Monocyte-suppressing effects of simvastatin in patients with isolated hypertriglyceridemia

BackgroundNo previous study investigated statin action on monocyte cytokine release and systemic inflammation in patients with isolated hypertriglyceridemia.MethodsOur study included 43 subjects with isolated hypertriglyceridemia and peripheral artery stenosis randomly allocated to one of two groups, treated for 12 weeks with either simvastatin (40 mg twice daily) or placebo. Plasma lipids, glucose homeostasis markers, plasma C-reactive protein and monocyte cytokine release were determined on the day of allocation and at the end of the treatment period.ResultsSimvastatin, but not placebo, reduced monocyte release of tumor necrosis factor-α, interleukin-6, interleukin-1β and monocyte chemoattractant protein-1, as well decreased plasma levels of C-reactive protein.ConclusionsOur study shows that simvastatin reduces monocyte secretory function and has systemic anti-inflammatory properties in patients with isolated hypertriglyceridemia.     

Anti-inflammatory effects of simvastatin in subjects with hypercholesterolemia

AIMS: Beneficial effects of statins in preventing cardiovascular events may depend, at least in part, on their anti-inflammatory action. The aim of the study was to assess the influence of simvastatin and aspirin on serum levels of C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in hypercholesterolemic subjects. METHODS AND RESULTS: In 33 asymptomatic men with total cholesterol (TC) >6.5 mmol l(-1) and in 25 men with coronary heart disease and borderline-high cholesterol levels (between 5.2 and 6.5 mmol l(-1)) chronically treated with low-dose aspirin (75 mg/d), serum levels of CRP, TNF-alpha, IL-6, and IL-8 were determined before and after a 3-month simvastatin therapy (20-40 mg daily). In the former group, these markers of inflammation were also measured before and after a 2-week treatment with aspirin (300 mg/d), implemented prior to and in combination with simvastatin. A distinct reduction of CRP and TNF-alpha was found in both groups; IL-6 levels were decreased only in subjects with marked hypercholesterolemia. Aspirin had no effect on the anti-inflammatory action of simvastatin. CONCLUSIONS: In men with hypercholesterolemia simvastatin treatment lowers serum levels of CRP and proinflammatory cytokines. Low-dose aspirin does not add to the anti-inflammatory action of simvastatin.     

The effects of gemfibrozil upon the metabolism of chylomicron-like emulsions in patients with endogenous hypertriglyceridemia

OBJECTIVE: To evaluate the effects of gemfibrozil upon the intravascular metabolism of chylomicron-like emulsions in endogenous hypertriglyceridemia. METHODS: We evaluated the plasma kinetics of a chylomicron-like emulsion in 39 subjects: 27 hypertriglyceridemics, total cholesterol (TC) expressed as median (%25; %75) 7.47 (6.1; 8.19) mmol/l and plasma triglycerides (TG) 4.28 (3.6; 18.5) mmol/l and in 12 normolipidemics, TC 4.7 (3.85; 5.37) mmol/l and TG 0.91 (0.64; 1.75) mmol/l. Hypertriglyceridemics were evaluated at baseline and after a 30-day 1200-mg/day gemfibrozil (n=8) or placebo treatment (n=7). The emulsion labelled with 14C-cholesteryl oleate (14C-CO) and 3H-triolein (3H-TO) was injected intravenously after a 12-h fast. The plasma kinetics of 3H-TO and 14C-CO were determined to assess, respectively, lipolysis and clearance of chylomicron and remnants by compartmental analysis. RESULTS: The residence times (in minutes) of 3H-TO and 14C-CO of hypertriglyceridemics were roughly twice the values of normolipidemics, i.e. 8.0 (5.5; 12.0) versus 15.0 (11.0; 24.0) and 21.5 (14.0; 33.0) versus 44.0 (32.0; 72.0), P=0.001. Gemfibrozil treatment of hypertriglyceridemic patients reduced the residence times of 3H-TO and 14C-CO, respectively, by 46% (P=0.003) and 53% (P=0.008). Effects were noted on the slow phase of emulsion plasma removal, which was reduced in hypertriglyceridemics. After treatment, the emulsion residence times determined in hypertriglyceridemics attained the values of the normolipidemic group. CONCLUSIONS: Gemfibrozil treatment normalised the defects in chylomicron-like emulsion catabolism observed in endogenous hypertriglyceridemia patients.     

Differential metabolic effects of pravastatin and simvastatin in hypercholesterolemic patients

BackgroundLocal wall shear stress (WSS) has an impact on local remodelling of the vessel wall. WSS in turn strongly depends on local geometry. Our aim was to characterize patterns of local wall shear stress associated with distinct types of remodelling in coronary arteries. Vessel size and flow rates are different between patients, however. To compare distribution patterns of WSS in analogy to fluid-dynamic modelling, non-dimensional WSS/area functions are calculated.MethodsRight coronary arteries from seven controls, five patients with coronary artery disease (CAD) and five patients with aneurysmatic CAD (AnCAD) were analyzed. Flow simulations were performed in three-dimensionally reconstructed coronary vessels from biplane angiographic projections. Local WSS was normalized as percentage of maximum value in a histogram (100 classes) and corresponding area was expressed as percentage of total area.ResultsThe normalized WSS distribution was characterized by a single peak with a large lower tie in controls, a loss of the single peak and a stochastic distribution in AnCAD and a narrowing of the lower tie in CAD. Correct classification of 16/17 coronary arteries was feasible by Fisher's discriminant functions based on median WSS, mean diameter, percentage of area with WSS ≤ 0.4 Pa and with WSS ≥ 15 Pa.ConclusionNormalized WSS distribution might be an efficient tool in comparing wall shear stress between different patient groups. Whether normalized WSS distribution curves are apt to grade severity of disease remains to be investigated.     

Effects of simvastatin treatment on sICAM-1 and sE-selectin levels in hypercholesterolemic subjects

This study was performed to determine whether the levels of soluble intercellular adhesion molecule-1 (sICAM-l) and soluble endothelial molecule-1 (sE-selectin) were elevated in subjects with hypercholesterolemia who presented with no other risk factors or evidence of atherosclerosis. The effects of administration of an HMG-CoA reductase inhibitor on the serum levels of these molecules were also examined. Forty hypercholesterolemic subjects (HCh) (19 males and 21 females), without hypertension or cardiovascular disease, received placebo for 4 weeks. The patients were then randomized in two groups; 20 of them (simvastatin group) were treated with simvastatin (20 mg/day) and the other 20 (placebo group) continued placebo administration. After 12 and 24 weeks of either simvastatin or placebo treatment, sICAM-1 and sE-selectin levels were measured. The same parameters were measured in 20 control subjects (C) with normal cholesterol levels, matched for sex and age. HCh had sICAM-1 basal values higher than C (352.4+/-57.9 ng/ml versus 114.9+/-89.6 ng/ml; P<0.001); however, sE-selectin basal values were not different in the two groups. No correlation was observed between HCh sICAM-1 levels and cholesterol levels (total and low-density lipoprotein). Furthermore, cholesterol-lowering treatment with simvastatin did not significantly diminish sICAM-1 levels. Our findings would support the hypothesis that patients with isolated hypercholesterolemia and without clinical atherosclerosis may be silent carriers of arterial subendothelial inflammation, expressed as an increase of sICAM-1.     

Haemostatic effects of simvastatin in subjects with impaired glucose tolerance

Background: Very little is known about extra‐lipid effects of statins in prediabetic subjects. Aim: Our study has assessed the effect of simvastatin on coagulation and fibrinolysis in patients with impaired glucose tolerance (IGT), comparing this effect with that exhibited by simvastatin in isolated hypercholesterolaemia. Methods: Lipid profile, fasting and 2‐h post‐glucose challenge plasma glucose levels, the homeostatic model assessment (HOMA) ratio, glycated haemoglobin, the prothrombin and partial thromboplastin time, plasma fibrinogen, plasminogen activator inhibitor‐1 (PAI‐1), von Willebrand factor (vWF), factor X levels and factor VII coagulant activity were assessed at baseline, and after 30 and 90 days of simvastatin treatment (20 mg daily) in 28 patients with IGT and 28 subjects with primary isolated hypercholesterolaemia. The control group included 26 age‐, sex‐ and weight‐matched dyslipidaemia‐free individuals with normal glucose tolerance. The experiments comply with the current law of Poland. Results: Compared to the control subjects, hypercholesterolaemic and IGT patients exhibited increased baseline plasma levels of fibrinogen, PAI‐1 and vWF, and increased factor VII activity, with no difference between the two groups of patients. All these haemostatic abnormalities were alleviated or normalized after simvastatin treatment, which was accompanied by a prolongation of the prothrombin and partial thromboplastin time. In both treatment groups simvastatin reduced total and low‐density lipoprotein (LDL)‐cholesterol, oxidized LDL and apoprotein B but did not affect glucose metabolism marker levels. Conclusions: Our study shows that haemostasis is disturbed to a similar degree in IGT and isolated hypercholesterolaemia. Simvastatin exhibits a multidirectional, lipid‐independent favourable action on coagulation and fibrinolysis in IGT patients, which may play a role in the prevention of initiation and progression of atherosclerosis in this prediabetic state.     

Randomized trial of the effects of simvastatin on cognitive functioning in hypercholesterolemic adults

PURPOSE: In our initial study of the potential effects of cholesterol-lowering interventions on cognitive functioning, treatment with lovastatin as compared with placebo caused performance decrements on several neuropsychological tests, whereas scores on other tests were unaffected. The current study was designed to confirm and extend those findings. METHODS: The study comprised 308 hypercholesterolemic adults between 35 and 70 years of age. Employing a randomized double-blind design, we assigned participants to daily treatment with placebo, 10 mg of simvastatin, or 40 mg of simvastatin for 6 months. A neuropsychological test battery was administered to assess cognitive functioning at baseline and at the end of the treatment period. RESULTS: A total of 283 subjects completed the study: 94 subjects on placebo, 96 taking 10 mg of simvastatin, and 93 taking 40 mg of simvastatin. Compared with placebo, decremental effects of simvastatin treatment were found on tests previously observed to be sensitive to statins (P = 0.008; difference in summary z scores = 0.18; 95% confidence interval [CI]: 0.07 to 0.29) and on tests not previously administered (P = 0.04; difference in summary z scores = 0.17; 95% CI: 0.05 to 0.29), but not on tests previously observed to be insensitive to statins (P = 0.84; difference in summary z scores = 0.02; 95% CI: -0.07 to 0.10). For the three tests specifically affected by simvastatin, effects on cognitive performance were small, manifest only as failure to improve during the 6 months of treatment (compared with placebo), and were confounded by baseline differences on one test. CONCLUSION: This study provides partial support for minor decrements in cognitive functioning with statins. Whether such effects have any long-term sequelae or occur with other cholesterol-lowering interventions is not known.     

Efficacy and safety of ezetimibe/simvastatin versus simvastatin monotherapy in hypercholesterolemic patients with metabolic syndrome

Background: The combination of ezetimibe and simvastatin (EZE/SIMVA) inhibits intestinal absorption and hepatic synthesis of cholesterol, providing significantly greater LDL-C-lowering compared to either drug alone. We examined the efficacy and safety of EZE/SIMVAin hypercholesterolemic patients with metabolic syndrome (MetS). Methods: We evaluated pooled data from three similarly designed, randomized, doubleblinded, placebo-controlled studies in patients with primary hypercholesterolemia. After a 6- to 8-week washout and a 4-week diet/placebo run-in, patients received one of the following treatments for 12 weeks: EZE/SIMVA (10/10, 10/20, 10/40 or 10/80 mg); SIMVA (10, 20, 40 or 80 mg); EZE 10 mg; or placebo. For this analysis, the efficacy of EZE/SIMVA versus SIMVA was evaluated in patients with and without MetS. The primary endpoint was mean percent change from baseline in LDL-C for EZE/SIMVA (pooled across doses) versus SIMVA (pooled across doses). Results: Of 2394 patients who received SIMVA or EZE/SIMVA and for whom MetS status at baseline could be determined, 31% were identified as having MetS. In the entire cohort, treatment with EZE/SIMVA led to a significant incremental reduction in low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B, triglyceride (TG), and C-reactive protein compared to SIMVA and these effects were similar across the MetS and non-MetS subgroups. EZE/SIMVA was well tolerated in both the MetS and non-MetS subgroups. Conclusion: EZE/SIMVA significantly improved the lipid and inflammatory profiles of hypercholesterolemic patients with MetS and was well tolerated. Thus, EZE/SIMVA offers an efficacious and safe treatment option for these patients.     

高三酰甘油血症患者调脂治疗前后酰化作用刺激蛋白和瘦素水平的变化

目的 :探讨高三酰甘油 (TG)血症患者调脂治疗前后酰化作用刺激蛋白 (ASP)和瘦素 (leptin)水平的变化及其意义。方法 :选取单纯高TG血症患者 38例 ,其中男 16例 ,女 2 2例 ,服用吉非贝齐 ,每次 0 .6 g ,每天 2次 ,服用 1个月 ,观察其治疗前后血脂、ASP及leptin水平的变化。ASP的检测采用三明治Elisa法 ,leptin采用放免药盒测定 ,血脂全套采用药盒测定。结果 :治疗前 ,男、女组之间ASP水平差异无显著意义〔(5 1.2 6± 19.5 3)∶(5 3.9± 2 6 .72 )mmol/L ,P >0 .0 5〕 ,但男性leptin水平显著低于女性患者〔(17.4 3± 6 .5 2 )∶(2 3.4 1± 8.35 ) μg/L ,P <0 .0 5〕。采用吉非贝齐治疗 1个月后 ,血TG、载脂蛋白B及男、女性ASP水平〔(39.5 0± 18.34)、(4 0 .5 4±2 3.4 0 )mmol/L〕明显下降 (均P <0 .0 1) ,HDL C明显升高 (P <0 .0 0 1) ,但男、女性leptin水平变化不显著〔分别为 (14 .34± 6 .12 )、(2 1.76± 5 .86 ) μg/L ,均 P >0 .0 5〕。而无论治疗前后 ,ASP水平与TG水平呈正性相关。结论 :ASP水平受血TG水平的影响 ,ASP与leptin水平之间不存在相增相减的关系 ,ASP对血TG水平起着重要的调控作用 ,leptin对血TG的影响可能更为复杂。     

Effects of therapy with diet and simvastatin on atherosclerosis in hypercholesterolemic patients

Summary We evaluated the effect of cholesterol reduction on atherosclerotic coronary artery lesions using diet and simvastatin, a potent HMG CoA reductase inhibitor. Fifteen subjects aged 28–69 years (mean 44), each of whom demonstrated significant (>50%) narrowing of a coronary artery and a baseline cholesterol level greater than 278 mg/dl, were studied. Coronary arteriography was performed prior to and after 20±2.5 months of therapy. A 42% reduction in total serum cholesterol, a 52% reduction in LDL cholesterol, and an 87% increase in the HDL/LDL cholesterol ratio (p<0.01) were achieved. Pretreatment and posttreatment angiograms were reviewed by three experienced angiographers with temporal order masked. Improvement in the overall status of coronary atherosclerotic lesions was demonstrated in two patients (13%), while deterioration occurred in one patient (7%). No overall change was found in the remaining 12 patients (80%). We conclude that a cholesterol-lowering regimen using a nonatherogenic diet and simvastatin therapy may at least stabilize coronary atherosclerosis.     

Effects of simvastatin,an HMG-CoA reductase inhibitor,in patients with hypertriglyceridemia

BACKGROUND: Patients with elevated levels of serum triglycerides (TG) often have other associated lipid abnormalities (e.g., low levels of high-density lipoprotein cholesterol [HDL-C]) and are at increased risk of developing coronary heart disease. Although the therapeutic benefits of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) in hypercholesterolemic patients have been well established, less is known about the effects of statins in patient populations with hypertriglyceridemia. HYPOTHESIS: The purpose of this study was to evaluate the lipoprotein-altering efficacy of simvastatin in hypertriglyceridemic patients. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study. In all, 195 patients with fasting serum triglyceride levels between 300 and 900 mg/dl received once daily doses of placebo or simvastatin 20, 40, or 80 mg for 6 weeks. RESULTS: Compared with placebo, simvastatin treatment across all doses resulted in significant reductions (p < 0.05 - < 0.001) in serum levels of triglycerides (-20 to -31% decrease) and TG-rich lipoprotein particles. Significant (p < 0.001) reductions were also seen in low-density lipoprotein cholesterol (-25 to -35%) and non-HDL-C (-26 to -40%). Levels of HDL-C were increased (7-11%) in the simvastatin groups compared with placebo (p < 0.05 - < 0.001). CONCLUSION: The results of this study demonstrate the beneficial effects of simvastatin in patients with hypertriglyceridemia.     

Vascular effects of simvastatin combined with ramipril in hypercholesterolemic patients with coronary artery disease, compared with simvastatin alone: a randomized, double-blind, placebo-controlled, crossover study

Because the mechanisms of the biological effects of statin and angiotensin converting enzyme inhibitor therapies differ, we studied the vascular responses to these therapies in hypercholesterolemic patients with coronary artery disease. We administered simvastatin 20 mg and placebo or ramipril 10 mg daily during 2 months with washout 2 months to 32 hypercholesterolemic patients with coronary artery disease. This study was randomized, double-blind, placebo-controlled, crossover in design. Simvastatin alone or combined with ramipril significantly changed lipoproteins, and improved the percent flow-mediated dilator response to hyperemia relative to baseline measurements by 33 +/- 6% and by 50 +/- 14%, respectively (both P <0.001) and reduced plasma levels of nitrate relative to baseline measurements (P=0.413 and 0.037, respectively), the plasma MDA levels relative to baseline measurements by 8 +/- 8% and by 18 +/- 9% (P=0.039 and P <0.001, respectively) and MCP-1 relative to baseline measurements by 7 +/- 4% and by 13 +/- 3%, respectively (P=0.019 and P <0.001, respectively), and CRP from 0.22 to 0.14 mg/dl and from 0.22 to 0.15 mg/dl, respectively (P=0.124 and 0.002, respectively), and PAI-1 antigen relative to baseline measurements (P=0.690 and 0.018, respectively). However, simvastatin combined with ramipril changed to greater but statistically insignificant extent the percent flow-mediated dilator response to hyperemia and plasma levels of nitrate, MDA, MCP-1, and PAI-1 antigen than simvastatin alone. Simvastatin alone or combined with ramipril showed significant beneficial effects on endothelial function in hypercholesterolemic patients with coronary artery disease. However, simvastatin combined with ramipril did not significantly change, compared with simvastatin alone.     

Comparison of intermittent with continuous simvastatin treatment in hypercholesterolemic patients with end stage renal failure

Coronary artery disease is the most important cause of morbidity and mortality in patients with end-stage renal failure (RF). Hypercholesterolemia is an important risk factor for coronary heart disease. Patients with chronic renal failure (CRF) have difficulties in compliance with their care and treatment. Intermittent simvastatin treatment may help to increase compliance and can be a treatment alternative in patients with CRF at risk of coronary artery disease. We investigated the effects of simvastatin and compared intermittent with continuous simvastatin treatment in hypercholesterolamic patients with CRF. The study group included 40 of 422 CRF patients on dialysis in our clinic. The inclusion criterion was low density lipoprotein cholesterol (LDL-C) of 130 mg/dL or more. Twenty patients received simvastatin 10 mg/day (continuous group) and 20 patients received simvastatin 20 mg three times a week (only dialysis days- intermittent group) for four months. Nineteen patients served as controls and they were given a prescribed diet only. Total cholesterol (TC) and LDL-C decreased markedly in patients receiving intermittent and continuous simvastatin compared to controls. Continuous simvastatin decreased TC by 23% (P < 0.001) and LDL-C by 39% (P < 0.001). Intermittent simvastatin decreased TC by 26% (P < 0.001) and LDL-C by 40% (P < 0.001). The atherogenic index ratios in both the continuous and intermittent groups (TC/High density lipoprotein-cholesterol (HDL-C) and LDL-C/HDL-C) decreased significantly. There was no significant difference in patient compliance between the two groups. Intermittent simvastatin is as effective and reliable as continuous simvastatin treatment and can be an alternative treatment in hypercholesterolemic patients on dialysis.     

Fenofibrate increases high molecular weight adiponectin in subjects with hypertriglyceridemia

Beneficial effects of peroxisome proliferator-activated receptor alpha (PPAR alpha) agonists have been reported in improving insulin sensitivity and raising serum total adiponectin. High molecular weight (HMW) adiponectin, which is secreted from adipocytes, and visfatin, which is also expressed in adipose tissue, is related to glucose metabolism. In view of the additive effects of PPAR alpha agonists on these adipocytokines and glucose metabolism, we investigated male hypertriglyceridemic subjects who were treated with fenofibrate. Eleven male subjects with hypertriglyceridemia were treated with fenofibrate and serum total cholesterol (T-cho), triglyceride, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), fasting glucose, fasting insulin, total and HMW adiponectin, and serum visfatin levels were determined before and 3 months after treatment. Fenofibrate treatment significantly lowered T-cho, triglyceride, and LDL-C levels. There was a statistically significant increase of HDL-C. No differences in insulin sensitivity indices (G/I ratio and HOMA-IR) were observed between before and after treatment with fenofibrate. The treatment did not alter the levels of serum total adiponectin and visfatin in the hypertriglyceridemic patients, while serum HMW adiponectin increased significantly. This study demonstrates that fenofibrate increases serum HMW adiponectin levels, whereas visfatin is not regulated by fenofibrate in hypertriglyceridemic subjects. Further investigations are warranted to determine whether the elevation of HMW adiponectin caused by fenofibrate might improve insulin sensitivity.     

Sustained reduction of serum cholesterol in low-dose 6-year simvastatin treatment with minimum side effects in 51,321 Japanese hypercholesterolemic patients.

The Japan Lipid Intervention Trial (J-LIT) study, a nationwide cohort study utilizing the clinical practice of general physicians, was designed to clarify the relationship between the incidence of coronary heart disease and serum lipid concentrations during simvastatin therapy, as well as the safety of the therapy, in a large number of Japanese hypercholesterolemic patients. All the enrolled patients were treated with simvastatin. The current study analyzed the lipid lowering effect and safety of the low-dose simvastatin therapy used in the J-LIT study. Open-labeled simvastatin was given to 51,321 patients at an initial dose of mostly 5 mg/day. After 6 months of the treatment, the average serum total cholesterol (TC) and low density lipoprotein-cholesterol concentrations in all the patients followed up were reduced by 18.3% and 26.0%, respectively, and that of high density lipoprotein-cholesterol increased 2.3% on average. These concentrations were well maintained throughout the 6-year treatment period. A minority of patients (1.4%) unexpectedly had a remarkable reduction in TC concentration by more than 40%. Hyper-responders, even to low-dose statin, were found for the first time in this large-scale and long-term investigation. Overall adverse drug reactions occurred in 3.3% of subjects during the 6-year treatment, the major events being hepatic and musculoskeletal disorders, of which the incidence was less than 1%. Low-dose simvastatin therapy of 5 mg/day effectively controlled the serum TC concentration by reducing it by approximately 20% on average in hypercholesterolemic Japanese patients, a reduction that corresponds to the effect of simvastatin 20 mg/day in Western studies. In addition, the low incidence of drug-related adverse events in this study may be also related to the low dosage of simvastatin.