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Majority of patients with type 2 diabetes mellitus who can be initially managed with diet and exercise alone, eventually require at least oral agents if not insulin to maintain control. Numerous studies have referred covertly to the importance of adequate glycemic control in patients with type 2 diabetes mellitus to avoid complications. Strict long-term glycemic control reduces the incidence of complications associated with diabetes. Repaglinide is one of the newer agents that has been developed recently to provide better glycaemic control devoid of the adverse effects often seen with the conventional antidiabetic agents.

Repaglinide - The New Thrapeutic Option In Treatment Of Type 2 Diabetes Mellitus

The highest demand on insulin secretion occurs in connection with meals1. Following a meal, the insulin secretion increases rapidly and reaches peak concentrations in the blood within an hour, in a normal individual . But in patients with type 2 diabetes mellitus the meal time insulin response is blunted and delayed, where as the basal levels often remain within the normal range. ‘Prandial glucose regulators’ are drugs that are characterized by a very rapid onset and short duration of action in stimulating insulin secretion. The restoration of insulin pattern at meal time (prandial phase) – without stimulating insulin secretion in the ‘postabsorptive’ phase is the rationale for the development of these drugs1.

Repaglinide, a carbamoyl methyl benzoic derivative of oral hypoglycaemic agent used for the treatment of type 2 diabetes mellitus, mimics the action of insulin2. It is a new non-sulfonylurea insulin secretagogue agent, the first available from the meglitinide class. Although it is structurally and chemically unrelated to any of the current existing hypoglycaemic agents, mechanism of action of repaglinide closely resembles that of the sulfonylureas3.

Repaglinide has a rapid onset of action and a short half life. It stimulates the release of insulin from the pancreatic beta cells by closing the ATP dependant potassium channel. This action is however mediated through a different binding site than those of sulfonylureas. These characteristics differ from the sulfonylureas in common use which are marked by a longer duration of action3.

Repaglinide is rapidly absorbed from the gastrointestinal tract. Plasma blood levels begin to rise within 15 minutes following oral administration with peak plasma concentrations occurring within 30-40 minutes. Repaglinide is rapidly eliminated with a mean half life of one hour. Food does not delay the rate of absorption but may affect the extent of absorption. It is metabolized almost completely in the liver to inactive metabolites. In subjects with chronic renal failure, repaglinide concentrations were higher and were maintained longer than in healthy subjects and hence should be used in caution in patients with moderate to severe liver impairment. Plasma concentrations have been reported to be higher in patients with pre-existing renal impairment after repeated dosing, hence close monitoring is warranted in these patients3.

The starting dose of repaglinide is 0.5 mg immediately before each meal. Because of its rapid onset of action, patients should be instructed to eat directly following the administration of repaglinide. If a meal is omitted throughout the day, the patient should be asked to skip the corresponding dose of repaglinide to prevent hypoglycaemia. Repaglinide can be titrated to a dose of 4 mg before each meal (maximum 16 mg/ day)3.

Repaglinide – Clinical And Pharmacokinetic Studies

Gomis R has reviewed clinical studies which were performed to establish the effective dose range of repaglinide2. In one placebo controlled study it was observed that, repaglinide (0.25-4.0 mg preprandially) caused a dose-dependent decrease in blood glucose and a non-dose-dependent increase in insulin over 4 weeks (all doses p < 0.001 vs. placebo). In the second study, repaglinide (0.25-8.0 mg preprandially) was titrated over 6 weeks to obtain the optimum response (fasting plasma glucose < 8.9 mmol/L). The titration period was followed by a 12-week dose-maintenance period. At the end of the study, repaglinide had decreased fasting plasma glucose by 3.4 mmol/L (p < 0.05) and 2-h postprandial blood glucose by 5.8 mmol/L (p < 0.001) versus placebo. Glycated haemoglobin (HbA1c) decreased significantly from 8.5% to 7.9% in the repaglinide group and increased significantly from 8.1% to 9.2% in the placebo group (p < 0.001 between groups). In five 1-year, multicentre, randomized, double-blind, phase III trials, repaglinide (0.5-4.0 mg preprandially) was compared with the sulphonylureas glibenclamide, glipizide and gliclazide. Repaglinide was more effective than glipizide at maintaining glycaemic control and was equivalent to glibenclamide and gliclazide on the basis of change in HbA1c. Hypoglycaemic events were reported in 16% of repaglinide-treated patients and 15-20% of sulphonylurea-treated patients. These data indicate that repaglinide monotherapy, with diet and exercise, is effective in patients with Type 2 diabetes2.

A 24-week multicentre, double-blind, randomized, fixed dose trial was carried out in type 2 diabetic patients who received daily pre prandial treatment with placebo (n=75), repaglinide 1 mg (n=140), or repaglinide 4 mg (n=146)4. Repaglinide 1 mg or 4 mg treatment decreased mean fasting plasma glucose values by -47mg/dL or -49mg/dL respectively, while the placebo group had increased fasting plasma glucose value by 19mg/dL. Also at the end of the study, it was observed that in the repaglinide treatment groups the changes in HbA1c from base line values ranged from 1.8 to 1.9 percentage points lower than the placebo group. There were no events of severe hypoglycemia observed during the study. The author concluded that repaglinide was well tolerated in a preprandial fixed-dose regimen of 1 mg or 4 mg, assigned without for clinical parameters4.

In order to investigate subject variability following oral administration of repaglinide, and to determine the relative and absolute bioavailabilities of repaglinide following oral or intravenous administration, two single-centre, open-label, randomized, crossover clinical studies were conducted by Hatrop et al5. The 1st study was conducted in 24 healthy male subjects (aged 18 to 49 years), who received repaglinide 2 mg, as either tablet or oral solution, twice each on 4 separate occasions at least 7 days apart. The 2nd study was conducted in 12 healthy male subjects (aged 18 to 45 years), who received repaglinide 2 mg, either as a tablet or as an intravenous infusion over 15 minutes, once each on 2 separate occasions, with a washout period of 7-10 days. It was observed that in study 1 there was no significant difference between administration of repaglinide 2 mg, in either tablet or oral solution form with regard to intra subject variation in AUC and Cmax. However, the intrasubject variation in tmax and mean residence time (MRT) was significantly (p = 0.001) larger for the tablets than for the oral solution. Intersubject variation (CV) in AUC ranged from 44.7% to 62.1% after oral administration. The relative bioavailability of repaglinide (AUC(tablet)/AUC(oral solution)) was 110% (95% CI, 103%-117%). In study 2 the absolute bioavailability of repaglinide administered as a tablet was 62.5% (95% CI, 49.2%-79.5%) relative to an intravenous infusion of the same dose. The authors concluded that there was no evidence from either study that the tablet formulation led to greater variation in serum profiles of repaglinide. Also it was concluded that repaglinide is rapidly absorbed and eliminated in healthy subjects when administered orally or intravenously under fasting conditions, and that the total availability of repaglinide is similar in the tablet and oral solution formulations, though that the rate of absorption is slower for the tablet formulation5.

The pharmacokinetic profiles of single and multiple dose regimens of repaglinide were evaluated in 12 elderly subjects of average age 65.5 years with type 2 diabetes for an average duration of 9.6 years6. The mean serum repaglinide concentration peaked at a higher level after multiple dosing compared to a single dose, but declined similarly after both dosing regimens. Mean log (AUC) values for repaglinide were higher after multiple dosing compared to values obtained after a single dose. The values for log (Cmax) and Tmax after each dosing were not significantly different. The mean T1/2 of repaglinide after multiple dosing was 1.7 hours. The low T1/2 for repaglinide indicated that it was rapidly eliminated from the body in elderly patients. The study demonstrated that repaglinide was rapidly eliminated from the body, did not accumulate and was well tolerated in elderly patients6.

Conclusion:

Repaglinide, thus is a fast acting cell mediated prandial glucose regulator – the first of a new chemical class of oral antidiabetic agents. Although its action is very similar to the sulfonyureas, it possesses different characteristics from these agents because it has a short duration of action. When taken in a preprandial dosing regimen it stimulates insulin secretion at mealtimes, avoiding unnecessary stimulation of the cells during fasting periods. Advantages of repaglinide may include greater reductions in post prandial glucose concentrations, fewer hypoglycemic episodes as a result of omitted meals, and greater flexibility of dosage regimens.

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