Comparative Effects of Repaglinide Versus Glibenclamide on Glycemic Control in Newly Diagnosed Type 2 Diabetic Patients

Repaglinide is an oral prandial glucose regulator indicated for treatment of type 2 diabetic patients through its mechanism in improving first phase insulin secretion which can lower postprandial plasma glucose. To compare the effects of repaglinide versus glibenclamide on glycemic control in newly diagnosed type 2 diabetic patients. Twenty-four recently diagnosed diabetic patients were enrolled in this non-randomized clinical trial. They were classified into two groups, 12 patients received repaglinide and 12 patients received glibenclamide. Fasting plasma glucose (FPG), 2hour postprandial plasma glucose (2h. PPG) and glycated hemoglobin (HbA1c) were measured at the baseline and after 8 weeks follow up. Repaglinide decreased 2h. PPG significantly more than glibenclamide after 8 weeks without significant differences in reducing FPG and HbA1c between both treatment groups after 8 weeks. Repaglinide can be considered as an ideal agent in controlling postprandial hyperglycemia as a monotherapy or in combination with other oral hypoglycemic agents. Repaglinide, glibenclamide, postprandial hyperglycemia.


Introduction
Type-2 diabetes mellitus (T2DM) is a heterogeneous disorder characterized by two interrelated metabolic defects: insulin resistance coupled with impaired insulin secretion by β-cells in the pancreas (1) .It's a multifactorial disease in which environmental factors appear to interact with multiple genetic variants in modulating the predisposition to the disease (2) .Fasting plasma glucose (FPG) is the plasma glucose level measured after an extended period (8-12 hours) with no caloric intake (3) .FPG levels ≥ 126mg/dl (7mmol/L) on two separate occasions constitute a diagnosis of diabetes (4).It is the measure preferred by the American Diabetes Association (ADA) for the diagnosis of diabetes because of its ease, relatively low cost, and extensive standardization (3) .Postprandial plasma glucose (PPG) is the plasma glucose level measured 2hour after eating (5) .A plasma glucose level ≥ 200mg/dl (11.1mmol/L) 2h. after meal is diagnostic of diabetes (4) .Although the use of FPG is simpler and more reproducible, the omission of the 2-h.PG will miss a proportion of diabetic subjects who have normal FPG but elevated 2-h.PG levels (6) .Recent studies have shown that mealtime hyperglycemia may be a more accurate predictor of HbA1c levels and of cardiovascular mortality than fasting hyperglycemia (7)   .Glycated hemoglobin (HbA1c) expressed, as the percentage of adult hemoglobin that is glycated, is the most widely used measure of chronic glycemia (8) .HbA1c is the gold standard for assessing glucose homeostasis and it is an integration of both fasting and postprandial glucose variations over a 2-3 months period (9) .Repaglinide is a novel, fast acting, oral prandial glucose regulator indicated for the treatment of T2DM.It is the first member of the carbamoylmethy benzoic acid chemical family to be used in a clinical setting representing a new chemical class of insulin secretagogues (10) .It was approved by FDA in 1997 and it's developed for use as a prandial glucose regulator in a flexible mealtime dosing schedule ('one meal, one dose, no meal, no dose') (11) .Repaglinide increases the amount of insulin released in a natural and physiological pulsatile pattern and is not effective in the absence of functioning β-cells (12)   .Thus, repaglinide is the first insulin secretagogue developed to target postprandial hyperglycemia and its rapid onset of action and short-lived hypoglycemic effect, makes it an ideal agent for controlling postprandial hyperglycemia (13,14) .The aim of the present work is to compare the effects of repaglinide and glibenclamide on glycemic control in newly diagnosed type 2 diabetic patients at the baseline and after 8 weeks follow-up of repaglinide monotherapy.

Patients and methods
This study was carried out with ethical and scientific approval of the regional research committee of Mosul health administration, and was conducted at Al-Wafaa Center of Diabetes Management and Research in Mosul during the period from 1 st of December 2010 to 10 th of April 2011.Nonrandomized clinical trial follow-up study design was adopted to achieve the aims of the current study.Twentyfour diabetic patients were enrolled in this study classified into 2 groups: 1. Group (1)  (15) which is highly specific for D-glucose, using a kit supplied from Randox (U.K.).HbA1c was measured in whole blood sample by ion-exchange resin quantitative colorimetric determination (16) , using a kit supplied from Stanbio (USA).

Statistical analysis
paired t-test was used to compare the results of various biochemical parameters between the diabetic patients before and after therapy.Analysis of Variance (ANOVA) and Duncan multiple range test were used to compare the results of various biochemical parameters between different groups.P-value ≤0.05 was considered to be statistically significant.

Table (3): Comparative effects of repaglinide versus glibenclamide on glycemic control after 8 weeks
Different litters horizontally indicate significant difference.
By comparing the results of FPG, 2h.PPG and HbA1c between the studied groups after 8 weeks follow up period; there was no significant difference in FPG and HbA1c between the two groups and a significant difference in 2h.PPG was observed between patients on repaglinide therapy after completing the follow up period against patients on glibenclamide treatment.

Discussion
The present study showed that both repaglinide and glibenclamide lowered FPG to a similar degree without significant difference between the both groups.These results were in  (17) , Abbatecola et al. (18) and Yngen et al. (19).While Esposito et al. (20) found that glibenclamide lowered FPG more than repaglinide.In contrast, Papa et al (21) stated that repaglinide lower FPG significantly more than glibenclamide.As repaglinide is absorbed faster and has a shorter plasma half-life than glibenclamide, the morning FPG level in patients who received repaglinide was expected to be slightly higher than in those who received glibenclamide, owing to the long period since last dose.In fact, FPG did not differ significantly between the two treatment groups.Regarding postprandial hyperglycemia, the present study revealed that patients treated with repaglinide had a lower mean 2h.PPG level than patients who had received glibenclamide with significant difference between the two groups at the end of this trail.This was in agreement with Cozma et al (22) whose study showed that repaglinide maintained their efficacy on decreasing the postprandial glucose peaks in T2DM patients but glibenclamide does not significantly impact the peak postprandial glucose, similarly, this finding was consistent with other studies (23,24,25,17) .This result may be explained by the rapid absorption of repaglinide which ensures maximum effects during meal-related glucose absorption.

Glibenclamide
In diabetes, the postprandial phase is characterized by a rapid and large increase in blood glucose levels, and the possibility that these postprandial "hyperglycemic spikes" may be relevant to the pathophysiology of late diabetes complications, in particular cardiovascular complications (26).Therefore, treatment with repaglinide, in the long term, may reduce the risk of both micro and macrovascular complications in diabetic patients (27) .
Long glycemic control, assessed by HbA1c, was found to be clinically equivalent in the repaglinide and glibenclamide groups, with no significant difference between the two treatment groups at the end of the study.In the repaglinide group, the mean HbA1c value decreased from 9.10% at the baseline to 7.50% at the end of the study, compared with a decrease from 8.64% to 7.75% in the glibenclamide group.This result was differing from that reported by Papa et al (21) who stated that repaglinide decreases HbA1c significantly more than glibenclamide in elderly type 2 diabetic patients following 24 weeks of treatment and in the 16-week study Moses et al (28) found that repaglinide produced significant decreases in HbA1c in type 2 diabetic patients.This difference between these studies and the present study could be attributed to the long duration of follow up and large sample size in the above two studies.The present study conclude that repaglinide is an insulin secretagogue developed to target postprandial hyperglycemia and its rapid onset of action and short-lived hypoglycemic effect, makes it an ideal agent for controlling postprandial hyperglycemia, thus it is a promising new drug in the treatment of T2DM, as a monotherapy or in combination with other hypoglycemic agents.
reported byManzella et al.