People with type 2 diabetes who have underlying heart disease or who are at high risk of heart attack should talk with their health care provider about the revised warning as they evaluate treatment options. FDA advises health care providers to closely monitor patients who take Avandia for cardiovascular risks.

"FDA has moved expeditiously to review the cardiovascular risks of this drug so that we could inform patients and doctors at the earliest possible time of our findings," said Janet Woodcock, M.D., FDA’s deputy commissioner for scientific and medical programs, chief medical officer, and acting director of the Center for Drug Evaluation and Research. "FDA remains committed to making sure that doctors and patients have the latest information about the risks and benefits of medicines."

Avandia, manufactured by GlaxoSmithKline (GSK), Philadelphia, Pa., was approved in 1999 as an adjunct to diet and exercise to improve control of blood sugar levels. Avandia is approved to be used as a single therapy or used in combination with metformin and sulfonylureas, other oral anti-diabetes treatments.

During the past year, FDA has carefully weighed several complex sources of data, some which show conflicting results, related to the risk of chest pain, heart attacks and heart-related deaths, and deaths from any cause in patients treated with Avandia.

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 to an active control agent. GSK has agreed to conduct the study and FDA will ensure it is initiated promptly.

The revision of Avandia’s existing boxed warning – FDA’s strongest form of warning – includes the following statement:

A meta-analysis of 42 clinical studies (mean duration 6 months; 14,237 total patients), most of which compared Avandia to 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 to 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 previous upgraded warning, added to certain diabetes drugs (in class of drugs related to Avandia) on Aug. 14, 2007, emphasized that these types of drugs may worsen heart failure, a condition in which the heart does not adequately pump blood, in some patients. GSK is also developing a Medication Guide for patients to provide additional information about the benefits and risks and safe use of Avandia.

To date, no oral anti-diabetes drug has been conclusively shown to reduce cardiovascular risk. Consequently, the agency also will be requesting that labeling of all approved oral anti-diabetes drugs contain language describing the lack of data showing this benefit.

Today’s action follows recommendations made at the July 2007 joint meeting of FDA’s Endocrine and Metabolic Drugs and Drug Safety and Risk Management Advisory Committees. At the meeting, members voted 22-1 to recommend that Avandia stay on the market, pending a review of additional data. The committee also advised that information warning of the potential for increased risk of heart attacks should be added to the drug labeling.

For more information:
Rosiglitazone maleate (marketed as Avandia, Avandamet, and Avandaryl) Information www.fda.gov/cder/drug/infopage/rosiglitazone/default.htm

FDA Issues Safety Alert on Avandia
www.fda.gov/bbs/topics/NEWS/2007/NEW01636.html

In addition to being equally effective (and in some cases, superior), side-effects were considered less severe and costs considerably lower. Glucophage (metformin) is available in generic form at about $100 for a year’s supply; a month’s supply of Avandia or Actos can be more than twice that.

Consumer Reports created a users’ guide to the information presented in the study, naming the metformin generic as a CR Best Buy. Users for whom metformin alone is ineffective or not well tolerated should consider either glimepiride (Amaryl and generic) or glipizide (Glucotrol and generic). Consumer Reports argued that only the small number of people for whom all of the preceeding drugs prove unusable should consider Actos or Avandia.

While the safety of Avandia is set to be debated before the FDA on July 30th, the drug’s maker GlaxoSmithKline defended the safety and effectiveness of their product in a July 16 press release, arguing that "Avandia is superior in long-term control of blood sugar over five years compared to metformin." However according to a July 16, 2007 article by CNN, the results come as no suprise to diabetes experts:

The conclusions mirror those of an expert panel that leading U.S. and European diabetes groups convened last year, said Dr. David Nathan, diabetes chief at Massachusetts General Hospital. He has received speaker fees from several diabetes drug makers.

Metformin is "an incredibly inexpensive generic drug, which is why we found it so appealing," Nathan said.

Also See:

"Older drugs are the best choice for most people with type 2 diabetes." Consumer Reports. July 2007. <http://www.consumerreports.org/… .htm> (July 17, 2007.)

"Most people with type 2 diabetes should avoid new, heavily advertised drugs–notably Avandia and Actos–because older medications are cheaper, just as effective, and as safe if not safer, according to a new study and a report based on it from Consumer Reports Best Buy Drugs."

"Analysis: Older, cheaper diabetes drugs get high marks." CNN.com. July 16, 2007. <http://www.cnn.com/2007/HEALTH/conditions/07/16/diabetes.drugs.ap/index.html> (July 17, 2007.)

"The clear winner: metformin, sold as Glucophage and generically for about $100 a year. It works as well as other diabetes pills but does not cause weight gain or too-low blood sugar, the analysis found. It also lowers LDL or bad cholesterol."

Press Release: "GlaxoSmithKline Responds to Reviews of Oral Diabetes Medications." GlaxoSmithKline. July 16, 2007 <http://www.gsk.com/media/press-kits/avandia-16july2007.pdf> (July 17, 2007.)

Bolen, et al. "Systematic Review: Comparative Effectiveness and Safety of Oral Medications for Type 2 Diabetes Mellitus." Annals of Internal Medicine. September 18, 2007, Volume 147 Issue 6.<http://www.annals.org/cgi/content/full/0000605-200709180-00178v1> (July 17, 2007.)

“Conclusions: Compared with newer, more expensive agents (thiazolidinediones, α-glucosidase inhibitors, and meglitinides), older agents (second-generation sulfonylureas and metformin) have similar or superior effects on glycemic control, lipids, and other intermediate end points. Large, long-term comparative studies are needed to determine the comparative effects of oral diabetes agents on hard clinical end points.”

Earlier this spring, The New England Journal of Medicine released a study by Dr. Steven Nissen that analyzed the combined results of 42 clinical trials. Their findings indicated that patients on rosiglitazone experienced an increased risk of heart attack by 43% and other cardiovascular-related deaths by 64%.

In the wake of the study results, the FDA requested that Avandia label get a "black box warning," the most serious warning the FDA can request. Additionally, "Safety alert on Avandia" was issued by the FDA which said, in part:

Patients who are taking Avandia, especially those who are known to have underlying heart disease or who are at high risk of heart attack should talk to their doctor about this new information as they evaluate the available treatment options for their type 2 diabetes.

The House Oversight and Government Reform Committee subsequently held a hearing to debate the FDA’s role in evaluating the safety of Avandia. At the hearing, diabetes expert Dr. John Buse testified to feeling intimidated by drug maker GlaxoSmithKline when he expressed misgivings about the drug’s safety as early as 1999.

According to a June 5 article in The New York Times, Buse wrote a letter in March of 2000 to the FDA in which he "criticized [GlaxoSmithKline's] marketing, saying it employed ‘blatant selective manipulation of data’ to overstate the drug’s benefits and understate its risks."

The drug’s detractors claim overagressive marketing, both to doctors and direct to consumers, despite GlaxoSmithKline’s awareness of the risks will provide for failure-to-warn lawsuits similar to those resulting from arthritis drug Vioxx. Avandia’s supporters, however, cite several studies that do not show a correlating increase in risk.

Debate will likely increase, both over the safety of Avandia and the effectiveness of the FDA’s procedures surrounding drug approval, specifically, the lacking requirement for subsequent safety and effectiveness evaluations by drug makers after receiving approval to market their drug.

In an interview with USA Today, former deputy director of the Division of Drug Risk Evaluation, Rosemary Johann-Liang, the burden of proof required to call a drug’s safey into question is greater than that required to show its effectiveness:

The FDA approves diabetes drugs such as Avandia if clinical trials show they meet the "surrogate endpoint," or goal, of lowering blood sugar, [Johann-Liang] says, but then doesn’t require makers to do follow-up studies of whether patients actually feel better and live longer.

On the other hand, Johann-Liang says, "if there is a safety issue with the drug, it must be confirmed. I just don’t think that that’s appropriate." As a result, "we’re not doing things in a timely way."

Sources & Further Reading

• Rubin, Rita. "FDA scientist says she was reprimanded for warning." USA Today. June 10, 2007. <http://www.usatoday.com/news/health/2007-06-10-fda-insider_n.htm>. June 29, 2007.
• "FDA Issues Safety Alert on Avandia." FDA.gov. May 21, 2007. <http://www.fda.gov/bbs/topics/NEWS/2007/NEW01636.html>. June 29, 2007.
• Saul, Stephanie. “Doctor Says Drug Maker Tried to Quash His Criticism of Avandia.” The New York Times. June 2, 2007. <http://www.nytimes.com/2007/06/02/business/02drug.html?…ei=5070>. June 29, 2007.
• Nissen, Steven E., M.D., and Kathy Wolski, M.P.H. “Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes.” The New England Journal of Medicine. Volume 356:2457-2471; June 14, 2007; Number 24. <http://content.nejm.org/cgi/content/short/356/24/2457>. June 29, 2007.
• Hearing on FDA’s Role in Evaluating Safety of Avandia. Committee on Oversight and Government Reform. June 6, 2007. <http://oversight.house.gov/story.asp?ID=1325>. June 29, 2007.

Patients who are taking Avandia, especially those who are known to have underlying heart disease or who are at high risk of heart attack should talk to their doctor about this new information as they evaluate the available treatment options for their type 2 diabetes.

FDA’s analyses of all available data are ongoing. FDA has not confirmed the clinical significance of the reported increased risk in the context of other studies. Pending questions include whether the other approved treatment from the same class of drugs, pioglitazone, has less, the same or greater risks. Furthermore, there is inherent risk associated with switching patients with diabetes from one treatment to another even in the absence of specific risks associated with particular treatments. For these reasons, FDA is not asking GlaxoSmithKline, the drug’s sponsor, to take any specific action at this time. FDA is providing this emerging information to prescribers so that they, and their patients, can make individualized treatment decisions.

"FDA remains committed to assuring that doctors and patients have the latest information available to make treatment and medication use decisions. In this case, FDA is carefully weighing several complex sources of data, some of which show conflicting results, related to the risk of heart attack and heart-related deaths in patients treated with Avandia," said Steven Galson, M.D., M.P.H., director of FDA’s Center for Drug Evaluation and Research. "We will complete our analyses and make the results available as soon as possible. FDA will take the issue of cardiovascular risk associated with Avandia and other drugs in this class to an Advisory Committee as soon as one can be convened."

Avandia was approved in 1999 for treatment of type 2 diabetes, a serious and life threatening disease that affects about 18 to 20 million Americans. Diabetes is a leading cause of coronary heart disease, blindness, kidney failure and limb amputation. Since the drug was approved, FDA has been monitoring several heart-related adverse events (e.g., fluid retention, edema and congestive heart failure) based on signals seen in previous controlled clinical trials of Avandia alone and in combination with other drugs, and from postmarketing reports. FDA has updated the product’s labeling on several occasions to reflect these new data, most recently in 2006. The most recent labeling change for Avandia also included a new warning about a potential increase in heart attacks and heart-related chest pain in some individuals using Avandia. This new warning was based on the result of a controlled clinical trial in patients with existing congestive heart failure.

Recently, the manufacturer of Avandia provided FDA with a pooled analysis (meta analysis) of 42 randomized, controlled clinical trials in which Avandia was compared to either placebo or other anti-diabetic therapies in patients with type 2 diabetes. The pooled analysis suggested that patients receiving short-term (most studies were 6-months duration) treatment with Avandia may have a 30-40 percent greater risk of heart attack and other heart-related adverse events than patients treated with placebo or other anti-diabetic therapy. These data, if confirmed, would be of significant concern since patients with diabetes are already at an increased risk of heart disease.

Avandia is manufactured by GlaxoSmithKline, which is based in Research Triangle Park, N.C.