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Gliclazide

A Preliminary Review of its Pharmacodynamic Properties and Therapeutic Efficacy in Diabetes Mellitus

  • Drug Evaluation
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Summary

Synopsis: Gliclazide1 is a ‘second generation’ oral hypoglycaemic agent. The particular interest with this drug is that it has shown certain effects on the blood for which it is hoped there may be some clinical benefit in diabetic angiopathies. Both in animal and human studies it has demonstrated a reduction in platelet adhesiveness and aggregation, whilst possible enhancement of platelet metabolism, reduction of coagulant factors, as well as increased fibrinolytic activity, are still being investigated. Initial trials have suggested that gliclazide therapy may reverse or at least slow down the progression of diabetic retinopathy. However, a few additional well-designed long term controlled studies are needed to confirm these findings, and to clarify whether any beneficial effect on diabetic retinopathy is unique to gliclazide or also occurs with other oral hypoglycaemic drugs.

Both newly diagnosed maturity onset diabetics as well as those previously treated with sulphonylureas respond well to gliclazide therapy. In the small comparative studies which have been reported, gliclazide was of comparable efficacy to other oral hypoglycaemic agents.

Gliclazide has been well tolerated by most patients, the most frequently reported side effects being gastrointestinal in nature which occurred in less than 2% of patients.

Pharmacodynamic Studies: The ability of gliclazide to lower blood glucose concentrations has been demonstrated in various animals, as well as in a small number of healthy subjects and in patients with maturity onset diabetes. On a weight basis, gliclazide was many times more potent than tolbutamide, the relative potency varying between species (e.g. potency ratio of about 1 : 8 in rabbits and 1 : 27 in rats). As with other sulphonylurea oral hypoglycaemic drugs, gliclazide was not active in pancreatectomised animals, suggesting it has a direct action on the pancreas (postulated to be mediated by increased calcium uptake in pancreatic islet cells) to increase insulin secretion. Single doses of gliclazide 80mg in diabetic patients have brought about significant decreases in both fasting and postprandial blood glucose levels, the effect being slightly less prolonged than that of glibenclamide 5mg which produces more abrupt changes in blood glucose concentrations, whilst tolbutamide 500mg produces a milder and relatively less prolonged effect. Therapy with gliclazide has produced decreases in plasma cholesterol, triglyceride and fatty acid levels, with at least 1 of the decreased levels reaching a statistically significant value at some stage during the administration of the drug. Gliclazide has demonstrated some effects on the blood in both animal and human studies which it is postulated may limit the progression of diabetic or other angiopathies. They include a reduction of platelet adhesiveness and aggregation, whilst possible enhancement of platelet metabolism and anticoagulant factors as well as increased fibrinolytic activity are being investigated.

Pharmacokinetics: Gliclazide has been consistently well absorbed after oral administration in animals, but peak plasma concentrations (2.8 and 3.9 mg/L) after a dose of 80mg, as well as time to reach peak concentrations (0.4 and 4.8 hours), have shown greater variability in studies in man. Its relatively low volume of distribution (15.9 to 17.4L) suggesting only limited tissue distribution may in part be explained by its extensive binding to plasma albumin (85 to 97%). In common with other sulphonylureas, gliclazide is apparently metabolised to either hydroxylated metabolites or N-oxygenated compounds and the corresponding alcohol and carboxylic acid. 60 to 70% of a dose is eliminated in the urine, with less than 20% of this as unchanged drug, while a further 10 to 20% of a dose is eliminated in the faeces. In contrast, 90% of all drug-related material in the plasma is unchanged gliclazide. The elimination half-life of gliclazide may vary between sexes, with values for males of around 8 hours and for females of 11 hours.

Therapeutic Trials: In open trials, 60 to 100% of maturity onset non-ketosis-prone diabetes mellitus patients achieved satisfactory control of their blood glucose levels on gliclazide therapy. These patients included those who were newly diagnosed as well as those previously treated with other sulphonylurea drugs. However, as would be expected, gliclazide was not effective in insulin dependent diabetics, in whom substitution of insulin with gliclazide resulted in loss of blood glucose control while addition of gliclazide therapy conferred no additional benefit compared with insulin alone. Combined therapy involving gliclazide and a biguanide was sometimes effective in patients resistant to a sulphonylurea alone. In mostly small comparative studies, gliclazide was generally comparable to other oral hypoglycaemic drugs in terms of overall quality of control of blood glucose levels. In patients with diabetic retinopathy, gliclazide therapy for periods up to several years resulted in a significantly lower rate of deterioration of disease compared with control groups treated with another hypoglycaemic agent, whilst overall stability in the progress of the disease during gliclazide therapy was noted in shorter term open studies. Gliclazide did not significantly alter renal function in patients with diabetic nephropathy.

Side Effects: Gliclazide is well tolerated by most patients. The most frequently reported side effects have been gastrointestinal upset such as abdominal pain, nausea, vomiting, dizziness, skin reactions and symptoms of hypoglycaemia, the latter in most cases resulting from overdosage or inadequate diet rather than an adverse effect of the drug.

Dosage and Administration: The recommended adult dose in maturity onset non-ketotic diabetes mellitus is from 80 to 240mg daily. Maximum doses of 320mg have been administered in an attempt to achieve control of blood sugar concentrations and should this fail, addition of a biguanide may be successful in some cases, provided ketosis has not developed.

Gliclazide, like other sulphonylurea drugs, is indicated only where diet fails to control hyperglycaemia and glycosuria. It has no place in the treatment of juvenile diabetes or where there is severe metabolic decompensation with acidosis.

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  1. ADIS Drug Information Services, P.O. Box 34-030, Birkenhead, Auckland 10, New Zealand

    B. Holmes, R. C. Heel, R. N. Brogden, T. M. Speight & G. S. Avery

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  1. B. Holmes
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Various sections of the manuscript reviewed by: A.L. Bloom, Department of Haematology, University Hospital of Wales, Cardiff, Wales; R.H. Jones, Andover, England; K. Kobayashi, Department of Clinical Pathology and Clinical Laboratory, Hyogo College of Medicine, Nishinomiya, Japan; F.X. Lesbre, Lyon, France; A. Marble, Joslin Diabetes Center, Boston, Massachusetts, USA; R.C. Paton, Department of Medicine, University of Leeds, Leeds, England; L.I. Rose, Division of Endocrinology and Metabolism, Hahnemann University, Philadelphia, USA; C.Th. Smit Sibinga, Red Cross Blood Bank Groningen-Drenthe, Groningen, The Netherlands; D.F. Violi, Institute of Clinical Medicine, University of Rome, Rome, Italy; J.R.B. Williams, Lister Hospital, Steverage, England.

‘Diamicron’ (Servier); ‘Glimicron’ (Dai Nippon).

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Holmes, B., Heel, R.C., Brogden, R.N. et al. Gliclazide. Drugs 27, 301–327 (1984). https://doi.org/10.2165/00003495-198427040-00002

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