Hundreds of patients of Type 2 diabetes taking Avandia (rosiglitazone – GlaxoSmithKline) needlessly suffer heart attacks and heart failure each month, according to confidential government reports that recommend the drug be removed from the market. The reports say that if every diabetic now taking Avandia were instead given a similar drug named Actos (pioglitazone HCl- Takeda), about 500 heart attacks and 300 cases of heart failure would be averted every month. Avandia was linked to 304 deaths during the third quarter of 2009.

“Rosiglitazone should be removed from the market,” one report, by Dr. David Graham and Dr. Kate Gelperin of the Food and Drug Administration, concludes. Both authors recommended that Avandia be withdrawn.

Avandia (Rosiglitazone) is a widely used treatment for Type 2 diabetes. It works to control blood sugar by increasing the body’s sensitivity to insulin. It is often taken as part of a regimen that includes other diabetes medications. Approved in 1999 by the Food and Drug Administration as a safer alternative to Rezulin, banned because it caused liver problems. Avandia was heavily marketed and quickly became one of the biggest selling products manufactured by GlaxoSmithKline. In 2006, sales of Avandia were $3.4 billion.

Concerns that Avandia increases the risk of a heart attack were widely publicized in May 2007 in an article in The New England Journal of Medicine [1]. The article’s lead author, Dr. Steven E. Nissen of the Cleveland Clinic, estimated that users of Avandia faced a 43 percent higher risk of a heart attack or other cardiovascular events. Other doctors raised questions about whether Avandia should remain on the market, as alternative like Actos, which is manufactured by Takeda Pharmaceuticals, did not appear to carry the same risks.

Dr. Nissen’s findings were based on the results of a meta-analysis, a compilation of studies. GlaxoSmithKline disputed Dr. Nissen’s conclusions and released preliminary results of its own study that did not show significantly increased risks among users of the drug.

The debate highlighted internal dissension at the Food and Drug Administration. GlaxoSmithKline had presented data similar to Dr. Nissen’s findings to the FDA in 2005, but the agency did not take action or inform the public because of disagreements among officials about the importance of the data.

Following Dr. Nissen’s article, the Food and Drug Administration convened a special advisory panel to review the drug’s safety risks in July 2007.  But after reviewing Dr. Nissen’s findings, as well as other data, panel members concluded that the evidence was too murky to warrant removing Avandia from the market, voting 22-1 to recommend that it remain available, and opted to issue a news alert instead [3].

Sales of the drug declined dramatically after that. In a related decision, the FDA decided to strengthen labels on Avandia and Actos warning that patients using the drugs should watch for fluid accumulation in the legs, ankles and lungs that could lead to heart failure [2].

Since 2007, more studies have been done. In a December 2009 internal memorandum, the director of the FDA’s drug centre wrote that “there are multiple conflicting opinions” about Avandia within the agency, and she ordered officials to assemble another advisory committee to reconsider whether the drug should be sold.

“I await the recommendations of the advisory committee,” the agency’s commissioner, Dr. Margaret Hamburg, said Friday night. “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.”

The multiyear Senate investigation — whose results are expected to be released publicly on Monday — sharply criticizes GlaxoSmithKline, saying it failed to warn patients years earlier that Avandia was potentially deadly.

Mr. Grassley said the internal agency battle showed that the agency needed to be restructured to give more power to safety officials over their counterparts who approve medicines and deal more directly with drug makers.  “It doesn’t make any sense to have these experts who study drugs after they have been on the market for several years under the thumb of the officials who approved the drug in the first place and have a natural interest in defending that decision.”

  1. New England Journal of Medicine – Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes 14 June 2007
  2. FDA NEWS RELEASE – FDA Adds Boxed Warning for Heart-related Risks to Anti-Diabetes Drug Avandia  14 November 2007
  3. FDA NEWS RELEASE – FDA Issues Safety Alert on Avandia  21 May 2007