Diabetes drug fails to shake fears
Regulators are feeling the heat as a safety row continues to dog Avandia, write Robin Pagnamenta and Adam Cresswell
WHEN he first saw the results of his study about the cardiovascular risks of the diabetes drug rosiglitazone — sold under the trade name Avandia — several weeks ago, Steven Nissen said that he felt sick and was unable to sleep.
‘‘ It was very striking,’’ he said after the publication of his report on the medicine that is GlaxoSmithKline’s second best-selling drug. ‘‘ When you see a signal this strong, I was truly frightened on behalf of our patients.’’
The outcome of his meta-analysis of 42 previous clinicial trials was, indeed, troubling. It indicated a 43 per cent increase in the risk of heart attacks. It also showed a 64 per cent increase in the risk of death from cardiovascular causes, although this finding was said to be of borderline statistical significance, which means it may not be reliable.
‘‘ I moved as quickly as humanly possible to publish the data,’’ Nissen said.
Six days later, on May 22, the publication online of his report in the New England Journal of Medicine proved explosive. Within hours, shares in GlaxoSmithKline (GSK) had dropped 8 per cent amid fears that the drug, which generated $US3 billion in sales last year and is used by millions, could be pulled or could result in an expensive legal battle.
In Australia too the drug has proved a hit, reaching number 66 on the list of drugs that cost taxpayers the most money in 2005-06. In that year nearly 300,000 prescriptions for rosiglitazone were written, each of which cost just over $75 to fill — costing the federal Government’s Pharmaceutical Benefits Scheme nearly $20 million.
The publication of Nissen’s findings sparked a furore in both the medical profession and the media, a furore that was further stoked by the online publication of more data by the New England Journal of Medicine recently.
The new data were interim findings from an ongoing trial that was set up with the aim of showing that Avandia was no worse than existing treatments in terms of its effect of cardiovascular events, including heart attack. Unfortunately for GSK, the new findings failed to deliver the longed-for exoneration.
Nor do they condemn the drug, and like Nissen’s original meta-analysis, the latest findings have divided experts — with some still strongly attacking suggestions the drug is unsafe.
Nissen, cardiology chief of the Cleveland Clinic, Ohio, is not to be dismissed lightly. One of the most respected medical researchers in the US, he was among the first to find a link between Vioxx, the anti-inflammatory drug, and an increased risk of heart attacks.
The scandal that followed forced the drug’s withdrawal in 2004 and thrust Merck, Vioxx’s manufacturer and one of the world’s biggest pharmaceutical companies, into a bruising legal battle that is still continuing.
Speaking before the latest interim results were released, Nissen made no effort to avoid comparison between Avandia and Vioxx — a parallel that Glaxo has been keen to downplay. ‘‘ I hope that GSK does not go the same way as Merck did,’’ he said. ‘‘ They [GSK] have been marketing a drug with very serious problems. In my view, a lot of people have been harmed.’’
When asked for his views on just how many, Nissen pointed to comments made by US Senator Charles Grassley, an Iowa Republican. He claimed that an evaluation by the US Food and Drug Administration (FDA) had suggested that between 60,000 and 100,000 heart attacks could be linked to the drug since its launch in 1999 — more than 20 per day. ‘‘ I feel pretty strongly that our findings are conclusive,’’ Nissen said. ‘‘ There is something odd about this drug that increases the risk of cardiovascular problems and death.’’
However, GSK is not the only party that disagrees with Nissen. While Nissen’s analysis conceded it had flaws, many independent experts say these are so fundamental that its hypothesis, that Avandia causes heart attacks, has little weight. The flaws they point out include the fact that many of the 42 studies Nissen reviewed to reach his conclusions were small and short-term, and dealt with such small numbers of heart attacks that the findings were open to statistical doubt.
Another was that few of the studies were designed to assess effect on heart attacks, and so did not establish that the events recorded as heart attacks were not in fact something less serious, such as acute angina.
Within days of the release of Nissen’s work The Lancet, the British medical journal, urged caution about the findings. In an editorial published online, it gave warning of the dangers of ‘‘ alarmist headlines and confident declarations that help nobody’’.
In Australia, many experts have also been sceptical. Associate Professor Shane Hamblin, director of diabetes at Melbourne’s Western Health, told a recent edition of the GP weekly Medical Observer there were ‘‘ a lot of holes in this (Nissen’s) meta-analysis’’, while Professor Nikolai Petrovsky, director of the diabetes and endocrinology department at Flinders Medical Centre in Adelaide, was reported in AustralianDoctor as saying he was ‘‘ amazed’’ the NEJM had published Nissen’s study.
All the Australian experts asked for their views said patients already taking Avandia should not stop, although some said doctors should not prescribe it to new patients who had ‘‘ major cardiovascular conditions’’.
But the picture was complicated further by the NEJM’s publication of the second study — an interim analysis of data from a long-term trial involving over 4400 patients that has been specifically designed to demonstrate Avandia’s cardiovascular safety.
These interim findings found that patients treated with rosiglitazone had double the risk of heart failure — in which the heart beats too weakly. While this is a previously recognised side-effect, the study sheds light on how commonly treated patients will experience it.
The interim results also found a trend towards more heart attacks among patients treated with rosiglitazone as opposed to patients on alternative drugs. But these results were not so stark that the study’s authors could confidently say they were not the play of chance.
This lack of statistical significance has been interpreted by GSK and some experts as evidence that Avandia is safe, and by others — including the authors of three NEJM editorials — that serious safety questions remain.
But as in the US — where the Food and Drug Administration is coming under pressure over a growing perception that it has been too slow to act over safety fears — some experts say the Avandia case raises questions about how effectively in Australia we regulate medicines.
David Henry, professor of clinical pharmacology at the University of Newcastle, said following the latest interim trial results, it ‘‘ doesn’t look good for rosiglitazone’’ in terms of the drug’s safety.
‘‘ You can be fairly confident [from the latest results] that rosiglitazone is no better — and it may be worse — than existing therapies,’’ Professor Henry said.
‘‘ The whole purpose of the drug is to improve diabetic control and reduce complications — and here we are several years down the track since the drug’s launch, beginning to question whether the drug is safe.
‘‘ We shouldn’t be asking these questions so long after these drugs have been introduced. It’s a failure of drug development, and a failure of drug regulatory processes.’’
Henry says that just as critics are using the Avandia controversy to argue for more power for the FDA, the Therapeutic Goods Administration should have power to force drug companies to conduct properly designed studies to answer safety questions much earlier.
Previous studies on Avandia established that it was effective at controlling blood sugar levels — but the longstanding assumption that patients would automatically be healthier as a result has been rocked by the findings about increased cardiovascular risk.
However, Henry is not hopeful of this being workable under current funding arrangements.
‘‘ It’s hard when these agencies rely on fees raised from the drug companies to pay their staff, and it’s hard when they don’t have strong support from politicians,’’ he says. The Times
Doubt: TheLancet, the British medical journal has urged caution over research findings on Avandia use