nateglinide and Prediabetic-State

The Nateglinide and Valsartan Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial is exploring two pharmacological strategies (nateglinide and valsartan, both alone and in combination) in the prevention of overt diabetes mellitus (DM) and the reduction of cardiovascular disease (CVD) in subjects at high risk for these events. In this analysis, we provide baseline characteristics of the randomized NAVIGATOR study population and contrast them with those from other trials of DM prevention. Key eligibility criteria include impaired glucose tolerance (IGT) and impaired fasting glucose (IFG), a history of CVD (in patients aged > or =50 years), and > or =1 cardiovascular risk factor (in patients aged > or =55 years). Baseline demographic characteristics, laboratory findings, cardiovascular risk factors, CVD history, and medication use are described and compared with other trials of DM prevention. The full analysis set of subjects (N = 9306) showed a clustering of risk factors consistent with the metabolic syndrome: high rates of hypertension (77.5%), dyslipidemia (44.7%), increased waist circumference (101.0 cm), and high body mass index (BMI) (47.5% with BMI > or =30 kg/m(2)). A minority of patients had a history of CVD (24.3%); of these, 11.7% had a history of myocardial infarction and most of the remainder had evidence of coronary artery disease. Subjects also had elevated blood pressure (BP) (predominantly systolic) (139.7/82.6 mm Hg), increased serum low-density lipoproteins cholesterol levels (3.27 mmol/L), and borderline elevation of triglyceride levels (1.97 mmol/L). Demographic data, BP, and lipid profiles in NAVIGATOR were similar to those of previous DM prevention trials, which were also based largely on meeting criteria for IGT. Medication use at baseline among NAVIGATOR subjects, which frequently included aspirin, beta-blockers, calcium channel blockers, diuretics, and lipid-lowering agents, reflects enhanced CVD risk. However, little prescribing of renin-angiotensin-aldosterone system blockers was observed, likely due to protocol exclusion criteria. In conclusion, the NAVIGATOR study comprises prediabetic subjects who typically have concurrent BP and metabolic disturbances and an enhanced risk of CVD, and are thus at higher risk for cardiovascular events than subjects in previous DM prevention trials.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Blood Glucose; Blood Pressure; Cardiovascular Diseases; Cyclohexanes; Diabetes Mellitus; Female; Glucose Intolerance; Humans; Hypoglycemic Agents; Male; Middle Aged; Nateglinide; Patient Selection; Phenylalanine; Prediabetic State; Research Design; Risk Assessment; Risk Factors; Tetrazoles; Valine; Valsartan

The purpose of this study was to evaluate the metabolic effectiveness, safety, and tolerability of nateglinide in subjects with impaired glucose tolerance (IGT) and to identify a dose appropriate for use in a diabetes prevention study.. This multicenter, double-blind, randomized, parallel-group, fixed-dose study of 8 weeks' duration was performed in a total of 288 subjects with IGT using a 2:2:2:1 randomization. Subjects received nateglinide (30, 60, and 120 mg) or placebo before each main meal. Metabolic effectiveness was assessed during a standardized meal challenge performed before and after the 8-week treatment. All adverse events (AEs) were recorded, and confirmed hypoglycemia was defined as symptoms accompanied by a self-monitoring of blood glucose measurement < or =3.3 mmol/l (plasma glucose < or =3.7 mmol/l).. Nateglinide elicited a dose-related increase of insulin and a decrease of glucose during standardized meal challenges, with the predominant effect on early insulin release, leading to a substantial reduction in peak plasma glucose levels. Nateglinide was well tolerated, and symptoms of hypoglycemia were the only treatment-emergent AEs. Confirmed hypoglycemia occurred in 28 subjects receiving nateglinide (30 mg, 0 [0%]; 60 mg, 5 [6.6%]; 120 mg, 23 [26.7%]) and in 1 (2.3%) subject receiving placebo.. Nateglinide was safe and effective in reducing postprandial hyperglycemia in subjects with IGT. Preprandial doses of 30 or 60 mg nateglinide would be appropriate to use for longer-term studies to determine whether a rapid-onset, rapidly reversible, insulinotropic agent can delay or prevent the development of type 2 diabetes.

Topics: Adult; Aged; Blood Glucose; Body Mass Index; Cyclohexanes; Double-Blind Method; Female; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Middle Aged; Nateglinide; Phenylalanine; Postprandial Period; Prediabetic State

This study was designed to determine the effect of a novel insulin secretagogue, nateglinide, on the glycemic response curve and early insulin secretion following oral glucose load in impaired glucose tolerance (IGT) subjects. Thirteen subjects were given a 75 g oral glucose tolerance test (75 g OGTT), the findings of which resulted in the diagnosis of IGT. The subjects returned to our hospital immediately. Eight subjects, in whom neither body weight nor life style (daily diet and exercise) was significantly altered during this period, were given 90 mg of nateglinide 5 min before a second oral glucose load in order to examine restoration of impaired early insulin secretion. Nateglinide administration resulted in the almost normalization of the glycemic response curve with restoration of impairment in early insulin response at 30 and 60 min after an oral glucose load. The area under the secreted insulin-time curve was not changed significantly by nateglinide administration. A single dose of nateglinide was shown to almost normalize the glycemic response curve after a 75 g OGTT and to restore impairment in early insulin response in IGT subjects.

Topics: Area Under Curve; Blood Glucose; Cyclohexanes; Female; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Middle Aged; Nateglinide; Phenylalanine; Postprandial Period; Prediabetic State

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

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