nateglinide and Diabetic-Angiopathies

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

Diabetic macroangiopathy has already developed before diagnosis of diabetes mellitus. Postprandial hyperglycemia has been known as a risk factor for diabetic macroangiopathy and may be more powerful than fasting hyperglycemia. To intervene in hyperglycemia, insulin secretagogues, glinides which selectively stimulate early meal-induced insulin secretion and improve postprandial hyperglycemia, and sulfonylureas which enhance total daily insulin secretion and improve fasting hyperglycemia, have been prescribed as major oral antidiabetic agents. Few evidences that amelioration of glycemic control with insulin secretagogues lower the risk of cardiovascular diseases have been reported. But current studies have shown that intervention in postprandial hyperglycemia with drugs including glinides decreased thickness of carotid IMT as a surrogate marker of atherosclerosis. Results from on-going large scale intervention study with glinides may clarify whether amelioration of hyperglycemia lower the risk of atherosclerotic events.

Topics: Arteriosclerosis; Cardiovascular Diseases; Cyclohexanes; Diabetic Angiopathies; Glucose Intolerance; Hyperglycemia; Hypoglycemic Agents; Indoles; Insulin; Insulin Secretion; Isoindoles; Nateglinide; Phenylalanine; Postprandial Period; Risk Factors; Sulfonylurea Compounds

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

Studies have shown that repeated post-prandial hyperglycemia may play an important role in the development of atherosclerosis by suppressing endothelial function. α-Glucosidase inhibitors (α-GIs), which reduce post-prandial hyperglycemia without stimulating insulin secretion, significantly reduce the risk of coronary artery disease (CAD), whereas glinides, which improve post-prandial hyperglycemia through post-prandial insulin secretion, do not appear to affect CAD.. A total of 104 diabetic patients with CAD were randomly divided into 2 groups: those treated with miglitol (M-group; n=52) and those treated with nateglinide (N-group; n=52). After 4 months' treatment, although hemoglobin A1c and 1,5-anhydroglucitol were significantly improved in both groups, only the M-group had significant reductions in insulin resistance index and triglyceride/high-density lipoprotein cholesterol (TG/HDL-C; a beneficial index for assessing the presence of small dense low-density lipoprotein, and a marker of atherogenic dyslipidemia). Furthermore, only the M-group had improvement in percentage flow-mediated dilatation (%FMD) and reactive oxygen metabolites. In the M-group, multiple regression analysis showed that improvement in TG/HDL-C, in addition to 1,5-anhydroglucitol, was an independent predictor of improvement in %FMD.. The ameliorating effect of α-GI on post-prandial hyperglycemia without stimulating insulin secretion may improve atherogenic dyslipidemia by reducing insulin resistance. These effects are associated with its beneficial impact on oxidative stress, consequently leading to an improvement in endothelial dysfunction.

Topics: 1-Deoxynojirimycin; Aged; Aged, 80 and over; Coronary Artery Disease; Cyclohexanes; Diabetic Angiopathies; Dyslipidemias; Endothelium, Vascular; Enzyme Inhibitors; Female; Glycoside Hydrolase Inhibitors; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin Resistance; Lipids; Male; Middle Aged; Nateglinide; Phenylalanine

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

Patients with impaired glucose tolerance (IGT) have increased risk for developing type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). Lifestyle modification and medication can prevent or delay progression to diabetes (PD), but whether such interventions also reduce the risk of CVD has not been rigorously tested. The Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial is a multinational, randomized, double-blind, 2 x 2 factorial trial in subjects with IGT (on a screening oral glucose tolerance test [OGTT]) aged > or = 50 years with known CVD or aged > or = 55 years with > or = 1 CVD risk factor. Enrollment began in January 2002 and was completed January 2004, with 9,518 patients randomized to receive 1 of 4 possible treatment combinations as follows: nateglinide with valsartan, nateglinide with valsartan-placebo, nateglinide-placebo with valsartan, or nateglinide-placebo with valsartan-placebo. All subjects are participating in a clinic-based and telephone-based lifestyle intervention aimed at reducing weight and dietary fat and increasing physical activity. The 3 coprimary end points are new onset of T2DM, a "core" composite of major cardiovascular events (death, myocardial infarction, stroke, or hospitalization for heart failure), and an "extended" composite including the components of the core composite plus coronary revascularization and hospitalization for unstable angina. The study was designed to evaluate whether reducing postprandial hyperglycemia, blockade of the renin-angiotensin-aldosterone system, or both interventions reduce the risk of T2DM or cardiovascular events in patients with IGT.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Cyclohexanes; Diabetic Angiopathies; Disease Progression; Double-Blind Method; Glucose Intolerance; Humans; Hypoglycemic Agents; Life Style; Nateglinide; Outcome Assessment, Health Care; Phenylalanine; Research Design; Tetrazoles; Valine; Valsartan

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

Topics: Arteriosclerosis; Blood Glucose; Cyclohexanes; Diabetic Angiopathies; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Islets of Langerhans; Metformin; Nateglinide; Phenylalanine; Postprandial Period; Risk