Comparison of the Effects of Three Insulinotropic Drugs on Plasma Insulin Levels After a Standard Meal

Lawrence S. Cozma, MRCP, Stephen D. Luzio, PHD, Gareth J. Dunseath, BSC, Kirsten W. Langendorg, MSC, Thomas Pieber and David R. Owens, MD, FRCP

Disclosures

Diabetes Care. 2002;25(8) 

In This Article

Results

All 24 subjects who were recruited completed the study. Demographic and glycemic parameters of the study population are shown in Table 1 . The only significant differences between the diabetic population and the control group were in the fasting glucose and the HbA1c levels.

The AUC -15 to 240 min for glucose, insulin, and C-peptide was significantly different with all three secretagogues versus placebo in both groups of subjects. Maximum insulin and C-peptide concentrations (Cmax) were significantly higher with all active drugs compared with placebo. Glucose Cmax, however, was decreased significantly only by repaglinide and glipizide. In addition, in nondiabetic subjects, the AUC -15 to 240 min for glucose was smaller, and glucose Cmax was significantly lower with repaglinide compared with glibenclamide. The mean concentration-time profiles for glucose and insulin are shown in Figs. 1 and 2.

Mean concentration-time profiles of glucose in type 2 diabetic and nondiabetic subjects.

Mean concentration-time profiles of insulin in type 2 diabetic and nondiabetic subjects.

There was no difference between the active treatment groups in the total insulin (AUC -15 to 240 min) secreted over 4 h after the meal, confirming the equivalence between the doses used in the study with respect to overall prandial insulin secretion. There were nonsignificant differences in the Tmax for insulin between the active treatment and placebo in both groups. The difference between glibenclamide and repaglinide in the control group became significant, suggesting that glibenclamide has a delayed effect on the pancreatic secretion. Tmax for C-peptide was increased by all secretagogues compared with placebo, but the only significant difference was noted with glibenclamide in nondiabetic subjects. The difference between glipizide and glibenclamide was also significant in these subjects, suggesting that the latter has a more protracted action on the -cell than glipizide.

Separate analysis of the insulin secretion over the first 30 min (AUC -15 to 30 min) and the last 120 min (AUC 120-240 min) after the meal is shown in Table 2 .

There were clear interdrug differences in the early-phase insulin output (AUC -15 to 30 min). Therefore, in the diabetic subjects, insulin AUC -15 to 30 min was significantly higher with both repaglinide (+37%) and glipizide (+47%) compared with placebo. In addition, glipizide reached significance against glibenclamide. Glibenclamide had only a minor effect on this phase of secretion (3% increase versus placebo).

In the nondiabetic group, repaglinide increased the early-phase -cell secretion by ~61% compared with placebo (P < 0.02) and reached significance against glibenclamide. Glipizide increased the secretion by ~34% (not significant versus placebo) but reached significance compared with glibenclamide.

Glibenclamide, but not the other two drugs, significantly increased the insulin output in the late phase in nondiabetic subjects (142% increase relative to placebo). These effects were notably higher compared with repaglinide in this group of subjects. In type 2 diabetic subjects, all three drugs significantly increased the insulin secretion in the late phase compared with placebo: glipizide by ~52%, repaglinide by 57%, and glibenclamide by 93%.

The rates of insulin secretion (ISR) were reconstructed from plasma C-peptide concentration and demographic data, using ISEC (Insulin SECretion) software developed by Hovorka et al. (version 3.4a, 1994). This software package allows an estimation of the pancreatic insulin secretion (before hepatic extraction) by using the point-area deconvolution method in a mathematical model. The temporal profiles relative to placebo in both groups of subjects are presented in Fig. 3.

Mean estimated insulin secretion rates relative to placebo for the first 60 min after the meal. Significant difference against placebo: P < 0.05 (†), P < 0.01 (*). Significant difference against glibenclamide: P < 0.05 (‡), P < 0.01 (‡).

Secretion rates in the diabetic group were significantly higher with repaglinide and glipizide compared with placebo at any time point beginning with 10 min after consuming the meal (repaglinide from 0 min). Glibenclamide, however, became significant only 30 min after the meal. Moreover, both repaglinide and glipizide were significantly more potent than glibenclamide at the 20- and 30-min time points; glipizide was higher than glibenclamide, even at the 40-min point.

In the nondiabetic subjects, the secretion rates with repaglinide became significant against placebo after the 0-min time point. Glipizide reached significance versus placebo slightly later than repaglinide (after 20 min). Furthermore, both drugs were significantly more potent than glibenclamide between 30 and 50 min after the meal; repaglinide was still notably higher than glibenclamide at the 60-min time point.

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