Rosiglitazone’s withdrawal in Europe last week had a sense of sad inevitability. The history of the thiazolidinedione or glitazone family has been one of high promise and popularity with patients, but it has also been dogged by disaster.
In 1997, for example, troglitazone was withdrawn in Europe when evidence of adverse liver effects emerged after launch. And even the survivor, pioglitazone, is now under investigation in the US over suggestions it may be linked to an increase in risk of bladder cancer.
Rosiglitazone was launched in 2000, initially marketed as the single drug formulation Avandia, but later made available in combined formulations with metformin as Avandamet and with the sulphonylurea glimepiride as Avaglim.
Since then the cardiovascular issues have been particularly important in relation to rosiglitazone, with accusations that the drug causes oedema leading to heart failure, and that patients taking the drug are at increased risk of cardiovascular events.
In 2007 the European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use reminded prescribers of the prescribing regulations applying to rosiglitazone. Then, in January 2008, it tightened the rules in relation to when rosiglitazone could be prescribed.
Then two studies, published simultaneously on June 28 in the Journal of the American Medical Association and Archives of Internal Medicine, intensified things. A storm of argument followed, with articles in the New England Journal of Medicine and the BMJ, and a BBC Panorama programme focused on the secrecy surrounding the EMA’s decision-making.
Then, on September 23, the EMA made its announcement: despite GSK’s efforts in support of its blockbuster product, rosiglitazone was to be withdrawn in Europe, based on evidence that had come to light since an earlier review in March 2010.
The committee concluded that the benefits of rosiglitazone-containing medicines no longer outweighed their risks. Although, perhaps surprisingly, on the same day and based on the same evidence, the US medicines authorities came to a different conclusion. Rosiglitazone remains available to US doctors and patients if they cannot control their diabetes using other medications.
So what will be the impact of the EMA decision? The MHRA has set the estimated number of patients taking rosiglitazone at 90,000; other organisations have suggested 100,000, and others still more. Whatever the true figure, this is a big number of patients, and pharmacy will be one of the places the effects of change will be felt first.
“Where patients hear that the drug they are taking is being withdrawn for safety reasons and that they have to take this same drug the following morning, it can
be quite concerning,” Anthony Cox, Aston Pharmacy School lecturer in clinical therapeutics, told C+D.
Patient organisation Diabetes UK is relieved at the announcement following concerns that patients have been receiving conflicting information from the press. But the key information may not reach everyone at the same time, care director Simon O’Neill told C+D. “Many patients on polypharmacy are likely to be seen by prescribers once every one or two months, but some patients will have a couple of months’ supply of their antidiabetic drugs and so may not attend their GP practice for some weeks. This group may only find out in the pharmacy.”
Diabetes UK is also advising patients that there are a lot of good alternatives to rosiglitazone, one of which is the surviving pioglitazone with a safer profile.
Mr O’Neill says: “Whether GPs will transfer patients from one glitazone to another is not clear. There is a need for prescribers and patients to look at all options, and the newer drugs have not been on the market so long and many of them are injectable.”
Datamonitor healthcare analyst Christine Henry says the glitazone class of drugs has often been the best possible type treatment for some patients, and she also anticipates patients switching from one class member to another. “They have long-term effects in some patients and are particularly useful in younger patients who are unlikely to have heart failure or fracture risks,” she explains.
Others may want to steer away from the class, though, and Ms Henry predicts many patients will switch to the DPP4 class including sitagliptin (Januvia), vildagliptin (Galvus) and saxagliptin (Onglyza), as recommended by Nice as a second line.
“However, pioglitazone will come off-patent and so will be cheaper in a couple of years. It will be interesting to see how the tension between safety and cost plays out in this area,” she says. And at a time when the government is desperate to cut public spending, Ms Henry raises an important point.
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