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Results for “Simvastatin”

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PubMed1998

Grapefruit juice-simvastatin interaction: effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors.

BACKGROUND: Simvastatin is a cholesterol-lowering agent that is metabolized through CYP3A4. We studied the effect of grapefruit juice on the pharmacokinetics of orally administered simvastatin. METHODS: In a randomized, 2-phase crossover study, 10 healthy volunteers took either 200 mL double-strength grapefruit juice or water 3 times a day for 2 days. On day 3, each subject ingested 60 mg simvastatin with either 200 mL grapefruit juice or water, and an additional 200 mL was ingested 1/2 and 1 1/2 hours after simvastatin administration. Serum concentrations of simvastatin and simvastatin acid were measured by liquid chromatography-tandem mass spectrometry (LC-MS-MS) and those of active (naive) and total (after hydrolysis) 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors by a radioenzyme inhibition assay. RESULTS: Grapefruit juice increased the mean peak serum concentration (Cmax) of unchanged simvastatin about 9-fold (range, 5.1-fold to 31.4-fold; P < .01) and the mean area under the serum simvastatin concentration-time curve [AUC(0-infinity)] 16-fold (range, 9.0-fold to 37.7-fold; P < .05). The mean Cmax and AUC(0-infinity) of simvastatin acid were both increased about 7-fold (P < .01). Grapefruit juice increased the mean AUC(0-infinity) of active and total HMG-CoA reductase inhibitors 2.4-fold (P < .01) and 3.6-fold (P < .01), respectively. The time of the peak concentration of active and total HMG-CoA reductase inhibitors was increased by grapefruit juice (P < .05). CONCLUSION: Grapefruit juice greatly increased serum concentrations of simvastatin and simvastatin acid and, to a lesser extent, those of active and total HMG-CoA reductase inhibitors. The probable mechanism of this interaction was inhibition of CYP3A4-mediated first-pass metabolism of simvastatin by grapefruit juice in the small intestine. Concomitant use of grapefruit juice and simvastatin, at least in large amounts, should be avoided, or the dose of simvastatin should be greatly reduced.

Adult↗

PubMed2005

Comparison of ezetimibe plus simvastatin versus simvastatin monotherapy on atherosclerosis progression in familial hypercholesterolemia. Design and rationale of the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial.

BACKGROUND: Lipid lowering through statin therapy significantly reduces the risk of cardiovascular events. The ENHANCE study is an international 2-year, randomized, double-blind, controlled trial designed to test the hypothesis that treatment of hypercholesterolemia by use of 2 complementary agents, ezetimibe (a specific cholesterol absorption inhibitor) and simvastatin (a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor), will result in larger beneficial effects on carotid artery intima-media thickness (CA IMT) than simvastatin monotherapy. METHODS: The study will recruit 725 men and women with heterozygous familial hypercholesterolemia. After a placebo washout period, participants are randomized to receive daily administration of either simvastatin 80 mg and ezetimibe 10 mg or simvastatin 80 mg and placebo. The ENHANCE trial uses novel state-of-the-art single-frame digital image acquisition and rigorous quality assurance and control. RESULTS: The primary end point is mean change from baseline to 2 years in CA IMT, using composite measures from the right and left far wall common carotid artery, carotid bulb, and internal carotid artery. Secondary end points include (1) the proportion of participants who exhibit reductions in CA IMT, (2) the change in maximum far wall IMT, (3) the proportion of participants who develop new carotid artery plaques, and (4) the changes in carotid plus common femoral artery IMT. CONCLUSIONS: This study addresses the question of whether a regimen that uses drugs with different mechanisms of action will be of further benefit in terms of atherosclerosis reduction compared to statin monotherapy.

Adult↗

PubMed2004

Treatment of high-risk patients with ezetimibe plus simvastatin co-administration versus simvastatin alone to attain National Cholesterol Education Program Adult Treatment Panel III low-density lipoprotein cholesterol goals.

This study assessed whether the co-administration of ezetimibe and simvastatin would be more effective than simvastatin monotherapy in allowing high-risk patients to achieve a low-density lipoprotein (LDL) cholesterol goal of <100 mg/dl. Men and women with LDL cholesterol >/=130 mg/dl and meeting National Cholesterol Education Program Adult Treatment Panel III criteria for coronary heart disease (CHD) or CHD risk equivalent were randomized to 1 of 4 daily treatments for 23 weeks: simvastatin 20 mg (n = 253), ezetimibe 10 mg plus simvastatin 10 mg (n = 251), ezetimibe 10 mg plus simvastatin 20 mg (n = 109), and ezetimibe 10 mg plus simvastatin 40 mg (n = 97). In all groups, patients not at goal had their simvastatin doses doubled at weeks 6, 12, and/or 18, up to a maximum of 80 mg. The primary efficacy objective was LDL cholesterol goal attainment (<100 mg/dl) after 5 weeks of treatment. Ezetimibe plus any dose of simvastatin produced greater reductions in LDL cholesterol and allowed more patients to achieve goal after 5 weeks (p <0.001) and at the end of the study (p <0.001) than simvastatin 20 mg alone. At 5 weeks, 75%, 83%, and 87% of patients receiving ezetimibe plus simvastatin 10, 20, and 40 mg had LDL cholesterol <100 mg/dl compared with 46% of patients receiving simvastatin 20 mg. In patients who started on ezetimibe plus simvastatin 10, 20 and 40 mg, 33%, 22%, and 12%, respectively, required simvastatin titration during the study compared with 68% of patients who started on simvastatin 20 mg. The corresponding median simvastatin doses used were 10, 20, 40, and 40 mg, respectively. Ezetimibe plus simvastatin was well tolerated, with an overall safety profile similar to that of simvastatin monotherapy. Thus, through the dual inhibition of cholesterol absorption and synthesis, ezetimibe plus simvastatin allowed more patients to reach LDL cholesterol <100 mg/dl at a lower simvastatin dose and with fewer dose titrations than simvastatin monotherapy.

Adult↗

PubMed2000

Rifampin greatly reduces plasma simvastatin and simvastatin acid concentrations.

BACKGROUND: Rifampin (rifampicin) is a potent inducer of several cytochrome P450 (CYP) enzymes, including CYP3A4. The cholesterol-lowering drug simvastatin has an extensive first-pass metabolism, and it is partially metabolized by CYP3A4. This study was conducted to investigate the effect of rifampin on the pharmacokinetics of simvastatin. METHODS: In a randomized cross-over study with two phases and a washout of 4 weeks, 10 healthy volunteers received a 5-day pretreatment with rifampin (600 mg daily) or placebo. On day 6, a single 40-mg dose of simvastatin was administered orally. Plasma concentrations of simvastatin and its active metabolite simvastatin acid were measured up to 12 hours with a sensitive liquid chromatography-ion spray tandem mass spectrometry method. RESULTS: Rifampin decreased the total area under the plasma concentration-time curve of simvastatin and simvastatin acid by 87% (P < .001) and 93% (P < .001), respectively. Also the peak concentrations of both simvastatin and simvastatin acid were reduced greatly (by 90%) by rifampin (P < .001). On the other hand, rifampin had no significant effect on the elimination half-life of simvastatin or simvastatin acid. CONCLUSIONS: Rifampin greatly decreases the plasma concentrations of simvastatin and simvastatin acid. Because the elimination half-life of simvastatin was not affected by rifampin, induction of the CYP3A4-mediated first-pass metabolism of simvastatin in the intestine and the liver probably explains this interaction. Concomitant use of potent inducers of CYP3A4 can lead to a considerably reduced cholesterol-lowering efficacy of simvastatin.

Adult↗

PubMed2003

Carbamazepine markedly reduces serum concentrations of simvastatin and simvastatin acid.

OBJECTIVE: The aim of this study was to examine the effect of carbamazepine on the pharmacokinetics of orally administered simvastatin in healthy volunteers. METHODS: In a randomised, two-phase crossover study and a wash out of 2 weeks, 12 healthy volunteers took carbamazepine for 14 days (600 mg daily except 200 mg daily for the first 2 days) or no drug. On day 15, each subject ingested 80 mg simvastatin. Serum concentrations of simvastatin and its active metabolite simvastatin acid were measured up to 24 h. RESULTS: Carbamazepine decreased the mean total area under the serum concentration-time curve of simvastatin and simvastatin acid by 75% ( P<0.001) and 82% ( P<0.001), respectively. The mean peak concentrations of both simvastatin and simvastatin acid were reduced by 68% ( P<0.01), and half-life of simvastatin acid was shortened from 5.9+/-0.3 h to 3.7+/-0.5 h ( P<0.01) by carbamazepine. CONCLUSION: Carbamazepine greatly reduces the serum concentrations of simvastatin and simvastatin acid, probably by inducing their metabolism. Concomitant administration of carbamazepine and simvastatin should be avoided or the dose of simvastatin should be considerably increased.

Adolescent↗

PubMed1998

Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations.

OBJECTIVE: To study the effects of erythromycin and verapamil on the pharmacokinetics of simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. METHODS: A randomized, double-blind crossover study was performed with three phases separated by a washout period of 3 weeks. Twelve young, healthy volunteers took orally either 1.5 gm/day erythromycin, 240 mg/day verapamil, or placebo for 2 days. On day 2, 40 mg simvastatin was administered orally. Serum concentrations of simvastatin, simvastatin acid, erythromycin, verapamil, and norverapamil were measured for up to 24 hours. RESULTS: Erythromycin and verapamil increased mean peak serum concentration (Cmax) of unchanged simvastatin 3.4-fold (p < 0.001) and 2.6-fold (p < 0.05) and the area under the serum simvastatin concentration-time curve from time zero to 24 hours [AUC(0-24)] 6.2-fold (p < 0.001) and 4.6-fold (p < 0.01). Erythromycin increased the mean Cmax of active simvastatin acid fivefold (p < 0.001) and the AUC(0-24) 3.9-fold (p < 0.001). Verapamil increased the Cmax of simvastatin acid 3.4-fold (p < 0.001) and the AUC(0-24) 2.8-fold (p < 0.001). There was more than tenfold interindividual variability in the extent of simvastatin interaction with both erythromycin and verapamil. CONCLUSIONS: Both erythromycin and verapamil interact considerably with simvastatin, probably by inhibiting its cytochrome P450 (CYP) 3A4-mediated metabolism. Concomitant administration of erythromycin, verapamil, or other potent inhibitors of CYP3A4 with simvastatin should be avoided. As an alternative, the dosage of simvastatin should be reduced considerably, that is, by about 50% to 80%, at least when a simvastatin dosage higher than 20 mg/day is used. Possible adverse effects, such as elevation of creatine kinase level and muscle tenderness, should be closely monitored when such combinations are used.

Adult↗

PubMed2000

Direct-injection LC-MS-MS method for high-throughput simultaneous quantitation of simvastatin and simvastatin acid in human plasma.

A direct-injection liquid chromatography-mass spectrometry-mass spectrometry (LC-MS-MS) method was developed and validated for the simultaneous quantitation in human plasma of the widely used cholesterol-lowering prodrug simvastatin and its in vivo generated active drug, simvastatin acid. The plasma samples were injected into the LC-MS-MS system after simply adding the internal standard solution in an aqueous buffer and centrifuging. The analytes in the buffered plasma samples were found to be stable for at least 24 h at 4 degrees C. The method was successfully validated under the challenging condition of using a large number of quality control (QC) samples including those in which the ratio of the simvastatin concentration to the simvastatin acid concentration was different from the concentration ratio in the calibration curve standards. Under the dual stabilizing conditions of lower temperature (4 degrees C) and lower plasma pH of 4.9, the in-process hydrolysis of simvastatin to simvastatin acid or the lactonization of simvastatin acid to simvastatin was minimized to < or = 1.0%. Although the entire run time for on-line cleanup and analysis was only 2.5 min, chromatographic base-line separation of simvastatin from simvastatin acid, which was required to avoid the interference by simvastatin acid with the simvastatin selected reaction monitoring channel, was achieved. The desired lower limit of quantitation of 0.5 ng/ml was achieved by injecting only an equivalent of 8.0 microl of the plasma sample. The extraction column lasted for at least 500 injections.

Anticholesteremic Agents↗

PubMedDate not supplied

Reduced coronary events in simvastatin-treated patients with coronary heart disease and diabetes or impaired fasting glucose levels: subgroup analyses in the Scandinavian Simvastatin Survival Study.

BACKGROUND: Patients with diabetes mellitus (DM) have a marked increase in coronary heart disease (CHD) events relative to those without DM. In a previous report from the Scandinavian Simvastatin Survival Study using a clinical case definition of DM (n = 202), simvastatin-treated patients had significantly fewer CHD events compared with placebo-treated control subjects. OBJECTIVE: To examine the effect of simvastatin therapy on CHD in patients with DM and impaired fasting glucose levels. METHODS: Using the 1997 American Diabetes Association diagnostic criteria, we assessed the effect of simvastatin therapy post hoc for an average of 5.4 years in Scandinavian Simvastatin Survival Study patients with normal fasting glucose (n = 3237), impaired fasting glucose (n = 678), and DM (n = 483). RESULTS: Simvastatin-treated patients with DM had significantly reduced numbers of major coronary events (relative risk [RR] = 0.58; P = .001) and revascularizations (RR = 0.52; P = .005). Total (RR = 0.79; P = .34) and coronary (RR = 0.72; P = .26) mortality were also reduced in DM, but not significantly, due to small sample size. In impaired fasting glucose (IFG) subjects, simvastatin use significantly reduced the number of major coronary events (RR = 0.62; P = .003), revascularizations (RR = 0.57; P = .009), and total (RR = 0.57; P = .02) and coronary (RR = 0.45; P = .007) mortality. CONCLUSION: Our results extend previous findings in patients with DM to a larger cohort, confirming the benefit of cholesterol lowering with simvastatin treatment on CHD events. In addition, significant decreases in total mortality, major coronary events, and revascularizations were observed in simvastatin-treated patients with impaired fasting glucose levels. These results strongly support the concept that cholesterol lowering with simvastatin therapy improves the prognosis of patients with elevated fasting glucose levels (> or =6.0 mmol/L [> or =110 mg/ dL]) or DM and known CHD.

Anticholesteremic Agents↗

PubMed1999

Effect of simvastatin treatment on cardiovascular resource utilization in impaired fasting glucose and diabetes. Findings from the Scandinavian Simvastatin Survival Study.

OBJECTIVE: The Scandinavian Simvastatin Survival Study showed that simvastatin treatment reduced cardiovascular events in hypercholesterolemic subjects with coronary heart disease. The clinical benefits of therapy were similar in all three subgroups: normal fasting glucose (NFG, n = 3,237), impaired fasting glucose (IFG, n = 678), and diabetes (n = 483). This analysis compared the costs of simvastatin treatment with the costs of cardiovascular disease-related hospitalizations in the three subgroups. RESEARCH DESIGN AND METHODS: The cost of simvastatin treatment was defined as the average retail price and the cost of drug safety monitoring and adverse experiences. The costs of cardiovascular disease-related hospitalizations were determined by actual rates of hospitalization and 1995 MEDSTAT diagnosis-related group costs. RESULTS: Within trial, simvastatin treatment cost approximately $6,000 per patient. Simvastatin treatment reduced cardiovascular disease-related hospitalizations by 23% in NFG (P = 0.001), 30% in IFG (P = 0.015), and 40% in diabetic subjects (P = 0.007) within trial (median follow-up of 5.4 years). Average length of stay was reduced by 2.4 days in diabetic subjects (P = 0.021). Total cardiovascular disease-related hospital days were reduced by 28% (P < 0.001) in NFG, 38% (P = 0.005) in IFG, and 55% (P < 0.001) in diabetic subjects. For NFG subjects, simvastatin reduced the average cost of cardiovascular disease-related hospitalizations by $3,585, which offset 60% of the cost of simvastatin therapy. For IFG subjects, average cardiovascular disease-related hospitalization costs were reduced by $4,478, which offset 74% of the drug cost. For diabetic subjects, there was a net cost savings of $1,801 per subject within trial. CONCLUSIONS: Simvastatin significantly reduced cardiovascular disease-related hospitalizations and total hospital days for all three groups and significantly reduced length of stay for the diabetic group in addition to providing significant clinical benefits. The benefits were greatest in the diabetic group, with estimated cost savings within trial from simvastatin treatment.

Cardiovascular Diseases↗

PubMed2006

Effect of combined simvastatin and cyclosporine compared with simvastatin alone on cerebral vasospasm after subarachnoid hemorrhage in a canine model.

OBJECT: The object of this study was to determine whether the combination of cyclosporine and simvastatin could ameliorate cerebral vasospasm after subarachnoid hemorrhage (SAH) in a canine model to a greater extent than simvastatin alone. METHODS: Animals were assigned to one of three groups: control (five dogs), simvastatin alone (four), or simvastatin and cyclosporine (four). A double SAH model was used. Baseline basilar artery (BA) angiograms were obtained. These were repeated at Days 3, 7, and 10. Measurement of the BA diameter was performed. Decreased BA diameter was seen on Day 3 in the control and simvastatin/cyclosporine group. A return to baseline diameters was seen by Day 7. An increase from baseline diameter was seen in the simvastatin group at Day 10. CONCLUSIONS: Cyclosporine may interfere with the vasodilatory effects of simvastatin. Vasodilation greater than baseline is seen at Day 10 in the simvastatin group. The combination of simvastatin and cyclosporine does not ameliorate cerebral vasospasm in a canine model to a greater extent than simvastatin alone.

Analysis of Variance↗

PubMed1992

Effect of simvastatin, ursodeoxycholic acid and simvastatin plus ursodeoxycholic acid on biliary lipid secretion and cholic acid kinetics in nonfamilial hypercholesterolemia.

It has been recently shown that the newest hypocholesterolemic agent, simvastatin, lowers the biliary cholesterol saturation index and that its association with ursodeoxycholic acid renders it more effective. To determine the mechanism by which simvastatin decreases the biliary cholesterol saturation index, we evaluated hepatic secretion rates of cholesterol, bile acids and phospholipids, and cholic acid pool size, turnover and synthesis in eight hyperlipidemic patients (five women and three men, age range = 38 to 65 yr). These assessments were conducted before treatment, after 4 wk of simvastatin (40 mg/day), after 4 wk of ursodeoxycholic acid (600 mg/day) and after a further 4 wk of a combination therapy of simvastatin (40 mg/day) plus ursodeoxycholic acid (600 mg/day). The cholesterol saturation index was significantly reduced with simvastatin (from 1.51 +/- 0.10 to 0.94 +/- 0.05, mean +/- S.E.; p less than 0.02), with ursodeoxycholic acid (from 1.51 +/- 0.10 to 0.86 +/- 0.03, mean +/- S.E.; p less than 0.02) and with the combination of simvastatin plus ursodeoxycholic acid (from 1.51 +/- 0.01 to 0.70 +/- 0.05, p less than 0.02). The cholesterol saturation index during combination therapy was significantly lower (p less than 0.02) than that reached during the use of simvastatin and ursodeoxycholic acid. Both simvastatin and ursodeoxycholic acid significantly reduced the hepatic secretion rate of cholesterol (from 130 +/- 14 mumols/hr to 81 +/- 12 mumols/hr, p less than 0.01, and 70 +/- 9 mumols/hr, p less than 0.01) without affecting bile acid and phospholipid outputs.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2006

Efficacy, safety and LDL-C goal attainment of ezetimibe 10 mg-simvastatin 20 mg vs. placebo-simvastatin 20 mg in UK-based adults with coronary heart disease and hypercholesterolaemia.

It is increasingly accepted that more intensive lipid-lowering treatment is associated with greater cardiovascular risk reductions in patients with coronary heart disease (CHD), thus providing a rationale for more aggressive LDL-cholesterol (LDL-C) targets. Ezetimibe in combination with statin therapy provides an additional approach to lipid management by utilising the additive action of two different mechanisms of LDL-C reduction. In this multicentre, randomised, double-blind, placebo-controlled study, a total of 98 men and 55 women with CHD and primary hypercholesterolaemia, naïve to statin therapy, were randomised to receive treatment for 6 weeks with either ezetimibe 10 mg-simvastatin 20 mg (n = 77) or placebo-simvastatin 20 mg (n = 75). At 6 weeks, ezetimibe 10 mg-simvastatin 20 mg provided a mean additional LDL-C reduction of 14.6% (95% CI 10.1-19.1) compared with simvastatin monotherapy (p < 0.0001). Moreover, a higher proportion of patients on ezetimibe/simvastatin achieved the National Standard Framework LDL-C standard (<3.0 mmol/l; 93% vs. 75%, p < 0.001) or the new Joint British Societies (JBS 2) goal of LDL-C < 2.0 mmol/l (49.3% vs. 11.1%, p < 0.001). On logistic regression analysis, the odds ratio of achieving target LDL-C with ezetimibe 10 mg-simvastatin 20 mg was 5.1 (95% CI 1.8-15.0) times higher than with simvastatin monotherapy (p = 0.003). Clinical chemistry profiles and proportions of adverse events were similar in both groups at baseline and follow-up. In conclusion, ezetimibe 10 mg-simvastatin 20 mg is a practical, effective and safe option for the treatment of primary hypercholesterolaemia in CHD patients, and brings more patients to new aggressive cholesterol targets compared with simvastatin 20 mg monotherapy.

Adult↗

PubMed2000

A randomised comparison of simvastatin versus simvastatin and low cholesterol diet in the treatment of hypercholesterolaemia.

There is little evidence to show that strict dietary modification alone confers any significant impact on cardiac events in primary and secondary prevention of coronary heart disease. Given the efficacy of the statins, the need for strict dietary modification in patients on statin therapy has been questioned. This study was performed to assess 1) the added benefit on serum lipid levels of a strict low-fat dietary regimen in patients with hypercholesterolaemia already treated with simvastatin; 2) the efficacy of simvastatin on the lipid profile of our sample Asian population; and 3) the tolerability and side-effect profile of simvastatin. This study was a prospective evaluation of 60 patients with hypercholesterolaemia treated with simvastatin who were subjected to either a normal diet or a dietitian guided low-fat diet. Assessment of the effects on serum lipid levels, side-effects, biochemical and haematological markers were performed. After 24 weeks of treatment, a strict dietitian guided low-fat diet conferred no additional benefit over and above what was achieved by simvastatin alone. Furthermore, a higher dose of simvastatin was needed in the dietitian guided diet group to achieve the target LDL-cholesterol level. Simvastatin resulted in a significant positive alteration of lipid profiles in all patients. The drug was well tolerated, with no significant change in either haematological or biochemical indices. Simvastatin is a highly effective cholesterol-lowering drug with a beneficial effect on the entire lipid spectrum in a cross-section of Asian patients, and is well tolerated. A dietitian guided dietary approach confers no additional advantage once statin therapy has been initiated.

Adult↗

PubMed2005

LDL-C goal attainment with ezetimibe plus simvastatin coadministration vs atorvastatin or simvastatin monotherapy in patients at high risk of CHD.

AIMS: To compare the proportion of patients at high risk for coronary heart disease (CHD) achieving the recommended low-density lipoprotein cholesterol (LDL-C) treatment goal of < 100 mg/dL and the optional LDL-C target of < 70 mg/dL with coadministration of ezetimibe and simvastatin (EZE/SIMVA) vs either atorvastatin or simvastatin monotherapy. PATIENTS: Patients with established CHD or CHD risk equivalent according to National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria with baseline LDL-C = 130 mg/dL and triglycerides (TG) < or = 350 mg/dL. METHODS: A post hoc analysis from 2 separate studies assessed the percentage of high-risk patients achieving the LDL-C targets (< 100 and < 70 mg/dL) after 6 weeks on the usual recommended starting doses of the following treatments: EZE/SIMVA (10/20 mg) vs atorvastatin (10 mg) or simvastatin (20 mg). Depending on the study, EZE/SIMVA 10/10 or 10/40 mg was also compared with either atorvastatin 10 mg or simvastatin 20 mg. Percent change in other lipid parameters from baseline to study endpoint was also examined. RESULTS: In both studies, the proportions of patients achieving an LDL-C of < 100 mg/dL were significantly (P < .001) greater for EZE/SIMVA 10/10, 10/20, or 10/40 mg vs either atorvastatin 10 mg or simvastatin 20 mg after 6 weeks. The percentage reaching the optional LDL-C treatment target of < 70 mg/dL was also significantly higher with EZE/SIMVA compared with either atorvastatin or simvastatin. Percent reduction in LDL-C was significantly (P < .001) larger with all doses of EZE/SIMVA (46% to 59%) compared with either atorvastatin 10 mg (37%) or simvastatin 20 mg (38%) monotherapy after 6 weeks. Changes in other lipid parameters consistently favored EZE/SIMVA vs statin monotherapy. All treatments were well tolerated in both studies. CONCLUSION: Patients at high risk for CHD are more likely to attain LDL-C treatment targets with the usual recommended starting dose of EZE/SIMVA (10 or 20 mg) therapy than with that of atorvastatin (10 mg) or simvastatin (20 mg) monotherapy.

Aged↗

PubMed1989

Effects of simvastatin and probucol in hypercholesterolemia (Simvastatin Multicenter Study Group II).

This 12-week, randomized, double-blind, multicenter study compared the efficacy, tolerability and safety of simvastatin (a potent HMG-CoA reductase inhibitor) and probucol. Two doses of simvastatin, 20 or 40 mg once daily, were compared to probucol, 500 mg twice daily. Both simvastatin doses were significantly more effective than probucol in improving the plasma lipid profile. Mean reduction in low density lipoprotein (LDL) cholesterol was 34% with 20-mg simvastatin and 40% with the 40-mg dosage, compared to a mean reduction of 8% with probucol. Simvastatin significantly decreased total cholesterol, triglycerides and apolipo-protein B, and increased high density lipoprotein (HDL) cholesterol and apolipoprotein A-I. Probucol caused some reduction in LDL cholesterol but significantly decreased HDL cholesterol. Both simvastatin and probucol were well tolerated and no serious drug-related events occurred. Simvastatin appears to be a well-tolerated and effective new agent used once-a-day as an adjunct to diet in the management of patients with hypercholesterolemia.

Adult↗

PubMed2004

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.

Anticholesteremic Agents↗

PubMed2005

Effects of increasing doses of simvastatin on fasting lipoprotein subfractions, and the effect of high-dose simvastatin on postprandial chylomicron remnant clearance in normotriglyceridemic patients with premature coronary sclerosis.

Postprandial hyperlipidemia has been linked to premature coronary artery disease (CAD) in fasting normotriglyceridemic patients. We investigated the effects of increasing doses of simvastatin up to 80 mg/day on fasting and postprandial lipoprotein metabolism in 18 normotriglyceridemic patients with premature CAD. Fasting lipoprotein subfractions and cholesteryl ester transfer protein (CETP) activity were determined after each 5-week dose titration (0, 20, 40 and 80 mg/day). At baseline and after treatment with simvastatin 80 mg/day, standardised Vitamin A oral fat loading tests (50 g/m2; 10 h) were carried out. Ten normolipidemic healthy control subjects matched for gender, age and BMI underwent tests without medication. Treatment with simvastatin resulted in dose-dependent reductions of fasting LDL-cholesterol, without changing cholesterol levels in the VLDL-1, VLDL-2 and IDL fractions. In addition, simvastatin decreased CETP activity dose-dependently, although HDL-cholesterol remained unchanged. Simvastatin 80 mg/day decreased fasting plasma triglycerides (TG) by 26% (P < 0.05), but did not decrease significantly TG levels in any of the subfractions. The TG/cholesterol ratio increased in all subfractions. The plasma TG response to the oral fat loading test, estimated as area under the curve (TG-AUC), improved by 30% (from 21.5 +/- 2.5 to 15.1 +/- 1.9 mmol h/L; P < 0.01). Treatment with simvastatin 80 mg/day improved chylomicron remnant clearance (RE-AUC) by 36% from 30.0 +/- 2.6 to 19.2 +/- 3.3 mg h/L (P < 0.01). After therapy, remnant clearance in patients was similar to controls (19.2 +/- 3.3 and 20.3 +/- 2.7 mg h/L, respectively), suggesting a normalization of this potentially atherogenic process. In conclusion, high-dose simvastatin has beneficial effects in normotriglyceridemic patients with premature CAD, due to improved chylomicron remnant clearance, besides effective lowering of LDL-cholesterol. In addition, the lipoprotein subfractions became more cholesterol-poor, as reflected by the increased TG/cholesterol ratio, which potentially makes them less atherogenic.

Apolipoproteins↗

PubMed2003

Simvastatin inhibits expression of tissue factor in advanced atherosclerotic lesions of apolipoprotein E deficient mice independently of lipid lowering: potential role of simvastatin-mediated inhibition of Egr-1 expression and activation.

Recent studies suggest that the beneficial effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) in reducing cardiovascular events may in part, be independent of their capacity to lower plasma lipids. To test this hypothesis, simvastatin (50 mg/kg/d) was administered to 30-week-old apolipoprotein E deficient mice (apo E-/-) for 12, 18 and 24 weeks. In contrast to other experimental models and humans, simvastatin treatment increases plasma cholesterol levels in apo E-/- mice. Quantitative real-time polymerase chain reaction was used to quantify expression of tissue factor (TF) and monocyte chemoattractant protein-1 (MCP-1) in the aorta of each mouse. Expression of TF was reduced to 34, 24, and 13% of control levels at 12, 18 and 24 weeks, respectively, of simvastatin administration. Advanced lesions in the innominate arteries of the simvastatin treated mice had reduced levels of TF, fewer macrophages and reduced expression of early growth response-1 (Egr-1). In vitro studies in mouse macrophages demonstrated decreased lipopolysaccharide induced binding of nuclear proteins to the Egr-1 consensus DNA sequence following pretreatment with simvastatin. RNA levels for MCP-1 were reduced to 30% of control values following 24 weeks of simvastatin treatment. In conclusion, these data suggest that chronic administration of simvastatin to older apo E-/- mice can inhibit the expression of pro-thrombotic/pro-inflammatory genes within established atherosclerotic lesions via mechanisms that are independent of reductions in plasma lipids.

Animals↗