Research Design and Methods
This multicenter, double-blind, randomized, parallel-group fixed-dose study of 8 weeks' duration was performed to define the maximum tolerated dose of nateglinide in a prediabetic population. The effects of nateglinide on prandial glucose and insulin, fructosamine, fasting plasma glucose (FPG), and HbA1c levels were also assessed. A total of 288 nondiabetic subjects (FPG <7.0 mmol/l) with IGT were randomized to receive 30 mg (n = 83), 60 mg (n = 76), or 120 mg (n = 86) nateglinide or placebo (n = 43) before (within 10 min of) each main meal using a 2:2:2:1 randomization. To determine the effects of nateglinide on prandial glucose and insulin levels, a standardized meal challenge was performed before the first dose (week 0) and after the final dose (week 8).
The study was carried out in 32 centers in six countries and enrolled male and female subjects with an FPG <7.0 mmol/l and with IGT confirmed by two 2-h post-glucose challenge values ≥7.8 mmol/l but <11.1 mmol/l measured during oral glucose tolerance tests (OGTTs) performed within 1 year and repeated within 2 weeks before study entry. Subjects agreed to maintain their prior diet and to provide written informed consent to participate. Main exclusion criteria were prior or concomitant antidiabetic agents, investigational drugs within 4 weeks, cardiovascular events within 6 months, liver disease, or persistent elevations of liver enzymes. The study protocol received Institutional Review Board approval at all sites and was conducted in accordance with the U.S. Code of Federal Regulations, the rules governing medical procedures in the European Community and the Declaration of Helsinki.
During the baseline (week 0) visit, subjects underwent physical exams, electrocardiograms, and standard laboratory tests (hematology, chemistry, and urinalysis) after an overnight fast. Samples were obtained for assessment of FPG, HbA1c, and fructosamine, then the subjects underwent the week 0 standardized breakfast meal challenge. Dosing was initiated before lunch, and subjects were instructed to take one tablet before each main meal for a minimum of two and a maximum of four meals per day and to not take study medication if a meal was missed. Subjects returned for assessment of FPG and fructosamine at weeks 2 and 4 and for standard laboratory tests, FPG, fructosamine, and HbA1c at week 8. The final dose was followed by a standardized meal challenge.
During the meal challenge, a fasting plasma sample (-15 min) was obtained, then 150 ml of water (week 0) or study medication with water (week 8) was taken and a 500 kcal breakfast meal was initiated within 10 min and consumed within the next 15 min. The breakfast was composed of orange juice (180 ml), toasted bread (60 g), jam or preserves (20 g), butter or margarine (10 g), whole milk (120 ml), and coffee or tea with nonnutritive sweetener if desired. Plasma samples for measurement of glucose and insulin were obtained at 10, 20, 30, 40, 60, 120, and 180 min after initiation of the meal.
All subjects were provided with a home glucose monitoring device and were instructed to perform a fingerstick glucose test for all episodes of suspected hypoglycemia. Confirmed hypoglycemia was defined as an event for which SMBG value was ≤3.3 mmol/l, corresponding to a plasma glucose ≤3.7 mmol/l.
Glucose was measured by an enzymatic method (Boehringer Mannheim, Mannheim, Germany) and fructosamine was measured by a spectrophotometric method (Roche Diagnostics, Basel, Switzerland) using a Cobas Bio analyzer (Roche). Blood levels of HbA1c were measured by high-performance liquid chromatography standardized to the Diamat ion-exchange method (upper limit of normal [ULN] = 6.0%). Insulin was measured by radioimmunoassay (Pharmacia, Uppsala, Sweden). All laboratory samples were analyzed at a central laboratory (CRL, Brussels, Belgium).
Baseline and demographic variables were compared among groups with an F test for numeric parameters and by a Mantel-Haenszel test for catergorical variables. The primary safety evaluation was based on the incidence of confirmed hypoglycemia. Acceptable safety was defined prospectively as an incidence of severe (grade B -- requiring assistance from an outside party) hypoglycemia <0.1% in the combined nateglinide groups and a discontinuation rate of <5% within a dose group. Binomial tests were performed on these two primary safety criteria. In post hoc analyses, the frequency of adverse events (AEs) was compared between groups by Fisher's exact test (two-sided, not adjusted for multiplicity). Efficacy analyses were performed to assess the effects of nateglinide on prandial glucose and insulin (3-h area under the curves [AUCs] calculated by the trapezoidal method), FPG, HbA1c, and fructosamine. The change from baseline at week 8 was analyzed by ANCOVA with treatment and center as factors and baseline as covariate. Summary statistics of absolute values and changes from baseline by treatment group and time point were calculated for the intent-to-treat population. No formal hypothesis testing was performed. P values derived from the ANCOVA were explorative and were not adjusted for multiplicity.
Diabetes Care. 2002;25(12) © 2002 American Diabetes Association, Inc.
Cite this: Nateglinide Improves Early Insulin Secretion and Controls Postprandial Glucose Excursions in a Prediabetic Population - Medscape - Dec 01, 2002.