Avandia (Rosiglitazone)

The diabetes drug Avandia (rosiglitazone) has been in the news recently as questions arise about its safety. The safety concern was brought into the public light after a study by Dr. Steven Nissen, a cardiologist at the Cleveland Clinic, showed that the drug increased heart attacks by 43 percent in patients given Avandia versus those given a placebo.

Avandia is a medication used in type II diabetes to control blood sugars by making the body more sensitive to insulin. It was approved by the FDA in 1999 based on the findings that it reduced blood glucose levels. There was no evidence that it reduced any known diabetes complications.

The study by Dr. Nissen was a meta-analysis of 42 previous studies. It revealed a significant increase in cardiovascular events (heart attack, heart failure, and stroke), an increase in risk of bone fractures and osteoporosis by interfering with the bone's process of replenishing bone cells. In addition, it has been shown to increase cholesterol and possibly the risk of liver failure.

In addition, a study performed by SmithKline Beecham (now Glaxo SmithKline) showed an increased risk of cardiovascular side effects, but the company did not report the results of this study as is required. According to a Glaxo SmithKline spokesperson, the study results were not provided because they did not contribute to any significant information.

One of the questions that faced the special advisory committee is to whether Avandia should be withdrawn from the market. Several questions need to be answered prior to making any decision.

1. How serious is the illness?
2. How big is the risk of continuing the medication?
3. How frequent do the risks occur?
4. Risks versus benefits
5. Are there safer alternatives?

After reviewing over 1000 pages of information and over 12 speakers, the FDA, in a split decision, voted to keep Avandia on the market. The committee concluded that there was sufficient evidence of a concern for increased cardiovascular risk, but stated that there was no conclusive evidence that it increases overall risk of death.  A significant number (twelve) voted to remove Avandia from the market, but the majority voted to keep it on the market. Ten voted for stronger black box warning, sales restrictions and closer supervision of administration. Seven voted for only a stronger black box warning, three voted to keep on the market with any change in status. One member abstained from voting.  A final decision is pending.

The FDA also recommended that Glaxo SmithKline be allowed to continue a large international study that compares Avandia to Actos (pioglitazone) an Avandia alternative with a similar clinical effect without the cardiovascular side effects. Critics say this raises an ethical question as patients will be given a medication with known safety concerns.

The FDA also have recommendations for patients:

• Do not stop taking their medication without talking with their healthcare professional.
• Discuss any questions or concerns they have about rosiglitazone with their healthcare professional.
• Read the Medication Guide that comes with each rosiglitazone prescription to better understand the risks and benefits of their medication.
• Report any side effects with rosiglitazone to FDA's MedWatch program using the information at the bottom of the page.

and for healthcare professionals:

• Follow the recommendations in the drug label when prescribing rosiglitazone. This includes a Boxed Warning stating that:
  • Use of rosiglitazone in patients with established NYHA Class III or IV heart failure is contraindicated. Further, rosiglitazone is not recommended in patients with symptomatic heart failure.
  • Rosiglitazone causes or exacerbates congestive heart failure in some patients. Healthcare professionals should monitor for the signs and symptoms of heart failure (including excessive, rapid weight gain, difficulty breathing, and/or swelling) after starting treatment and after dose increases of rosiglitazone. If heart failure signs and symptoms occur, the heart failure should be managed appropriately and discontinuation or dose reduction of rosiglitazone must be considered.
  • Available data on rosiglitazone and risk of myocardial ischemia are inconclusive. A meta-analysis of 42 clinical studies (mean duration 6 months; 14,237 total patients), most of which compared rosiglitazone to placebo, found an association between rosiglitazone use and an increased risk of myocardial ischemic events such as angina or heart attack. Three other studies (mean duration 41 months; 14,067 total patients), comparing rosiglitazone to other oral diabetes medications or placebo, have not confirmed or excluded this risk. The recently completed RECORD study, currently being reviewed by FDA, is one of these three studies.
• Discuss with patients the risks of rosiglitazone treatment, taking into account the clinical utility of rosiglitazone, the risks/benefits of other anti-diabetic medications, and the risks associated with poorly controlled blood glucose.
• Discuss with patients the importance of adhering to their diabetes medication regimen.
• Report any adverse events associated with the use of rosiglitazone to FDA's MedWatch program.