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24 September 2010
Suspension of marketing authorisations for rosiglitazone (Avandia® and the combination product with metformin, Avandamet®) has been recommended by the European Medicines Agency (EMA), following concerns over excess cardiovascular risks. These medicines will stop being available in Europe within the next few months, assuming the adoption of a legally binding decision by the European Commission.
Action
The UK Commission for Human Medicines (CHM) has advised that:
- Prescribers should put in place a system to ensure that all patients are reviewed and changed to another suitable treatment in line with NICE recommendations (see below for further information).
- Although this change could happen at the next routine appointment, prescribers may wish to see patients sooner rather than later to reduce patient anxiety.
- Patients who are concerned should not stop their treatment but should contact the healthcare professional who is supervising their diabetic treatment
Background
Issues around the cardiovascular safety of rosiglitazone have been extensively discussed in previous MeReC Rapid Reviews. In a letter to health professionals, Prof Sir Gordon Duff, chairman of the CHM, says that a Europe-wide review of rosiglitazone was initiated in July 2010, to which the CHM contributed. The CHM concluded that the accumulated data support an increased cardiovascular risk associated with rosiglitazone compared with both placebo and with pioglitazone▼, which is of clinical and public health importance. In view of the restrictions already in place on the use of rosiglitazone, the CHM could not identify additional measures that would mitigate the cardiovascular risk. On the evidence available, the CHM concluded that the risks of rosiglitazone outweighed its benefits and that it no longer had a place in UK clinical use. The MHRA has produced a question and answer document, which may be helpful when talking to patients.
More information about the European suspension of marketing authorisations for rosiglitazone products can be found on the EMA website. In the USA, the FDA has announced that it will significantly restrict the use of rosiglitazone to patients with type 2 diabetes who cannot control their diabetes on other medications.
What alternatives are there?
The usual first line hypoglycaemic agent recommended by NICE is metformin. The next drug to be considered would normally be a sulphonylurea. If this combination does not achieve the appropriately agreed desired changes in blood glucose, the next step recommended by NICE is to consider adding NPH (isophane) insulin. Other drugs are alternatives in particular circumstances. As a result of the EMA’s recommendations, NICE has temporarily withdrawn its advice on the use of rosiglitazone in the type 2 diabetes guideline.
This is an opportunity to review patients’ medication on an individual basis. Pioglitazone may be a suitable alternative to rosiglitazone for some patients, but prescribers should note that, like rosiglitazone, pioglitazone is associated with weight gain, fluid retention and an increased risk of heart failure and fractures: see MeReC Rapid Review 524. In addition, the FDA is reviewing data from an ongoing, ten-year epidemiological study designed to evaluate whether or not pioglitazone is associated with an increased risk of bladder cancer.
Although other drugs may be appropriate for individuals, prescribers should note the lack of long term safety data for many of them. In addition, insulin has been associated with increased mortality in type 2 diabetes, and higher doses of the insulin analogue insulin glargine have been associated with cancer.
More fundamentally, patients and prescribers should review the target blood glucose for which they are aiming. The risk of microvascular and macrovascular complications of type 2 diabetes is strongly associated with increased HbA1c. However, as we have discussed previously, it remains uncertain whether intensive glucose control (the addition of hypoglycaemic drugs to reduce HbA1c to levels significantly below that of standard treatments) in type 2 diabetes offers any significant benefit in addition to that achievable by successful implementation of other interventions to reduce cardiovascular risk (including smoking cessation, exercise, losing weight, controlling blood pressure, taking statins, etc). NICE recommends that patients should be involved in setting their individual HbA1c target, which may be above the general target of 6.5% (48mmol/mol). A large observational study of patients receiving intensive glucose control treatment suggests that the risk of all-cause mortality increases above and below an HbA1c level of about 7.5% (59mmol/mol). Intensifying treatment with insulin was associated with a greater risk of these events than intensifying treatment with oral hypoglycaemic agents. See MeReC Rapid Review 1017 for more information.
More information can be found on the type 2 diabetes section of NPC
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