Avandia Story Heats Up

Will doctors and patients pay a price?

By Daniel TrecrociDaniel Trecroci

It seems every week there is a new twist to the Avandia® plot that makes it more and more of a soap opera—as the TZDs turn!

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®.

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 ®.

Only a Hypothesis

John Buse, MD, PhD, is professor of medicine at the University of North Carolina School of Medicine. In a telephone interview with dLife, 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.”

Cardiovascular Warning Surfaced in 1999

As of late, media reports have surfaced that, prior to Avandia’s approval, Buse warned the FDA that there was potential cardiovascular risk (“Years Ago, Agency Was Warned of a Drug’s Risks,” The New York Times, May 24, 2007). Buse tells dLife that what really happened “wasn’t such a big deal.”

“Avandia® is associated with an increase in LDL cholesterol, so I did some math based on some freely available data and just pointed out that there seemed to be, in one kind of an analysis, an increase in risk. I didn’t say that that means Avandia® is a bad drug and it needs to be withdrawn from the market.”

Buse says what he suggested were two things:

1) That the FDA should make sure that Avandia® isn’t marketed as providing cardiovascular benefit, and
2) That long-term outcome studies be done in patients at high risk for cardiovascular disease.

NEJM Data Called ‘Premature’
Richard Bernstein, MD, FACE, FACN, FACCWS, of the Diabetes Center in Mamaroneck, New York, and author of “Dr. Bernstein’s Diabetes Solution,” feels that the NEJM report on Avandia® was “premature.”

“It doesn’t have adequate information,” he says, “and then, to write an editorial based upon uncertain info is not that smart.”

Bernstein points out that the diabetes community has known for years that TZDs like Avandia® increase fluid retention. However, the main cause of heart problems in people with diabetes is not a drug that you take, but simply, high blood sugars.

“So any agent—it doesn’t matter if its Avandia® or metformin or a sulfonylurea—is not going to give you the kind of blood sugar improvement that insulin does when your initial sugars are as high as in the study.”

In using data from the actual NEJM article, Bernstein points out that there was one huge flaw: “They have no indication of the final A1Cs. They have the starting A1Cs, but not the final, and it could well be that the drugs that had the highest final A1Cs had the highest risks. They have no evidence one way or another. They either ignored the final blood sugars or were unable to find them.”

The average A1C of the participants in the NEJM study was 8.2% — which corresponds to an average blood sugar of around 228 mg/dl (12.66 mmol/L) — at the start of the study. Bernstein was aghast at this data.

“If a patient walked into my office with an A1C that high, he should be on insulin and a low-carb diet. Insulin-sensitizing agents can be added later for those who are obese in order to reduce total insulin requirements. Symlin, or possibly Byetta, can also be added to curb overeating.”

Bernstein adds that what the NEJM data is saying is that the study participants — already at risk of heart problems because of their high A1Cs — are being treated with an oral agent and probably no attention to diet whatsoever.

“There is no mention of diet made in the article,” says Bernstein. “So, that just reiterates the grossly inadequate care being administered to [people with diabetes].”

Don’t Stop Taking Avandia Without First Talking to Your Doctor

Buse said that since the NEJM article and subsequent bombardment of news stories in the mainstream press were published about Avandia®, he has recommended that his patients not stop taking Avandia® without coming in to review with him what their diabetes plan will be from that point forward.

“What we’ve told patients that are well controlled on Avandia® and whose cholesterol is well controlled, is that the risk of switching their drug is greater than the risk of continuing the drug,” says Buse, who stresses that there is no diabetes drug that is a “spotless” drug. “There is no perfect diabetes drug yet. Diabetes is a terrible disease…This is a disease that eats people alive. These drugs that are ‘imperfect,’ in my practice, have dramatically improved patient’s health.”

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

“Byetta® is not as strong,” he says. “It’s not going to lower the A1C as much as a TZD. It’s also an injectable and often causes nausea. And then there is Januvia®. It’s another oral option, but it is clearly weaker than Avandia®.”

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, Byetta® and insulin.”

Buse says if the fallout continues and Avandia® — and even Actos® — are removed from the market — essentially eliminating the TZD class of drug s— 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.”

Read Daniel Trecroci's bio.

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NOTE: The information is not intended to be a replacement or substitute for consultation with a qualified medical professional or for professional medical advice related to diabetes or another medical condition. Please contact your physician or medical professional with any questions and concerns about your medical condition.

 

Last Modified Date: November 28, 2012

All content on dLife.com is created and reviewed in compliance with our editorial policy.

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