(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Metabolic-Syndrome

This pooled analysis of 30 completed clinical trials assessed the efficacy and safety profile in reducing cardiovascular disease (CVD) risk of fluvastatin in the treatment of dyslipidemia in patients with and without the metabolic syndrome (metS).. Data from 30 double-blind, randomized, placebo-controlled or fluvastatin-controlled trials with > or =6 weeks of active treatment and daily fluvastatin doses of 20, 40, and 80 mg were pooled. Patients received fluvastatin or placebo. Linear contrasts from an analysis of covariance model containing factors for trial and treatment group (immediate-release fluvastatin 20, 40, 80 mg; extended-release fluvastatin 80 rag; or placebo), and using the baseline value as covariate, were used to compare the percentage changes from baseline to the first postbaseline assessment of all lipid parameters. A Cox regression analysis compared the all-fluvastatin group to the placebo group with regard to the time to occurrence of clinical end points from 5 pooled studies, each with a mean treatment duration >1 year wherein clinical end points were reviewed by an adjudication committee. These analyses were performed separately for patients with and without metS.. This pooled analysis included data from 7043 patients (4095 men, 2948 women; all-fluvastatin group with and without metS, 2529 and 2052 patients, respectively; placebo group with and without metS, 1514 and 948 patients, respectively). Patients with metS in the pooled fluvastatin group had a greater mean reduction in triglyceride levels (24.1% vs 6.7%), a greater mean increase in high-density lipoprotein cholesterol levels (10.3% vs -0.6%), and a similar mean reduction in low-density lipoprotein cholesterol levels (26.8% vs 26.7%) compared with the subgroup of patients without metS. Treatment with fluvastatin was associated with a significantly lower incidence of major adverse cardiovascular events (MACEs) (16.4% vs 22.0%) and an increase in the time to first MACE in patients with metS compared with placebo (hazard ratio = 0.728; P = 0.001). The incidences of adverse events, particularly those of concern (ie, myalgia and/ or increased blood creatine phosphokinase, alanine aminotransferase, and/or aspartate aminotransferase) with lipid-lowering therapy, were statistically similar between the patients who received fluvastatin and those who received placebo in the 2 subgroups.. The results from this pooled analysis found that fluvastatin was effective in reducing CVD risk in the treatment of dyslipidemia in these patients with metS.

Topics: Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Dyslipidemias; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Incidence; Indoles; Male; Metabolic Syndrome; Middle Aged; Triglycerides

Postprandial lipemia is known to exert a reversible detrimental effect on endothelium-dependent flow-mediated vasodilation (FMD). Fasting FMD has shown to be improved by fluvastatin. In this study, we investigated whether lipemia-induced endothelial dysfunction can be mitigated by fluvastatin in two (immediate-release and extended-release) formulations.. In 27 patients with the metabolic syndrome, randomized in a three-period crossover design for 5 weeks each to 80 mg extended-release fluvastatin daily, 40 mg immediate-release fluvastatin twice daily (b.i.d.) or placebo, the fasting and postprandial lipids and FMD of the brachial artery were measured at baseline and after 5 weeks of each treatment period. Postprandial lipemia was induced by administration of whipping cream containing 33% fat (1 g fat/kg body weight). FMD was determined by two-dimensional ultrasonography of the brachial artery in the fasting state and 4 h after the fatty meal. Lipids were determined using routine methods.. Fasting triglycerides were reduced after immediate-release and extended-release fluvastatin by 16 and 23%, respectively, and postprandial triglycerides by 20 and 29%, respectively. The fasting FMD was also improved by each treatment. The postprandial FMD impairment, however, was mitigated only after 40 mg b.i.d. After 80 mg fluvastatin, the last dose of which had been administered the previous evening, the lipemic FMD impairment was the same as after the placebo.. Fluvastatin improves fasting FMD regardless of whether it is administered as 40 mg b.i.d. or 80 mg daily given in the evening. The lipemic FMD impairment, in contrast, is improved only by 40 mg b.i.d. when the tablet is taken in the morning of the test day. As the half-life of fluvastatin is about 2 h, we surmise that an improvement occurs only when sufficient amounts of fluvastatin are present in the bloodstream.

Topics: Administration, Oral; Aged; Brachial Artery; Capsules; Chemistry, Pharmaceutical; Cross-Over Studies; Delayed-Action Preparations; Dietary Fats; Double-Blind Method; Drug Administration Schedule; Endothelium, Vascular; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Indoles; Male; Metabolic Syndrome; Middle Aged; Postprandial Period; Regional Blood Flow; Tablets; Time Factors; Treatment Outcome; Triglycerides; Ultrasonography; Vasodilation

Patients with metabolic syndrome (MS) and type 2 diabetes (T2DM) show increased risk for coronary artery disease. Lipoprotein metabolism is characterized by elevated triglycerides (TG), low high-density lipoprotein cholesterol (HDL-C) and predominance of atherogenic small, dense low-density lipoprotein (sdLDL), while low-density lipoprotein (LDL) cholesterol is only slightly elevated.. Multicentre, randomized, open-label cross-over study investigating the effect of combination of fluvastatin/fenofibrate (80/200 mg) (F&F) on LDL-subfractions compared with combination of simvastatin/ezetimibe (20/10 mg) (S&E) in patients with MS/T2DM.. Seventy-five patients were randomized, 69 completed the study and LDL-subfractions of 56 patients were analysed. Thirty-eight out of 56 patients (68%) showed a profile dominated by sdLDL. In these, TG and total cholesterol (TC) were elevated compared with non-sdLDL patients. In all patients, reduction of TC and LDL cholesterol (LDL-C) by S&E was stronger than by F&F. The increase of HDL-C was stronger with S&E in the non-sdLDL group, whereas in the sdLDL group, there was no difference between treatments. In non-sdLDL patients, there was no effect on TG or LDL-radius. However, in the sdLDL group, F&F was more effective in reducing TG and increased LDL radius, whereas S&E reduced LDL radius even further.. S&E is more efficient in reducing TC and LDL-C. This is also true for HDL-C increase in non-sdLDL patients. However, in patients with sdLDL, F&F was more efficient in reducing TG and increasing LDL radius.

Topics: Anticholesteremic Agents; Azetidines; Cholesterol, LDL; Coronary Artery Disease; Drug Administration Schedule; Drug Therapy, Combination; Ezetimibe; Fatty Acids, Monounsaturated; Female; Fenofibrate; Fluvastatin; Humans; Indoles; Male; Metabolic Syndrome; Middle Aged; Simvastatin; Treatment Outcome

Elevated concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, are associated with endothelial dysfunction. Metabolic syndrome (MetS) is also a condition associated with impaired endothelial function. To test the hypothesis that lipid lowering treatment with a statin lowers ADMA levels, we investigated the effect of fluvastatin treatment on serum ADMA levels in patients with MetS. A total of 85 hypercholesterolemic MetS patients (53 females, 32 males; mean age, 55.8+/-9.1 years) were included in this prospective, randomized, controlled study. Patients were randomly assigned to either the treatment (n=42) or control group (n=43). Recommendations for lifestyle modification were provided to both groups. In addition, the patients in the treatment group received fluvastatin, extended release tablets, 80 mg/day, orally for 6 weeks. Serum levels of ADMA and lipids were assessed at baseline and at the completion of treatment. High performance liquid chromatography was used to measure serum ADMA concentrations. In the fluvastatin group, there was a significant reduction in serum ADMA levels compared to baseline (from 1.57+/-1.07 micromol/L to 1.17+/-1.41 micromol/L, P<0.05), whereas in the control group no significant change was observed (from 1.06+/-0.46 micromol/L to 1.24+/-1.38 micromol/L, P>0.05). There was a statistically significant difference between the groups in terms of mean percent change from baseline (P=0.047). Fluvastatin treatment for hypercholesterolemia in patients with MetS is associated with a decrease in serum ADMA levels at 6 weeks. This finding is consistent with known beneficial effects of statin treatment on endothelial function in hypercholesterolemic patients.

Topics: Adult; Arginine; Cholesterol; Endothelium, Vascular; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Indoles; Male; Metabolic Syndrome; Middle Aged; Treatment Outcome

Topics: Anticholesteremic Agents; Azetidines; Cardiovascular Diseases; Cholesterol, LDL; Drug Therapy, Combination; Ezetimibe; Fatty Acids, Monounsaturated; Fenofibrate; Fluvastatin; Humans; Hypolipidemic Agents; Indoles; Metabolic Syndrome; Simvastatin

Inflammation plays an important role in the pathogenesis of metabolic syndrome (MS). We investigated the effect of fluvastatin treatment on inflammatory markers in patients with MS.. The study included 47 patients (36 females; 11 males; mean age 55+/-8 years) with MS. The diagnosis of MS was based on the presence of at least three criteria of the NCEP ATP III guidelines. All the patients received 80 mg fluvastatin treatment for six weeks. Laboratory parameters were measured before and after treatment, and flow cytometric analysis of peripheral blood leukocytes was performed. The results were compared with those of 47 age- and sex-matched healthy controls (33 females, 14 males; mean age 52+/-8 years).. Fluvastatin treatment resulted in significant decreases in levels of total cholesterol, LDL cholesterol, triglyceride (p<0.005), and C-reactive protein (p<0.05). Thirty-three patients (70.2%) had insulin resistance, which remained unchanged following treatment. Flow cytometric analysis after treatment showed significant decreases in total lymphocytes, and in surface antigens of CD16+56 and CD8+(CD28+) on leukocytes, CD11c on granulocytes, and a significant increase in the CD4/CD8 ratio (p<0.05). Compared to the control group, the mean baseline values of fluorescence density (FD) of CD14, CD11b, CD11c, and CD63 on monocytes, and CD11b and CD11c on granulocytes were significantly higher in patients with MS (p<0.05). Following fluvastatin treatment, there were significant decreases in the mean FD of CD3 on lymphocytes, and of CD11b and CD11c on both monocytes and granulocytes (p<0.05); of these, all FD values were similar to those in the control group (p>0.05).. Our data demonstrate that inflammation may have a significant role in the pathogenesis of MS and that this effect can be controlled with statin treatment.

Topics: Antigens, CD; Biomarkers; C-Reactive Protein; Cholesterol; Cholesterol, LDL; Fatty Acids, Monounsaturated; Female; Flow Cytometry; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Inflammation; Insulin Resistance; Lymphocyte Count; Male; Metabolic Syndrome; Middle Aged; Triglycerides

Angiotensin II (Ang II) is able to induce free radical generation in neutrophils, which is more elevated in neutrophils of patients with hypercholesterolemia (HC). In addition, the signal processing through angiotensin I (Ang I) receptors is altered. In present study, we compared the Ang II-triggered free radical generation of neutrophils obtained from patients with relatively isolated forms of metabolic syndrome (MS) with membrane-bound cholesterol content and membrane fluidity. We determined the enhancement of Ang II-induced superoxide anion and leukotriene C(4) (LTC(4)) generation, membrane fluidity and cell-bound cholesterol content of neutrophils obtained from 12 control subjects, 11 patients with obesity (Ob), 10 patients with type 2 diabetes mellitus (t2-DM) and 12 patients with HC. The alteration of signal processing was studied after preincubation with different inhibiting drugs. Superoxide anion, LTC(4) production and membrane rigidity were increased in the following order: control < Ob < t2-DM < HC. Both Ang II-induced superoxide anion and LTC(4) generation were decreased in control cells by pertussis toxin and fluvastatin (Flu), whereas in each patient group, mepacrin, verapamil and Flu were effective, suggesting alterations in signal pathways, which may be attributed to isoprenylation. The enhancement of superoxide anion and LTC(4) generation correlated significantly with membrane rigidity, independently from the experimental groups and membrane-bound cholesterol content. Membrane rigidity of neutrophils, obtained from patients with MS, plays a role in Ang II-induced free radical generation independent of intracellular cholesterol homeostasis.

Topics: Adult; Angiotensin I; Angiotensin II; Anticholesteremic Agents; Cholesterol; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Fatty Acids, Monounsaturated; Female; Fluvastatin; Homeostasis; Humans; Hypercholesterolemia; Indoles; Leukotriene C4; Male; Membrane Fluidity; Metabolic Syndrome; Middle Aged; Neutrophils; Pertussis Toxin; Protein Prenylation; Quinacrine; Signal Transduction; Superoxides; Vasoconstrictor Agents; Vasodilator Agents; Verapamil