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PubMed2000

Irbesartan does not affect the pharmacokinetics of simvastatin in healthy subjects.

This open-label, single-dose, crossover study was conducted to assess the effect of irbesartan on the pharmacokinetics of total simvastatin acid in 14 healthy subjects. Subjects were randomized to receive one simvastatin 40 mg tablet or one simvastatin 40 mg tablet + one irbesartan 300 mg tablet. Subjects were crossed over to the other treatment after a 7- to 10-day washout period. Serum samples were collected at specified times before and over a 24-hour period after dosing. Safety was assessed by monitoring vital signs, laboratory tests, and adverse events. Irbesartan did not exhibit a clinically significant effect on the peak serum concentration and area under the concentration versus time curve to infinity (AUC0-infinity) of total simvastatin acid. The mean AUC0-infinity of total simvastatin acid was 74.55 ng x h/mL when simvastatin was given alone and 67.55 ng x h/mL when simvastatin and irbesartan were given concomitantly. The time to peak serum concentration for both treatments was 3 hours. No serious adverse events occurred during the study, and both agents were well tolerated. In summary, irbesartan had no significant effect on the single-dose pharmacokinetics of total simvastatin acid.

Adult↗
PubMed2005

Studies to investigate the pharmacokinetic interactions between ranolazine and ketoconazole, diltiazem, or simvastatin during combined administration in healthy subjects.

The interactions of ranolazine, a new antianginal compound, with inhibitors and substrates of the CYP3A isoenzyme family were studied in 1 open-label and 4 double-blind, randomized, multiple-dose studies. In healthy adult volunteers, the authors sought (1) to determine the steady-state pharmacokinetics, safety, and tolerability of immediate- and sustained-release ranolazine with and without ketoconazole, diltiazem, or simvastatin and (2) to evaluate the effect of ranolazine on the pharmacokinetics of diltiazem, simvastatin, simvastatin metabolites, and HMG-CoA reductase activity. Ketoconazole increased ranolazine plasma concentrations and reduced the CYP3A4-mediated metabolic transformation of ranolazine, confirming that CYP3A4 is the primary metabolic pathway for ranolazine. Diltiazem reduced oral clearance of ranolazine in a dose-dependent manner. Simvastatin did not affect ranolazine pharmacokinetics, although ranolazine increased the AUC and C(max) of simvastatin, simvastatin acid, 2 simvastatin metabolites, and HMG-CoA reductase activity by <2-fold. Administration of ranolazine in combination with diltiazem or simvastatin was safe and well tolerated during the interval studied.

Acetanilides↗
PubMed1991

Studies on the mechanism of simvastatin-induced thyroid hypertrophy and follicular cell adenoma in the rat.

Female Sprague-Dawley rats were treated with either simvastatin (a novel competitive inhibitor of HMG CoA reductase) or phenobarbital (positive control) to ascertain the possible relationship between the effects of simvastatin on hepatic metabolism and the thyroid hypertrophy and follicular cell adenomas which it produces in this strain of rat. The test compounds were administered orally at doses of 100 mg/kg (divided doses at 50 mg/kg, b.i.d.). (This dose of simvastatin represents approximately 250 times the human dose.) After 5 weeks of treatment, either simvastatin or phenobarbital produced significant increases (35% and 39% above control, respectively) in serum thyroid stimulating hormone (TSH), a significant increase (39% and 120% above control, respectively) in the systemic clearance of 125I-thyroxine, and slight decreases in serum thyroxine levels. Statistically significant increases in liver and thyroid weights were associated with phenobarbital treatment. With simvastatin, increased liver weights occurred. At the microscopic level, thyroid hypertrophy was observed in all phenobarbital-treated rats and to a lesser degree in most simvastatin-treated animals. Simvastatin did not markedly alter liver microsomal enzyme activities with the exception of the anticipated induction of HMG CoA reductase (which increased approximately 4.4-fold). Conversely, phenobarbital produced large increases in liver microsomal enzymes, including glucuronosyl transferase, but did not affect the activity of HMG CoA reductase. Therefore, the increased clearance of thyroxine in simvastatin-treated female rats was not associated with enzyme induction but may have been related to the increase in functional liver mass produced by this compound at this dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenoma↗
PubMed2004

Effectiveness of simvastatin therapy in raising HDL-C in patients with type 2 diabetes and low HDL-C.

OBJECTIVE: To evaluate the efficacy of high and moderate doses of simvastatin (80 and 40 mg), for raising high density lipoprotein-cholesterol (HDL-C), improving HDL sub-fractions, and affecting other parameters, including high sensitivity C-reactive protein (hs-CRP), in patients with type 2 diabetes mellitus (DM) and low HDL-C. RESEARCH DESIGN AND METHODS: This double-blind, placebo-controlled, randomized, 3-period, complete block, 6-week crossover study examined the efficacy of simvastatin in adult men and women (N = 151) with stable type 2 DM (HbA(1C) < 9%), low density lipoprotein-cholesterol (LDL-C) > 100 mg/dL (2.6 mmol/L), HDL-C < 40 mg/dL (< 1 mmol/L), and fasting triglyceride level > 150 (> 1.7 mmol/L) and < 700 mg/dL (< 7.9 mmol/L). This study included adult men (71%) and women (29%) of various races (89% white, 6% black, 1% Asian, 3% other) enrolled from 29 practice-based sites in the United States. MAIN OUTCOME MEASURES: Percentage change in HDL-C from baseline at the end of each 6-week treatment interval. RESULTS: Both simvastatin 80 and 40 mg significantly increased total HDL-C from baseline (mean increases of 8% +/- 1 [SE] and 5% +/- 1, respectively; p < 0.001) compared with placebo, and significantly reduced plasma concentrations of LDL-C (p < 0.001), triglycerides (p < 0.001), apolipoprotein B (p < 0.001), and hs-CRP (p < or = 0.012). Compared with simvastatin 40 mg, the 80 mg dose provided additional efficacy. Simvastatin 80 mg also significantly (p < 0.001) increased HDL(2) from baseline (14% +/- 3[SE]) and placebo phases (10 +/- 3). An exploratory analysis showed 87% (simvastatin 80 mg) and 82% (simvastatin 40 mg) of patients reached the NCEP ATP III treatment goals for LDL-C compared with 14% on placebo. CONCLUSIONS: Both simvastatin 80 and 40 mg raise HDL-C and improve other measures associated with elevated coronary risk in patients with type 2 DM and low HDL-C.

Adult↗
PubMed1995

Simvastatin inhibits the cellular signaling and proliferative action of arginine vasopressin in cultured rat glomerular mesangial cells.

The present study was undertaken to determine whether an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, simvastatin, modulates the cellular action of arginine vasopressin (AVP) in the cultured rat glomerular mesangial cells. AVP increases cellular free calcium ([Ca2+]i) in a dose-dependent manner. The 1 x 10(-7) M AVP-mobilized [Ca2+]i was significantly reduced in the cells pretreated with 1 x 10(-6) M simvastatin. AVP produced a biphasic change in cellular pH, namely, an early acidification followed by a sustained alkalinization, and the AVP-induced cellular alkalinization disappeared after exposing to simvastatin. 1 x 10(-7) M AVP activated mitogen-activated protein (MAP) kinase from 15.5-30.4 pmol/mg protein, an effect significantly less in the presence of simvastatin. Also, 1 x 10(-7) M AVP significantly increased [3H]thymidine incorporation by 1.6-fold, and its incorporation was totally diminished in cells pretreated with simvastatin. The AVP-induced [Ca2+]i mobilization and MAP kinase activation were totally restored when cells were preexposed to a mixture of mevalonate and simvastatin. [3H]AVP receptor binding was not affected by the simvastatin treatment. 1 x 10(-7) AVP increased inositol trisphosphate production by 1.8-fold, which was significantly reduced by the presence of simvastatin. These results may indicate that nonsterol pathway plays a crucial role in the cellular action of AVP to produce cell growth of glomerular mesangium.

Animals↗
PubMed2006

Pretreatment with simvastatin reduces lung injury related to intestinal ischemia-reperfusion in rats.

In this rat model study we evaluated whether pretreatment with simvastatin affects the severity of acute lung injury caused by intestinal ischemia-reperfusion (I/R). Twenty-four animals were randomly allocated to three equal groups (sham, control, simvastatin). The simvastatin group was pretreated with simvastatin 10 mg x kg(-1) x day(-1) for 3 days, whereas the other groups received placebo. The simvastatin and control groups underwent 60 min of superior mesenteric artery occlusion and 90 min of reperfusion. Compared with the simvastatin group, the control group exhibited significantly more severe intestinal I/R-induced acute lung injury, as indicated by lower Pao2 and oxygen saturation (P = 0.01 and P = 0.005, respectively) and higher mean values for neutrophil infiltration of the lungs (P = 0.003), total lung histopathologic injury score (P = 0.003), lung wet-to-dry weight ratio (P = 0.009), and lung-tissue malondialdehyde levels (P = 0.016). The control and simvastatin groups had similar serum levels and similar bronchoalveolar lavage fluid levels of cytokines (interleukin-1, interleukin-6, and tumor necrosis factor-alpha) and P-selectin at all measurements, except for a significantly higher level of bronchoalveolar lavage fluid P-selectin in the control group (P = 0.006). Pretreatment with simvastatin reduces the severity of acute lung injury induced by intestinal I/R in rats.

Animals↗
PubMed2006

Risk factors for rhabdomyolysis with simvastatin and atorvastatin.

OBJECTIVE: To assess the frequency of risk factors for rhabdomyolysis with simvastatin and atorvastatin in cases reported to the Australian Adverse Drug Reactions Advisory Committee (ADRAC). DESIGN: Reports meeting the definition of rhabdomyolysis were reviewed for risk factors including age > or = 70 years, dose > or = 40 mg, hepatic dysfunction, diabetes mellitus, hyperkalaemia, hypothyroidism and the use of concomitant interacting medications. RESULTS: Only one report associated with simvastatin and five reports associated with atorvastatin did not list any risk factors for rhabdomyolysis. Interacting medicines featured in 77% of reports of rhabdomyolysis associated with simvastatin and 44% of reports associated with atorvastatin. A comparison of the age profile for reports of atorvastatin- and simvastatin-associated rhabdomyolysis with that for all adverse drug reaction reports received, and for all reports of muscle disorders, suggested a trend towards an increasing risk of rhabdomyolysis with increasing age with simvastatin but not with atorvastatin. Similarly, comparing prescribed tablet strengths from Pharmaceutical Benefits Scheme data with the HMG-CoA reductase inhibitor ('statin') doses in reports of rhabdomyolysis suggested a dose-related risk with simvastatin, but a less increased risk with high-dose atorvastatin. CONCLUSION: Risk factors for rhabdomyolysis featured in nearly all of the reports of statin-associated rhabdomyolysis and the majority of reports listed multiple risk factors, although dependence on risk factors appeared to be stronger with simvastatin than atorvastatin. The multiplication of risk factors in patients taking simvastatin and atorvastatin should be minimised.

Atorvastatin↗
PubMed2006

Bioequivalence of an ezetimibe/simvastatin combination tablet and coadministration of ezetimibe and simvastatin as separate tablets in healthy subjects.

OBJECTIVE: To assess the bioequivalence of an ezetimibe/simvastatin (EZE/SIMVA) combination tablet compared to the coadministration of ezetimibe and simvastatin as separate tablets (EZE + SIMVA). METHODS: In this open-label, randomized, 2-part, 2-period crossover study, 96 healthy subjects were randomly assigned to participate in each part of the study (Part I or II), with each part consisting of 2 single-dose treatment periods separated by a 14-day washout. Part I consisted of Treatments A (EZE 10 mg + SIMVA 10 mg) and B (EZE/SIMVA 10/10 mg/mg) and Part II consisted of Treatments C (EZE 10 mg + SIMVA 80 mg) and D (EZE/SIMVA 10/80 mg/mg). Blood samples were collected up to 96 hours post-dose for determination of ezetimibe, total ezetimibe (ezetimibe + ezetimibe glucuronide), simvastatin and simvastatin acid (the most prevalent active metabolite of simvastatin) concentrations. Ezetimibe and simvastatin acid AUC(0-last) were predefined as primary endpoints and ezetimibe and simvastatin acid Cmax were secondary endpoints. Bioequivalence was achieved if 90% confidence intervals (CI) for the geometric mean ratios (GMR) (single tablet/coadministration) of AUC(0-last) and Cmax fell within prespecified bounds of (0.80, 1.25). RESULTS: The GMRs of the AUC(0-last) and Cmax for ezetimibe and simvastatin acid fell within the bioequivalence limits (0.80, 1.25). EZE/ SIMVA and EZE + SIMVA were generally well tolerated. CONCLUSIONS: The lowest and highest dosage strengths of EZE/SIMVA tablet were bioequivalent to the individual drug components administered together. Given the exact weight multiples of the EZE/SIMVA tablet and linear pharmacokinetics of simvastatin across the marketed dose range, bioequivalence of the intermediate tablet strengths (EZE/SIMVA 10/20 mg/mg and EZE/SIMVA 10/40 mg/mg) was inferred, although these dosages were not tested directly. These results indicate that the safety and efficacy profile of EZE + SIMVA coadministration therapy can be applied to treatment with the EZE/SIMVA tablet across the clinical dose range.

Adolescent↗
PubMed1999

Comparative effects of simvastatin and cholestyramine on plasma lipoproteins and CETP in humans.

Cholesteryl ester transfer protein (CETP) mediates neutral lipid transport in plasma, resulting in a net transfer of cholesteryl ester from high density lipoprotein to very low density lipoprotein. CETP gene expression is regulated by cholesterol, and plasma CETP level increases in patients with hyperlipidemia and with cholesterol feeding. Simvastatin, unlike cholestyramine, reduces hydroxymethylglutaryl coenzyme A reductase activity and may decrease a cellular pool of cholesterol, which is regulatory for CETP gene expression. The effects of simvastatin and cholestyramine on plasma lipids and CETP in 24 male and 19 female patients with primary hypercholesterolemia were compared. Following a four-week placebo period, patients were randomly assigned to receive either simvastatin or cholestyramine. Medication was increased in a stepwise fashion (from 10 to 40 mg for simvastatin and from 8 to 24 g for cholestyramine) as required at six-week intervals to maintain a low density lipoprotein cholesterol (LDL-C) level below 3.4 mmol/L. At the end of the 18-week study, the mean dose of simvastatin was 28.6 mg/day and of cholestyramine 19.3 g/day. Simvastatin was more effective than cholestyramine in lowering LDL-C (-36.8% versus -27. 2%; P=0.031) and triglycerides (-8.5% versus +12.5%; P=0.045). Plasma CETP level decreased by 14.8% following treatment with simvastatin (P=0.003) but did not change following cholestyramine treatment. This study demonstrates that, compared with cholestyramine, simvastatin results in more favourable improvements in the plasma lipoprotein profile and also lowers plasma levels of CETP.

Adolescent↗
PubMed2001

Drug interaction between simvastatin and itraconazole in male and female rats.

Taking into account the species and sex differences in drug interactions based on the inhibition of cytochrome P450 (P450)-mediated drug metabolism, we examined whether the interaction between simvastatin and itraconazole observed in humans could also occur in rats, the most commonly used animal species for pharmacokinetic studies. Itraconazole inhibited the in vitro metabolism of simvastatin in female rat liver microsomes, but not in male rat liver microsomes. Using anti-P450 antisera, the main P450 isozyme responsible for the metabolism of simvastatin was identified as CYP3A in female rats and CYP2C11 in male rats. Therefore, the sex difference in the inhibition of simvastatin metabolism by itraconazole seems to be caused by a difference in the P450 isozymes responsible for the metabolism of simvastatin in male and female rats and the different ability of itraconazole to inhibit CYP3A and CYP2C11. In addition, the effect of itraconazole on the pharmacokinetics of simvastatin in rats was also investigated. The area under the curve value of simvastatin was increased approximately 1.6-fold by the concomitant use of itraconazole (50 mg/kg) in female rats, whereas in male rats, itraconazole had no effect. In conclusion, it was found that the results obtained in male rats did not reflect the results in humans as far as the inhibition of simvastatin metabolism by itraconazole was concerned. The P450 isozymes involved in the metabolism of drugs should be taken into consideration when rats are used as a model animal for humans in the investigation of drug interactions.

Animals↗
PubMedDate not supplied

Influence of simvastatin on aspects of thrombogenesis in CAPD patients.

BACKGROUND: Patients on continuous ambulatory peritoneal dialysis (CAPD) are prone to dyslipidemia and have a high risk of cardiovascular death. Statins show beneficial effects on serum lipids and thrombogenesis in various groups of patients, but prospective studies have so far not been performed on CAPD patients. AIM: To determine the effects of 6 months' treatment with simvastatin on platelet function and some hemostatic parameters, markers of endothelial cell injury, in 14 CAPD patients with hypercholesterolemia. METHODS: Simvastatin was given in a dose of 10 mg at bedtime. Commercially available kits were used for all determinations. RESULTS: Cholesterol and low density lipoprotein fell significantly as early as after 1 month of the therapy (p < 0.001). Platelet aggregation in whole blood and platelet-rich plasma was transiently decreased by simvastatin therapy. The fibrinolytic activity index increased significantly after 6 months of simvastatin administration (p < 0.05), reaching values observed in the control group, whereas euglobulin clot lysis time, which was also significantly shortened after 6 months (p < 0.05), did not reach values obtained in healthy volunteers. Vascular cell adhesion molecule, thrombomodulin, and protein Z decreased significantly after 3 months of the therapy (p < 0.05, p < 0.05, and p < 0.01, respectively), whereas intercellular adhesion molecule decreased after 6 months (p < 0.05). Vascular endothelial growth factor and its receptor, protein Z, total tissue factor pathway inhibitor (TFPI),TFPI/Xa complexes, and thrombin activatable fibrinolysis inhibitor concentration and activity fell significantly after 6 months of treatment with simvastatin (all p < 0.05). Tissue plasminogen activator concentration increased after 1 month (p < 0.01 after 1 month, p < 0.05 after 3 and 6 months), whereas total homocysteine fell after 6 months of simvastatin therapy (p < 0.05). Truncated TFPI decreased significantly as early as after 1 month of therapy (p < 0.05 after 1 month, p < 0.01 after 3 and 6 months). CONCLUSION: Simvastatin is an effective hypolipemic agent in CAPD patients. It favorably affects platelet aggregation and the extrinsic coagulation pathway, improves fibrinolysis, and ameliorates endothelial dysfunction. Simvastatin might reduce the risk of thrombotic complications in CAPD patients.

Adult↗
PubMed2004

[The effects of simvastatin combined with different antioxidant vitamin regimens on serum lipid profile in patients with low HDL cholesterol levels].

OBJECTIVE: This study was designed to compare the effects of simvastatin versus a combination of simvastatin with vitamin C or E on serum lipid profile, particularly, high-density lipoprotein (HDL)-cholesterol (C) level, in patients with a low HDL-C level. METHODS: Fifty-nine women and 49 men, who had a baseline HDL-C level equal to or lower than 40 mg/dl were randomized to one of the following study treatment groups: Group S (n=39) simvastatin 20 mg/day, Group S+C (n=33) simvastatin 20 mg/day + vitamin C 500 mg/day, and Group S+E (n=36) simvastatin 20 mg/day + vitamin E 400 IU/day. The groups' lipid profiles were obtained at baseline, 3rd and 6th months. RESULTS: Comparing with baseline values, total-C and low-density cholesterol (LDL-C) values significantly reduced (p<0.001) and HDL-C values significantly increased (Group S--33.9+/-3.9 mg/dl vs. 39.8+/-6.9 mg/dl, Group S+C--34.2+/-3.5 mg/dl vs. 38.1+/-6.1 mg/dl, Group S+E--33.1+/-3.6 mg/dl vs. 34.8+/-5.9 mg/dl, p<0.001) on therapy within the groups; however, there were no significant differences among the groups with regards to these parameters. The HDL-C levels increased from baseline by 14.0%, 11.7% and 10.2% in Group S, S+C, and S+E, respectively (p>0.05). CONCLUSION: A combination of simvastatin with antioxidant vitamins does not offer any beneficial effect over simvastatin alone. Particularly vitamin E seems to blunt the simvastatin induced HDL-C increase.

Administration, Oral↗
PubMed1995

[Simvastatin in the treatment of familial hypercholesterolemia].

BACKGROUND: The association between hypercholesterolemia and premature atherosclerosis is almost universally accepted. Treatment of hyperlipoproteinemias represents a reasonable approach in preventive cardiology. The aim of the study was to prove a hypolipidemic effect of simvastatin, Zocor tablets à 10 mg, produced by MSD, U:S.A. in patients with familial hypercholesterolemia. METHODS AND RESULTS: 29 familial hypercholesterolemia heterozygotes have been treated with increasing dose of simvastatin (10 and 20 mg/day with the evening meal) for three months. All patients have been on AHA step I diet. The basic parameters of lipid and lipoprotein metabolism have been measured, as well the concentrations of apolipoproteins A-I and B, and the level of lipoprotein(a). Concentration of total cholesterol decreased after treatment with 10 and 20 mg of simvastatin by 20%, resp. 26%. The hypolipidemic effect was even more pronounced in LDL-cholesterol level, which was reduced by 24% respectively 34%. On the other hand therapy with simvastatin did not influence HDL-cholesterol at all. Also triglycerides concentration did not changed very significantly after administration of simvastatin (triglycerides levels were reduced by 7% respectively by 18%). Decline of LDL-cholesterol has been accompanied by decrease of apolipoprotein B concentration by 24%, resp. 26%. The concentration of lipoprotein (a) has not been statistically significantly influenced, even its level increased slightly. The body weight of the patients did not changed during the study. Simvastatin treatment has been well tolerated by the patients. CONCLUSIONS: Simvastatin, Zocor, seems to be powerful hypolipidemic drug, which is to be used even in the treatment of familial hypercholesterolemia heterozygotes, who are usually very resistant to the therapy. The dose of 10 mg of simvastatin is usually sufficient to influence plasma lipids and lipoproteins. A double dose intensifies the hypolipidemic effect but this additional effect is not so expressive. Zocor is tolerated well by the patients and in safety laboratory we did not notice any important undesirable result.

Adult↗
PubMed1994

Effect of simvastatin on coronary atheroma: the Multicentre Anti-Atheroma Study (MAAS)

It has yet to be established whether substantial reduction of plasma lipids will lead to retardation, and to what extent and how quickly, of diffuse and focal coronary atheroma. The Multicentre Anti-Atheroma Study (MAAS) is a randomised double-blind clinical trial of 381 patients with coronary heart disease assigned to treatment with diet and either simvastatin 20 mg daily or placebo for 4 years. Patients on simvastatin had a 23% reduction in serum cholesterol, a 31% reduction in low-density lipoprotein cholesterol, and a 9% increase in high-density lipoprotein cholesterol compared with placebo over 4 years. Quantitative coronary angiography was done at baseline, and after 2 and 4 years. 167 patients (89%) on placebo and 178 (92%) on simvastatin had baseline and follow-up angiograms. In the placebo group there were reductions in mean lumen diameter (-0.08 mm) and in minimum lumen diameter (-0.13 mm). Treatment effects were +0.06 (95% CI 0.02 to 0.10) and +0.08 mm (0.03 to 0.14) for mean and minimum lumen diameter, respectively (combined p = 0.006). Patients on placebo had an increase in mean diameter stenosis of 3.6% and the treatment effect of simvastatin was -2.6% (-4.4 to -0.8). Treatment effects were observed regardless of diameter stenosis at baseline. On a per-patient basis, angiographic progression occurred less often in the simvastatin group, 41 versus 54 patients; and regression was more frequent, 33 versus 20 patients (combined p = 0.02). Significantly more new lesions and new total occlusions developed in the placebo group, 48 versus 28, and 18 versus 8, respectively. There was no difference in clinical outcome. The numbers of patients who died or had a myocardial infarction were 16 and 14 in the placebo and simvastatin groups, respectively. In the placebo group more patients underwent coronary angioplasty or re-vascularisation, 34 versus 23 on simvastatin. The trial showed that 20 mg simvastatin daily over 4 years reduces hyperlipidaemia and slows progression of diffuse and focal coronary atherosclerosis.

Angioplasty, Balloon, Coronary↗
PubMed1997

Cost-effectiveness of simvastatin in the secondary prevention of coronary artery disease in Canada.

OBJECTIVE: To determine the cost-effectiveness of simvastatin in the secondary prevention of coronary artery disease (CAD) in Canada. DESIGN: Cost-effectiveness model based on results from the Scandinavian Simvastatin Survival Study (45 study) and cost and resource utilization data from Canadian sources to simulate the economic impact of long-term simvastatin treatment (15 years). PATIENTS: Subjects with mean age of 59.4 years at recruitment into 4S study. OUTCOME MEASURES: Overall death rate and incidence of 5 major nonfatal events associated with CAD: myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, stroke and transient ischemic attack. Direct medical costs associated with CAD were assessed from the perspective of provincial ministries of health (i.e., costs borne by the ministries); the impact of simvastatin treatment on these costs was determined. RESULTS: The 4S study, with a median follow-up of 5.4 years, showed significantly reduced mortality and morbidity among the patients given simvastatin compared with the control subjects. Three premises were designed to predict the consequences of simvastatin treatment of CAD in Canada over 15 years, 10 years beyond the end of the 4S study. The 2 most probable premises, which assumed that the clinical benefits of simvastatin would be cumulative for either the first 10 years or the full 15 years of the model, had incremental costs per year of life gained (cost-effectiveness ratio) of $9867 and $6108 respectively. CONCLUSION: This model suggests that simvastatin provides a cost-effective approach to the long-term prevention of secondary CAD in Canada.

Aged↗
PubMed1996

Efficacy and Tolerability of Low-dose Simvastatin and Niacin, Alone and in Combination, in Patients With Combined Hyperlipidemia: A Prospective Trial.

BACKGROUND: Combination lipid-lowering therapy may be desirable in patients with elevated low-density lipoprotein cholesterol, high triglycerides, and low high-density lipoprotein cholesterol. This study was conducted to determine the lipid-lowering efficacy of the combination of low-dose simvastatin and niacin in patients with combined hyperlipidemia and low high-density lipoprotein cholesterol. METHODS AND RESULTS: In this multicenter, prospective, randomized trial, 180 patients with hypercholesterolemia and hypertriglyceridemia and/or low high-density lipoprotein cholesterol were randomized to combination simvastatin (10 mg/day) and niacin (0.75 g/day) or to either drug alone for 9 weeks. The dose of niacin was doubled (from 0.75 g/day to 1.5 g/day) in both the combination and niacin arms for the remaining 8 weeks. The combination of simvastatin, 10 mg/day, and niacin, 1.5 g/day, reduced total, low-density lipoprotein, and very low-density lipoprotein cholesterol and triglycerides by 24%, 29%, 45%, and 31%, respectively, while increasing high-density lipoprotein cholesterol by 31%. The addition of niacin to simvastatin did not enhance the low-density lipoprotein cholesterol by 31%. The addition of niacin to simvastatin did not enhance the low-density lipoprotein cholesterol-lowering effect of simvastatin; however, the combination was more effective than either monotherapy at raising high-density lipoprotein cholesterol and lowering very low-density lipoprotein cholesterol (P <.05). More patients discontinued treatment because of an adverse event in the niacin (P <.03) and combination groups (P =.06) than the simvastatin group. CONCLUSIONS: Treatment of patients with combined hyperlipidemia and/or low high-density lipoprotein with combination low-dose simvastatin and niacin resulted in large reductions in total, low-density lipoprotein, and very low-density lipoprotein cholesterol and increases in HDL cholesterol. Although the combination was well tolerated in the current trial, its safety needs to be evaluated in larger trials of longer duration.

Journal Article↗
PubMed2006

Effect of ezetimibe and/or simvastatin on coenzyme Q10 levels in plasma: a randomised trial.

BACKGROUND: HMG-CoA reductase inhibitors ('statins') have been associated with a decrease in ubidecarenone (ubiquinone) levels, a lipophilic enzyme also known as coenzyme Q10 (CoQ10), due to inhibition of mevalonate synthesis. There is speculation that a decrease in CoQ10 levels may be associated with statin-induced myopathy. The cholesterol absorption inhibitor ezetimibe increases endogenous cholesterol synthesis. The purpose of this study was to examine (i) the effects of ezetimibe and simvastatin on plasma CoQ10 levels and (ii) whether ezetimibe coadministered with simvastatin abrogates the suggested statin-induced decrease in the CoQ10 plasma levels. METHODS: Seventy-two healthy male subjects were enrolled in a single-centre, randomised, parallel-group study with three arms. Subjects received ezetimibe 10 mg/day, simvastatin 40 mg/day or the combination of ezetimibe 10 mg/day plus simvastatin 40 mg/day for 14 days. RESULTS: Baseline CoQ10 (0.99 +/- 0.30 mg/L) levels for the combined groups remained unchanged in the ezetimibe group (0.95 +/- 0.24 mg/L), and significantly decreased in the simvastatin and combination groups (0.82 +/- 0.18 mg/L, p = 0.0002 and 0.7 +/- 0.22 mg/L, p < 0.0001, respectively). There was a correlation between the percentage change in the levels of low-density lipoprotein-cholesterol (LDL-C) and the percentage change in CoQ10 levels in all treatment groups (correlation coefficient [R] = 0.67, p < 0.0001). The ratios of CoQ10 levels to LDL-C levels were significantly increased in all treatment groups (p < 0.0001). CoQ10 level was independent of cholesterol synthesis or absorption markers. CONCLUSIONS: Simvastatin and the combination of simvastatin and ezetimibe significantly decrease plasma CoQ10 levels whereas ezetimibe monotherapy does not. There is a significant correlation between the CoQ10 level decrease and the decrease in total and LDL-C levels in all three treatment groups, suggesting that the CoQ10 decrease may reflect the decrease in the levels of its lipoprotein carriers and might not be statin-specific. The statin-associated CoQ10 reduction is not abrogated through ezetimibe coadministration. Changes of CoQ10 levels are independent of cholesterol synthesis and absorption.

Adult↗
PubMed2006

Effect of systemic administration of simvastatin on retinal circulation.

OBJECTIVE: To investigate the effect of systemic administration of simvastatin on the retinal circulation. METHODS: The effects of systemic administration of simvastatin on the retinal circulation after 90 minutes and after 7 days were studied in a placebo-controlled, double-masked, clinical trial among 12 healthy men. We used laser Doppler velocimetry to measure vessel diameter and blood velocity and calculated the blood flow in retinal arteries and veins. We also measured the intraocular pressure and the plasma nitrite/nitrate levels, the stable end products of nitric oxide metabolism. RESULTS: There were no significant changes in any retinal circulatory parameters at 90 minutes after administration of simvastatin. Daily administration of simvastatin for 7 days significantly increased blood velocity and blood flow in retinal arteries and veins but did not significantly change vessel diameter. The intraocular pressure significantly decreased at 90 minutes and at 7 days after administration of simvastatin. Simvastatin also significantly increased the plasma nitrite/nitrate levels. CONCLUSION: Simvastatin induced an increase in blood velocity and blood flow in retinal arteries and veins, increased the plasma nitrite/nitrate levels, and decreased the intraocular pressure, probably through the increase in nitric oxide.

Administration, Oral↗