Repaglinide Versus Nateglinide Monotherapy : A randomized, multicenter study

This clinical trial was conducted in accordance with the provisions of the Declaration of Helsinki for participation of subjects in human research. The protocol received approval of relevant institutional review boards before initiation of any trial-related activities.

This study was a multicenter, randomized, parallel-group, open-label comparison of repaglinide and nateglinide treatment for a period of 16 weeks. The primary efficacy end points for comparison were final HbA_1c values (HPLC assay; Icon Laboratories, Tinton Falls, NJ) and changes in HbA_1c values from baseline. Secondary efficacy end points included changes in FPG values. Enrolled patients were adults (age ≥18 years) who had type 2 diabetes for at least 3 months with BMI values in the range of 24–42 kg/m². Subjects were stratified by baseline HbA_1c value (<9% or ≥9%), and were asked to conduct self-monitoring of their blood glucose levels (SMBG) from the randomization visit onward.

Enrolled patients had been treated with only diet and exercise during the previous 3 months (HbA_1c values <7 and ≥12%). Subjects were randomly assigned to either mealtime repaglinide therapy (n = 76) or mealtime nateglinide monotherapy (n = 74) with an initial 3-week dose titration. Both agents were to be given 1–30 min before daily meals. Target glycemic control during the initial 3-week period was SMBG preprandial values of 80–140 mg/dl, with dose adjustments possible in the following 13 weeks if needed. Patients initiated repaglinide treatment at doses of 0.5 mg before each meal, and doses were increased stepwise from 0.5 to 1.0, to 2.0, and to 4.0 mg at weekly visits based upon the results of an 8-point SMBG (maximum dose 16 mg/day). Doses of nateglinide were started at 60 mg/meal and increased to 120 mg/meal after 1 week if target glycemic control was not achieved. Doses were determined by the labeling of each agent. The labeling for nateglinide allows for a maximum dose of 360 mg/day, corresponding to three meals at the maximum dose of 120 mg/meal. The labeling for repaglinide allows for a total of up to 16 mg/day, corresponding to as many as four meals at the 4-mg dose. The number of meals was not recorded by patients, so average doses per meal were not calculated. HbA_1c values were determined at baseline and at weeks 4, 8, 12, and 16.

A liquid test meal evaluation (two cans of Boost equal 480 kcal; 67% carbohydrate, 17% protein, and 16% fat) was conducted at the baseline and week 16 visits with determination of plasma glucose (hexokinase assay), insulin (immunometric assay), and glucagon (radioimmunoassay) from −10 min to 240 min (Icon Laboratories). At week 16, doses of repaglinide or nateglinide were administered 10 min before the liquid test meal.

Patients were requested to record an 8-point SMBG profile (before breakfast, 2 h after breakfast, before lunch, 2 h after lunch, before dinner, 2 h after dinner, bedtime, and at 2:00 a.m.) at each visit. Patients were provided instructions that included regular calibration of the meter as recommended by the manufacturer.

Adverse events and reports of hypoglycemic episodes were recorded at all study visits. Hypoglycemic episodes were defined as follows. Major hypoglycemic episodes were events having severe central nervous system symptoms consistent with hypoglycemia in which the subject was unable to treat him/herself, having blood glucose readings <50 mg/dl and/or reversal of symptoms by treatment (food intake, glucagon, or intravenous glucose). Minor hypoglycemic episodes included events having hypoglycemia symptoms and confirmed blood glucose levels <50 mg/dl and events with asymptomatic blood glucose levels <50 mg/dl.

Missing values of HbA_1c and FPG after baseline were substituted by imputed data (calculated by the incremental mean imputation [IMI] method) (15). Simulations of datasets resembling the output of this clinical trial have demonstrated that the IMI method is more precise than the last observation carried forward method (15). Differences between the monotherapy groups in the change in HbA_1c or FPG values were compared by ANOVA (with and without adjustment for baseline imbalance). An enrollment of ∼150 patients was calculated based upon the assumption of a 10% drop-out rate and an intent-to-treat analysis with 80% power to detect an HbA_1c difference of 0.6%.

Demographic and baseline characteristics of the 150 enrolled patients are summarized in Table 1. The repaglinide and nateglinide therapy groups were very comparable in age, sex, ethnic background, BMI values, and duration of di-agnosed diabetes. None of these variables differed significantly by treatment group. Only 8% of the patients in the repaglinide group and 16% of the patients of the nateglinide group failed to complete 16 weeks of therapy (Table 1). The nateglinide monotherapy group had a slightly higher rate of discontinuation due to lack of efficacy (at the judgment of the investigator; patients were to be withdrawn for unacceptable persistent hyperglycemia [two FPG readings >270 mg/dl, in the absence of a treatable intercurrent illness, in 3 days] when the maximum allowed dose of repaglinide [4 mg before each main meal, maximum dose 16 mg/day] or nateglinide [120 mg before each main meal, maximum dose 360 mg/day] was being given) and other reasons. Two subjects discontinued in the repaglinide group due to adverse events: one due to right side pain and one due to diarrhea and cramping after dosing.

Mean HbA_1c values during treatment are graphically represented in Fig. 1A. The mean baseline HbA_1c value was 8.9% in both groups. From week 8 onward, mean HbA_1c values were significantly lower for repaglinide than nateglinide, and by week 16, such treatment-related differences appeared to have stabilized. The mean end of study reductions in HbA_1c values from baseline was significantly greater for repaglinide than nateglinide (IMI method, 1.57 vs. 1.04%, P = 0.002; last observation carried forward (LOCF) method, 1.55 vs. 1.02%, P = 0.003).

At the end of the study, 54% of repaglinide-treated patients had HbA_1c values of ≤7 vs. 42% of nateglinide-treated patients (P = 0.18 between treatments). Only 11% of nateglinide-treated patients having initial HbA_1c values >8% had final HbA_1c values of ≤7%. In contrast, 40% of repaglinide-treated patients with initial HbA_1c values >8% had final HbA_1c values of ≤7% (P = 0.004 between treatments).

By week 16 of treatment, only nine repaglinide-treated patients (12%) had escalated mealtime doses to the maximal level of 16 mg/day (mean time at maximum dose was 44 days). However, 57 (77%) nateglinide monotherapy patients had remained at the highest dosage level of 360 mg/day up to the end of the study (mean time at maximum dose was 94 days). Median daily doses of secretagogues were 6.0 mg/day for repaglinide and 360 mg/day for nateglinide. A subanalysis of subjects on the maximum dose of nateglinide showed that the mean HbA_1c reduction (adjusted for baseline difference with the repaglinide group) was 1.08% versus a mean HbA_1c reduction for subjects treated with repaglinide (all doses) of 1.67% (P = 0.0031).

The subset of subjects who received a nateglinide dose of 60 mg/meal had mean baseline HbA_1c values significantly lower than those treated at 120 mg/meal (7.32 vs. 9.41%). The lower dose was thus used in patients who had near-goal HbA_1c when treatment was initiated, as recommended in the nateglinide package insert (2).

Mean FPG values over time are presented by treatment group in Fig. 1B. The repaglinide group had significantly lower FPG values than the nateglinide group after 1 week of therapy with FPG values reaching a steady state by week 4. FPG values remained lower in the repaglinide group for the following 12 weeks until the end of the study. Mean final FPG values were 156 mg/dl for repaglinide and 183 mg/dl for nateglinide (Table 2). Mean final reductions in FPG values from baseline were significantly greater for repaglinide (−57 mg/dl) than nateglinide therapy (−18 mg/dl, P < 0.001) (LOCF method, −57 and −19 mg/dl, respectively). A subanalysis of subjects on the maximum dose of nateglinide showed that the mean FPG reduction (adjusted for baseline difference with the repaglinide group) was 20 mg/dl compared with the mean FPG reduction for repaglinide (all doses) of 59 mg/dl (P < 0.0001).

The mean 8-point SMBG profiles collected by patients at the end of the study are presented in Fig. 2 and were consistent with observed differences in the FPG response of the two treatments. Repaglinide monotherapy showed significantly lower mean SMBG values than nateglinide at all time points measured (P < 0.05).

Liquid meal challenge testing resulted in the plasma glucose profiles shown in Fig. 3A. From baseline to the end of the study, both treatments showed decreased levels of postprandial glucose, increased levels of postprandial insulin, and decreased levels of postprandial glucagon (Fig. 3B; Table 2). Changes in the area under the postprandial plasma glucose curve (ΔAUC_0–240min) were not significantly different for repaglinide and nateglinide. Changes in postprandial insulin AUC_0–240min were likewise comparable for the two treatments (Table 2). Glucagon AUC_0–240min showed reductions from week 0 to week 16 that were significantly greater for repaglinide than nateglinide (P = 0.005).

There were no major hypoglycemic episodes (requiring the assistance of another person) in either treatment group. There were five patients (7%) receiving repaglinide treatment who had events of minor hypoglycemia (two in the absence of symptoms), and no reported minor hypoglycemic events during nateglinide therapy. The frequency of hypoglycemic events is 0.016 events per patient per month for subjects treated with repaglinide, as compared with 0 events per patient per month (P = 0.3 based on the Poisson rare-event model.)

Mean weight gains (adjusted for baseline and age) from baseline to end of study were +1.8 kg for repaglinide and +0.7 kg for nateglinide (IMI method calculation, P = 0.04; LOCF method calculation, P = 0.034).

The most common adverse events (between 3 and 10% of patients in both treatment groups) were upper respiratory tract infection, sinusitis, constipation, arthralgia, headache, and vomiting. There were no notable differences in the pattern of adverse events for the two treatment groups.

With an increasing number of therapeutic choices for oral therapy of type 2 diabetes, the comparative efficacy of various agents and their optimal conditions for use are important considerations. Such comparisons have numerous implications regarding the best therapy to institute in a particular patient population, including the choice of agents to begin monotherapy when diet and exercise fail or the choice of agents to add to monotherapy to potentiate glucose-lowering effects. In a 1-year comparison trial, repaglinide had similar efficacy to glyburide, but a direct comparison of the efficacy of repaglinide with nateglinide has not previously been reported (6).

This clinical trial demonstrated that under conditions of dose titration to the same glycemic targets, repaglinide had significantly greater reductions of glycemic parameters than nateglinide when used as monotherapy in patients who had been treated with diet and exercise therapy in the previous 3 months. Efficacy differences between the two treatments were evident in changes in FPG or HbA_1c within the first 4 weeks. Greater glycemic efficacy of repaglinide (with a lowering of HbA_1c values from baseline by 1.57%) was not attributable to an inadequacy of nateglinide dosage, because the majority (77%) of nateglinide-treated patients received the maximal recommended daily dosage of 360 mg/day, whereas 12% of patients using repaglinide were at the maximal dose. The observed efficacy of nateglinide in this clinical trial of a 1.04% reduction of HbA_1c relative to baseline in 16 weeks was comparable with previous reports of nateglinide monotherapy of a 0.6% reduction in 16 weeks (16) or a 0.8% reduction in 24 weeks in the oral antidiabetic drug–naive subset of patients (12).

It is of interest to note that effects of these short-acting secretagogues upon postprandial hyperglycemia has typically been emphasized as the mechanism of action, but in this study, the glycemic effects of the two agents on postprandial glucose or insulin AUC values were similar. This finding underscores the value of controlling nocturnal and fasting hyperglycemia in which repaglinide effects appeared greater, suggesting a longer duration of action for this compound. Because the two treatment groups had similar reductions of postprandial glucose peaks after a liquid test meal, the greater reduction of HbA_1c, FPG, or SMBG values for repaglinide is likely to be due to subtle differences in repaglinide performance during the night and at late postprandial times or between meals. Effects of such differences might culminate rapidly in a mealtime dosing regimen: although the two agents have similar elimination half-lives (1 h for repaglinide and 1.5 h for nateglinide), their affinity for their β-cell receptors is dramatically different (half-maximal inhibitory concentration for ATP-sensitive K⁺ channel-blocking effect in rat β-cells is 5 nmol/l for repaglinide vs. 7.4 μmol/l for nateglinide) (1,2,17). Preclinical experimental data have indicated that the inhibitory effects of nateglinide upon ATP-sensitive K⁺ channels are reversed more rapidly than those of repaglinide (17).

Postprandial insulin measurements indicate that the two secretagogues are clinically similar in their stimulation of mealtime insulin release. In this clinical trial, the two secretagogues had no obvious differences in their effects upon the early stages of insulin secretion. The clinical significance of a significantly greater reduction of postprandial glucagon levels for repaglinide monotherapy remains to be established.

Regarding hypoglycemia, both agents showed a desirable hypoglycemic episode profile in this clinical trial with no reported events of major hypoglycemia. It should be noted that any treatment that results in an improvement in glycemic control might also lead to an increase in hypoglycemic events. The mean weight changes associated with repaglinide or nateglinide were statistically different, and the clinical importance of this difference is unknown. Both drugs were generally well tolerated.

In patients having inadequate glycemic control in a regimen of diet and exercise, repaglinide monotherapy led to significantly greater reductions in HbA_1c and FPG values than nateglinide monotherapy with similar postprandial effects.

Steven S. Bimson, Jonathon Bortz, Shari A. Brazinky, Dennis Buth, John Cappleman, James Farrell, Vincente Florida, David R. Hassman, Priscilla Hollander, C. Scott Horn, Edward Kerwin, Allen King, Nelson Kopyt, Robert Madder, Janet McGill, Joseph Milburn, Jorge Pino, Larry Popeil, Julio Rosenstock, Don Schumacher, Barry Seidman, Richard Sievers, Stephen A. South, and Scott Touger.

This study was supported by Novo Nordisk Pharmaceuticals of Princeton, New Jersey.