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Synergistic Effects of Nateglinide and Meal Administration on Insulin Secretion in Patients with Type 2 Diabetes Mellitus

Clinical Research Management (L.K.), Portland, Maine 04102; Lee Coast Research Center (S.M.), Fort Myers, Florida 33901; and Novartis Pharmaceuticals Corp. (Y.H.W., S.S., J.F.M.), East Hanover, New Jersey 07936

Address all correspondence and requests for reprints to: James F. McLeod, M.D., Clinical Pharmacology, Novartis Pharmaceuticals Corp., 59 Route 10, East Hanover, New Jersey 07936. E-mail: james.mcleod{at}pharma.novartis.com

	Abstract

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This study assessed the synergistic effects of nateglinide (a nonsulfonylurea D-phenylalanine derivative) and meals on insulin secretion in 24 patients with type 2 diabetes. Oral doses of 60 and 180 mg or 120 and 240 mg were administered to two cohorts of subjects 10 min before meals (or fasting) three times daily for 7 days, with washout intervals between treatment periods. Dose-dependent increases in plasma insulin occurred, with the peak effect within 2 h after treatment. Significantly greater insulin secretion was observed when nateglinide was taken before a meal compared to nateglinide given in the fasted state or in response to just the meal. Nateglinide lowered plasma glucose concentrations significantly vs. placebo at all doses, and doses of 120 and 240 mg were more effective than 60 mg (P < 0.05). Adverse event rates were similar for nateglinide and placebo, and no hypoglycemic episodes or serious adverse events were reported during the study. Nateglinide (120 mg) was the maximum effective dose in this study and was shown to be a safe and well tolerated therapy for control of mealtime glucose excursions in patients with type 2 diabetes. Results indicate that a synergistic interaction occurs between nateglinide and elevated mealtime plasma glucose concentrations to stimulate insulin secretion.

	Introduction

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TYPE 2 DIABETES is a heterogeneous disorder characterized by impaired insulin secretion, insulin resistance, and increased hepatic glucose production. The treatment strategy in this population is to control blood glucose levels with the goals of improving patients’ well-being and reducing the risk of microvascular and macrovascular complications. The traditional focus of oral antidiabetic therapy has been on reducing fasting blood glucose levels, and sulfonylureas have been used as the first line treatment of hyperglycemia for more than 40 yr. Treatment with sulfonylureas, however, is associated with a number of problems, including weight gain and hypoglycemia, especially in the elderly (1). Over the last several years, additional drugs, such as metformin and troglitazone, have become available in the United States to treat these patients. More recently, attempts to treat type 2 diabetes, especially in patients with newly diagnosed and mild to moderate disease, have focused on lowering mealtime glucose excursions. The greatest demand on insulin secretion occurs with meals, and the secretion of insulin in response to a meal in patients with type 2 diabetes is delayed and blunted. Restoration of early insulin secretion at mealtime should have a beneficial effect on mealtime glucose control and prevent long term hyperinsulinemia (2, 3). Sulfonylureas, metformin, and troglitazone have less obvious effects on mealtime glucose levels. The search for a therapeutic agent that would reduce mealtime glucose excursions by stimulating the physiological release of insulin thus led to the development of nateglinide.

Nateglinide (A4166), an amino acid derivative, represents a new chemical class of drugs for treating type 2 diabetes that is pharmacologically and therapeutically distinct from currently existing agents (4, 5). Nateglinide binds to and inhibits the K⁺_ATP channel of the ß-cell, causing membrane depolarization, with a subsequent influx of extracellular calcium that results in insulin secretion (6, 7). Studies in dogs, rats, and mice as well as several rodent models of type 2 diabetes have demonstrated the rapid onset and short duration of insulin effects after nateglinide administration (4, 8).

Studies in normal patients and those with type 2 diabetes have shown that nateglinide stimulates early insulin secretion and reduces mealtime glucose excursions when given before meals (9, 10). In one study of patients with type 2 diabetes, nateglinide taken before meals reduced mealtime blood glucose excursions by 64%, with no hypoglycemia (11). During clinical development, nateglinide has been well tolerated, without establishing a maximum tolerated dose. The insulin secretory response has progressively increased after single doses of nateglinide up to 180 mg. Glucose-lowering effects, however, have been variable after single doses, and the potential benefits of higher doses of nateglinide require further examination.

The effects of nateglinide on insulin secretion under fed and fasted conditions were studied in the context of an ascending dose study, which also assessed tolerability and dose response. The current study was conducted to evaluate the pharmacodynamic effects of four different dose strengths of nateglinide given to patients with type 2 diabetes three times daily 10 min before meals (or fasting) for 7 days.

	Experimental Subjects

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Inclusion criteria

The target population for this study was 20 volunteers of either gender with type 2 diabetes who were 30–65 yr old and between -10% and +60% of their ideal body weight. To participate, patients must have been diagnosed with type 2 diabetes for at least 6 months and have no physical or biochemical abnormalities other than those associated with type 2 diabetes. Laboratory testing criteria included the following: mean fasting blood glucose of 140–220 mg/dL after a 2-week washout period, cholesterol less than 350 mg/dL, triglycerides less than 450 mg/dL, glycosylated hemoglobin less than 12.5%, and normal TSH levels. Patients were required to discontinue treatment with sulfonylureas or other hypoglycemic agents for at least 14 days before treatment and throughout the study.

Exclusion criteria

Patients with any medical or surgical condition that could affect the absorption, distribution, metabolism, or excretion of any drug were excluded. Any recent illness, blood donation, or use of certain medications, such as ß-blockers or thiazide diuretics, precluded study entry unless the sponsor approved.

	Materials and Methods

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Protocol

This two-cohort, double blind, placebo-controlled study used a randomized, escalating, multiple dose design. All patients were screened within 21 days before the start of treatment, and their eligibility was confirmed by baseline evaluations 36 h before each treatment period began. Patients were screened and evaluated at one of two study centers (Portland, ME, and Fort Myers, FL).

Patients were admitted to the study center 36 h before each treatment period, domiciled through day 8, and given 3 meals a day plus a snack, except on day 4, when no breakfast was provided. While domiciled, patients followed a standard diabetic weight-maintaining diet (55% carbohydrate, 25% fat, and 20% protein), with caloric composition adjusted for gender and height as follows: 2400 Cal for a 160-cm male, 2000 Cal for a 160-cm female, with a 15 Cal/cm adjustment for height. Nutritional counseling was provided according to American Diabetes Association guidelines, and patients were to report their compliance outside the study facility. Each cohort comprised 10 randomly assigned patients, 7 of whom received nateglinide for 2 treatment periods, and 3 of whom received placebo. Nateglinide was administered as 60-mg tablets, and placebo as matching tablets.

The treatment schedule (Table 1) included four sequential 7-day treatment periods, each separated by a washout period lasting from 72 h to 4 weeks. Patients received nateglinide or placebo 10 min before the three major meals of the day. During the first treatment period, patients in cohort 1 received 60 mg nateglinide or placebo, and during the third period, they received 180 mg nateglinide or placebo. During the second treatment period, patients in cohort 2 received 120 mg nateglinide or placebo, and during the fourth, they received 240 mg nateglinide or placebo.

Study measurements

Pharmacodynamic responses were evaluated on days -1 (baseline), 1, 4, and 7 of each treatment period. Plasma concentrations of insulin and glucose were measured at specific intervals (0, 0.5, 1, 1.5, 2, 3, and 4 h) after the first, or breakfast, dose. The derived variables AUE (area under the effect curve) and AUE-R (area under the effect curve relative to predose) were calculated by the trapezoidal rule for both insulin and glucose. Venous blood samples were collected at specified intervals on days 1, 2, 4, 6, and 7 for determination of nateglinide plasma concentrations with phosphate-free Vacutainer (Becton Dickinson, Franklin Lakes, NJ) tubes containing tris-2-butoxyethyl. Safety evaluations throughout the study included monitoring for adverse events, electrocardiographic (ECG) monitoring, measurement of vital signs, and routine clinical laboratory testing.

Assays

Plasma concentrations of nateglinide were determined with a modification of the high performance liquid chromatography method of Sato et al. (4), and plasma concentrations of insulin and glucose were determined by Medical Research Laboratories (Highland Heights, KY). Plasma insulin concentrations were determined by the Coat-A-Count RIA procedure, and assay sensitivity was 7.2 pmol/L. Intra- and interassay coefficients of variation for plasma insulin were 5% and 15% maximum, respectively.

Plasma glucose concentrations were determined by the hexokinase method using UV detection, with an assay sensitivity of 1 mg/dL. Intra- and interassay coefficients of variation were 1.1% and 3% maximum, respectively. Standard procedures were followed for the Hitachi 747 chemistry analyzer (Roche Molecular Biochemicals, Indianapolis, IN).

Data from all 24 patients were included in the safety and pharmacodynamic analyses.

Statistical analysis

Paired t test comparisons, or two-sample t tests if the treatments occurred in a different sequence, were conducted. The variables of interest were glucose and insulin AUE_{(0 - t)} and AUE-R_{(0 - t)}, where t = 4 h after dosing. Statistical analyses were performed on the differences in glucose or insulin response between days within each treatment period. Data from patients receiving placebo were pooled separately for each treatment period. Comparisons involving placebo and drug used all placebo observations during the treatment period in which drug was administered. Mean pooled data from all placebo treatment groups are displayed in the figures. The level of statistical significance was set at P < 0.05 by two-tailed test. Data are expressed as the mean ± SD or SEM.

	Results

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Patients

Study participants included 7 women and 17 men, all Caucasian, with a mean age of 59 ± 6 yr (±SD; range, 42–67 yr) and a mean body mass index of 31.0 ± 4.9 kg/m² (±SD; range, 22.0–44.1 kg/m²). Participants had an average hemoglobin A_1c of 8.8 ± 1.3% (range, 7.1–11.3) and had been diagnosed with type 2 diabetes for 7 ± 5 yr (range, 1–17). Except for two subjects who were not taking any medications for hyperglycemia, all patients were taking sulfonylureas before enrollment. The mean fasting plasma glucose and insulin concentrations at study baseline were 239 ± 38 mg/dL and 15.4 ± 3.3 µU/mL, respectively. Mean Homeostatic model assessment scores were 37.5 ± 11.8% (range, 21–68%, not corrected for glucosuria).

Twenty patients completed the study. Cohort 2 had four patients discontinue prematurely who were replaced, but the reasons for discontinuation were unrelated to the study. Three placebo-treated patients discontinued because of visual difficulties, a urinary tract infection, and increased back pain related to ankylosing spondylitis, respectively. The spouse of one of these patients subsequently withdrew after completing the 120-mg dose. Replacement patients were required to complete only the unfinished treatment periods, not the entire sequence. Although one patient had a 3-day washout period, most patients underwent at least 7 days of washout between treatments.

Effects on plasma insulin concentrations

Before the start of nateglinide treatment (day -1), all groups had similar mealtime insulin concentration profiles (P = NS). Once treatment began (day 1), a dose-dependent increase in plasma insulin concentrations occurred when nateglinide was given before meals (i.e., the fed state; Fig. 1A). The maximum change from baseline appeared to be reached at 2 h, after which time the insulin concentrations began to decline. Insulin concentrations after 60 and 120 mg were comparable to those of placebo by 3 h postdose.

View larger version (21K): [in this window] [in a new window]   Figure 1. Mean (±SEM) changes in plasma insulin concentration, by dose, to 4 h after treatment with nateglinide or placebo 10 min before breakfast on day 1 (A) and while fasting on day 4 (B). Mean placebo data from all treatment groups are displayed. Filled circles, 60 mg nateglinide; filled squares, 120 mg nateglinide; open circles, 180 mg nateglinide; open squares, 240 mg nateglinide; open diamonds, placebo.

The dose dependence of the integrated insulin response (AUE-R_0–4) was clearly evident on day 1 of nateglinide treatment (Fig. 2). The plasma insulin response to a meal increased significantly vs. placebo for 120, 180, and 240 mg nateglinide (P < 0.05). Similarly, the insulin response was significantly greater than the response to the meal alone on day -1 (P < 0.05). Plasma insulin responses to nateglinide while fasting (day 4) were minimal and not significantly different, except for the dose of 180 mg, which yielded a greater plasma insulin response than placebo during the same treatment period (P < 0.05).

View larger version (21K): [in this window] [in a new window]   Figure 2. Mean (±SEM) integrated plasma insulin response from before treatment to 4 h after breakfast (AUE-R(0–4)) on day -1 (baseline), after nateglinide administration 10 min before breakfast on day 1, and after nateglinide administration while fasting on day 4. Mean placebo data for all treatment groups are displayed. NAT, Nateglinide; , placebo; 60 mg nateglinide; 120 mg nateglinide; , 180 mg nateglinide; , 240 mg nateglinide. *, P < 0.05 for the comparison of days 1 and 4, dose vs. placebo, in the same treatment period.

Plasma glucose concentrations rose in all treatment groups after a standard breakfast on day 1 (as would be expected after a meal), peaking at 1–2 h (Fig. 3A). This mealtime glucose excursion was reduced by all doses of nateglinide, the effect of which was first evident at 1 h, with the greatest effects occurring 1.5–4 h after treatment. Plasma glucose concentrations were 60–70 mg/dL lower in all nateglinide groups than those in the placebo-treated group during the same period. By 4 h after treatment, the plasma glucose concentrations in all nateglinide groups returned to near pretreatment levels, in contrast to those in the placebo-treated group, which continued to be 40 mg/dL higher than baseline concentrations.

View larger version (21K): [in this window] [in a new window]   Figure 3. Mean (±SEM) changes in plasma glucose concentrations, by dose, to 4 h after treatment with nateglinide or placebo 10 min before breakfast on day 1 (A) and while fasting on day 4 (B). Mean placebo data from all treatment groups are displayed. •, 60 mg nateglinide; , 120 mg nateglinide; , 180 mg nateglinide; , 240 mg nateglinide; , placebo.

The integrated glycemic excursion (AUE-R_(0–4)) was reduced after all nateglinide doses on day 1 (Fig. 4). At doses of 120, 180, and 240 mg, nateglinide decreased the glucose response to a meal compared with the pretreatment value (day -1). Reductions were significantly greater than with placebo at 120 and 240 mg (P < 0.05). The reductions seen with 120 and 240 mg nateglinide were significantly greater than that with 60 mg after 7 days of treatment compared with the pretreatment value (P < 0.05). The plasma glucose-lowering effects were similar at all dose levels for days 1 and 7 (P = NS).

View larger version (26K): [in this window] [in a new window]   Figure 4. Mean (±SEM) integrated glycemic excursion from before treatment to 4 h after breakfast (AUE-R(0–4)) on day -1 (baseline) and after nateglinide administration 10 min before meals on days 1 and 7. Mean placebo data from all treatment groups are displayed. , placebo; , 60 mg nateglinide; , 120 mg nateglinide; , 180 mg nateglinide; , 240 mg nateglinide. *, P < 0.05 for the comparison of days -1 to 1 for 120 and 240 mg nateglinide vs. placebo in the same treatment period; , P < 0.05 for the comparison of days -1 to 7 for 120 and 240 mg nateglinide vs. 60 mg nateglinide.

Pharmacokinetics

Nateglinide was rapidly absorbed at all dose levels studied (60, 120, 180, and 240 mg), with peak plasma concentrations occurring between 0.5–1.9 h. Thereafter, plasma concentrations declined rapidly, with an overall mean half-life of approximately 1.25 h. As a result of this short elimination half-life, no drug accumulation was observed at any dose level after 7 days of before meal treatment. Nateglinide exhibited linear pharmacokinetics over a dose range of 60–240 mg, and the time to peak concentration was not dose dependent.

Safety and tolerability

No severe or serious reactions were seen in the 17 patients reporting adverse events, and the incidence of adverse events was similar for placebo and nateglinide. Eight patients given placebo reported 27 events. Twenty-seven of 62 reported events were possibly related to study medication. Mild to moderate adverse events included diarrhea, nausea, abdominal pain, headache, dizziness, and light-headedness. None of the reported adverse events was associated with changes in blood glucose or blood pressure. No clinically meaningful changes from pretreatment occurred in vital signs or physical examination and ECG variables.

	Discussion

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Dependence of the insulin-stimulating effects on the presence of energy-generating nutrients may confer a relative protection against hypoglycemia in vivo. Preclinical studies in perfused rat pancreas and incubations of isolated islets have demonstrated the glucose sensitivity of the insulin response to nateglinide (12, 13). Similar data have been reported for repaglinide (14). Recently, ß-cell electrophysiological studies showed that increasing glucose from euglycemic to hyperglycemic levels (5 to 16 mmol/L) reduced (by 3-fold) the IC₅₀ for nateglinide to inhibit ß-cell K⁺_ATP current. In contrast, the IC₅₀ values for glyburide and repaglinide were modestly (not significantly) increased with increasing glucose levels (15). Preclinical studies in several species have shown that nateglinide has more effect on early insulin secretion, as opposed to later after the meal, resulting in superior control of mealtime glucose excursions compared with that provided by other agents such as sulfonylureas (16, 17) or repaglinide (18, 19). A similar effect on early insulin secretion has been observed in clinical trials (20, 21).

In the present study nateglinide increased plasma insulin concentrations and decreased mealtime plasma glucose excursions when administered before meals to patients with type 2 diabetes. The insulin response is rapid and peaks within 2 h after administration, consistent with results seen with nateglinide in other studies (11, 22). When nateglinide is administered before meals, a synergistic effect on insulin secretion occurs, demonstrating that nateglinide is more effective when glucose concentrations are the highest. In the absence of nateglinide (pretreatment), insulin concentrations increased about 15 µU/mL in response to a meal, compared with a maximum insulin response of 5 µU/mL in the fasted state after nateglinide administration. When nateglinide was given with a meal, elevations as high as 50 µU/mL from pretreatment values were noted, clearly a greater response than that seen with no drug and fasting combined. This synergy of nateglinide with a meal should contribute favorably to its safety and efficacy profile.

More recently, oral hypoglycemic therapy has focussed on reducing mealtime hyperglycemia in the less severely diabetic patient. Drug-induced hypoglycemia presents a particular risk for this population and has been reported with the lowest dose of repaglinide taken 3 h after a meal (23). A more nutrient-sensitive, rapid onset, short acting agent such as nateglinide is uniquely suitable. When nateglinide was administered in the fasted state, as in the present study, insulin secretion was minimal, and the glucose-lowering effects did not increase as the dose was increased from 60 to 240 mg. The hypoglycemic action of nateglinide under fed conditions was concentrated on the first 3 h after the meal. This finding is similar to that of another study, in which 120 mg was the maximally effective nateglinide dose for lowering glucose without the occurrence of hypoglycemia (11). These results suggest that administration of 120 mg nateglinide before meals may be optimal for control of mealtime glucose excursions without the risk of delayed hypoglycemia.

The safety profile of nateglinide was confirmed when no episodes of hypoglycemia, defined as symptoms of tremulousness, diaphoresis, and hypothermia accompanied by confusion or other central nervous system manifestations, were reported in this study. Additionally, no serious or unexpected adverse events or clinically meaningful changes in vital signs, hematological findings, physical examinations, or ECGs were reported. The alterations seen in serum and urinary concentrations of glucose were similar to those expected in patients with diabetes. The most frequently reported adverse events during treatment were diarrhea, headache, and dizziness.

In summary, nateglinide increased plasma insulin concentrations in a dose-related fashion in patients with type 2 diabetes, and its effects were clearly enhanced by administration before meals. When given in the fasting state, nateglinide caused minimal changes in plasma concentrations of insulin and glucose. When given before meals, nateglinide produced rapid and short-lived insulin secretion, effectively reducing mealtime glucose excursions, yet lowering the risk of hypoglycemic episodes. Nateglinide offers the promise of improved physiological control of plasma glucose concentrations in patients with type 2 diabetes.

	Acknowledgments

 
The assistance of Dr. Adel Karara and Stephen Garreffa with pharmacokinetic and statistical analysis is much appreciated. The authors are also grateful to the staff at Clinical Research Management (Portland, ME) and the Lee Coast Research Center (Fort Myers, FL) for their expertise.

Received August 31, 1999.

Revised November 11, 1999.

Accepted November 23, 1999.

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Top Abstract Introduction Experimental Subjects Materials and Methods Results Discussion References

 

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