Advanced glycolysation end products (AGEs) and the
free radicals generated in this process can both be implicated in the accelerated
atherosclerosis and vascular and prothrombotic microangiopathic changes typified by diabetes. The rate of formation of
free radicals is dependent on the rate of protein glycosylation and therefore the level and duration of
hyperglycemia. Glycation and oxidation are inextricably linked. Increased oxidative stress due to excess
free radical activity may be central to
diabetic vascular disease, since endothelial cell damage,
lipoprotein oxidation, and modification of platelet reactivity and the
arachidonic acid cascade are all properties of
free radicals and their reaction products,
lipid peroxides. The importance of the demonstration of the mechanism whereby
hyperglycemia contributes to vascular damage opens the possibility of scavenging
free radicals, which will have effects independently of improving diabetic control. Over the past 15 years, studies have shown that
gliclazide not only lowers
blood glucose but also confers beneficial effects on the hemorrheologic abnormalities seen in
diabetic vascular disease. Clinically,
gliclazide reduces platelet reactivity and stimulates endothelial
prostacyclin synthesis; it also increases fibrinolysis by its effects on
tissue plasminogen activator. These effects, seen both in vitro and in vivo, are independent of
glycemic control and are not seen with other sulfonylureas. In clinical studies, the beneficial effects of
gliclazide on platelets have been related to a reduction in oxidative stress. This property is due to
gliclazide's
free radical scavenging ability that relates to the unique aminoazabicyclo-
octane ring grafted onto the sulfonylurea. It is fully maintained by the
gliclazide modified-release preparation. In diabetes, therefore, where increased glycation and oxidation are fundamental to the pathogenesis of
diabetic vascular disease, agents such as
gliclazide with its
antioxidant activities may have an enhanced therapeutic role.