Repaglinide--prandial glucose regulator: a new class of oral antidiabetic drugs.

The highest demand on insulin secretion occurs in connection with meals. In normal people, following a meal, the insulin secretion increases rapidly, reaching peak concentration in the blood within an hour. The mealtime insulin response in patients with Type 2 diabetes is blunted and delayed, whereas basal levels often remain within the normal range (albeit at elevated fasting glucose levels). Restoration of the insulin secretion pattern at mealtimes (prandial phase)--without stimulating insulin secretion in the 'postabsorptive' phase--is the rationale for the development of 'prandial glucose regulators', drugs that are characterized by a very rapid onset and short duration of action in stimulating insulin secretion. Repaglinide, a carbamoylmethyl benzoic acid (CMBA) derivative is the first such compound, which recently has become available for clinical use. Repaglinide is very rapidly absorbed (t(max) less than 1 hour) with a t1/2 of less than one hour. Furthermore, repaglinide is inactivated in the liver and more than 90% excreted via the bile. The implications of tailoring repaglinide treatment to meals were examined in a study where repaglinide was dosed either morning and evening, or with each main meal (i.e. breakfast, lunch, dinner), with the total daily dose of repaglinide being identical. The mealtime dosing caused a significant improvement in both fasting and 24-hour glucose profiles, as well as a significant decrease in HbA1c. In other studies, repaglinide caused a decrease of 5.8 mmol x l(-1) in peak postprandial glucose levels, and a decrease of 3.1 mmol x l(-1) in fasting levels with a reduction in HbA1c of 1.8% compared with placebo. In comparative studies with either sulphonylurea or metformin, repaglinide caused similar or improved control (i.e. HbA1c, mean glucose levels) and the drug was well tolerated (e.g. reported gastrointestinal side-effects were more than halved when patients were switched from metformin to repaglinide). A hallmark of repaglinide treatment is that this medication follows the eating pattern, and not vice versa. Hence the risk of developing severe hypoglycaemia (BG < or = 2.5 mmol x l(-1)) in connection with flexible lifestyles should be reduced. This concept was examined in a study in which patients well controlled on repaglinide skipped their lunch on one occasion. When a meal (i.e. lunch) was skipped--so was the repaglinide dose, whereas in the comparative group on glibenclamide the recommended morning and evening doses were taken. Twenty-four per cent of the patients in the glibenclamide group developed severe hypoglycaemia, whereas no hypoglycaemic events occurred in the group receiving repaglinide. However, in long-term studies the overall prevalence of hypoglycaemia was similar to that found with other insulin secretagogues. In summary, current evidence shows that the concept of prandial glucose regulation offers good long-term glycaemic control combined with a low risk of severe hypoglycaemia with missed meals. The concept should meet the needs of Type 2 diabetic patients, allowing flexibility in their lifestyle.