if they have serious heart problems.

The decision divided agency staff. Ultimately, FDA officials decided the scientific evidence wasn’t conclusive, and they asked Avandia’s manufacturer to conduct a long-term study.

In a statement, the FDA said it would review the results from the Canadian study, but it needs more evidence before taking any further action. “This new study we have just seen today does not change FDA’s recommendations,” the agency said.

GlaxoSmithKline, Avandia’s maker, dismissed the Canadians’ findings as limited and misleading because the elderly studied might have been at higher risk of heart problems.

The Philadelphia company, which is conducting a long-term study of Avandia’s side effects, said in a statement that many other studies show Avandia is safe and effective.

The new study is the first to review side effects in real patients, rather than test subjects, according to Lipscombe, a researcher at the Institute for Clinical Evaluative Sciences in Toronto.

Beginning in March, Lipscombe and her colleagues analyzed health care records for all elderly Ontario residents who took an oral diabetes medicine between 2002 and 2006.

Lipscombe said they focused on the elderly because 40 percent of diabetes patients in Ontario are 65 and older, but the elderly tend to be underrepresented in scientific drug studies.

The researchers didn’t find a higher heart risk among users of Actos, an Avandia competitor that belongs to the same class of diabetes drugs, but Lipscombe said there weren’t enough Actos users to draw a firm conclusion.

December 12th, 2007 by Jonathan D. Rockoff with baltimoresun.com

SOURCE: Avandia Recall › Avandia risks highlighted

For four years, the study followed patients over age 65, who have the highest rate of type 2 diabetes but aren’t well-represented in clinical trials, says lead author Lorraine Lipscombe, a Toronto endocrinologist and researcher at the Institute for Clinical Evaluative Science, funded by the Ontario government.

Lipscombe’s team looked at how patients fared on Avandia or Actos, the only two drugs in their class, compared with those on other diabetes pills.

Since August, the U.S. labels for Avandia and Actos have carried a “black box” warning against their use in patients with advanced congestive heart failure. However, the new study found Avandia raised heart failure risk even in patients with no history of the condition, suggesting the heart failure warning doesn’t go far enough, Lipscome’s team writes in The Journal of the American Medical Association.

About 8% of patients went to a hospital for congestive heart failure or a heart attack during the study. Compared with patients on other diabetes pills, those on only Avandia or Actos had a 60% higher risk of congestive heart failure and a 40% higher heart attack risk. They also had a 29% higher risk of death.

For reasons not yet clear, the increased heart risks seen in the Avandia/Actos group were predominantly in those on Avandia. That doesn’t mean Actos is safer, Lipscombe says. Her study might have had too few Actos patients – half the number on Avandia – to detect a higher risk, she says.

In observational studies such as this, factors other than the drugs in question might skew results, so clinical trials that randomly assign patients to treatments are considered the gold standard.

“The problems with the study become obvious with regard to the CHF (congestive heart failure) findings,” Nancy Pekarek, spokeswoman for Avandia maker Glaxo-SmithKline, said in an e-mail. “We know (Avandia and Actos) have well-documented and similar CHF events, yet this study somehow finds an increase in these events with Avandia vs. Actos.”

But Steven Nissen, the Cleveland Clinic’s chief of cardiovascular surgery, says Lipscombe’s study “has a lot of appeal. It’s independent, it’s not funded by industry, and it’s huge.” And, “it’s real-life data.”

Nissen reported in The New England Journal of Medicine in May the pooled results of 42 short-term clinical trials showed Avandia patients were 43% more likely to have a heart attack or be hospitalized for blocked coronary arteries than others in the trials.

Based on Nissen’s study and others, the Food and Drug Administration last month added information to Avandia’s black box about a potential increased heart attack risk. The FDA has asked Glaxo to compare Avandia’s heart attack risk with those of other diabetes pills. That clinical trial is not expected to be done until March 2014.

December 11th, 2007 by Rita Rubin USA TODAY with USA Today

SOURCE: Avandia Recall › New Avandia study reaffirms heart risk

Experts fear that, over the long term, Avandia (rosiglitazone) may speed osteoporosis, the thinning of the bones that can lead to dangerous and even fatal fractures.

The findings appear in the Dec. 2 online issue of Nature Medicine.
“Our study suggests that long-term rosiglitazone usage in the treatment of type II diabetes may cause osteoporosis due to both increased bone resorption and decreased bone formation,” said study senior author Ron Evans, a professor at the Salk Institute for Biological Studies in La Jolla, Calif. “Because Avandia is effective in controlling glucose and restoring the body’s sensitivity to insulin, we do not recommend that people stop their treatment. You must balance the benefits against the complications.”

“Anyone who is already at risk for osteoporotic fractures should consider an alternative anti-diabetic drug,” added Paul Brandt, an associate professor of neuroscience and experimental therapeutics at Texas A&M Health Science Center College of Medicine, in College Station. “There are many alternatives, ” he said.

“It may [also] be possible to blunt some of Avandia’s effects with anti-osteoporosis drugs such as bisphosphonates, raloxifene, vitamin D and calcium,” Brandt added.

Earlier this year, Avandia and four other diabetes drugs from the same class were given a “black box” warning by the U.S. Food and Drug Administration. That warning advises users of an increased risk of heart failure while on the drug.

The black box message is the FDA’s strongest label warning.

With an estimated 3.5 million or more U.S. patients taking Avandia, the public health impact from the point of view of both heart failure and bone degradation could be substantial, experts say.

Avandia affects a key cellular protein called the peroxisome proliferator-activated receptor (PPAR-gamma). In their study, the California team discovered that, in mice, activating this receptor also stimulates the production of osteoclasts, cells whose key function is to degrade bone.

Proper bone health is maintained by a balance between osteoclasts and osteoblasts, the cells that build bone up.

If either side is out of whack, so to speak, bones become thinner, more fragile and prone to fracture.

The current results are particularly disturbing in light of prior studies, the experts said.

“It was previously known that Avandia mediates bone loss by inhibiting bone formation,” Evans explained. “Our work identified an additional mechanism, in which Avandia promotes bone resorption. These are the two parts of the checks-and-balance system that maintains bone in good shape. The drug weakens both sides of the balance mechanism, leading to an increased risk for osteoporosis.”

“Previous research showed that Avandia reduced osteoblasts,” Brandt added. “Combine the two, and you’re going to get thinning of the bone.”

December 2nd, 2007 by Amanda Gardner with U.S. News

SOURCE: Avandia Recall › Diabetes drug Avandia could weaken bones

The moves by Prime Therapeutics and HealthTrans mark the latest example of U.S. healthcare providers deciding to limit access to the drug, following an earlier decision by the U.S. Department of Veterans Affairs to severely restrict use.

Such actions, particularly if followed by others, may further undermine sales of the once-popular medicine, which have been hit hard recently by a report linking it to heart attacks.

Prime and HealthTrans said in separate statements they had made their decisions after a thorough analysis of the clinical literature examining the safety and efficacy of Avandia.

“Prime takes drug safety warnings very seriously and our primary concern is the safety of our members,” said Craig Mattson, senior director of drug technology assessment and formulary development.

Britain-based Glaxo, Europe’s biggest drugmaker, said it was surprised and disappointed.

“It limits options for treatment and could be detrimental for patients. The FDA (Food and Drug Administration) has said the data remains inconclusive and therefore to limit patients’ options in this is disappointing,” a spokeswoman said.

Concerns about the safety of Avandia were triggered in May by a U.S. analysis linking it to a 43 percent higher risk of heart attack. Avandia was Glaxo’s second-biggest drug in 2006, with worldwide revenue of 1.6 billion pounds ($3.2 billion), but sales have plunged since May, with revenue in the United States down 48 percent in the third quarter from the year-ago period.

SOURCE: Avandia Recall › Two U.S. healthcare providers drop Glaxo’s Avandia

Initially, it was thought that rosiglitazone, the generic term for the drug that is marketed as Avandia, was serving as a governor to the bone-building process. In other words, as bones evolve in the human body (much like skin), it was originally thought that Avandia somehow contributed towards an inability to effectively regenerate bone lost in the natural regenerative process.

However, this latest conclusion-arrived at quite by accident-reveals that rosiglitazone actually contributes to bones loss over long treatment periods. Rather then prevent bone from regenerating, Avandia contributes to actual bone loss.

The finding leads to “a better understanding of the challenges associated with long-term treatment of patients with Type II diabetes,” according to Ronald M. Evans of the Salk Institute for Biological Studies in La Jolla, Calif., lead author of the report.

Researchers were conducting studies on diabetic mice, when they stumbled upon their surprising conclusion. Their findings offer hope that this aspect of Avandia as a contributor to bone loss could be further studied and isolated and, one day, ‘dialed-out’ of a future generation of drugs dedicated to the treatment of Type 2 Diabetes.

The Howard Hughes Medical Institute, and the National Institutes of Health funded the research. The findings appeared in this week’s online issue of Nature Medicine.

Researchers found that rosiglitazone-Avandia-stimulates the cells that break down bone in the body, for future regeneration. Osteoporosis occurs when the body loses more bone that it has the capacity to regenerate. Osteoporosis is of particular concern to older women, and this latest research suggests that Avandia should not be prescribed to patients with a history of osteoporosis.

Further, for Avandia patients who also suffer from chronic osteoporosis, there is now the possibility of a contributing cause to the bone loss.

It may not just be from aging. Avandia may be helping it along.

SOURCE: Avandia Recall › Avandia now linked to Osteoporosis

New research raises the possibility that long-term treatment with rosiglitazone, as Avandia is also called, could lead to osteoporosis. The diabetes drug is used to improved response to insulin.

While bones seem solid, they constantly are being broken down and rebuilt by the body. Researchers found that in mice, the drug increased the activity of the cells that degrade bones, according to a report in this week’s online issue of Nature Medicine.

Avandia recently was labeled with warnings about the risk of heart failure in some patients. GlaxoSmithKline, which markets the drug, already has acknowledged that a study found a higher risk of fractures among women who take the drug. But this report is the first to attempt to explain the link between the drug and fractures.

The finding “has led to a better understanding of the challenges associated with long-term treatment of patients with Type II diabetes,” said Ronald M. Evans of the Salk Institute for Biological Studies in La Jolla, Calif., lead author of the report.

“It also provides a basis for the development of a ‘next generation’ of drug that can specifically dial out this side effect and a new insight into a previously unrecognized aspect of bone physiology that has important medical consequences,” he said in an interview via e-mail.

Nearly 21 million people in the United States have diabetes. Rosiglitazone is widely used in people with Type II, or adult onset diabetes, the most common form of the disease.

Evans said the discovery was fortuitous. Researchers were looking at different aspects of the diabetic mice and did not realize they would be able to change the bone-removing activity.

The assumption had been that more brittle bones in diabetics were the result of a reduced bone-building activity, not increased bone removal.

“Considering the widespread use of these drugs and the known action in people it is surprising that such a key observation had been missed,” he said.

“The long-term use of rosiglitazone should be cautious in patients with higher risk of fractures such as older women,” he added. Using it in combination with anti-osteoporosis drugs could be beneficial, he said.

The research was funded by the Howard Hughes Medical Institute and the National Institutes of Health.

December 3rd, 2007 by Randolph E. Schmid with Associated Press

SOURCE: Avandia Recall › Diabetes drug may increase bone thinning

The U.S. Food and Drug Administration (FDA) advised that GlaxoSmithKline, Avandia’s maker, agreed to add the new warning to the existing black box warning. But, despite the revision, the FDA will not withdraw Avandia from the market, claiming that evidence for increased heart attack is inconclusive and does not appear to be higher in Avandia than other type 2 diabetes treatments. In the meantime, the FDA asked GlaxoSmithKline to conduct a long-term study comparing Avandia with other type 2 diabetes drugs. The trial will likely commence in a year; however, full results will not be available until 2014. Patient advocates and FDA critics consider the black box warning a weak response to Avandia’s safety issues and have requested Avandia be pulled from the market.

Avandia breaks down the body’s resistance to insulin but has long been known to cause fluid retention, a major risk factor for congestive heart failure. Evidence does not indicate Avandia and other oral anti-diabetes drugs-thiazolidinediones-prevent cardiovascular risk as a result of reducing blood sugar.

The American Diabetes Association and the European Association for the Study of Diabetes released a revised consensus statement stating that emerging information suggests additional hazards associated with thiazolidedione and rosiglitazone (Avandia) and may result in increased risk of myocardial infarctions. In October, the US Department of Veterans Affairs (VA) announced it was dropping Avandia from its prescription drug formulary stating their review concluded that, in some, Avandia did not afford the same margin of safety as other diabetes medications. The VA accounted for nearly 10-percent of Avandia’s US sales.

In November, Health Canada sent a letter to Canadian health professionals advising Avandia could no longer be prescribed as monotherapy for type 2 diabetes or in combination with sulfonylurea. In May, research based on 42 Avandia studies confirmed a 43-percent increased risk of heart attack among patients taking the drug. In August, Avandia’s warning label was changed to warn that Avandia and others in its class might worsen heart failure.

A Congressional Committee Report found that company executives made a concerted effort to intimidate a diabetes expert into keeping quiet about Avandia’s safety problems, alleging that Glaxo Chief Executive Jean-Pierre Garnier and former research chief Tachi Yamada were involved. An internal government memo dated July 16, 2002 analyzed 47 early FDA reports of patients who went into heart failure and required hospitalization while taking Avandia. The report contained warnings from Federal investigators that Avandia might cause heart failure.

Over six million Americans have used the drug to treat adult-onset, or type 2, diabetes and the concern about Avandia is nothing new. The association between Avandia and increased heart failure risk has been known since 1999 when the drug was first approved.

Avandia was Glaxo’s second most popular drug in 2006, with sales of $3.3 billion. Sales have plummeted since publication of evidence linking Avandia with increased risk of heart attack and failure.

November 29th, 2007 by Staff with NewsInferno.com

SOURCE: Avandia Recall › Avandia heart attack controversy results in black box warning

The Association announced on Tuesday that it was updating its “consensus statement” on the use of oral diabetes medications in light of the increased heart attack risks linked to some diabetes medicines, such as Avandia.

Avandia’s heart attack link came to light in May, when an analysis of 42 clinical trails published by the Cleveland Clinic showed that patients taking the drug had a 43% higher risk of having a heart attack. Earlier this month, the Food & Drug Administration (FDA) announced the addition of a long-awaited black box warning for Avandia’s increased risk of heart attacks.

However, many patient advocates and FDA critics thought the black box warning was a weak response to Avandia’s safety issues, and have called on both GlaxoSmithKline, the maker of Avandia, and the FDA to pull the drug from the market.

The American Diabetes Association’s revised consensus statement was formulated in cooperation with European Association for the Study of Diabetes. The statement reads in part: “New information suggests additional hazards associated with the use of either thiazolidedione, and rosiglitazone (Avandia) in particular may result in an increased frequency of myocardial infarctions. . .

We therefore recommend greater caution in using thiazolidediones, especially in patients at risk of, or with, congestive heart failure.”

The American Diabetes Association’s new Avandia stance is only the latest development that could hurt the drug’s sagging sales. In October, the United States Department of Veterans Affairs (VA) announced that it was dropping Avandia from its prescription drug formulary. In a statement announcing the move, the VA said that it had conducted its own review and concluded that, for some patients, Avandia did not afford the same margin of safety as other diabetes medications.

Prior to its announcement, the VA accounted for about 8% of Avandia’s sales in the United States. And in November, Health Canada sent a letter to Canadian health professionals informing them that Avandia could no longer be prescribed as monotherapy for type 2 diabetes, except when metformin use is contraindicated or not tolerated. Health Canada also withdrew its approval for Avandia to be used in combination with a sulfonylurea, except when metformin is contraindicated or not tolerated.

Last week, Glaxo got more bad news on the Avandia front when a Congressional Committee Report found that company executives made a concerted effort to intimidate Dr. John Buse, a diabetes expert, into keeping quiet about some of the Avandia’s safety problems. The report alleged that Glaxo Chief Executive Jean-Pierre Garnier and former research chief Tachi Yamada were involved in the intimidation.

November 27th, 2007

SOURCE: Avandia Recall › Avandia side effects prompt new caution from American Diabetes Association

Avandia has been a subject of debate since May 21, when an analysis of 42 clinical trails published by the Cleveland Clinic showed that patients taking the drug had a 43-percent higher risk of having a heart attack. Since the Cleveland Clinic study was published, a great deal of controversy has swirled around Avandia. In June, Congress held hearings to discuss Avandia and the FDA’s handling of its safety issues. At those hearings, it was revealed that GlaxoSmithKline, Avandia’s manufacturer, had informed the FDA of a study it had conducted that produced similar results. However, both the agency and the manufacturer felt that more investigation was needed before conclusions could be made about Avandia’s possible safety issues. Since those revelations were made public, the FDA has been under a great deal of pressure to take action on Avandia.

In July, the FDA convened a panel to discuss the issues surrounding Avandia’s heart attack risk. The panel voted 20-3 that the drug did in fact raise the chance of heart attacks, yet the panel still voted 22-1 to allow it to remain on the market. They recommended that Avandia be given a warning label about the cardiac problems. The FDA did finally add that black box warning to the Avandia label this month.

Now, Dr. Robert Misbin, an FDA safety reviewer who worked on the original Avandia approval, has called for changes in the way such drugs are handled by the FDA. Currently, an experimental drug is tested against a placebo. But Dr. Misbin now feels that diabetes drugs like Avandia, should be tested against other drugs currently on the market. In his interview with the Journal of Diabetic Care, Dr. Misbin likened comparing a drug’s effectiveness to a placebo to evaluating it in a vacuum. Dr. Misbin argued that putting an experimental medication up against a tried and true existing drug would give medical reviewers a better idea of the new medication’s efficacy and safety.

Dr. Misbin focused his comments on diabetes drugs, because he was part of the Avandia approval process, and because the subsequent safety issues surrounding Avandia highlighted weaknesses in the FDA approval system. Misbin also said because there are so many safe and effective diabetes medications on the market now, experimental diabetes drugs should have to pass more hurdles to be approved by the FDA.

November 27th, 2007 by Staff with NewsInferno.com

SOURCE: Avandia Recall › Avandia reviewer calls for changes in FDA drug approval process

The reason is that while short term studies have linked Avandia to an increased heart attack risk, longer term studies have been inconclusive.

In the meantime, experts suggest that people with heart disease take something other than Avandia.

November 15th, 2007 by Staff with Health News

SOURCE: Avandia Recall › Confusing new warning label on Avandia

Methods We conducted searches of the published literature, the Web site of the Food and Drug Administration, and a clinical-trials registry maintained by the drug manufacturer (GlaxoSmithKline). Criteria for inclusion in our meta-analysis included a study duration of more than 24 weeks, the use of a randomized control group not receiving rosiglitazone, and the availability of outcome data for myocardial infarction and death from cardiovascular causes. Of 116 potentially relevant studies, 42 trials met the inclusion criteria. We tabulated all occurrences of myocardial infarction and death from cardiovascular causes.

Results Data were combined by means of a fixed-effects model. In the 42 trials, the mean age of the subjects was approximately 56 years, and the mean baseline glycated hemoglobin level was approximately 8.2%. In the rosiglitazone group, as compared with the control group, the odds ratio for myocardial infarction was 1.43 (95% confidence interval [CI], 1.03 to 1.98; P=0.03), and the odds ratio for death from cardiovascular causes was 1.64 (95% CI, 0.98 to 2.74; P=0.06).

Conclusions Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular causes that had borderline significance. Our study was limited by a lack of access to original source data, which would have enabled time-to-event analysis. Despite these limitations, patients and providers should consider the potential for serious adverse cardiovascular effects of treatment with rosiglitazone for type 2 diabetes.

June 14th, 2007 by Steven E. Nissen, M.D., and Kathy Wolski, M.P.H. with The New England Journal of Medicine

SOURCE: Avandia Recall › Avandia on the risk of heart attack and death from cardiovascular causes

In a floor statement placed in the Senate record, Sen. Charles Grassley also said that safety watchdogs within the federal Food and Drug Administration “several months ago” recommended a “black box” on the drug’s label, the strongest possible warning.It is the first confirmation that the FDA’s own analysis of Avandia shows a similar magnitude of heart attack risks, dangers that were first publicly raised in a medical journal report published earlier this week.

Grassley complained that FDA higher-ups have said they want to wait for results of an ongoing study that will not be available for two more years before making a decision.

“That’s a long time from now when you have millions of Americans taking this drug,” said the statement by the Iowa Republican. “Those numbers seem like a high enough threshold to me for the FDA to warn the American people of the possibility of a problem.”

The FDA has been under fire since Monday’s report came out, attacked by consumer advocates for dropping the ball on drug safety and for taking no stronger action in light of the new warning signs.

Avandia, sold by the British company GlaxoSmithKline PLC, is a blockbuster medication used to treat Type 2 diabetes, the most common form of the disease. More than 6 million people worldwide have taken the drug, whose U.S. sales topped $2.2 billion last year.

On Monday, an analysis led by Cleveland Clinic cardiology chief Dr. Steven Nissen of 42 separate studies on Avandia concluded that it raised the risk of heart attacks by 43 percent, compared to the rates among people taking no or other diabetes drugs. The analysis also indicated that Avandia might increase the risk of heart-related deaths.

GlaxoSmithKline strongly disputes the conclusions. Company officials said that while their own similar analysis suggested a 31 percent greater risk _ information it shared with the FDA as early as 2005 _ more rigorous, albeit smaller, individual studies did not show that.

Critics have accused the FDA of being lax in monitoring drug safety, and some members of Congress scheduled hearings and have subpoenaed key people to appear.

Grassley’s staff has been meeting with FDA staffers and others and gathering documents all week to investigate the issue, said Jill Kozeny, press officer for the Senate Finance Committee, of which Grassley is ranking member.

FDA spokeswoman Julie Zawisza confirmed Thursday the internal analysis that Grassley’s statement revealed, but added, “we have conflicting data” from individual studies, and therefore “are continuing to review the results of GSK’s ongoing trial to determine the actual risk.”

She said she could not discuss “ongoing regulatory matters” like the black box warning that Grassley’s statement says was urged months ago by the FDA’s Division of Drug Risk Evaluation.

As for the number of heart attacks possibly linked to the drug _ as many as 20 a day, Grassley contends _ Zawisza said: “A relationship between the drug and these deaths has not been established. We don’t have data to support such a conclusion.”

Any increase in heart attack risk is especially worrisome for diabetics because two-thirds of them die of heart problems.

About 1 million Americans are currently taking Avandia, which costs from $90 to $170 for a one-month supply. The FDA and diabetes experts are advising users of the medication to talk to their doctors and not to immediately discontinue the drug, which helps keep blood-sugar levels under control.

May 24th, 2007 by Marilynn Marchione with The Associated Press

SOURCE: Avandia Recall › FDA study said to show Avandia risk

Posted 05/21/2007 FDA informed healthcare professionals of a potential safety issue related to Avandia (rosiglitazone). An on-going analysis of safety data for the treatment of type 2 diabetes mellitus using Avandia showed differing rates of ischemic cardiovascular events including heart attack or heart-related adverse events, some fatal, relative to other drugs used to treat diabetes mellitus. The clinical studies reviewed to date vary with respect to their populations, treatment regimens, and length of follow-up. Based on these data, the risk of ischemic cardiovascular events due to Avandia remain unclear. Prescribers should continue to carefully make individualized treatment decisions for patients with diabetes mellitus.

May 21st, 2007 by Staff with FDA

SOURCE: Avandia Recall › MedWatch 2007 Avandia