Oral antidiabetic drugs: an overview.

Chronic hyperglycaemia, i.e. impaired glucose tolerance (IGT) and NIDDM, conveys a great risk of macrovascular disease. Both insulin resistance and impaired insulin secretion seem necessary to establish chronic hyperglycaemia, and untreated it appears to promote and worsen both insulin resistance and impaired insulin secretion. The prevention and treatment of chronic hyperglycaemia should include measures directed at both derangements, and the therapeutic goal should be normoglycaemia. As this is rarely achieved by non-pharmacologic treatment alone, addition of oral antidiabetic drugs are often indicated. Their ability to attain euglycaemia is greater the earlier they are employed, but they should never be introduced until after optimization of non-pharmacologic measures. Delayed early insulin response to glucose or a meal always accompanies chronic hyperglycaemia and is not normalized by non-pharmacologic treatment. This justifies the use of insulin-releasing drugs with a rapid onset of action, e.g. the sulphonylurea glipizide. The non-sulphonylureas, repaglinide and A-4166, are even more rapid- and also short-acting, representing a reduced risk of long-lasting, and hence dangerous, hypoglycaemia. Continuous exposure to high concentrations of sulphonylureas may downregulate beta-cell sensitivity. Maximum doses are much lower than previously assumed. The most effective improvers of insulin action seem to be the thiazolidinediones, but they are not yet marketed. Metformin is the only globally available drug for improving insulin action. It is as antihyperglycaemic as sulphonylureas but does not cause hyperinsulinaemia, weight increase or hypoglycaemia. The risk of lactic acidosis can be minimized by avoiding metformin in subjects with renal impairment. Combined treatment with sulphonylurea and metformin can be highly effective even in advanced NIDDM.