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

Conclusions

Insulin secretagogues have different effects on the insulin secretion, largely conditioned by their individual pharmacokinetic profiles and their actions on the pancreatic ATP-sensitive potassium channels (KATP). For instance, repaglinide is rapidly absorbed from the gut and the time to peak (Tmax) plasma concentration in humans is 30-50 min.[22] By contrast, glibenclamide and glipizide have a much slower absorption with Tmax over 120 min.[23,24] Although all secretagogues lead to inhibition of the KATP channel and depolarization of the -cell with subsequent insulin exocytosis, the duration and magnitude of this effect are variable among the antidiabetic agents. Therefore, repaglinide has been shown to inhibit the KATP channels more potently than glibenclamide in animal models,[25] with a higher stimulation of the insulin release in vitro and in vivo.[26]

We have previously shown that repaglinide increased the insulin secretion rate within 30 min after a solid meal and improved the early phase of secretion in diabetic subjects.[20] Similarly, nateglinide, another member of the meglitinide family, improved the early insulin secretion and reduced the prandial glucose excursions after a liquid meal[21] and after an intravenous glucose challenge.[27] The effects of the sulfonylureas on the early insulin secretion have been studied less. Gliclazide has been shown to increase the early insulin response after an intravenous glucose tolerance test in both nondiabetic and diabetic subjects.[28] In a study using hyperglycemic clamp technique in nondiabetic volunteers, glibenclamide had no effect on the first phase of insulin secretion.[29] Glibenclamide was also less effective than nateglinide in reducing the incremental glucose AUC after a liquid meal.[30]

Our study confirmed that the three test drugs--repaglinide, glipizide, and glibenclamide--were all powerful insulin secretagogues. An increase of >47% (47% glipizide, 54% repaglinide, and 61% glibenclamide) in the total insulin (AUC -15 to 240 min) secretion was noted in diabetic patients when compared with placebo. The diabetic subjects in our study had relatively preserved -cell function, and therefore, a good secretory response was expected. In a real clinical context, however, this group of patients represents a minority of the type 2 diabetic population requiring pharmacological intervention. An extrapolation of these results to all diabetic populations requiring drug treatment should be undertaken with care.

We found that repaglinide, as previously reported,[20] significantly increased the insulin secretion in the early phase both in diabetic and nondiabetic subjects. Interestingly, glipizide was very similar to repaglinide with respect to the effects on the early phase. Moreover, glipizide reached significance against glibenclamide in both groups of subjects, whereas repaglinide was significantly more effective than glibenclamide only in the nondiabetic group.

Due to its pharmacokinetic properties, the effects of repaglinide become apparent within 30 min after intake.[22] Calculated insulin secretion rates in our study confirmed these observations. Repaglinide boosted the secretion significantly more than placebo, as early as 15 min after drug ingestion (0 min on the ISEC profiles). Glipizide, on the other hand, increased the secretion rates slightly later (after the 10-min point in diabetics and after the 20-min point in nondiabetic control subjects) but well before glibenclamide had any significant effect. Our findings were confirmed by a recent study done in rats.[31] Repaglinide and nateglinide stimulated an early increase in the insulin secretion with a subsequent decrease of the prandial glucose excursions after the meal (powdered rodent diet), whereas glibenclamide had no significant effect. Glipizide, on the other hand, had intermediate effects, with less early insulin secretion than repaglinide and nateglinide but still significant decreasing the glucose excursions compared with the vehicle (control).

The differences in the insulin secretion were partly associated with corresponding effects on blood glucose in the nondiabetic subjects. Therefore, repaglinide was more effective than glibenclamide in reducing postmeal glucose peaks (glucose Cmax). Furthermore, whereas both repaglinide and glipizide significantly lowered the peaks compared with placebo (mean reduction 1.1 mmol/l with repaglinide and 0.8 mmol/l with glipizide), glibenclamide had no significant effect. The clinical significance of a decrease in the glucose Cmax of the magnitude shown in our study is unclear. On the other hand, total postprandial glucose exposure may be at least as important as the acute exposure (glucose Cmax) with respect to harmful consequences. Glibenclamide was significantly less effective than repaglinide in decreasing the total glucose AUC in this group of subjects. Glipizide also seemed to have greater effects than glibenclamide on the total glucose AUC, although it did not reach statistical significance on direct comparison. Interestingly, these differences were noted despite significantly more insulin being secreted by glibenclamide in the late phase (AUC -120 to 240 min).

Insulin resistance and reduced -cell insulin secretory capacity are important factors in the pathogenesis of type 2 diabetes. Glucose toxicity accentuates and compounds the secretory defect and also enhances the insulin resistance.[32] The effects of various insulin secretagogues are expected, therefore, to be less evident in the diabetic patients compared with the normal subjects. Our study showed that both repaglinide and glipizide maintained their efficacy on decreasing the postprandial glucose peaks (glucose Cmax) in type 2 diabetic patients with preserved -cell function compared with placebo (mean reduction 1.1 mmol/l with repaglinide and 1.3 mmol/l with glipizide). Again, similar to the effects in nondiabetic subjects, glibenclamide did not significantly impact the peak postprandial glucose. All study drugs, on the other hand, similarly reduced total glucose AUC (AUC -15 to 240 min). The latter contrasts with the observations in nondiabetic population, in which significant differences were noted between repaglinide and glibenclamide. Also, the magnitude of the reduction in the total glucose AUC (AUC -15 to 240 min) versus placebo was smaller in the diabetic population compared with their nondiabetic peers. These data suggest a reduction in the insulin action with an effacement of the interdrug differences in the diabetic subjects, most likely due to increased resistance to insulin in this population.

Our study compared the effects of a single dose of each of the three drugs on the insulin and glucose profiles after a single meal. This scenario, however, could be different in the clinical practice situation. Therefore, whereas repaglinide has a short half-life and the effects of one dose would have entirely disappeared before the next meal, the other two drugs have a long duration of action. The effects of glipizide and glibenclamide on subsequent meals during a 24-h period cannot be assumed to be identical to the observations after a single meal.

In summary, our data show that repaglinide significantly enhanced the early phase of insulin secretion in both nondiabetic and diabetic subjects. This resulted in a significant reduction in the postprandial glucose peaks compared with placebo.

We also showed that glipizide, a second-generation sulfonylurea, has similar effects to repaglinide on the early phase of insulin secretion. Therefore, in both groups of subjects, insulin levels were significantly higher than with glibenclamide. Postprandial glucose peaks were significantly lower compared with placebo.

Glibenclamide had no significant effect on the early phase of insulin secretion and consequently failed to significantly change the postprandial glucose peaks. Its action became evident only on the late phase of insulin secretion. However, total postprandial glucose-lowering effect (AUC -15 to 240 min) was similar to the other two drugs in the diabetic patients.

Received for publication 4 November 2001 and accepted in revised form 26 March 2002.

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