Nature Medicine | Spoonful of Medicine

A thiazolidinedione by any other name would still be as sweet

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Things are not looking good for Avandia’s chances at the moment. This morning, the New York Times led with the story of a damning clinical trial that GlaxoSmithKline sought to hide. In that study, conducted in 1999, GSK found that Avandia had a higher risk of causing heart problems compared to its chief rival, Actos. Since then, independent studies have called attention to Avandia’s danger and confirmed that it’s riskier. How different are the two drugs? Let’s break it down.

Pharmacologically speaking, GSK’s Avandia (rosiglitazone) and Takeda’s Actos (pioglitazone) are quite similar. They belong to a class of drugs known as thiazolidinediones, or TZDs, and both can be used alone or in conjunction with other medications like metformin, sulfonylureas and insulin. But whereas other diabetes medications act by stimulating the body to produce more insulin, TZDs work by increasing the senstivity of cells to insulin that’s already in the body. Avandia and Actos block PPAR-gamma, a transcription factor inside cell nuclei that normally binds to fatty acids. When activated, PPAR-gamma upregulates genes that increase insulin resistance in tissues.


It’s still unclear why Avandia might cause heart incidents, or what subtle difference between the two compounds makes Actos less risky. The 2007 Cleveland Clinic study that initially sounded the alarm about Avandia’s effects on the heart suggests that Avandia’s tendency to increase LDL cholesterol levels may have something to do with it. But the authors of that report concede that lipid levels alone can’t be responsible for such a severe increase in risk, and that antagonizing PPAR-gamma has effects on other genes as well, with any number of downstream results. Meanwhile, observational study after observational study confirms that Actos is safer (which isn’t to suggest that it’s completely safe: both drugs are known to have side effects including fluid retention, weight gain and anemia).

Since the two drugs gained FDA approval in 1999, they have been about even in sales numbers, but Avandia has, quite understandably, taken a hit over the past few years. In 2005, the two diabetes medications were neck and neck, with Actos at $2.1 billion and Avandia at $1.8 billion. But in 2009 Actos led with $3.4 billion, and Avandia had dropped down to $521 million.

Even so, things aren’t completely rosy for Actos’ Japanese manufacturer, Takeda Pharmaceuticals. Early this year, the company cut nearly 1,600 jobs in the US alone, and expected its net profit to fall 26% in the 2010 fiscal year. That will probably worsen when Actos goes off patent next year. Avandia will retain patent protection until 2012, though how ultimately useful that will be to GSK could be decided at the Food and Drug Administration’s hearings this week.

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