Uncertainty is the very condition to impel man to unfold his powers.

The words of German philosopher and psychoanalyst Erich Fromm will hopefully embolden cardiologists and primary care physicians, who remain confused by the consistently conflicting data about the controversial and widely prescribed diabetes drug rosiglitazone (Avandia, GlaxoSmithKline), to make the proper decisions with their patients. The controversy was further confounded by a multitude of studies that further confused clear-cut clinical decision making.

Avandia is part of the thiazolidinedione (TZD) class of drugs, the safety of which were called into question in a 2007 meta-analysis published by Dr. Steven Nissen and Kathy Wolski from the Cleveland Clinic in the New England Journal of Medicine. At the time, the researchers concluded that Avandia was associated with a significant increase in the risk of MI and with an increase in the risk of death from cardiovascular causes, after a review of 42 previously published investigations.

In November 2007, the FDA added a warning label to the drug regarding potential heart risks.
 
The following year, researchers conducting the Veterans Affairs Diabetes Trial (VADT), a large-scale clinical trial in which 80 percent of patients were taking Avandia, which added further, while still inconclusive, information to this discussion. During the 2008 American Diabetes Association (ADA) conference, the VADT researchers reported that a specific analysis of Avandia found that it did not appear to cause excess cardiovascular events and may in fact provide protective benefits for cardiovascular health.

For the past two years, the Senate Committee on Finance, led by Senators Max Baucus, D-Mont., and Charles Grassley, R-Iowa, has been pouring over hundreds of thousands of documents while investigating what GlaxoSmithKline knew about cardiovascular risk  associated with its drug and what the company possibly did to hide those risks. The committee's report can be read here.

This month, the FDA has planned a much-anticipated meeting that will review the safety of Avandia.

In advance of that meeting, several studies emerged this week that will inform the committee. In a JAMA publication, Dr. David J. Graham, from the FDA's Center for Drug Evaluation and Research, and colleagues found that Avandia is associated with an increased risk of stroke, heart failure and all-cause mortality when compared with pioglitazone (Actos), which also is in the TZD class. In addition, Nissen and Wolski released an updated meta-analysis in the Archives of Internal Medicine, including 56 trials through February 2010, finding that Avandia demonstrates an increased risk for MI associated with its use and suggested an unfavorable benefit-to-risk ratio.

However, one bright (and confusing) spot for the drug came from the BARI 2D trial, which was presented at this week’s ADA annual conference in Orlando Fla. That analysis found that Avandia poses no significant increased risk of death, stroke or heart attack, though it does increase the risk of fractures. Researchers analyzed 2,368 patients with cardiovascular disease and type 2 diabetes.

While it would be quite difficult to claim authority about Avandia due to the conflicting data, and therefore, each physician who is the position to prescribe the drug or the drug’s class is left to his or hew own knowledge and clinical experience to make that decision, as Fromm suggests about all positions of authority: Authority is not a quality one person "has," in the sense that he has property or physical qualities.

On these topics, or any others, please feel free to contact me.

Justine Cadet
jcadet@cardiovascularbusiness.com