ArticlesEffect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34)
Introduction
The UK Prospective Diabetes Study reported that intensive blood-glucose control with sulphonylureas or insulin substantially reduced the risk of complications but not macrovascular disease.1
Metformin is a biguanide that decreases blood glucose concentration by mechanisms different from those of sulphonylurea or insulin. It lowers, rather than increases, fasting plasma insulin concentrations2 and acts by enhancing insulin sensitivity, inducing greaterperipheral uptake of glucose, and decreasing hepatic glucose output.3 The improved glucose control is achieved without weight gain.4 Biguanides also decrease concentrations of plasminogen-activator inhibitor type 1(PAI-1)5 and may thus increase fibrinolytic activity. This effect may be secondary either to enhanced insulin sensitivity or to lower insulin concentrations, because therapy with troglitazone (a thiazolidinedione) also decreases production of PAI-1 and increases insulin sensitivity.6
The only long-term outcome data on biguanides available were from the University Group Diabetes Program (UGDP) study of phenformin. An unexpected outcome was higher mortality from cardiovascular causes with phenformin than with placebo, and for total mortality for phenformin than with a combination of insulin and placebo allocations.7 The study design did not allow comparison of phenformin with the sulphonylurea used in the UGDP (tolbutamide). One death from lactic acidosis occurred in the phenformin group. Phenformin was withdrawn from clinical use in many countries, partly because of the UGDP data and partly because of the association with lactic acidosis.8
Metformin is now the only biguanide in general use, since it has a 10–20-fold lower risk of lactic acidosis than phenformin, and is regarded as a safe drug provided it is not used in at-risk patients, such as those in renal failure.9
Metformin was included as a randomisation option in overweight patients in the UK Prospective Diabetes Study (UKPDS) from 1977 as part of the original protocol in the first 15 centres. The primary aim was to compare conventional treatment (primarily with diet alone) with intensive treatment with metformin,10, 11, 12 with a secondary aim of comparing the group allocated metformin with overweight patients allocated sulphonylurea or insulin therapies.
In 1990, increasing glycaemia despite maximum sulphonylurea therapy was noted. Following a UKPDS protocol amendment, normal-weight and overweight patients allocated sulphonylurea treatment, who hadfasting plasma glucose (FPG) concentrations of 6·1–15·0 mmol/L but no symptoms on maximum doses, were then assigned either continuing treatment with sulphonylurea alone or addition of metformin to sulphonylurea.
We report here on whether addition of metforminreduces the risk of clinical complications of diabetes.
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Patients
UKPDS has been described in the accompanying paper.1, 10 Inbrief, between 1977 and 1991, general practitioners in 23 centres in the UK referred patients with newly diagnosed type 2 diabetes, aged 25–65 years, for possible inclusion in UKPDS. 5102 diabetic patients with FPG above 6·0 mmol/L on two mornings were recruited. The patients were advised to follow a diet high in carbohydrates and fibre and low in saturated fats, with energy restriction in overweight patients. After 3 months on diet,
Intensive blood-glucose control with metformin versus conventional treatment in overweight patients
Table 1 shows the baseline data for overweight patients at the time of randomisation to conventional treatment or intensive treatment with chlorpropamide, glibenclamide, insulin, or metformin. The mean bodymass index for overweight patients with type 2 diabetes was 31·4 kg/m2 (SD 4·6); 99·5% of patients had bodymass index greater than 25 kg/m2, and 54·0% had bodymass index greater than 30 kg/m2.
The median follow-up (to the last known date at which vital status was known or to the end of the
Discussion
The main trial reported in this paper evaluated the effect of metformin in diet-treated overweight patients with type 2 diabetes. The study design parallels that in the accompanying paper,1 comparing conventional blood-glucose control primarily with diet alone and intensive treatment with sulphonylurea or insulin. The data shown here suggest that metformin therapy in diettreatedover weight patients reduced the risk for any diabetes-related endpoint, diabetes-related death, and all-cause
Conclusion
The addition of metformin in patients already treated with sulphonylureas requires further study. On balance, metformin treatment appears to be advantageous as afirst-line pharmacological therapy in diet-treated overweight patients with type 2 diabetes.
References (18)
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)
Lancet
(1998)UK Prospective Diabetes Study 24: relative efficacy of sulfonylurea, insulin and metformin therapy in newly diagnosed non-insulin dependent diabetes with primary diet failure followed for six years
Ann Intern Med
(1998)- et al.
Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus
J Clin Endocrinol Metab
(1996) Biguanides and NIDDM
Diabetes Care
(1992)- et al.
Effects of metformin on insulin resistance, risk factors for cardiovascular disease, and plasminogen activator inhibitor in NIDDM subjects: a study of two ethnic groups
Diabetes Care
(1993) - et al.
Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone
N Engl J Med
(1994) A study of the effects of hypoglycemic agents on vascular complications on patients with adult-onset diabetes: V– evaluation of phenformin therapy
Diabetes
(1975)- et al.
Biguanides
Diabetologia
(1978) - et al.
Metformin
N Engl J Med
(1996)
Cited by (0)
Study organisation given at end of paper