Combination treatment with metformin and glibenclamide versus single-drug therapies in type 2 diabetes mellitus: a randomized, double-blind, comparative study

doi:10.1016/S0026-0495(03)00101-X

Metabolism

Volume 52, Issue 7, July 2003, Pages 862-867

https://doi.org/10.1016/S0026-0495(03)00101-X Get rights and content

Abstract

To compare efficacy and tolerability of combination treatment with metformin and sulfonylurea with each of these drugs alone in the treatment of type 2 diabetes, 88 type 2 diabetic subjects (hemoglobin A_1c [HbA_1c] levels, 8.0% ± 1.0%; age, 57.3 ± 7.1 years; body mass index [BMI]. 27.0 ± 2.6 kg/m²; diabetes duration, 9.8 ± 8.2 years; means ± SD) were randomly assigned to double-blind treatment with metformin (500 to 3,000 mg/d), glibenclamide (5 to 15 mg/d), or their combination (metformin 400 to 2,400 mg/d + glibenclamide 2.5 to 15 mg/d) for 6 months. Thereafter, groups were crossed over for the following 6 months. Thus, each patient received metformin or glibenclamide alone, and the combination treatment. Doses were titrated to obtain HbA_1c levels ≤ 6.0% and fasting plasma glucose levels less than 140 mg/dL. Eighty patients concluded both treatment periods and were included in the analysis of treatment efficacy. In patients receiving metformin or glibenclamide alone, the maximal dose was reached in 21 and 25 patients, respectively; 8 and 15 of these subjects, respectively, required the maximal dose when they were on the combination treatment. During the study, 4 (10.0%) subjects receiving metformin, 7 (17.1%) receiving glibenclamide, and 31 (39.2%) receiving the combination treatment reached HbA_1c levels ≤ 6.0%. Moreover, when efficacy of the combination treatment on glycemic control was compared with that of single-drug therapies in each individual patient, the combination was significantly more effective than either metformin or glibenclamide (HbA_1c after treatment, 6.1% ± 1.1% v 7.3% ± 1.4%, and 6.5% ± 0.7% v 7.6% ± 1.5%, respectively, both P < .0001). In conclusion, combination treatment with metformin and sulfonylurea is more effective than these drugs alone in improving glycemic control in type 2 diabetes, while also allowing a reduction of the dosage of each drug.

Section snippets

Subjects

Eighty-eight type 2 diabetic patients (56 males and 32 females) were recruited among the outpatients of our Division. All of them had fasting plasma glucose greater than 140 mg/dL and hemoglobin A_1c (HbA_1c) ≥ 6.3%. Insulin-treated patients and those with ketonuria, concurrent medical illness, severe diabetic complications, or severe cardiovascular, hepatic, renal, respiratory, or pancreatic diseases were excluded from the study. Ten patients (11.4%) had newly diagnosed type 2 diabetes mellitus.

Tolerability

During the first phase of the study, 3 patients, 2 in the metformin group and 1 in the glibenclamide group, dropped out for causes not related to treatment. Another 3 patients dropped out for causes that were considered possibly related to treatment: 1 subject presented marked hyperglycemia with ketonuria, during treatment with metformin 2,000 mg/d; 1 subject reported hypoglycemia, while taking the lowest dose of glibenclamide; and 1 subject, taking the highest dose of glibenclamide +

Discussion

The present controlled study demonstrated that the antihyperglycemic efficacy of combined glibenclamide and metformin was better than treatments with either drug alone. About 40% of patients treated with this combination achieved good glycemic control (ie, HbA_1c ≤ 6%), compared with only 10% to 17% of those treated with metformin or glibenclamide alone. Moreover, many patients given the combined treatment reached HbA_1c levels just above the target value. Remarkably, the mean absolute decline of

References (17)

A.J. Garber et al.
Efficacy of metformin in type II diabetesResults of a double-blind, placebo-controlled, dose-response trial
Am J Med
(1997)
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)
Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34)
Lancet
(1998)
R.A. DeFronzo
Pathogenesis of type 2 (non-insulin dependent) diabetes mellitusA balanced overview
Diabetologia
(1992)
L.S. Hermann et al.
Therapeutic comparison of metformin and sulfonylurea, alone and in various combinations. A double blind controlled study
Diabetes Care
(1994)
W.T. Friedewald et al.
Estimation of the concentration of low density lipoprotein cholesterol in plasma, without use of preparative ultracentrifuge
Clin Chem
(1972)
D.R. Matthews et al.
Homeostasis model assessmentinsulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man
Diabetologia
(1985)
R.R. Henry
Glucose control and insulin resistance in non-insulin-dependent diabetes mellitus
Ann Intern Med
(1996)

There are more references available in the full text version of this article.

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^☆: Supported by Guidotti Laboratories (Pisa, Italy) and by a grant from the Italian Ministry of University and Scientific and Technological Research (MURST 60%).

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Combination treatment with metformin and glibenclamide versus single-drug therapies in type 2 diabetes mellitus: a randomized, double-blind, comparative study☆

Abstract

Section snippets

Subjects

Tolerability

Discussion

Am J Med

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

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

Lancet

Pathogenesis of type 2 (non-insulin dependent) diabetes mellitusA balanced overview

Diabetologia

Therapeutic comparison of metformin and sulfonylurea, alone and in various combinations. A double blind controlled study

Diabetes Care

Estimation of the concentration of low density lipoprotein cholesterol in plasma, without use of preparative ultracentrifuge

Clin Chem

Homeostasis model assessmentinsulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man

Diabetologia

Glucose control and insulin resistance in non-insulin-dependent diabetes mellitus

Ann Intern Med