The two licensed glitazone antidiabetics, pioglitazone (Actos, Takeda) and rosiglitazone (Avandia, GlaxoSmithKline), now account for more than 50% of expenditure on oral hypoglycaemic drugs in the UK’s National Health Service (NHS).

Yet there is “no convincing evidence” that they offer any benefits as monotherapy over the older – and considerably cheaper – metformin or sulphonylureas, concludes a recent review by the Drug and Therapeutics Bulletin (DTB). The evidence for the glitazones’ utility in triple therapy is also “weak” and the drugs should be reserved for patients in whom insulin is contraindicated or is likely to be poorly tolerated, the DTB recommends.

The journal was re-assessing the glitazones in the light of published efficacy data and the safety concerns raised over the drugs in recent years. Moreover, new guidance on the glitazones is expected next month from the National Institute for Health and Clinical Excellence (NICE).

In 2001, the DTB concluded that evidence from short-term studies with pioglitazone and rosiglitazone supported their use in combination with metformin or a sulphonylurea in patients unsuited to one or other of these drugs, but not as monotherapy or part of triple therapy, while the drugs’ long-term effects were not yet clear.

Since then, both glitazones have also been licensed in the UK for monotherapy, as part of triple therapy including metformin and a sulphonylurea, and – in the case of pioglitazone – for use with insulin.

On the safety issue, the DTB said the glitazones increase weight, can cause heart failure and peripheral oedema (especially when given with insulin) and aggravate fracture rates in women. There is also evidence to suggest that rosiglitazone raises the likelihood of myocardial infarction and cardiovascular disease, the journal added, noting that GSK’s drug is now contraindicated in patients with acute coronary syndrome and not recommended in those with ischaemic heart disease or peripheral arterial disease.

If a glitazone is regarded as necessary, pioglitazone “is probably safer” but should only be used as an adjunct to other hypoglycaemics where there is a contraindication or intolerance to metformin or sulphonylureas, the DTB advises.

As with rosglitazone, pioglitazone should not be used if there is any risk of heart failure and “should probably be avoided” in women at high risk of fracture, the journal says. And while pioglitazone is licensed for use with insulin therapy, this combination can lead to a higher incidence of weight gain, oedema and potentially heart failure, it warns.

The estimated annual cost for the recommended daily doses (15-45mg and 4-8mg respectively) of pioglitazone and rosiglitazone is given as £315-£482 (€394-€ 604) for both drugs. This compares with £4-£18 for the recommended daily dose of metformin (500-2,000mg), £4-£35 for gliclazide (40-320mg) and £35-£165 for glimepiride (1-6mg).