Both sulphonylureas (SU) and metformin (MET) reduce hyperglycaemia in patients with Type II (non-insulin-dependent) diabetes mellitus, but they do so by entirely different mechanisms. Therefore, SU and MET can be combined, and a few controlled studies have shown pronounced reductions in hyperglycaemia following treatment with this combination [1±3]. As SU and MET also have beneficial long-term effects on diabetic microvascular disease [4,5] and MET even on macrovascular disease [5], it would seem logical to presume that the combination of SU and MET would be highly beneficial for ischaemic heart disease (IHD) and stroke in patients with Type II diabetes. A UKPDS substudy instead reported a higher risk of diabetes-related death with this type of combination therapy compared with SU therapy alone [5]. Therefore, we decided to analyse cause- Diabetologia (2000) 43: 558±560 Articles Short communicationIncreased mortality in Type II diabetic patients using sulphonylurea and metformin in combination: a population-based observational study

The sulphonylurea dose-effect curve may be bell-shaped, perhaps due to down regulation of sulphonylurea receptors during chronic exposure. Alternatively, the finding could be a rebound phenomenon, secondary to preceding hypoglycaemia. The optimum dose for NANSY was found to be 1 mg glimepiride.

The Nepi ANtidiabetes StudY (NANSY) is a 5-year randomized, double-blind, placebo-controlled trial in Swedish primary care, examining whether the development of type 2 diabetes (T2D) and retinopathy (separately reported) would be delayed in 40- to 70-year-old subjects with impaired fasting glucose (IFG) who, in addition to lifestyle changes, were treated with either placebo or low-dosage sulphonylurea (SU) (1-mg glimepiride; Amaryl). Of 274 subjects (163 men, 111 women), 138 were allocated to placebo (46.0% men, 56.8% women) and 136 to glimepiride (54.0% men, 43.2% women). The primary endpoint was conversion to diabetes. Average follow-up time was 3.71 years; 96 subjects converted to diabetes, 55 allocated to placebo and 41 to glimepiride (absolute difference 9.8%; p = 0.072). In conclusion, the study failed to support the notion that low-dose SU added to lifestyle changes in IFG subjects would help to delay the conversion to diabetes.

Glucose control in routine care was better when most patients were treated by a diabetes specialist and were exposed to more intense pharmacotherapy.