Remove Diabetes Drug Avandia From Market: FDA Documents

22 feb 2010-- The blockbuster type 2 diabetes drug Avandia raises users' odds for heart attack and heart failure and should be removed from the market, according to confidential U.S. government reports.

The New York Times on Saturday reported on documents from the U.S. Food and Drug Administration that find that if people now taking Avandia (rosiglitazone) switched to a similar medication, Actos, about 500 heart attacks and 300 cases of heart failure would be eliminated each month. And in a report from the Institute for Safe Medication Practice, Avandia was linked to 304 deaths in the third quarter of 2009 alone, the highest for any prescribed drug in that time period, the Times reported.

In one of the FDA documents, dated October 2008, Drs. David Graham and Kate Gelperin -- drug safety officials at the agency -- agreed that "rosiglitazone should be removed from the market."

The reports, obtained early by the Times, are yet another chapter in Avandia's checkered history. The drug was once taken by millions worldwide, but that changed after a study released in early May of 2007 by the Cleveland Clinic suggested that Avandia carried cardiovascular risks. That study, which included more than 28,000 people, found that Avandia increased a user's odds of heart attack by 43 percent compared to those not taking the medicine.

At the time, Dr. Bruce M. Psaty of the University of Washington -- who also co-wrote an accompanying editorial in the New England Journal of Medicine -- urged the FDA to restrict access to Avandia and cited both the agency and the drug's maker, GlaxoSmithKline, for poor oversight.

"The primary problem here is that studies that were needed early on about the health benefits of this drug were never done," Psaty told HealthDay. "As a result of the failure of the sponsor to do long-term clinical trials to show health benefits, as a result of the failure of the FDA to insist on it, we have data that are weak."

Following on the Cleveland Clinic study, the FDA demanded "black box" warnings on labeling for both Avandia and Actos, warning of a potentially heightened risk for heart failure. However, other studies found no raised level of heart risk, and at the time the agency said it had not reached a definitive conclusion on the data.

In November of the same year, the FDA updated Avandia's labeling to include a caution regarding heart attack risk. At the time, Dr. Janet Woodcock, acting director of the FDA's Center for Drug Evaluation and Research, said that, "we are keeping Avandia on the market because we have concluded there isn't enough evidence to indicate that the risk of heart attack is higher for Avandia than other type 2 diabetes treatments."

The story got more complicated in 2008, as a number of studies emerged tying the use of Avandia to increased bone fracture risk.

Throughout 2009, more studies reiterating the drug's heart risks also came to light, including one published in the BMJ suggesting that Avandia's risk for heart failure seemed to outstrip those of its related rival, Actos.

By that point, "most clinicians [had] stopped using Avandia -- some will use Actos instead or go to another class completely," Dr. Carl J. Lavie, medical director of cardiac rehabilitation at the Ochsner Heart and Vascular Institute in New Orleans, told HealthDay at the time.

The emergence of the leaked documents on Saturday comes at a time when officials within the FDA seem to be at loggerheads over whether to ban Avandia or not, the Times reported. The newspaper said that some officials believe that safer alternatives exist, while others say the evidence on Avandia's safety is conflicted and the drug should remain available as a treatment option.

Trying to sort things out, in December of 2009 Woodcock asked officials at the FDA to convene another advisory committee to determine whether Avandia should remain on the market, with a decision expected this summer.

In the meantime, a bipartisan Senate investigation -- overseen by Sen. Max Baucus (D-Mont.) and Sen. Charles E. Grassley(R-Iowa) -- has pored over 250,00 internal documents from GlaxoSmithKline. The investigation has placed much of the blame for the Avandia debacle on the company, contending that it neglected to warn patients for years of the drug's dangers.

"G.S.K. executives attempted to intimidate independent physicians, focused on strategies to minimize or misrepresent findings that Avandia may increase cardiovascular risk, and sought ways to downplay findings that a competing drug might reduce cardiovascular risk," according to the Senate investigation report, which is slated for release Monday but was obtained early by the Times.

Speaking to the newspaper Friday night, agency commissioner Dr. Margaret Hamburg said that, "I await the recommendations of the advisory committee. Meanwhile, I am reviewing the inquiry made by Senators Baucus and Grassley and I am reaching out to ensure that I have a complete understanding and awareness of all of the data and issues involved."

In a statement released Saturday, GlaxoSmithKline said it "rejects the conclusions about the safety of Avandia (rosiglitazone)" as reported in that day's Times story.

"Contrary to the assertions in the story, and consistent with the FDA-approved labeling, the scientific evidence simply does not establish that Avandia increases ischemic cardiovascular risk or causes myocardial ischemic events," the company said. "In 2007, the FDA considered all the available scientific evidence on Avandia, including Dr. Graham's assertions of elevated heart attack risk and demands that the product be withdrawn. Based on the scientific evidence and a recommendation by an independent advisory committee of experts convened by the FDA, the agency has ruled that Avandia remain available to patients for the treatment of Type 2 diabetes."

In the wake of the controversy, GlaxoSmithKline had been directed by the FDA to conduct a trial comparing rates of heart attacks, strokes and heart-linked deaths among users of Avandia, Actos or a placebo. But according to internal documents accessed by the Times, Graham and Gelperin characterized the study, called TIDE, as "unethical and exploitive," with patients being given Avandia despite the fact that it appears to come with greater risks and no added benefit over Actos.

One of the Graham/Gelperin reports -- dated October 2008 -- concludes that, "Although the proposed TIDE trial is motivated by a desire for definitive answers regarding the cardiovascular safety of the drug rosiglitazone, the safety of the study itself cannot be assured and is not acceptable."

However, other FDA officials overruled those concerns and TIDE is still enrolling patients, with preliminary results expected by 2014. Responding to the criticism, GlaxoSmithKline noted Saturday that, "TIDE has been approved by an independent review board and appropriate safety boards that are responsible for assessing the safety of conducting the trial."

The ongoing controversy has dampened patients' and physicians' enthusiasm for Avandia. According to the Times, while sales of the drug topped $3.2 billion in 2006, those numbers plummeted soon after the first studies suggesting risk emerged a year later.

Still, "hundreds of thousands" of people still take Avandia, the Times noted. GlaxoSmithKline's patent on the drug expires in 2012.

Diabetes Drug Linked to Higher Mortality in Medicare Patients

By Peggy Peck
BOSTON, 01 dez 2008-- Medicare patients started on a thiazolidinedione for diabetes had a higher mortality rate and were more likely to develop congestive heart failure if given rosiglitazone (Avandia) than pioglitazone (Actos), researchers here reported.
Analysis of data from prescription records of 28,361 patients showed that rosiglitazone use was associated with a 7% to 15% increased risk of mortality compared with pioglitazone therapy, Wolfgang C. Winkelmayer, M.D., Sc.D., of Brigham and Women's Hospital, and colleagues reported in the November 24 issue of Archives of Internal Medicine.
The analysis also found an 11% to 13% increased risk of developing congestive heart failure in the rosiglitazone arm, but, importantly, no increase in the rate of myocardial infarction or stroke.
This latest analysis comes on top of negative findings from the APPROACH trial and the decision by the American Diabetes Association to exclude rosiglitazone from its latest treatment guidelines. (See AHA: Rosiglitazone Fails to Slow Plaque Progression http://www.medpagetoday.com/MeetingCoverage/AHA/11761 )
"This study confirms the safety concerns that have been raised for rosiglitazone compared with pioglitazone, which, in turn, also cannot be considered a very safe drug given its well-documented effect on the risk of CHF," the authors wrote.
GlaxoSmithKline, maker of rosiglitazone, continued to defend the safety and efficacy of the drug.
In a prepared statement, the company said the new study was "inconsistent with evidence from randomized clinical trials and has significant limitations.
"The primary outcome in this observational analysis is all cause mortality. The [rosiglitazone] prescribing information includes data from RECORD, an ongoing, long-term randomized clinical trial that has shown no statistically significant differences between the [rosiglitazone] group and the control group regarding death from cardiovascular causes or any cause."
Although the company cited the RECORD study, that trial compared rosiglitazone plus metformin with a sulfonyurea plus metformin--it did not compare rosiglitazone with pioglitazone, as is the case in the Winkelmayer study.
The company added that the results of the study by Winkelmayer et al might be "biased due to imbalances in comorbid conditions (cardiovascular disease, chronic obstructive pulmonary disease and malignancies) between the two treatment groups."
Finally GlaxoSmithKline said, "long-term, randomized clinical trials are considered to be the gold standard for answering safety questions and making clinical decisions about prescription medicines." It urged clinicians to await results of two such trials -- RECORD and BARI2D.
But unlike other analyses that have suggested an increased risk of MI and stroke with rosiglitazone, this study found no such association.
Faced with that apparent dilemma, Dr. Winkelmayer and colleagues devised a guilt-by-supposition rather than a guilt-by-association scenario.
They reasoned that, because cardiovascular disease "represents more than 75% of mortality in patients with diabetes, there must almost certainly be a link."
The explanation, they wrote, was that many of the deaths were from MI or stroke, but those "presumably cardiovascular deaths in our cohort of elderly patients may have occurred suddenly or before the diagnosis was established."
The study findings, therefore, "suggest a higher cardiovascular case fatality rate for rosiglitazone."
Leading Dr. Winkelmayer to conclude that the "difference in all cause mortality may be even more important to consider in elderly patients."
All patients in the study were 65 or older and all participated in state-sponsored prescription drug plans in New Jersey or Pennsylvania. All patients initiated rosiglitazone or pioglitazone therapy from January 1, 2000 through December 31, 2005.
Slightly more patients (50.3%) were initiated on rosiglitazone. The baseline characteristics of the two groups were similar, although rosiglitazone users were more likely to have a history of coronary artery disease and congestive heart failure and were less likely to be on beta blocker and statin therapy prior to the index date.
Rosiglitazone users were also more likely to be nursing home residents and more likely to have been hospitalized in the previous six months.
Among the findings:
There were 1,869 deaths during 29,060 person-years of follow-up
Median time exposed to the study drug was 217 days for pioglitazone and 215 days for rosiglitazone
The on-drug incidence rate ratio for all-cause mortality was 1.15 (95% CI, 1.05-1.26) for rosiglitazone
Constant-exposure incidence rate ratio for all-cause mortality was 1.07 (95% CI 1.01-1.14)
The on-drug incidence rate ratio for CHF hospitalization was 1.13 (95% CI 1.01-1.26) for rosiglitazone
Constant-exposure incidence rate ratio for CHF hospitalization was 1.11 (95% CI 1.03-1.19)
The authors noted a number of limitations of the study ranging from the lack of randomized data to the lack of laboratory data on glycemic control.
Those limitations were, however, balanced by the large database of lower-middle class senior citizens that generated "a large cohort of new TZD users," the researchers said.
Moreover, by "focusing on the specific comparison between two similar drugs that were perceived as equal at the time, we were able to avoid dealing with unobserved confounding that is arguably present in studies comparing TZDs with other diabetes regimens," they wrote.
The study was supported by the American Heart Association, Satellite Healthcare, Amgen, Fresenius Medical Care, and GlaxoSmithKline.
Dr. Winkelmayer disclosed that he served as an unpaid member of advisory boards of Amgen, Roche, Genzyme, and Fresenius.
Primary source: Archives of Internal MedicineSource reference:Winkelmayer WC et al "Comparison of Cardiovascular Outcomes in Elderly Patients with Diabetes Who Initiated Rosiglitazone vs. Pioglitazone Therapy" Arch Intern Med 2008; 168: 2368-2375

Diabetes Drug Linked to Higher Risk of Death

By RONI CARYN RABIN
26 nov 2008--Elderly people with diabetes who took the controversial drug rosiglitazone, sold under the brand name Avandia, were more likely to develop congestive heart failure and more likely to die than those receiving a similar drug called pioglitazone, sold as Actos, researchers reported on Monday.
In a surprise finding, however, patients taking rosiglitazone did not suffer more heart attacks or strokes than those taking pioglitazone, researchers said.
Rosiglitazone has been the subject of considerable controversy since 2007, when an analysis of 42 published studies concluded that the drug may dramatically increase the risk of heart attacks and other cardiovascular events, compared to various other treatments.
Researchers at Harvard Medical School used a database of Medicare beneficiaries to track 28,361 patients for up to five years. About half were treated with rosiglitazone and half were taking pioglitazone.
Death rates were 15 percent higher among patients treated with rosiglitazone, compared to those taking pioglitazone, and the incidence of congestive heart failure was 13 percent higher, the researchers found.
“Rosiglitazone was associated with greater mortality,” said Dr. Wolfgang C. Winkelmayer, assistant professor of medicine at the Harvard Medical School and first author of the study, published in The Archives of Internal Medicine.
The study published today is an observational study, and officials at GlaxoSmithKline, which manufactures rosiglitazone, dismissed the findings, saying they are inconsistent with evidence from more rigorous randomized clinical trials.
These include interim results reported from a six-year trial involving 4,447 patients, which company officials noted has found no significant increases in deaths from cardiovascular disease or other causes in patients taking rosiglitazone.
Although the current study also found no differences in heart attack and stroke rates, Dr. Winkelmayer suggested the higher death rates among patients taking rosiglitazone may be due to underlying cardiovascular disease that was never diagnosed in the elderly patients, whose average age was 78.
“In much older adults, it is possible if they do have a stroke or myocardial infarction, they might actually die immediately and never make it to the hospital for a diagnosis, so the excess cardiac events might show up as deaths,” Dr. Winkelmayer said.
Dr. John Buse, chief of endocrinology at the University of North Carolina School of Medicine and president of the American Diabetes Association, said the new study is important but limited.
“This is about the tenth report suggesting that rosiglitazone is associated with excess cardiovascular problems,” he said. “We don’t have proof yet.”
Both the American Diabetes Association and the European Association for the Study of Diabetes have removed rosiglitazone from lists of recommended treatments for type 2 diabetes.
The consumer watchdog group Public Citizen went further last month, calling on the Food and Drug Administration to ban the drug and claiming that it causes liver failure, vision impairment and other serious side effects, in addition to heart problems.
Dr. Sidney Wolfe, director of Public Citizen’s Health Research Group, said he hoped this study would be “the last nail in the coffin of this drug.”
“The big attraction of these drugs is that they are insulin-sensitizing drugs and forestall the time when someone would have to go on to insulin,” Dr. Wolfe added. “But with a 15 percent excess mortality over even pioglitazone, which itself is dangerous, that doesn’t seem like a very good tradeoff.”
A federal scientific advisory panel that reviewed rosiglitazone’s safety profile last year recommended that it remain on the market. Sales have plummeted, however.
About one million Americans still take the drug, which helps control blood sugar by increasing the body’s sensitivity to insulin, often as part of a regimen that includes other diabetes medications.

Consumer group asks government to ban Avandia

WASHINGTON, 31 oct 2008 – The government should ban the diabetes drug Avandia because of a wide variety of life-threatening risks, including heart and liver damage, a consumer group said Thursday.
The consumer group, Public Citizen, filed a petition with the Food and Drug Administration to have Avandia taken off the market.
It was the second setback in as many weeks for the GlaxoSmithKline medication, which at one time had shown great promise in reducing the blood sugar levels of people with Type 2 diabetes. Last week, the American Diabetes Association and a European counterpart jointly released updated treatment guidelines for doctors that pointedly recommended against using Avandia.
"The FDA is in possession of clear, unequivocal evidence that (Avandia) causes a wide variety of toxicities," Public Citizen said in its petition. "Many of these are life-threatening, such as heart attacks, heart failure (and) liver failure."
The FDA said it will "carefully review" the petition, and it continues to monitor Avandia's safety record.
Avandia's heart risks were brought to light two years ago in a medical journal article that reported a 43 percent higher risk of heart attacks among Avandia patients when compared with those taking other diabetes drugs. Although scientists are still debating a link between the drug and heart attacks, concerns about the medical evidence led to stronger warnings.
As a result, Avandia use dropped sharply but about a million U.S. patients still take it.
Public Citizen said its own research found 14 cases of liver failure associated with Avandia, 12 of which led to death. The petition also said Avandia predisposes some patients to eye problems, anemia and bone fractures.
Glaxo, in a statement, said it does not believe Avandia causes liver failure. The company said its own data shows the drug has a good safety record when it comes to liver problems. The company said the data on heart attacks is inconclusive and that Avandia is safe and effective, when used according to directions. Glaxo shares initially fell on the news, but later rose to close at $37.90, up 1.6 percent.
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On the Net:
Public Citizen Web site: http://www.citizen.org/

Canadians Document Excess Mortality with Rosiglitazone (Avandia)

By Peggy Peck
TORONTO, Dec. 11 -- More than three years of thiazolidinedione monotherapy for diabetes was associated with a 40% increase in relative risk of myocardial infarction and a 29% increase in relative risk of death, researchers here found.The thiazolidinedione treatment's adverse effects were "primarily with rosiglitazone (Avandia)," Lorraine I. Lipscombe, M.D., M.Sc., of the University of Toronto, and colleagues, concluded in the Dec. 12 issue of the Journal of the American Medical Association. There was also a 60% rise in the relative risk of congestive heart failure associated with rosiglitazone.
Dr. Lipscombe and colleagues concluded that the excess cardiovascular events appeared to be limited to rosiglitazone, But they also said they found no evidence that pioglitazone (Actos) reduced the risk of MI and cardiovascular death, a protective effect reported by other researchers.
"In contrast to clinical trial data, which suggested that both pioglitazone and rosiglitazone are associated with an increased risk of congestive heart failure, we observed this association only with rosiglitazone," they wrote.
Last month the FDA ordered that an MI warning be added to the black box on the rosiglitazone label, and it asked for extensive long-term trials to determine the drug's cardiovascular safety. Both rosiglitazone and pioglitazone carry black box warnings for congestive heart failure.
The nested case-control study of almost 160,000 diabetes patients age 66 or older who were taking at least one hypoglycemic agent was the latest analysis to report a 40% or greater increase in MI among patients taking rosiglitazone, a finding first reported by Steven Nissen, M.D. of the Cleveland Clinic, in a meta-analysis published online by the New England Journal of Medicine more than six months ago.
Dr. Lipscombe and colleagues compared risks of MI, congestive heart failure, and death between patients treated with thiazolidinediones -- rosiglitazone and pioglitazone -- and other oral hypoglycemic agent combinations, after matching and adjusting for prognostic factors.
During a median follow-up of almost four years, 12,491 patients were hospitalized at least once for heart failure, 12,578 for MI, and there were 30,265 deaths.
Over four years, the estimated numbers needed to harm with thiazolidinediones therapy were 34 patients for congestive heart failure, 26 for MI, and 22 for death, Dr. Lipscombe wrote.
The study, the authors wrote, was "to our knowledge the first study to evaluate thiazolidinedione-related outcomes among an entire population of older patients with diabetes." And the study was, they added, the first to "document an increase in mortality among thiazolidinedione users.
"Although we could not determine the cause of death in our study, the fact that cardiovascular events were also increased with thiazolidinediones suggests a possible cardiovascular etiology in this older, high-risk population," they wrote.
Dr. Nissen, who wasn't involved in the study, said the Canadian data provided a fairly good snapshot of the rosiglitazone effect in a real-world clinical setting. Dr. Nissen's meta-analysis was based on published data from 42 clinical trials.The study was funded by the Ontario Ministry of Health and Long-Term Care. Dr. Lipscombe is supported by a clinician scientist award from the Canadian Diabetes Association and the Canadian Institutes of Health. Dr. Nissen reported receiving research support to perform clinical trials through the Cleveland Clinic Cardiovascular Coordinating Center from Pfizer, AstraZeneca, Daiichi Sankyo, Roche, Takeda, sanofi-aventis, and Eli Lilly. He also consults for many pharmaceutical companies, but requires them to donate all honoraria or consulting fees directly to charity so that he receives neither income nor a tax deduction.
Primary source: Journal of the American Medical AssociationSource reference:Lipscombe LI, et al "Thiazolidinediones and cardiovascular outcomes in older patients with diabetes" JAMA 2007; 298: 2634-2643.

Avandia may raise osteoporosis risk

By RANDOLPH E. SCHMID, AP Science WriterSun Dec 2, 4:49 PM ET
The popular diabetes drug marketed as Avandia may increase bone thinning, a discovery that could help explain why diabetics can have an increased risk of fractures.
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.

Rosiglitazone to Stay on US Market With New Warnings About MI

Sue Hughes
Heartwire 2007. © 2007 Medscape
November 14, 2007 (Rockville MD) – The US FDA has decided to allow the diabetes drug rosiglitazone (Avandia, GlaxoSmithKline [GSK]) to stay on the market with increased warnings about the risk of cardiovascular events, while further studies are conducted to investigate the issue.
The Canadian authorities have taken similar action, albeit with a more strongly worded warning.
An FDA press release, issued today, states: "At this time, FDA has concluded that there isn't enough evidence to indicate that the risks of heart attacks or death are different between Avandia and some other oral type 2 diabetes treatments. Therefore, FDA has requested that GSK conduct a new long-term study to evaluate the potential cardiovascular risk of Avandia, compared with an active control agent. GSK has agreed to conduct the study, and FDA will ensure it is initiated promptly."
More black-box warnings
The existing boxed warning on the product's labeling will have the following statement added: "A meta-analysis of 42 clinical studies (mean duration six months; 14 237 total patients), most of which compared Avandia with placebo, showed Avandia to be associated with an increased risk of myocardial ischemic events such as angina or myocardial infarction. Three other studies (mean duration 41 months; 14 067 patients), comparing Avandia with some other approved oral antidiabetic agents or placebo, have not confirmed or excluded this risk. In their entirety, the available data on the risk of myocardial ischemia are inconclusive." The boxed warning already cautions that rosiglitazone may worsen heart failure, a warning that is also on the labeling for pioglitazone (Actos, Takeda Pharmaceuticals).
The Avandia label also has been updated to add that the drug is not recommended--although not contraindicated--for use with patients who are taking insulin or nitrates.
Lack of CV risk reduction to be highlighted for all diabetes drugs
The FDA notes that, to date, no oral antidiabetes drug has been conclusively shown to reduce cardiovascular risk, and it will therefore also be requesting that labeling of all approved oral antidiabetes drugs contain language describing the lack of such data.
The agency says that people with type 2 diabetes who have underlying heart disease or who are at high risk of heart attack should talk with their healthcare provider about the revised warning for rosiglitazone as they evaluate treatment options. It also advises healthcare providers to closely monitor rosiglitazone patients for cardiovascular risks.
Canadian warning stronger
The Canadian regulatory authorities have also updated the labeling for rosiglitazone but have used stronger language, stating that "rosiglitazone is no longer approved for use alone or in combination with a sulfonylurea drug to treat type 2 diabetes, except when metformin use is contraindicated or not tolerated."
The updated warnings for rosiglitazone follow recommendations made at a US FDA advisory committee meeting in July that the drug should stay on the market with extra warnings, pending a review of additional data. The advisory meeting was called to discuss a meta-analysis by Nissen and Wolski published in the New England Journal of Medicine in May that suggested an increase in cardiovascular events with rosiglitazone and several other subsequent analyses of cardiovascular risk with the drug.
Nissen wanted stronger US warning
Commenting on the FDA's actions, Dr Steven Nissen (Cleveland Clinic, OH) said that while he welcomed the addition of the black-box warning on ischemic heart disease in the US labeling for rosiglitazone, he would have preferred stronger language to have been used. "I would have preferred a warning with greater clarity. I strongly preferred the language chosen by the Canadian authorities. But having said that, a black box is the strongest warning the FDA can make, short of drug withdrawal, and I think the message is unmistakable. By putting a black-box warning on a drug you are telling people to be extremely careful, and I think that message will be heard," he told heartwire.
Nissen added that while the proposed study to investigate cardiovascular risk with rosiglitazone was desirable, the results would not be available until 2014. "This is too long to wait. Patients need our advice now," he said.
Kaul happy
Dr Sanjay Kaul (Cedars Sinai Medical Center, Los Angeles, CA), who coauthored a paper criticizing Nissen's meta-analysis, said he was happy with the FDA's warning. "The FDA's decision accurately reflects the uncertainty surrounding the cardiovascular risk associated with rosiglitazone. Clearly, more data are needed to adjudicate this uncertainty. Only prospective clinical trials designed for the specific purpose of establishing the cardiovascular benefit or risk of rosiglitazone will resolve the controversy about its safety. I am pleased to learn that the FDA has requested that GSK conduct a new long-term study to evaluate the potential cardiovascular risk of rosiglitazone and that GSK has agreed to conduct the study. Reason and logic seem to have prevailed over publicity blitz and fear-mongering," he commented to heartwire. "In the face of uncertainty, the best advice for the clinician is a 'don't stop, don't start' strategy. No need to stop rosiglitazone in patients who have tolerated it long term without any adverse events and whose blood sugars are under good control. No need to start patients on rosiglitazone before exhausting safer treatment options," he added.
GSK statement
GSK says the latest changes are now included in the labeling for Avandia and will be incorporated into future revised labeling for all approved rosiglitazone-containing products. It is also preparing a medication guide to help educate patients about potential benefits and risks and to provide other information on the drug. GSK chief medical officer Dr Ronald Krall commented: "Avandia remains a safe and effective medicine for most patients with type 2 diabetes when used appropriately. Given the severity of this disease and the importance of Avandia in helping patients manage their diabetes, we will continue to work with the FDA to conduct more studies about the safety and benefits of our medicine."

Diabetes drug to warn of risk to heart

By LAURAN NEERGAARD, AP Medical WriterWed Nov 14, 6:22 PM ET
The government slapped a prominent, though confusing, warning on the popular diabetes drug Avandia on Wednesday — telling patients that it may, or may not, increase the risk of heart attacks.
The move is less stringent than steps Canada took last week to restrict the drug's use to hard-to-treat diabetics.
But the U.S. Food and Drug Administration concluded that studies are too contradictory to tell if Avandia really is riskier than other treatments for Type 2 diabetes.
So the FDA described the controversy in a black box on Avandia's label — the most severe type of warning the agency can require — pending further research. Unlike most black-box warnings that urge strong caution, Avandia's says, "The available data on the risk ... are inconclusive."
"It's still an open question," said Dr. John Jenkins, FDA's drug chief. Still, he said, "We want to make sure health care providers and patients are aware this signal of risk has been identified."
Patients may need a medical dictionary to interpret the new warning. It says Avandia may be associated with "myocardial ischemic events such as angina or myocardial infarction."
In layman's terms, that's chest pain or a heart attack. Manufacturer GlaxoSmithKline PLC is to develop a pamphlet that will come with each bottle putting the warning in easier-to-understand language.
Glaxo also agreed to FDA's demand for a major study directly comparing Avandia and its competitors' heart effects. The study will begin by next November and won't end until 2014, but the FDA will order interim checks to see how patients are faring and if it's possible to settle the issue any sooner.
"It isn't as if we're going to be clueless until 2014," said Dr. Janet Woodcock, FDA's chief medical officer.
For now, Type 2 diabetics who also have heart disease or are at especially high risk for it should talk with their doctor about Avandia's potential heart effects as they decide among treatment options, FDA advised.
In contrast, Canada's drug regulators last week withdrew approval of Avandia as a stand-alone therapy except for patients who can't tolerate older competitors. Health Canada announced that Avandia should be used only in combination with certain other drugs for hard-to-control blood sugar.
Dr. Steven Nissen of the Cleveland Clinic, who first brought the heart attack issue to public attention, said he preferred Canada's approach — but that Wednesday's warning is important, if imprecise.
"It is a black-box warning, and no matter what the language says, it's telling you something," Nissen said. "A black-box warning is telling you there's enough evidence here that physicians and patients ought to be concerned."
What should Avandia users do?
"The easy answer is talk to your doctor, but that doesn't help much because the doctors are just as much in the dark as the patient," said Dr. Thomas Pickering, a cardiovascular disease expert at Columbia University Medical Center and an FDA adviser. While he isn't convinced of the heart attack risk, he advises trying other drugs first, and adding Avandia if they're not enough.
It is not the first warning about Avandia's heart effects. In August, the FDA ordered a black-box warning for both Avandia and a competitor, Actos, that they may cause or worsen heart failure, a different cardiac problem.
About 1 million Americans with Type 2 diabetes use Avandia. It helps control blood sugar by increasing the body's sensitivity to insulin.
Diabetics already are at increased risk of heart disease. Type 2 diabetes, the most common form, is linked to obesity, which in turn harms the heart. Plus, high blood sugar over time damages blood vessels. Lowering glucose prevents many diabetes complications, such as blindness and kidney failure.
The hope is that intensive treatment also will lower the risk of a heart attack.
But on Wednesday, the FDA also said Avandia's competitors must change their own labels — to say none has been proven to reduce diabetics' risk of heart disease. That includes the treatment mainstay metformin, a family of medicines called sulfonylureas, and Actos.
The Avandia question, however, is whether it might actually increase heart attacks.
Last May, Nissen and colleagues published an analysis that found Avandia users had a 43 percent higher risk of heart attack than other diabetics. The analysis added 42 different studies that included 14,000 patients, most that compared Avandia users with diabetics given a dummy pill and tracked them for six months.
But three other studies together tracked the same number of patients for a few years — and neither confirmed nor refuted the heart attack risk, FDA found. Those studies mostly compared Avandia to other diabetes medications, and some suggested Avandia might even help diabetics live longer, Jenkins said.
Last summer, FDA's independent scientific advisers ruled the heart risk probably was real but that Avandia should stay on the market with warnings. In further debate, FDA's own employees sharply split on how to address Avandia, although Woodcock said a majority wanted it kept on the market.
___
On the Net:
Food and Drug Administration: http://www.fda.gov/

Metabolic effects of a conversion from rosiglitazone to pioglitazone in Native American patients with type 2 diabetes

Jodi Sparkman, PharmD, Jeffrey Stroup, PharmD, BCPS, Ryan Schupbach, PharmD, BCPS, and Ryan Carnahan, PharmD, MS, BCPP

In this retrospective electronic chart review, we evaluated the metabolic changes that occurred in Native American patients with type 2 diabetes who were treated with rosiglitazone and then converted to pioglitazone with no other changes in medication regimens for diabetes or dyslipidemia. Thirty-four patients were included in the analysis. After the conversion from rosiglitazone to pioglitazone, significant decreases in the levels of total cholesterol (10.1%), low-density lipoprotein cholesterol (11.7%), and triglycerides (15.3%) were seen. No significant changes occurred in weight, body mass index, fasting glucose, hemoglobin A1c, high-density lipoprotein cholesterol, blood pressure, or liver function tests. Significantly more patients achieved low-density lipoprotein cholesterol and triglyceride target goals when taking pioglitazone than when taking rosiglitazone. No drug discontinuations or adverse effects were reported among the evaluable population. These results are consistent with results of other studies evaluating these two drug therapies.

AHA: More Evidence Against Broad Cardiovascular Risk with Pioglitazone

ORLANDO, Nov. 9 -- Pioglitazone (Actos) appeared, at worst, neutral for cardiovascular risk, except heart failure, in yet another meta-analysis examining thiazolidinedione safety.
Action Points
Explain to interested patients that the thiazolidinediones pioglitazone and rosiglitazone do appear to carry a risk of heart failure, but this study supports that other cardiovascular risks may be different between the two.
Note that this study was published as an abstract and presented orally at a conference. The data and conclusions should be considered to be preliminary until published in a peer-reviewed publication.
Pioglitazone did not increase risk of MI, stroke, revascularization, death, or various combinations thereof, according to the five-trial meta-analysis reported here at the American Heart Association meeting.
But neither did it significantly reduce risk aside from unstable coronary syndromes (P=0.039) and stroke and MI combined (P=0.024), reported Nagapradeep Nagajothi, M.D., of the Rosalind Franklin University of Medicine and Science in North Chicago, Ill., and colleagues.
Nevertheless, they concluded that their findings supported those of a much larger but less specific meta-analysis that appeared in the September issue of the Journal of the American Medical Association.
The JAMA analysis suggested an 18% reduction in risk of MI, stroke, or death with the drug (P=0.02). (See: Ups and Downs of Thiazolidinediones for Diabetes Assessed by Dueling Meta-Analyses)
"These are two comparable studies that show similar results," Dr. Nagajothi said.
But despite the researchers' enthusiasm, the results were suggestive rather than confirmatory.
The meta-analysis included five randomized controlled trials with a total of 9,965 patients in which MI outcomes were reported for pioglitazone monotherapy.
The comparison drug was metformin or gliclazide in one trial, glyburide in another, and glimepiride (Amaryl) in a third. Two trials used placebo as the comparator arm. Study duration ranged from six to 34.5 months.
Comparing pioglitazone with controls, the findings included:
MI risk was 14% lower, though not significantly so (hazard ratio: 0.86, 95% confidence interval: 0.69 to 1.07, P=0.17).
Stroke risk was 21% lower with a trend for significance (HR: 0.79, 95% CI: 0.61 to 1.02, P=0.07).
Revascularization risk was 60% lower but still not significant (HR: 0.4, 95% CI: 0.13 to 1.23, P=0.11).
All-cause mortality was similar between treatment groups (HR: 0.94, 95% CI: 0.78 to 1.15, P=0.56).
The combined endpoint of stroke, MI, revascularization, and death was 37% lower (HR: 0.63, 95% CI: 0.376 to 1.06, P=0.08).
MI and unstable angina together were significantly reduced (HR: 0.83, 95% CI: 0.68 to 0.99, P=0.039).
Stroke and MI together were significantly reduced as well (HR: 0.83, 95% CI: 0.71 to 0.98, P=0.024).
The flurry of cardiovascular risk studies sparked by a meta-analysis in the New England Journal of Medicine that suggested rosiglitazone (Avandia) increased MI risk by 43% have consistently found an increased risk of heart failure, so the researchers did not look at that outcome.
However, the heart failure risk for pioglitazone may be related to fluid retention rather than damage to the heart muscle itself, other researchers have suggested. The differences seen in cardiovascular risk between the drugs suggest that there is not a class effect, which might be explained by pioglitazone's relatively more favorable effects on lipids, Dr. Nagajothi said.
"Thiazolidinediones turn on or off more than 100 genes each, which are not identical," he added.
The researchers reported no conflicts of interest.
Primary source: American Heart Association meetingSource reference: Nagajothi N, et al "Pioglitazone and cardiovascular outcomes" AHA meeting 2007; Abstract 3732.

AHA: Doctors Dispute 'Bad News' About Thiazolidinediones

By Ed Susman, Contributing Writer, MedPage TodayNovember 06, 2007
ORLANDO, Nov, 6 -- Media hysteria rather than hard science resulted in black box warnings on supposed dangers of thiazolidinediones for treatment of patients with diabetes, some doctors here suggested.
In an industry-sponsored symposium held in conjunction with the American Heart Association meeting, Burton Sobel, M.D., of the University of Vermont in Burlington, noted that the drugs -- specifically rosiglitazone (Avandia) and pioglitazone (Actos) -- have been at the center of a "maelstrom of controversy that has come about for whatever reason."
Particularly singled out for criticism was the recent meta-analysis authored by Steve Nissen, M.D., director of cardiology at the Cleveland Clinic (NEJM, May 21, 2007).
The validity of Dr. Nissen's findings was challenged by Silvio E. Inzucchi, M.D., clinical director of the Section of Endocrinology at Yale. "Any minor manipulations to this information can be done to show either how much harm rosiglitazone is doing, or how much good it has done," Dr. Inzucchi claimed.
He said that in the Nissen paper researchers "took results from small trials, calculated the odds and they came up with a 43% increase in myocardial infarction."
In a follow-up analysis, he said, researchers used the "faulty" Nissen data. "This is why they had a similar outcome," he said.
Dr. Inzucchi agreed there was some data that indicated rosiglitazone patients appeared to experience a "modest increase in heart failure." But, he said, the news accounts of these studies created an atmosphere that made it necessary for the Food and Drug Administration to require black box labeling for the drugs. "That label is an FDA reaction to the media hysteria surrounding thiazolidinediones," he said.
Another speaker at the symposium, sponsored by Takeda Pharmaceuticals, the developer of pioglitazone, William Chutkow, M.D., Ph.D., of Harvard and Brigham and Women's Hospital, reviewed data on drugs used in treatment of diabetes, including the thiazolidinediones. "[Thiazolidinediones] seem capable of improving all of the insults a diabetic patient would have to face," he said.
Although he discussed metformin, niacin, and other medications, Dr. Chutkow said, "there is still a lot of confusing data, even as late as the year 2007, out there about these drugs to figure out which amongst them is the 'safe' one."

Rosiglitazone (Avandia) Deleted from VA Formulary for Diabetes

WASHINGTON, Oct. 30 -- The U.S. Department of Veterans Affairs has deleted rosiglitazone (Avandia), the diabetes drug that has been linked to increased risk of myocardial infarction and heart failure, from its formulary.
The action followed an internal review of medical records of diabetes patients treated in the VA system. Moreover, the VA representative to the FDA's 15-member Drug Safety Oversight Board (DSOB) rallied other members in an attempt to have rosiglitazone pulled from the market.
According to Senator Chuck Grassley (R-Iowa), the move to ban rosiglitazone fell only one vote short. Grassley said the DSOB met on Oct. 2 and seven members of the DSOB voted to pull the drug.
In a letter to FDA Commissioner Andrew C. von Eschenbach, M.D., Grassley demanded that the FDA make public both the DSOB vote and "information from the FDA regarding the internal policies and procedures governing the DSOB and the terms and conditions governing release of information from the DSOB to the public."
In July members of two FDA advisory boards, meeting jointly, voted 22 to one to keep the drug on the market. But those same advisers also overwhelmingly agreed that the drug should carry a black box warning about ischemic heart disease. The drug already has a black box warning for heart failure. (See: FDA Advisers Vote to Keep Rosiglitazone (Avandia) But Cite Risks)
The FDA is expected to announce rosiglitazone label changes within the next few weeks and although the agency is not required to follow the advice of its advisers, it is widely expected that the agency will order a black box warning about ischemic heart disease.
In his letter, dated Oct. 26, Grassley said he has been investigating the FDA's handling of rosiglitazone since May when the New England Journal of Medicine published a meta-analysis that reported a 43% increase in the relative risk of MI and a 64% increase in relative risk of cardiovascular deaths. (See: Meta-Analysis Links Rosiglitazone (Avandia) to Risk of Myocardial Infarction)
Rosiglitazone is marketed by GlaxoSmithKline.

Tougher Avandia Warning Is Urged

New Label for DrugWould Detail RiskOf Heart Attack
By ANNA WILDE MATHEWSOctober 24, 2007; Page A14
The Food and Drug Administration wants GlaxoSmithKline PLC to add the strongest form of safety warning about heart-attack risk to the label of its diabetes drug Avandia, according to people with knowledge of the matter, a move that would compound the commercial woes of the once-popular medication.
Agency officials are pushing for a "black box" warning, these people say. The new label is still being discussed with the company and its final form isn't yet clear. In high-profile safety matters, the agency tends to have strong leverage.
The new warning would be a blow to GlaxoSmithKline, which had said there isn't clear evidence Avandia is more dangerous than competitors. Avandia already carries a black-box warning about a different side effect -- heart failure -- but a heart-attack warning would be more serious. Avandia's main rival drug, Takeda Pharmaceutical Co.'s Actos, carries a heart-failure caution, but doesn't have one for heart-attack risk.
An FDA spokeswoman said the agency "is still involved in internal discussions on this matter" and that when there is a final decision it will become public. A GlaxoSmithKline spokeswoman said the company is "working diligently with the FDA to finalize the label, but it would be inappropriate for us to discuss the ongoing conversations with the agency."
The new label warning would represent the latest reversal for Avandia, Glaxo's second biggest-selling drug last year, with global sales of $3.38 billion, or 7% of the United Kingdom company's total sales. Avandia's prescriptions plunged after a medical journal article by Cleveland Clinic cardiologist Steven Nissen in May raised concerns about its possible heart risk.
If it goes into effect, the new warning would focus on Avandia's potential for increased ischemic risk: a risk of events in which blood is choked off from the heart. An FDA analysis that crunched together multiple Avandia studies found that the drug appeared to be linked to a 38% higher risk of ischemic events. The company has said that such analyses aren't typically considered the strongest form of medical evidence, and that other data didn't show a similar risk.
A black-box warning would still represent something of a middle ground in the debate over Avandia. During a public meeting in July, some FDA officials said the drug should no longer be sold in the U.S. because of the potential heart danger. A committee of FDA advisers, though, voted that it should remain on the market, even though the panel said the drug was tied to increased ischemic risk.
Avandia's woes would likely benefit Actos. Doctors may also look at older medications such as metformin and newer options such as Merck & Co.'s Januvia.
The potential Avandia label-change has played out amid pressure from outside researchers and scrutiny from Capitol Hill. In June, there was a congressional hearing focused on the drug's safety, and the FDA's handling of it. The drug is the subject of continuing investigations by lawmakers.
Separately, Glaxo and Mylan Inc. yesterday agreed to settle a patent dispute over the antidepressant Paxil CR. As part of the deal, Mylan, a U.S. maker of generics, will have the right to market its version of Glaxo's drug, generically known as paroxetine hydrochloride, beginning no later than Oct. 1, 2008.

This Time It's A Draw for Rosiglitazone (Avandia) and Pioglitazone (Actos)

BURLINGTON, Mass., Sept. 28 -- Pooled data from seven randomized trials of thiazolidinediones for type 2 diabetes confirmed a significant risk of congestive heart failure with either pioglitazone (Actos) or rosiglitazone (Avandia), but neither increased the risk of cardiovascular death.Compared with controls patients treated with either drug an a 72% increase in risk of congestive heart failure (RR 1.72, 95% CI 1.22-2.42, P=0.002), but the pooled risk for cardiovascular death was 0.91 (95% CI 0.63-1.32, P =0.063) with rosiglitazone and 1.01 (95% CI 0.51-2.01 P =0.98) with pioglitazone,
So found Rodrigo M. Lago, M.D., of the Lahey Clinic Medical Center here, and colleagues. They reported the data in the Sept. 29 issue of The Lancet.
"The pooled RR for development of congestive heart failure was 2.18 (95% CI 1.44 -3.32, P =0.0003) in the five trials of rosiglitazone, and 1.32 (1.04-1.68, P =0.02) in two studies with pioglitazone," they wrote.
The seven studies enrolled 20,191 patients who were followed for a mean of about 30 months. During that time 360 patients, including 214 who were given either rosiglitazone or pioglitazone, developed congestive heart failure. The congestive heart failure rate was 2.3% among patients treated with thiazolidinediones versus 1.4% for controls.
The estimated number-needed-to-harm for congestive heart failure was 107 across all seven studies but that number varied from 35 patients in one rosiglitazone trial to 491 to another rosiglitazone trial.
Absence of increased risk of cardiovascular mortality in the face of significant increase in the risk of congestive heart failure, suggests that thiazolidinedione-related fluid retention is more benign than other causes of heart failure, but the investigators said that hypothesis cannot be confirmed with a meta-analysis.
They noted that one trial initially found more heart failure and heart failure mortality for patients treated with pioglitazone, but subsequent analyses found that although more cases of heart failure were associated with pioglitazone than with controls, the number of primary and secondary events were similar in each group.
One interpretation of those data would be that pioglitazone-associated heart failure was indeed more benign that that caused by other factors, they wrote. But another, just as likely, interpretation was that "despite the potential for more adverse cardiovascular events associated with congestive heart failure, pioglitazone could have a cardioprotective effect compared with placebo."
The authors said their analysis was subject to all the limits of the meta-analysis methodology-reliance on aggregated data, varying definitions of heart failure, control groups that included both placebo and active treatments, and a lack of patient-specific outcome information.
Randomized trials of these two drugs is proving to be a mother-lode for data-mining researchers and this analyses is the latest in along line of meta-analyses, post-hoc analyses, and systemic reviews of the two drugs, most of which have been published in the four months since the New England Journal of Medicine published a meta-analysis of 42 trials by Cleveland Clinic investigators, which found a 43% increase in risk of myocardial infarction with rosiglitazone.
Earlier this month the Journal of the American Medical Association published a second rosiglitazone analysis that appeared to confirm the Cleveland Clinic paper along with a meta-analysis of pioglitazone studies that revealed an 18% reduction in cardiovascular mortality with pioglitazone.
A commentary and editorial in The Lancet offerred weary and wary advice about the interpreting the new paper by Dr. Lago and colleagues.
John G. F. Cleland, MD., and Stephen L. Atkin, M.D., of Castle Hill Hospital at the University of Hull in England, pointed out that although the analysis suggested that neither drug was associated with increased cardiovascular deaths "the confidence interval cannot exclude a 25% increase."
But the real problem-the elephant in the room-they wrote was that treatment should be "effective rather than merely innocuous." Both agents are most effective at improving glycemic control, but improved "glycemic control is not a surrogate for effective care of patients who have diabetes, which should be to reduce disability and increase lifespan."
The Lancet's editors pointed out shortcomings of meta-analyses. But they agreed that the reliance on surrogate markers-in this case hemoglobin A1C-"skirts the outcomes that matter most to patients-microvascular and macrovascular complications, quality of life, and survival."
The editors concluded with advice to the FDA and other regulatory agencies to demand better safety data or face the consequences, i.e. that "thiazolidinediones might simply become the latest in a series of preventable drug disasters."
Richard W. Nesto of the Lahey Clinic, senior author of the meta-analysis, disclosed financial support from GlaxoSmithKline and Takeda. No funding source was revealed for the study. Dr. Cleland disclosed support from the British Heart Foundation, GlaxoSmithKline, Roche, AstraZeneca, Pfizer, Sanofi, and Servier. Dr. Atkin disclosed support from GlaxoSmithKline, Takeda, and the British Heart Foundation. Primary source: The LancetSource reference: Lago RM "Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomized clinical trials." The Lancet 2007;370:1129-36
Cleland JGF and Atkin SL "Thiazolidinediones, deadly sins, surrogates, and elephants" The Lancet 2007; 370: 1103-1104
Editorial: "Ensuring drug safety: lessons from the thiazolidinediones" The Lancet 2007; 370: 1101

More Studies Cast Doubt on Safety of Diabetes Drug

By GARDINER HARRIS
Two more studies published in yet another prominent medical journal have raised questions about the safety of Avandia, a once-popular diabetes medicine.
One study found that Avandia, made by GlaxoSmithKline, doubled the risks of heart failure and raised the risks of heart attack by 42 percent. A second study found that Actos, a similar drug made by Takeda, actually lowered the risks of heart attacks, strokes and death but, like Avandia, also raised risks of heart failure.
Taken together, some of the authors said, the two studies in The Journal of the American Medical Association confirm what doctors and patients using Avandia have already done in great numbers, that is, switch to another drug. Sales of Avandia have plunged.
GlaxoSmithKline said in a written statement that the studies were flawed and “offered no new information on the safety of Avandia.” The company “continues to support Avandia as safe and effective when used appropriately,” the statement said.
In July, a federal advisory panel voted overwhelmingly that Avandia should remain on the market even though it raised the risks of heart attacks. In June, the Food and Drug Administration said it would place its strictest warnings on the labels of both Avandia and Actos because of heart failure risks.
Riven by internal disagreements, the drug agency is still pondering further regulatory actions regarding Avandia. Some in the agency say that the drug should be withdrawn, while others say that all diabetes drugs have risks and that doctors need a variety of options.
The controversy began in May when The New England Journal of Medicine published a combined analysis of more than 40 studies of Avandia that found that it significantly raised the risks of heart attacks. The study attracted wide attention, but it was also criticized by the company and some on Capitol Hill as flawed.
In the study’s aftermath, the drug agency said that it had been told in 2005 of a similar study conducted by GlaxoSmithKline that came to a similar conclusion. Critics denounced the agency’s delay in alerting patients.
Dr. Richard Hellman, president of the American Association of Clinical Endocrinologists, said that the new studies were “more evidence that we should have a very high level of caution” regarding the use of Avandia. The drug agency should further strengthen the warnings on Avandia’s label to make it clear that the drug should be used very sparingly.
In the first study, researchers from Wake Forest University did yet another combined analysis of Avandia studies, this time limiting themselves to four long-term studies. The authors’ hope was that, by focusing on such a select set, their analysis would avoid some of the limitations of the May analysis.
The redo came to a conclusion almost identical to that of the study published in May. Dr. Sonal Singh, an assistant professor of internal medicine at the Wake Forest School of Medicine and a co-author of the study, said the drug agency should consider withdrawing Avandia from the market.
In addition to its deleterious effects on the heart, Avandia can cause blindness, and it doubles the risks of bone fractures in women, Dr. Singh said in an interview.
“If you use Avandia to treat patients with Type 2 diabetes,” he said, “their chance of getting heart failure due to Avandia is one in 30 and their risk of getting a heart attack is one in 220. All due to the drug.”
Dr. Singh added, “There are older and cheaper drugs that are far better to treat diabetes.”
In the second study, researchers at the Cleveland Clinic combined data from 19 trials of Actos and found that the drug seemed to lower the risks of heart attack, stroke and death by about 20 percent. The study confirmed that Actos increased the risks of heart failure, but this problem is mostly reversible.
“I think this shows that these drugs aren’t the same,” said Dr. A. Michael Lincoff, vice chairman for research in the department of cardiovascular medicine at the Cleveland Clinic.
Dr. Lincoff said that Actos not only appeared to be safer than Avandia, but also offered some protection to the heart. Most diabetics die of heart disease.
In an accompanying editorial, two doctors from Brigham and Women’s Hospital in Boston wrote that Avandia would probably not have been approved in 1999 had its heart risks been known.
In an interview, Dr. Daniel H. Solomon, a co-author of the editorial, called Avandia “a drug of last resort.”
Dr. Solomon wrote that the Avandia situation should be used to improve the nation’s drug-safety system. Among his proposals is that when several drugs are available to treat a condition, new drugs must prove that they improve or extend people’s lives before they are approved. Now, many drugs are approved only after they improve laboratory results, like blood sugar or cholesterol levels.

Glaxo Diabetes Drug Is Dealt Fresh Blows

By JEANNE WHALEN

Two new studies dealt fresh blows to diabetes drug Avandia and boosted rival treatment Actos, as Avandia's maker, GlaxoSmithKline PLC, continues to fight safety concerns about one of its major drugs.
The articles, published online by the Journal of the American Medical Association, follow months of debate about the cardiovascular risks of Avandia, which was Glaxo's second-biggest drug last year with global sales of £1.65 billion ($3.35 billion).
The Food and Drug Administration is considering whether Avandia's use should be restricted. In July, an FDA advisory committee found that Avandia was tied to a risk of heart attacks, but stopped short of recommending that the drug be pulled from the market.
Some doctors have been switching their patients to Takeda Pharmaceutical Co.'s drug Actos from Avandia because they have generally perceived Actos as being safer for the heart. The new papers in JAMA could accelerate that trend. One concluded that Actos appears to reduce patients' risk of heart attack, stroke and death. The other paper confirmed some earlier studies suggesting that Avandia raises patients' risk of heart attack. The studies didn't compare the drugs against each other.
Actos is the only other marketed drug that works in the same way as Avandia. Before concerns about Avandia surfaced in May, the two drugs were selling neck and neck in the U.S. By mid-July, Avandia had dropped to 33% of the U.S. market while Actos had soared to 67% of the market. Yesterday, a Glaxo spokeswoman said that Avandia prescriptions have started to rebound over the past two weeks.
Glaxo, in a statement, said the papers "do not confirm a difference in the safety profile" of Avandia and Actos. The studies "do not yield data robust enough to guide doctors in selecting appropriate diabetes treatments for patients," Glaxo said. Glaxo, of the United Kingdom, said the totality of evidence available on Avandia shows that it is as safe for the heart as Actos and other oral diabetes drugs.
Bob Spanheimer, senior medical director for diabetes at Takeda, said the Japanese company would promote the new studies in JAMA about Actos to doctors and patients. Together with other data, the JAMA results "really should give physicians the confidence to prescribe Actos," he said.
In one of the JAMA papers, cardiologists from the Cleveland Clinic analyzed 19 previous clinical trials of Actos and found patients taking Actos had 18% less of a chance of dying from any cause or having a nonfatal heart attack or stroke than those in the control group. Heart attack, stroke or death occurred in 375, or 4.4%, of 8,554 patients taking Actos and in 450, or 5.7%, of 7,836 patients taking other drugs or placebo. The study was funded by Takeda; three of the four authors reported receiving research support or consulting fees from Takeda and other drug companies.
In a separate paper, physicians from Wake Forest University School of Medicine analyzed four clinical trials of Avandia lasting at least one year each. They found that patients taking Avandia had a 42% greater chance of having a heart attack than those in the control group. Heart attack occurred in 94, or 1.46%, of 6,421 patients taking Avandia and in 83, or 1.05%, of 7,870 patients taking other medications or placebo. Similar findings were published in May, by Cleveland Clinic cardiologist Steven Nissen.
Both studies in JAMA were meta-analyses, which means researchers pooled previous clinical studies for analysis. The authors acknowledged that the meta-analysis technique is flawed because it attempts to draw conclusions from studies that were designed and conducted differently.

More Studies Cast Doubt on Safety of Diabetes Drug

By GARDINER HARRIS
Two more studies published in yet another prominent medical journal have raised questions about the safety of Avandia, a once-popular diabetes medicine.
One study found that Avandia, made by GlaxoSmithKline, doubled the risks of heart failure and raised the risks of heart attack by 42 percent. A second study found that Actos, a similar drug made by Takeda, actually lowered the risks of heart attacks, strokes and death but, like Avandia, also raised risks of heart failure.
Taken together, some of the authors said, the two studies in The Journal of the American Medical Association confirm what doctors and patients using Avandia have already done in great numbers, that is, switch to another drug. Sales of Avandia have plunged.
GlaxoSmithKline said in a written statement that the studies were flawed and “offered no new information on the safety of Avandia.” The company “continues to support Avandia as safe and effective when used appropriately,” the statement said.
In July, a federal advisory panel voted overwhelmingly that Avandia should remain on the market even though it raised the risks of heart attacks. In June, the Food and Drug Administration said it would place its strictest warnings on the labels of both Avandia and Actos because of heart failure risks.
Riven by internal disagreements, the drug agency is still pondering further regulatory actions regarding Avandia. Some in the agency say that the drug should be withdrawn, while others say that all diabetes drugs have risks and that doctors need a variety of options.
The controversy began in May when The New England Journal of Medicine published a combined analysis of more than 40 studies of Avandia that found that it significantly raised the risks of heart attacks. The study attracted wide attention, but it was also criticized by the company and some on Capitol Hill as flawed.
In the study’s aftermath, the drug agency said that it had been told in 2005 of a similar study conducted by GlaxoSmithKline that came to a similar conclusion. Critics denounced the agency’s delay in alerting patients.
Dr. Richard Hellman, president of the American Association of Clinical Endocrinologists, said that the new studies were “more evidence that we should have a very high level of caution” regarding the use of Avandia. The drug agency should further strengthen the warnings on Avandia’s label to make it clear that the drug should be used very sparingly.
In the first study, researchers from Wake Forest University did yet another combined analysis of Avandia studies, this time limiting themselves to four long-term studies. The authors’ hope was that, by focusing on such a select set, their analysis would avoid some of the limitations of the May analysis.
The redo came to a conclusion almost identical to that of the study published in May. Dr. Sonal Singh, an assistant professor of internal medicine at the Wake Forest School of Medicine and a co-author of the study, said the drug agency should consider withdrawing Avandia from the market.
In addition to its deleterious effects on the heart, Avandia can cause blindness, and it doubles the risks of bone fractures in women, Dr. Singh said in an interview.
“If you use Avandia to treat patients with Type 2 diabetes,” he said, “their chance of getting heart failure due to Avandia is one in 30 and their risk of getting a heart attack is one in 220. All due to the drug.”
Dr. Singh added, “There are older and cheaper drugs that are far better to treat diabetes.”
In the second study, researchers at the Cleveland Clinic combined data from 19 trials of Actos and found that the drug seemed to lower the risks of heart attack, stroke and death by about 20 percent. The study confirmed that Actos increased the risks of heart failure, but this problem is mostly reversible.
“I think this shows that these drugs aren’t the same,” said Dr. A. Michael Lincoff, vice chairman for research in the department of cardiovascular medicine at the Cleveland Clinic.
Dr. Lincoff said that Actos not only appeared to be safer than Avandia, but also offered some protection to the heart. Most diabetics die of heart disease.
In an accompanying editorial, two doctors from Brigham and Women’s Hospital in Boston wrote that Avandia would probably not have been approved in 1999 had its heart risks been known.
In an interview, Dr. Daniel H. Solomon, a co-author of the editorial, called Avandia “a drug of last resort.”
Dr. Solomon wrote that the Avandia situation should be used to improve the nation’s drug-safety system. Among his proposals is that when several drugs are available to treat a condition, new drugs must prove that they improve or extend people’s lives before they are approved. Now, many drugs are approved only after they improve laboratory results, like blood sugar or cholesterol levels.

Study Suggests How Two Diabetes Drugs May Exacerbate Heart Failure

NEW YORK, Sept. 6 -- Experiments in mice suggest that the type 2 diabetes drugs rosiglitazone (Avandia) and pioglitazone (Actos) increase uptake of both glucose and triglycerides in cardiac tissue, causing or exacerbating heart failure.
Transgenic mice bred to over-express the nuclear receptor targeted by the drugs (peroxisome proliferator-activated receptor-gamma, or PPARg), developed dilated cardiomyopathy associated with increased lipid and glycogen stores, reported Ira J. Goldberg, M.D., of the Columbia College of Physicians and Surgeons here, and colleagues.
What's more, signs of heart failure worsened when mice bred for low-level overexpression were exposed to rosiglitazone, the authors wrote in a study published online today by the Journal of Clinical Investigation.
"While PPARγ agonists appear to have multiple beneficial effects, their direct actions on the myocardium have the potential to lead to deterioration in heart function," they wrote.
Rosiglitazone and pioglitazone, two of the most widely prescribed drugs for type 2 diabetes, are PPARg agonists. Both carry black-box warnings about the potential for the drugs to cause or exacerbate congestive heart failure. The drugs are not recommended in patients with symptomatic heart failure, and are contraindicated in patients with established New York Heart Association Class III or IV heart failure.
"In some rodent models of lipotoxic dilated cardiomyopathy, PPARγ agonist treatment improves heart function," the investigators wrote. "It has been postulated that PPARγ agonists have salutary effects due to direct actions on the heart; this is surprising, since PPARγ causes lipid accumulation in other tissue."
Since one of the actions of PPARγ agonists is to channel plasma triglycerides and fatty acids to adipose tissue, it's possible that doing so might reduce lipid uptake by cardiac myocytes, thereby reducing lipotoxicity, the authors speculated.
To evaluate the cardiac effects of PPARg agonists, the authors bred two strains of mice that overexpress PPARg at either low or high levels. They found that both lines of mice had increased cardiac expression of genes that encode for fatty acid oxidation, as well as increased uptake of triglycerides compared with wild-type animals.
The hearts of the transgenic mice also had dilated left ventricles, impaired systolic function, and increased heart-to-body ratios at four months in the high-PPARg expression animals, and at eight months in the low-expression mice, with the high expression mice having more severe cardiac dysfunction, greater left ventricular systolic dimension (P<0.001) and a greater reduction in fractional shortening (P<0.001).
The expression of genes for brain-type natriuretic peptide and atrial natriuretic factor, both markers for heart failure, was increased in the high-expression mice by four months, and in the low expression mice by eight months.
When the authors exposed eight-month-old low-expression mice to rosiglitazone, the treatment caused further deterioration of cardiac function, including increased lipid accumulation, larger hearts, and decreased fractional shortening.
In addition, when they compared PPARg expression levels in the hearts of wild-type mice, mice with streptozocin-induced diabetes, and human hearts, they found that the diabetic mice had two-fold greater expression of the receptor than the wild-type mice, and the expression in human hearts was about eight to 14 times higher than in wild-type mice, suggesting that PPARg has greater physiologic effect in human hearts, the authors wrote.
"It is possible that cardiotoxic effects of PPARγ agonists in humans occur due to glucolipotoxocity," they wrote in their conclusion. "Fortunately, this is seen in only a minority of patients whose diabetes and perhaps genetic variation make them unusually sensitive to what is otherwise a useful form of therapy."
The study was funded by grants from the Specialized Centers of Clinically Oriented Research and the National Heart, Lung, and Blood Institute. The authors reported that they had no conflicts of interest. Additional source: Journal of Clinical InvestigationSource reference: Goldberg IJ et al. "Cardiomyocyte expression of PPARγ leads to cardiac dysfunction in mice." J. Clin. Invest. doi:10.1172/JCI30335.

Boxed Heart Failure Warning Added to Two Diabetes Drugs

ROCKVILLE, Md., Aug. 14 -- The makers of rosglitazone (Avandia) and pioglitazone (Actos), have agreed to add a black box warning to the type 2 diabetes drugs' labels about an increased risk of heart failure, the FDA said today.
The congestive heart failure warning has been in the works for several months and it does not reflect recommendations of an FDA advisory committee that met July 30 to review the cardiovascular safety of rosiglitazone.
That advisory committee agreed that rosiglitazone was associated with an increased risk of ischemic heart disease and recommended that the rosiglitazone label be changed to reflect that.
The boxed warning will also be added to the labels of several combination products that contain the two drugs-Avandaryl (rosiglitazone and glimepiride), Avandamet (rosiglitazone and metformin) and Duetact (pioglitazone and glimepride). The upgraded warning emphasizes that the drugs may cause or worsen heart failure in certain patients.
The link between the drugs and increased risk of heart failure has been well known for some time, but the "drugs are still being prescribed to patients without careful monitoring for signs of heart failure," said Steven Galson, M.D., M.P.H., director of FDA's Center for Drug Evaluation and Research. That lack of caution prompted the boxed warning, he said.
The FDA's review of adverse event reports found cases of significant weight gain and edema-warning signs of heart failure. In some reports, FDA noted, continuation of therapy has been associated with poor outcomes, including death.
The strengthened warning advises clinicians to observe patients carefully for the signs and symptoms of heart failure, including excessive, rapid weight gain, shortness of breath, and edema after starting drug therapy. Patients with these symptoms who then develop heart failure should receive appropriate management of the heart failure and use of the drug should be reconsidered. People who have questions should contact their health care providers to discuss alternative treatments.
The warning also states that these drugs should not be used by patients with serious or severe heart failure who have marked limits on their activity and who are comfortable only at rest or who are confined to bed or a chair.
Rosglitazone is made by GlaxoSmithKline and pioglitazone is a Takeda product.

Diabetes drugs to include new warnings

Tue Aug 14, 8:14 PM ET
The diabetes drugs Avandia and Actos will be labeled with severe warnings about a risk of heart failure to some patients, health officials said Tuesday.
The makers of the drugs, GlaxoSmithKline Plc and Takeda Pharmaceutical Company Ltd., have agreed to add the "black-box" warnings, the Food and Drug Administration said. The warnings, the most severe that prescription drugs can bear, stress the medicines may cause or worsen heart failure and that patients should be closely monitored.
The warnings also apply to combination drugs that include the active ingredients in Avandia, made by Glaxo, or Takeda's Actos. The drugs help patients with Type 2 diabetes control their blood sugar levels.
The warnings, which the FDA said in June it would seek, are separate from concerns that Avandia also raises the risk of heart attack. FDA advisers said last month the risk appeared real but that the evidence wasn't conclusive enough to merit pulling Avandia from the market. They did recommend Avandia's label be updated to include information on that risk. The FDA said it was continuing its review of the issue.
Separately, an FDA review of reports of side effects in patients taking either Avandia or Actos found cases of significant weight gain and build up of fluids, both of which are warning signs of heart failure, the agency said.
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On the Net:
FDA Avandia information: http://www.fda.gov/cder/drug/infopage/rosiglitazone/default.htm
FDA Actos information: http://www.fda.gov/cder/drug/infopage/pioglitazone/default.htm