Optimizing Insulin Secretagogue Therapy in Patients With Type 2 Diabetes

Abstract

OBJECTIVE -Repaglinide, a novel antidiabetic agent that has a rapid onset and short duration of action, was developed for mealtime dosing. The purpose of this pharmacodynamic study was to validate a prandial regimen of repaglinide by comparing meal-related dosing with a regimen in which the same total daily dose was divided into only two doses at morning and evening meals. RESEARCH DESIGN AND METHODS -The study was a double-blind, randomized, parallel-group trial in 19 antidiabetic agent-naive subjects with type 2 diabetes (mean age 58 years, known duration of diabetes 3.5 years, HbA 1c 7.3%, and BMI 32 kg/m 2 ). Patients were randomly assigned to receive repaglinide either before each of the three main meals or before breakfast and before the evening meal. Patients in both groups received the same total daily dose of repaglinide. Twenty-four hour profiles of blood glucose, plasma insulin, and plasma Cpeptide concentrations were measured at baseline and after 4 weeks of treatment.RESULTS -Repaglinide increased postprandial insulin levels and markedly reduced postprandial glucose levels relative to baseline in both groups. Significant reductions were also recorded in fasting blood glucose and HbA 1c levels. The repaglinide regimen, in which a dose was taken before each main meal, was more effective in improving glycemic control (including postprandial glucose and HbA 1c levels) than the same total dose of repaglinide divided into morning and evening mealtime doses.CONCLUSIONS -These data support the strategy of mealtime dosing with repaglinide. The improvements in glycemic control observed in these patients are encouraging. In addition to classic parameters of glycemic control, improvements in postprandial glucose excursions may prove to be important because postprandial hyperglycemia has been suggested to be an independent risk factor for cardiovascular disease in diabetes. Diabetes Care 25:342-346, 2002T ype 2 diabetes is characterized by impaired insulin secretion, usually with concomitant impaired insulin sensitivity (1,2). Insulin secretagogue therapy is therefore a logical part of therapy of type 2 diabetes when diet and lifestyle modifications fail. Secretagogue therapy is the appropriate means to augment circulating insulin levels in patients with a moderate degree of ␤-cell dysfunction; in individuals with more advanced ␤-cell dysfunction, exogenous insulin therapy may be necessary.Sulfonylureas have been used for almost five decades as insulin secretagogues in the management of type 2 diabetes. Sulfonylureas stimulate insulin secretion and thereby reduce hyperglycemia, with few side effects. Nevertheless, the long plasma half-life and the long-lasting effect of some sulfonylureas increase the risk of hypoglycemia, especially in elderly patients and in patients with renal insufficiency (3-5). As the need to achieve nearnormoglycemia becomes recognized in the light of the findings of large prospective studies, hypoglycemia is likely to become an increasingly common feature of type 2 diabetes (6,7). In add...

Sulfonylurea Treatment of Type 2 Diabetes Mellitus: Focus on Glimepiride

“…23,26 Several clinical studies have investigated the impact of insulin secretagogues on first-phase insulin release. 17,27,28 Tolbutamide, a short-acting sulfonylurea, improved first-phase insulin secretion in patients with type 2 diabetes who had severe hyperglycemia. However, it did not provide this benefit in patients with type 2 diabetes who had only mild hyperglycemia.…”

Compared to glibenclamide, repaglinide treatment results in a more rapid fall in glucose level and beta‐cell secretion after glucose stimulation

“…Repaglinide represents a new class of insulin secretagogues, with a chemical structure different from SU, but a mechanism of action quite similar to that of SU; closure of ATP‐dependent potassium channels triggers insulin release. Repaglinide appears equally effective at lowering HbA 1 c as glibenclamide 4–6. The shorter half‐life (1 h) may decrease the frequency of hypoglycaemic events and may have the advantage that, after a meal, insulin levels decline rapidly when blood glucose concentrations drop, decreasing the tendency of persistent hyperinsulinaemia and/or sustained beta‐cell stimulation.…”

Regression of Carotid Atherosclerosis by Control of Postprandial Hyperglycemia in Type 2 Diabetes Mellitus

“…Repaglinide selectively increases meal-related early insulin secretion and may result in better control of postprandial hyperglycemia than glyburide. [7][8][9] …”