Early findings from their study, presented at the European Association for the Study of Diabetes in Barcelona, Spain this week, suggested patients prescribed sulfonylureas were 58% more likely to die than those on metformin.
Lead author Professor Craig Currie from Cardiff University said first-line monotherapy with sulfonylureas, which is advised by NICE in some cases, may not be appropriate.
The results support previous research that also suggested an increased risk of death.
Over 180,000 patients with type 2 diabetes in the UK are prescribed sulfonylureas such as glipizide, gliclazide or glibenclamide. NICE advises GPs to prescribe sulfonylurea as first-line treatment if patients cannot tolerate metformin or it is contraindicated.
In the study, supported by Bristol-Myers Squibb, researchers used data from 10% of all GP records in the UK to find patients with type 2 diabetes where first-line glucose-lowering treatment was initiated between 2000 and 2012.
They compared 76,811 patients treated with metformin and 15,687 on sulfonylureas over three years, adjusting for factors such as age, sex, BMI and HbA1c. The analysis found a 58% raised risk of all-cause mortality among those prescribed sulfonylureas compared with metformin.
Professor Currie concluded: 'Mortality was significantly increased in patients prescribed sulfonylureas as first-line, glucose lowering monotherapy, compared with metformin monotherapy.
'Whilst residual confounding and confounding by indication may remain, this study indicates that treatment with first-line monotherapy with sulfonylureas should be reconsidered.'
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