Repaglinide

Abstract

Repaglinide, a carbamoylmethyl benzoic acid derivative, is the first of a new class of oral antidiabetic agents designed to normalise postprandial glucose excursions in patients with type 2 diabetes mellitus. Like the sulphonylureas, repaglinide reduces blood glucose by stimulating insulin release from pancreatic β-cells, but differs from these and other antidiabetic agents in its structure, binding profile, duration of action and mode of excretion. In clinical trials of up to 1-year’s duration, repaglinide maintained or improved glycaemic control in patients with type 2 diabetes mellitus. In comparative, 1-year, double-blind, randomised trials (n = 256 to 544), patients receiving repaglinide (0.5 to 4mg before 3 daily meals) achieved similar glycaemic control to that in patients receiving glibenclamide (glyburide) ≤15 mg/day and greater control than patients receiving glipizide ≤15 mg/day. Changes from baseline in glycosylated haemoglobin and fasting blood glucose levels were similar between patients receiving repaglinide and glibenclamide in all studies; however, repaglinide was slightly better than glibenclamide in reducing postprandial blood glucose in 1 short term study (n = 192). Patients can vary their meal timetable with repaglinide: the glucose-lowering efficacy of repaglinide was similar for patients consuming 2, 3 or 4 meals a day. Repaglinide showed additive effects when used in combination with other oral antidiabetic agents including metformin, troglitazone, rosiglitazone and pioglitazone, and intermediate-acting insulin (NPH) given at bedtime. In 1-year trials, the most common adverse events reported in repaglinide recipients (n = 1228) were hypoglycaemia (16%), upper respiratory tract infection (10%), rhinitis (7%), bronchitis (6%) and headache (9%). The overall incidence of hypoglycaemia was similar to that recorded in patients receiving glibenclamide, glipizide or gliclazide (n = 597) [18%]; however, the incidence of serious hypoglycaemia appears to be slightly higher in sulphonylurea recipients. Unlike glibenclamide, the risk of hypoglycaemia in patients receiving repaglinide was not increased when a meal was missed in 1 trial. In conclusion, repaglinide is a useful addition to the other currently available treatments for type 2 diabetes mellitus. Preprandial repaglinide has displayed antihyperglycaemic efficacy at least equal to that of various sulphonylureas and is associated with a reduced risk of serious hypoglycaemia. It is well tolerated in a wide range of patients, including the elderly, even if a meal is missed. Furthermore, glycaemic control is improved when repaglinide is used in combination with metformin. Thus, repaglinide should be considered for use in any patient with type 2 diabetes mellitus whose blood glucose cannot be controlled by diet or exercise alone, or as an adjunct in patients whose glucose levels are inadequately controlled on metformin alone. Repaglinide is a carbamoylmethyl benzoic acid derivative. Like the sulphonylureas, repaglinide acts by stimulating release of insulin from the β-cells of the pancreas. There are some notable differences between repaglinide and the sulphonylureas: repaglinide acts on a unique receptor site on the β-cell membrane and inhibition of ATP-sensitive potassium channels appears to be the sole mechanism through which repaglinide stimulates insulin secretion. Furthermore, in vitro experimentation has indicated that, unlike sulphonylureas, repaglinide does not stimulate insulin secretion in the absence of glucose, does not inhibit glucose-stimulated proinsulin biosynthesis in isolated rat β-cells and is able to overcome the metabolic stress induced by 2,4-dinitrophenol. In in vitro and in vivo studies, repaglinide displayed greater insulinotropic and hypoglycaemic potency than glibenclamide (glyburide) and glimepiride, and had a faster onset of action. In patients with type 2 diabetes mellitus, preprandial repaglinide causes a dose-related increase in insulin levels and a corresponding decrease in postprandial glucose levels. In 1 study (n = 143), blood glucose levels were significantly reduced in patients receiving preprandial repaglinide (3 times daily) versus those receiving placebo over 4 weeks of treatment. In a dose-regimen study, 3-times-daily preprandial administration of repaglinide was shown to be more effective at lowering blood glucose than the same total dosage given twice daily. In 2 further studies, patients with type 2 diabetes mellitus receiving repaglinide were able to miss a meal or add an extra meal (and the corresponding repaglinide dose) without significantly affecting blood glucose levels. Repaglinide is rapidly and completely absorbed, with maximum plasma concentrations (C_max) occurring ≈1 hour after oral administration. Absolute oral bioavailability of repaglinide ranged from 56 to 63% and the volume of distribution was between 24 and 3 1L in healthy volunteers; repaglinide is >98% bound to human serum albumin. Repaglinide C_max and area under the plasma concentration-time curve increased in a dose-dependent fashion in patients with type 2 diabetes mellitus receiving total daily doses ranging from 0.125 to 16mg; no accumulation of repaglinide was noted over 4 weeks of treatment. Repaglinide is rapidly cleared from the bloodstream with a terminal elimination half-life of ≤1 hour and is extensively metabolised in the liver by cytochrome P450 (CYP) to inactive metabolites. The primary route of elimination of repaglinide and its metabolites is via biliary-faecal excretion. In a study of radiolabelled repaglinide, 90% of a single 2mg oral dose of 14C-repaglinide was recovered in the faeces (<2% was excreted unchanged) with 8% excreted in urine within 96 hours after administration. Mild to moderate renal impairment (creatinine clearance ≥30 ml/min) and advanced age had little influence on the...