Article: Avandia: how the warning signs were ignored

This is a draft of an article  that was published in The Daily Mail on 26 July 2010 [Daily Mail permalink]

It is about the extensive efforts to cover up the problems with the diabetes drug Avandia. It reveals a serious confusion by the drug watchdog the MHRA about what evidence to follow and how quickly to act. It also shows how Yellow Card data reports of side effects) was ignored. Shortly after this was published the drug was pulled from the market in Europe and the UK but it is still available in the USA

The diabetes drug Avandia is used by hundreds of thousands of British patients – but how safe is it? In the last few months GlaxoSmithKline in America has paid out over 500 million dollars (330 million pounds) to settle over 2700 claims for damage such as heart attacks, strokes and heart failure caused by the drug.

Avandia, also known as rosiglitazone, is prescribed for type 2 diabetes but growing concerns about its side effects prompted a two day hearing by a committee of the US Food and Drug Administration last week (July 13 and 14). This looked at the question of whether Avandia could dangerously raise your risk of a heart attack.

However the experts were so divided in their opinion that there hasn’t been a clear conclusion.

A majority of the committee voted to say they were worried that the drug raised the risk of heart attacks, but a majority also voted to leave the drug on the market with even more warnings on the label.

So where does this leave British patients? The drug is regulated by the European Medicines Agency which has said it is going to conduct its own investigation to see if Avandia should stay on the market later this week (between 19th and the 22nd July). For the last few years the Agency’s official response to any concerns about the drug has been to say that the “benefits outweigh the risks”.

However this view seems to be trailing some way behind the approach taken by diabetes experts and GPs when deciding how best to treat their patients. “We have had serious doubts about the safety of Avandia for a number of years,” says Dr Ralf Abraham who heads a private clinic – the London Diabetes and Lipid Centre.

“We rarely prescribe Avandia now because of the risks and because there’s a very similar drug called Actos that is just as effective in controlling blood sugar but it doesn’t carry the same risks. So why use Avandia?”

In fact the main effect of the mixed findings of the committee is likely to be that even more patients will be put on Actos. Both Avandia and Actos work by improving the body’s sensitivity to insulin. They were hailed as a breakthrough when they were first licensed in 2000 because they meant some patients could stop injecting insulin.

Both can cause a number of unpleasant and unhealthy side effects including weight gain, fluid retention, heart failure and osteoporosis. But it is widely agreed that adverse reactions such as heart attack and stroke are far less likely to show up with Actos.

Doctors voting with their prescription pads

But what about patients who can’t afford to buy specialist knowledge at a private clinic? Hundreds of thousands of them are still getting Avandia.
Abraham is concerned that this is one of the results of the recent policy of handing over treatment of diabetes to GPs’.

“They don’t have time to keep up with the all the latest drug trials,” he says. “They have to rely on official guidelines.” And the European Agency makes no significant distinction between the two drugs. Very recently the American Diabetes Association has come out clearly in favour of Actos.

However an investigation by the Daily Mail has found that regardless of the official UK guidelines, many doctors have been voting for Actos with the prescription pads.

By last year prescriptions for Avandia had plunged to half what they had been in 2006 while those of Actos have soared to replace them.

Back in 2006 1.1 million prescriptions were written for Avandia in England and just over 450,000 for Actos. By last year the situation had completely reversed. Actos prescriptions were running at 1.2 million and Avandia only managed just over 550.000. However Abraham believes that that is still too many.

Dr Brian Karet spokesperson on diabetes for the Royal College of GPs agrees. “Recently an editorial in the Lancet asked why the diabetes guidelines had to be so confusing. They have nothing clear to say about the difference between these two drugs so lots of patients will have been left on Avandia when they almost certainly shouldn’t have been.”

The European regulators’ advice hasn’t been helpful in another way.

“It does warn against giving Avandia to people with heart problems but anyone who has had diabetes for several years is very likely to have markers for heart disease such as raised plaque and narrowed arteries,” says Anthony Barnett endocrinologist and professor of medicine at the University of Birmingham “so why give it at all?

“Actos reduces heart disease risk and brings down triglycerides and LDL cholesterol while there’s evidence Avandia raises both of them.”

The Mail investigation found another set of official figures that also point in the direction of a greater risk to the heart from Avandia. Both doctors and patients have been reporting a much higher rate of heart problems connected to Avandia via the Yellow Card scheme, which is designed to flag up problems with drugs once they are on the market.

In fact Avandia showed up as having *eight* times as many reports of deaths linked to heart problems compared to Actos – 25 vs. 3. A similar but less dramatic pattern showed up with non-fatal side effects linked to the heart
275 compared with 75.

Drug Watchdog ignored warning signs

Did that set any alarm bells ringing at the European Medicine Agency, the official body that licensed the drug for use in the UK? “The agency takes notice of all information about the effects of any drug after it has been licensed,” says a spokesperson. “Yellow card data is considered as well as other sources.”

The Agency refused to comment on whether the information about the drugs it gave to doctors could have been clearer, saying that the whole matter would be considered at the meeting later this week.

So could patients and doctors in the UK benefit from a more responsive early warning about disagreements between experts on drug safety? “I do think we do need some better system to bring these concerns out in the open much sooner,” says Professor Barnett.

“Worries about the links with heart attack date back at least three years yet officially it still isn’t an issue. At the moment there isn’t any way to raise such concerns and make a stronger case for choosing other options.”
Even though the US hearings didn’t produce a clear result they did provide a rare glimpse of how messy decisions about the safety of drugs can be. Unlike such hearings in Europe and the UK that are held behind closed doors, they were open to the public.

The two sides, those in favour of keeping the drug on the market and those wanting it withdrawn, disagreed vehemently about the best way to interpret the evidence.

For instance a major plank in GlaxoSmithKline’s evidence was a big trial that reported no increase in the risk of heart disease among nearly 4,500 patients getting Avandia. Called Record it began in 2002/3 and the results were published last year.

Airbrushing out side effects

However Dr Thomas Marciniack, a scientist working for the Food and Drug Administration described it as “seriously flawed” because, he claimed, the data had been tampered. He reported that he had conducted a detailed examination of only a small percentage of all the cases and found a dozen instances where patients taking Avandia appeared to suffer serious heart problem that were not counted in the total of adverse events.

For instance, one patient was hospitalised after a severe stroke but the study record doesn’t list them as having a cardiovascular problem.

GlaxoSmithKline said that it stood by the Record Study and that five further studies had all concluded that Avandia was safe. “Overall when used appropriately Avandia has a positive risk-benefit profile” said Murray Stewart, vice president of clinical development at the company.

“It should remain a treatment option for patients with type 2 diabetes.” The company also denied tampering with any data

The most high profile and persistent critic of Avandia is the cardiologist Dr Steven Nissen of the Cleveland Clinic in Ohio. He carried out the study in 2007 which set alarm bells ringing with its conclusion that Avandia raised the risk of heart attack or stroke by 40%.

At the hearing he presented new data which estimated the number of people who would have to take Avandia for one of them to be harmed.
“Even if you accept the favourable Record data, you would still get one extra heart attack for every 52 people treated with Avandia,” he said.

“If it’s not accepted there could be a heart attack for every 37 people treated.” Scaled up to the half a million prescriptions written for the drug in the UK that is a huge amount of harm. But the fact the Avandia wasn’t withdrawn means that he failed to convince the committee.

So given this very public clash of experts what should the ordinary diabetes patient do?

“If you are taking Avandia you need to ask your doctor some detailed questions,” says Dr Karet, who also advises Diabetes UK. “Ask why you are on it. In my opinion about the only reason would be if you also have a condition like polycystic ovary which makes you very insulin resistant.

“Ask if you should be on Actos instead or be taking another type of diabetes drug altogether. You should be pushing your health care professional to get up to date with the data. There is lots of information available on Google. Just put in rosiglitazone.”

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