Gliclazide

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Abstract
Gliclazide is a second generation sulphonylurea oral hypoglycaemic agent used in the treatment of non-insulin-dependent diabetes mellitus (NIDDM). It improves defective insulin secretion and may reverse insulin resistance observed in patients with NIDDM. These actions are reflected in a reduction in blood glucose levels which is maintained during both short and long term administration, and is comparable with that achieved by other sulphonylurea agents. Gradually accumulating evidence suggests that gliclazide may be useful in patients with diabetic retinopathy, due to its haemobiological actions, and that addition of gliclazide to insulin therapy enables insulin dosage to be reduced. Thus, gliclazide is an effective agent for the treatment of the metabolic defects associated with NIDDM and may have the added advantage of potentially slowing the progression of diabetic retinopathy. These actions, together with its good general tolerability and low incidence of hypoglycaemia have allowed gliclazide to be well placed within the array of oral hypoglycaemic agents available for the control of NIDDM. Gliclazide reduces blood glucose levels in healthy volunteers and patients with non-insulin-dependent diabetes mellitus (NIDDM) by correcting both defective insulin secretion and peripheral insulin resistance. Unstimulated and stimulated insulin secretion from pancreatic β-cells is increased following administration of gliclazide, with both the first and second phases of secretion being affected. This occurs via the binding of gliclazide to specific receptors on pancreatic β-cells which results in a decrease in potassium efflux and causes depolarisation of the cell. Subsequently, calcium channels open, leading to an increase in intracellular calcium and induction of insulin release. In addition, gliclazide increases the sensitivity of β-cells to glucose. Gliclazide may have extrapancreatic effects which restore peripheral insulin sensitivity, such as decreasing hepatic glucose production, and increasing glucose clearance and skeletal muscle glycogen synthase activity. These effects do not appear to be mediated by an effect on insulin receptor number, affinity or function. There is some evidence that gliclazide improves defective haemobiological activity in patients with NIDDM. A reduction in platelet adhesion has consistently been observed but the effect of the drug on platelet aggregation is less well defined. Data available regarding the effect of gliclazide on platelet function and production of arachidonic acid metabolites are encouraging but require further substantiation. Limited data suggest that gliclazide may increase levels of tissue plasminogen activator, and reduce levels of free radicals hence preventing vascular damage mediated by these chemical species. These properties appear to be specific actions of the drug on platelets and blood vessel walls, rather than an indirect effect of improved glycaemic control. Data regarding the effect of gliclazide on plasma lipids are inconsistent, with reports of decreases or no change in plasma cholesterol and triglyceride levels after repeated administration. Oral absorption of gliclazide is similar in patients and healthy volunteers, although intersubject variation in time to reach peak plasma concentrations (tmax) and age-related differences in peak plasma concentrations (Cmax) and tmax have been observed. Single-dose oral administration of gliclazide 40 to 120mg results in a Cmax of 2.2 to 8 mg/L within 2 to 8 hours. Cmax and tmax are increased after repeated gliclazide administration, although drug accumulation has not been observed. Steady-state concentrations are achieved after 2 days’ administration of gliclazide 40 to 120mg. Administration of gliclazide with food reduces Cmax and delays tmax. The volume of distribution of gliclazide in healthy volunteers and patients is low (13 to 24L) which may be partially explained by extensive protein binding (85 to 97%). The elimination half-life (t½) of gliclazide after single-dose and repeated oral administration of 40 to 120mg to healthy volunteers and patients is 8.1 to 20.5 hours, although age- and gender-related differences in t½ have been reported. Plasma clearance is approximately 0.78 L/h (13 ml/min). Gliclazide is extensively metabolised to 7 metabolites which are predominantly excreted in the urine, the most abundant urinary metabolite being the carboxylic acid derivative. 60 to 70% of the dose is excreted in the urine and 10 to 20% in the faeces. While very little of the dose recovered in the urine is unchanged parent compound, this represents over 90% of all drug-related material in the plasma. Renal insufficiency has little effect on the pharmacokinetic profile of gliclazide. Gliclazide effectively controls blood glucose levels in patients with NIDDM, with good or excellent control achieved in 62 to 97% of patients. Recent studies have found that gliclazide reduces fasting (by 12 to 62.1%) and postprandial (by 18 to 26.7%) glucose levels and the increase in plasma glucose induced by the glucose tolerance test. These effects are observed in newly diagnosed and previously treated patients, although effects may be reduced in the latter group of patients, and do not appear to be affected by the severity (assessed by pretreatment fasting blood glucose levels) or duration of disease. Good glycaemic control is also indicated by a reduction in glycosylated haemoglobin levels in patients treated with gliclazide. When combined with insulin therapy, gliclazide allows a reduction in insulin dosage which may prove advantageous in reducing macroangiopathic complications of hyperinsulinaemia. Limited data suggest that gliclazide is associated with a low rate of secondary failure. Data from comparative trials have demonstrated that gliclazide is equivalent to other oral hypoglycaemic agents in terms of glycaemic control; however, data accumulating from small scale studies suggest that long term administration of gliclazide may delay the progression of diabetic retinopathy to a greater extent than other sulphonylureas or diet. Nevertheless, these encouraging initial findings require further clarifiaction. Preliminary findings suggest that gliclazide has little or no effect on diabetic nephropathy. It has no consistent effect on bodyweight in obese or non-obese patients. Data derived before 1984 from large patient numbers, and from more recent small scale trials, indicate that gliclazide is well tolerated by most patients. Mild gastrointestinal and central nervous system disturbances, and dermatological effects are occasionally noted, while haematological disorders are rarely observed. Gliclazide is associated with a low incidence of hypoglycaemia. Gliclazide is recommended for the treatment of NIDDM in adults who have failed to respond to dietary restrictions. The daily dose generally required for adequate glycaemic control is 160mg but this may be increased to a maximum of 320 mg/day. Dosages of over 160 mg/day should be administered in 2 doses with morning and evening meals. Gliclazide is contraindicated in insulin-dependent diabetes mellitus, diabetes complicated by ketosis and acidosis, diabetic pre-coma and coma, pregnancy and after severe trauma or infection. Use should be avoided in patients with severe renal and/or hepatic failure. The risk of hypoglycaemia can be reduced by careful monitoring of blood glucose levels and appropriate adjustment of the dosage. In the case of hypoglycaemia due to overdosage, gastric lavage and intravenous administration of hypertonic glucose should be performed. Several metabolic drug interactions may occur which can increase plasma gliclazide concentrations and lead to hypoglycaemia, such as displacement from plasma proteins, reduced clearance and inhibition of metabolism of gliclazide. Induction of metabolism of gliclazide leading to reduced glycaemic control can also occur. Concomitant administration of gliclazide with agents that suppress the manifestations of hypoglycaemia or increase insulin secretion should be avoided. Administration of gliclazide with drugs that increase blood glucose levels should be accompanied by monitoring of blood glucose levels to prevent hyperglycaemia.