Glibenclamide: A Review

Summary

Glibenclamide (glyburide, USAN)² is a new sulphonylurea oral hypoglycaemic agent for the control of non-ketotic maturity-onset diabetes mellitus.

Glibenclamide is active at low dosage, and the administered dose is therefore small (i.e. 5 mg glibenclamide is approximately equivalent to 1 g tolbutamide or glymidine, to 0.5 g aceto-hexamide, or to 0.25 g chlorpropamide or tolazamide). Its range of therapeutic effect is that of the sulphonylureas and it may be used in a single morning dose. Initial studies indicate that it is at least as well tolerated as tolbutamide.

Animal pharmacological studies show that, like the other sulphonylureas, glibenclamide acts by stimulating the production and release of insulin from pancreatic islets. Its action in diabetic patients is therefore dependent upon the presence of functioning β-cells in the islets of Langerhans.

There is some evidence which suggests that glibenclamide effects a qualitatively more powerful stimulus to insulin secretion than tolbutamide.

Human pharmacological studies suggest that glibenclamide may possibly have some mechanism of action (as yet undefined) differing from that of other oral sulphonylureas. It effects a more intense and prolonged stimulation of insulin release than tolbutamide. Although higher plasma insulin levels can be attained with glibenclamide than with tolbutamide these were not reflected in greater falls in blood glucose. This lack of correlation between percentage changes in blood sugar and plasma insulin suggests that a more complex mechanism than peripheral insulin effects may be responsible for the decrease in blood sugar. In fasting diabetic patients the mean plasma insulin level increases about two-fold, and with food the mean plasma insulin level increases about four-fold. The maximum reduction in blood glucose level in newly diagnosed diabetic patients is usually about 35 % and reduced levels can persist for up to 15 hours following a single oral dose.

About half of an oral dose is absorbed and peak blood levels are attained two to four hours after administration. There was no evidence of cumulation in animal experiments. Glibenclamide is distributed in various organs with highest concentrations being found in the kidney. It is highly protein bound. At least three metabolites have been identified and two identified as hydroxylated compounds; they have no significant hypoglycaemic activity in the concentration present in the blood and are rapidly eliminated. The hydroxylated metabolites are excreted in the faeces and urine and the unabsorbed unchanged drug only in the faeces. The mean plasma half-life is about five hours.

Clinical studies reporting on the use of glibenclamide in diabetic patients are reviewed below and demonstrate the overall therapeutic usefulness of the drug and show that its range of effect is that of the sulphonylureas. Any superiority over other sulphonylureas has not yet been demonstrated.

Although some of the trials have made an indirect comparison with previously used sulphonylureas, there has been only one controlled trial published to date which compares alternating periods of glibenclamide with another sulphonylurea hypoglycaemic drug. This trial did not show any difference in control between the two active treatments. Results of this and other trials suggest that glibenclamide is at least as effective as full doses of tolbutamide and probably as effective as chlorpropamide. The secondary failure rate with glibenclamide has not yet been fully assessed since most of the trials reported to date average only 10 to 12 months of treatment.

Glibenclamide has been successfully used in newly diagnosed cases of maturity-onset diabetes and in patients who could not be controlled by adequate dietary measures alone. It has been successful in most patients who had been previously stabilised on other oral hypoglycaemic drugs. Successful control has been obtained in a few patients who were primary or secondary failures to other oral drugs.

To regain control after a secondary failure, glibenclamide has been successfully combined in approximately 50 % of cases with a biguanide hypoglycaemic drug. It was, however, relatively ineffective when used alone in patients who previously were not controlled by combined sulphonylurea and biguanide therapy.

As with other sulphonylureas, certain patients on small doses of insulin have been carefully and successfully transferred to glibenclamide.

Initial dosage is 2.5 to 5 mg and maintenance dosage has ranged from 2.5 mg to 40 mg daily, but the majority of patients who have been well controlled on glibenclamide needed 10 mg daily or less; as a single dose taken with or immediately after breakfast. Increasing the dose beyond 15 to 20 mg did not usually produce an increased effect, but the addition of a biguanide did, and resulted in improved control in many patients. When the daily dose exceeds 10 mg, it is recommended that the total daily dose be given in two divided doses; one dose with breakfast and the other with the evening meal. When glibenclamide is taken as a single morning dose, variations in blood-glucose over a 24-hour period have been shown to be small.

Side-effects have been infrequent. Allergic skin reactions have occurred in a few patients, but some patients have continued treatment with glibenclamide and the rash disappeared. Some patients who had previously had an allergic reaction to other sulphonylureas have had no reaction from glibenclamide. Gastro-intestinal upsets appear to occur less frequently than with tolbutamide. Transient leucopenia and thrombocytopenia have been noted.

Hypoglycaemic reactions have been associated usually with a high initial dose of the drug and with initial therapy in cases of newly diagnosed diabetes, older patients particularly. Hypoglycaemia is not prolonged and can be controlled by appropriate therapeutic measures. However, two case reports of severe hypoglycaemic reactions illustrate the need for caution in commencing use of glibenclamide in elderly patients. Important drug interactions may occur with glibenclamide, as with other sulphonylureas, and readers are referred to the relevant sub-heading.