nateglinide and Hypoglycemia

Topics: Acarbose; Cyclohexanes; Diet, Carbohydrate-Restricted; Dietary Fiber; Dumping Syndrome; Enzyme Inhibitors; Gastrectomy; Glucose Intolerance; Glucose Tolerance Test; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Nateglinide; Phenylalanine; Weight Loss

Topics: 1-Deoxynojirimycin; Acarbose; Aged; Blood Glucose; Carbamates; Contraindications; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Enzyme Inhibitors; Fasting; Follow-Up Studies; Germany; Glucosamine; Glyburide; Glycated Hemoglobin; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemia; Hypoglycemic Agents; Imino Pyranoses; Insulin; Metformin; Middle Aged; Nateglinide; Obesity; Patient Compliance; Phenylalanine; Pioglitazone; Piperidines; Practice Guidelines as Topic; Risk Factors; Rosiglitazone; Sulfonylurea Compounds; Thiazolidinediones; Time Factors

Topics: Animals; Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Nateglinide; Phenylalanine

The complications of diabetes mellitus, arising from inadequate glycemic control, have serious consequences for society as well as individuals. It is now urged that tight glycemic control be the goal for all patients, regardless of type of diabetes. Unfortunately, hypoglycemia can be a consequence of this aggressive approach. Treatment with a combination of agents and improved therapies are needed to maintain glycemic balance in patients. A better understanding of the pathophysiology of diabetes has yielded many treatment options based on various mechanisms of action. The sulfonyluereas, repaglinide, metformin, acarbose and the thiazolidinediones are effective in decreasing fasting plasma glucose levels, but their limitations may include adverse effects, such as weight gain and hypoglycemia, and an inability to modify some of the important comorbidities of diabetes. Therapies aimed at treating mealtime hyperglycemia are gaining attention. One promising investigational agent in this category is nateglinide. Early data suggest that its rapid onset and short duration of action result in increased early mealtime insulin release, reduced mealtime glucose excursions, and improved glycemic control.

Topics: Acarbose; Administration, Oral; Blood Glucose; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Combinations; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Insulin-Secreting Cells; Metformin; Nateglinide; Phenylalanine; Piperidines; Randomized Controlled Trials as Topic; Thiazolidinediones; United States; Weight Gain

To compare the effect of adding nateglinide or placebo on postprandial glucose excursions (PPGEs), glycated haemoglobin (HbA(1c)), diurnal glucose profiles and hypoglycaemia in patients with Type 2 diabetes treated with the combination of basal insulin and metformin.. This was an investigator-initiated, double-blind, randomized, parallel-group, study in five centres. Patients with Type 2 diabetes (n = 88, age 56.0 +/- 0.9 years, duration of diabetes 9.4 +/- 0.5 years, HbA(1c) 7.8 +/- 0.1%, body mass index 32.4 +/- 0.5 kg/m(2)) treated with basal insulin and metformin entered a 24-week period, during which basal insulin was titrated to optimize glucose control. Thereafter, the patients were randomized to receive either nateglinide (120 mg three times daily) or placebo before their main meals for 24 weeks.. During the optimization period, HbA(1c) decreased by -0.3 +/- 0.1 and -0.4 +/- 0.2% (NS) and insulin doses increased by 10.0 IU (2.0-32.0) [0.09 IU/kg (0.02-0.34)] and 10.0 IU (0.0-19.0) [0.11 IU/kg (0.0-0.25)] (NS) in the nateglinide and placebo groups. Mean postprandial glucose during weeks 20-24 averaged 9.0 +/- 0.3 and 10.0 +/- 0.3 mmol/l in the nateglinide and placebo groups (P = 0.025) and mean PPGE averaged 2.4 +/- 0.2 and 3.1 +/- 0.2 mmol/l, respectively (P = 0.019). At 24 weeks as compared with 0 weeks, mean HbA(1c) had decreased by 0.41 +/- 0.12% in the nateglinide group and by 0.04 +/- 0.12% in the placebo group (P = 0.023). The frequency of confirmed, symptomatic hypoglycaemia was 7.7 episodes/patient-year vs. 4.7 episodes/patient-year in the nateglinide and placebo groups (P = 0.031).. Addition of a short-acting insulin secretagogue at main meals improves postprandial hyperglycaemia during combination therapy with basal insulin and metformin, but increases the frequency of hypolycaemia.

Topics: Adult; Aged; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Metformin; Middle Aged; Nateglinide; Phenylalanine; Postprandial Period; Young Adult

The aim of this work was to assess the efficacy and tolerability of nateglinide alone or in combination with metformin in elderly patients with type 2 diabetes (T2DM).. Study 1 was a 12-week, multicentre, randomized, double blind and placebo-controlled study of nateglinide monotherapy (120 mg, before meals) in 66 drug-naïve patients with T2DM aged >or=65 years. Study 2 was a 104-week, multicentre, randomized, double blind and active-controlled study of nateglinide (120 mg, before meals) or glyburide (up to 5 mg bid) in combination with metformin (up to 1000 mg bid) in 69 treatment-naïve patients with T2DM aged >or=65 years. HbA(1c), fasting and postprandial glucose levels, and safety assessments were made.. In Study 1, nateglinide significantly reduced HbA(1c) from baseline (7.6 +/- 0.1% to 6.9 +/- 0.1%; Delta = -0.7 +/- 0.1%, p < 0.001) and compared with placebo (between-group difference = -0.5%, p = 0.004 vs. nateglinide). No hypoglycaemia was reported. In Study 2, combination therapy with nateglinide/metformin significantly reduced HbA(1c) from baseline (7.8 +/- 0.2% to 6.6 +/- 0.1%; Delta = -1.2 +/- 0.2%, p < 0.001), as did glyburide/metformin (7.7 +/- 0.1% to 6.5 +/- 0.1%; Delta = -1.2 +/- 0.1%, p < 0.001). There was no difference between treatments (p = 0.310). One nateglinide/metformin-treated patient experienced a mild hypoglycaemic episode compared with eight episodes in eight patients on glyburide/metformin; one severe episode led to discontinuation. Target HbA(1c) (<7.0%) was achieved by 60% of patients receiving nateglinide (Study 1) and 70% of nateglinide/metformin-treated patients (Study 2).. Initial drug treatment with nateglinide, alone or in combination with metformin, is well tolerated and produces clinically meaningful improvements in glycaemic control in elderly patients with T2DM.

Topics: Aged; Aged, 80 and over; Blood Glucose; Body Mass Index; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Female; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Metformin; Middle Aged; Nateglinide; Phenylalanine; Treatment Outcome

To compare long-term efficacy and safety of nateglinide plus metformin with those of gliclazide plus metformin in patients with type 2 diabetes not adequately controlled with metformin monotherapy.. Double-blind, double-dummy, multicentre study extended to a total of 52 weeks. Patients with inadequate glucose control on maximal doses of metformin were randomized to nateglinide (N = 133) or gliclazide (N = 129) add-on treatment. After the initial 6-month study, the majority of patients in the nateglinide group [n = 112 (93.3%)] and in the gliclazide group [n = 101 (92.7%)] entered a 6-month, double-blind, extension study.. There was no significant difference between treatment regimens in haemoglobin Alc (HbA1c) change from baseline to 52 weeks (-0.14% for nateglinide vs. -0.27% for gliclazide; p = 0.396). Proportions of patients achieving an endpoint HbA1c of <7% were similar (40 vs. 47.4%) for nateglinide and gliclazide groups. There was no significant between-treatment difference in fasting plasma glucose change from baseline to 52 weeks (nateglinide: -0.2 mmol/l and gliclazide: -0.7 mmol/l; p = 0.096). The decreases in prandial plasma glucose area under the curve(0-4 h) from baseline were -3.26 and -1.86 h x mmol/l in the nateglinide and the gliclazide groups respectively, and the change was statistically significant in the nateglinide group only (p = 0.006). Initial insulin response to a meal was augmented with nateglinide treatment only, without between-treatment difference in 2-h insulin response. The overall rate of hypoglycaemic events was similar with nateglinide and gliclazide combinations with metformin. Nateglinide plus metformin treatment was not associated with weight gain.. No significant difference was seen between nateglinide plus metformin and gliclazide plus metformin in terms of HbA1c. Treatment with nateglinide plus metformin for up to 12 months was not associated with weight gain.

Topics: Aged; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Gliclazide; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Metformin; Middle Aged; Nateglinide; Phenylalanine; Safety; Time Factors

To study the effect of the short-acting insulin secretagogue nateglinide in patients with maturity-onset diabetes of the young type 3 (MODY3), which is characterized by a defective insulin response to glucose and hypersensitivity to sulfonylureas.. We compared the acute effect of nateglinide, glibenclamide, and placebo on prandial plasma glucose and serum insulin, C-peptide, and glucagon excursions in 15 patients with MODY3. After an overnight fast, they received on three randomized occasions placebo, 1.25 mg glibenclamide, or 30 mg nateglinide before a standard 450-kcal test meal and light bicycle exercise for 30 min starting 140 min after the ingestion of the first test drug.. Insulin peaked earlier after nateglinide than after glibenclamide or placebo (median [interquartile range] time 70 [50] vs. 110 [20] vs. 110 [30] min, P = 0.0002 and P = 0.0025, respectively). Consequently, compared with glibenclamide and placebo, the peak plasma glucose (P = 0.031 and P < 0.0001) and incremental glucose areas under curve during the first 140 min of the test (P = 0.041 and P < 0.0001) remained lower after nateglinide. The improved prandial glucose control with nateglinide was achieved with a lower peak insulin concentration than after glibenclamide (47.0 [26.0] vs. 80.4 [71.7] mU/l; P = 0.023). Exercise did not induce hypoglycemia after nateglinide or placebo, but after glibenclamide six patients experienced symptomatic hypoglycemia and three had to interrupt the test.. A low dose of nateglinide prevents the acute postprandial rise in glucose more efficiently than glibenclamide and with less stimulation of peak insulin concentrations and less hypoglycemic symptoms.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Cross-Over Studies; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Exercise Test; Female; Glucagon; Glyburide; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged; Nateglinide; Phenylalanine; Postprandial Period

An open-label prospective cross-over trial was performed to compare the efficacy and adverse effects of nateglinide with those of voglibose on Japanese early type 2 diabetes (who were oral hypoglycemic agent naïve and whose HbA(1C) levels were between 7.0 and 7.9% before treatment). Fourteen patients received 270 mg/day of nateglinide and 15 patients received 0.6 mg/day of voglibose. After 12 weeks of either therapy, the drugs were switched and treatment was continued for another 12 weeks. After 3-month treatment with each drug, HbA(1C) value decreased significantly (baseline HbA(1C) 7.24 +/- 0.42%, 6.70 +/- 0.47% with nateglinide: p<0.01, 6.93 +/- 0.62% with voglibose: p<0.05) but the difference in the effect between nateglinide and voglibose was not significant (p = 0.121). Symptoms related to hypoglycemia (e.g., increased appetite, palpitation, sweating, tremor) were scarcely observed with either voglibose or nateglinide treatments. Abdominal fullness/borborygmi was frequently reported, with variable severity, by patients on voglibose but this was absent or mild in those on nateglinide. After completion of both arms of the study, more patients favored nateglinide than voglibose. Our results suggest that nateglinide is an effective and safe drug in the treatment of early type 2 diabetes, similar to voglibose.

Topics: Aged; alpha-Glucosidases; Appetite; Body Weight; Cross-Over Studies; Cyclohexanes; Diabetes Mellitus, Type 2; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Gastrointestinal Tract; Glycated Hemoglobin; Humans; Hypoglycemia; Inositol; Lipids; Liver Function Tests; Male; Middle Aged; Nateglinide; Phenylalanine; Treatment Outcome

Nateglinide is a fast-acting insulin secretion agent that specifically targets postprandial hyperglycemia in patients with type 2 diabetes. The recent reduction in the diagnostic criteria for diabetes and improved understanding of the importance of early insulin secretion served as the rationale for this multicenter, double-blind, randomized, parallel-group, 24-wk study performed in 675 patients with type 2 diabetes but only moderately elevated fasting plasma glucose (FPG) (FPG = 7.0-8.3 mmol/liter) to assess the efficacy and safety of three fixed doses of nateglinide (30, 60, or 120 mg, with meals). A substudy of the effects on early insulin release and prandial glucose excursions following a standardized breakfast was performed in 127 subjects. Nateglinide was well tolerated and elicited a dose-dependent reduction of placebo-adjusted hemoglobin A(1c) (Delta = -0.26 to -0.39%) and FPG (Delta = -0.51 to -0.73 mmol/liter) accompanied by a dose-related increase in suspected hypoglycemic episodes. However, confirmed hypoglycemia occurred in only 5.3% of patients treated with the highest dose, compared with 1.2% in placebo-treated patients (P < 0.05). Nateglinide increased early insulin release and reduced prandial glucose excursions (P < 0.05 vs. placebo). In sum, nateglinide is a safe and effective therapeutic option for treatment of patients with mild to moderate fasting hyperglycemia.

Topics: Adult; Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Fasting; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incidence; Insulin; Insulin Secretion; Male; Nateglinide; Phenylalanine; Racial Groups; Treatment Outcome

Serious hypoglycemia is a major adverse event associated with insulin secretagogues. Previous studies have suggested a potential relationship between angiotensin-converting enzyme inhibitors (ACEIs) used with sulfonylureas and serious hypoglycemia, and widely used drug compendia warn of this potential drug-drug interaction. We investigated the association between serious hypoglycemia and concomitant use of ACEIs in patients receiving insulin secretagogues, using the self-controlled case series design and Medicaid claims data from 5 US states linked to Medicare claims from 1999-2011. The exposure of interest was active prescription for ACEIs during insulin secretagogue or metformin (negative control object drug) episodes. The outcome was hospital presentation for serious hypoglycemia, identified by discharge diagnosis codes in inpatient and emergency department claims (positive predictive value ~ 78-89%). We calculated confounder-adjusted rate ratios (RRs) and 95% confidence internals (CIs) of outcome occurrence during ACEI-exposed vs. ACEI-unexposed time using conditional Poisson regression. The RRs for ACEIs were not statistically elevated during observation time of glipizide (RR, 1.06; CI, 0.98-1.15), glyburide (RR, 1.05; CI, 0.96-1.15), repaglinide (RR, 1.15; CI, 0.94-1.41), or metformin (RR, 1.02; CI, 0.97-1.06); but was modestly elevated with glimepiride (RR, 1.23; CI, 1.11-1.37) and modestly reduced with nateglinide (RR, 0.73; CI, 0.56-0.96). The overall pattern of results do not suggest that ACEIs used with insulin secretagogues were associated with increased rates of serious hypoglycemia, with the possible exception of glimepiride.

Topics: Administrative Claims, Healthcare; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Carbamates; Databases, Factual; Diabetes Mellitus, Type 2; Drug Interactions; Female; Glipizide; Glyburide; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Medicaid; Metformin; Middle Aged; Nateglinide; Pharmacoepidemiology; Piperidines; Secretagogues; Sulfonylurea Compounds; United States

This nested case-control study evaluated the potential interaction between repaglinide and clopidogrel. Cases were defined by inpatient admissions or emergency department visits due to hypoglycemia. Concomitant use of repaglinide and clopidogrel within 3 days before the hypoglycemic event was the exposure of interest. For each case, up to four controls were randomly selected and matched by age, sex, type of glinide used (repaglinide or nateglinide), and time since cohort entry to the index date. Hypoglycemic risk was estimated by conditional logistic regressions. Concomitant use of repaglinide and clopidogrel was associated with an increased risk of hypoglycemia compared with repaglinide alone (adjusted odds ratio: 2.42; 95% confidence interval: 1.75-3.35). No significant associations were found with the two negative control object drug concomitants: nateglinide and clopidogrel and repaglinide and aspirin (without clopidogrel use). Our study suggests drug interaction between clopidogrel and repaglinide is clinically relevant and could increase the risk for hypoglycemia.

Topics: Aged; Aspirin; Carbamates; Case-Control Studies; Clopidogrel; Drug Interactions; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Middle Aged; Nateglinide; Piperidines; Platelet Aggregation Inhibitors

Drug-drug interactions with insulin secretagogues are associated with increased risk of serious hypoglycemia in patients with type 2 diabetes. We aimed to systematically screen for drugs that interact with the five most commonly used secretagogues-glipizide, glyburide, glimepiride, repaglinide, and nateglinide-to cause serious hypoglycemia.. We screened 400 drugs frequently coprescribed with the secretagogues as candidate interacting precipitants. We first predicted the drug-drug interaction potential based on the pharmacokinetics of each secretagogue-precipitant pair. We then performed pharmacoepidemiologic screening for each secretagogue of interest, and for metformin as a negative control, using an administrative claims database and the self-controlled case series design. The overall rate ratios (RRs) and those for four predefined risk periods were estimated using Poisson regression. The RRs were adjusted for multiple estimation using semi-Bayes method, and then adjusted for metformin results to distinguish native effects of the precipitant from a drug-drug interaction.. We predicted 34 pharmacokinetic drug-drug interactions with the secretagogues, nine moderate and 25 weak. There were 140 and 61 secretagogue-precipitant pairs associated with increased rates of serious hypoglycemia before and after the metformin adjustment, respectively. The results from pharmacokinetic prediction correlated poorly with those from pharmacoepidemiologic screening.. The self-controlled case series design has the potential to be widely applicable to screening for drug-drug interactions that lead to adverse outcomes identifiable in healthcare databases. Coupling pharmacokinetic prediction with pharmacoepidemiologic screening did not notably improve the ability to identify drug-drug interactions in this case.

Topics: Area Under Curve; Carbamates; Cyclohexanes; Databases, Factual; Diabetes Mellitus, Type 2; Drug Interactions; Glipizide; Glyburide; Humans; Hypoglycemia; Hypoglycemic Agents; Medical Informatics; Nateglinide; Pharmacoepidemiology; Phenylalanine; Piperidines; Sulfonylurea Compounds

Hypoglycaemia is an acute complication associated with intensive treatment of patients with diabetes mellitus. This complication poses a major challenge in diabetes management. Furthermore, severe hypoglycaemia may be life threatening. Although hypoglycaemia is more often associated with insulin treatment, oral hypoglycaemic agents have the potential to trigger hypoglycaemia.. The aim of this study was to quantify the incidence of hypoglycaemic events and to describe the pattern of these incident events during the first 9 months of treatment with four oral antidiabetic drugs, rosiglitazone, pioglitazone, nateglinide and repaglinide, prescribed in general practice in England.. We used data collected for prescription-event monitoring (PEM) studies of rosiglitazone, pioglitazone, nateglinide and repaglinide. PEM is an observational, non-interventional, incept cohort study. Observation time for each patient and incidence rate (IR) per 1000 patient-years of treatment for hypoglycaemia was calculated for each drug cohort. Smoothed hazard estimates were plotted over time. Case/non-case analysis was performed to describe and compare patients who had at least one hypoglycaemic event in the first 9 months of treatment with those who did not.. The total number of patients included in the analysis was 14,373, 12,768, 4,549 and 5,727 in rosiglitazone, pioglitazone, nateglinide and repaglinide cohorts, respectively. From these, 276 patients experienced at least one episode of hypoglycaemia. The IR was between 50% and 100% higher in patients receiving treatment with meglitinides compared with those treated with the thiazolidinediones (TZDs) [IR = 9.94, 9.64, 15.71 and 20.32 per 1,000 patient-years for rosiglitazone, pioglitazone, nateglinide and repaglinide, respectively]. The plot of the hazard function and the estimated shape parameter from the Weibull regression model showed that pioglitazone, nateglinide and repaglinide had non-constant (decreasing) hazards over time, whereas the hazard for rosiglitazone-treated patients was approximately constant over time. Nateglinide and repaglinide had similar shape hazard function, indicating a significantly higher number of hypoglycaemic episodes shortly after starting treatment. For women treated with TZDs, hypoglycaemia was reported more frequently than for men.. This analysis shows that the frequency of reported hypoglycaemia within the study cohorts was relatively low. The rates of hypoglycaemia were not equal between drug classes. Treatment with nateglinide or repaglinide was characterized by a higher incidence of hypoglycaemia at the beginning of treatment. Further investigation is necessary to assess whether women treated with TZDs are more prone to hypoglycaemia than men. Findings from this study should be taken into account with other clinical and pharmacoepidemiological studies.

Topics: Administration, Oral; Adult; Adverse Drug Reaction Reporting Systems; Carbamates; Cohort Studies; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Monitoring; Drug Prescriptions; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Incidence; Male; Middle Aged; Nateglinide; Phenylalanine; Pioglitazone; Piperidines; Rosiglitazone; Sex Factors; Thiazolidinediones

Topics: Aged; Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Female; Gastrointestinal Agents; Glucose; Humans; Hypoglycemia; Hypoglycemic Agents; Nateglinide; Octreotide; Phenylalanine; Treatment Outcome

Topics: Administration, Oral; Cardiovascular Diseases; Cyclohexanes; Diabetes Complications; Diabetes Mellitus; Drug Therapy, Combination; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemia; Hypoglycemic Agents; Indoles; Inositol; Insulin; Insulin Resistance; Insulin Secretion; Isoindoles; Nateglinide; Phenylalanine; Risk Factors; Stimulation, Chemical; Sulfonylurea Compounds; Thiazolidinediones

A 56-year-old woman with diabetic triopathy, rheumatoid arthritis and chronic renal failure was admitted for severe hypoglycemic coma. Arthralgia had been deteriorating for 6 months. Therefore, 5 mg of prednisolone was administered. Postprandial blood glucose (PPG), however, elevated from 260 to 290 mg/dl, although fasting blood glucose (FBG) levels ranged from 80 to 110 mg/dl. Three months after, 270 mg of nateglinide was given in addition to acarbose. After 2 days, hypoglycemia occurred at 02:00 h. Nateglinide was then decreased to 180 mg (before breakfast and lunch). After 5 days, hypoglycemia re-occurred at 01:00 h. Nateglinide was subsequently decreased to 90 mg before breakfast. The PPG levels ranged from 130 to 150 mg/dl. Hypoglycemia did not occur during the next 2 months. On admission, FBG; 59 mg/dl, fasting immunoreactive insulin; 34 microU/ml, indicated hyperinsulinemic hypoglycemia. We administered 20 g of glucose intravenously, however, hypoglycemia recurred 4 times and 20 g of glucose was then administered. Although the plasma nateglinide level decreased, the nateglinide metabolite, N-[trans-4-(1-hydroxy-1methylethyl)-cyclohexanecarbonyl]-D-phenylalanine levels still had not decreased 29 h after nateglinide administration. Therefore, chronic renal failure appeared to alter the pharmacokinetic parameters of the nateglinide metabolite, which had accumulated by chronic renal failure. The nateglinide metabolite caused severe hypoglycemia in this case.

Topics: Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Kidney Failure, Chronic; Middle Aged; Nateglinide; Phenylalanine

Nateglinide (A-4166) is an amino acid derivative with insulinotrophic action in clinical development for treatment of type 2 diabetes. The aim of this study was to determine whether nateglinide's interaction at the K(ATP) channel/sulfonylurea receptor underlies its more rapid onset and shorter duration of action in animal models. Binding studies were carried out with membranes prepared from RIN-m5F cells and HEK-293 cells expressing recombinant human sulfonylurea receptor 1 (SUR1). The relative order for displacement of [(3)H]glibenclamide in competitive binding experiments with RIN-m5F cell membranes was glibenclamide > glimepiride > repaglinide > glipizide > nateglinide > L-nateglinide > tolbutamide. The results with HEK-293/recombinant human SUR1 cells were similar with the exception that glipizide was more potent than repaglinide. Neither nateglinide nor repaglinide had any effect on the dissociation kinetics for [(3)H]glibenclamide, consistent with both compounds competitively binding to the glibenclamide-binding site on SUR1. Finally, the inability to measure [(3)H]nateglinide binding suggests that nateglinide dissociates rapidly from SUR1. Direct interaction of nateglinide with K(ATP) channels in rat pancreatic beta-cells was investigated with the patch-clamp method. The relative potency for inhibition of the K(ATP) channel was repaglinide > glibenclamide > nateglinide. Kinetics of the inhibitory effect on K(ATP) current showed that the onset of inhibition by nateglinide was comparable to glibenclamide but more rapid than that of repaglinide. The time for reversal of channel inhibition by nateglinide was also faster than with glibenclamide and repaglinide. These results suggest that the unique characteristics of nateglinide are largely the result of its interaction at the K(ATP) channel.

Topics: Animals; ATP-Binding Cassette Transporters; Binding, Competitive; Carbamates; Cell Membrane; Cell Separation; Cells, Cultured; Cyclohexanes; Glucose; Glyburide; Glycosyltransferases; Humans; Hypoglycemia; Hypoglycemic Agents; In Vitro Techniques; Insulin; Islets of Langerhans; KATP Channels; Kinetics; Male; Membrane Proteins; Nateglinide; Patch-Clamp Techniques; Phenylalanine; Piperidines; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Inwardly Rectifying; Rats; Rats, Sprague-Dawley; Repressor Proteins; Saccharomyces cerevisiae Proteins; Sulfonylurea Compounds