Comparative effects of atorvastatin,simvastatin, and fenofibrate on serum homocysteine levels in patients with primary hyperlipidemia

Hyperhomocysteinemia is regarded as an independent risk factor for cardiovascular disease. Lipid-lowering agents, such as fibrates, can modify homocysteine levels. However, less is known about the effect of statin therapy on homocysteine. The authors compared the effects of atorvastatin (40 mg/day), simvastatin (40 mg/day), and micronized fenofibrate (200 mg/day) on the serum concentrations of total homocysteine, vitamin B12, and folic acid in patients with primary hyperlipidemia. A total of 128 patients with primary hyperlipidemia (total cholesterol > 240 mg/dL and triglycerides < 350 mg/dL) were assigned to atorvastatin, simvastatin, or fenofibrate. Serum lipid and metabolic parameters were measured at baseline and at 6 and 12 weeks of treatment. Homocysteine correlated positively with serum creatinine and uric acid levels and inversely with serum folic acid levels. All treatment modalities reduced total, low-density lipoprotein (LDL) cholesterol, and triglyceride concentrations. High-density lipoprotein (HDL) cholesterol levels significantly increased only in the fenofibrate-treated patients (47.9 +/- 12.5 vs. 50.7 +/- 12.6 vs. 51.2 +/- 12.8 mg/dL, p < 0.01). Atorvastatin and fenofibrate treatment resulted in a significant reduction of serum uric acid levels (5.3 +/- 1.6 vs. 4.9 +/- 1.4 vs. 4.8 +/- 1.4 mg/dL, p < 0.0001 for atorvastatin; 5.6 +/- 1.6 vs. 4.3 +/- 1.4 vs. 4.4 +/- 1.4 mg/dL, p < 0.0001 for fenofibrate). Homocysteine levels were significantly increased only by fenofibrate (10.3 +/- 3.3 vs. 14.1 +/- 3.8 vs. 14.2 +/- 3.6 microU/L, p < 0.001) but did not change from baseline following statin treatment. Neither statins nor fenofibrate had any effect on serum vitamin B12 and folic acid levels. In contrast to fenofibrate, therapeutic dosages of atorvastatin and simvastatin have a neutral effect on serum homocysteine levels, which is in favor of their "cardioprotective" properties.     

ABCB1 and ABCC1 expression in peripheral mononuclear cells is influenced by gene polymorphisms and atorvastatin treatment

This study investigated the effects of atorvastatin on ABCB1 and ABCC1 mRNA expression on peripheral blood mononuclear cells (PBMC) and their relationship with gene polymorphisms and lowering-cholesterol response. One hundred and thirty-six individuals with hypercholesterolemia were selected and treated with atorvastatin (10 mg/day/4 weeks). Blood samples were collected for serum lipids and apolipoproteins measurements and DNA and RNA extraction. ABCB1 (C3435T and G2677T/A) and ABCC1 (G2012T) gene polymorphisms were identified by polymerase chain reaction-restriction (PCR)-RFLP and mRNA expression was measured in peripheral blood mononuclear cells by singleplex real-time PCR. ABCB1 polymorphisms were associated with risk for coronary artery disease (CAD) (p<0.05). After atorvastatin treatment, both ABCB1 and ABCC1 genes showed 50% reduction of the mRNA expression (p<0.05). Reduction of ABCB1 expression was associated with ABCB1 G2677T/A polymorphism (p=0.039). Basal ABCB1 mRNA in the lower quartile (<0.024) was associated with lower reduction rate of serum low-density lipoprotein (LDL) cholesterol (33.4+/-12.4%) and apolipoprotein B (apoB) (17.0+/-31.3%) when compared with the higher quartile (>0.085: LDL-c=40.3+/-14.3%; apoB=32.5+/-10.7%; p<0.05). ABCB1 substrates or inhibitors did not affect the baseline expression, while ABCB1 inhibitors reversed the effects of atorvastatin on both ABCB1 and ABCC1 transporters. In conclusion, ABCB1 and ABCC1 mRNA levels in PBMC are modulated by atorvastatin and ABCB1 G2677T/A polymorphism and ABCB1 baseline expression is related to differences in serum LDL cholesterol and apoB in response to atorvastatin.     

Effects of atorvastatin on low-density lipoprotein cholesterol phenotype and C-reactive protein levels in patients undergoing long-term dialysis

STUDY OBJECTIVES: To determine the effects of atorvastatin on low-density lipoprotein cholesterol (LDL) particle size and C-reactive protein (CRP) concentrations in patients undergoing long-term hemodialysis. Another objective was to compare the effects of atorvastatin on lipoprotein profiles as determined by direct versus indirect assessment of lipoprotein composition. DESIGN: Randomized, parallel-group substudy. SETTING: Two university-affiliated outpatient hemodialysis centers. PATIENTS: Nineteen patients with LDL levels above 100 mg/dl and with at least two cardiovascular risk factors. INTERVENTION: Patients were randomized in a 1:1 ratio to atorvastatin 10 mg/day or no treatment (control) for 20 weeks. MEASUREMENTS AND MAIN RESULTS: We compared the differences between LDL particle size and CRP levels at baseline and 20 weeks in the atorvastatin versus control groups. Baseline demographic characteristics were similar between the two groups. Atorvastatin therapy was associated with no change in mean LDL particle size (p=0.23) and with a 90% decrease in mean CRP level (p=0.52). When evaluated by standard chemical analysis, atorvastatin therapy reduced total cholesterol levels by 29% (p=0.025) and resulted in nonsignificant reductions in LDL, high-density lipoprotein cholesterol, and triglyceride levels. Treatment with atorvastatin was not associated with significant changes in lipoprotein profile as determined by nuclear magnetic resonance (NMR) spectroscopy. CONCLUSION: Treatment with atorvastatin did not affect LDL particle size but was associated with a sizable, yet nonsignificant, reduction in CRP concentrations. The drug had variable effects on lipoprotein concentrations as determined by chemical and NMR analytical methods. A larger study is necessary to provide definitive information on the effects of atorvastatin on LDL phenotype and CRP in patients with kidney disease.     

LDL‐C/HDL‐C ratio in subjects with cardiovascular disease and a low HDL‐C: results of the RADAR (Rosuvastatin and Atorvastatin in different Dosages And Reverse cholesterol transport) study

ABSTRACT

Background: The ratio of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol (LDL‐C/HDL‐C) is a reliable predictor of cardiovascular risk. Low HDL‐C levels in patients with coronary artery disease are associated with a high risk for cardiovascular events.

Objectives: This study compared the effects of rosuvastatin and atorvastatin on the LDL‐C/HDL‐C ratio in patients with cardiovascular disease and low HDL‐C.

Methods: Patients aged 40–80 years with established cardiovascular disease and HDL‐C < 1.0?mmol/L (< 40?mg/dL) entered a 6‐week dietary run-in period, before randomisation to open-label treatment with rosuvastatin 10?mg (n = 230) or atorvastatin 20?mg (n = 231) for 6 weeks. Doses were increased after 6 weeks to rosuvastatin 20?mg or atorvastatin 40?mg, and after 12 weeks to rosuvastatin 40?mg or atorvastatin 80?mg. Serum lipid parameters were measured at baseline and 6, 12 and 18 weeks.

Results: After 6 weeks of treatment, mean percentage change from baseline in LDL‐C/HDL‐C ratio was –47.0% in the rosuvastatin group and –41.9% in the atorvastatin group (?p < 0.05 for between-group comparison). After 12 and 18 weeks of treatment, change from baseline was –53.0% and –57.3%, respectively, for rosuvastatin, compared with –47.9% and –49.6%, respectively, for atorvastatin (?p < 0.01 and p < 0.001, respectively, for between-group comparison). Rosuvastatin also reduced LDL‐C, total cholesterol and non-HDL‐C significantly more than atorvastatin at all three time points, and significantly improved total cholesterol/HDL‐C and apolipoprotein B/A‐I ratios.

Conclusions: Rosuvastatin 10, 20 and 40?mg is significantly more effective than atorvastatin 20, 40 and 80?mg, respectively, in improving the LDL‐C/HDL‐C ratio in patients with cardiovascular disease and low HDL‐C. Further studies are required to clarify the benefits of rosuvastatin for reduction of cardiovascular risk.     

LDL-C/HDL-C ratio in subjects with cardiovascular disease and a low HDL-C: results of the RADAR (Rosuvastatin and Atorvastatin in different Dosages And Reverse cholesterol transport) study

BACKGROUND: The ratio of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol (LDL-C/HDL-C) is a reliable predictor of cardiovascular risk. Low HDL-C levels in patients with coronary artery disease are associated with a high risk for cardiovascular events. OBJECTIVES: This study compared the effects of rosuvastatin and atorvastatin on the LDL-C/HDL-C. METHODS: Patients aged 40-80 years with established cardiovascular disease and HDL-C < 1.0 mmol/L (< 40 mg/dL) entered as a 6-week dietary run-in period, before randomisation to open-label treatment with rosuvastatin 10 mg (n = 230) or atorvastatin 20 mg (n = 231) for 6 weeks. Doses were increased after 6 weeks to rosuvastatin 20 mg or atorvastatin 40 mg, and after 12 weeks to rosuvastatin 40 mg or atorvastatin 80 mg. Serum lipid parameters were measured at baseline and 6, 12 and 18 weeks. RESULTS: After 6 weeks of treatment, mean percentage change from baseline in LDL-C/HDL-C ratio was -47.0% in the rosuvastatin group and -41.9% in the atorvastatin group (p < 0.05 for between-group comparison). After 12 and 18 weeks of treatment, change from baseline was -53.0% and -57.3%, respectively, for rosucastatin, compared with -47.9% and -49.6%, respectively, for atorvastatin (p < 0.01 and p < 0.001, respectively, for between-group comparison). Rosuvastatin also reduced LDL-C, total cholesterol/HDL-C significantly more than atorvastatin at all three time points, and significantly improved total cholesterol/HDL-C and apolipoprotein B/A-I ratios. CONCLUSIONS: Rosuvastatin 10, 20 and 40 mg is significantly more effective than atorvastatin 20, 40 and 80 mg, respectively, in improving the LDL-C/HDL-C ratio in patients with cardiovascular disease and low HDL-C. Further studies are required to clarify the benefits of rosuvastatin for reduction of cardiovascular risk.     

Efficacy of combination of atorvastatin and micronised fenofibrate in the treatment of severe mixed hyperlipidemia

OBJECTIVES: In patients with mixed lipid disorders, monotherapy may not effectively control all lipid abnormalities. We undertook this study to assess the efficacy of fenofibrate in combination with atorvastatin in patients with severe mixed dyslipidemia. METHODS: This was an 18-week, open-label study conducted in our lipid clinic. After a 6-week dietary baseline phase, patients received 200 mg/day micronised fenofibrate for 6 weeks. At the end of this period the subjects discontinued this treatment and received 40 mg/day atorvastatin for 6 weeks. Finally 200 mg/day of micronised fenofibrate was added to the statin therapy. RESULTS: Administration of micronised fenofibrate reduced serum triglycerides (P < 0.01) and total cholesterol and low-density lipoprotein (LDL) cholesterol (P < 0.05 for both parameters), while it evoked a significant increase in serum high-density lipoprotein (HDL) cholesterol levels (P < 0.05). Atorvastatin monotherapy induced a more pronounced decrease of total and LDL cholesterol. However, plasma triglycerides, although significantly lower than baseline values (P < 0.05), were higher than the values observed during treatment with fenofibrate. Moreover, serum HDL cholesterol concentrations were higher during fibrate therapy than during the statin one. During the combination therapy, the decrease in triglycerides was greater than that observed with fenofibrate alone, while the decrease in LDL cholesterol was more pronounced than that observed with atorvastatin alone. CONCLUSION: The combination of atorvastatin with micronised fenofibrate in patients with severe mixed dyslipidemia may have a favourable effect on some major coronary artery disease risk factors.     

阿托伐他汀对颈动脉粥样硬化患者血清sCD40L水平的影响

目的探讨阿托伐他汀对颈动脉粥样硬化患者血清sCD40L浓度的影响,并探究其阻断CD40/CD40L信号途径的作用。方法选取颈动脉粥样硬化患者80例,随机分为对照组和试验组,每组40例。分别给予饮食控制和阿托伐他汀治疗,随访12周。治疗前、治疗后第4周、第12周检测血清sCD40L、血总胆固醇、甘油三酯、低密度脂蛋白。结果治疗组治疗后第4周、第12周所测指标浓度水平显著低于治疗前水平(P<0.05),且第12周指标血清浓度低于第4周血清浓度(P<0.05)。而对照组以上指标无明显变化。尚不能认为低密度脂蛋白水平异常对于阿托伐他汀的降血清sCD40L浓度作用有影响。结论阿托伐他汀能够显著降低颈动脉粥样硬化患者血清sCD40L浓度,具有除调脂作用外抗动脉粥样硬化的作用。     

The effects of converting from simvastatin to atorvastatin on plasminogen activator inhibitor type-1.

Plasminogen activator inhibitor type-1 (PAI-1) is an important regulatory component of fibrinolysis and is elevated in the presence of endothelial dysfunction. Endothelial dysfunction and PAI-1 in patients with coronary artery disease (CAD) have been demonstrated to improve following simvastatin therapy. The effect of converting from simvastatin to atorvastatin on PAI-1 has not been reported and may be an additional consideration when making a formulary medication switch. Fourteen adult patients with hypercholesterolemia and CAD who were receiving simvastatin for a minimum of 3 months were randomized to continue on simvastatin or be converted to atorvastatin. Doses were adjusted to achieve or sustain a low-density lipoprotein (LDL) cholesterol of < or = 100 mg/dL. A fasting lipid panel and PAI-1 were obtained at baseline and following 10 weeks of treatment. Mean +/- SD LDL cholesterol at baseline (95.6 +/- 13.8 vs. 87.0 +/- 12.3 dL, p = 0.24) and following 10 weeks of simvastatin or atorvastatin (96.6 +/- 8.9 vs. 87.4 +/- 20.3 mg/dL, p = 0.29) were similar. No differences in PAI-1 were observed at baseline (47.7 +/- 19.3 vs. 64.6 +/- 22.2 ng/mL, p = 0.15) or at 10 weeks (51.1 +/- 32.5 vs. 63.9 +/- 26.9 ng/mL, p = 0.44). These data suggest that the conversion from simvastatin to atorvastatin does not adversely affect PAI-1 plasma concentrations in patients with CAD.     

Impact of short‐term low‐dose atorvastatin on low‐density lipoprotein and high‐density lipoprotein subfraction phenotype

Statins can significantly reduce low‐density lipoprotein–cholesterol (LDL‐C) and modestly raise or not alter high‐density lipoprotein–cholesterol (HDL‐C). However, their impact on high‐density lipoprotein (HDL) and low‐density lipoprotein (LDL) subfractions has been less examined. The aim of the present study was to investigate the short‐term impact of low‐dose atorvastatin on HDL and LDL subfractions in humans. In this randomized study, data from 52 subjects were analysed. Thirty‐seven patients with atherosclerosis were randomized to treatment with atorvastatin 10 mg/day (n = 17) or 20 mg/day (n = 20) for 8 weeks, with 15 healthy subjects without therapy used as a control group. The lipid profile and lipoprotein subfractions were determined using the Lipoprint system at baseline and at 8 weeks. The data suggest that atorvastatin treatment (10 and 20 mg/day) for 8 weeks significantly decreases LDL‐C levels and reduces the cholesterol concentration of all LDL subfractions, which is accompanied by an increase of the mean LDL particle size. Although 10 mg/day atorvastatin treatment for 8 weeks had no impact on the HDL subfraction, 20 mg/day atorvastatin for 8 weeks significantly increased the cholesterol concentration of large HDL particles and decreased the cholesterol concentration of small HDL particles without changing serum HDL‐C levels in patients with atherosclerosis. Therefore, the results suggest that 20 mg/day atorvastatin treatment for 8 weeks may result in a favourable modification of the HDL subfraction phenotype in addition to its effects on the cholesterol concentration of all LDL subfractions and mean LDL particle size.     

Cholesterol-lowering effect of NK-104, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, in guinea pig model of hyperlipidemia

Although benefits of statins have been demonstrated even in normolipidemic patients at high risk, the main target of statin therapy is the hypercholesterolemic patient. The aim of this study was to examine the hypocholesterolemic effect of NK-104 ((+)-monocalcium bis((3R,5S,6S)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]- 3,5-dihydroxy-6-heptenoate), CAS 147526-32-7), a potent 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, and its mechanism of action in hypercholesterolemic animals. In guinea pigs fed a diet containing 15% (w/w) fat rich in laurate for 6 weeks, the liver cholesterol content was markedly increased and plasma total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and LDL-apoB were elevated 4.8, 5.2 and 1.7 times, respectively, compared with normal diet fed animals. These changes were maintained by reduced LDL clearance in the presence of markedly cholesterol-enriched LDL in the plasma. In this model, the LDL-C reduction rates by 0.1, 0.3 and 1 mg/kg of NK-104 orally administered for 2 weeks (from week 4 to week 6), were 11, 27 and 32%, respectively, from controls, being similar in normal guinea pigs previously examined. Those for 3 and 10 mg/kg of atorvastatin (CAS 134523-00-5) were 25 and 39%, respectively. Thus about 10 times higher doses of atorvastatin were required than of NK-104 to cause a similar cholesterol-lowering effect. This reduction of plasma cholesterol was accompanied by an improvement of LDL clearance (24 and 47% increase in fractional catabolic rate by 1 mg/kg of NK-104 and 10 mg/kg of atorvastatin, respectively) and LDL composition. In conclusion, in guinea pig hypercholesterolemia caused by high-laurate diet, NK-104 and atorvastatin lowered plasma cholesterol levels with an improvement of LDL composition and with an increase in LDL clearance, presumably through reduction of the liver cholesterol content, although hepatic cholesterol synthesis might have been markedly suppressed in this model.     

瑞舒伐他汀对急性心肌梗死患者血清炎症因子和脂联素水平的影响

目的比较瑞舒伐他汀与阿托伐他汀对急性心肌梗死（AMI）患者的血清胆固醇（TC）、低密度脂蛋白（LDL-C）、高敏c反应蛋白（hs-CRP）、可溶性白细胞分化抗原40配体（sCD40L）和脂联素（APN）水平的影响。方法选择54例AMI患者,随机分为瑞舒伐他汀组（瑞舒伐他汀10～20mg,qd,28例）和阿托伐他汀组（阿托伐他汀20-40mg,qa,26例）,分别检测治疗前及治疗4周后2组患者TC、LDL-C、hs—CRP、sCD40L和APN水平。结果瑞舒伐他汀组和阿托伐他汀组治疗后血清,TC、LDL-C、hs-CRP、sCD40L水平较治疗前明显降低,APN水平明显升高,差异有统计学意义（P〈0．05）。治疗4周后瑞舒伐他汀组血清hs-CRP、sCD40L水平与阿托伐他汀组相比明显降低,APN水平明显升高,差异有统计学意义（P〈0．05）。结论瑞舒伐他汀和阿托伐他汀都能降低TC、LDL-C、sCD40L、hs—CRP水平,升高APN水平,但瑞舒伐他汀治疗急性心肌梗死的效果明显优于阿托伐他汀。     

Long-term impact of a community pharmacist intervention on cholesterol levels in patients at high risk for cardiovascular events: extended follow-up of the second study of cardiovascular risk intervention by pharmacists (SCRIP-plus)

STUDY OBJECTIVE: To determine the effect of a community pharmacist intervention in patients at high risk for coronary heart disease on low-density lipoprotein cholesterol (LDL) levels 1 year after completion of the Second Study of Cardiovascular Risk Intervention by Pharmacists (SCRIP- plus ). METHODS: Patients who completed the original study were invited to make a single return visit to their community pharmacy so that the pharmacist could measure their fasting LDL level using a point-of-care device. The primary outcome was change in LDL level from the 6-month (final) visit to the extended follow-up evaluation. RESULTS: Of the 359 patients who completed the original 6-month visit, data were collected for 162 (45%) patients. The mean +/- SD LDL level at completion of the original study was 107.9 +/- 33.6 mg/dl (2.79 +/- 0.96 mmol/L) (an increase of 2.7 mg/dl [0.07 mmol/L], 95% confidence interval -19.3-7.3 [-0.5-0.19]). Sixty-one (38%) patients were at the target LDL level (< 96.7 mg/dl [< 2.50 mmol/L]). CONCLUSION: The LDL reduction was maintained 1 year after completion of the extended follow-up. Since most patients were still not at the target LDL level, this finding suggests that continuing intervention is necessary to help patients reach this target.     

阿托伐他汀对不稳定型心绞痛患者血脂与血管内皮功能的影响

目的观察阿托伐他汀对不稳定型心绞痛患者的血脂、血管内皮生长因子（VEGF）和NO的影响。方法选择2011年5—12月不稳定型心绞痛患者30例,口服阿托伐他汀片40mg／次,1次／d,连用60d。分别于清晨空腹抽取治疗前和治疗60d后患者的肘静脉血,检测血清TC、LDL—C、HDL—C、TG、VEGF和NO的水平,比较治疗前后的变化。结果阿托伐他汀治疗60d后患者TC、LDL—C、TG水平较治疗前明显降低,差异有统计学意义[TC：（4．7±0．9）mmol／L比（7．0±0．5）mmol／L,LDL—C：（2．85±0．57）mmol／L比（4．45±0．26）mmoL／L,TG：（1．8±0．5）mmoL／L比（2．6±0．3）nllno]／／L,均P〈0．01];HDL—C、VEGF和NO水平较治疗前明显升高,差异有统计学意义[HDL—C：（1．49-4-0．13）mmol／L比（1．32±0．15）mmol／L,VEGF：（308±47）ng／L比（17±22）ng／L,NO：（82±13）txmol／L比（61±9）mmol／L,均P〈0．01]。结论阿托伐他汀治疗不稳定型心绞痛不仅具有降脂作用,而且对改善血管内皮功能具有重要意义。     

Ciprofibrate increases plasma concentration of platelet-derived growth factor AB in patients with advanced atherosclerosis and hyperlipidemia independently of its hypolipidemic effects

Fibrates, besides their hypolipidemic action, share alternative effects, such as decreased plasma fibrinogen and uric acid levels. Because of their complex action, additional effects have been investigated. A group of 23 patients with clinical signs of atherosclerosis and hyperlipoproteinemia was randomly allocated after a 1-month washout period and treated with either 100 mg/d of ciprofibrate or 100 mg/d of aspirin for 2 months. Patients were then treated with a combination of these two agents for the next 2 months. Ciprofibrate decreased plasma concentrations of triglycerides (-29%) and very-low-density lipoprotein cholesterol (-27%) in monotherapy and a larger reduction was observed if ciprofibrate was added to the aspirin therapy: triglycerides (-39%), very-low-density lipoprotein cholesterol (-33%), total cholesterol (-18%), low-density lipoprotein cholesterol (-17%), and increased high-density lipoprotein cholesterol (+36%). Ciprofibrate increased plasma levels of platelet-derived growth factor (PDGF) AB in both monotherapy patients (+162.9 pg/ml, +297%) and in aspirin-pretreated patients (+129.8 pg/ml, +134%); the increase of PDGF AB platelet store was significant only in aspirin-pretreated patients (+11.1 ng/ml, +51%). Aspirin in monotherapy did not modulate either plasma or platelet store of PDGF AB. Ciprofibrate did not inhibit thromboxane B 2 synthesis in platelets. Aspirin did not influence plasma thromboxane B 2 concentration at all, whereas it decreased thromboxane B 2 platelet production markedly in monotherapy (-85%) and in combination with ciprofibrate (-91%). Ciprofibrate increases PDGF AB content, which is amplified by aspirin pretreatment without correlation with its hypolipidemic action. The increase of PDGF production is suggested to participate in plaque stabilization.     

Short-term atorvastatin treatment improves endothelial function in hypercholesterolemic women

Endothelial dysfunction represents the earliest stage of atherosclerosis and is usually present in hypercholesterolemia. Treatment with statins has been shown to normalize endothelial function in middle-aged men with hypercholesterolemia. We evaluated the effect over time of atorvastatin on the endothelial reactivity in postmenopausal hypercholesterolemic women (mean age, 58 +/- 6 years), receiving atorvastatin, 10 mg daily (n = 20) or American Heart Association step 1 diet (n = 10) for 8 weeks. Lipid profile and brachial artery flow-mediated vasodilation (FMV) were determined at baseline and after 1, 2, 4, and 8 weeks. FMV increased progressively in subjects treated with atorvastatin, and the difference was significant (p < 0.05 vs. baseline) after the second week (baseline 3.8 +/- 3%; first week, 4.8 +/- 3%; second week, 9.2 +/- 3%; fourth week, 11.0 +/- 3%; eighth week, 11.7 +/- 3%). No significant changes were observed in subjects receiving diet (baseline, 3.1 +/- 4%; first week, 2.4 +/- 2%; second week, 2.9 +/- 2%; fourth week, 3.1 +/- 2%; eighth week, 3.3 +/- 2%; p = NS). In the atorvastatin group, low-density lipoprotein (LDL) cholesterol showed a significant decrease since the first week (baseline, 228 +/- 37 mg/dl; first week, 171 +/- 32; second week, 147 +/- 27; fourth week, 139 +/- 29; eighth week, 135 +/- 27; all p < 0.05). In the control group, LDL cholesterol showed a smaller but significant (p < 0.05) reduction after the second week (baseline, 226 +/- 17 mg/dl; first week, 225 +/- 16; second week, 220 +/- 17; fourth week, 203 +/- 27; eighth week, 198 +/- 27). In conclusion, hypercholesterolemic women treated with atorvastatin show a significant improvement in endothelial reactivity after as early as 2 weeks of therapy. The extent to which these beneficial effects are attributable to cholesterol reduction or to a direct effect of the drug remains to be established.     

Hypocholesterolemic effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in the guinea pig: atorvastatin versus simvastatin.

Male Hartley guinea pigs were fed a hypercholesterolemic diet rich in lauric and myristic acids with 0, 10, or 20 mg/kg of simvastatin or atorvastatin for 21 days. Atorvastatin and simvastatin resulted in a lowering of plasma low-density lipoprotein (LDL) cholesterol in a dose-dependent manner by an average of 48 and 61% with 10 and 20 mg/kg, respectively. Both statins were equally effective in lowering plasma LDL cholesterol and apolipoprotein B (apo-B) levels. Atorvastatin and simvastatin treatments yielded LDL particles that differed in composition from the control. Due to the relevance of LDL oxidation and cholesteryl ester transfer in plasma to the progression of atherosclerosis, these parameters were analyzed after statin treatment. Atorvastatin and simvastatin treatment decreased the susceptibility of LDL particles to oxidation by 95% as determined by the formation of thiobarbituric acid reactive substances. An 80% decrease in the transfer of cholesteryl ester between high-density lipoprotein (HDL) and the apo-B-containing lipoproteins was observed after simvastatin and atorvastatin treatment. In addition, statin effects on plasma LDL transport were studied. Simvastatin- and atorvastatin-treated guinea pigs exhibited 125 and 175% faster LDL fractional catabolic rates, respectively, compared with control animals. No change in LDL apo-B flux was induced by either treatment; however, LDL apo-B pool size was reduced after statin treatment. Hepatic microsomal free cholesterol was lower in the atorvastatin and simvastatin groups. However, only atorvastatin treatment resulted in an 80% decrease of acyl-CoA:cholesterol acyltransferase activity (P < 0.001). In summary, atorvastatin and simvastatin had similar LDL cholesterol lowering properties, but these drugs modified LDL transport and hepatic cholesterol metabolism differently.     

Treatment of type IIb familial combined hyperlipidemia with the combination pravastatin-piperazine sultosilate

The risk of coronary heart disease is increased for any given low-density lipoprotein (LDL) cholesterol level in patients with high levels of triglycerides because some triglyceride-rich lipoproteins are atherogenic. This paper reports the results of a pilot clinical trial aimed to evaluate a novel triglyceride-lowering drug in combination with pravastatin to treat combined hyperlipidemia. Twenty-six patients with type 2b hyperlipoproteinemia were randomized to receive pravastatin 40 mg/day or pravastatin 40 mg/day plus piperazine-sultosilate 1000 mg/day for 12 weeks if their cholesterol levels, but not triglyceride levels, had responded to therapeutic lifestyle changes and treatment with 40 mg/day of pravastatin. Concentrations of triglycerides, cholesterol and apolipoproteins A and B were measured in duplicate before and after the intervention. There were no significant differences between groups in the change from baseline in the concentration of serum triglycerides. Conversely, significant differences were found for LDL cholesterol, which increased slightly with pravastatin alone but decreased with the combination (12.605+/-22.777% vs. -6.396+/-13.157%, respectively; p=0.022). Apolipoprotein-B levels increased with pravastatin alone but remained stable with the combined treatment (10.464+/-8.446% vs. 0.767+/-12.335%; P=0.028). The increase in the pravastatin group was significant. Although sultosilate was not efficacious in reducing triglycerides, it helped to decrease the concentration of small, dense, atherogenic LDL particles that are less receptor-sensitive and which could accumulate during long-term statin therapy in patients with high levels of triglycerides.     

Postsynaptic alpha 1-blockade with terazosin does not modify insulin sensitivity in nonobese normotensive subjects.

Plasma insulin levels and the sensitivity of peripheral tissue to insulin (SI) have pathophysiological, therapeutic, and possibly also prognostic relevance. To investigate the effects of short-term selective alpha 1-adrenergic receptor blockade in nonobese normotensive humans on glucose and lipoprotein homeostasis, we assessed SI (determined by the minimal model method of Bergman), before and after glucose load plasma, glucose, and insulin levels, serum total triglycerides and lipoprotein cholesterol fractions, and some other variables in 20 healthy young men (26 +/- 1 years old, mean +/- SEM) during placebo and after 5 weeks of terazosin administration at a dose up to 10 mg once daily. Measurements were made after 3 days of standard diet (2,500 kcal/day, 45% carbohydrates, 40% fat, and 15% proteins) and after an overnight fast. Compared to placebo, terazosin decreased the upright systolic blood pressure (placebo vs. terazosin: 125 +/- 2 vs. 117 +/- 2 mm Hg, p less than 0.05) and increased supine (63 +/- 2 vs. 70 +/- 1 beats/min, p less than 0.05) and upright (77 +/- 2 vs. 88 +/- 2 beats/min, p less than 0.01) heart rates, while the body weight was unaltered. Terazosin did not significantly modify fasting plasma glucose (5.08 +/- 0.09 vs. 5.23 +/- 0.08 mmol/L, respectively), or insulin (8.9 +/- 0.5 vs. 8.6 +/- 0.6 microU/ml), SI (14.3 +/- 1.8 vs 11.8 +/- 1.5 x 10(-4)/min/microU/ml), the areas under the insulin or glucose curves, serum total triglycerides, and cholesterol or lipoprotein cholesterol fractions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of fenofibrate and simvastatin on plasma sICAM-1 and MCP-1 concentrations in patients with hyperlipoproteinemia

OBJECTIVE: The most important mechanism through which high plasma lipid levels trigger the formation of atherosclerotic lesions involves a change in the expression of adhesion molecules on endothelial and smooth muscle cells. The aim of this study was to evaluate an extralipid effect of fenofibrate and simvastatin by examination of MCP-1 and ICAM-1 plasma concentration after 1-month hypolipemic therapy as well as MCP-1 and ICAM-1 plasma concentration after 1-month therapy with low-fat diet alone. METHODS: Twenty patients with HLPIIb or HLPIIa, who did not respond to a low-fat diet, were treated with micronized fenofibrate or simvastatin, respectively, for 1 month. The control group included 18 normo-lipidemic, healthy age-matched participants; 10 patients with HLPIIa were effectively treated with a low-fat diet for 1 month. This group was compared to a control group of 10 healthy subjects. The plasma adhesion molecule levels were measured by an ELISA method before and after the treatment. To accurately evaluate the adhesion molecule levels, we excluded hyperlipidemic patients and control subjects with any inflammatory disease. RESULTS: sICAM-1 levels were significantly higher in HLPIIa and HLPIIb patients (331 +/- 19 ng/ml and 423 +/- 23 ng/ml, respectively) compared with the control group (236 +/- 12 mg/ml). MCP-1 levels were also significantly higher in HLPIIa and HLPIIb patients (170 +/- 9 pg/ml and 183 +/- 15 pg/ml, respectively) compared with the control group (100 +/- 4 pg/ml). Fenofibrate (200 mg daily) significantly decreased sICAM-1 (by 17%) and MCP-1 levels (by 12.5%). Simvastatin (20 mg daily) caused a significant decrease (by 10.5%) in sICAM-1 levels only. Restriction in dietary lipids resulted in a significant decrease in the levels of cholesterol (8%), LDL cholesterol (14.9%) and ApoB (12.7%), which was accompanied by a significant decrease in the levels of sICAM-1 (8.7%) and MCP-1 (16.1%). CONCLUSION: The results of this study suggest that high lipid levels are accompanied by increased levels of sICAM-1 and MCP-1 and that hypolipidemic therapy only slightly decreases the levels of these molecules compared with plasma lipids. The hypolipidemic diet-related decrease in the levels of lipids, ICAM-1 and MCP-1 suggests that it is a drug-induced decrease in lipid levels but not a direct action of the drugs on endothelial cells, smooth muscle cells or macrophages that leads to a decrease in the levels of adhesion molecules.