nateglinide and Body-Weight

While bidirectional relationships exist between body weight and physical activity, direction of causality remains uncertain and previous studies have been limited by self-reported activity or weight and small sample size. We investigated the prospective relationships between weight and physical activity.. Observational analysis of data from the Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) study, a double-blinded randomised clinical trial of nateglinide and valsartan, respectively.. Multinational study of 9306 participants.. Participants with biochemically confirmed impaired glucose tolerance had annual measurements of both weight and step count using research grade pedometers, worn for 7 days consecutively. Along with randomisation to valsartan or placebo plus nateglinide or placebo, participants took part in a lifestyle modification programme.. Longitudinal regression using weight as response value and physical activity as predictor value was conducted, adjusted for baseline covariates. Analysis was then repeated with physical activity as response value and weight as predictor value. Only participants with a response value preceded by at least three annual response values were included.. Adequate data were available for 2811 (30%) of NAVIGATOR participants. Previous weight (χ(2)=16.8; p<0.0001), but not change in weight (χ(2)=0.1; p=0.71) was inversely associated with subsequent step count, indicating lower subsequent levels of physical activity in heavier individuals. Change in step count (χ(2)=5.9; p=0.02) but not previous step count (χ(2)=0.9; p=0.34) was inversely associated with subsequent weight. However, in the context of trajectories already established for weight (χ(2) for previous weight measurements 747.3; p<0.0001) and physical activity (χ(2) for previous step count 432.6; p<0.0001), these effects were of limited clinical importance.. While a prospective bidirectional relationship was observed between weight and physical activity, the magnitude of any effect was very small in the context of natural trajectories already established for these variables.. NCT00097786.

Topics: Body Weight; Cyclohexanes; Double-Blind Method; Glucose Intolerance; Humans; Hypoglycemic Agents; Life Style; Motor Activity; Nateglinide; Phenylalanine; Prospective Studies; Valsartan

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

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

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

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

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 was designed to compare the pharmacodynamic effects of single doses of nateglinide (A-4166), repaglinide, and placebo on mealtime insulin secretion and glycemic control in healthy subjects.. Fifteen healthy volunteers participated in this open-label five-period crossover study. They received single 10-min preprandial doses of 120 mg nateglinide, 0.5 or 2 mg repaglinide, or placebo or 1 min preprandially of 2 mg repaglinide. Subjects received each dose only once, 48 h apart. Pharmacodynamic and pharmacokinetic assessments were performed from 0 to 12 h postdose.. Nateglinide induced insulin secretion more rapidly than 2 and 0.5 mg repaglinide and placebo (10 min preprandial), with mean rates of insulin rise of 2.3, 1.3, 1.15, and 0.8 microU x ml(-1) x min(-1), respectively, over the 0- to 30-min postmeal interval. After peaking, insulin concentrations decreased rapidly in the nateglinide-treated group and were similar to placebo within 2 h postdose. After 2 mg repaglinide, peak insulin concentrations were delayed and returned to baseline more slowly than with nateglinide treatment. Nateglinide treatment produced lower average plasma glucose concentrations in the 0- to 2-h postdose interval than either dose of repaglinide and placebo (P < 0.05 vs. 0.5 mg repaglinide and placebo). Plasma glucose concentrations returned more rapidly to predose levels with nateglinide treatment than with either dose of repaglinide. Treatment with repaglinide produced a sustained hypoglycemic effect up to 6 h postdose.. In this single-dose study in nondiabetic volunteers, nateglinide provided a more rapid and shorter-lived stimulation of insulin secretion than repaglinide, resulting in lower meal-related glucose excursions. If similar results are observed in diabetes, nateglinide may produce a more physiological insulin secretory response with the potential for a reduced risk of postabsorptive hypoglycemia.

Topics: Adolescent; Adult; Blood Glucose; Body Mass Index; Body Weight; Carbamates; Cross-Over Studies; Cyclohexanes; Female; Food; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Kinetics; Male; Middle Aged; Nateglinide; Phenylalanine; Piperidines; Placebos; Time Factors

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

The metabolic syndrome is strongly associated with insulin resistance and has been recognized as a cluster of risk factors for cardiovascular disease. Insulin resistance and/or impaired early-phase insulin secretion are major determinants of postprandial hyperglycemia. In this study, we investigated the potential utility of combination therapy with telmisartan, an angiotensin II receptor blocker and nateglinide, a rapid-onset/short-duration insulinotropic agent, for the treatment of postprandial hyperglycemia and metabolic derangements in Zucker Fatty (ZF) rats. ZF rats fed twice daily were given vehicle, 50 mg/kg of nateglinide, 5 mg/kg of telmisartan, or both for 6 weeks. Combination therapy with nateglinide and telmisartan for 2 weeks ameliorated postprandial hyperglycemia in ZF rats fed twice daily. Furthermore, 6-week treatment with nateglinide and telmisartan not only decreased fasting plasma insulin, triglycerides, and free fatty acid levels, but also improved the responses of blood glucose to insulin and subsequently reduced the decremental glucose areas under the curve in the ZF rats. Combination therapy also restored the decrease of plasma adiponectin levels in the ZF rats. Monotherapy with nateglinide or telmisartan alone didnot significantly improve these metabolic parameters. These observations demonstrate that combination therapy with nateglinide and telmisartan may improve the metabolic derangements by ameliorating early phase of insulin secretion as well as insulin resistance in ZF rats fed twice daily. Our present findings suggest that the combination therapy with nateglinide and telmisartan could be a promising therapeutic strategy for the treatment of the metabolic syndrome.

Topics: Adiponectin; Angiotensin II Type 1 Receptor Blockers; Animals; Benzimidazoles; Benzoates; Blood Glucose; Blood Pressure; Body Weight; Cyclohexanes; Drug Therapy, Combination; Glycated Hemoglobin; Hypoglycemic Agents; Insulin; Lipids; Male; Metabolic Diseases; Nateglinide; Phenylalanine; Rats; Rats, Zucker; Telmisartan

Epidemiological studies demonstrated the importance of postprandial hyperglycemia on the progression of atherosclerosis. However, whether treatment of postprandial hyperglycemia by insulin or insulin secretagogues has a beneficial effect on atherosclerosis has not been elucidated. To elucidate the effects of reduction of postprandial rise of blood glucose by insulin and nateglinide on monocyte adhesion to endothelial cells, we used non-obese type 2 diabetic Goto-Kakizaki (GK) rats fed twice daily, as a model of repetitive postprandial hyperglycemia. We investigated the effects of insulin injection and nateglinide administration just before each meal for 12 weeks on monocyte adhesion to endothelial cells. By setting the doses of insulin and nateglinide, both treatment significantly reduced postprandial hyperglycemia without significant reduction of HbA1c. Nateglinide also reduced serum insulin level just after 1 h meal. Both nateglinide and insulin therapy reduced the number of monocytes adherent to the aortic endothelial layer. Nateglinide, but not insulin, reduced intimal thickness of the thoracic aorta. While increased serum insulin level might be regarded as a factor responsible for the progression of atherosclerosis, our data showed that treatment with pre-meal insulin or nateglinide, which reduces postprandial hyperglycemia, reduced monocyte adhesion to endothelial cells.

Topics: Animals; Aorta; Blood Glucose; Body Weight; Cell Adhesion; Cyclohexanes; Endothelial Cells; Gene Expression Regulation; Insulin; Intercellular Adhesion Molecule-1; Male; Monocytes; Nateglinide; Phenylalanine; Rats; RNA, Messenger; Vascular Cell Adhesion Molecule-1

A-4166, a phenylalanine derivative, is a hypoglycemic agent, which has been shown to improve blood glucose levels mainly due to the rapid and short term stimulation of insulin release. Nevertheless, a possible extrapancreatic action of A-4166 has not yet been investigated. Therefore, insulin action (euglycemic hyperinsulinemic 6.4 mU.kg-1.min-1 clamp plus 3H-2-deoxyglucose tracer administration) was studied after 3 weeks on either standard (BD) or high fat (HF) diet in normal control (C) or in hereditary insulin resistant (hHTg) rats which were given a single dose of A-4166 (10 mg per kg BW, i.v.) 60 min after clamp commencement. HF feeding reduced the glucose infusion rate (GIR) required to maintain euglycemia to about 50% of C (p < 0.001). In hHTg rats, HF did not further pronounce the pre-existing decrease of GIR of hHTg animals fed BD. A-4166 changed GIR neither in C, nor in the hHTg group. The estimated glucose disposal (Rd) (C-BD: 32.3 +/- 1.9 vs C-HF: 25.5 +/- 1.9 mg.kg-1.min-1, p < 0.001) and glucose metabolic index (Rg') in skeletal muscles (Q. femoris: C-BD: 25.6 +/- 1.5 vs C-HF: 12.3 +/- 1.1 mmol.100 g-1.min-1, p < 0.001) were reduced by HF in control rats but were not restored by a concomitant bolus of A-4166. Nevertheless, in hHTg rats fed the HF diet a single dose of A-4166 brought back their Rd (hHTg-HF: 23.5 +/- 1.3 vs hHTg-HF plus A-4166: 31.0 +/- 3.5 p < 0.03) and Rg' (Soleus muscle: hHTg-HF: 29.2 +/- 3.2 vs hHTg-HF plus A-4166: 41.3 +/- 4.0) to values of the control group on BD. In summary, a) a single bolus administration of A-4166 to the control or to the insulin resistant hHTg rats, fed either the BD or HF diets, did not abolish the reduction of GIR required to maintain euglycemia during hyperinsulinemic clamps; b) nevertheless, A-4166 caused a significant increase of the estimated plasma glucose disposal (Rd) and skeletal muscle glucose metabolic index (Rg') of hHTG rats fed the HF diet; c) we suggest that A-4166 may have an extrapancreatic action but this needs to be proven using a long-term administration plan of A-4166.

Topics: Animals; Body Weight; Cyclohexanes; Deoxyglucose; Dietary Fats; Glucose; Glucose Clamp Technique; Hypoglycemic Agents; Insulin Resistance; Male; Nateglinide; Phenylalanine; Phosphorylation; Rats; Rats, Wistar