Of Mice and Men Avandia and Heart Attacks

posted on:
September 14, 2007

author:
Staff

 New York, NY- A research report published on-line September 6 in the Journal of Clinical Investigation may provide important clues as to why GlaxoSmithKline's diabetes drug Avandia has such a deadly effect on some diabetics. 

Ten scientists working at the Columbia University College of Physicians and Surgeons conducted a serious of experiments on mice, in order to find out why Avandia works well in mice but not so well in some humans. For diabetic mice, Avandia works to lower blood sugar levels and even improves heart function. But for some diabetic humans, Avandia leads to heart failure and death.

Avandia was the target of high-level scrutiny earlier this year. The Food and Drug Administration considered whether the drug should be withdrawn from the market altogether, and in the end settled on a Black Box warning on Avandia's packaging that use of the drug carried with it an increased risk of heart failure. The FDA was forced into action following publication May 21 by the Cleveland Clinic of an overview analysis of 42 clinical trials of Avandia, concluding that Avandia increased the risk of heart attack by 43%.

Avandia (rosiglitazone) is described as a PPARg agonist-that is, a drug that works by binding itself to this particular cellular receptor. The cellular receptor PPARg is a protein that plays a role in cellular metabolism and cellular differentiation.

In the Columbia University experiments, the scientists found that humans have somewhere between 8 and 14 times more PPARg activity in their hearts than is found in the hearts of mice. Diabetic mice have double the PPARg activity of healthy mice. When the researchers created a strain of diabetic mice with abnormally high levels of active PPARg in their hearts, and dosed them with Avandia, the mice all died of heart failure. Their hearts had weakened and stretched out of shape in a way that indicated abnormal accumulation of fats and sugars, and their heart muscles were damaged and distorted at a cellular level. Avandia was toxic to the hearts of these mice.

The Columbia University report shows that:
• Lab tests on animals cannot be relied on to demonstrate accurately how humans will react to a drug.
• The processes involved in the human metabolism are so complex and poorly understood that no one really knows how many bodily processes a drug like Avandia alters.
• Avandia can have a deadly effect on certain patients whose diabetes, physiology and perhaps genetic disposition render them unusually vulnerable to heart muscle damage.
• So far, there is no way to predict which diabetics will fall into this group.

The researchers conclude that "while PPARg agonists (drugs such as Avandia) appear to have multiple beneficial effects, their direct actions on the myocardium (heart muscle) have the potential to lead to deterioration in heart function".

GlaxoSmithKline continues to sell Avandia, although no one really understands everything the pill unleashes after it is swallowed. Scary, isn't it.

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