nateglinide and Diabetes-Mellitus--Type-2

Nateglinide is a meglitinide used for the treatment of type 2 diabetes mellitus. Individual studies demonstrated the association of CYP2C9, SLCO1B1, and MTNR1B variants with the safety and efficacy of nateglinide. The current study aimed to develop a pharmacogenomic algorithm to optimize nateglinide therapy.. Multiple linear regression (MLR) and classification and regression tree (CART) were used to develop a pharmacogenomic algorithm for nateglinide dosing based on the published nateglinide pharmacokinetic data on the area under the curve data (AUC) and C. CYP2C9, SLCO1B1, and MTNR1B genotyping help in optimizing nateglinide therapy based on this algorithm and ensuring safety and efficacy.

Topics: Algorithms; Area Under Curve; Aryl Hydrocarbon Hydroxylases; Cyclohexanes; Cytochrome P-450 CYP2C9; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Liver-Specific Organic Anion Transporter 1; Nateglinide; Pharmacogenetics; Phenylalanine

The projected rise in the incidence of type 2 diabetes mellitus (T2DM) could develop into a substantial health problem worldwide. Whether insulin secretagogues (sulphonylureas and meglitinide analogues) are able to prevent or delay T2DM and its associated complications in people at risk for the development of T2DM is unknown.. To assess the effects of insulin secretagogues on the prevention or delay of T2DM and its associated complications in people with impaired glucose tolerance, impaired fasting blood glucose, moderately elevated glycosylated haemoglobin A1c (HbA1c) or any combination of these.. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform, and the reference lists of systematic reviews, articles and health technology assessment reports. We asked investigators of the included trials for information about additional trials. The date of the last search of all databases was April 2016.. We included randomised controlled trials (RCTs) with a duration of 12 weeks or more comparing insulin secretagogues with any pharmacological glucose-lowering intervention, behaviour-changing intervention, placebo or no intervention in people with impaired fasting glucose, impaired glucose tolerance, moderately elevated HbA1c or combinations of these.. Two review authors read all abstracts and full-text articles/records, assessed quality and extracted outcome data independently. One review author extracted data which were checked by a second review author. We resolved discrepancies by consensus or the involvement of a third review author. For meta-analyses we used a random-effects model with investigation of risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We carried out trial sequential analyses (TSAs) for all outcomes that could be meta-analysed. We assessed the overall quality of the evidence by using the GRADE instrument.. We included six RCTs with 10,018 participants; 4791 participants with data on allocation to intervention groups were randomised to a second- or third-generation sulphonylurea or a meglitinide analogue as monotherapy and 29 participants were randomised to a second-generation sulphonylurea plus metformin. Three trials investigated a second-generation sulphonylurea, two trials investigated a third-generation sulphonylurea and one trial a meglitinide analogue. A total of 4873 participants with data on allocation to control groups were randomised to a comparator group; 4820 participants were randomised to placebo, 23 to diet and exercise, and 30 participants to metformin monotherapy. One RCT of nateglinide contributed 95% of all participants. The duration of the intervention varied from six months to five years. We judged none of the included trials as at low risk of bias for all 'Risk of bias' domains.All-cause and cardiovascular mortality following sulphonylurea (glimepiride) treatment were rarely observed (very low-quality evidence). The RR for incidence of T2DM comparing glimepiride monotherapy with placebo was 0.75; 95% CI 0.54 to 1.04; P = 0.08; 2 trials; 307 participants; very low-quality evidence. One of the trials reporting on the incidence of T2DM did not define the diagnostic criteria used. The other trial diagnosed T2DM as two consecutive fasting blood glucose values ≥ 6.1 mmol/L. TSA showed that only 4.5% of the diversity-adjusted required information size was accrued so far. No trial reported data on serious adverse events, non-fatal myocardial infarction (MI), non-fatal stroke, congestive heart failure (HF), health-related quality of life or socioeconomic effects.One trial with a follow-up of five years compared a meglitinide analogue (nateglinide) with placebo. A total of 310/4645 (6.7%) participants allocated to nateglinide died compared with 312/4661 (6.7%) participants allocated to placebo (hazard ratio (HR) 1.00; 95% CI 0.85 to 1.17; P = 0.98; moderate-quality evidence). The two main criteria for diagnosing T2DM were a fasting plasma glucose level ≥ 7.0 mmol/L or a 2-hour post challenge glucose ≥ 11.1 mmol/L. T2DM developed in 1674/4645 (36.0%) participants in the nateglinide group and in 1580/4661 (33.9%) in the placebo group (HR 1.07; 95% CI 1.00 to 1.15; P = 0.05; moderate-quality evidence). One or more serious adverse event was reported in 2066/4602 (44.9%) participants allocated to nateglinide compared with 2089/4599 (45.6%) participan. There is insufficient evidence to demonstrate whether insulin secretagogues compared mainly with placebo reduce the risk of developing T2DM and its associated complications in people at increased risk for the development of T2DM. Most trials did not investigate patient-important outcomes.

Topics: Adult; Benzamides; Blood Glucose; Cardiovascular Diseases; Cyclohexanes; Diabetes Mellitus, Type 2; Fasting; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Metformin; Middle Aged; Nateglinide; Phenylalanine; Randomized Controlled Trials as Topic; Sulfonylurea Compounds

Glinides, including repaglinide, nateglinide and mitiglinide, are a type of fasting insulin secretagogue that could help to mimic early-phase insulin release, thus providing improved control of the postprandial glucose levels. Glinides stimulate insulin secretion by inhibiting ATP-sensitive potassium channels in the pancreatic β-cell membrane. Although glinides have been widely used clinically and display excellent safety and efficacy, the response to glinides varies among individuals, which is partially due to genetic factors involved in drug absorption, distribution, metabolism and targeting. Several pharmacogenomic studies have demonstrated that variants of genes involved in the pharmacokinetics or pharmacodynamics of glinides are associated with the drug response. Polymorphisms of genes involved in drug metabolism, such as CYP2C9, CYP2C8 and SLCO1B1, may influence the efficacy of glinides and the incidence of adverse effects. In addition, Type 2 diabetes mellitus susceptibility genes, such as KCNQ1, PAX4 and BETA2, also influence the efficacy of glinides. In this article, we review and discuss current pharmacogenomics researches on glinides, and hopefully provide useful data and proof for clinical application.

Topics: Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Inactivation, Metabolic; Insulin; Insulin Secretion; Insulin-Secreting Cells; Isoindoles; KATP Channels; Nateglinide; Pharmacogenetics; Phenylalanine; Piperidines

Type 2 diabetes mellitus (T2DM) is characterized by multiple pathophysiologic abnormalities. With time, multiple glucose-lowering medications are commonly required to reduce and maintain plasma glucose concentrations within the normal range. Type 2 diabetes mellitus individuals also are at a very high risk for microvascular complications and the incidence of heart attack and stroke is increased two- to three-fold compared with non-diabetic individuals. Therefore, when selecting medications to normalize glucose levels in T2DM patients, it is important that the agent not aggravate, and ideally even improve, cardiovascular risk factors (CVRFs) and reduce cardiovascular morbidity and mortality. In this review, we examine the effect of oral (metformin, sulfonylureas, meglitinides, thiazolidinediones, DPP4 inhibitors, SGLT2 inhibitors, and α-glucosidase inhibitors) and injectable (glucagon-like peptide-1 receptor agonists and insulin) glucose-lowering drugs on established CVRFs and long-term studies of cardiovascular outcomes. Firm evidence that in T2DM cardiovascular disease can be reversed or prevented by improving glycaemic control is still incomplete and must await large, long-term clinical trials in patients at low risk using modern treatment strategies, i.e., drug combinations designed to maximize HbA1c reduction while minimizing hypoglycaemia and excessive weight gain.

Topics: Carbamates; Clinical Trials as Topic; Coronary Artery Disease; Cyclohexanes; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Insulin; Metformin; Nateglinide; Phenylalanine; Piperidines; Sodium-Glucose Transport Proteins; Sulfonylurea Compounds; Thiazolidinediones; Treatment Outcome

Insulin secretagogues promote insulin release by binding to sulfonylurea receptors on pancreatic β-cells (SUR1). However, these drugs also bind to receptor isoforms on cardiac myocytes (SUR2A) and vascular smooth muscle (SUR2B). Binding to SUR2A/SUR2B may inhibit ischaemic preconditioning, an endogenous protective mechanism enabling cardiac tissue to survive periods of ischaemia. This study was designed to identify insulin secretagogues that selectively bind to SUR1 when given at therapeutic doses.. Using accepted systematic review methods, three electronic databases were searched from inception to 13 June 2011. Original studies measuring the half-maximal inhibitory concentration (IC(50)) for an insulin secretagogue on K(ATP) channels using standard electrophysiological techniques were included. Steady-state concentrations (C(SS)) were estimated from the usual oral dose and clearance values for each drug.. Data were extracted from 27 studies meeting all inclusion criteria. IC(50) values for SUR1 were below those for SUR2A/SUR2B for all insulin secretagogues and addition of C(SS) values identified three distinct patterns. The C(SS) for gliclazide, glipizide, mitiglinide and nateglinide lie between IC(50) values for SUR1 and SUR2A/SUR2B, suggesting that these drugs bind selectively to pancreatic receptors. The C(SS) for glimepiride and glyburide (glibenclamide) was above IC(50) values for all three isoforms, suggesting these drugs are non-selective. Tolbutamide and repaglinide may have partial pancreatic receptor selectivity because IC(50) values for SUR1 and SUR2A/SUR2B overlapped somewhat, with the C(SS) in the midst of these values.. Insulin secretagogues display different tissue selectivity characteristics at therapeutic doses. This may translate into different levels of cardiovascular risk.

Topics: Animals; ATP-Binding Cassette Transporters; Carbamates; Cardiovascular Diseases; Cricetinae; Cyclohexanes; Diabetes Mellitus, Type 2; Gliclazide; Glipizide; Glyburide; Humans; Hypoglycemic Agents; Ischemic Preconditioning, Myocardial; Isoindoles; Mice; Muscle, Smooth, Vascular; Myocytes, Cardiac; Nateglinide; Phenylalanine; Piperidines; Potassium Channels, Inwardly Rectifying; Rats; Receptors, Drug; Risk Factors; Sulfonylurea Compounds; Sulfonylurea Receptors; Tolbutamide

The recent Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial reported that nateglinide, a non-sulfonylurea insulin secretagogue, failed to prevent progression from impaired glucose tolerance to diabetes. In order to determine the beneficial effect of insulin secretagogues as a class in diabetes prevention, we performed a literature search for randomized controlled studies and review articles on diabetes prevention and use of sulfonylureas, nateglinide, and meglitinide in PubMed and Ovid Medline since 1950. Three studies were identified with none of them reporting success in preventing diabetes, indicating that insulin secretagogues should not be recommended for diabetes prevention.

Topics: Benzamides; Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Disease Progression; Evidence-Based Medicine; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Nateglinide; Phenylalanine; Preventive Health Services; Sulfonylurea Compounds; Treatment Outcome

Topics: Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metabolic Syndrome; Nateglinide; Phenylalanine; Sulfonylurea Compounds

It has been hypothesized that reducing postprandial glucose spikes would result both in improved overall glycemic control and long-term (especially cardiovascular) outcomes in patients with type 2 diabetes. Nateglinide, a short-acting insulin secretagogue of the meglitinide class of antidiabetic agents, has been marketed for the past decade specifically to address the diminished postprandial insulin secretion. It is thus timely to review our experience with this agent.. This review summarizes findings from the key preclinical and pivotal clinical research studies that eventually led to drug approval. The literature search involved both original experimental studies and subsequent comprehensive reviews of the subject. The search included the databases (in English language) in the PubMed (maintained by the US Library of Medicine) domain as well as review of the articles in the author's files spanning the years 1995 - 2011.. The author's subjective feelings about our understanding of the importance of controlling postprandial glucose excursions and what, if any, effect nateglinide has had in that respect since its introduction are given. Despite promising animal and human research data, no evidence has accumulated to date to suggest that addressing postprandial hyperglycemia with nateglinide (or any other antidiabetic medication for that matter) leads to improved outcomes in patients with type 2 diabetes mellitus.

Topics: Animals; Blood Glucose; Clinical Trials, Phase II as Topic; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hyperglycemia; Hypoglycemic Agents; Nateglinide; Phenylalanine; Randomized Controlled Trials as Topic

The purpose of this study is to evaluate efficacy and safety of nateglinide tablet administration in comparison with those of repaglinide tablet as control on treating type 2 diabetes mellitus in China. Pooled-analysis with analysis of covariance (ANCOVA) method was applied to assess the efficacy and safety based on original data collected from four independent randomized clinical trials with similar research protocols. However meta-analysis was applied based on the outcomes of the four studies. The results by meta-analysis were comparable to those obtained by pooled-analysis. The means of HbA(1c), and fasting blood glucose in both the nateglinide and repaglinide groups were reduced significantly after 12 weeks duration but no statistical differences in reduction between the two groups. The adverse reaction rates were 9.89 and 6.51% in the nateglinide and repaglinide groups respectively, with the rate difference showing no statistical significance, and the Odds Ratio of adverse reaction rate (95% confidence interval) was 1.59 (0.99, 2.55). Both nateglinide and repaglinide administration have similarly significant effects on reducing HbA(1c) and FBG. However, the adverse reaction rate in the nateglinide group is higher than that in the latter using repaglinide but no statistical significance difference as revealed in the four clinical trials detailed below.

Topics: Carbamates; China; Cyclohexanes; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Nateglinide; Phenylalanine; Piperidines

Topics: alpha-Galactosidase; Biguanides; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Combinations; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Insulin; Nateglinide; Phenylalanine; Piperidines; Pyrazines; Sitagliptin Phosphate; Sulfonylurea Compounds; Thiazolidinediones; Triazoles

The increasing prevalence of type 2 diabetes provides impetus for both development of new drugs to improve glycemic control and for reconsideration of treatment strategies with existing agents. Combination therapy with complementary drug classes that act on different aspects of glycemic control has been a particularly effective strategy. This work reviews the published literature reporting efficacy and safety/tolerability of nateglinide, a rapid-onset insulinotropic agent with a predominant effect to reduce postprandial glucose, when combined with metformin, a first-line agent that suppresses hepatic glucose production and thereby reduces fasting plasma glucose. The nateglinide/metformin combination has consistently been found to be both efficacious and well tolerated, whether given as initial combination therapy in drug-naïve patients or when added to metformin monotherapy. Maximum efficacy (Delta glycosylated hemoglobin [HbA(1c)]= -1.4% to -1.9%, sustained for up to 2 years of treatment) was seen in studies of drug-naïve patients in whom pharmacotherapy was initiated with the combination of nateglinide and metformin, and modest reductions in HbA(1c) (Delta = -0.5% to -1.2%, sustained for up to 24 weeks) were found when nateglinide was added to ongoing metformin monotherapy.. the combination of nateglinide and metformin provides a sustained degree of glycemic control not achievable with either agent given as monotherapy.

Topics: Blood Glucose; Clinical Trials as Topic; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Metformin; Nateglinide; Phenylalanine; Treatment Outcome

In type 2 diabetes mellitus, impairment of insulin secretion is an important component of the disease. Meglitinide analogues are a class of oral hypoglycaemic agents that increase insulin secretion, in particular, during the early phase of insulin release.. The aim of this review was to assess the effects of meglitinide analogues in patients with type 2 diabetes mellitus.. We searched several databases including The Cochrane Library, MEDLINE and EMBASE. We also contacted manufacturers and searched ongoing trials databases, and the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) websites.. We included randomised controlled, parallel or cross-over trials comparing at least 10 weeks of treatment with meglitinide analogues to placebo, head-to-head, metformin or in combination with insulin.. Two authors independently extracted data and assessed trial quality.. Fifteen trials involving 3781 participants were included. No studies reported the effect of meglitinides on mortality or morbidity. In the eleven studies comparing meglitinides to placebo, both repaglinide and nateglinide resulted in a reductions in glycosylated haemoglobin (0.1% to 2.1% reduction in HbA1c for repaglinide; 0.2% to 0.6% for nateglinide). Only two trials compared repaglinide to nateglinide (342 participants), with greater reduction in glycosylated haemoglobin in those receiving repaglinide. Repaglinide (248 participants in three trials) had a similar degree of effect in reducing glycosylated haemoglobin as metformin. Nateglinide had a similar or slightly less marked effect on glycosylated haemoglobin than metformin (one study, 355 participants). Weight gain was generally greater in those treated with meglitinides compared with metformin (up to three kg in three months). Diarrhoea occurred less frequently and hypoglycaemia occurred more frequently but rarely severely enough as to require assistance.. Meglitinides may offer an alternative oral hypoglycaemic agent of similar potency to metformin, and may be indicated where side effects of metformin are intolerable or where metformin is contraindicated. However, there is no evidence available to indicate what effect meglitinides will have on important long-term outcomes, particularly mortality.

Topics: Benzamides; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin; Nateglinide; Phenylalanine; Piperidines; Randomized Controlled Trials as Topic

Impaired insulin secretion occurs early in the pathogenesis of type 2 diabetes mellitus (T2DM) and is chronic and progressive, resulting initially in impaired glucose tolerance (IGT) and eventually in T2DM. As most patients with T2DM have both insulin resistance and insulin deficiency, therapy for T2DM should aim to control not only fasting, but also postprandial plasma glucose levels. While oral glucose-lowering treatment with metformin and thiazolidinediones corrects fasting plasma glucose, these agents do not address the problem of mealtime glucose spikes that have been shown to trigger atherogenic processes. Nateglinide is a derivative of the amino acid D-phenylalanine, which acts directly on the pancreatic beta-cells to stimulate insulin secretion. Nateglinide monotherapy controls significantly mealtime hyperglycemia and results in improved overall glycemic control in patients with T2DM by reducing glycosylated hemoglobin (HbA1c) levels. The combination of nateglinide with insulin-sensitising agents, such as metformin and thiazolidinediones, targets both insulin deficiency and insulin resistance and results in reductions in HbA1c that could not be achieved by monotherapy with other antidiabetic agents. In prediabetic subjects with IGT, nateglinide restores early insulin secretion and reduces postprandial hyperglycemia. Nateglinide has an excellent safety and tolerability profile and provides a lifetime flexibility that other antidiabetic agents could not accomplish. The aim of this review is to identify nateglinide as an effective "gate-keeper" in T2DM, since it restores early-phase insulin secretion and prevents mealtime glucose spikes throughout the day and to evaluate the results of ongoing research into its potential role in delaying the progression to overt diabetes and reducing its complications and mortality.

Topics: Cyclohexanes; Diabetes Mellitus, Type 2; Fasting; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; KATP Channels; Nateglinide; Phenotype; Phenylalanine; Postprandial Period

Topics: Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metabolic Syndrome; Nateglinide; Phenylalanine; Sulfonylurea Compounds

Topics: Cardiovascular Diseases; Clinical Trials as Topic; Cyclohexanes; Diabetes Mellitus, Type 2; Glucose Intolerance; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Nateglinide; Obesity; Phenylalanine; Postprandial Period; Risk Factors

Topics: Cardiovascular Diseases; Cyclohexanes; Diabetes Mellitus, Type 2; Endpoint Determination; Glucose Intolerance; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Life Style; Nateglinide; Phenylalanine; Primary Prevention; Randomized Controlled Trials as Topic; Risk

Topics: Acarbose; Cyclohexanes; Diabetes Mellitus, Type 2; Diet Therapy; Enzyme Inhibitors; Exercise Therapy; Glucose; Glucose Intolerance; Glycogen; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Metformin; Nateglinide; Phenylalanine; Sulfonylurea Compounds; Thiazolidinediones

Therapy for type 2 diabetes mellitus should aim to control not only fasting, but also postprandial glucose levels. Nateglinide, a d-phenylalanine derivative, restores postprandial early phase insulin secretion in a transient and glucose-sensitive manner without affecting basal insulin levels. As nateglinide is administered immediately before meals it provides greater lifestyle flexibility than agents that require patients to eat to avoid hypoglycemic events (e.g. long-acting sulfonylureas). In randomised, double-blind trials in patients with type 2 diabetes, nateglinide monotherapy (mealtime treatment of 120 mg three times daily) significantly improved long-term glycaemic control by significantly reducing glyated haemoglobin (HbA 1c) and preventing mealtime glucose spikes. The combination of nateglinide with insulin-sensitising agents, for example, metformin and thiazolidinediones, addresses the dual defects of loss of insulin secretion and insulin resistance to provide optimal management of type 2 diabetes, and more patients achieve HbA 1c goal with nateglinide combination therapy rather than with monotherapy with other oral agents. Nateglinide also restores early insulin secretion and reduces postprandial hyperglycaemia in prediabetic subjects with impaired glucose tolerance (IGT) and appears similarly effective in elderly and non-elderly populations with type 2 diabetes. It has an excellent safety and tolerability profile, with a low propensity to cause hypoglycaemia due to its transient, selective effect on early phase insulin secretion. Nateglinide as monotherapy or combination therapy is an effective option to reduce mealtime glucose in patients with type 2 diabetes. The results of ongoing research into its potential role in delaying progression to overt diabetes, and protecting against cardiovascular events, in prediabetic patients with IGT are awaited.

Topics: Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin; Nateglinide; Phenylalanine

The mechanisms by which postprandial hyperglycemia is elicited were discussed through therapies of type 2 diabetes using "glinides". It has been believed that the earliest determinant of progression to type 2 diabetes is a loss of early insulin secretion, a defect which results in postprandial hyperglycemia and is often believed to reflect insulin resistance. To prove that, we improved insulin secretion pattern without increase of total amount of insulin secretion using glinide and assessed glucose response. Glinide which selectively enhances early meal-induced insulin secretion improved postprandial hyperglycemia, could provide a valuable treatment option in the prevention and treatment of type 2 diabetes.

Topics: Cyclohexanes; Diabetes Mellitus, Type 2; Eating; Humans; Hyperglycemia; Hypoglycemic Agents; Indoles; Insulin; Insulin Secretion; Isoindoles; Nateglinide; Phenylalanine

Topics: Adult; Blood Glucose; Blood Glucose Self-Monitoring; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Insulin; Metformin; Nateglinide; Patient Education as Topic; Phenylalanine; Sulfonylurea Compounds

The prevalence and medical and economic impact of type 2 diabetes mellitus is increasing in Western societies. New agents have been developed that act primarily to reduce postprandial glucose excursions, which may be of particular significance now that postprandial glucose excursions are known to be correlated with cardiovascular morbidity and mortality. Nateglinide is a phenylalanine derivative that blocks K+ channels in pancreatic beta-cells, facilitating insulin secretion. Nateglinide sensitises beta-cells to ambient glucose, reducing the glucose concentration needed to stimulate insulin secretion. The pharmacokinetics of nateglinide are characterised by rapid absorption and elimination, with good (73%) bioavailability. Nateglinide is more rapidly absorbed when given 0-30 minutes prior to meal ingestion than if given during the meal. Nateglinide is extensively metabolised, primarily by cytochrome P450 2C9, and eliminated primarily by the kidney. Nateglinide pharmacokinetics are linear over the dose range 60-240 mg. No significant pharmacokinetic alterations occur in renally impaired patients, in the elderly, or in mildly hepatically impaired patients. Nateglinide administered prior to meals stimulates rapid, short-lived insulin secretion in a dose-dependent manner, thus decreasing mealtime plasma glucose excursions. Its effects on insulin secretion are synergistic with those of a meal. With increasing nateglinide doses, the risk of hypoglycaemia also increases, but its incidence is low. Even if a meal is missed, and the patient skips the dose of nateglinide (as recommended in the event of a missed meal), the incidence of subsequent hypoglycaemia remains low compared with long-acting agents. The postprandial insulinotropic effects of nateglinide are more rapid than those of repaglinide and more rapid and greater than those of glibenclamide (glyburide), while producing less prolonged insulin exposure and less risk of delayed hypoglycaemia. Further investigation is required to determine if nateglinide inhibition of postprandial glucose excursions will help to prevent diabetic complications or preserve pancreatic beta-cell function.

Topics: Area Under Curve; Biological Availability; Clinical Trials as Topic; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Interactions; Food; Half-Life; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Liver; Metabolic Clearance Rate; Nateglinide; Phenylalanine; Protein Binding; Structure-Activity Relationship; Tissue Distribution

To evaluate the impact of renal impairment (RI) (estimated creatinine clearance [Cl(cr)] <60 ml/min per 1.73 m(2)) and low baseline HbA(1c) (<7.5%) on comorbidity in patients with type 2 diabetes, and to assess the efficacy and safety of nateglinide monotherapy in these patients and in subgroups of patients over age 64 years (elderly) and elderly with RI.. Retrospective subgroup analyses were performed on pooled data from all completed nateglinide studies (12 randomized, double blind trials and 1 open trial) in patients with type 2 diabetes. A total of 3,702 patients with > or =1 postbaseline safety evaluation received monotherapy with nateglinide (n = 2,204), metformin (n = 436), glyburide (n = 293), or placebo (n = 769). Efficacy (HbA(1c)) was evaluated in pooled data from four studies with similar design using 120 mg nateglinide (n = 544) versus placebo (n = 521). Evaluations were performed in the overall population and subgroups of patients over age 64 years. Specific considerations were given to RI, comorbidity, and baseline HbA(1c).. Patients over age 64 years (n = 1,170) represented 31.6% of the study population. Undiagnosed RI was common in the elderly with 83.4% of all patients being in this subgroup. Patients over 64 years with RI had a higher prevalence of cardio- and microvascular comorbidity compared with the overall population and all patients over age 64 years. Statistically significant HbA(1c) reductions versus placebo were observed with nateglinide in patients over age 64 years and elderly with RI patients at study end point (-0.9% and -1.1% in each subgroup, P < 0.01). Nateglinide was well tolerated with a low incidence of hypoglycemia in all subgroups, including those with RI and low baseline HbA(1c).. RI and comorbidity are common in patients over age 64 years with type 2 diabetes. Nateglinide was effective and well tolerated in all treated patients. In subgroups in which metformin and long-acting sulfonylureas must be used with caution, nateglinide had a low risk of adverse events and hypoglycemia.

Topics: Aged; Blood Glucose; Body Mass Index; Comorbidity; Cyclohexanes; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Metformin; Nateglinide; Phenylalanine; Randomized Controlled Trials as Topic; Retrospective Studies

Several epidemiological studies have shown an association between postprandial hyperglycemia and mortality from cardiovascular disease. Postprandial hyperglycemia is frequently associated with visceral obesity which plays a key role in metabolic abnormalities such as dyslipidemia and hypertension. Inhibitors of alpha-glucosidase and nateglinide have beneficial effects on the metabolic syndrome associated with visceral obesity. Voglibose in combination with diet therapy reduces visceral fat deposition and ameliorates insulin resistance. Acarbose slightly reduces blood pressure of hypertensive diabetic patients. Nateglinide, a rapidly acting insulin secretagogue, lowers postprandial glucose levels without significant body weight gain. These drugs may protect pancreatic beta-cells from postprandial glucose toxicity and prevent the progression of diabetes.

Topics: Acarbose; Cyclohexanes; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Glycoside Hydrolase Inhibitors; Humans; Hyperglycemia; Hypertension; Hypoglycemic Agents; Inositol; Insulin Resistance; Nateglinide; Obesity; Phenylalanine; Postprandial Period

Patients with type 2 diabetes mellitus are associated with insulin resistance and/or impaired insulin secretion. Previous observations indicate that Japanese patients with type 2 diabetes tend to have impaired insulin response after glycemic load more often than Caucasian counterparts. Recently it has been reported that hyperglycemia after glucose load is itself a risk factor for the development of cardiovascular complications in the absence of elevated fasting plasma glucose. Recent observations on the association of post-challenge or post-prandial hyperglycemia with cardiovascular events suggest that lowering post-prandial plasma glucose may protect patients from developing cardiovascular diseases. Results of STOP-NIDDM trial suggest that nateglinide, which attenuates post-prandial glycemic surge in type 2 diabetes, may also be helpful for the protection against cardiovascular events. Nateglinide exerts its effects shortly after its administration and the effects continue for only about 3 hours. The patients receiving this agent rarely gain weight and develop hypoglycemia. This agent exerts hypoglycemic effects additively with alpha-gulucosidase inhibitors or metformin.

Topics: Cardiovascular Diseases; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Hyperglycemia; Hypoglycemic Agents; Indoles; Insulin; Insulin Resistance; Insulin Secretion; Isoindoles; Metformin; Nateglinide; Phenylalanine; Postprandial Period; Stimulation, Chemical

[symbol: see text] Nateglinide (Starlix-Novartis) and [symbol: see text] repaglinide (NovoNorm-Novo Nordisk) are two of a new class of orally active antidiabetic drugs, the meglitinides. They have a rapid-onset and short-lasting stimulating effect on insulin secretion. Both are licensed for combination therapy with metformin in patients with type 2 diabetes mellitus who are inadequately controlled by maximally tolerated doses of metformin alone. In addition, repaglinide is licensed for use as monotherapy in patients with type 2 diabetes whose hyperglycaemia can no longer be controlled satisfactorily by diet, weight reduction and exercise. Here we discuss whether repaglinide and nateglinide offer worthwhile advantages in the management of patients with type 2 diabetes.

Topics: Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Humans; Hypoglycemic Agents; Nateglinide; Phenylalanine; Piperidines; Randomized Controlled Trials as Topic; Treatment Outcome

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

The expression meglitinide analogs was introduced in 1995 to cover new molecules proposed as non-sulfonylurea insulinotropic agents and displaying structural analogy with meglitinide, such as repaglinide, nateglinide, and mitiglinide. Meglitinide analogs display, as judged by conformation analysis, a U-shaped configuration similar to that of antihyperglycemic sulfonylureas such as glibenclamide (glyburide) and glimepiride. In rat pancreatic islets incubated in the presence of 7.0 mmol/L D-glucose, repaglinide and mitiglinide demonstrate comparable concentration-response relationships for stimulation of insulin release, with a threshold value < 10 nmol/L and a maximal secretory response at about 10 nmol/L. Several findings indicate that meglitinide analogs provoke the closing of adenosine triphosphate-sensitive potassium channels, with subsequent gating of voltage-sensitive calcium channels. The effects of meglitinide analogs upon the binding of [3H]glibenclamide to islet cells membranes reinforces this concept. At variance, however, with other meglitinide analogs, the ionic and secretory response to repaglinide (10 micromol/L) is not rapidly reversible in perifused rat islets. In experiments conducted in vivo in control and diabetic rats, repaglinide provokes a greater and more rapid increase in plasma insulin concentration and an earlier fall in glycemia than glibenclamide or glimepiride. Onset of effect is also more rapid and duration of effect shorter with nateglinide versus glibenclamide. In clinical studies, single or repeated daily administration of repaglinide increased plasma insulin concentration in a dose-dependent manner, with an incremental peak reached about 2 hours after repaglinide intake. Plasma concentrations of repaglinide are about 5.0 microg/L 2-2.5 hours after oral intake of the drug. Despite the slow reversibility of repaglinide action in vitro, this drug offers advantages over glibenclamide in terms of the possible occurrence of hypoglycemia if a meal is missed. In volunteers receiving a single oral dose of nateglinide (120mg) 10 minutes before a standardized 800 Kcal breakfast, the plasma insulin concentration was higher 5, 10, and 20 minutes after meal intake than when they received a single dose of repaglinide (0.5 or 2.0mg) or placebo 10 minutes before breakfast. Peak plasma concentrations of nateglinide were reached within 2 hours in most volunteers. Peak plasma concentrations of mitiglinide were reached 30 minutes after a sing

Topics: Animals; Benzamides; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Nateglinide; Phenylalanine; Piperidines

Existing oral insulin secretagogues, sulphonylureas, are associated with hyperinsulinaemia, risk of hypoglycaemia and weight gain. Furthermore, they are not able to offer durable glycaemic control in patents with type 2 diabetes and are associated with progressive decline of beta-cell function. New insulin secretagogues offer an exciting opportunity. Repaglinide, the first prandial glucose regulator, now has convincing data that, compared to sulphonylurea use, it has a lower risk of hypoglycaemia. When used in a flexible dosing regime in a large cohort of patients, it is associated with better glycaemic control, a reduction in HbA1c, weight loss and improved quality of life compared to sulphonylureas. Early data shows the possibility of an effective combination with night time isophane insulin with significant falls in HbA1c and lower doses of insulin required. Nateglinide is an amino acid derivative. It again acts directly on the pancreatic beta-cell. Because of its very short duration of action, and the fact that it appears to secrete insulin in a glucose-dependent manner, it appears to secrete insulin in the closest way to that seen in a person without diabetes. Early data, both in monotherapy and in combination with metformin, show that it is an effective agent in terms of lowering HbA1c, has a low risk of hypoglycaemia and potentially less risk of significant weight gain. These characteristics mean that it may be the ideal agent to be used very early in the disease process, or even in subjects with impaired glucose tolerance, in whom early-phase insulin response is already lost. However these concepts, at the present time, are unproven.

Topics: Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Hyperglycemia; Hyperinsulinism; Hypoglycemic Agents; Insulin; Insulin Secretion; Islets of Langerhans; Nateglinide; Phenylalanine; Piperidines; Postprandial Period; Sulfonylurea Compounds; United Kingdom

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

Topics: Acarbose; Biguanides; Clinical Trials as Topic; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Insulin; Metformin; Nateglinide; Patient Selection; Phenylalanine; Sulfonylurea Compounds; Treatment Outcome

Tight blood glucose control is a primary aim of type 2 diabetes treatment. Combining metformin with the amino acid derivative, nateglinide, tackles both beta cell dysfunction and insulin resistance, and produces a greater decrease in haemoglobin A1c levels than treatment with either drug alone.

Topics: Blood Glucose; Clinical Trials as Topic; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Metformin; Nateglinide; Phenylalanine; Postprandial Period

Increasingly, type 2 diabetes takes a toll on public health and healthcare costs in the United States. Although the remedy for this growing problem is very complex, two critical components of its control are prevention and effective therapy. Progress in diabetes prevention is likely to take decades. But fortunately, growth in our understanding of what occurs in this chronic disease has led to advances in the pharmacologic options aimed at decreasing hyperglycemia, the main clinically measurable metabolic consequence of diabetes. In this article, Drs Ahmann and Riddle provide an overview of the oral agents now available for the treatment of diabetes and discuss the clinical factors that help determine when to use which medication and what outcome to expect.

Topics: Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Monitoring; Drug Therapy, Combination; Glycoside Hydrolases; Humans; Hypoglycemic Agents; Metformin; Nateglinide; Phenylalanine; Piperidines; Receptors, Cytoplasmic and Nuclear; Sulfonylurea Compounds; Transcription Factors

Topics: Blood Glucose; Clinical Trials as Topic; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Interactions; Humans; Hypoglycemic Agents; Nateglinide; Phenylalanine

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, interactions, and dosage of nateglinide are reviewed. Nateglinide is an oral hypoglycemic agent approved for use alone or in combination with metformin as an adjunct to diet and exercise for the treatment of type 2 diabetes mellitus. Nateglinide, an amino acid derivative of D-phenylalanine, stimulates the secretion of insulin by binding to the ATP potassium channels in pancreatic beta cells. The result is an increase in beta-cell calcium influx, which leads to rapid, short-lived insulin release. The drug is rapidly and completely absorbed in the small intestine. The estimated bioavailability is 72%. Nateglinide is highly bound to plasma proteins, is metabolized extensively by the liver, and has an elimination half-life of 1.4 hours. Several clinical trials of nateglinide, alone and in combination with other oral hypoglycemic agents, have found the drug to be safe, effective, and well tolerated. The most common adverse effects are nausea, diarrhea, dizziness, and lightheadedness. There is a potential for interactions between nateglinide and medications affected by the cytochrome P-450 isoenzyme system. Dosage regimens ranging from 60 to 240 mg have been evaluated. The maximum effective dosage is 120 mg taken 10 minutes before meals three times a day. Nateglinide is an alternative to second-generation sulfonylureas for the treatment of type 2 diabetes mellitus. Additional comparative trials are needed to fully elucidate nateglinide's role.

Topics: Biological Availability; Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Administration Schedule; Half-Life; Humans; Hypoglycemic Agents; Male; Nateglinide; Phenylalanine; Randomized Controlled Trials as Topic

The loss of early insulin secretion appears to be a critical event in the deterioration in glucose tolerance during the development of type 2 diabetes. There is therefore a strong rationale for developing new antidiabetic agents aimed at restoring or replacing early prandial insulin secretion and thereby curbing mealtime glucose excursions in patients with type 2 diabetes. Four such new agents are either now available (repaglinide and nateglinide) or in clinical development (KAD-1229 and BTS 67 582). Preclinical studies suggest that each of these new insulinotropic agents share a common receptor/effector mechanism with the sulfonylureas (SUs) but that each may have distinct characteristics that differentiate them from the SUs and from each other. Nateglinide and KAD-1229 clearly stimulate biphasic insulin secretion in vitro and in vivo and their effects are rapidly reversible, whereas the effects of repaglinide and BTS 67 582 are prolonged well beyond their removal from perfusion media in vitro or their clearance in vivo. Available data from human studies indicate that the pharmacokinetics of repaglinide and nateglinide are similar, i.e., they are both rapidly absorbed and eliminated, but consistent with findings from animal studies, the insulinotropic and glucose-lowering effects of repaglinide are slower in onset and more prolonged than those of nateglinide. Repaglinide and nateglinide have been shown to be safe and well-tolerated in patients with type 2 diabetes and to produce clinically-meaningful reductions of HbA1c, both alone and in combination with agents with complementary modes of action (e.g., metformin and thiazolidinediones). Because these new agents can potentially bring patients to near normoglycemia without an undue risk of hypoglycemia, they are important additions to the therapeutic armamentarium.

Topics: Animals; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Glucose; Guanidines; Humans; Hypoglycemic Agents; Indoles; Insulin; Insulin Secretion; Isoindoles; Nateglinide; Phenylalanine; Piperidines

The United Kingdom Prospective Diabetes Study has shown that tight glycaemic control significantly reduces microvascular complications in Type 2 diabetes, but the effects on macrovascular complications were less impressive and did not reach statistical significance. Epidemiological studies have shown that post-prandial hyperglycaemia, rather than fasting hyperglycaemia, is more closely related to cardiovascular complications. It is, therefore, possible that previous studies may have overlooked the possible benefits of tight control of post-prandial hyperglycaemia as an important factor in reducing the cardiovascular mortality. Nateglinide is a novel D-phenylalanine derivative that inhibits ATP-sensitive K+ channels in pancreatic beta-cells in the presence of glucose and thereby restores first phase insulin response in patients with Type 2 diabetes. This helps in reducing post-prandial glucose excursion. Combination studies with metformin have shown it to be effective in controlling hyperglycaemia. While metformin reduces the basal plasma glucose, nateglinide helps in controlling post-prandial peaks. Nateglinide provides a new therapeutic option for treating Type 2 diabetes by specifically targeting post-prandial hyperglycaemia.

Topics: Animals; Clinical Trials as Topic; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Guidelines as Topic; Humans; Hyperglycemia; Hypoglycemic Agents; Metformin; Microcirculation; Molecular Structure; Nateglinide; Phenylalanine; Postprandial Period

To review the pharmacology, pharmacokinetics, dosing guidelines, adverse effects, drug interactions, and clinical efficacy of nateglinide.. Primary and review articles regarding nateglinide were identified by MEDLINE search (from 1966 to January 2001); abstracts were identified through the Institute for Scientific Information Web of Science (from 1995 to January 2001) and the American Diabetes Association; additional information was obtained from the nateglinide product information.. All articles and meeting abstracts identified from the data sources were evaluated and all information deemed relevant was included in this review. Much of the information was from abstracts or the product labeling, since few clinical studies have been published in the medical literature.. Nateglinide is a novel nonsulfonylurea oral antidiabetic agent that stimulates insulin secretion from the pancreas. It has a rapid onset and short duration of action, allowing administration before a meal to reduce postprandial hyperglycemia. Improvement in glycemic control with nateglinide monotherapy has been demonstrated in patients not previously treated with antidiabetic medications. Greater improvement in glycemic control was observed when nateglinide was administered in combination with metformin.. Nateglinide is similar to repaglinide, but has a quicker onset of action, quicker reversal, and does not usually require dosage titration. Based on the pharmacodynamics of nateglinide and repaglinide, nateglinide produces a more rapid postprandial increase in insulin secretion, and its duration of response is shorter than that of repaglinide. The risk of postabsorptive hypoglycemia should be lower than with either sulfonylureas or repaglinide.

Topics: Animals; Clinical Trials as Topic; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Nateglinide; Phenylalanine

The loss of early-phase insulin secretion is an important and early event in the natural history of type 2 diabetes. Because a normal pattern of insulin secretion is essential for the effective control of postprandial metabolism, a rational basis for the development of agents that target early-phase insulin release exists. Conventional oral hypoglycaemic agents do not target, or adequately control, postprandial glycaemia. The emergence of new classes of oral agent with a more specific mode of action provides, for the first time, an opportunity to restore early-phase insulin release. One such drug class is the meglitinide analogues (repaglinide, nateglinide, and mitiglinide). These drugs are ideally suited for combination use with metformin. They could also prove effective in combination with a thiazolidinedione, a drug class that targets insulin resistance. Exogenous insulin is frequently required in the late management of type 2 diabetes. However, one hope for newer combinations of diabetic drugs is that the functional life of the beta cell can be extended, thereby delaying the need for insulin injections.

Topics: Adult; Animals; Benzamides; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Nateglinide; Phenylalanine; Piperidines; Rats

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

A central finding of the UKPDS was that in type 2 diabetic patients, tight glycemic control with HbA1c targets as close to the normal range as possible must be achieved to further reduce diabetes related-complications, -mortality, and -cardiovascular disease, highlighting the need for new, optimized treatment strategies. With a focus on clinical efficacy, this paper discusses the results from the 20 major therapeutical trials published in the years 1997-1999, that evaluated the new insulinsensitizing thiazolidinediones Rosiglitazone and Pioglitazone and the new insulin-releasing potassium channel blockers Repaglinide and Nateglinide. While for Nateglinide, promising, but only preliminary data is available at current, Rosiglitazone, Pioglitazone, and Repaglinide have been shown appropriate for both mono- and combination therapy with current standard drug treatment of type 2 diabetes. Similar to the known, older antidiabetic drugs, the new agents discussed have comparable blood glucose lowering potentials with a dose-related capacity of 0.5 to 1.5% HbA1c reduction. These beneficial effects were both seen in drug-naive patients previously treated with diet only and in combination therapies where patients had previous antidiabetic standard drug treatment suggesting effectiveness of glitazones and glinides also in more advanced stages of the disease. Problems with adverse effects appeared minor although long-range implications of weight gain, edema, lowering of hemoglobin, increase of total cholesterol for the glitazones, and hypoglycemia for glinides warrant further consideration. What becomes clear from the variety of most recent mono- and combination treatment studies with as much as five different classes of antidiabetic drugs is that individually tailored therapies that recognize quality of life parameters and target the predominant features of metabolic pathology (such as early postprandial versus fasting hyperglycemia, degree of insulin resistance, progressive loss of 1-cell function) may become a feasible goal in the future.

Topics: Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Nateglinide; Phenylalanine; Pioglitazone; Piperidines; Rosiglitazone; Thiazoles; Thiazolidinediones

Nateglinide is a novel D-phenylalanine derivative that inhibits ATP-sensitive K+ channels in pancreatic beta-cells in the presence of glucose and thereby stimulates the prandial release of insulin. Nateglinide reduces fasting and mealtime blood glucose levels in animals, healthy volunteers, and patients with type 2 (non-insulin-dependent) diabetes mellitus, and produces prompt prandial insulin responses with return to baseline insulin levels between meals. In randomised, double-blind 24-week studies in patients with type 2 diabetes, oral nateglinide 120 mg 3 times daily before meals improved glycaemic control significantly relative to placebo. Nateglinide 120 mg plus metformin 500 mg, both 3 times daily, conferred greater glycaemic improvement than either drug given alone, and nateglinide 60 or 120 mg 3 times daily plus metformin 1 g twice daily was superior to metformin plus placebo. Nateglinide 120 mg 3 times daily significantly reduced hyperglycaemia relative to placebo in a 16-week double-blind study in patients with type 2 diabetes mellitus. Combination therapy with troglitazone 600 mg daily produced significantly better glycaemic control than either drug given as monotherapy. Mild hypoglycaemia was the most frequently reported adverse event (1.3% of patients) after treatment with nateglinide 120 mg 3 times daily in a 16-week clinical study. No clinically significant abnormalities in laboratory results, ECGs, vital signs or physical examination findings have been noted in patients taking the drug.

Topics: Administration, Oral; Clinical Trials as Topic; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypercalcemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Nateglinide; Pancreas; Phenylalanine

An early defect in Type 2 diabetes is the loss of acute insulin release after food intake, which causes prolonged elevation of postprandial glucose levels. Suppressing postprandial hyperglycemia is considered to be very important for preventing diabetic complications. Sulfonylureas are well-known insulin secretagogues and have been widely used in the treatment of Type 2 diabetes. These agents, however, do not appear to be able to ameliorate impairment of the first phase of insulin secretion and postprandial hyperglycemia. Nateglinide, which is a derivative of D-phenylalanine, is a non-sulfonylurea insulin secretagogue. Although the in vitro insulin-releasing effect of nateglinide is similar to that of sulfonylureas, its hypoglycemic effect is more rapid and short lasting. The in vivo unique pharmacodynamic profile of nateglinide is likely to result from its rapid absorption and elimination. This novel antidiabetic agent has made it possible to compensate for the impaired first phase insulin response and thus suppresses postprandial hyperglycemia. In clinical trials, nateglinide reduced prandial glucose excursion and improved early phase of insulin release dose-dependently after 12 weeks treatment. Nateglinide is a highly physiologic mealtime glucose regulator, which rapidly increases insulin secretion when taken before meals, mimicking early-phase insulin release lost in patients with Type 2 diabetes.

Topics: Animals; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Nateglinide; Phenylalanine

Type 2 diabetes mellitus is a complex heterogenous metabolic disorder in which peripheral insulin resistance and impaired insulin release are the main pathogenetic factors. The rapid response of the pancreatic beta-cells to glucose is already markedly disturbed in the early stages of type 2 diabetes mellitus. The consequence is often postprandial hyperglycaemia, which seems to be extremely important in the development of secondary complications, especially macrovascular disease. Therefore one of the main aims of treatment is to minimise blood glucose oscillations and attain near-normal glycosylated haemoglobin levels. Meglitinide analogues belong to a new family of insulin secretagogues which stimulate insulin release by inhibiting ATP-sensitive potassium channels of the beta-cell membrane via binding to a receptor distinct from that of sulphonylureas (SUR1/KIR 6.2). The pharmacokinetic and pharmacodynamic properties of repaglinide, the first drug of these new antihyperglycaemic agents on the market, and of nateglinide, which will be available soon, differ markedly from the currently used sulphonylureas [mainly glibenclamide (glyburide) and glimepiride]. Repaglinide and nateglinide are absorbed rapidly, stimulate insulin release within a few minutes, are rapidly metabolised in the liver and are mainly excreted in the bile. Therefore, following preprandial administration of these drugs, insulin is more readily available during and just after the meal. This leads to a significant reduction in postprandial hyperglycaemia without the danger of hypoglycaemia between meals. The short action of these compounds and biliary elimination makes repaglinide and nateglinide especially suitable for patients with type 2 diabetes mellitus who would like to have a more flexible lifestyle, need more flexibility because of unplanned eating behaviour (e.g. geriatric patients) or in whom one of the other first-line antidiabetic drugs, i.e. metformin, is strictly contraindicated (e.g. nephropathy with creatinine clearance < or = 50 ml/min). Meglitinide analogues act synergistically with metformin and thiazolidinediones (pioglitazone and rosiglitazone) and can be also combined with long-acting insulin (NPH insulin at bedtime). Therefore, these drugs enrich the palette of antidiabetic drugs and make the treatment more flexible and better tolerated, which both add to better metabolic control and support the empowerment and compliance of the patient. However, this will only be the

Topics: Benzamides; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Glyburide; Humans; Hypoglycemic Agents; Molecular Structure; Nateglinide; Phenylalanine; Piperidines

The chemical structures, mechanisms of actions, bioavailabilities, insulinotrophic and hypoglycemic actions, and clinical trials of three novel oral hypoglycemic agents, NN-623, A-4166 and KAD-1229 are overviewed. They are non-SU insulin secretagogues and they induce quicker and shorter hypoglycemia than sulphonylureas do, presumably because they are rapidly absorbed into (Tmax: < 30 min) and excreted from blood (T 1/2: < 60 min). They bind to the SU-receptors and suppress K-ATP channels like sulphonylureas do. They stimulate mainly the initial phase of insulin release and evoke a decrease in postprandial rises in plasma glucose in several animals and humans. Clinical trials demonstrated they are efficacious and safe in the treatment of NIDDM subjects. They are useful as a first choice drug for the early stage of NIDDM.

Topics: Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Indoles; Isoindoles; Nateglinide; Phenylalanine

Topics: Carbamates; Chromans; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin Resistance; Metformin; Nateglinide; Phenylalanine; Piperidines; Thiazoles; Thiazolidinediones; Troglitazone

Topics: Animals; Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Nateglinide; Phenylalanine

Topics: Clinical Trials, Phase II as Topic; Cyclohexanes; Diabetes Mellitus, Type 2; Eating; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Nateglinide; Phenylalanine; Time Factors

Two novel oral hypoglycaemic agents, NN623 and A4166, have been developed and are now in phase II clinical trial. Both agents have several common characteristics from sulphonylureas. NN623 is a stereoisomer of derivatives of benzoic acid and A4166 is also a stereoisomer of phenylalanine derivative. The predominant mechanism of the action is thought to be like sulphonylureas. Both NN623 and A4166 occupy, at least partly, a common receptor site with glibenclamide and close the ATP-dependent K+ channel. They are rapidly absorbed from the intestine and are eliminated mainly into the bile. NN623 is about 10 times more potent in hypoglycaemic action than glibenclamide and 100 times more than A4166 in terms of dosage. When 1.0 mg NN623 or 60 mg A4166 was given orally in the post-absorptive state to healthy volunteers, both agents evoked hypoglycaemia by 40 min. The duration of hypoglycaemia after NN623 was longer than after A4166 by about 1 hour. The effect of food on their bioavailability is similar. Food has marked influence on the absorption of both drugs and on their efficacy. When 1 mg of NN623 or 60 mg of A4166 was administered just before the meal, Tmax of NN623 and A4166 was 34 +/- 18 min and 18 +/- 6 min, while T1/2 was 0.64 +/- 0.12 h and 0.98 +/- 0.06 h, respectively. The postprandial rise in plasma glucose was reduced at 45 min and thereafter over 4-h after 1.0 mg NN623 and at 30 min to 90 min after 60 mg A4166. Plasma insulin levels rose more than those after placebo from 30 to 90 min after NN623 and at 20 to 40 min after A4166. Both agents stimulated insulin release much more in the postprandial than in the fasting state. There was no difference in the bioavailability after 5 or 7 days of administration. However, when administered immediately after the meal, the absorption of both drugs was delayed and the rise in plasma absorption was not suppressed until 60 min after the meal. Both fasting and postprandial hyperglycaemia were reduced after 1 to 4 weeks of premeal treatment with 0.5 mg NN623 or 60 mg A4166 in subjects with NIDDM. Plasma glucose levels were decreased over 4 h after NN623 and over 1 h after A4166. The meal-induced insulin response was almost doubled by NN623 over 2 h and 1 h by A4166. There was no difference in the bioavailability after breakfast between the first and last administrations of both drugs. In conclusion, a rapid rise in plasma insulin levels is associated with the suppression of postprandial hyperglycaemia.

Topics: Administration, Oral; Biological Availability; Blood Glucose; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Glyburide; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Intestinal Absorption; Molecular Structure; Nateglinide; Phenylalanine; Piperidines; Reference Values; Stereoisomerism

To elucidate the long-term cardiovascular benefit of lowering postprandial hyperglycemia (PPG) in early-stage T2DM patients.. This 10-year post-trial follow-up study included 243 patients from the DIANA (DIAbetes and diffuse coronary Narrowing) study, a multi-center randomized controlled trial which compared the efficacy of one-year life-style and pharmacological (voglibose/nateglinide) intervention lowering PPG on coronary atherosclerosis in 302 early-stage T2DM subjects [impaired glucose tolerance (IGT) or newly-diagnosed T2DM] (UMIN-CTRID#0000107). MACE (all-cause death, non-fatal MI or unplanned coronary revascularization) were compared in (1) three assigned therapies (life-style intervention/vogliose/nateglinide) and (2) patients with and without improvement of PPG (reversion from IGT to NGT or from DM to IGT/NGT on 75 g oral glucose tolerance test).. During the 10-year post-trial observational period, voglibose (HR = 1.07, 95%CI: 0.69-1.66, p = 0.74) or nateglinide (HR = 0.99, 95%CI: 0.64-1.55, p = 0.99) did not reduce MACE. Similarly, achieving the improvement of PPG was not associated with a reduction of MACE (HR = 0.78, 95%CI: 0.51-1.18, p = 0.25). However, in IGT subjects (n = 143), this glycemic management significantly reduced the occurrence of MACE (HR = 0.44, 95%CI: 0.23-0.86, p = 0.01), especially unplanned coronary revascularization (HR = 0.46, 95%CI: 0.22-0.94, p = 0.03).. The early improvement of PPG significantly reduced MACE and unplanned coronary revascularization in IGT subjects during the post-trial 10-year period.

Topics: Blood Glucose; Coronary Artery Disease; Diabetes Mellitus, Type 2; Follow-Up Studies; Glucose Intolerance; Humans; Nateglinide

Tofogliflozin is an oral hypoglycemic agent with a novel mechanism of action that reduces blood glucose levels by promoting glucose excretion in urine, achieved by selectively inhibiting sodium-glucose co-transporter 2 (SGLT2). We evaluated the effects of several selected anti-type 2 diabetes mellitus (T2DM) drugs-glimepiride, metformin, sitagliptin, pioglitazone, miglitol, nateglinide, and voglibose-on the pharmacokinetics and pharmacodynamics of tofogliflozin, and the effects of tofogliflozin on the pharmacokinetics of these anti-T2DM drugs in healthy male volunteers.. A single dose of either tofogliflozin alone, one of the anti-T2DM drugs alone, or co-administration of tofogliflozin and the anti-T2DM drug was administered to 108 healthy men. Cmax, AUCinf, and cumulative urine glucose excretion after co-administration of tofogliflozin and each of the anti-T2DM drugs was evaluated relative to the values of those parameters after administration of each drug alone.. None of the anti-T2DM drugs had any effect on tofogliflozin exposure. Tofogliflozin had no or little effect on the exposure of any anti-T2DM drug. No anti-T2DM drug had any major effect on the cumulative urine glucose excretion induced by tofogliflozin. There were no safety concerns evident after administration of any drug alone or in co-administration.. Neither the pharmacokinetics nor the pharmacodynamics of tofogliflozin was affected by any of the anti-T2DM drugs evaluated in this study, nor was the pharmacokinetics of any of the anti-T2DM drugs affected by tofogliflozin in healthy male volunteers.

Topics: 1-Deoxynojirimycin; Adult; Benzhydryl Compounds; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Interactions; Glucose; Glucosides; Healthy Volunteers; Humans; Hypoglycemic Agents; Inositol; Male; Metformin; Middle Aged; Nateglinide; Phenylalanine; Pioglitazone; Sitagliptin Phosphate; Sodium-Glucose Transporter 2 Inhibitors; Sulfonylurea Compounds; Thiazolidinediones; Urine; Young Adult

Dyslipidemia is commonly seen in patients with type 2 diabetes mellitus (T2DM). The current study sought to compare the effects of nateglinide and acarbose, two antihyperglycemic agents, on both fasting and postprandial lipid profiles in Chinese subjects with T2DM.. For this multicenter, open-label, randomized, active-controlled, parallel-group study, 103 antihyperglycemic agent-naive patients with T2DM were recruited from four hospitals in China. In total, 85 subjects (44 in the nateglinide group, 41 in the acarbose group) with a known complete lipid profile underwent the entire clinical trial and were included in the final analysis. Serum was collected in the fasting state and 30 and 120 min after a standardized meal (postprandial states) to measure the baseline lipid profiles; the same testing was performed upon completion of a 2-week course of nateglinide (120 mg three times a day) or acarbose (50 mg three times a day).. Fasting triglyceride (TG) levels were significantly reduced by both nateglinide and acarbose (P<0.001), with acarbose providing a significantly more robust improvement (vs. nateglinide, P=0.005). Additionally, the TG levels at both postprandial times were significantly reduced by acarbose (P<0.001 at 30 min and P=0.002 at 120 min), whereas nateglinide treatment only significantly reduced the 30-min postprandial TG (P=0.029). Neither nateglinide nor acarbose treatment had significant impact on total cholesterol, high-density lipoprotein, low-density lipoprotein, or non-high-density lipoprotein cholesterol.. Compared with nateglinide, acarbose has superior therapeutic efficacy for reducing fasting and postprandial TG levels in patients with T2DM.

Topics: Acarbose; Adult; China; Cholesterol, HDL; Cholesterol, LDL; Cyclohexanes; Diabetes Mellitus, Type 2; Dyslipidemias; Fasting; Female; Humans; Hypoglycemic Agents; Lipids; Male; Middle Aged; Nateglinide; Phenylalanine; Postprandial Period; Prospective Studies; Time Factors; Triglycerides

Thiazoledinediones decrease blood glucose by their insulin-sensitizing properties. Here, we examined whether pioglitazone plus nateglinide (PIO) interferes with hepatocellular lipid (HCL) content and/or improves insulin sensitivity in well-controlled non-obese patients with type 2 diabetes mellitus (T2DM).. Sixteen patients [body mass index (BMI): 28 ± 1 kg/m(2) ; HbA1c: 7.1 ± 0.6%] were studied in a randomized, double-blind, 12-week parallel group trial, whereas matched healthy humans [non-diabetic control subjects (CON), BMI: 26 ± 1 kg/m(2)] were studied once. Treatment with pioglitazone (30 mg/day) plus nateglinide (PIO arm) to control for glimepiride-induced insulin secretion was compared to treatment with glimepiride (2 mg/day) plus placebo (GLI arm). Multinuclei magnetic resonance spectroscopy (MRS) was combined with pancreatic normoglycaemic-two-step-insulin clamps and stable isotopes to assess glucose turnover, glucose transport/phosphorylation, HCL and intramyocellular lipid (IMCL) contents, non-esterified fatty acids (NEFA) and adipokines.. At baseline, HCL was approximately 5.6-fold higher in T2DM (p < 0.05 vs. CON). This was paralleled by approximately doubled leptin : adiponectin ratios (p < 0.05). HCL decreased by approximately 39% (p < 0.05) after PIO and only tended to decrease after GLI (p = 0.12). Treatment with PIO did not affect leptin : adiponectin ratios, but slightly improved (p < 0.05) insulin-mediated NEFA suppression, which related to lower HCL. PIO further prevented the insulin-induced increase in IMCL content of soleus and tibialis anterior muscles. Peripheral and hepatic insulin sensitivity, glucose transport and glycaemic control did not change in both groups.. Short-term, low-dose thiazolidendione treatment improves insulin sensitivity of lipolysis and HCL, without affecting muscle and liver insulin sensitivity. It appears that metabolic PIO action in T2DM is primarily mediated via a decline in HCL associated with greater sensitivity of lipolysis to insulin.

Topics: Adiponectin; Blood Glucose; Body Mass Index; C-Reactive Protein; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glycated Hemoglobin; Hepatocytes; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Lipid Metabolism; Lipolysis; Male; Middle Aged; Nateglinide; Phenylalanine; Pioglitazone; Sulfonylurea Compounds; Thiazolidinediones; Treatment Outcome

Recent studies have identified postprandial glycemic excursions as risk factors for diabetes complications. This study aimed to compare the effects of nateglinide and acarbose treatments on postprandial glycemic excursions in Chinese subjects with type 2 diabetes.. This was a multicenter, open-label, randomized, active-controlled, parallel-group study. One hundred three antihyperglycemic agent-naive subjects with type 2 diabetes (hemoglobin A1c range, 6.5-9.0%) were prospectively recruited from four hospitals in China. The intervention was nateglinide (120 mg three times a day) or acarbose (50 mg three times a day) therapy for 2 weeks. A continuous glucose monitoring system was used to calculate the incremental area under the curve of postprandial blood glucose (AUCpp), the incremental glucose peak (IGP), mean amplitude of glycemic excursions, SD of blood glucose, the mean of daily differences, and 24-h mean blood glucose (MBG). Subjects' serum glycated albumin and the plasma insulin levels were also analyzed.. Both agents caused significant reductions on AUCpp and IGP. Similarly, both treatment groups showed significant improvements in the intra- and interday glycemic excursions, as well as the 24-h MBG and serum glycated albumin compared with baseline (P<0.001). However, neither of the agents produced a significantly better effect (P>0.05). Moreover, the nateglinide-treated group had significantly increased insulin levels at 30 min and at 120 min after a standard meal compared with baseline, whereas the acarbose-treated group decreased. No serious adverse events occurred in either group. The rates of hypoglycemic episodes were comparable in the two groups, and no severe hypoglycemic episode occurred in either group.. Nateglinide and acarbose were comparably effective in reducing postprandial glycemic excursions in antihyperglycemic agent-naive Chinese patients with type 2 diabetes, possibly through different pathophysiological mechanisms.

Topics: Acarbose; Adolescent; Adult; Antihypertensive Agents; Area Under Curve; Blood Glucose; China; Cyclohexanes; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Glycemic Index; Humans; Hypertension; Hypoglycemic Agents; Male; Middle Aged; Nateglinide; Phenylalanine; Postprandial Period; Prospective Studies; Treatment Outcome

The role of dysglycemia as an additional risk factor for atrial fibrillation (AF) is controversial. Therefore, it was of interest to assess risk factors for incident AF in a large, representative population of patients with cardiovascular risk factors and impaired glucose tolerance but not overt diabetes in NAVIGATOR.. Predictors of incident AF were analyzed in 8,943 patients without AF at baseline by Cox proportional hazards regression. Study treatments (valsartan vs no valsartan and nateglinide vs no nateglinide) and the time-dependent covariate for progression to type 2 diabetes mellitus were added separately to the model.. The median age of the 8,943 patients included in the present analysis of the NAVIGATOR trial was 63 years. Half of those patients were men, 6,922 (77.4%) had a history of hypertension, and 255 (2.9%) had heart failure. The median glycated hemoglobin was 6%. During the study, 613 of the 8,943 patients without AF at baseline presented with at least 1 episode of AF (6.9% 5-year incidence). Besides established predictors of incident AF, a 1 mmol/L increment of baseline fasting glucose, but not progression to diabetes, was found to be associated with a 33% increased risk of incident AF. Neither valsartan nor nateglinide affected AF incidence.. In a trial population with impaired glucose tolerance, fasting plasma glucose and well-known risk factors (age, hypertension, and elevated body weight), but not progression to diabetes, predict risk of AF.

Topics: Aged; Atrial Fibrillation; Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucose Intolerance; Humans; Hypoglycemic Agents; Incidence; Male; Middle Aged; Nateglinide; Outcome Assessment, Health Care; Phenylalanine; Proportional Hazards Models; Risk Assessment; Risk Factors; Tetrazoles; Valine; Valsartan

This study was performed to examine the efficacy and safety of mitiglinide in type 2 diabetes patients (T2DM). Enrolled patients had received treatment with diet and exercise in the previous 3 months with glycosylated haemoglobin (HbA1c) 7-10%, and were randomized to receive mitiglinide (n = 111, 5-20 mg/meal) or nateglinide (n = 114,60-120 mg/meal) for 16 weeks. Primary and secondary efficacy endpoints were assessed by the changes in HbA1c, fasting blood glucose (FBG) and postprandial glucose (PBG) levels. The baseline HbA1c value was 8.2 and 8.3% in both groups. At the end of study, the reduction of HbA1c values from baseline by mitiglinide was slightly more than that by nateglinide (-1.11% vs. -0.76%), but not statically significant (p = 0.06). Final FBG and PBG were comparable for the two treatments. There were 2.8% subjects treated with nateglinide who had hypoglycaemic episodes, but none in the mitiglinide treatment group. The results indicate that mitiglinide and nateglinide had similar effects on FBG, PBG and HbA1c in T2DM patients after the 16-week treatments.

Topics: Blood Glucose; Body Mass Index; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Isoindoles; Male; Middle Aged; Nateglinide; Phenylalanine; Postprandial Period; Treatment Outcome; Waist-Hip Ratio

We examined the postprandial glucose regulators nateglinide and GLP-1, separately and in combination, in people with type 2 diabetes. Nateglinide inhibited DPP-4 activity, reduced GLP-1 degradation and enhanced its insulinotropic and blood glucose lowering effect. Combining nateglinide and GLP-1 derivatives may effectively control postprandial glycaemia.

Topics: Aged; Blood Glucose; Cross-Over Studies; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Synergism; Drug Therapy, Combination; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Male; Nateglinide; Phenylalanine; Postprandial Period; Treatment Outcome

Postprandial hyperglycaemia in patients with Type 2 diabetes mellitus has been linked to the development of cardiovascular disease. This study compared the effects of mealtime (thrice-daily) nateglinide with once-daily glyburide on postprandial glucose levels in patients with Type 2 diabetes and postprandial hyperglycaemia.. Patients with Type 2 diabetes aged ≥ 21 years with 2-h postprandial glucose levels ≥ 11.1 mmol/l, HbA(1c) of 6.5-8.5% (48-69 mmol/mol) and BMI of 22-30 kg/m(2) were randomized to 6 weeks' double-blind treatment with nateglinide 120 mg three times daily prior to meals, or glyburide 5 mg once daily before breakfast. The primary endpoint was the baseline-adjusted change in plasma glucose from preprandial (fasting plasma glucose) to 2-h postprandial glucose levels (2-h postprandial glucose excursion) at 6 weeks.. Patients were randomized to nateglinide (n = 122) or glyburide (n = 110). The treatment groups were similar in terms of age, gender, BMI, fasting plasma glucose, 2-h postprandial glucose and HbA(1c). At endpoint, nateglinide recipients had significantly greater reductions than those receiving glyburide in both the 2-h (-2.4 vs. -1.6 mmol/l; P = 0.02) and 1-h (-1.7 vs. -0.9 mmol/l; P = 0.016) postprandial glucose excursions. Adverse events, most commonly symptomatic hypoglycaemia, were reported in 26% of recipients of glyburide and 22% of recipients of nateglinide. Episodes of suspected mild hypoglycaemia were reported in 24% of recipients of glyburide and 10% of recipients of nateglinide.. Nateglinide leads to greater reductions in postprandial glucose excursions and is associated with a lower risk of hypoglycaemia than glyburide in this selected population of patients with Type 2 diabetes.

Topics: Adult; Aged; Aged, 80 and over; Cardiovascular Diseases; Cyclohexanes; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Double-Blind Method; Fasting; Female; Glyburide; Glycated Hemoglobin; Humans; Hyperglycemia; Middle Aged; Nateglinide; Phenylalanine; Postprandial Period

Basal insulin treatment is frequently used in type 2 diabetes, but the successful control of postprandial glucose is challenging. We compared the effect of preferential postprandial glucose targeting drugs for postprandial glucose control after optimizing fasting glucose with basal insulin.. This study was performed in 58, insulin naïve type 2 diabetes. After fasting glucose was optimized by insulin glargine, nateglinide or acarbose was initiated and then crossed over after second wash out period. 75 g oral glucose tolerance test and 7 point self monitoring blood glucose for 3 days at the end of each period was performed.. Both drugs effectively reduced postprandial glucose levels compared with the insulin glargine monotherapy. No significant differences were found between nateglinide and acarbose in terms of mean glucose level, standard deviation of glucose levels, mean average glucose excursion and average daily risk range. Homeostasis model analysis (HOMA)% β, corrected insulin response and insulin-to-glucose ratio were significantly higher in the responder group compared with the non-responder. There was no episode of severe hypoglycemia.. Nateglinide and acarbose are equally effective in type 2 diabetes for postprandial glucose excursions during basal insulin treatment. The markers of beta cell function might be used for predicting response. (Clinical trial reg. no. NCT 00437918, clinicaltrial.gov.).

Topics: Acarbose; Adult; Aged; Aged, 80 and over; Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Fasting; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Nateglinide; Phenylalanine; Postprandial Period; Treatment Outcome

The ability of short-acting insulin secretagogues to reduce the risk of diabetes or cardiovascular events in people with impaired glucose tolerance is unknown.. In a double-blind, randomized clinical trial, we assigned 9306 participants with impaired glucose tolerance and either cardiovascular disease or cardiovascular risk factors to receive nateglinide (up to 60 mg three times daily) or placebo, in a 2-by-2 factorial design with valsartan or placebo, in addition to participation in a lifestyle modification program. We followed the participants for a median of 5.0 years for incident diabetes (and a median of 6.5 years for vital status). We evaluated the effect of nateglinide on the occurrence of three coprimary outcomes: the development of diabetes; a core cardiovascular outcome that was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure; and an extended cardiovascular outcome that was a composite of the individual components of the core composite cardiovascular outcome, hospitalization for unstable angina, or arterial revascularization.. After adjustment for multiple testing, nateglinide, as compared with placebo, did not significantly reduce the cumulative incidence of diabetes (36% and 34%, respectively; hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15; P=0.05), the core composite cardiovascular outcome (7.9% and 8.3%, respectively; hazard ratio, 0.94, 95% CI, 0.82 to 1.09; P=0.43), or the extended composite cardiovascular outcome (14.2% and 15.2%, respectively; hazard ratio, 0.93, 95% CI, 0.83 to 1.03; P=0.16). Nateglinide did, however, increase the risk of hypoglycemia.. Among persons with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors, assignment to nateglinide for 5 years did not reduce the incidence of diabetes or the coprimary composite cardiovascular outcomes. (ClinicalTrials.gov number, NCT00097786.)

Topics: Angiotensin II Type 1 Receptor Blockers; Blood Glucose; Body Weight; Cardiovascular Diseases; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Exercise; Female; Follow-Up Studies; Glucose Intolerance; Humans; Hypoglycemic Agents; Incidence; Kaplan-Meier Estimate; Male; Middle Aged; Nateglinide; Phenylalanine; Proportional Hazards Models; Risk Factors; Tetrazoles; Treatment Failure; Valine; Valsartan

It is not known whether drugs that block the renin-angiotensin system reduce the risk of diabetes and cardiovascular events in patients with impaired glucose tolerance.. In this double-blind, randomized clinical trial with a 2-by-2 factorial design, we assigned 9306 patients with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors to receive valsartan (up to 160 mg daily) or placebo (and nateglinide or placebo) in addition to lifestyle modification. We then followed the patients for a median of 5.0 years for the development of diabetes (6.5 years for vital status). We studied the effects of valsartan on the occurrence of three coprimary outcomes: the development of diabetes; an extended composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, arterial revascularization, or hospitalization for unstable angina; and a core composite outcome that excluded unstable angina and revascularization.. The cumulative incidence of diabetes was 33.1% in the valsartan group, as compared with 36.8% in the placebo group (hazard ratio in the valsartan group, 0.86; 95% confidence interval [CI], 0.80 to 0.92; P<0.001). Valsartan, as compared with placebo, did not significantly reduce the incidence of either the extended cardiovascular outcome (14.5% vs. 14.8%; hazard ratio, 0.96; 95% CI, 0.86 to 1.07; P=0.43) or the core cardiovascular outcome (8.1% vs. 8.1%; hazard ratio, 0.99; 95% CI, 0.86 to 1.14; P=0.85).. Among patients with impaired glucose tolerance and cardiovascular disease or risk factors, the use of valsartan for 5 years, along with lifestyle modification, led to a relative reduction of 14% in the incidence of diabetes but did not reduce the rate of cardiovascular events. (ClinicalTrials.gov number, NCT00097786.)

Topics: Angiotensin II Type 1 Receptor Blockers; Blood Glucose; Blood Pressure; Body Weight; Cardiovascular Diseases; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Exercise; Female; Follow-Up Studies; Glucose Intolerance; Humans; Hypoglycemic Agents; Incidence; Male; Middle Aged; Nateglinide; Phenylalanine; Proportional Hazards Models; Risk Factors; Tetrazoles; Valine; Valsartan

Postprandial hyperglycemia is believed to affect vascular endothelial function. The aim of our study was to compare the effects of acarbose and nateglinide on postprandial endothelial dysfunction.. We recruited a total of 30 patients with newly diagnosed type 2 diabetes (19 men and 11 women, age 67.8 +/- 7.3 years). Patients were randomly assigned to 3 groups receiving either 300 mg/day acarbose, 270 mg/day nateglinide, or no medication. A cookie test (consisting of 75 g carbohydrate, 25 g butter fat, and 7 g protein for a total of 553 kcal) was performed as dietary tolerance testing. During the cookie test, glucose and insulin levels were determined at 0, 30, 60, and 120 min after load. In addition, endothelial function was assessed by % flow-mediated dilation (FMD) of the brachial artery at 0 and 120 min after cookie load.. Postprandial glucose and insulin levels were similar in the 3 groups. Postprandial endothelial dysfunction was similar in the 3 groups before treatment. After 12 weeks of intervention, postprandial FMD was significantly improved in the acarbose group compared with the control group (6.8 +/- 1.3% vs 5.2 +/- 1.1%, p = 0.0022). Area under the curve (AUC) for insulin response was significantly increased in the nateglinide and control groups; however, no significant change was observed in the acarbose group.. Our results suggest that acarbose improves postprandial endothelial function by improvement of postprandial hyperglycemia, independent of postprandial hyperinsulinemia. Acarbose may thus have more beneficial effects on postprandial endothelial function in patients with type 2 diabetes than nateglinide.

Topics: Acarbose; Aged; Blood Glucose; Brachial Artery; Cyclohexanes; Diabetes Mellitus, Type 2; Endothelium, Vascular; Female; Food; Humans; Hypoglycemic Agents; Insulin; Laser-Doppler Flowmetry; Male; Middle Aged; Nateglinide; Phenylalanine; Vasodilation

NAVIGATOR ("Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research") is a large international placebo-controlled trial that randomised 9,031 individuals at high risk because of impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors. This trial aimed at investigating whether valsartan (a selective AT1 receptor antagonist) and/or nateglinide (a short-acting insulin-secreting agent) are able to reduce the incidence of type 2 diabetes and cardiovascular events. After a median follow up of 6.5 years, neither valsartan nor nateglinide improved cardiovascular prognosis in the tested population, which already benefited from a protective pharmacotherapy at baseline and a reinforcement of lifestyle modification throughout the trial. Nateglinide did not diminish the risk of new onset diabetes. In contrast, valsartan reduced the incidence of type 2 diabetes by 14%, confirming the potential interest of the blockade of the renin-angiotensin system in this high-risk population.

Topics: Angiotensin II Type 1 Receptor Blockers; Belgium; Cardiovascular Diseases; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hypoglycemic Agents; Male; Middle Aged; Nateglinide; Phenylalanine; Renin-Angiotensin System; Tetrazoles; Treatment Outcome; Valine; Valsartan

Most antidiabetic agents target only one of several underlying causes of diabetes. The complementary actions of the glinides and the biguanides may give optimal glycemic control in patients with type 2 diabetes mellitus. The aim of the present study was to compare the effects of nateglinide plus metformin with glibenclamide plus metformin on glucose and lipid metabolism, and haemodynamic parameters in patients with type 2 diabetes mellitus.. We enrolled 248 type 2 diabetic patients. Patients were randomly assigned to receive nateglinide (n = 124) or glibenclamide (n = 124), after 6 months of run-in, in which we titrated nateglinide (starting dose 180 mg/day), glibenclamide (starting dose 7.5 mg/day), and metformin (starting dose 1500 mg/day). The final doses were (mean +/- standard deviation), 300 +/- 60, 12.5 +/- 2.5, and 2500 +/- 500 mg/day, respectively. We followed these patients for 1 year after titration. We assessed body mass index (BMI), fasting (FPG) and post-prandial (PPG) plasma glucose, glycosylated haemoglobin (HbA(1c)), fasting (FPI) and post-prandial (PPI) plasma insulin, homeostasis model assessment (HOMA) index, and lipid profile [total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), triglycerides (Tg), apolipoprotein A-I (Apo A-I), and apolipoprotein B (Apo B)], systolic blood pressure (SBP), and diastolic blood pressure (DBP). All variables were evaluated at baseline and after 3 and 6 months in the run-in period, and at baseline, and after 3, 6, 9 and 12 months for both treatment groups.. Body mass index did not show any significant change during the study. We observed a significant improvement from baseline to 1 year on HbA(1c) (P < 0.01 vs. baseline and vs. glibenclamide group, respectively), FPG (P < 0.01 vs. baseline), PPG (P < 0.01 vs. baseline), and on HOMA index (P < 0.05 vs. baseline) in the nateglinide group. In the glibenclamide group, we found significant changes in HbA(1c) (P < 0.05 vs. baseline), FPG (P < 0.01 vs. baseline), PPG (P < 0.05 vs. baseline), and HOMA index (P < 0.05 vs. baseline). No significant change was observed in TC, LDL-C, HDL-C, Tg, Apo A-I, Apo B, SBP, DBP and HR in either group after 3, 6, 9 and 12 months. These effects of nateglinide and glibenclamide on insulin-resistance parameters are in agreement with previous reports. Contrarily to previous reports, we did not observe any significant BP change in patients treated with glibenclamide. Although both nateglinide and glibenclamide attenuated PPG and HOMA index, they did not have significant effects on lipid metabolism, as already shown in subjects with type 2 diabetes and good glycemic control.. Nateglinide improved glycemic control better than glibenclamide in combination with metformin.

Topics: Blood Glucose; Body Mass Index; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glyburide; Glycated Hemoglobin; Hemodynamics; Homeostasis; Humans; Hypoglycemic Agents; Insulin; Lipids; Male; Metformin; Middle Aged; Nateglinide; Phenylalanine

The purpose of this study is to evaluate efficacy and safety of nateglinide tablet administration in comparison with those of repaglinide tablet as control on treating type 2 diabetes mellitus in China. Pooled-analysis with analysis of covariance (ANCOVA) method was applied to assess the efficacy and safety based on original data collected from four independent randomized clinical trials with similar research protocols. However meta-analysis was applied based on the outcomes of the four studies. The results by meta-analysis were comparable to those obtained by pooled-analysis. The means of HbA(1c), and fasting blood glucose in both the nateglinide and repaglinide groups were reduced significantly after 12 weeks duration but no statistical differences in reduction between the two groups. The adverse reaction rates were 9.89 and 6.51% in the nateglinide and repaglinide groups respectively, with the rate difference showing no statistical significance, and the Odds Ratio of adverse reaction rate (95% confidence interval) was 1.59 (0.99, 2.55). Both nateglinide and repaglinide administration have similarly significant effects on reducing HbA(1c) and FBG. However, the adverse reaction rate in the nateglinide group is higher than that in the latter using repaglinide but no statistical significance difference as revealed in the four clinical trials detailed below.

Topics: Carbamates; China; Cyclohexanes; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Nateglinide; Phenylalanine; Piperidines

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

To compare the efficacy and tolerability of nateglinide with those of acarbose in Chinese type 2 diabetes mellitus (T2DM) patients.. This multi-center, randomized, double-blind, parallel-arm study compared the efficacy and tolerability of nateglinide (120 mg, 3/d, n = 119) and those of acarbose (100 mg, 3/d, n = 118) during a 12-week treatment in T2DM patients uncontrolled by diet with glycosylated haemoglobin (HbA1c) 6.5% - 11.0%.. Monotherapy with nateglinide (120 mg, 3/d) or acarbose (100 mg, 3/d) decreased HbA1c to a similar extent during 12-week treatment. The mean change from baseline to end-point in HbA1c was (-0.90 +/- 0.98)% and (-0.83 +/- 0.81)% in patients receiving nateglinide and acarbose, respectively, with no significant difference between the two groups (P > 0.05). The decrease in fasting plasma glucose (FPG) was similar between nateglinide and acarbose (P > 0.05). The mean change in 2-hour postprandial plasma glucose (PG2h) was (-1.45 +/- 2.74) mmol/L and (-2.20 +/- 2.21) mmol/L in patients receiving nateglinide and acarbose (P = 0.0017). Body weight was significantly decreased in both groups at the end-point (P < 0.05), although the decrease was more with acarbose than nateglinide [(-0.66 +/- 1.79) kg vs (-2.06 +/- 2.00) kg, P = 0.0000]. And the proportion of patients experiencing any presumed drug related adverse events was not significantly different between the two groups.. Nateglinide (120 mg, 3/d) is effective and well tolerated in T2DM patients uncontrolled by diet, demonstrating similar HbA1c reductions as compared with acarbose (100 mg, 3/d).

Topics: Acarbose; Adult; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Follow-Up Studies; Humans; Insulin Resistance; Male; Middle Aged; Nateglinide; Phenylalanine

Nateglinide restores early-phase insulin secretion to feeding and reduces postprandial hyperglycaemia in type 2 diabetes. This study evaluated the effects of nateglinide on dipeptidyl peptidase-IV (DPP-IV) activity and glucose-dependent insulinotropic polypeptide (GIP) degradation. Research design and methods Blood samples were collected from type 2 diabetic subjects (n=10, fasting glucose 9.36+/-1.2 mmol/l) following administration of oral nateglinide (120 mg) 10 min prior to a 75 g oral glucose load in a randomised crossover design.. Plasma glucose reached 18.2+/-1.7 and 16.7+/-1.7 mmol/l at 90 min in control and placebo groups (P<0.001). These effects were accompanied by prompt 32% inhibition of DPP-IV activity after 10 min (19.9+/-1.6 nmol/ml per min, P<0.05), reaching a minimum of 1.9+/-0.1 nmol/ml per min at 120 min (P<0.001) after nateglinide. Insulin and C-peptide levels increased significantly compared with placebo, to peak after 90 min at 637.6+/-163.9 pmol/l (P<0.05) and 11.8+/-1.4 mg/l (P<0.01) respectively. DPP-IV-mediated degradation of GIP was significantly less in patients receiving nateglinide compared with placebo. Inhibition of DPP-IV activity corresponded with a time- and concentration-dependent inhibitory effect of nateglinide on DPP-IV-mediated truncation of GIP(1-42) to GIP(3-42) in vitro. Comparison of in vitro inhibition of DPP-IV by nateglinide and vildagliptin revealed IC(50) values of 17.1 and 2.1 microM respectively.. Although considerably less potent than specified DPP-IV inhibitors, the possibility that some of the beneficial actions of nateglinide are indirectly mediated through DPP-IV inhibition and increased bioavailability of GIP and other incretins merits consideration.

Topics: Adamantane; Cyclohexanes; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Female; Gastric Inhibitory Polypeptide; Humans; Insulin; Insulin Secretion; Male; Middle Aged; Nateglinide; Nitriles; Phenylalanine; Pyrrolidines; Vildagliptin

We studied the effects of nateglinide on serum adiponectin in 26 patients with type 2 diabetes mellitus. The changes in serum insulin at 30min significantly correlated with those in serum high-molecular weight adiponectin. Nateglinide may ameliorate hypoadiponectinemia as well as postprandial hyperglycemia in patients with type 2 diabetes mellitus.

Topics: Adiponectin; Aged; Cyclohexanes; Diabetes Mellitus, Type 2; Female; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged; Molecular Weight; Nateglinide; Phenylalanine

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

It has been speculated that oral hypoglycaemic agents that block K-ATP channels could potentially increase blood pressure by blocking such channels in vascular myocytes. No information about this issue exists regarding nateglinide.. A multicentre, double-blind, placebo-controlled, randomized trial was conducted in 109 drug-naive 30- to 75-year-old patients with type 2 diabetes and < 5 years of diabetes diagnosis, who are not taking antihypertensive drugs. These patients were assigned to receive placebo or fixed doses of nateglinide (120 mg before each main meal: breakfast, lunch and dinner) and evaluated at weeks 0 and 12 for (i) body mass index and blood pressure; (ii) standard laboratory tests, including haemoglobin A1c (HbA1c) and fasting plasma glucose; and (iii) incremental area under the curve for glucose and C-peptide after a standardized liquid breakfast challenge, homeostasis model assessment (HOMA)-B% (as surrogate of beta-cell activity) and HOMA-S% (as surrogate of insulin sensitivity).. At the end of the follow-up period, patients in the nateglinide group (n = 55), compared to patients in the placebo group (n = 54), showed lower values of HbA1c (6.7 +/- 0.6 vs. 7.2 +/- 0.7%, respectively; P < 0.001), fasting plasma glucose (7.9 +/- 2.1 vs. 8.5 +/- 2.0 mmol L(-1); P = 0.023) and systolic blood pressure (125.3 +/- 15.4 vs. 129.3 +/- 18.7 mmHg; P = 0.015), and higher values of HOMA-B%[75.7 (51.8-99.4) vs. 57.7 (42.2-83.4); P = 0.033]. A positive correlation was found between changes in HbA1c and systolic blood pressure in the nateglinide group (r = 0.355, P = 0.011).. In drug-naive patients with type 2 diabetes, the improvement in glycaemic control with nateglinide is associated with a decrease in systolic blood pressure.

Topics: Adult; Aged; Area Under Curve; Blood Glucose; Blood Pressure; Cholesterol; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Nateglinide; Phenylalanine; Triglycerides

To evaluate the efficacy and safety of nateglinide, a new antidiabetic agent, in the treatment of type 2 diabetes.. A total of 219 treatment-naïve patients with type 2 diabetes from 6 centers were enrolled in this study and blindly divided into nateglinide group (n = 105) and repaglinide group (n = 114). In all patients, the disease was confirmed for at least three months. The whole observation lasted for 12 weeks. The efficacy indicators measured include glycohemoglobin A1c (HbA1c), fasting blood glucose, and 2 hours postprandial blood glucose, and the safety parameters measured included renal and hepatic function, serum lipids, and blood and urea profiles.. Similar decreases in fasting blood glucose, 2 hours postprandial blood glucose, and HbA1 c were found in both nateglinide group and repaglinide group without significant differences. No severe adverse events were noted. The hypoglycemia event reports were not significantly different between these two groups.. Nateglinide is an effective and safe drug in treating type 2 diabetes.

Topics: Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Humans; Hypoglycemic Agents; Male; Middle Aged; Nateglinide; Phenylalanine; Treatment Outcome

To determine the effect of adding nateglinide to therapy with insulin glargine in adults with Type 2 diabetes previously treated with insulin and with poor blood glucose control.. In this 16-week, double-blind, placebo-controlled study, people with Type 2 diabetes [n = 55, HbA(1c) 8.2 +/- 1.0 (+/- sd)%, duration of diabetes 12.8 +/- 6.0 years, duration of insulin treatment 6.0 +/- 4.0 years] were transferred to single bedtime injection of insulin glargine for a titration period of 4 weeks, and then randomized to nateglinide or matching placebo before meals in addition to insulin glargine. Metformin was continued if taken. Doses of insulin and oral medication were titrated to protocol for the treatment period of 12 weeks.. Baseline-adjusted self-monitored capillary blood glucose concentration at 12 weeks was significantly lower with nateglinide + insulin glargine compared with placebo + insulin glargine after breakfast [difference -2.3 (95% confidence interval -4.4, -0.2) mmol/l, P = 0.030], before lunch [-2.5 (-4.6, -0.3) mmol/l, P = 0.029], and after lunch [-2.3 (-4.3, -0.4) mmol/l, P = 0.021], but not at other times. Baseline-adjusted HbA(1c) was not lower with nateglinide + insulin glargine as compared with placebo + insulin glargine [7.8 +/- 1.4 vs. 8.3 +/- 1.0%, difference -0.43 (-0.98, 0.12)%].. Addition of nateglinide before meals to once-daily insulin glargine in people with long-standing diabetes already requiring insulin therapy improves blood glucose control in the early part of the day after breakfast and lunch, but does not provide good control of blood glucose levels overall.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Blood Glucose; Blood Glucose Self-Monitoring; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Male; Metformin; Middle Aged; Nateglinide; Phenylalanine; Time Factors

To investigate the acute and chronic effects of nateglinide versus acarbose on plasma asymmetric dimethylarginine (ADMA) levels and lipid profiles in patients with newly-diagnosed type 2 diabetes.. A crossover trial of nateglinide and acarbose was conducted on 16 drug-naïve patients with newly-diagnosed type 2 diabetes during a total period of 9 weeks. Plasma glucose, serum insulin, free fatty acids (FFA), lipids and lipoproteins, and plasma ADMA were measured.. The efficiencies of a single dose of nateglinide (120 mg) and acarbose (50 mg) for lowering postprandial hyperglycemia were similar. Compared to acarbose, nateglinide significantly increased postprandial insulin release after a standard meal test in patients with type 2 diabetes. Nateglinide acutely decreased postprandial 120 min FFA concentrations and 240 min ADMA levels more significantly than acarbose. The fasting high-density lipoprotein cholesterol level increased and the low-density lipoprotein cholesterol level decreased significantly, but the fasting levels of triglycerides, total cholesterol, and ADMA were unchanged after 4 weeks of treatment with nateglinide. Acarbose did not affect fasting lipid profiles or the ADMA levels after 4 weeks of treatment.. These results suggest that the reduction of postprandial FFA and ADMA concentrations induced by nateglinide may be associated with the partial restoration of early-phase insulin secretion and may impart a cardiovascular advantage in comparison with acarbose.

Topics: Acarbose; Arginine; Blood Glucose; Cross-Over Studies; Cyclohexanes; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Insulin; Lipids; Male; Middle Aged; Nateglinide; Phenylalanine; Prospective Studies

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 evaluate the efficacy of nateglinide vs. repaglinide in blood glucose (BG) control and the effect on insulin resistance and beta-Cell function in patients with type 2 diabetes.. A randomized controlled double-blind and double-dummy multicentre clinical trial was conducted. A total of 230 Chinese patients with type 2 diabetes were enrolled in five clinical centres. The patients were divided randomly into group A [repaglinide 1.0 mg three times daily (t.i.d.), n = 115] or group B (nateglinide 90 mg t.i.d., n = 115). At baseline and end of the 12-week clinical trial, standard mixed meal tolerance tests were performed.. A total of 223 patients (96.9%) completed the trial. There was no significant difference between repaglinide and nateglinide groups in the effects of reducing fasting blood glucose (FBG), 30-, 60- and 120-min BG during 12 weeks (p > 0.05). At week 12, no significant difference was shown between the two groups in BG or haemoglobin A(1c) (HbA(1c)) (p > 0.05). However, the effect on HbA(1c) in repaglinide group was stronger than that in nateglinide group (p < 0.05). After 12-week treatment, area under the curve (AUC) of BG decreased (p < 0.05), and AUC of insulin and C-peptide (CP) increased in both groups (p < 0.05). The effects of nateglinide on AUC of BG, insulin and CP were similar to that of repaglinide (p > 0.05). There was no significant difference between the two groups in AUC of BG, insulin or CP in week 12 (p > 0.05). Furthermore, homeostasis model assessment of insulin resistance (HOMA-IR) and beta-cell function indexes measured by HOMA-beta, DeltaI(30)/DeltaG(30) and (DeltaI(30)/DeltaG(30))/HOMA-IR were improved significantly in both groups during 12 weeks (p < 0.05). The effects of improving HOMA-IR and beta-cell function indexes in nateglinide group were comparable with that of repaglinide group (p > 0.05).. The efficacy of repaglinide and nateglinide in FBG, postprandial glucose excursion and early-phase insulin secretion is similar. But the effect of repaglinide 1.0 mg t.i.d. on HbA(1c) is stronger than that of nateglinide 90 mg t.i.d.. This trial had shown that nateglinide and repaglinide could comparably improve insulin sensitivity and beta-cell function.

Topics: Adult; Age of Onset; Aged; Area Under Curve; Asian People; Blood Glucose; Carbamates; China; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Middle Aged; Nateglinide; Phenylalanine; Piperidines

Postprandial hyperglycemia observed in type 2 diabetes mellitus is a risk factor for atherosclerosis. The aim of this study was to investigate the effect of strict glycemic control by nateglinide on common carotid far wall intima-media thickness in type 2 diabetic patients who were already under good glycemic control.. We performed an open labeled randomized prospective trial on 78 drug-naive type 2 diabetic patients whose HbA1c was less than 6.5%. Thirty-eight patients were randomly assigned to receive nateglinide (270 mg/dL) and 40 to control group (no treatment). After 12 months, a significant reduction in HbA1c was observed in the nateglinide group, whereas a significant increase of HbA1c was observed in the untreated group. The carotid intima-media thickness at the end of 1-year follow-up was significantly reduced in the nateglinide group compared with the untreated group (-0.017+/-0.054 mm/year versus 0.024+/-0.066 mm/year, P=0.0064). Whereas nateglinide treatment also reduced triglyceride, highly-sensitive C-reactive protein, and E-selectin, multiple regression analysis identified HbA1c as the only significant independent determinant of the change in carotid intima-media thickness.. In type 2 diabetic patients with good glycemic control, further strict glycemic control by nateglinide results in regression of carotid intima-media thickness.

Topics: Aged; Blood Glucose; Carotid Arteries; Coronary Artery Disease; Cyclohexanes; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Nateglinide; Phenylalanine; Tunica Intima; Tunica Media

To evaluate the effect on coagulation and fibrinolysis parameters and on non-conventional cardiovascular risk factors of metformin plus nateglinide or glibenclamide in naïve type 2 diabetes patients.. A total of 248 type 2 diabetic patients were enrolled and randomly assigned to receive nateglinide or glibenclamide, and metformin for 12 months. We assessed body mass index (BMI), glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), postprandial plasma insulin (PPI), homeostasis model assessment index (HOMA index), lipid profile with lipoprotein (a) [Lp(a)], fibrinogen (Fg), plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (t-PA), homocysteine (Hcy), systolic blood pressure (SBP), diastolic blood pressure (DBP).. After 9 months of treatment, both tested drug combinations were similarly associated with a significant reduction in FPG (nateglinide, -17.2%; glibenclamide, -16.9%, both p<0.05) compared to the baseline, while HbA1c (-17.3%, p<0.05) and PPG (-15.2%, p<0.05) significantly decreased only in the nateglinide group. After one year of treatment, compared to the baseline the nateglinide group showed a significant reduction in HbA1c (-21%, p<0.01), FPG (-20.7%), p<0.01, PPG (-21.5%, p<0.05), HOMA index (-25.4%, p<0.05); the glibenclamide group, showed a significant reduction in HbA1c (-11%, p<0.05), FPG (-23.2%, p<0.05), PPG (-11.2%, p<0.05), and HOMA index (-23.9%, p<0.05) but to a minor extent. Moreover, the HbA1c difference value from baseline observed in the nateglinide-treated group was significantly higher than that observed in the glibenclamide group. Therefore the nateglinide-treated patients showed a significant reduction in some prothrombotic parameters (PAI-1=-19%, Lp(a)=-31%, and Hcy=-32.3%, all p<0.05), whereas the glibenclamide-treated patients did not.. Nateglinide appears to improve glycemic control as well as the levels of some prothrombotic parameters compared to glibenclamide when administered in combination with metformin.

Topics: Adult; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glyburide; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Nateglinide; Phenylalanine; Plasminogen Activator Inhibitor 1; Tissue Plasminogen Activator

The effect of rapid-acting insulin secretagogues (glinides) on glycemic control when included with insulin therapy for type 2 diabetes remains uncertain. To examine this, we added glinide once a day to twice daily injections of premixed insulin.. Seventy-four type 2 diabetic patients, taking twice daily injections of premixed insulin and whose diabetic control was stable, were registered at 6 independent institutions. After a 3-month observation period, 60 patients were administered 10 mg mitiglinide or 90 mg nateglinide at lunchtime without changing their insulin regimen. After 12 weeks, administration of glinide was discontinued and observation was continued. HbA1c levels were measured at the start of glinide administration, after 12 weeks of glinide , and at 12 weeks after discontinuation.. HbA1c improved from 7.72+/-0.66% to 7.55+/-0.71% (p <0.01) at Week 12 of glinide administration. Twelve weeks after discontinuation, HbA1c returned to the baseline level (7.72+/-0.81%).. This study indicates that the addition of glinide once a day at lunchtime to twice daily injections of premixed insulin is effective for the treatment of type 2 diabetes.

Topics: Aged; Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Isoindoles; Japan; Male; Middle Aged; Multicenter Studies as Topic; Nateglinide; Phenylalanine; Treatment Outcome

Nateglinide, a rapid insulin secretagogue, is known to facilitate the early phase of insulin secretion and has been used for the treatment of type 2 diabetic patients with postprandial hyperglycemia. The aim of this study is to evaluate the effect of nateglinide on insulin resistance as well as insulin secretory defects in type 2 diabetic patients. Insulin secretion ability was evaluated by the hyperglycemic clamp test, and insulin sensitivity was evaluated by the euglycemic hyperinsulinemic clamp test, using an artificial pancreas. The hyperglycemic clamp test showed that a 7-day treatment with nateglinide significantly increased insulin secretion in response to high glucose. Interestingly, although nateglinide is known to facilitate insulin secretion, daily urinary C-peptide excretion was decreased after nateglinide treatment. Moreover, in the euglycemic hyperinsulinemic clamp test, glucose infusion rate was significantly increased by nateglinide treatment, indicating that nateglinide functions to decrease insulin resistance. Nateglinide ameliorates insulin resistance as well as insulin secretory defects in type 2 diabetic patients.

Topics: Blood Glucose; Body Mass Index; Cyclohexanes; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Middle Aged; Nateglinide; Phenylalanine; Postprandial Period

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

An endothelial barrier for the insulin transport from the circulation to the target tissues of insulin has previously been suggested to contribute to insulin resistance. The interstitial insulin concentration (I-insulin) and insulin kinetics following a mixed meal have, however, previously not been characterized in human adipose tissue.. Eight nondiabetic first-degree relatives (FDR) of type 2 diabetes patients were recruited. Their I-insulin was measured by microdialysis after a test meal with or without oral administration of the insulin secretagogue nateglinide (120 mg). In parallel, adipose tissue blood flow and lipolysis were measured by xenon-clearance and microdialysis, respectively.. The I-insulin increased after the test meal, and this response was more prominent on the day the subjects received the nateglinide tablet when compared with the day the subjects received the placebo tablet [I-insulin incremental area under the curve (IAUC) nateglinide 7612 +/- 3032 vs. Plac 4682 +/- 2613 pmol L(-1) min; P < 0.05, mean +/- SE]. However, the postprandial I-insulin(max)/P-insulin(max) ratio was similar on the two test days (nateglinide: 213 +/- 62 vs. 501 +/- 92 pmol L(-1), I/P-ratio: 0.38 +/- 0.06 and placebo: 159 +/- 39 vs. 410 +/- 74 pmol L(-1), I/P-ratio: 0.36 +/- 0.05). There was no difference in time of onset of insulin action in situ, or responsiveness, when comparing placebo and nateglinide.. Microdialysis can now be used to measure the I-insulin in human adipose tissue following a mixed meal. The data also showed that the transendothelial delivery of insulin occurs rapidly, supporting the concept that transcapillary insulin transfer is a nonsaturable process in nondiabetic first-degree relatives of type 2 diabetes patients.

Topics: Adipose Tissue; Adult; Anthropometry; Biological Transport; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Lipolysis; Male; Microdialysis; Middle Aged; Nateglinide; Phenylalanine; Postprandial Period; Regional Blood Flow

To compare the effects of nateglinide plus metformin with gliclazide plus metformin on glycaemic control in patients with Type 2 diabetes.. Double-blind, double-dummy, parallel group, randomized, multicentre study over 24 weeks. Patients with inadequate glucose control on maximal doses of metformin were randomized to additionally receive nateglinide (n = 133) or gliclazide (n = 129). Changes from baseline in HbA1c, fasting plasma glucose (FPG) and mealtime glucose and insulin excursions were examined.. HbA1c was significantly (P < 0.001) decreased from baseline in both treatment groups (mean changes: nateglinide -0.41%, gliclazide -0.57%), but with no significant difference between treatments. Proportions of patients achieving a reduction of HbA1c >or= 0.5% or an end point HbA1c < 7% were also similar (nateglinide 58.1%, gliclazide 60.2%). Changes from baseline in FPG were similarly significant in both treatment groups (nateglinide -0.63, gliclazide -0.82 mmol/l). Reduction from baseline in maximum postprandial glucose excursion were significant in the nateglinide group only (nateglinide -0.71, gliclazide -0.10 mmol/l; P = 0.037 for difference). Postprandial insulin levels were significantly higher with nateglinide compared with gliclazide. The overall rate of hypoglycaemia events was similar in the nateglinide group compared with the gliclazide group.. No significant difference was seen between nateglinide plus metformin and gliclazide plus metformin in terms of HbA1c. However, the nateglinide combination demonstrated better postprandial glucose control.

Topics: Adult; Aged; Aged, 80 and over; Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Gliclazide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Metformin; Middle Aged; Nateglinide; Phenylalanine; Postprandial Period; Treatment Outcome

The respiratory quotient (RQ) is useful for evaluating glucose and lipid metabolism in vivo. We previously reported that the RQ value, even after fasting, was high in diabetics being treated with sulphonylurea (SU), which might explain the accumulation of fat, leading to weight gain in such individuals. In the present study, we measured the RQ in type II diabetic patients who were being treated with a rapid-onset/short-duration insulinotropic agent, nateglinide, and compared it with those being treated with SU.. A glucose tolerance test was performed in 20 patients with type II diabetes mellitus treated with nateglinide and in 14 patients treated with SU, and the RQ was simultaneously measured.. The RQ values in the patients treated with nateglinide, were similar to those in healthy adults, but was lower than in those treated with SU. No weight gain was observed in patients treated with nateglinide.. A significant weight gain was reported in subjects treated with SU, accompanied by an increase in RQ. However, weight gain was less frequent in diabetics treated with nateglinide.

Topics: Aged; Blood Glucose; Body Weight; Cyclohexanes; Diabetes Mellitus, Type 2; Female; Glyburide; Humans; Hypoglycemic Agents; Insulin Resistance; Lipid Metabolism; Lipids; Male; Middle Aged; Nateglinide; Phenylalanine; Weight Gain

To evaluate effects of the oral antidiabetic insulinotropic agent nateglinide on myocardial blood flow (MBF) and microvascular reactivity in Type 2 diabetic patients.. Forty-seven Type 2 diabetic patients were randomly assigned 2 : 1 to nateglinide 120 mg (t.i.d., n = 33) or placebo (n = 14). At baseline and after 16 weeks of treatment, MBF was quantified using positron emission tomography with N-13 ammonia at rest, during endothelial-dependent stimulation by cold pressor test and during adenosine-mediated vasodilation. Additional blood samples were taken to assess glycaemic control and lipid profile.. MBF at rest and during adenosine did not change during the study. The percentage of flow increase from rest during cold pressor test did not improve significantly in the nateglinide group vs. placebo (from 26.1 +/- 37.2% to 29.1 +/- 27.8% between week 0 to week 16 for nateglinide vs. 14.9 +/- 37.1% to 18.1 +/- 28.4% for placebo; P = 0.07 for nateglinide when adjusted for higher baseline values). Nateglinide decreased HbA1c by 0.4% (from 7.6 +/- 0.9% to 7.2 +/- 1.3%) compared to an increase of 0.5% in the placebo group (from 7.9 +/- 0.8% to 8.4 +/- 1.7%; P = 0.02 for nateglinide). No differences between the two groups were observed in insulin levels and lipid status.. Nateglinide neither improved, nor impaired myocardial blood flow in Type 2 diabetic patients. Potential effects on endothelial-dependent myocardial blood flow remain to be investigated further. Positron emission tomography is a sensitive approach to assess the effects of therapeutic agents on myocardial blood flow in patients with diabetes.

Topics: Aged; Blood Glucose; Blood Pressure; Coronary Circulation; Cyclohexanes; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Lipids; Male; Microcirculation; Middle Aged; Nateglinide; Phenylalanine; Positron-Emission Tomography; Treatment Outcome

To compare the efficacy of nateglinide with repaglinide in the treatment of type 2 diabetes mellitus.. Forty-six type 2 diabetic patients were randomly treated with repaglinide (group A, 1.0 mg tid, n=23) or nateglinide (group B, 90.0 mg tid, n=23). The trial consisted of a 4-week equilibrated period followed by 12 weeks of treatment course.. In group A, the fasting blood glucose (FBG) and 30-, 60-, 120- min postprandial blood glucose (PBG), as well as hemoglobin A1c were decreased significantly (P<0.05). In group B, the 60-min and 120-min PBG decreased remarkably (P<0.05), but FBG, 30-min PBG and A1c decreased with no statistical significance (P>0.05). After 12 weeks treatment, the 30-, 60-, 120-min postprandial insulin level, area under the curve of insulin and C peptide (0 to 120 min) increased in both groups (P<0.05). No significant difference was found between the effects of repaglinide and nateglinide on early phase insulin secretion.. The glucose lowering effect of repaglinide at a dosing level of 1.0 mg tid was better than that of nateglinide 90 mg tid on fasting blood glucose and A1c during 12 weeks treatment period, yet the insulinotropic effects of the two drugs were similar.

Topics: Adult; Blood Glucose; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Middle Aged; Nateglinide; Phenylalanine; Piperidines

We studied the effects of the oral insulin secretagogue nateglinide on insulin secretion using a modeling approach to obtain beta-cell function parameters from a meal test and examined the impact of the beta-cell improvement on glucose tolerance.. Mild type 2 diabetic men and women (n = 108; fasting glucose 7.0-8.3 mmol/l) on diet treatment alone randomly received 30, 60, or 120 mg nateglinide or placebo for 24 weeks. Beta-cell function parameters were derived by modeling (based on C-peptide deconvolution) from a standardized meal test at baseline and after 24 weeks of treatment.. The baseline demographic and metabolic characteristics of the four groups were similar. Nateglinide treatment resulted in dose-dependent reductions in the mean postprandial glucose response and at the 120-mg dose in fasting glucose. Fasting or total insulin secretion during the meal were not different. In contrast, we found differences in the model parameters. Rate sensitivity (expressing early insulin secretion when glucose is rising) was significantly enhanced at 24 weeks with the lowest nateglinide dose, with no further stimulation at higher doses. Early potentiation (expressing an initial insulin secretion enhancement), glucose sensitivity (the slope of the glucose-insulin secretion relationship), and insulin secretion at a fixed- reference 7-mmol/l glucose concentration all showed a trend toward increasing, with increasing nateglinide dose, and were significantly greater than placebo at the 120-mg dose. In multiple regression analyses, changes in rate sensitivity, glucose sensitivity, and potentiation all contributed to the observed glucose changes.. The model-derived parameters are sensitive measures of beta-cell function, showing improvements after nateglinide treatment and predicting changes in glucose tolerance.

Topics: Aged; Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Insulin Resistance; Islets of Langerhans; Male; Middle Aged; Models, Biological; Nateglinide; Phenylalanine; Placebos; Severity of Illness Index

Postprandial glycaemia and lipaemia are known risk factors for atherosclerosis in type 2 diabetes. Coagulation activation in the postprandial state also contributes to acceleration of atherosclerosis. Nateglinide is effective in reducing postprandial glycaemia. Its effect on glycaemia may also be beneficial in postprandial lipaemia and coagulation. The aim of this study was to examine the potential effect of a single dose of nateglinide on postprandial triglyceridaemia, coagulation, and fibrinolysis in patients with type 2 diabetes.. Ten subjects with type 2 diabetes, treated with diet alone were recruited in a crossover randomized study. In the morning, after a 12- to 14-h fast, each subject received a standard mixed meal (total energy 783 kcal), preceded by one tablet of 120 mg nateglinide or placebo. Venous blood samples were drawn prior to meal consumption and 6h afterwards for the measurement of plasma glucose, insulin, and C-peptide, lipids, coagulation, and fibrinolysis factors. As expected, there was a significant reduction in postprandial glycaemia after nateglinide administration compared to placebo (P<0.001). Plasma insulin levels were significantly higher after nateglinide than after placebo (P=0.002). Nateglinide administration resulted in a lower overall postprandial reduction of tissue-plasminogen activator than placebo (-2.9+/-1.3 vs. -8.3+/-3.7 ng/ml h, P=0.003). In addition, a significant reduction of postprandial plasminogen activator inhibitor-1 was observed in comparison with the baseline values after nateglinide (P=0.001), although the overall response was not significantly different after nateglinide and placebo (P=0.31). Plasma concentrations of C-peptide, lipids and the remaining coagulation parameters studied were not different between nateglinide and placebo.. Acute nateglinide administration improves postprandial glycaemia and fibrinolytic activity in patients with type 2 diabetes. This combined effect, if confirmed by a long-treatment study, might reduce cardiovascular risk in type 2 diabetes.

Topics: Adult; Aged; Blood Coagulation; Cardiovascular Diseases; Cross-Over Studies; Cyclohexanes; Diabetes Mellitus, Type 2; Female; Fibrinolysis; Humans; Hypoglycemic Agents; Lipids; Male; Metabolism; Middle Aged; Nateglinide; Phenylalanine; Postprandial Period; Treatment Outcome

To compare long-term efficacy and safety of initial combination therapy with nateglinide/metformin versus glyburide/metformin.. We conducted a randomized, multicenter, double-masked, 2-year study of 428 drug-naïve patients with type 2 diabetes. Patients received 120 mg a.c. nateglinide or 1.25 mg q.d. glyburide plus 500 mg q.d. open-label metformin for the initial 4 weeks. During a subsequent 12-week titration period, glyburide and metformin were increased by 1.25- and 500-mg increments to maximum daily doses of 10 and 2,000 mg, respectively, if biweekly fasting plasma glucose (FPG) > or = 6.7 mmol/l. Nateglinide was not titrated. Blinding was maintained by use of matching placebo for nateglinide and glyburide. An 88-week monitoring period followed, during which HbA1c (A1C), FPG, and postprandial glucose excursions (PPGEs) during an oral glucose tolerance test were measured.. In nateglinide/metformin-treated patients, mean A1C was 8.4% at baseline and 6.9% at week 104. In glyburide/metformin-treated patients, mean A1C was 8.3% at baseline and 6.8% at week 104 (P < 0.0001 vs. baseline for both treatments, NS between treatments). The deltaPPGE averaged -96 +/- 19 (P < 0.0001) and -57 +/- 22 mmol.l(-1).min(-1) (P < 0.05) in patients receiving nateglinide/metformin and glyburide/metformin, respectively, whereas deltaFPG was -1.6 +/- 0.2 (P < 0.0001) and -2.4 +/- 0.2 mmol/l (P < 0.0001) in patients receiving nateglinide/metformin and glyburide/metformin, respectively (P < 0.01 between groups). Thus, the two treatments achieved similar efficacy with differential effects on FPG versus PPGE. Hypoglycemia occurred in 8.2 and 17.7% of patients receiving nateglinide/metformin and glyburide/metformin, respectively.. Similar good glycemic control can be maintained for 2 years with either treatment regimen, but nateglinide/metformin may represent a safer approach to initial combination therapy.

Topics: Body Mass Index; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Female; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Nateglinide; Phenylalanine; Placebos

This was a randomized, double blind, three period crossover study. The objective was to compare glucose, insulin and C-peptide 24 h profiles in patients with type 2 diabetes mellitus after dosing with nateglinide (given preprandially before three test meals), glibenclamide (administered once before breakfast) or placebo (given before three test meals).. Fourteen patients underwent screening followed within 3 weeks by three treatment periods of 1 day, each separated by 7 days. Dosing followed a six-sequence balanced, two 3 x 3-replicated Latin square.. Mean peak serum insulin levels were lower after nateglinide (115 mU/l) than after glibenclamide (145 mU/l.h; p = 0.017) but higher than after placebo (79 mU/l; p = 0.001). However, peak insulin levels were reached earlier after nateglinide [mean time to peak (tmax) 1.7 h] compared to glibenclamide (mean tmax 2.1 h, p = 0.06). Total insulin exposure over the day was higher after glibenclamide compared with that following nateglinide (1216 vs. 1067 mU/l.h; p = 0.009). Similar findings were seen with serum C-peptide. Despite this, mean peak plasma glucose concentrations were lower following nateglinide (11.4 mmol/l from a baseline of 8.3 mmol/l) compared with glibenclamide (13.2 mmol/l from a baseline of 8.5 mmol/l; p = 0.001) and placebo (14.0 mmol/l from a baseline of 8.0 mmol/L; p < 0.001).. Nateglinide improves early prandial measures of insulin and glucose response to a standard meal, more so than glibenclamide, in people with type 2 diabetes.

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

Nateglinide, a new insulinotropic agent, specifically targets prandial glycemic excursions. Recently, innovative technologies have become available that provide the possibility to measure 72-h blood glucose values continuously. The aim of this study was to evaluate the effects of nateglinide on 24-h blood glucose profiles in diabetic patients. Eighteen patients with type 2 diabetes mellitus--seven on diet only and 11 on metformin monotherapy--participated in the study. Mean age was 60 years, mean diabetes' duration was 7.4 years, and mean hemoglobin A1c was 8.4%. They underwent a 72-h glucose monitoring using a continuous glucose monitoring system (CGMS, Medtronic MiniMed, Northridge, CA) under their usual diabetes therapy and a standardized breakfast. After this period, therapy with nateglinide, 120 mg three times a day before meals, was initiated. Three days later patients again underwent 72-h glucose monitoring. Mean blood glucose values and mean fasting blood glucose values decreased significantly, from 172 mg/dL before to 131 mg/dL (P< 0.0004) and from 172 mg/dL before to 126 mg/dL (P< 0.0005), respectively, with nateglinide therapy. Postprandial hyperglycemia, expressed as mean blood glucose over a time period of 2 h after a meal, declined significantly after all three daily meals. The number of blood glucose values above 140 mg/dL decreased from 207 without to 98 during nateglinide therapy. Nateglinide was not associated with hypoglycemia or other adverse events. We found in this study, using CGMS, that nateglinide has a glucose-lowering potency that not only affects postprandial hyperglycemia, but also overnight and fasting blood glucose values.

Topics: Blood Glucose; Blood Glucose Self-Monitoring; Cyclohexanes; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Nateglinide; Phenylalanine; Postprandial Period; Prospective Studies; Statistics, Nonparametric

A randomized, parallel-group, open-label, multicenter 16-week clinical trial compared efficacy and safety of repaglinide monotherapy and nateglinide monotherapy in type 2 diabetic patients previously treated with diet and exercise.. Enrolled patients (n = 150) had received treatment with diet and exercise in the previous 3 months with HbA(1c) >7 and < or =12%. Patients were randomized to receive monotherapy with repaglinide (n = 76) (0.5 mg/meal, maximum dose 4 mg/meal) or nateglinide (n = 74) (60 mg/meal, maximum dose 120 mg/meal) for 16 weeks. Primary and secondary efficacy end points were changes in HbA(1c) and fasting plasma glucose (FPG) values from baseline, respectively. Postprandial glucose, insulin, and glucagon were assessed after a liquid test meal (baseline, week 16). Safety was assessed by incidence of adverse events or hypoglycemia.. Mean baseline HbA(1c) values were similar in both groups (8.9%). Final HbA(1c) values were lower for repaglinide monotherapy than nateglinide monotherapy (7.3 vs. 7.9%). Mean final reductions of HbA(1c) were significantly greater for repaglinide monotherapy than nateglinide monotherapy (-1.57 vs. -1.04%; P = 0.002). Mean changes in FPG also demonstrated significantly greater efficacy for repaglinide than nateglinide (-57 vs. -18 mg/dl; P < 0.001). HbA(1c) values <7% were achieved by 54% of repaglinide-treated patients versus 42% for nateglinide. Median final doses were 6.0 mg/day for repaglinide and 360 mg/day for nateglinide. There were 7% of subjects treated with repaglinide (five subjects with one episode each) who had minor hypoglycemic episodes (blood glucose <50 mg/dl) versus 0 patients for nateglinide. Mean weight gain at the end of the study was 1.8 kg in the repaglinide group as compared with 0.7 kg for the nateglinide group.. In patients previously treated with diet and exercise, repaglinide and nateglinide had similar postprandial glycemic effects, but repaglinide monotherapy was significantly more effective than nateglinide monotherapy in reducing HbA(1c) and FPG values after 16 weeks of therapy.

Topics: Biomarkers; Body Mass Index; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Diet, Diabetic; Exercise; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Nateglinide; Phenylalanine; Piperidines; Time Factors

To assess the efficacy and tolerability of the combination of nateglinide (120 mg, ac) and metformin (500 mg, tid) as initial treatment in drug-naïve patients with type 2 diabetes mellitus (T2DM).. This study reports data from the treatment-naïve (TN) subgroup of patients in a previously published, randomized, multicenter, placebo-controlled, 24- week trial that compared nateglinide, metformin, and the combination therapy (CT) in 701 patients with T2DM with baseline HbA(1c) between 6.8% and 11.0%. Of the 401 TN patients, 104, 104, 89, and 104 patients received nateglinide (120 mg, ac), metformin (500 mg, tid), CT, and placebo, respectively. The baseline characteristics of each group were similar, with mean age, BMI, duration of diabetes, HbA(1c), and fasting plasma glucose (FPG) levels of approximately 58 years, 30 kg/m(2), 4 Gastrointestinal side effects occurred in 27% of years, 8.2%, and 10.2 mmol/L, respectively.. In patients receiving initial CT, HbA(1c) decreased substantially (Delta = -1.6 +/- 0.1%, p < 0.0001 vs. baseline or placebo) from a mean baseline of 8.2 +/- 0.1%, an effect significantly greater than the 0.8% reduction observed with both monotherapies (p < 0.001); whereas, in placebo-treated patients, HbA(1c) increased modestly (Delta = +0.3 +/- 0.1%, p < 0.05) from an identical baseline value. Seventy percent of CT-treated patients achieved a target HbA(1c) of < 7.0%. Both fasting plasma glucose (FPG) and the 2-hour postprandial glucose excursion (PPGE) after a liquid meal challenge decreased by 2.3 mmol/L in patients receiving CT, while the changes from baseline values in FPG and PPGE were +0.2 +/- 0.3 mmol/L and -0.5 +/- 0.2 mmol/L, respectively, in placebo-treated patients. The incremental 30-minute post-load insulin levels increased by 88 +/- 32 pmol/L (p = 0.006) in patients receiving CT and did not change significantly in placebo-treated patients. patients receiving CT (vs. 27.9% in the metformin monotherapy, and 14.4% in the placebo groups). Confirmed hypoglycemia (glucose

Topics: Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Nateglinide; Phenylalanine; Placebos; Treatment Outcome; United States

To assess the effect of nateglinide on efficacy [fasting plasma glucose (FPG), postprandial plasma glucose (PPG) plasma glucose and HbA1c], tolerability and safety in patients with type 2 diabetes mellitus (T2Dm) on diet alone or on metformin in subjects up to an age of 84.. In an open-labelled 12-week, parallel study of 358 patients, aged 35-84 years with T2Dm, nateglinide was given as either monotherapy in patients previously on diet alone or low-dose sulfonylureas, which required washout before the study (group 1), or as an addition therapy in patients on steady dose of metformin (group 2). Nateglinide 120 mg was given before main meals. HbA1c, FPG and PPG values were taken at the time of breakfast at the beginning and the end of the study.. HbA1c fell by a mean of 0.83%, 95% confidence interval (CI) (-0.97, -0.69) (p < 0.001) in group 1, and 0.67%, 95% CI (-0.77, -0.58) (p < 0.001) in group 2. There was a significant improvement in PPG in group 1 by a mean reduction of -3.47 mmol/l, 95% CI (-4.08, -2.87) (p < 0.0001) and in group 2 of -2.41 mmol/l, 95% CI (-2.84, -1.99) (p < 0.0001). There was an improvement in FPG of -1.2 mmol/l, 95% CI (-1.49, -0.81) (p < 0.0001) and -0.8 mmol/l, 95% CI -(1.07, -0.53) (p < 0.0001) in group 1 and 2 respectively. 44% of patients in group 1 and 34% in group 2 achieved target of HbA1c < 7.0 and 66% in group 1 and 59% in group 2 achieved of HbA1c < 7.5%. Only one subject on nateglinide and metformin was withdrawn due to the side effect of hypoglycaemia. No patient required third-party assistance nor was admitted to hospital due to hypoglycaemia.. These data demonstrate that nateglinide is a safe and effective agent in treatment to target in patients with T2Dm up to an age of 84 years.

Topics: Adult; Aged; Aged, 80 and over; Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Nateglinide; Phenylalanine; Postprandial Period; Prospective Studies; Regression Analysis

This randomized crossover placebo-controlled study aimed to assess the efficacy of nateglinide, a phenylalanine-derived insulin secretagogue, on forearm endothelial function in diabetic subjects before and after an oral glucose load.. Forearm blood flow (FBF) was measured using strain-gauge plethysmography during reactive hyperaemia before and after an oral glucose load (75 g) with a prior use of placebo or nateglinide (90 mg) in 15 diet-treated Type 2 diabetic patients or age-matched controls with normal glucose tolerance.. The peak FBF response and total reactive hyperaemic flow (flow debt repayment: FDR), indices of resistance artery endothelial function, were decreased after an oral glucose load in diabetic patients, but unchanged in controls. Nateglinide administered to diabetic patients accelerated insulin secretion and reduced post-challenge plasma glucose, and also abolished the post-challenge impairment of endothelial function. The peak FBF and FDR were well correlated with 120-min glucose levels and 30-min insulinogenic index.. A single challenge of glucose was shown to impair endothelial function in diabetic patients, and the post-challenge endothelial dysfunction was improved by a prior use of nateglinide. Long-term effects of nateglinide on endothelial function in Type 2 diabetic patients need to be clarified in future studies.

Topics: Administration, Oral; Blood Glucose; Cross-Over Studies; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Endothelium; Female; Forearm; Glucose; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Nateglinide; Phenylalanine; Regional Blood Flow

An open-label prospective cross-over trial was performed to compare the efficacy and safety of once daily low-dose gliclazide (20 mg/day) with that of nateglinide at the usual dosage (270 mg/day, 90 mg t.i.d.) in Japanese type 2 diabetics with relatively good glycemic control (HbA1c<7.0%). Eight patients received 20 mg/day of gliclazide and 16 received 270 mg/day of nateglinide. After at least 12 weeks of gliclazide or nateglinide therapy, the drugs were switched and treatment was continued for another 12 weeks. The final HbA1c value was modestly, but significantly, lower after gliclazide treatment than after nateglinide treatment (6.2% vs. 6.4%). However, symptoms related to hypoglycemia were significantly more common with gliclazide treatment than nateglinide treatment (7 vs. 0 cases), although there were no severe hypoglycemic events. While gliclazide acts as a free radical scavenger, there was no effect on parameters of oxidative stress such as malondialdehyde-modified low density lipoprotein and thiobarbituric acid-reactive substances at the low dosage tested. In conclusion, both drugs are reasonable options for early type 2 diabetes. Compared with the regular dose of nateglinide, 20 mg/day of gliclazide achieved modestly better glycemic control with an increased frequency of hypoglycemia in diabetic patients with relatively good glycemic control.

Topics: Adult; Cross-Over Studies; Cyclohexanes; Deoxyglucose; Diabetes Mellitus, Type 2; Gliclazide; Glycated Hemoglobin; Glycated Serum Albumin; Glycation End Products, Advanced; Humans; Hypoglycemic Agents; Lipoproteins, LDL; Malondialdehyde; Nateglinide; Phenylalanine; Prospective Studies; Serum Albumin; Thiobarbituric Acid Reactive Substances

Antidiabetic agents that augment insulin secretion can cause hypoglycemia. With the current trend toward early and aggressive treatment of patients with type 2 diabetes, the hypoglycemic potential of insulinotropic agents is of concern. This study aimed to compare the propensity of the "glinide," nateglinide, and the sulfonylurea (SU), glyburide, to elicit hypoglycemia in type 2 diabetic patients with moderately elevated fasting plasma glucose (FPG). Hyperglycemic clamps (target plasma glucose = 11.1 mmol/L) were initiated, and 30 minutes later patients received a single oral dose of nateglinide (120 mg, n = 15) or glyburide (10 mg, n = 12) in a double-blind fashion. At the end of the 2-hour clamp when the glucose infusion was terminated, plasma glucose and insulin levels were measured for 4 additional hours. The minimum plasma glucose level achieved after terminating the glucose infusion (glucose nadir) was used as an index of hypoglycemic potential. The mean (+/-SEM) glucose nadir was significantly lower in patients given glyburide (3.3 +/- 0.2 mmol/L) versus nateglinide (4.4 +/- 0.3 mmol/L, P = .025). Confirmed hypoglycemia (plasma glucose < or = 2.8 mmol/L) occurred in 2 of 12 patients given glyburide and in none of those given nateglinide. Plasma insulin levels were significantly higher from 100 to 240 minutes after clamp termination in patients given glyburide versus nateglinide. Nateglinide has less hypoglycemic potential than glyburide, suggesting that nateglinide may be a more appropriate insulinotropic agent for patients with moderate fasting hyperglycemia, such as elderly patients and those with comorbid cardiac ischemia.

Topics: Adult; Aged; Area Under Curve; Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucose Clamp Technique; Glyburide; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Nateglinide; Phenylalanine

To elucidate the role of early insulin response in post-prandial hyperlipidemia, we examined triglyceride (TG) and remnant-like particle triglyceride (RLP-TG) levels, using a meal tolerance test (MTT) with or without the administration of nateglinide (NAT). The MTTs were performed 2 d apart in 36 drug-naive patients with type 2 diabetes who had been hospitalized for glycemic control while receiving diet therapy. Before the second MTT, patients were treated with 90 mg NAT. Treatment with NAT was associated with a significant increase in insulin levels in the treated patients 1 h after the test meal, compared to levels in non-treatment. NAT treatment was also associated with a significant decrease in the level of free fatty acids 1 and 2 h after the meal, and with a significant decrease in plasma glucose levels 1, 2, and 4 h after the meal, compared to those in non-treatment. During the first MTT with NAT non-treatment, 13 patients showed serum TG levels of 200 mg/dL or greater when measured 2 h after the meal. In these 13 patients, NAT administration produced a significant decrease in TG levels 1, 2, and 6 h after the meal, as well as a significant reduction in RLP-TG levels 1 and 2 h after the meal. NAT administration was also associated with significant reductions in area under the curve (DeltaAUC) for TG and RLP-TG. These results suggest that, in a clinical setting, the early insulin response is closely associated with both postprandial glucose and postprandial lipid metabolism in Japanese patients with type 2 diabetes.

Topics: Blood Glucose; Cholesterol; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Japan; Lipoproteins; Middle Aged; Nateglinide; Phenylalanine; Postprandial Period; Triglycerides

Treatment of hyperglycemia in patients with diabetes mellitus and renal insufficiency is complicated by altered pharmacokinetics of hypoglycemic agents. This study evaluated the pharmacokinetic profile and safety of nateglinide, an amino acid derivative that improves early phase insulin secretion and reduces mealtime glucose excursions. This open-label, single-dose, two-center study included patients (mean age = 57 +/- 10 years) with type 1 or 2 diabetes with impaired renal function (IRF) (n = 10) or with renal failure undergoing hemodialysis (n = 10). Both groups were compared with age-, sex-, height-, and weight-matched healthy controls (n = 20). All participants received a single 120-mg dose of nateglinide immediately before breakfast. Pharmacokinetic and safety evaluations were undertaken up to 48 hours postdose. All 40 subjects completed the study. Plasma nateglinide concentrations increased rapidly in patients undergoing dialysis and matched healthy subjects (tmax = 0.95 vs. 0.78 h, respectively) and was comparable with patients with IRF and matched healthy subjects (tmax = 0.80 vs. 0.65 h, respectively). There were no statistically significant differences for Cmax or AUC0-t between the groups. Nateglinide was eliminated rapidly in all groups (t1/2 = 1.9-2.8 h). There was no correlation between the level of renal function and systemic exposure. There was a low extent of renal excretion of nateglinide in healthy subjects (11%) and diabetic patients with IRF (3%). Nateglinide was well tolerated. These data suggest that nateglinide is suitable for use in diabetic patients with IRF or with renal failure undergoing dialysis. Given the comparable absorption and elimination profiles of nateglinide in renally impaired and healthy subjects, no dose adjustment appears necessary in the renally impaired.

Topics: Adult; Aged; Area Under Curve; Blood Glucose; Case-Control Studies; Cyclohexanes; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Half-Life; Humans; Hypoglycemic Agents; Kidney Failure, Chronic; Male; Metabolic Clearance Rate; Middle Aged; Nateglinide; Phenylalanine; Renal Dialysis

One hundred and sixteen Latin American type 2 diabetic patients previously only on a diet were enrolled in this multicenter, multinational, nonrandomized, noncontrolled study. Only 109 completed the study. After 8 weeks of treatment with 120 mg of nateglinide, administered prior to each meal, the postprandial (2 h) glucose concentration decreased to 85.11 +/- 5.65 mg/dl (p < 0.0001), and HbA(1c) values decreased to 1.06 +/- 0.10% (p < 0.0001). No response differences were detected in relation to age, gender, or ethnicity, but we did encounter a better response in recently diagnosed patients (

Topics: Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Female; Humans; Hyperglycemia; Hypoglycemic Agents; Latin America; Male; Middle Aged; Nateglinide; Phenylalanine; Postprandial Period; Treatment Outcome

To determine the effects of nateglinide added to rosiglitazone monotherapy on glycemic control and on postprandial glucose and insulin levels in patients with type 2 diabetes.. This 24-week, multicenter, double-blind, randomized study compared the efficacy of nateglinide (120 mg a.c.) and placebo added to rosiglitazone monotherapy (8 mg q.d.) in 402 patients with type 2 diabetes with HbA(1c) between 7 and 11% (inclusive). Efficacy parameters tested included HbA(1c) and plasma glucose and insulin levels in the fasting state and after a standardized meal challenge. Safety data were also collected.. In placebo-treated patients, HbA(1c) did not change (Delta = 0.0 +/- 0.1%). In patients randomized to nateglinide, HbA(1c) decreased from 8.3 to 7.5% (Delta = -0.8 +/- 0.1%, P < 0.0001 vs. placebo). Target HbA(1c) (<7.0%) was achieved by 38% of patients treated with combination therapy and by 9% of patients remaining on rosiglitazone monotherapy. In nateglinide-treated patients, fasting plasma glucose levels decreased by 0.7 mmol/l, 2-h postprandial glucose levels decreased by 2.7 mmol/l, and 30-min insulin levels increased by 165 pmol/l compared with no changes from baseline of these parameters with placebo added to rosiglitazone (P < 0.001).. By selectively augmenting early insulin release and decreasing prandial glucose excursions, nateglinide produced a clinically meaningful improvement in overall glycemic exposure in patients with type 2 diabetes inadequately controlled with rosiglitazone. Therefore, nateglinide substantially improves the likelihood of achieving a therapeutic target of HbA(1c) <7.0%.

Topics: Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Eating; Fasting; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Middle Aged; Nateglinide; Phenylalanine; Placebos; Rosiglitazone; Safety; Single-Blind Method; Thiazolidinediones; Time Factors

An open-label, parallel-group, randomized, multicenter trial was conducted to compare efficacy and safety of repaglinide versus nateglinide, when used in a combination regimen with metformin for treatment of type 2 diabetes.. Enrolled patients (n = 192) had HbA(1c) >7% and < or =12% during previous treatment with a sulfonylurea, metformin, or low-dose Glucovance (glyburide < or =2.5 mg, metformin < or =500 mg). After a 4-week metformin run-in therapy period (doses escalated to 1,000 mg b.i.d.), patients were randomized to addition of repaglinide (n = 96) (1 mg/meal, maximum 4 mg/meal) or nateglinide (n = 96) (120 mg/meal, reduced to 60 mg if needed) to the regimen for 16 weeks. Glucose, insulin, and glucagon were assessed after a liquid test meal at baseline and week 16.. Final HbA(1c) values were lower for repaglinide/metformin treatment than for nateglinide/metformin (7.1 vs. 7.5%). Repaglinide/metformin therapy showed significantly greater mean reductions of HbA(1c) (-1.28 vs. -0.67%; P < 0.001) and of fasting plasma glucose (FPG) (-39 vs. -21 mg/dl; P = 0.002). Self-monitoring of blood glucose profiles were significantly lower for repaglinide/metformin before breakfast, before lunch, and at 2:00 A.M. Changes in the area under the curve of postprandial glucose, insulin, or glucagon peaks after a test meal were not significantly different for the two treatment groups during this study. Median final doses were 5.0 mg/day for repaglinide and 360 mg/day for nateglinide. Safety assessments were comparable for the two regimens.. The addition of repaglinide to metformin therapy resulted in reductions of HbA(1c) and FPG values that were significantly greater than the reductions observed for addition of nateglinide.

Topics: Area Under Curve; Blood Glucose; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Metformin; Middle Aged; Nateglinide; Phenylalanine; Piperidines; Postprandial Period; Safety

We evaluated the benefits and safety of nateglinide, a novel oral hypoglycemic agent, in type 2 diabetes patients with renal failure.. Single-dose pharmacokinetics were studied in 8 patients with type 2 diabetes and a low creatinine clearance (range 1.8-16.5 ml/min/1.73 m2) up to 6 hours after 90 mg nateglinide administration. Next, we treated another group of 8 patients undergoing regular hemodialysis with nateglinide 90 mg/day for 1-3 months. The effect of hemodialysis on metabolite accumulation was then tested.. After a single 90 mg dose, nateglinide significantly increased the post-prandial secretion of insulin and thereby reduced plasma glucose levels. Mean pharmacokinetic parameters (AUC(0-6) 10.45 mg/l/h; t(1/2) 1.89 h, Cl/F 10.19 l/h) were comparable with those reported in healthy subjects. A much larger AUC value than those previously reported of M1, a major metabolite in the urine of healthy subjects, was observed, and the plasma concentration of M1 did not decline up to 6 hours after. In patients treated on a regular basis, there was marked accumulation of M1, while nateglinide could not be detected 24 hours after the last dose. Plasma M1 levels were significantly reduced by the hemodialysis sessions.. Single 90 mg dose of nateglinide was safe and effective in patients with renal failure. However, repeated administrations could cause prolonged hypoglycemia due to accumulation of M1, which is known to have a modest hypoglycemic activity. Hemodialysis may help to eliminate excessive accumulation of M1.

Topics: Adult; Aged; Aged, 80 and over; Area Under Curve; Cyclohexanes; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Humans; Hypoglycemic Agents; Male; Middle Aged; Nateglinide; Phenylalanine; Renal Insufficiency; Time Factors

In a general practice observation study 11,476 patients with type 2 diabetes pretreated with oral antidiabetic drugs, mainly metformin, received an oral combination therapy of nateglinide with metformin. Mean age+/-SD of the participants was 61+/-10.3 years, range 19 to 97 years, the body mass index (mean+/-SD) was 29.4+/-4.5 kg/m2, range 14.9 to 68.7 kg/m2. The observation period lasted 3 to 4 months (mean 96 days). During this period the mean HbA1c decreased from 8.4 % to 7.2%, displaying a positive relation between initial value and degree of reduction. Postprandial glucose levels dropped from a mean of 210 to 152 mg/dl. At the beginning of the study the combination of the two target values for glucose control, HbAc <7% and postprandial glucose <180 mg/dl, was reached in only 5.8% of the participants, at the end in 44.9%. During the therapy, weight and blood pressure dropped slightly. Adverse events were reported in only 2.9% of the patients and involved a broad range of symptoms with mild gastrointestinal complaints being predominant (1.3%). This study demonstrated that the combination of nateglinide with metformin can be considered as an effective and safe option for treatment of patients with type 2 diabetes, with additional beneficial effects on body weight and blood pressure.

Topics: Adult; Aged; Aged, 80 and over; Blood Glucose; Blood Pressure; Body Weight; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Family Practice; Female; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Nateglinide; Phenylalanine; Postprandial Period; Product Surveillance, Postmarketing

Glycation of insulin has been demonstrated within pancreatic beta-cells and the resulting impaired bioactivity may contribute to insulin resistance in diabetes. We used a novel radioimmunoassay to evaluate the effect of nateglinide on plasma concentrations of glycated insulin and glucose tolerance in type 2 diabetes.. Ten patients (5 M/5 F, age 57.8+/-1.9 years, HbA(1c) 7.6+/-0.5%, fasting plasma glucose 9.4+/-1.2 mmol/l, creatinine 81.6+/-4.5 microM/l) received oral nateglinide 120 mg or placebo, 10 min prior to 75 g oral glucose in a random, single blind, crossover design, 1 week apart. Blood samples were taken for glycated insulin, glucose, insulin and C-peptide over 225 min.. Plasma glucose and glycated insulin responses were reduced by 9% (P=0.005) and 38% (P=0.047), respectively, following nateglinide compared with placebo. Corresponding AUC measures for insulin and C-peptide were enhanced by 36% (P=0.005) and 25% (P=0.007) by nateglinide.. Glycated insulin in type 2 diabetes is reduced in response to the insulin secretagogue nateglinide, resulting in preferential release of native insulin. Since glycated insulin exhibits impaired biological activity, reduced glycated insulin release may contribute to the antihyperglycaemic action of nateglinide.

Topics: Blood Glucose; C-Peptide; Cross-Over Studies; Cyclohexanes; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Glycosylation; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Islets of Langerhans; Male; Middle Aged; Nateglinide; Phenylalanine; Single-Blind Method

This study was designed to compare the efficacy of three insulinotropic agents in the control of postprandial hyperglycemia in type 2 diabetes. Fifteen subjects with noninsulin-requiring type 2 diabetes were admitted to the General Clinical Research Center on four separate occasions. During the control study and following 7-10 d on each study medication, daylong glucose profiles were performed to investigate the effects of the assigned medication on postprandial hyperglycemia. During each admission, placebo or study medications were administered before three isocaloric meals as follows: immediate-release glipizide 30 min before breakfast and 30 min before supper, glipizide gastrointestinal therapeutic system (GITS) 30 min before breakfast, or nateglinide 120 mg 10 min before breakfast, before lunch, and before supper. Blood was drawn for analysis of glucose, insulin, and C-peptide at -0.05, 0, 0.25, 0.5, 1, 2, 3, and 4 h relative to each test meal. Immediate-release glipizide, nateglinide, or glipizide GITS administration resulted in significantly lower integrated daylong (glucose area under the curve) and peak glucose levels, compared with placebo. There were no significant differences in the daylong integrated glucose levels among the three study medications. The peak postbreakfast glucose level (but not glucose area under the curve) was lower with nateglinide, compared with either immediate-release glipizide or glipizide GITS. Postlunch and postdinner integrated glucose levels were significantly lower with immediate-release glipizide or glipizide GITS, compared with nateglinide. C-peptide levels were significantly higher with immediate-release glipizide, compared with glipizide GITS. Insulin levels did not differ among the three study medications. Once-daily glipizide GITS, twice-daily immediate-release glipizide, or three-times-a-day administration of nateglinide results in equivalent control of postmeal hyperglycemia in type 2 diabetes. The decision to prescribe one of these three insulinotropic agents should be based on factors such as the patient's ability to comply with complex dosing regimens, the need to control fasting hyperglycemia, the risk of interprandial hypoglycemia, and pharmacoeconomic considerations, rather than postprandial glucose-lowering efficacy.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Cross-Over Studies; Cyclohexanes; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Female; Glipizide; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged; Nateglinide; Phenylalanine; Postprandial Period

To compare the effects of monotherapy using nateglinide and the thiazolidinedione troglitazone with initial combination of the two agents on glycated hemoglobin (HbA(1c)) in patients with type 2 diabetes inadequately controlled by diet alone.. This study consisted of a 28-week, double-blind, randomized, multicenter study that included a 4-week, single-blind, placebo, run-in period and a 24-week (shortened to 16 weeks), double-blind, active treatment period.. At the 16-week end point, nateglinide 120 mg, troglitazone 600 mg, and the combination of the agents achieved statistically significant decreases in HbA(1c) in comparison with placebo and a baseline HbA(1c) of 8.1-8.4% (P < 0.001). The reductions in HbA(1c) were similar in the nateglinide (0.6%) and troglitazone (0.8%) monotherapy groups. The reduction in HbA(1c) (1.7%) was greatest in the combination group; 79% of patients in the combination group achieved HbA(1c) levels of <7%. The combination group had a higher number of adverse events, primarily due to an increased incidence of mild hypoglycemia in this treatment group.. Nateglinide and troglitazone are equally effective in decreasing HbA(1c) levels. However, these reductions from baseline HbA(1c) values of >8% are not adequate to achieve HbA(1c) levels of <7%. In contrast, the combination of nateglinide and of a thiazolidinedione shows an additive effect that is highly effective in reducing HbA(1c) levels to the target of <7% in 66% of patients, from a baseline HbA(1c) that is just above 8%.

Topics: Adult; Aged; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Male; Middle Aged; Nateglinide; Phenylalanine; Thiazoles; Thiazolidinediones; 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

Nateglinide a new short-acting D-phenylalanine derivative represents a new chemical class of drugs for treating type 2 diabetes that is pharmacologically and therapeutically distinct from currently existing agents. Studies in normal patients and those with type 2 diabetes have shown that nateglinide reduces mealtime blood glucose excursions by physiologic regulation of insulin secretion. Nateglinide binds to and inhibits the K+(ATP) channel of the beta-cell, causing membrane depolarisation, with a subsequent influx of extracellular calcium that results in insulin secretion. A total of 105 patients in 5 centres with type II diabetes mellitus were taken according to the inclusion criteria and given drug treatment and were evaluated on their improvement in fasting and postprandial plasma glucose and glycosylated haemoglobin values for efficacy, besides physician's assessment of the overall safety and efficacy. Nateglinide in a dose of 60 mg before three main meals was given and increased to a maximum of 120 mg thrice daily over the first 3-4 weeks. Nateglinide had to be taken 10 minutes before meals. Duration of treatment was 12 weeks. The patients showed decrease in fasting plasma glucose from 2nd week onwards and reduction in glycosylated haemoglobin by 6th week onwards. Postprandial glucose reduction was also significant at the end of 12th week. The frequency of adverse effects was low and no serious adverse effects were encountered.

Topics: Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Nateglinide; Phenylalanine; Prospective Studies; Treatment Outcome

This study evaluated the addition of nateglinide, a d-phenylalanine derivative that restores early phase insulin release, to metformin in type 2 diabetes patients stabilized on high-dose metformin.. This multicentre, double-blind, parallel group trial included 467 metformin-treated patients with glycosylated haemoglobin (HbA1c) between 6.8% and 11%. Patients were randomized to add nateglinide 60 mg, 120 mg or placebo before three meals to metformin 1000 mg b.i.d. for 24 weeks.. HbA1c was significantly reduced with nateglinide 60 mg and 120 mg plus metformin compared with metformin control (-0.36%, p = 0.003; -0.59%, p < 0.001 respectively). Greater benefits occurred if patients had elevated HbA1c at baseline (-1.38% with nateglinide 120 mg in patients with HbA1c > 9.5%). A modest fasting plasma glucose reduction was observed. Most symptoms suggestive of hypoglycaemia occurred in patients with low HbA1c levels (

Topics: Aged; Blood Glucose; Body Mass Index; Body Weight; Cholesterol; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Nateglinide; Phenylalanine; Placebos; Racial Groups; Safety; Triglycerides

This study compared the effects of nateglinide, glyburide, and placebo on postmeal glucose excursions and insulin secretion in previously diet-treated patients with type 2 diabetes.. This randomized, double-blind, placebo-controlled multicenter study was conducted in 152 patients who received either nateglinide (120 mg before three meals daily, n = 51), glyburide (5 mg q.d. titrated to 10 mg q.d. after 2 weeks, n = 50), or placebo (n = 51) for 8 weeks. Glucose, insulin, and C-peptide profiles during liquid meal challenges were measured at weeks 0 and 8. At weeks -1 and 7, 19-point daytime glucose and insulin profiles, comprising three solid meals, were measured.. During the liquid-meal challenge, nateglinide reduced the incremental glucose area under the curve (AUC) more effectively than glyburide ( = -4.94 vs. -2.71 mmol. h/l, P < 0.05), whereas glyburide reduced fasting plasma glucose more effectively than nateglinide ( = -2.9 vs. -1.0 mmol/l, respectively, P < 0.001). In contrast, C-peptide induced by glyburide was greater than that induced by nateglinide ( = +1.83 vs. +0.95 nmol. h/l, P < 0.01), and only glyburide increased fasting insulin levels. During the solid meal challenges, nateglinide and glyburide elicited similar overall glucose control ( 12-h incremental AUC = -13.2 vs. -15.3 mmol. h/l), but the insulin AUC induced by nateglinide was significantly less than that induced by glyburide ( 12-h AUC = +866 vs. +1,702 pmol. h/l, P = 0.01).. This study demonstrated that nateglinide selectively enhanced early insulin release and provided better mealtime glucose control with less total insulin exposure than glyburide.

Topics: Aged; Area Under Curve; Blood Glucose; C-Peptide; Cyclohexanes; Diabetes Mellitus, Type 2; Diet, Diabetic; Double-Blind Method; Fasting; Female; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Middle Aged; Nateglinide; Phenylalanine; Placebos; Postprandial Period; Proinsulin; Single-Blind Method; Time Factors

This randomized crossover double-blind placebo-controlled study aimed to assess the efficacy of nateglinide (A-4166), a novel phenylalanine-derived insulin secretagogue, in type 2 diabetic subjects while fasting and 5 min before a standard meal.. A single dose of nateglinide (60, 120, or 180 mg) or placebo was given to eight diet-treated overnight-fasted type 2 diabetic patients and to seven patients 5 min before a standard breakfast. Plasma glucose, radioimmunoassay insulin, and nateglinide were measured at baseline and for a further 180 min.. The time-averaged 180-min postdose mean decrease in fasting plasma glucose concentration was greater after nateglinide (1.8 mmol/l; 95% CI 1.5-2.0) than after placebo (0.7 mmol/l; 95% CI 0.3-1.2) (P < 0.001). Hypoglycemia did not develop in any of the subjects. Insulin concentrations increased 1.5-, 1.8-, and 1.9-fold with the 60-, 120-, and 180-mg doses, respectively (P < 0.001), peaking approximately 30 min after the dose. Nateglinide concentrations peaked after approximately 30 min, decreasing to 21% of peak by 180 min. In the meal test, the mean increase (2.9 mmol/l, 2.3-3.6) in plasma glucose over 180 min after placebo was reduced by 1.8 mmol/l (P < 0.001) with the two higher doses of nateglinide.. A single dose of nateglinide administered to diet-treated type 2 diabetic patients with fasting hyperglycemia increased insulin secretion and reduced fasting glucose without hypoglycemia. Administered 5 min before a meal, nateglinide reduced the postprandial glucose excursion by 64%. With its rapid onset and short duration of action, nateglinide is a promising oral prandial therapy in type 2 diabetes.

Topics: Blood Glucose; Cross-Over Studies; Cyclohexanes; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Nateglinide; Phenylalanine; Postprandial Period

These studies examined the influence of timing of administration of nateglinide on the glucose profile and beta-cell secretory response to a standardized test meal and the effect of meal composition on the pharmacokinetic and pharmacodynamic profile. In study 1, nateglinide (60 mg) or placebo was given orally at -10, -1, or +10 min to healthy subjects (n = 12), in relation to a standardized test meal (500 kcal) that commenced at 0 min. In study 2, also in healthy subjects (n = 12), a single oral dose (60 mg) of nateglinide was given either 10 min before or 10 min after the start of each of three different test meals (i.e. high in carbohydrate, fat, or protein). In both studies, the postmeal observation period was a minimum of 240 min. In the first study premeal (-10,-1 min), administration of nateglinide led to earlier and higher peak plasma nateglinide concentrations, compared with postprandial dosing (+10 min). A significantly lower maximum postprandial glucose concentration was seen with preprandial dosing compared with either placebo (P < 0.01) or nateglinide given postprandially (P < 0.01). The impact on the glucose profile was consistent with the enhanced insulin profiles after nateglinide, resulting in higher peak plasma insulin concentrations compared with placebo (P < 0.01). Study 2 confirmed the greater impact of pre- vs. postprandial dosing on the glucose and insulin profiles, irrespective of meal type. Nateglinide administration, before a meal, resulted in a more rapid rise and higher peak nateglinide plasma concentrations, irrespective of meal composition. Preprandial administration of nateglinide was more effective in reducing prandial glucose excursions, compared with postmeal dosing (+10 min), a consequence of the earlier insulin response.

Topics: Area Under Curve; C-Peptide; Cross-Over Studies; Cyclohexanes; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Double-Blind Method; Humans; Hypoglycemic Agents; Nateglinide; Phenylalanine; Time Factors

Insulin secretion is impaired in type 2 diabetes with the early response being essentially absent. The loss of this early insulin secretion is hypothesized to be important in the deterioration of glucose tolerance. To determine whether enhancement of the early-phase insulin response can enhance glucose tolerance, we administered 1) 120 mg nateglinide, an insulinotropic agent that enhances early insulin secretion; 2) 10 mg glyburide, which enhances the later phases of insulin secretion; or 3) placebo in random order to 21 subjects with type 2 diabetes (14 males and 7 females; aged 59.2 +/- 2.1 yr, x +/- SEM; body mass index 29.7 +/- 1.0 kg/m(2); fasting plasma glucose 8.1 +/- 0.1 mM). beta-Cell function was quantified as the incremental area under the curve for different time periods for the 5 h following iv glucose administration and glucose tolerance as the glucose disappearance constant (Kg) from 10 to 60 min. Insulin release commenced immediately after nateglinide administration, even before glucose injection, but this was not observed with glyburide. Both nateglinide and glyburide enhanced glucose-induced insulin release, compared with placebo (area under the curve -15-300 min: nateglinide 23,595 +/- 11,212 pM/min, glyburide 54,556 +/- 15,253 pM/min, placebo 10,242 +/- 2,414 pM/min). The profiles of insulin release demonstrated significant enhancement of release between -15 and 30 min for nateglinide, compared with glyburide and between 60 and 300 min for glyburide over nateglinide. Kg increased by 15% with nateglinide (0.87 +/- 0.04%/min), but it did not increase significantly with glyburide (0.79 +/- 0.04%/min), compared with placebo (0.76 +/- 0.04%/min). The enhancement of insulin release by glyburide resulted in a lower minimal glucose concentration with glyburide (3.8 +/- 0.2 mM), compared with nateglinide (5.0 +/- 0.2 mM) and placebo (5.9 +/- 0.2 mM). Thus, enhancement of the early phase of insulin secretion improves iv glucose tolerance, whereas delaying it by 30 min results in a slower rate of glucose disappearance for the first 2 h after iv glucose administration. Further, the differences in the kinetics of nateglinide and glyburide action results in continued insulin release with glyburide despite the fact that glucose levels have returned to basal, thus resulting in a further reduction in glucose levels and a lower nadir.

Topics: Aged; Cross-Over Studies; Cyclohexanes; Diabetes Mellitus, Type 2; Female; Glucose; Glucose Tolerance Test; Glyburide; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Middle Aged; Nateglinide; Phenylalanine; Reproducibility of Results; Sodium Chloride; Time Factors

This study assessed the synergistic effects of nateglinide (a non-sulfonylurea 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.

Topics: Adult; Aged; Area Under Curve; Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Eating; Fasting; Female; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Nateglinide; Phenylalanine; Time Factors

The new non-sulphonylurea oral hypoglycaemic agent nateglinide has been shown to enhance insulin secretion in animals and in healthy human volunteers and thus offers a potential advance in the treatment of Type 2 diabetes mellitus. This study examined whether nateglinide can enhance insulin secretion, and particularly the first phase insulin response, in patients with Type 2 diabetes.. A double-blind, placebo-controlled trial, examining the effects of a single oral dose of 60 mg nateglinide, given 20 min prior to an intravenous glucose tolerance test (IGTT), on insulin secretion in 10 otherwise healthy Caucasian men with recently diagnosed Type 2 diabetes (duration since diagnosis 0-44 months).. Insulin secretion (both overall and first phase) was significantly increased by nateglinide (P < 0.001), as were C-peptide (P < 0.001) and proinsulin (P < 0.001) secretion. Overall glucose concentrations following glucose challenge were lower after nateglinide than after placebo (P = 0.05).. Nateglinide significantly increases insulin secretion in Type 2 diabetic patients, in particular restoring the first phase insulin response. Further study is necessary to determine the effects of chronic administration on insulin secretion and blood glucose concentration.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Kinetics; Male; Middle Aged; Nateglinide; Phenylalanine; Placebos; Proinsulin

The objective of the study was to assess the efficacy and safety of four fixed doses of nateglinide compared with placebo in the treatment of patients with type 2 diabetes with focus on the prandial state.. This randomized double-blind placebo-controlled multicenter study was conducted in 289 patients who received either nateglinide at doses of 30 mg (n = 51), 60 mg (n = 58), 120 mg (n = 63), or 180 mg (n = 57) or placebo (n = 60) before three main meals for 12 weeks. Levels of HbA1c, fasting plasma glucose (FPG), fructosamine, and plasma lipids were measured at predetermined intervals, and the effects of nateglinide on prandial glucose insulin, C-peptide, and triglyceride levels were measured after a liquid standard meal (Sustacal; Mead Johnson, Evansville, IN). Adverse events and hypoglycemic episodes were recorded.. After a liquid meal challenge, nateglinide rapidly increased mealtime insulin levels within 30 min of drug intake and reduced mealtime glucose excursions without affecting triglyceride levels. At study end point, reduction of HbA1c levels was statistically significantly greater with nateglinide at doses of 60, 120, and 180 mg than placebo (-0.45, -0.62, and -0.64%, respectively; P<0.05). The mean level of FPG was significantly reduced versus placebo in the nateglinide 120-mg group only (-1.14 mmol/l P<0.01). Overall, nateglinide was well tolerated.. This study demonstrated that nateglinide improves mealtime and mean glycemic control in a dose-dependent manner by restoring early insulin secretion phase. Nateglinide was well tolerated and is suitable for the treatment of patients with type 2 diabetes.

Topics: Adult; Aged; Area Under Curve; Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Eating; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Middle Aged; Nateglinide; Phenylalanine; Placebos; Safety

Nateglinide, a new short-acting D-phenylalanine derivative for treating type 2 diabetes, reduces mealtime blood glucose excursions by physiologic regulation of insulin secretion. This study evaluated the pharmacokinetic and pharmacodynamic interactions of nateglinide and metformin in subjects with type 2 diabetes.. A total of 12 type 2 diabetic subjects with the following baseline characteristics were enrolled: age, 56 +/- 13 years; BMI, 28.7 +/- 4.5 kg/m2; HbA1c, 8.4 +/- 1.3%; and fasting plasma glucose 13 +/- 2.8 mmol/l. All subjects had been previously treated with glyburide and were switched to metformin monotherapy for 3 weeks before study start. Subjects then randomly received, in combination with 500 mg metformin, either 120 mg nateglinide or placebo before meals for 1 day, followed by the alternate treatment 7 days later. After 1 week of washout from both drugs, subjects received 1 day of open-label nateglinide treatment. Plasma concentrations of glucose, insulin, nateglinide, and metformin were assessed frequently during inpatient periods.. Postmeal plasma glucose levels were significantly lower in subjects treated with nateglinide plus metformin than in those treated with either drug alone (P < 0.001), especially after lunch and dinner. Coadministration of nateglinide and metformin did not affect the pharmacokinetics of either drug. All treatments were safe and well tolerated.. Combination therapy with nateglinide and metformin was more effective than either treatment alone and did not result in any pharmacokinetic interactions. Coadministration of nateglinide and metformin appears to be an excellent option for treating patients with type 2 diabetes not controlled with monotherapy.

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

Pharmacodynamic effects of nateglinide, a novel antidiabetic agent, were investigated in patients with type-2 diabetes mellitus.. Ten patients participated in this single-center, double-blind, crossover study. Plasma glucose and insulin levels were measured over 24 h following five 7-day treatment periods with nateglinide (30, 60, or 120 mg) or placebo given three times daily before breakfast, lunch, and dinner. A fifth treatment consisted of 120 mg nateglinide four times daily, with the fourth dose given before an evening snack.. Taken 10 min before meals, doses of 30-120 mg nateglinide caused dose-dependent increases in plasma insulin levels that were significantly greater than with placebo. Higher doses were more effective and had a longer duration of action than lower doses. Nateglinide was also significantly better than placebo in lowering plasma glucose levels; the 60-mg and 120-mg doses were similarly effective and superior to the 30-mg nateglinide treatment. Following the fourth 120-mg dose, the glucose-lowering effects of treatment were maintained through the night. No serious adverse events occurred during the study. There were no events of hypoglycemia and no clinically meaningful changes in safety parameters.. Nateglinide produced rapid, short-lived, dose-related increases in plasma insulin that significantly lowered mealtime glucose excursions compared with placebo with no incidence of hypoglycemia. The decrease in mealtime glucose levels produced a significant improvement in overall 24-h glycemia.

Topics: Blood Glucose; Cross-Over Studies; Cyclohexanes; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Nateglinide; Phenylalanine; Placebos

To evaluate the efficacy and tolerability of nateglinide and metformin alone and in combination in type 2 diabetic patients inadequately controlled by diet, focusing on changes in HbA1c, fasting plasma glucose (FPG), and mealtime glucose excursions.. In this randomized double-blind study, patients with an HbA1c level between 6.8 and 11.0% during a 4-week placebo run-in received 24 weeks' treatment with 120 mg nateglinide before meals (n = 179), 500 mg metformin three times a day (n = 178), combination therapy (n = 172), or placebo (n = 172). HbA1c and FPG were evaluated regularly, and plasma glucose levels were determined after Sustacal challenge at weeks 0, 12, and 24. Hypoglycemia and other adverse events were recorded.. At study end point, HbA1c was reduced from baseline with nateglinide and metformin but was increased with placebo (-0.5, -0.8, and +0.5%, respectively; P < or = 0.0001). Changes in FPG followed the same pattern (-0.7, -1.6, and +0.4 mmol/l; P < or = 0.0001). Combination therapy was additive (HbA1c -1.4% and FPG -2.4 mmol/l; P < or = 0.01 vs. monotherapy). After Sustacal challenge, there was a greater reduction in mealtime glucose with nateglinide monotherapy compared with metformin monotherapy or placebo (adjusted area under the curve [AUC]0-130 min -2.1, -1.1, and -0.6 mmol x h(-1) x l(-1); p < or = 0.0001). An even greater effect was observed with combination therapy (AUC0-130 min -2.5 mmol x h(-1) x l(-1); P < or = 0.0001 vs. metformin and placebo). All regimens were well tolerated.. Nateglinide and metformin monotherapy each improved overall glycemic control but by different mechanisms. Nateglinide decreased mealtime glucose excursions, whereas metformin primarily affected FPG. In combination, nateglinide and metformin had complementary effects, improving HbA1c, FPG, and postprandial hyperglycemia.

Topics: Aged; Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Eating; Ethnicity; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Nateglinide; Phenylalanine; Prospective Studies; United States

The insulin secretory pattern as a phenotype of type 2 diabetes is an impairment in the rapid, pulsatile secretion of insulin in response to a rise in blood glucose after meal-intake. The restoration of endogenous rapid insulin secretion after oral glucose load was established for the first time by using nateglinide, which is a newly developed insulin secretagogue, in obese patients with type 2 diabetes mellitus. It was clearly demonstrated that with nateglinide, serum insulin levels were quickly raised, and glycemic response curves were almost normalized with the same amount of insulin secretion during 180 min. Therefore, the lack of rapid, pulsatile secretion of insulin in response to glycemic rise after oral glucose load, rather than insulin resistance, is responsible for postprandial glycemic response in obese type 2 diabetes patients.

Topics: Adult; Cyclohexanes; Diabetes Mellitus, Type 2; Female; Glucose; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Male; Middle Aged; Nateglinide; Obesity; Phenylalanine; Postprandial Period

Two novel oral hypoglycaemic agents, NN623 and A4166, have been developed and are now in phase II clinical trial. Both agents have several common characteristics from sulphonylureas. NN623 is a stereoisomer of derivatives of benzoic acid and A4166 is also a stereoisomer of phenylalanine derivative. The predominant mechanism of the action is thought to be like sulphonylureas. Both NN623 and A4166 occupy, at least partly, a common receptor site with glibenclamide and close the ATP-dependent K+ channel. They are rapidly absorbed from the intestine and are eliminated mainly into the bile. NN623 is about 10 times more potent in hypoglycaemic action than glibenclamide and 100 times more than A4166 in terms of dosage. When 1.0 mg NN623 or 60 mg A4166 was given orally in the post-absorptive state to healthy volunteers, both agents evoked hypoglycaemia by 40 min. The duration of hypoglycaemia after NN623 was longer than after A4166 by about 1 hour. The effect of food on their bioavailability is similar. Food has marked influence on the absorption of both drugs and on their efficacy. When 1 mg of NN623 or 60 mg of A4166 was administered just before the meal, Tmax of NN623 and A4166 was 34 +/- 18 min and 18 +/- 6 min, while T1/2 was 0.64 +/- 0.12 h and 0.98 +/- 0.06 h, respectively. The postprandial rise in plasma glucose was reduced at 45 min and thereafter over 4-h after 1.0 mg NN623 and at 30 min to 90 min after 60 mg A4166. Plasma insulin levels rose more than those after placebo from 30 to 90 min after NN623 and at 20 to 40 min after A4166. Both agents stimulated insulin release much more in the postprandial than in the fasting state. There was no difference in the bioavailability after 5 or 7 days of administration. However, when administered immediately after the meal, the absorption of both drugs was delayed and the rise in plasma absorption was not suppressed until 60 min after the meal. Both fasting and postprandial hyperglycaemia were reduced after 1 to 4 weeks of premeal treatment with 0.5 mg NN623 or 60 mg A4166 in subjects with NIDDM. Plasma glucose levels were decreased over 4 h after NN623 and over 1 h after A4166. The meal-induced insulin response was almost doubled by NN623 over 2 h and 1 h by A4166. There was no difference in the bioavailability after breakfast between the first and last administrations of both drugs. In conclusion, a rapid rise in plasma insulin levels is associated with the suppression of postprandial hyperglycaemia.

Topics: Administration, Oral; Biological Availability; Blood Glucose; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Glyburide; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Intestinal Absorption; Molecular Structure; Nateglinide; Phenylalanine; Piperidines; Reference Values; Stereoisomerism

Polypharmacy in type 2 diabetes is an issue of major concern as the prescription of multiple medi-cations for the management of diabetes-associated comorbidities can lead to drug-to-drug interactions, which can pose serious risks to patients' health. Within this context, the development of bioanalytical methods for monitoring the therapeutic levels of antidiabetic drugs is notably useful to ensure patients' safety. In the present work, a liquid chromatography-mass spectrometry method for the quantitation of pioglitazone, repaglinide, and nateglinide in human plasma is described. Sample preparation was performed by fabric phase sorptive extraction (FPSE), and hydrophilic interaction liquid chromatography (HILIC) was implemented for the chromatographic separation of the analytes, using a ZIC®-cHILIC analytical column (150 × 2.1 mm, 3 µm) under isocratic elution. The mobile phase consisted of 10 mM ammonium formate aqueous solution (pH = 6.5)/ acetonitrile, 10/90 v/v, and was pumped at a flow rate of 0.2 mL min

Topics: Chromatography, High Pressure Liquid; Chromatography, Liquid; Diabetes Mellitus, Type 2; Drug Monitoring; Humans; Hydrophobic and Hydrophilic Interactions; Nateglinide; Pioglitazone; Spectrometry, Mass, Electrospray Ionization

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

Genetic polymorphisms in the PPARD and NOS1AP is associated with type 2 diabetes mellitus (T2DM); however, there is no evidence about its impact on the therapeutic efficacy of nateglinide. This study was designed to investigate a potential association of PPARD rs2016520 (T/C) and NOS1AP rs12742393 (A/C) polymorphisms with efficacy of nateglinide in newly diagnosed Chinese patients with type 2 diabetes mellitus (T2DM).. Sixty patients with newly diagnosed T2DM were enrolled to identify PPARD rs2016520 and NOS1AP rs12742393 genotypes using the polymerase chain reaction-restriction fragment length polymorphism assay (PCR-RFLP). All subjects were treated with nateglinide (360 mg/day) for 8 weeks. Anthropometric measurements, clinical laboratory tests were obtained at baseline and after 8 weeks of nateglinide treatment.. After nateglinide treatment for 8 consecutive weeks, patients with at least one C allele of PPARD rs2016520 showed a smaller decrease in post plasma glucose (PPG), homeostasis model assessment for beta cell function (HOMA-B) than those with the TT genotype did (P < 0.05). In patients with the AA genotype of NOS1AP rs12742393, the drug showed better efficacy with respect to levels of fasting plasma glucose (FPG), fasting serum insulin (FINS), HOMA-B and homeostasis model assessment for insulin resistance (HOMA-IR) than in patients with the AC + CC genotype (P < 0.05). NOS1AP rs12742393 genotype distribution and allele frequency were associated with responsiveness of nateglinide treatment (P < 0.05).. The PPARD rs2016520 and NOS1AP rs12742393 polymorphisms were associated with nateglinide monotherapy efficacy in Chinese patients with newly diagnosed T2DM.. Chinese Clinical Trial Register ChiCTR13003536, date of registration: May 14, 2013.

Topics: Adaptor Proteins, Signal Transducing; China; Diabetes Mellitus, Type 2; Female; Genotype; Humans; Hypoglycemic Agents; Male; Nateglinide; Polymorphism, Single Nucleotide; PPAR delta; Treatment Outcome

Meglitinides are a group of oral hypoglycemic medications currently approved for the treatment of type 2 diabetes mellitus (T2DM). Two meglitinide molecules, Repaglinide and Nateglinide, are presently in use. Repaglinide is preferred because of its superior glycemic efficacy. They have modest efficacy with a mean decrement of glycosylated haemoglobin (HbA1c) ranging between -0.2 to -1.50% with individual therapy. Additional HbA1c reduction can occur with combination therapy with other oral hypoglycemics. This class of drugs is effective in controlling postprandial hyperglycemia with minimal risk of hypoglycemia. It is also useful in patients with variable meal timings, especially in the elderly, and in patients with renal failure. There are a dearth of long-term studies on meglitinides to assess cardiovascular outcomes or mortality in T2DM, although the Nateglinide and Valsartan in Impaired Glucose ToleranceOutcomes Research (NAVIGATOR) study showed no difference between Nateglinide and placebo with regard to the core composite cardiovascular outcomes. Based on a PubMed literature search using key words: 'meglitinides', 'repaglinide', 'nateglinide', 'HbA1c', 'glycated haemoglobin', 'cardiovascular safety', 'cardiovascular events', 'cardiovascular outcome trials', 'type 2 diabetes mellitus' and heart failure, and combining the search terms using Boolean operators 'AND', 'OR' and 'NOT' as needed we compiled current evidence for use of these oral hypoglycemic agents in clinical use. This article is an attempt to review the efficacy and cardiovascular (CV) safety of Meglitinides to help clinicians to use this class of oral hypoglycaemic agents prudently.

Topics: Aged; Benzamides; Blood Glucose; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Nateglinide

To assess the association of metformin monotherapy with the risk of all-cause deaths and cardiovascular deaths and events in type 2 diabetes patients in real clinical practice.. This retrospective, observational study comprised patients with type 2 diabetes initially treated with metformin or nonmetformin monotherapy over 2011-2016. Data were extracted from the National Healthcare Big Data database in Fuzhou, China. Propensity score matching (PSM) was performed, matching each patient on metformin to one on nonmetformin in terms of a set of covariates. The primary endpoint was all-cause death, and secondary endpoints were cardiovascular death, heart failure, and heart failure hospitalization. Covariate-adjusted associations of metformin use with all the endpoints were assessed by Cox proportional hazards models.. Among 24,099 patients, 5491 were initially treated with metformin and 18,608 with nonmetformin. PSM yielded 5482 patients in each cohort. During a median follow-up of 2.02 years, we observed 110 and 211 deaths in the metformin and nonmetformin groups, respectively. Metformin was significantly associated with reduced risk of all-cause death (adjusted hazard ratio (aHR) 0.52, 95% confidence interval (CI) 0.39-0.69), cardiovascular death (aHR 0.63, 95% CI 0.43-0.91), and heart failure (aHR 0.61, 95% CI 0.52-0.73), whereas the reduced risk in heart failure hospitalization was not statistically significant (aHR 0.70, 95% CI 0.47-1.02).. In this analysis of electronic health record data from a large database in China, metformin as first-line monotherapy greatly reduced the risk of all-cause death, cardiovascular death, and heart failure in diabetes patients as compared with nonmetformin medications.

Topics: Aged; Benzamides; Carbamates; Cardiovascular Diseases; Cause of Death; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glycoside Hydrolase Inhibitors; Heart Failure; Hospitalization; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Mortality; Nateglinide; Piperidines; Proportional Hazards Models; Retrospective Studies; Sulfonylurea Compounds; Thiazolidinediones

Participants enrolled into randomized controlled trials (RCTs) often do not reflect real-world populations. Previous research in how best to transport RCT results to target populations has focused on weighting RCT data to look like the target data. Simulation work, however, has suggested that an outcome model approach may be preferable. Here, we describe such an approach using source data from the 2 × 2 factorial NAVIGATOR (Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research) trial, which evaluated the impact of valsartan and nateglinide on cardiovascular outcomes and new-onset diabetes in a prediabetic population.. Our target data consisted of people with prediabetes serviced at the Duke University Health System. We used random survival forests to develop separate outcome models for each of the 4 treatments, estimating the 5-year risk difference for progression to diabetes, and estimated the treatment effect in our local patient populations, as well as subpopulations, and compared the results with the traditional weighting approach.. Our models suggested that the treatment effect for valsartan in our patient population was the same as in the trial, whereas for nateglinide treatment effect was stronger than observed in the original trial. Our effect estimates were more efficient than the weighting approach and we effectively estimated subgroup differences.. The described method represents a straightforward approach to efficiently transporting an RCT result to any target population.

Topics: Antihypertensive Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Disease Progression; Electronic Health Records; Evidence-Based Medicine; Humans; Hypoglycemic Agents; Machine Learning; Nateglinide; Outcome Assessment, Health Care; Prediabetic State; Randomized Controlled Trials as Topic; Translational Research, Biomedical; Valsartan

Regional differences in risk of diabetes mellitus and cardiovascular outcomes in people with impaired glucose tolerance are poorly characterized. Our objective was to evaluate regional variation in risk of new-onset diabetes mellitus, cardiovascular outcomes, and treatment effects in participants from the NAVIGATOR (Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research) trial.. NAVIGATOR randomized people with impaired glucose tolerance and cardiovascular risk factors or with established cardiovascular disease to valsartan (or placebo) and to nateglinide (or placebo) with a median 5-year follow-up. Data from the 9306 participants were categorized by 5 regions: Asia (n=552); Europe (n=4909); Latin America (n=1406); North America (n=2146); and Australia, New Zealand, and South Africa (n=293). Analyzed outcomes included new-onset diabetes mellitus; cardiovascular death; a composite cardiovascular outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke; and treatment effects of valsartan and nateglinide. Respective unadjusted 5-year risks for new-onset diabetes mellitus, cardiovascular death, and the composite cardiovascular outcome were 33%, 0.4%, and 4% for Asia; 34%, 2%, and 6% for Europe; 37%, 4%, and 8% for Latin America; 38%, 2%, and 6% for North America; and 32%, 4%, and 8% for Australia, New Zealand, and South Africa. After adjustment, compared with North America, European participants had a lower risk of new-onset diabetes mellitus (hazard ratio 0.86, 95% CI 0.78-0.94; P=0.001), whereas Latin American participants had a higher risk of cardiovascular death (hazard ratio 2.68, 95% CI 1.82-3.96; P<0.0001) and the composite cardiovascular outcome (hazard ratio 1.48, 95% CI 1.15-1.92; P=0.003). No differential interactions between treatment and geographic location were identified.. Major regional differences regarding the risk of new-onset diabetes mellitus and cardiovascular outcomes in NAVIGATOR participants were identified. These differences should be taken into account when planning global trials.. URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00097786.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Asia; Australia; Cardiovascular Diseases; Cyclohexanes; Diabetes Mellitus, Type 2; Europe; Female; Glucose Intolerance; Humans; Hypoglycemic Agents; Incidence; Latin America; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Nateglinide; New Zealand; North America; Outcome Assessment, Health Care; Phenylalanine; Proportional Hazards Models; Randomized Controlled Trials as Topic; Risk Factors; South Africa; Stroke; Valsartan

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

Although there is a significant effort in the discovery of effective therapies to contrast both the pathological endocrine and metabolic aspects of diabetes and the endothelial dysfunction associated with this disease, no hypoglycemic drug has been proven to defeat the cardiovascular complications associated with type II diabetes. The aim of this research was to design new compounds exhibiting a double profile of hypoglycemic agents/NO-donors. The synthesis of molecules obtained by the conjunction of NO-donor moieties with two oral insulin-secretagogue drugs (repaglinide and nateglinide) was reported. NO-mediated vasorelaxing effects of the synthesized compounds were evaluated by functional tests on isolated endothelium-denuded rat aortic rings. The most potent molecule (4) was tested to evaluate the hypoglycemic and the anti-ischemic cardioprotective activities. This study indicates that 4 should represent a new insulin-secretagogue/NO-donor prodrug with an enhanced cardiovascular activity, which may contrast the pathological aspects of diabetes and endowed of cardioprotective activity.

Topics: Animals; Cardiotonic Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Disease Models, Animal; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Nitric Oxide Donors; Rats; Rats, Wistar

The glinides are the therapeutic agents for indications for type 2 diabetic patients with postprandial hyperglycemia. These are a class of drug which have a similar response as sulfonylureas but act for a shorter time and are prescribed to be taken by patients with type 2 diabetes within 5-10 min before eating. As the drugs act for a shorter period than sulfonylureas, the side effects of hypoglycemia and weight gain have a smaller likelihood. Combination with glinides and DPP4 inhibitors is a good choice for type 2 diabetic patients in early stage. Also combination therapy with glinides and alpha-glucosidase inhibitors shows a good profile of daily blood glucose level in these patients.

Topics: Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Hyperglycemia; Hypoglycemic Agents; Isoindoles; Nateglinide; Phenylalanine

Topics: Acarbose; Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Humans; Hyperlipidemias; Hypoglycemic Agents; Nateglinide; Phenylalanine; Postprandial Period

To examine the degree to which use of β blockers, statins, and diuretics in patients with impaired glucose tolerance and other cardiovascular risk factors is associated with new onset diabetes.. Reanalysis of data from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial.. NAVIGATOR trial.. Patients who at baseline (enrolment) were treatment naïve to β blockers (n=5640), diuretics (n=6346), statins (n=6146), and calcium channel blockers (n=6294). Use of calcium channel blocker was used as a metabolically neutral control.. Development of new onset diabetes diagnosed by standard plasma glucose level in all participants and confirmed with glucose tolerance testing within 12 weeks after the increased glucose value was recorded. The relation between each treatment and new onset diabetes was evaluated using marginal structural models for causal inference, to account for time dependent confounding in treatment assignment.. During the median five years of follow-up, β blockers were started in 915 (16.2%) patients, diuretics in 1316 (20.7%), statins in 1353 (22.0%), and calcium channel blockers in 1171 (18.6%). After adjusting for baseline characteristics and time varying confounders, diuretics and statins were both associated with an increased risk of new onset diabetes (hazard ratio 1.23, 95% confidence interval 1.06 to 1.44, and 1.32, 1.14 to 1.48, respectively), whereas β blockers and calcium channel blockers were not associated with new onset diabetes (1.10, 0.92 to 1.31, and 0.95, 0.79 to 1.13, respectively).. Among people with impaired glucose tolerance and other cardiovascular risk factors and with serial glucose measurements, diuretics and statins were associated with an increased risk of new onset diabetes, whereas the effect of β blockers was non-significant.. ClinicalTrials.gov NCT00097786.

Topics: Adrenergic beta-Antagonists; Aged; Calcium Channel Blockers; Cardiovascular Diseases; Cyclohexanes; Diabetes Mellitus, Type 2; Diuretics; Double-Blind Method; Female; Follow-Up Studies; Glucose Intolerance; Glucose Tolerance Test; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Incidence; Male; Middle Aged; Models, Statistical; Nateglinide; Phenylalanine; Risk Factors; Tetrazoles; Treatment Outcome; Valine; Valsartan

To develop a rapid, easy and clinically relevant in vivo model to evaluate novel insulin secretagogues on human islets, we investigated the effect of insulin secretagogues on functional human islets in a humanized mouse model.. Human islets were transplanted under the kidney capsule of streptozotocin (STZ)-induced diabetic mice with immunodeficiency. Human islet graft function was monitored by measuring non-fasting blood glucose levels. After diabetes was reversed, human islet transplanted mice were characterized physiologically by oral glucose tolerance and pharmacologically with clinically proven insulin secretagogues, glucagon-like peptide-1 (GLP-1), exenatide, glyburide, nateglinide and sitagliptin. Additionally, G protein-coupled receptor 40 (GPR40) agonists were evaluated in this model.. Long-term human islet graft survival could be achieved in immunodeficient mice. Oral glucose challenge in human islet transplanted mice resulted in an immediate incremental increase of plasma human C-peptide, while the plasma mouse C-peptide was undetectable. Treatments with GLP-1, exenatide, glyburide, nateglinide and sitagliptin effectively increased plasma human C-peptide levels and improved postprandial glucose concentrations. GPR40 agonists also stimulated human C-peptide secretion and significantly improved postprandial glucose in the human islet transplanted mice.. Our studies indicate that a humanized mouse model with human islet grafts could mimic the in vivo characteristics of human islets and could be a powerful tool for the evaluation of novel insulin secretagogues or other therapeutic agents that directly and/or indirectly target human β cells.

Topics: Animals; Blood Glucose; Cyclohexanes; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Glyburide; Humans; Incretins; Insulin; Insulin Secretion; Islets of Langerhans; Islets of Langerhans Transplantation; Male; Mice; Mice, Nude; Nateglinide; Peptides; Phenylalanine; Pyrazines; Sitagliptin Phosphate; Specific Pathogen-Free Organisms; Triazoles; Venoms

Diabetes mellitus has become a major public health problem in China. This open-label, prospective, multicentre, post-marketing surveillance study was conducted to investigate the efficacy and safety of nateglinide in combination with metformin in Chinese patients with type 2 diabetes (T2DM).. A total of 892 patients with T2DM were included in the study, of whom 361 subjects had been pretreated with metformin and 531 subjects had not previously been treated with any oral antihyperglycaemic agent. All enrolled patients received 120 mg of nateglinide three times daily within 15 minutes before meals together with metformin (with no restrictions on dosage or frequency of administration) for 12 weeks. Physical examination, laboratory tests and relevant tests in terms of efficacy were performed, and adverse events and subject compliance were documented and monitored.. From baseline to week 12, glycosylated haemoglobin (HbA1c) was reduced by 1.52 % ± 1.25 % (mean ± SD), fasting plasma glucose (FPG) by 1.92 ± 1.78 mmol/L, and 2-h post-prandial plasma glucose (2-h PPG) by 4.55 ± 2.93 mmol/L (all p < 0.01); 61.66 % of subjects achieved the HbA1c goals of <7 %. A total adverse events incidence of 2.47 % was observed, including an incidence of 1.68 % treatment-emergent adverse events. The incidence of hypoglycaemia was 1.57 %. Other nateglinide-related adverse events (including gastrointestinal disorders, rash and allergic dermatitis) were also reported. There were no serious adverse effects.. The combination of nateglinide and metformin is a safe and effective means of achieving glycaemic target in Chinese patients with T2DM.

Topics: Aged; Body Weight; Cyclohexanes; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Nateglinide; Phenylalanine; Product Surveillance, Postmarketing; Prospective Studies

As part of a program to identify potent GPR40 agonists with drug-like properties suitable for clinical development, the incorporation of polar substituents was explored with the intention of decreasing the lipophilicity of our recently disclosed phenylpropanoic acid derivative 1. This incorporation would allow us to mitigate the cytotoxicity issues observed with compound 1 and enable us to move away from the multifunctional free fatty acid-like structure. Substitutions on the 2',6'-dimethylbiphenyl ring were initially undertaken, which revealed the feasibility of introducing polar functionalities at the biphenyl 4'-position. Further optimization of this position and the linker led to the discovery of several 4'-alkoxybiphenyl derivatives, which showed potent GPR40 agonist activities with the best balance in terms of improved cytotoxicity profiles and favorable pharmacokinetic properties. Among them, 3-{2-fluoro-4-[({4'-[(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy]-2',6'-dimethylbiphenyl-3-yl}methyl)amino]phenyl}propanoic acid (35) exhibited a robust plasma glucose-lowering effect and insulinotropic action during an oral glucose tolerance test in rats with impaired glucose tolerance.

Topics: Animals; Calcium; Caspases; Cell Survival; CHO Cells; Cricetinae; Cyclic S-Oxides; Diabetes Mellitus, Type 2; Female; Glucose Intolerance; Hep G2 Cells; Humans; Hypoglycemic Agents; Inhibitory Concentration 50; Male; Phenylpropionates; Rats; Receptors, G-Protein-Coupled; Structure-Activity Relationship

The common ATP-sensitive potassium (KATP) channel variants E23K and S1369A, found in the KCNJ11 and ABCC8 genes, respectively, form a haplotype that is associated with an increased risk for type 2 diabetes. Our previous studies showed that KATP channel inhibition by the A-site sulfonylurea gliclazide was increased in the K23/A1369 haplotype. Therefore, we studied the pharmacogenomics of seven clinically used sulfonylureas and glinides to determine their structure-activity relationships in KATP channels containing either the E23/S1369 nonrisk or K23/A1369 risk haplotypes.. The patch-clamp technique was used to determine sulfonylurea and glinide inhibition of recombinant human KATP channels containing either the E23/S1369 or the K23/A1369 haplotype.. KATP channels containing the K23/A1369 risk haplotype were significantly less sensitive to inhibition by tolbutamide, chlorpropamide, and glimepiride (IC50 values for K23/A1369 vs. E23/S1369=1.15 vs. 0.71 μmol/l; 4.19 vs. 3.04 μmol/l; 4.38 vs. 2.41 nmol/l, respectively). In contrast, KATP channels containing the K23/A1369 haplotype were significantly more sensitive to inhibition by mitiglinide (IC50=9.73 vs. 28.19 nmol/l for K23/A1369 vs. E23/S1369) and gliclazide. Nateglinide, glipizide, and glibenclamide showed similar inhibitory profiles in KATP channels containing either haplotype.. Our results demonstrate that the ring-fused pyrrole moiety in several A-site drugs likely underlies the observed inhibitory potency of these drugs on KATP channels containing the K23/A1369 risk haplotype. It may therefore be possible to tailor existing therapy or design novel drugs that display an increased efficacy in type 2 diabetes patients homozygous for these common KATP channel haplotypes.

Topics: ATP-Binding Cassette Transporters; Chlorpropamide; Cyclohexanes; Diabetes Mellitus, Type 2; Gene Expression Regulation; Gliclazide; Glyburide; Haplotypes; Homozygote; Humans; Isoindoles; Nateglinide; Patch-Clamp Techniques; Phenylalanine; Polymorphism, Single Nucleotide; Potassium Channels, Inwardly Rectifying; Receptors, Drug; Structure-Activity Relationship; Sulfonylurea Compounds; Sulfonylurea Receptors; Tolbutamide

Topics: Benzamides; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Nateglinide; Phenylalanine

Meglitinides (repaglinide and nateglinide) are insulin secretagogues used to treat diabetes mellitus. We present a case of hypersensitivity reaction to repaglinide in a 61-year-old man who developed a maculopapular rash 5 days after treatment. Skin prick tests including repaglinide (0.5 g/mL) and patch tests (0.05% in pet and saline) were performed, and the results were negative. A blind oral challenge test with repaglinide was performed and the therapeutic dose was subsequently taken at home every 24 hours for 7 days. The result was positive with a delayed reaction at day 3. A punch biopsy of the skin lesions revealed drug-induced exanthema. The clinical manifestations, the latency period, the reappearance of cutaneous lesions after rechallenge, and the histopathology report of the skin biopsy suggest a type IV mechanism.

Topics: Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Hypersensitivity; Erythema; Exanthema; Humans; Hypoglycemic Agents; Male; Middle Aged; Nateglinide; Patch Tests; Phenylalanine; Piperidines

The pharmacokinetics of (-)-N-(trans-4-isopropylcyclohexanecarbonyl)-D-phenylalanine (nateglinide) and its enantiomer (L-enantiomer) was studied in Goto-Kakizaki (GK) rats after intravenous administration of nateglinide or L-enantiomer at a dose of 40 micromol/kg body weight. Nateglinide, its L-enantiomer and their metabolites in serum, bile and urine were determined. The total clearance (CL(tot)) and the volume of distribution (Vd) was slightly higher for nateglinide than those for L-enantiomer in control rats, although the differences were not statistically significant. The cumulative excretions of L-M1 (major metabolite of L-enantiomer) and L-M2 (major metabolite of L-enantiomer) into bile were almost the same as that of M1 (major metabolite of nateglinide)and M2 (major metabolite of nateglinide). In GK rats, CL(tot) and Vd were higher for nateglinide than those for L-enantiomer. The cumulative excretion of L-M1 and L-M2 were not different from those of M1 and M2, respectively, into bile or urine. CL(tot) and Vd for nateglinide or L-enantiomer in GK rats were not different from those in control rats. The total excretion of M1, M2, L-M1, and L-M2 into bile or urine in GK rats was not substantially different from that of control rats. These results suggest that the L-enantiomer of nateglinide shows higher CL(tot) and Vd compared with nateglinide, especially in the diabetic state.

Topics: Animals; Cyclohexanes; Diabetes Mellitus, Type 2; Disease Models, Animal; Hypoglycemic Agents; Male; Nateglinide; Phenylalanine; Rats; Rats, Wistar; Stereoisomerism

Topics: Administration, Oral; Biguanides; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Combinations; Drug Therapy, Combination; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Nateglinide; Phenylalanine; Piperidines; Sulfonylurea Compounds

Topics: Angiotensin II Type 1 Receptor Blockers; Blood Glucose; Cardiovascular Diseases; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glucose Intolerance; Humans; Hypoglycemic Agents; Nateglinide; Phenylalanine; Tetrazoles; Valine; Valsartan

A diabetic patient may suffer simultaneously from cardiovascular disease; thus, lipid-lowering or anti-hypertensive agents could be given together with nateglinide. The pharmacokinetics of nateglinide were investigated in the presence and absence of HMG-CoA reductase inhibitors (fluvastatin, lovastatin) and calcium channel blockers (verapamil, nifedipine) in rabbits. A pharmacokinetic modeling approach was used to quantify the effects of the drugs that significantly influenced the pharmacokinetics of nateglinide. Fluvastatin and nifedipine shifted the time course of serum nateglinide concentrations upwards; there was no significant change with verapamil or lovastatin. The C(max) and AUC(inf) increased 1.5- (p<0.05) and 1.3-fold in the presence of fluvastatin and 1.8- (p<0.01) and 2.4-fold (p<0.01) in the presence of nifedipine, respectively. In a simultaneous nonlinear regression, fluvastatin and nifedipine decreased the elimination rate constant, by 76% and 32%, respectively. Fluvastatin and nifedipine increased the systemic exposure of nateglinide in rabbits, probably due to their inhibitory action on the metabolism of nateglinide by CYP2C5 (human CYP2C9). The concomitant use of fluvastatin and/or nifedipine with nateglinide is quite likely; therefore, the clinical consequences of long-term treatments must be considered.

Topics: Animals; Area Under Curve; Aryl Hydrocarbon Hydroxylases; Calcium Channel Blockers; Cyclohexanes; Cytochrome P-450 CYP2C9; Cytochrome P450 Family 2; Diabetes Mellitus, Type 2; Drug Interactions; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Indoles; Lovastatin; Male; Nateglinide; Nifedipine; Phenylalanine; Rabbits; Steroid 21-Hydroxylase; Verapamil

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

Most drugs currently employed in the treatment of type 2 diabetes either target the sulfonylurea receptor stimulating insulin release (sulfonylureas, glinides), or target the peroxisome proliferator-activated receptor (PPARgamma) improving insulin resistance (thiazolidinediones). Our work shows that sulfonylureas and glinides additionally bind to PPARgamma and exhibit PPARgamma agonistic activity. This activity was predicted in silico by virtual screening and confirmed in vitro in a binding assay, a transactivation assay, and by measuring the expression of PPARgamma target genes. Among the measured compounds, gliquidone and glipizide (two sulfonylureas), as well as nateglinide (a glinide), exhibit PPARgamma agonistic activity at concentrations comparable with those reached under pharmacological treatment. The most active of these compounds, gliquidone, is shown to be as potent as pioglitazone at inducing PPARgamma target gene expression. This dual mode of action of sulfonylureas and glinides may open new perspectives for the molecular pharmacology of antidiabetic drugs, because it provides evidence that drugs can be designed that target both the sulfonylurea receptor and PPARgamma. Targeting both receptors could increase pancreatic insulin secretion and improve insulin resistance. Glinides, sulfonylureas, and other acidified sulfonamides may be promising leads in the development of new PPARgamma agonists. In addition, we provide a unified concept of the PPARgamma binding ability of seemingly disparate compound classes.

Topics: ATP-Binding Cassette Transporters; Computer Simulation; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Evaluation, Preclinical; Gene Expression Regulation; Glipizide; Humans; Hypoglycemic Agents; Nateglinide; Phenylalanine; Pioglitazone; Potassium Channels; Potassium Channels, Inwardly Rectifying; PPAR gamma; Protein Binding; Receptors, Drug; Sulfonylurea Compounds; Sulfonylurea Receptors; Thiazolidinediones

Nateglinide (Starlix((R))) is licensed for the treatment of Type 2 diabetes in patients inadequately controlled with metformin. The study objective was to monitor the safety and use of nateglinide prescribed by primary care physicians (GPs) in England, using the observational cohort technique, Prescription-Event Monitoring. Exposure data were derived from dispensed nateglinide prescriptions issued October 2001-June 2004; demographic and outcome data, from questionnaires sent to patients' GPs at least 6 months after patients' first prescription. Incidence densities (IDs; number of first reports of an event/1,000 patient-months exposure) were calculated for month 1 (ID(1)), months 2-6 (ID(2-6)); rate differences [ID(1)-ID(2-6) (+99% CI)] were examined. Cohort comprised 4,557 patients, median age 60 (IQR 51, 68 years); 2,439 (53.5%) male; 3,463 (76.0%) received nateglinide in combination with metformin. GPs reported 1,625 reasons for stopping in 1,474 (32.3%) patients and 80 events as adverse drug reactions in 66 (1.5%) patients. Events associated with starting treatment included nausea/vomiting [ID(1)-ID(2-6) 9.6 (99% CI 5.3, 13.9)], malaise/lassitude [ID(1)-ID(2-6) 6.03 (99% CI 2.2, 9.9)]. No serious hypersensitivity reactions were reported. Two pregnancies (< 0.1%) and 73 deaths (1.6%) were reported. Nateglinide appeared to be generally well tolerated when used in combination with metformin for the treatment of Type 2 diabetes.

Topics: Aged; Confidentiality; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Monitoring; Drug Prescriptions; England; Family Practice; Female; Humans; Hypoglycemic Agents; Male; Middle Aged; Nateglinide; Phenylalanine; Safety

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

Topics: Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hyperlipidemias; Hypoglycemic Agents; Insulin; Insulin Secretion; Nateglinide; Phenylalanine; Postprandial Period; Triglycerides

The effect of single-dose mitiglinide on glucose and lipid metabolism was examined in OLETF rats with spontaneous type 2 diabetes in which the early insulin response following glucose challenge is known to diminish over time and become lost with aging.. (1) With catheters inserted into the portal veins, 12-wk-old prediabetic OLETF rats were given an OGTT of 1 g/kg after 17 h of fasting. Eight rats each were orally given mitiglinide 1 mg/kg, nateglinide 50 mg/kg, or glibenclamide 1 mg/kg, vs 0.5% carboxymethylcellulose (CMC) as control, and were given an OGTT immediately afterward. Following oral administration of mitiglinide, nateglinide, glibenclamide, or 0.5% CMC, the 24-wk-old overt-diabetic OLETF rats were immediately given an OGTT of 1g/kg. (2) After 17 h of fasting, 24-wk-old OLETF rats were subjected to a fat-loading test. Eight rats each were given mitiglinide 3 mg/kg, glibenclamide 1 mg/kg, or glimepiride 1 mg/kg, vs 0.5% CMC, and were given soy oil 2 g/kg immediately afterward. They were also given mitiglinide orally and examined for LPL mRNA expression in their adipose tissue.. (1) After OGTT, mitiglinide produced a significant increase in portal insulin levels 15 min after its administration, as well as a significant decrease in peripheral glucose levels 15-120 min after its administration in the OLETF rats. Likewise, nateglinide produced an increase in portal insulin levels and a decrease in peripheral glucose levels shortly after its administration in these rats. Glibenclamide increased portal insulin levels for an extended time after its administration, and significantly decreased peripheral glucose levels in the rats 120-300 min after its administration in the rats. In contrast, as in the 12-wk-old rats, a precipitous rise in insulin secretion was seen in the portal vein of 24-wk-old rats given mitiglinide, which peaked 15 min after mitiglinide administration, but the insulin levels continued to increase for 120 min or longer in the 24-wk-old rats given glibenclamide. In addition, as in the 12-wk-old rats, a significant decrease in glucose levels in peripheral blood was noted 30 and 60 min after mitiglinide administration and 300 min after glibenclamide administration in the 24-wk-old rats. (2) Mitiglinide increased LPL mRNA expression 120 min after its administration, and significantly decreased peripheral TG and chylomicron- TG levels after fat challenge in the 24-wk-old OLETF rats.. Mitiglinide exhibited fast-onset and short-acting insulin-secretagogic effects, inhibiting post-glucose challenge increases in glucose levels and post-fat challenge increases in TG levels.

Topics: Adipose Tissue; Animals; Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Glucose Tolerance Test; Glyburide; Indoles; Insulin; Insulin Secretion; Isoindoles; Lipoprotein Lipase; Male; Nateglinide; Phenylalanine; Portal Vein; Postprandial Period; Prediabetic State; Rats; Rats, Inbred OLETF; RNA, Messenger; Sulfonylurea Compounds; Triglycerides

To evaluate the function of the first phase of insulin secretion of pancreatic B cells in newly diagnosed type 2 diabetics using nateglinide-intravenous glucose insulin release test (NG-IVGIRT).. NG-IVGIRT and intravenous glucose insulin release test (IVGIRT) were done in 8 patients with newly diagnosed type 2 diabetes mellitus and NG-IVGIRT was done in 8 normal people. Insulin and glucose of blood were determined at - 15, 0, 2, 4, 6, 8 and 10 min in NG-IVGIRT or IVGIRT.. The response of 0 - 10 min insulin to NG-IVGIRT was significantly higher than that to IVGIRT in the diabetics. The response of insulin to NG-IVGIRT in the normal controls was much higher than that in the diabetics. The area under curve (AUC) of insulin to NG-IVGIRT was apparently elevated and the AUC of glucose to NG-IVGIRT reduced in the normal controls as compared with those in the diabetics.. The results indicated that the reserve of first phase insulin secretion in newly diagnosed type 2 diabetics could be provoked in some degree by NG-IVGIRT and there was a big difference in the reserve of the first phase of insulin secretion provoked by NG-IVGIRT between newly diagnosed type 2 diabetics and normal people.

Topics: Adult; Case-Control Studies; Cyclohexanes; Diabetes Mellitus, Type 2; Evaluation Studies as Topic; Female; Glucose; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male; Middle Aged; Nateglinide; Phenylalanine

Nateglinide is a novel rapid- and short-acting insulin secretagogue that ameliorates postprandial hyperglycemia by improving insulin secretory dynamics to a near normal level more effectively than sulfonylureas. Recent epidemiological studies have demonstrated that postprandial hyperglycemia can result in arteriosclerosis, and that advanced arteriosclerosis is present in the initial stage of impaired glucose tolerance. Since postprandial hyperglycemia could be well treated by nateglinide, we examined the background factors of type 2 diabetic patients to determine the optimal indication for nateglinide. Our results indicate that nateglinide is most effective in young and obese patients. Furthermore, fewer responders had microangiopathy or were previously on oral hypoglycemic agents or sulfonylureas compared with non-responders. Although nateglinide is generally indicated for patients with mild HbA1c level, the present findings indicate that the drug was effective in the aforementioned patients regardless of pretreatment HbA1c levels. In one obese patient, nateglinide improved late hyperinsulinemia to near normal secretory dynamics. Our findings suggest that nateglinide is a physiologically preferable and useful drug for early type 2 diabetes without microangiopathy.

Topics: Age Factors; Aged; Cyclohexanes; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Nateglinide; Obesity; Phenylalanine

We studied whether the rapid hypoglycemic action of nateglinide is associated with an increase in islet blood flow. Islet blood flow was measured using the two-colour microsphere method. Orally administered nateglinide with glucose acutely increased islet blood flow to levels greater than those after glucose alone or tolbutamide with glucose in conscious Sprague-Dawley rats (percent increase at 10 min after oral administration; nateglinide+glucose, 125+/-25%; glucose, 33+/-11%, p<0.001; tolbutamide+glucose, 42+/-23%, p<0.01). Nateglinide administered with non-metabolisable 3-O-methylglucose also increased islet blood flow (61+/-17%). The stimulated islet blood flow significantly correlated with serum insulin levels. N(G)-monomethyl-L-arginine, a nitric oxide synthase inhibitor, completely inhibited the increase in islet blood flow induced by nateglinide with glucose. Intravenously administered nateglinide did not significantly affect the already increased islet blood flow in diabetic Otsuka Long-Evans Tokushima Fatty rats. Our results indicated that nateglinide acutely increased islet blood flow at least in part through a nitric oxide-dependent mechanism.

Topics: 3-O-Methylglucose; Administration, Oral; Anesthesia; Animals; Blood Glucose; Blood Pressure; Consciousness; Cyclohexanes; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Gastrointestinal Tract; Glucose; Hypoglycemic Agents; Injections, Intravenous; Insulin; Insulin Secretion; Islets of Langerhans; Male; Nateglinide; Nitric Oxide Synthase; omega-N-Methylarginine; Phenylalanine; Rats; Rats, Inbred OLETF; Rats, Sprague-Dawley; Regional Blood Flow; Time Factors; Tolbutamide

Short-term hypoglycemic effects of single dose voglibose and nateglinide were compared after sucrose loading in spontaneously diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats.. After a 17-h fasting period, the animals received 0.06 mg/kg of voglibose (VOG group, n = 6), 50 mg/kg of nateglinide (NAT group, n = 6), or 0.5% methyl cellulose (control group, n = 6), immediately followed by 2.5 g/kg of sucrose.. Compared to control group values, glucose levels after sucrose loading were significantly decreased in the portal blood in the VOG group and in the peripheral blood in the NAT and VOG groups. The portal glucose AUC0-120 min was significantly lower in the VOG group than in the control and NAT groups, whereas the peripheral glucose AUC0-120 min was significantly lower in the VOG and NAT groups than in the control group. Portal insulin levels in the VOG group were significantly decreased compared to the control group. However, portal insulin levels in the NAT group were acutely increased, peaking 15 min after sucrose loading. Portal FFA levels were decreased in the NAT group 15, 30, and 60 min after sucrose loading; no FFA reductions were seen in the VOG group.. Although both drugs produced similar hypoglycemic effects after sucrose loading in the peripheral blood, these drugs generated vastly different results in portal blood. Reduced FFA in the portal blood, observed after single administration of nateglinide, may have a favorable impact not only on glucose metabolism but also on lipid metabolism.

Topics: Animals; Area Under Curve; Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Disease Models, Animal; Enzyme Inhibitors; Fatty Acids, Nonesterified; Hypoglycemic Agents; Inositol; Insulin; Insulin Secretion; Male; Nateglinide; Phenylalanine; Portal Vein; Postprandial Period; Rats; Rats, Inbred OLETF; Secretory Rate; Sucrose

In type 2 diabetes (T2D) insulin secretion after a meal is delayed; this may have an impact on the development of hyperglycaemia and hyperlipidaemia.. To investigate this, a meal was given to 15 T2D (age 52 +/- 2 years, BMI 25 +/- 0.8 kg m(-2)) on three different occasions: (1) without treatment, (2) after 120 mg of nateglinide before the meal (acute treatment), and (3) after 3 months of nateglinide (120 mg t.i.d., chronic treatment). Fifteen healthy subjects (CON, age 48 +/- 2 years, BMI 24 +/- 0.5 kg m(-2)) were also studied. Blood was withdrawn for 360 min from veins draining the anterior abdominal subcutaneous adipose tissue (AD) and from an arterialized hand vein. Blood flow (BF) in AD was measured with (133)Xe. Lipoprotein lipase activity (LPL) was calculated as the triacylglycerol (TAG) flux across AD, and hormone-sensitive lipase (HSL) as the glycerol flux minus LPL.. (1) In T2D the increase in prandial insulin secretion was delayed; postprandial nonesterified fatty acid (NEFA) and TAG levels in blood were increased, while BF, LPL and TAG clearance were blunted vs. CON. (2) Acute or chronic nateglinide treatment induced a prompt increase in prandial insulin secretion, resulting in a decrease in blood glucose and NEFA levels owing to suppression of HSL, while BF, LPL and TAG clearance remained suppressed.. In T2D, restoration of early phase insulin secretion improved postprandial hyperglycaemia and suppressed endogenous lipolysis, resulting in suppression of NEFA levels. These results suggest that in nonobese T2D, metabolic defects may result, to a large extent, from the delay in prandial insulin secretion.

Topics: Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Lipid Metabolism; Middle Aged; Nateglinide; Phenylalanine; Postprandial Period

As an example application of the CORE Diabetes Model in type 2 diabetes, we simulated the cost-effectiveness of repaglinide/metformin combination therapy versus nateglinide/metformin for treatment of individuals with type 2 diabetes with an inadequate response to sulphonylurea, metformin, or fixed dose glyburide/metformin.. The CORE Diabetes Model was used to simulate long-term outcomes for a cohort of individuals with type 2 diabetes treated with either repaglinide/metformin or nateglinide/metformin. HbA1c changes for each regimen were taken from a comparative study. At the end of the study, changes in HbA1c from baseline were -1.28% points and -0.67% points for repaglinide/metformin and nateglinide/metformin, respectively. Median final doses were 5.0 mg/day for repaglinide, 360 mg/day for nateglinide and 2000 mg/day metformin in each treatment arm. Costs were calculated as the annual costs for drugs plus costs of complications (US Medicare perspective) over a 30-year period. Life expectancy (LE) and quality-adjusted life expectancy (QALE) were calculated. Outcomes and costs were discounted at 3% annually.. With repaglinide/metformin, improved glycaemic control led to projected decreases in complication rates, improvement of LE and QALE by 0.15 and 0.14 years respectively, and total cost savings of 3,662 dollars/person over the 30-year period. Repaglinide/metformin had a 96% probability that the incremental costs per quality-adjusted life year gained would be 20,000 dollars or less, and a 66% probability that repaglinide/metformin would be cost-saving compared to nateglinide/metformin. Sensitivity analyses supported the validity and reliability of the results.. In the health economic context, repaglinide/metformin combination was dominant to nateglinide/metformin. The CORE Diabetes Model is a tool to help third-party reimbursement payers identify treatments for type 2 diabetes that are good value for money.

Topics: Carbamates; Cohort Studies; Computer Simulation; Cost of Illness; Cost-Benefit Analysis; Cyclohexanes; Decision Support Systems, Clinical; Diabetes Complications; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Health Care Costs; Humans; Male; Metformin; Middle Aged; Models, Econometric; Nateglinide; Outcome Assessment, Health Care; Phenylalanine; Piperidines; Quality-Adjusted Life Years

Topics: Blood Glucose; Clinical Trials as Topic; Cyclohexanes; Diabetes Mellitus, Type 2; Fasting; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Nateglinide; Phenylalanine; Postprandial Period

The aim of this study was to clarify the role of an early insulin secretion in postprandial hyperglycaemia and hyperlipidaemia; a study using spontaneously type 2 diabetic Otsuka Long-Evans Tokushima Fatty rats with visceral obesity was performed to investigate the acute effect of nateglinide (NAT) vs. glibenclamide (GB) on increases in glucose after glucose loading and on increases in triglyceride (TG) after fat loading.. Fasting rats were given 50 mg/kg of NAT, 1 mg/kg of GB or 5% methyl cellulose (vehicle) as control and then immediately given oral glucose 1 g/kg.. An acute increase in insulin levels in portal blood peaked at 15 min in the NAT group, while insulin levels in the GB group continued to increase significantly after 60 min. Glucose levels in peripheral blood were significantly lower in the NAT group at 30 and 60 min and in the GB group at 120, 180 and 270 min after glucose loading, compared with those in the vehicle group. Subsequently, fasting rats were given NAT, GB or vehicle and then immediately given oral fat emulsion (soy oil 2 g/kg). An acute increase in insulin secretion was seen with NAT, peaking at 30 min, while TG, chylomicron and very low-density lipoprotein levels after fat loading were shown to be significantly lower with NAT than with vehicle. However, the continued insulin secretion observed with GB led to no significant decrease in TG levels after fat loading. In addition, lipoprotein lipase mRNA expression in adipose tissue increased significantly 120 min after NAT administration in comparison with baseline. This increase was not noted with GB administration.. Abnormalities in early insulin secretion are closely associated with the pathogenesis of various disease conditions that combine to characterize type 2 diabetes, suggesting that normalizing early insulin response in portal blood represents an important treatment not only for postprandial hyperglycaemia but also for postprandial hyperlipidaemia.

Topics: Adipose Tissue; Animals; Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Dietary Fats; Gene Expression Regulation; Glyburide; Hyperglycemia; Hyperlipidemias; Hypoglycemic Agents; Insulin; Insulin Secretion; Lipoprotein Lipase; Male; Nateglinide; Phenylalanine; Postprandial Period; Rats; Rats, Inbred OLETF; Rats, Long-Evans; RNA, Messenger; Triglycerides

Topics: Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Administration Schedule; Eating; Humans; Hypoglycemic Agents; Nateglinide; Phenylalanine; Piperidines

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

Topics: Adult; Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Male; Nateglinide; Phenylalanine; Sulfonylurea Compounds; Time

Topics: Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Fasting; Humans; Hypoglycemic Agents; Metformin; Nateglinide; Phenylalanine; Postprandial Period

Topics: Adiponectin; Blood Glucose; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Intercellular Signaling Peptides and Proteins; Nateglinide; Phenylalanine; Piperidines; Proteins; Sulfonylurea Compounds

Topics: Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Metformin; Nateglinide; Phenylalanine; Piperidines

Topics: Cyclohexanes; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Therapy, Combination; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin Resistance; Metformin; Nateglinide; Phenylalanine; Postprandial Period

In the present study, we examined the effect of long-term suppression of postprandial hyperglycemia and glycemic fluctuation in Goto-Kakizaki (GK) rats, a type 2 diabetic animal model, by nateglinide (NG), a fast-acting hypoglycemic agent, on some measures of neuropathy and compared the outcome with the slow-acting effect of glibenclamide (GC). GK rats fed twice daily were given NG (50 mg/kg) or GC (1 mg/kg) orally before each meal for 24 weeks. The dose of NG and GC was determined by the data of their comparable suppressive effects on hyperglycemia as a total sum of glucose values after glucose load. At the end, there was no significant influence of treatment with NG or GC on body weight, fasting blood glucose, and glycated hemoglobin in GK rats. However, NG treatment suppressed postprandial hyperglycemia by 50% throughout the observation period, whereas this effect was not apparent in GC-treated rats. Delayed motor nerve conduction velocity was normalized by NG treatment, while GC had a partial (50%) effect. GK rats showed elevated contents of sorbitol and 3-deoxyglucosone in the sciatic nerve, and these changes were inhibited by NG treatment. Reduced Na(+)/K(+)-adenosine triphosphatase (ATPase) activity in GK rats was not affected by either NG or GC treatment. These results suggest that meticulous control of postprandial hyperglycemia is essential to inhibit the development of neuropathy in type 2 diabetes.

Topics: Animals; Area Under Curve; Blood Glucose; Cyclohexanes; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Glyburide; Glycated Hemoglobin; Hypoglycemic Agents; Insulin; Nateglinide; Phenylalanine; Postprandial Period; Rats; Rats, Inbred Strains; Rats, Wistar; Sciatic Nerve; Time Factors

Good glucose control is a prerequisite for the prevention of long-term complications in type 2 diabetics. In recent years, two new groups of substances have been approved for the oral treatment of type 2 diabetes: glinides and glitazones. The former are short-acting agents that promote insulin secretion and offer an alternative to the sulfonylureas, in particular in patients with irregular eating habits and high postprandial glucose peaks. The glitazones improve one of the disorders underlying type 2 diabetes, insulin resistance. They are used in particular in patients who are inadequately controlled with a sulfonylurea or metformin and who show insulin resistance. Both groups of substances are a useful addition to the antidiabetic drug armamentarium. Endpoint studies involving these substances have, however, not yet been performed.

Topics: Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Insulin; Nateglinide; Phenylalanine; Pioglitazone; Piperidines; Rosiglitazone; Thiazoles; Thiazolidinediones; Treatment Outcome

Type 2 diabetes mellitus is a common disease whose complications have great costs, both in quality of life and expense of treatment. Improving glycemic control, as measured by monitoring glycosylated hemoglobin (HbA1c) levels, can reduce the rate of such complications.. The aims of this study were to estimate the lifetime costs associated with diabetes-related complications in a theoretical population receiving metformin monotherapy and to predict the health and economic effect of improving glycemic control in this theoretical population by combining metformin with nateglinide.. A pharmacoeconomic model was developed to simulate the long-term (30 years) complication rates (microvascular and macrovascular) of a cohort of patients with type 2 diabetes mellitus. The model simulated each year of life for each patient in a theoretical cohort of 10,000 patients until diabetes-related complications were present or death occurred. The mean accumulated costs (direct medical costs for acute care and subsequent care for diabetes-related complications), mean survival time, and the frequency of each type of complication were estimated. Both effectiveness and cost data were discounted at 3%. Sensitivity analyses were conducted on key model input parameters.. Average costs of treating complications in theoretical patients undergoing metformin monotherapy were estimated at $29,565 per patient. Savings of $2,742 were estimated per patient for all complications--particularly, nephropathy ($1,166) and macrovascular disease ($632)--when nateglinide was added. The cost-effectiveness ratio of adding nateglinide to metformin was estimated at $27,131 per undiscounted life-year gained (95% CI, $23,710-$28,577) or $43,024 (95% CI, $37,285-$45,193) per additional discounted life-year gained. In the sensitivity analyses, decreasing HbA1c level at baseline, HbA1c upward drift, and duration of disease improved survival.. Combination therapy with nateglinide and metformin, compared with metformin alone, was predicted to reduce the frequency of complications and, thus, treatment costs in this theoretical model. The major factor in cost savings was fewer complications due to nephropathy. The increased drug treatment costs were expected to be offset by the long-term savings from reducing complication rates.

Topics: Adult; Aged; Aged, 80 and over; Blood Glucose; Cohort Studies; Costs and Cost Analysis; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Synergism; Drug Therapy, Combination; Female; Glycated Hemoglobin; Health Care Costs; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Models, Economic; Nateglinide; Phenylalanine; Postprandial Period

Topics: Blood Glucose; Cardiovascular Diseases; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Fasting; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin Resistance; Metformin; Nateglinide; Patient Selection; Phenylalanine; Postprandial Period; Practice Guidelines as Topic; Predictive Value of Tests

Topics: Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Metformin; Nateglinide; Phenylalanine; Piperidines

This discussion contains excerpts from the satellite symposium, "Achieving Better Glycemic Control Through Management of Mealtime Glucose," presented at the American Association of Clinical Endocrinologists Tenth Annual Meeting and Clinical Congress in San Antonio, Texas, May 2, 2001.

Topics: Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Metformin; Nateglinide; Phenylalanine; Sulfonylurea Compounds

Topics: Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Nateglinide; Phenylalanine; Postprandial Period; Risk Factors

Topics: Cyclohexanes; Diabetes Mellitus, Type 2; Drug Approval; Hypoglycemic Agents; Nateglinide; Phenylalanine; United States; United States Food and Drug Administration

Topics: Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Nateglinide; Phenylalanine

Topics: Administration, Oral; Cyclohexanes; Diabetes Mellitus, Type 2; Dizziness; Humans; Metformin; Nateglinide; Phenylalanine

Islet dysfunction, characterized by the loss of an acute insulin secretory response (AIR) to glucose is a well-established pathology of type 2 diabetes mellitus. Using oral insulin secreting agents with very different pharmacodynamic profiles, the present study was undertaken to test the hypothesis that, within the setting of an underlying insulin resistance, changes in the insulin response profile can differentially affect glycaemic control.. The mildly insulin resistant high-fat fed Sprague Dawley (HF) rat and the very insulin resistant Zucker fatty (fa/fa) rat, chronically fitted with indwelling jugular cannula were subjected to an oral glucose load. Compounds were administered 5 min before the oral glucose load. Nateglinide (Nateg) was administered to elicit only an early insulin secretory response and glipizide (Glip) to elicit a later but greater insulin secretory response. Acetaminophen was used as a marker to assess for potential effects of these compounds on gastric emptying rates.. Nateg rapidly increased early insulin release (from -5 to 0) while the effects on total insulin release were similar to those in the controls and glucose excursions were eliminated in both diabetic models with no evidence of sustained hypoglycaemia. Conversely, Glip did not affect early insulin release but increased total insulin release (- 15 to 120 min), but only after the oral glucose load. Glip partially curbed glucose excursions in the mildly insulin resistant HF rodent and was totally ineffective in the very insulin resistant Zucker rat. The differential effects could not be attributed to effects on gastric emptying rates.. These data support the importance of early insulin release in type 2 diabetes mellitus and indicate that, independent of the level of insulin resistance, stimulating insulin release early and briefly provides for more effective and tighter glycaemic control than increasing insulin exposure to a greater magnitude later.

Topics: Animals; Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Dietary Fats; Gastric Emptying; Glipizide; Glucose Tolerance Test; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Kinetics; Male; Nateglinide; Phenylalanine; Rats; Rats, Sprague-Dawley; Rats, Zucker

Topics: Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Administration Schedule; Humans; Hypoglycemic Agents; Nateglinide; Phenylalanine; Postprandial Period

We describe a type 2 diabetic patient who showed immediate-type allergy against human insulin associated with marked eosinophilia at initial insulin therapy. Three months after initiation of insulin therapy, he noticed itchy skin wheals at the site of the insulin injection. Laboratory data at that time showed marked eosinophilia (2,512 /mm3) and progression of renal dysfunction. Skin test with semisynthetic human insulin and protamine sulfate resulted in local immediate skin reactions such as itchy erythema and wheals. Histopathology of the biopsy specimen from skin showed perivascular infiltration of lymphocytes and numerous eosinophils in the dermis and subcutaneous fat. Although the titer of total IgE antibody was within normal range, that of insulin-specific IgE antibody was high. Insulin administration was discontinued to preserve his insulin secretion, and stable control of his hyperglycemia was obtained by initiating nateglinide treatment (360 mg/day). His itchy skin lesions disappeared within two weeks after cessation of the insulin therapy and both eosinophilia and renal dysfunction gradually improved. Although the widespread use of human insulin in diabetic patients has greatly reduced the incidence of insulin allergy, the possibility of human insulin allergy should be kept in mind when initiating such therapy.

Topics: Aged; Aged, 80 and over; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Hypersensitivity; Eosinophilia; Erythema; Humans; Hypersensitivity, Immediate; Hypoglycemic Agents; Immunoglobulin E; Insulin; Male; Nateglinide; Phenylalanine; Seasons; Skin Tests

Topics: Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Insulin; Metformin; Nateglinide; Phenylalanine; Thiazoles; Thiazolidinediones

Topics: Clinical Trials as Topic; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Nateglinide; Phenylalanine