Elsevier

The Lancet

Volume 352, Issue 9131, 12 September 1998, Pages 854-865
The Lancet

Articles
Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34)

https://doi.org/10.1016/S0140-6736(98)07037-8Get rights and content

Summary

Background

In patients with type 2 diabetes, intensive blood-glucose control with insulin or sulphonylurea therapy decreases progression of microvascular disease and may also reduce the risk of heart attacks. This study investigated whether intensive glucose control with metformin has any specific advantage or disadvantage.

Methods

Of 4075 patients recruited to UKPDS in 15centres, 1704 overweight (>120% ideal bodyweight) patients with newly diagnosed type 2 diabetes, mean age 53 years, had raised fasting plasma glucose (FPG;6·1–15·0 mmol/L) without hyperglycaemic symptoms after 3 months' initial diet. 753 were included in a randomised controlled trial, median duration 10·7 years, of conventional policy, primarily with diet alone (n=411) versus intensive blood-glucose control policy with metformin, aiming for FPG below 6 mmol/L (n=342). A secondary analysis compared the 342 patients allocated metformin with 951 overweight patients allocated intensive blood-glucose control with chlorpropamide (n=265), glibenclamide (n=277), or insulin (n=409). The primary outcome measures were aggregates of any diabetes-related clinical endpoint, diabetes-related death, and all-cause mortality. In a supplementary randomised controlled trial, 537 non-overweight and overweight patients, mean age 59 years, who were already on maximum sulphonylurea therapy but had raised FPG (6·1–15·0 mmol/L) were allocated continuing sulphonylurea therapy alone (n=269) or addition of metformin (n=268).

Findings

Median glycated haemoglobin (HbA1c) was 7·4%in the metformin group compared with 8·0% in the conventional group. Patients allocated metformin, compared with the conventional group, had risk reductions of 32% (95% CI 13–47, p=0·002) for any diabetes-related endpoint, 42% for diabetes-related death (9–63, p=0·017), and 36% for all-cause mortality (9–55, p=0·011). Among patients allocated intensive blood glucose control, metformin showed a greater effect than chlorpropamide, glibenclamide, or insulin for any diabetes-related endpoint (p=0·0034), all-cause mortality (p=0·021), and stroke (p=0·032). Early addition of metformin in sulphonylurea-treated patients was associated with an increased risk of diabetes-related death (96% increased risk [95% CI 2–275], p=0·039) compared with continued sulphonylurea alone. A combined analysis of the main and supplementary studies showed fewer metformin-allocated patients having diabetes-related endpoints (risk reduction 19% [2–33], p=0·033). Epidemiological assessment of the possible association of death from diabetes-related causes with the concurrent therapy of diabetes in 4416 patients did not show an increased risk in diabetes-related death in patients treated with a combination of sulphonylurea and metformin (risk reduction 5% [−33 to 32], p=0·78).

Interpretation

Since intensive glucose control with metformin appears to decrease the risk of diabetesrelated endpoints in overweight diabetic patients, and is associated with less weight gain and fewer hypoglycaemic attacks than are insulin and sulphonylureas, it may be the first-line pharmacological therapy of choice in these patients.

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.

Section snippets

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.

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