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Sulphonylureas raise mortality risk in diabetes, compared with metformin

By Christian Duffin

Monotherapy for type two diabetes patients with most sulphonylureas has a higher risk of all-cause and cardiovascular death compared with metformin, say researchers.

Compared to metformin, patients who had not suffered a heart attack had between 19% and 32% higher risk of death from any cause if they were taking glimepiride, glibenclamide, glipizide or tolbutamide. In patients with a history of heart attacks, this risk was 30%-53% higher.

In patients with a previous heart attack there was 63% extra risk of cardiovascular death with glipizide, and 50% extra for glibenclamide.

But patients taking gliclazide and repaglinide did not have statistically different risk levels than patients on metformin, however.

NICE recommends GP use sulfonylurea monotherapy in patients who are not overweight or in whom metformin is not tolerated or contraindicated, but the researchers said that this is the first study comparing long term risks of individual sulphonylureas with metformin.

The results come from an observational study involving 107,806 patients in Denmark who initiated with either sulphonylureas or metformin during 1997-2006.

The researchers, led by Dr Tina Ken Schramm, senior resident doctor at Copenhagen University Hospital, stressed it was wrong to assume that sulphonylureas directly cause harm.

Dr Schramm said: ‘Previous studies have shown that sulphonylureas are associated with a reduction in long term risk. Therefore, the increased risk from sulphonylureas shown in our study presumably has more to do with the beneficial effects of metformin, gliclazide and repaglinide, than the detrimental effect of the other sulphonylureas.'

Dr Brian Karet, a GP in Bradford and RCGP national lead for diabetes, said: ‘This is a reminder that sulphonylureas are not safe drugs. There has been a feeling for some time that they are safe, but they are not. The trouble for GPs is that – with the exception of metformin – the alternatives are just as risky and do not have good outcomes data.'

Dr Colin Kenny, a GP in Dromore, County Down, and editor of Diabetes and Primary Care journal, said GPs often do not have a straight choice between metformin and a sulfonylurea because combinations may be needed.

'Some patients use sulphonylureas because they experience diarrhoea and other side effects from metformin. We've had 50 or 60 years of sulphonylureas, and by and large they are successful.'

The new study is published in the European Heart Journal. In an accompanying editorial, Professor Darren McGuire, an associate professor of medicine at the University of Texas Southwestern Medical Center, Dallas, said that GPs should not terminate patient medications based only on this research. ‘Compared to metformin, most of the sulphonylureas were associated with worse outcomes, but they would almost certainly be similar to, or better, had the comparison been made against placebo treatment, with the added benefit on kidney, eye, and nerve disease of the glucose control they yield.'

European Heart Journal 2011 online April 6

Metformin Key findings

Risk of all-cause mortality in patients without previous MI compared with metformin

Glimepiride – 32%
Glibenclamide – 19%
Glipizide – 27%
Tolbutamide – 28%

Risk of all-cause mortality in patients with previous MI compared with metformin

Glimepiride – 30%
Glibenclamide – 47%
Glipizide – 53%
Tolbutamide – 47%

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