Abstract and Introduction
Objective: To compare the effects of repaglinide, glipizide, and glibenclamide on insulin secretion and postprandial glucose after a single standard 500-kcal test meal.
Research Design and Methods: A total of 12 type 2 diabetic patients with early diabetes (mean HbA1c of 6.1%) and 12 matched control subjects were enrolled in this randomized, double-blind, crossover trial. Subjects received placebo, 2 mg repaglinide, 5 mg glipizide, and 5 mg glibenclamide in a random fashion during the trial. Administration of each drug was followed by a single standard 500-kcal test meal. A washout period of 7-12 days existed between the four study visits.
Results: All three drugs were equally effective on the total prandial insulin secretion (area under the curve [AUC] -15 to 240 min). However, clear differences were noted in the early insulin secretion (AUC -15 to 30 min); both repaglinide and glipizide increased secretion in nondiabetic subjects by ~61 and 34%, respectively, compared with placebo. In the diabetic patients, the difference versus placebo was 37 and 47%, respectively. The difference between glipizide and glibenclamide reached significance in both groups of subjects, whereas repaglinide was more effective than glibenclamide only in the healthy nondiabetic subject group. All three drugs were effective in decreasing total glucose AUC in the nondiabetic and diabetic population. In the nondiabetic subjects, however, repaglinide was significantly more effective than glibenclamide. The differences disappeared in the diabetic subjects, probably as a result of increased prevalence of insulin resistance in this group.
Conclusions: Repaglinide and glipizide but not glibenclamide significantly enhanced the early insulin secretion in both nondiabetic and diabetic subjects with preserved -cell function after a single standard meal.
Cardiovascular disease (CVD) is the most important cause of morbidity and mortality in type 2 diabetes. The classical risk factors of hypertension, smoking, increased LDL, and reduced HDL with increased triglycerides account for <50% of the excess risk of CVD. Dysfunction of the vascular endothelium is present early in the history of diabetes and has been implicated in atherogenesis. Insulin resistance and its associated features are a major determinant of the abnormal endothelial function in the prediabetic stages. However, both chronic and acute hyperglycemia have been shown to worsen the function of the endothelium.
Recent prospective studies have attempted to assess the effects of fasting and postprandial hyperglycemia independent of each other. Postprandial hyperglycemia might be more important than fasting hyperglycemia in predicting CVD. However, despite indisputable evidence that better diabetes control reduces the incidence of microvascular complications, a reduction in the risk of developing CVD has not been proven convincingly.
Hemoglobin glycosylation is influenced by both fasting and postprandial glucose; the latter is more strongly correlated with HbA1c values. Therefore, targeting the postprandial glucose level when elevated seems logical and has been shown to achieve better control than focusing on the fasting glucose level alone.
Postprandial hyperglycemia is generated by a combination of impaired pancreatic insulin secretion, unsuppressed hepatic glucose production, and reduced glucose uptake in the periphery. Insulin secretion in normal subjects has a characteristic biphasic pattern, with an early phase lasting <10 min after food ingestion followed by a more sustained later phase of insulin release, which parallels the glucose absorption from the gut. In type 2 diabetes, there is a loss of the early phase and a delayed, blunted, and consequently more prolonged late phase. These changes occur very early in the natural history of this syndrome, and the degree of blunting relates to the fasting plasma glucose, the so-called "Starling curve" of the pancreas. The early-phase loss contributes to a lack of early suppression of the glucagon secretion after ingestion of carbohydrates, which in turn leads to continuing hepatic glucose production and an accentuation of the hyperglycemia. A loss of the early phase of secretion has been shown to cause postprandial glucose intolerance in nondiabetic subjects. In type 2 diabetes, restoration of the early phase using short-acting insulin analogs significantly improves the glucose tolerance by reducing the endogenous glucose output. However, despite the inhibitory effects on the hepatic glucose production, the impaired glucose utilization by the insulin-resistant tissues remains unchanged.
Among the agents available for management of type 2 diabetes, only -glycosidase inhibitors and short-acting insulinotropic agents such as repaglinide and nateglinide have definitely been shown to impact the postprandial glucose levels.The purpose of this study was to compare the effects on the -cell function of three insulinotropic agents available for the treatment of patients with type 2 diabetes: repaglinide, glipizide, and glibenclamide.
Diabetes Care. 2002;25(8) © 2002 American Diabetes Association, Inc.
Cite this: Comparison of the Effects of Three Insulinotropic Drugs on Plasma Insulin Levels After a Standard Meal - Medscape - Aug 01, 2002.