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May 28, 2007
Volume 85, Number 22
p. 8


Diabetes Drug Comes Under Fire

Safety questions about GSK's Avandia may drive patients to alternative treatments

Lisa Jarvis

A PAPER in the New England Journal of Medicine is questioning the safety of GlaxoSmithKline's multi-billion-dollar diabetes drug Avandia and could have a ripple effect on an entire range of type 2 diabetes treatments (DOI: 10.1056/NEJMoa072761).

The report presents findings from Steven Nissen, the Cleveland Clinic cardiologist who first raised concerns about the safety of the Merck & Co. painkiller Vioxx. Nissen analyzed combined data from 42 previous clinical trials of Avandia, all of which were available on a GSK website, and found that patients taking Avandia were about 43% more likely to have a heart attack than those who weren't. He claims that the increased risk of dying from cardiovascular causes when taking the drug is "statistically significant."

GSK says it "strongly disagrees with the conclusions" of the NEJM article, citing conflicting safety results from different trials. Last year, the company notified FDA of cardiovascular incidents in one trial and added a related warning to the drug's label.

With $3 billion in sales in 2006, Avandia is GSK's second-best selling drug and a critical component of its portfolio. The full impact of the NEJM study remains to be seen, but analysts believe doctors will start switching patients to other treatments, particularly those with a mechanism of action different from that of Avandia.

Avandia works by acting on the peroxisome proliferator-activated receptor (PPAR), a drug target that has caused safety concerns in the past.

In 2005, Merck and Bristol-Myers Squibb withdrew a New Drug Application for their PPAR agonist Pargluva after FDA asked for a five-year cardiovascular safety study. And Warner-Lambert pulled the drug Rezulin from the market in 2000 after it was shown to cause liver toxicity. FDA is now looking at the safety of Takeda Pharmaceutical's Actos, introduced in 1999, though large-scale studies suggest the drug doesn't have the same impact on heart health.

Morgan Stanley drug analyst Jami Rubin believes the lion's share of diverted Avandia prescriptions will go to Merck's Januvia and Amylin's Byetta, both of which act on a pathway of glucagenlike peptide-1, a gastrointestinal hormone. Rubin sees Merck's Januvia franchise winning anywhere from 30 to 60% of lost Avandia sales by 2010.

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