Repaglinide - Prandial glucose regulator: A new class of oral antidiabeticdrugs

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 insul in response in patients with Type 2 diabetes is blunted and delayed, wherea s basal levels often remain within the normal range (albeit at elevated fas ting glucose levels). Restoration of the insulin secretion pattern at mealt imes (prandial phase)-without stimulating insulin secretion in the 'postabs orptive' phase-is the rationale for the development of 'prandial glucose re gulators', drugs that are characterized by a very rapid onset and short dur ation of action in stimulating insulin secretion. Repaglinide, a carbamoylm ethyl benzoic acid (CMBA) derivative is the first such compound, which rece ntly has become available for clinical use. Repaglinide is very rapidly abs orbed (t(max) less than 1 hour) with a t(2) of less than one hour. Furtherm ore, repaglinide is inactivated in the liver and more than 90% excreted via the bile. The implications of tailoring repaglinide treatment to meals wer e examined in a study where repaglinide was dosed either morning and evenin g, or with each main meal (i.e. breakfast, lunch, dinner), with the total d aily dose of repaglinide being identical. The mealtime dosing caused a sign ificant improvement in both fasting and 24-hour glucose profiles, as well a s a significant decrease in HbA(1c). In other studies, repaglinide caused a decrease of 5.8 mmol.l(-1) in peak postprandial glucose levels, and a decr ease of 3.1 mmol.l(-1) in fasting levels with a reduction in HbA(1c) of 1.8 % compared with placebo. In comparative studies with either sulphonylurea o r metformin, repaglinide caused similar or improved control (i.e. HbA(1c), mean glucose levels) and the drug was well tolerated (e.g. reported gastroi ntestinal side-effects were more than halved when patients were switched fr om metformin to repaglinide). A hallmark of repaglinide treatment is that t his medication follows the eating pattern, and not vice verse. Hence the ri sk of developing severe hypoglycaemia (BG less than or equal to 2.5 mmol.l( -1)) in connection with flexible lifestyles should be reduced. This concept was examined in a study in which patients well controlled on repaglinide s kipped their lunch on one occasion. When a meal (i.e. lunch) was skipped-so was the repaglinide dose, whereas in the comparative group on glibenclamid e the recommended morning and evening doses were taken. Twenty-four per cen t of the patients in the glibenclamide group developed severe hypoglycaemia , whereas no hypoglycaemic events occurred in the group receiving repaglini de. However, in long-term studies the overall prevalence of hypoglycaemia w as similar to that found with other insulin secretagogues. In summary, curr ent evidence shows that the concept of prandial glucose regulation offers g ood long-term glycaemic control combined with a low risk of severe hypoglyc aemia with missed meals. The concept should meet the needs of Type 2 diabet ic patients, allowing flexibility in their lifestyle. (C) 1998 John Wiley & Sons, Ltd.