cerivastatin and Diabetes-Mellitus

Topics: Arteriosclerosis; Coronary Disease; Diabetes Complications; Diabetes Mellitus; Endothelium, Vascular; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Lipids; Pyridines; Randomized Controlled Trials as Topic

In a double-blind, placebo-controlled, randomized crossover study, 15 stable mild hyperglycemic patients without treatment and with features of metabolic syndrome were treated with cerivastatin (0.4 mg/day) or placebo for 3 months. The insulin sensitivity index during the euglycemic-hyperinsulinemic clamp (EHC; 5.4 mmol/l; 80 mU x m(-2) x min(-1)) was increased by cerivastatin treatment (66.39 +/- 3.9 nmol x lean body mass [LBM](-1) x min(-1) x pmol(-1) x l(-1)) as compared with placebo (58.37 +/- 3.69 nmol x LBM(-1) x min(-1) x pmol(-1) x l(- 1); P < 0.01) by 13.7%. Glucose oxidation during EHC was significantly higher with statin treatment (16.1 +/- 1.37 micromol x LBM(-1) x min(-1)) as compared with placebo (14.58 +/- 1.48 micromol x LBM(-1) x min(-1); P < 0.05). During hyperinsulinemia (approximately 800 pmol/l) in EHC steady-state, lipid oxidation was significantly decreased and respiratory quotient was significantly increased with statin treatment (0.33 +/- 0.05 mg x LBM(-1) x min(- 1), 0.94 +/- 0.01) as compared with placebo (0.48 +/- 0.06 mg x LBM(-1) x min(-1), 0.91 +/- 0.01; P < 0.01 and P < 0.05, respectively). During statin treatment, the first-phase insulin response increased from 2.07 +/- 0.28 to 2.82 +/- 0.38 pmol x l(-1) x pmol(-1) (P < 0.05). The second phase of insulin responses examined by C-peptide and insulin levels averaged during the hyperglycemic clamp (20 mmol/l) was unchanged. In conclusion, this study demonstrates that 0.4 mg cerivastatin therapy improves first-phase insulin secretion and increases insulin-mediated glucose uptake and respiratory quotient in the early state of obese type 2 diabetes.

Topics: Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Fructosamine; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperinsulinism; Infusions, Intravenous; Insulin; Male; Middle Aged; Obesity; Placebos; Pyridines

The short-term effects of hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) on endothelial function at doses that do not affect plasma lipid levels are not known.. We investigated the short-term effects of cerivastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor, on endothelial function and endothelium-related products in elderly diabetic patients. Twenty-seven elderly diabetic patients (aged 69.3+/-3.4 years), with or without mild hypercholesterolemia, were enrolled in this study, which tested cerivastatin treatment (0.15 mg/d) for 3 days. Endothelium-dependent flow-mediated dilatation, endothelium-independent dilatation by nitroglycerin in the brachial artery, nitric oxide-related products (nitrite/nitrate and cGMP), endothelium-related products (von Willebrand Factor, soluble vascular cell adhesion molecule-1, and soluble intercellular adhesion molecule-1), and a marker of oxidant stress (8-isoprostane) were assessed. Levels of plasma lipids were not changed before and after treatment with cerivastatin. Flow-mediated dilatation was significantly increased by cerivastatin treatment, as were plasma nitrite/nitrate levels (from 16.9+/-3.4 to 22.0+/-3.7 micromol/L, P<0.05) and cGMP values. The percent of nitroglycerin-induced dilatation was not changed. Plasma concentrations of 8-isoprostane decreased, and levels of soluble vascular cell adhesion molecule also tended to decrease with cerivastatin.. Improvement of endothelial function was in line with antiatherosclerotic effects. Cerivastatin improved impaired endothelial function in the short-term without affecting lipid profiles in elderly diabetic patients. This effect may be partly due to upregulation of endothelial nitric oxide synthase.

Topics: Aged; Brachial Artery; Cyclic GMP; Diabetes Complications; Diabetes Mellitus; Endothelium, Vascular; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Lipids; Male; Nitrates; Nitrites; Pyridines; Time Factors; Treatment Outcome; Vasodilation

A mutation of the CD36 gene that encodes a fatty acid transporter has been reported to play a role in insulin resistance in spontaneously hypertensive rat (SHR). Statins reduce circulating cholesterol and triglyceride concentrations. The objective of this study was to determine the role of CD36 and the significance of statin therapy in insulin-resistance syndromes. We determined the isometric relaxation induced by acetylcholine or lecithinized superoxide dismutase (SOD) in aortas obtained from Otsuka Long Evans Tokushima Fatty (OLETF) rats, a model of insulin resistance and dyslipidemia, and normal control (Long Evans Tokushima Otsuka; LETO) rats with or without cerivastatin treatment. We also determined the effect of cerivastatin on aortic expression of CD36 and PPARgamma. The CD36 genotype and microsatellite markers on chromosome 4 were also determined. The relaxation induced by acetylcholine and lecithinized SOD were attenuated in OLETF rats but restored by a low dose of cerivastatin without significant changes in serum cholesterol. These relaxations were also restored by a high dose of cerivastatin with significant reductions in serum cholesterol and triglyceride. Cerivastatin increased the aortic expression of CD36 and PPARgamma mRNA in both LETO and OLETF rats. However, the basal level of CD36 mRNA and the increase in CD36 mRNA in response to cerivastatin were significantly lower in OLETF rats than in LETO rats. Although the abnormal CD36 genotype reported in SHR was not found in OLETF rats, the microsatellite markers of D4Rat151 and D4Rat115 differed between OLETF and LETO rats. In conclusion, insulin resistance in OLETF rats may be partially due to an altered expression of CD36. Increased aortic expression of CD36 in response to cerivastatin could explain the reduction in serum triglyceride concentrations with statin therapy and may have pronounced beneficial effects in insulin-resistance syndromes.

Topics: Animals; Aorta; CD36 Antigens; Diabetes Mellitus; Disease Models, Animal; Endothelium, Vascular; Genotype; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Insulin Resistance; Male; Microsatellite Repeats; PPAR gamma; Pyridines; Rats; Rats, Inbred OLETF; RNA, Messenger

Topics: Aged; Arteriosclerosis; Diabetes Mellitus; Endothelium, Vascular; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Kinetics; Nitroglycerin; Pyridines; Reproducibility of Results; Ultrasonography; Vasodilation; Vasodilator Agents

Topics: Aged; Brachial Artery; Diabetes Mellitus; Endothelium, Vascular; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Nitroglycerin; Pyridines; Vasodilation; Vasodilator Agents

Topics: Antineoplastic Agents; Benzamides; Cholesterol; Colonic Neoplasms; Coronary Artery Bypass; Diabetes Mellitus; Drug and Narcotic Control; Genome, Human; Heart, Artificial; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Imatinib Mesylate; Information Dissemination; Obesity; Occult Blood; Office Visits; Piperazines; Pyridines; Pyrimidines; Tauopathies

To investigate the direct anti-atherosclerotic properties of statins.. Using in vitro and ex vivo models, the effect of different statins on key events involved in atherogenesis has been investigated. We studied the ability of statins to modulate modified LDL-induced cholesterol esterification, metalloproteinase secretion by macrophages, and arterial myocyte migration and proliferation. The mechanisms underlying the inhibitory effect of statins have also been explored. Finally, the antiproliferative effect of sera from statin-treated patients has been confirmed in a cell culture system.. Fluvastatin, simvastatin, lovastatin, atorvastatin, and cerivastatin, but not pravastatin, dose-dependently decrease smooth muscle cell (SMC) migration and proliferation. Moreover, statins are able to reduce cholesterol accumulation in macrophages in vitro by blocking cholesterol esterification and endocytosis of modified lipoproteins and matrix-degrading enzyme secretion. This in vitro inhibition was completely prevented by mevalonate and partially by all-trans farnesol and all-trans geranylgeraniol, confirming the specific role of isoprenoid metabolites (probably through prenylated protein[s]) in regulating these cellular events. The inhibitory effect of statins on SMC proliferation has been shown in different models of proliferating cells, such as cultured arterial myocytes and rapidly proliferating carotid and femoral intimal lesions in rabbits, independently of their ability to reduce plasma cholesterol. Finally, ex vivo studies showed that sera from fluvastatin-treated patients interfere with SMC proliferation.. These results suggest that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors exert a direct anti-atherosclerotic effect in the arterial wall, beyond their effects on plasma lipids that could translate into a more significant prevention of cardiovascular disease. These findings provide a basis for the beneficial effect of statins in clinical trials also involving diabetic patients--a population with a higher absolute risk of recurrent cardiovascular events.

Topics: Animals; Arteriosclerosis; Atorvastatin; Cell Division; Cell Movement; Cells, Cultured; Cholesterol; Cholesterol Esters; Diabetes Complications; Diabetes Mellitus; Diabetic Angiopathies; Endocytosis; Fatty Acids, Monounsaturated; Fluvastatin; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Lipoproteins; Lovastatin; Macrophages; Macrophages, Peritoneal; Mice; Mice, Inbred BALB C; Muscle, Smooth; Pyridines; Pyrroles; Simvastatin

Gemfibrozil-statin combination therapy is a well-known risk factor for myopathy and rhabdomyolysis. Cerivastatin is a currently available statin with dual elimination; it is therefore expected to cause less drug-drug interaction. This case is the second reported case with severe rhabdomyolysis caused by cerivastatin-gemfibrozil combination. Moreover, in this case, the rhabdomyolysis was more severe and caused severe renal failure and death. The authors discuss how these drugs cause rhabdomyolysis and how rhabdomyolysis can cause renal failure.

Topics: Diabetes Mellitus; Drug Interactions; Drug Therapy, Combination; Electrocardiography; Fatal Outcome; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypolipidemic Agents; Male; Middle Aged; Myocardial Ischemia; Pyridines; Renal Dialysis; Renal Insufficiency; Rhabdomyolysis