Nateglinide Improves Early Insulin Secretion and Controls Postprandial Glucose Excursions in a Prediabetic Population

Carola Saloranta, MD, Christiane Guitard, MD, Eckhard Pecher, MSC, Pedro de Pablos-Velasco, MD, Kaj Lahti, MD, Patrick Brunel, MD, Leif Groop, MD

Disclosures

Diabetes Care. 2002;25(12) 

In This Article

Abstract and Introduction

Objective: The purpose of this study was to evaluate the metabolic effectiveness, safety, and tolerability of nateglinide in subjects with impaired glucose tolerance (IGT) and to identify a dose appropriate for use in a diabetes prevention study.
Research Design and Methods: This multicenter, double-blind, randomized, parallel-group, fixed-dose study of 8 weeks' duration was performed in a total of 288 subjects with IGT using a 2:2:2:1 randomization. Subjects received nateglinide (30, 60, and 120 mg) or placebo before each main meal. Metabolic effectiveness was assessed during a standardized meal challenge performed before and after the 8-week treatment. All adverse events (AEs) were recorded, and confirmed hypoglycemia was defined as symptoms accompanied by a self-monitoring of blood glucose measurement ≤3.3 mmol/l (plasma glucose ≤3.7 mmol/l).
Results: Nateglinide elicited a dose-related increase of insulin and a decrease of glucose during standardized meal challenges, with the predominant effect on early insulin release, leading to a substantial reduction in peak plasma glucose levels. Nateglinide was well tolerated, and symptoms of hypoglycemia were the only treatment-emergent AEs. Confirmed hypoglycemia occurred in 28 subjects receiving nateglinide (30 mg, 0 [0%]; 60 mg, 5 [6.6%]; 120 mg, 23 [26.7%]) and in 1 (2.3%) subject receiving placebo.
Conclusions: Nateglinide was safe and effective in reducing postprandial hyperglycemia in subjects with IGT. Preprandial doses of 30 or 60 mg nateglinide would be appropriate to use for longer-term studies to determine whether a rapid-onset, rapidly reversible, insulinotropic agent can delay or prevent the development of type 2 diabetes.

Several studies have shown that weight loss and exercise can delay or prevent progression from impaired glucose tolerance (IGT) to type 2 diabetes[1,2,3]; however, such changes in lifestyle are notoriously difficult to maintain. Very recently, results from the Diabetes Prevention Program[4], the STOP-NIDDM Diabetes Trial[5], and the TRIPOD Study[6] have suggested that pharmacotherapy (with metformin, acarbose, and thiazolidinediones, respectively) is a valid approach to diabetes prevention in patients with IGT at high risk of developing diabetes, such as those with a family history of diabetes[5] or women with recent gestational diabetes[6]. These data raise the question of whether another agent, acting by a different mechanism, may be equally or more effective in the prevention of type 2 diabetes.

TheD-phenylalanine derivative, nateglinide, is a new insulinotropic agent that specifically targets mealtime glucose excursions by restoring or replacing early prandial insulin release that is markedly impaired early in the progression of type 2 diabetes[7] and, indeed, in IGT[8]. Unlike most sulfonylureas (SUs), nateglinide is found to have a low risk of hypoglycemia in patients with diabetes[9,10] because its stimulation of insulin release is rapidly reversible and glucose dependent[11,12]. Since nateglinide addresses the key factor that determines whether an individual with IGT progresses to overt diabetes[7], it may be a particularly attractive option for use in diabetes prevention.

However, an insulin secretion agent used in subjects with minimal fasting hyperglycemia must have an acceptably low hypoglycemic potential. Further, an agent used for an extended period of time must have an excellent overall safety and tolerability profile. Thus, before nateglinide could be used in a diabetes prevention study, it would be essential to demonstrate, in the target prediabetic population, that it has these properties. The purpose of the present study was to assess the safety, tolerability, and metabolic effectiveness of nateglinide in subjects with IGT and to identify an appropriate dose for use in long-term studies to assess its potential to delay or prevent the development of type 2 diabetes.

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