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Sulphonylureas 'increase mortality' in patients with diabetes compared with metformin

By Lilian Anekwe

The role of sulphonylureas as keystone drugs for hundreds of thousands of patients with diabetes has been called into question by research finding they have a ‘relatively unfavourable risk profile' compared with metformin.

The major new analysis of UK general practice data, published online by the BMJ, found patients with type 2 diabetes on a sulphonylurea have a 61% higher risk of death and 30% higher risk of heart failure than with metformin.

The retrospective study may encourage GPs to consider alternative second-line drugs, although that has serious cost implications for the NHS.

In May, NICE approved two new diabetes drugs – sitagliptin and vildagliptin – for use by GPs alongside glitazones as a second line drug in patients who cannot tolerate sulphonylureas, or are at significant risk of hypoglycaemia.

Compared with metformin, monotherapy with sulphonylureas was associated with an increased risk of between 24% and 61% for all-cause mortality, and an additional risk of congestive heart failure of between 18 and 30%.

In a third class of oral antidiabetes drugs, the glitazones, rosiglitazone was associated with a 35-41% higher risk of all-cause mortality than pioglitazone.

But contrary to trial data, the glitazones as a class were not associated with risk of a heart attack, and pioglitazone reduced the risk of all-cause mortality by up to 39% compared with metformin.

The researchers, who included several GPs, estimated the risks of a heart attack, death from any cause or incidence of heart failure associated with exposure to medication, by analysing records of 91,000 people with diabetes on the UK general practice research database.

Study leader Dr Ioanna Tzoulaki, a lecturer in epidemiology at Imperial College London, said: ‘The jury is still out on the best second-line drug for type 2 diabetes.

‘There is some evidence on all-cause mortality that glitazones might be better than sulphonylureas, but then they both have an increased risk of heart failure. We'll need more trial evidence before the guidance can be reviewed.'

Dr Brian Karet, a GPSI in diabetes and member of the Primary Care Diabetes Society committee, said the study ‘muddied the waters with respect to which drug to use second line'.

‘The NICE guidance is still pertinent and people should use sulphonylureas but don't persevere with them too long if glycaemic control is not being achieved.

‘There are unquestionably whopping cost implications. It's quite a dramatic step moving from £3-4 a month for metformin and sulphonylureas up to around £30 a month for the newer drugs.'

Current guidance on type 2 diabetes

• Use metformin first line
• Add a sulfonylurea as second-line therapy when blood glucose control remains or becomes inadequate with metformin
• Consider a glitazone or a DPP-4 inhibitor (sitagliptin or vildagliptin) instead if the person is at significant risk of hypoglycaemia, intolerant of or contraindicated against sulfonylurea
• When selecting a glitazone take into account cost, safety and prescribing issues and do not prescribe to people with heart failure or at risk of fractures
• Consider adding exenatide as third-line therapy in patients with a BMI of 35 kg/m2 or higher
Source: NICE guidance CG87, May 2009

Diabetes

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