Quo Vadis Avandia?

While I spent three weeks in hospital for bone
graft surgery - it seemed every week there was 
a new twist to the Avandia plot that makes it 
more and more of a soap opera!

It all started with the publication of a study in the May 21, 2007 online version of The New England Journal of Medicine by Steven Nissen. The study stated that people taking Avandia® have a 43 percent greater chance of developing myocardial infarction compared to people not taking Avandia®, and a 64 percent greater chance of death from cardiovascular causes. Nissen stated, “… patients and providers should consider the potential for serious adverse cardiovascular effects of treatment with [Avandia®,] for type 2 diabetes.”

The FDA quickly followed suit by issuing a safety alert on Avandia®.

As a long term user of Avandia – over a decade – I avidly read….

Avandia Maker Goes on the Defensive
GlaxoSmithKline, which manufactures Avandia®, quickly went on the defensive issuing a statement saying it “strongly disagrees with the conclusions reached in the NEJM article, which are based on incomplete evidence and a methodology that the author admits has significant limitations.”

A few weeks later, GlaxoSmithKline reported an interim analysis of RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycemia in Diabetes) — a prospective clinical trial designed specifically to determine cardiovascular outcomes in more than 4,400 patients with type 2 diabetes. The study, which is scheduled to be completed in June 2008, compares cardiovascular hospitalization and death in patients treated with Avandia® dual therapy (Avandia® plus metformin or sulfonylurea) and in patients treated with metformin and sulfonylurea in combination. After following patients for an average of 3.75 years, the interim analysis found a low number of events overall, and a similar number of events in each group. GlaxoSmithKline claims that the interim findings of the RECORD trial, which were published in the June 5, 2007 online edition of The New England Journal of Medicine, adds further evidence to the overall cardiovascular safety profile of Avandia ®. 

That warmed my heart! [and protected it?]

Only a Hypothesis –more support….

John Buse, MD, PhD, is professor of medicine at the University of North Carolina School of Medicine. Buse says that the Nissen paper published in NEJM generates a hypothesis, but does not generate proof of any issues whatsoever.

“Meta-analysis is not designed to answer questions just to raise them,” says Buse. “That said: it raises an important question. The RECORD study is designed to provide proof, but this is an interim analysis so we don’t have the full result. The balance between the two, frankly, doesn’t tell us much. So, a concern has been raised about particular cardiovascular issues and what the RECORD study tells us is that the concern could be valid or invalid. But the answer isn’t there.”

I felt even better! Till I read Tanenberg….

Robert J. Tanenberg, MD, FACP is a professor of medicine at East Carolina University and director of the Diabetes and Obesity Centre. He states that there are alternatives to Avandia, but other than insulin, many are not as effective for controlling glucose.

Eliminating TZDs Would Be ‘Disastrous’

Tanenberg says that he will not be writing any new prescriptions for Avandia®. He is currently changing concerned patients on Avandia® to Actos®. His main concern is that both drugs may eventually be taken off the market.

“Unfortunately, until the drug is vindicated, there will continue to be patient concerns and possibly liability for prescribing it,” he says. “In medicine, the first rule is to ‘do no harm,’ so when there is a drug in controversy and I have a good alternative, I will most likely not prescribe a potentially harmful drug.”

David Kliff, publisher of the Diabetic Investor, he is not very optimistic that anything good will come out of the Avandia® drama.

“From a business perspective, we already know that GlaxoSmithKline is taking a beating,” says Kliff. “I think Takeda [which manufactures Actos—another TZD drug like Avandia] is also in a difficult situation because of guilt by association.”

Kliff’s personal opinion is that the FDA will put black-box warnings on both Avandia® and Actos®, and ask both GlaxoSmithKline and Takeda to do further, long-term clinical trials.

“In effect, this will kill [Avandia® and Actos®] in the marketplace,” says Kliff. “Because once the black-box warning goes on, the physicians who are already worried about being sued for using the drug will never prescribe them. Why take the chance when you have options like metformin, sulfonylureas and insulin.”

Buse says if the fallout continues and Avandia® — and even Actos® — are removed from the market — essentially eliminating the TZD class of drugs— it would be disastrous.”

“Clearly, more people would be harmed from withdrawing both Avandia® and Actos® than could possibly benefit,” says Buse. “The reason for that is that, in my experience, and, to some extent with some support from the literature, you just cannot control the average patient with type 2 diabetes with any combination of drugs as well as you can with [Avandia or Actos] plus insulin. There would be no substituting for it. You can use other drugs whose safety record is less well known, but, just at face value, there is no other class of insulin-sensitizing drugs, so you cannot replace that.”

There you have it – I promise to monitor the controversy daily now that I am back in my office …. And, continuing with my Avandia.

Technorati Tags: Actos, Avandia, GlaxoSmithKline, side effects of diabetes treatments, Takeda, treatements for type 2 diabetes, Treatment for diabetes, TZD