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

Results

Table 1 reports the baseline characteristics of the study population. There were no differences among treatment groups in demographics or in metabolic indexes (HbA1c, FPG, and fructosamine). Nearly all subjects were Caucasian, women outnumbered men by a ratio of ~60:40, mean age was ~57 years (with ~25% of each treatment group >65 years), and the mean BMI in each group was 30 kg/m2. Reflecting the selection criteria, mean FPG ranged from 5.9 to 6.2 mmol/l in the four groups; HbA1c and fructosamine levels were near their respective ULNs.

Nateglinide was very well tolerated. The overall incidence of AEs, other than symptoms of hypoglycemia, was low and similar among all treatment groups. No deaths occurred during the study, and the incidence of serious AEs (SAEs) was 1 (1.2%), 0, 1 (1.2%), and 2 (4.7%) in the nateglinide 30, 60, and 120 mg and placebo groups, respectively. Only one SAE was suspected to be related to study medication, but upon unblinding, this subject was found to be in the placebo group. Three (3.6%), two (2.6%), and none of the subjects in the 30, 60, and 120 mg nateglinide groups and one (2.3%) in the placebo-treated group, respectively, withdrew due to any AE other than hypoglycemia. The incidence of clinically notable laboratory parameters (hematology and biochemistry) was low in all subjects and none were dose-related.

Because the purpose of this study was to determine the maximum tolerated dose and thus to define an appropriate dose for a long-term diabetes prevention study, particular attention was paid to hypoglycemia. There were no incidents of severe hypoglycemia (requiring assistance from an outside party) during this study. Given the sample size of 245 subjects in the combined nateglinide groups, the binomial CI for the true underlying incidence ranged from 0.0 to 1.2%. A total of three subjects on nateglinide (1.2%) discontinued because of hypoglycemic symptoms (one on 60 mg and two on 120 mg). As reported in Table 2 , the incidence of confirmed hypoglycemia in the nateglinide-treated groups was 0 in the 30 mg, 5 (6.6%) in the 60 mg, 23 (26.7%) in the 120 mg, and 1 (2.3%) in the placebo group. There was clear statistical evidence for a higher incidence in the 120-mg group, but other analyses should be interpreted with caution in view of the low number of events and sample size. All plasma glucose levels during any confirmed hypoglycemic episode in the 60- mg nateglinide group and in the group who took placebo were >3.1 mmol/l. In the 120-mg group, 11 subjects (12.8%) experienced hypoglycemia with a plasma glucose equivalent ≤3.1 mmol/l; however, the other 17 confirmed episodes had plasma glucose values >3.1 mmol/l. In all groups, a missed or delayed meal, strenuous exercise, or stress were the most frequently assigned precipitating factors, but no recognizable precipitating factor was identified by the subjects in most episodes observed with the 120-mg dose. Most hypoglycemic events occurred <4 h from the last meal and took <30 min to resolve following oral carbohydrate intake. All events occurred during the day, mainly during the afternoon, but many of the symptoms experienced by the subjects in the 120-mg group occurred during the morning.

Figure 1 depicts the immunoreative insulin (IRI) and glucose profiles during standardized breakfast challenges performed at weeks 0 and 8 of treatment with nateglinide (60 mg, before meals). This dose of nateglinide modestly and selectively increased the early insulin response to the meal and greatly reduced the prandial glucose excursion. A lower dose produced a smaller increment of insulin and decrement of glucose, and a higher dose produced a larger and more prolonged augmentation of meal-stimulated insulin release and a marginally greater reduction of postprandial glucose levels.

Plasma insulin (IRI) and glucose during standardized breakfast challenges performed prior to the first dose at week 0 and after the final dose at week 8 with 60 mg nateglinide in 72 nondiabetic subjects with IGT. Mean ± SEM.

This is illustrated in Figure 2, which shows the change from week 0 to week 8 in the 3-h prandial AUCs of insulin and glucose in the four treatment groups. The effects of nateglinide to increase insulin and to curb prandial glucose excursions were dose related, but only the highest dose (120 mg) significantly increased the total insulin exposure.

Change from week 0 to week 8 in the insulin (IRI) and glucose AUCs during standardized breakfast challenges. Least squares mean ± SE. *P < 0.025; **P < 0.001 vs. placebo.

As would be predicted from the characteristics of the study population, the duration of study, and the mechanism of nateglinide action, this agent had no significant effect on FPG or on fasting insulin levels. The change from baseline HbA1c was not statistically significant except in the 120-mg group ( = -0.12 ± 0.04, P < 0.05). Nateglinide did, however, modestly but significantly decrease fructosamine levels ( = 30 mg, -8.3 ± 0.4; 60 mg -8.6 ± 2.1; and 120 mg, -8.1 ± 2.0 µmol/l; P < 0.05 vs. placebo), although the effect was not dose related.

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