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PubMed2000

Simvastatin improves disturbed endothelial barrier function.

BACKGROUND: Recent clinical trials have established that inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) reduce the risk of acute coronary events. These effects of statins cannot be fully explained by their lipid-lowering potential. Improved endothelial function may contribute to the positive effects of statin treatment. METHODS AND RESULTS: In the present study, we report that simvastatin reduces endothelial barrier dysfunction, which is associated with the development of atherosclerosis. Treatment of human umbilical vein endothelial cells for 24 hours with 5 micromol/L simvastatin reduced the thrombin-induced endothelial barrier dysfunction in vitro by 55+/-3%, as assessed by the passage of peroxidase through human umbilical vein endothelial cell monolayers. Similar effects were found on the thrombin-induced passage of (125)I-LDL through human aortic endothelial cell monolayers. This reduction in barrier dysfunction by simvastatin was both dose and time dependent and was accompanied by a reduction in the thrombin-induced formation of stress fibers and focal adhesions and membrane association of RhoA. Simvastatin treatment had no effect on intracellular cAMP levels. In Watanabe heritable hyperlipidemic rabbits, treatment for 1 month with 15 mg/kg simvastatin reduced vascular leakage in both the thoracic and abdominal part of the aorta, as evidenced by the Evans blue dye exclusion test. The decreased permeability was not accompanied by a reduction of oil red O-stainable atherosclerotic lesions. CONCLUSIONS: These data show that simvastatin, in a relatively high concentration, improves disturbed endothelial barrier function both in vitro and in vivo. The data also support the beneficial effects of simvastatin in acute coronary events by mechanisms other than its lipid-lowering effect.

Animals↗
PubMed2003

Cytoskeletal activation and altered gene expression in endothelial barrier regulation by simvastatin.

The statins, a class of HMG-CoA reductase inhibitors, directly affect multiple vascular processes via inhibition of geranylgeranylation, a covalent modification essential for Rho GTPase interaction with cell membrane-bound activators. We explored simvastatin effects on endothelial cell actomyosin contraction, gap formation, and barrier dysfunction produced by the edemagenic agent, thrombin. Human pulmonary artery endothelial cells exposed to prolonged simvastatin treatment (5 microM, 16 h) demonstrated significant reductions in thrombin-induced (1 U/ml) barrier dysfunction ( approximately 70% inhibition) with accelerated barrier recovery, as measured by transendothelial resistance. Furthermore, simvastatin attenuated basal and thrombin-stimulated (1 U/ml, 5 min) myosin light chain diphosphorylation and stress fiber formation while dramatically increasing peripheral immunostaining of actin and cortactin, an actin-binding protein, in conjunction with increased Rac GTPase activity. As both simvastatin-induced Rac activation and barrier protection were delayed (maximal after 16 h), we assessed the role of gene expression and protein translation in the simvastatin response. Simultaneous treatment with cycloheximide (10 microg/ml, 16 h) abolished simvastatin-mediated barrier protection. Robust alterations were noted in the expression of cytoskeletal proteins (caldesmon, integrin beta4), thrombin regulatory elements (PAR-1, thrombomodulin), and signaling genes (guanine nucleotide exchange factors) in response to simvastatin by microarray analysis. These novel observations have broad clinical implications in numerous vascular pathobiologies characterized by alterations in vascular integrity including inflammation, angiogenesis, and acute lung injury.

Actins↗
PubMed2006

Study of the pharmacokinetic interaction between simvastatin and prescription omega-3-acid ethyl esters.

The coadministration of prescription omega-3-acid ethyl esters (P-OM3) with a statin may present a treatment option for patients with mixed hyperlipidemia. This open-label, randomized, 2-way crossover, drug-drug interaction study evaluated the impact of P-OM3 capsules on plasma simvastatin pharmacokinetics in 24 healthy volunteers. Under fasted conditions, 80 mg simvastatin was administered with or without 4 g P-OM3 for two 14-day periods. After 14 days of dosing to achieve steady state, no significant differences were found in either the extent (AUC(tau)) or rate (Cmax) of exposure to simvastatin or its major beta-hydroxy metabolite after coadministration of P-OM3 with simvastatin compared with administration of simvastatin alone. At steady state, the coadministration of P-OM3 capsules did not appear to affect the pharmacokinetics of simvastatin tablets. The combination of P-OM3 capsules and simvastatin appeared to be well tolerated.

Administration, Oral↗
PubMed2007

Effect of polymorphic CYP3A5 genotype on the single-dose simvastatin pharmacokinetics in healthy subjects.

Simvastatin, a cholesterol-lowering agent, is mainly metabolized by CYP3A4/5. The objective of this study was to investigate the effect of CYP3A5*3 genotype on the pharmacokinetics of simvastatin in humans. Twenty-two men with CYP3A5*1/*1 (n = 4), CYP3A5*1/*3 (n = 8), or CYP3A5*3/*3 (n = 10) genotypes were enrolled. Each subject ingested a 20-mg dose of simvastatin, and plasma simvastatin concentrations were measured for 12 hours after dosing. The mean (+/-SD) area under the plasma concentration-time curve for simvastatin in the CYP3A5*1/*1 carriers (4.94 +/- 2.25 ng x h/mL) was significantly lower than CYP3A5*3/*3 carriers (16.35 +/- 6.37 ng x h/mL; P = .013, Bonferroni test). The mean (+/-SD) oral clearance was also significantly different between CYP3A5*1/*1 carriers (4.80 +/- 2.35 L/h) and CYP3A5*3/*3 carriers (1.35 +/- 0.61 L/h; P < .05, Dunn's test). However, other pharmacokinetic parameters including peak plasma concentrations and half-life did not show any difference between genotype groups. These findings suggest that the polymorphic CYP3A5 gene affects the disposition of simvastatin and provides a plausible explanation for interindividual variability of simvastatin disposition.

Administration, Oral↗
PubMed2004

Efficacy and safety of simvastatin in Asian and non-Asian coronary heart disease patients: a comparison of the GOALLS and STATT studies.

BACKGROUND: Asians are thought to be more responsive to the lipid-lowering effects of statins than non-Asians although there are no head-to-head trials that examine this perception. OBJECTIVE: To compare the results of the GOALLS and STATT studies that used similar titrate-to-goal protocols with 20 mg up to 80 mg simvastatin in Asian and non-Asian coronary heart disease (CHD) patients. METHODS: GOALLS (N = 198; included non-Asians and Asians) and STATT (N = 133; included Asians only) were both multi-center, open-label 14-week studies in CHD patients with serum low density lipoprotein cholesterol (LDL-C) levels 115 mg/dL-180 mg/dL and triglycerides (TG) levels < or = 400 mg/dL. Simvastatin was titrated from 20 mg/day up to 80 mg/day in order to achieve the National Cholesterol Education Program (NCEP) LDL-C target < or = 100 mg/dL. The primary efficacy variable was the percentage of patients attaining the NCEP LDL-C target at Week 14. Secondary endpoints included proportion of patients achieving the European Society of Cardiology/European Atherosclerosis Society/European Society of Hypertension (European) LDL-C target < or = 115 mg/dL at Week 14 and percentage change in lipid parameters. Safety and tolerability were assessed by monitoring adverse experiences and safety laboratory tests. Fifteen Asian patients were part of the GOALLS cohort and their data were compared separately with results of non-Asians from GOALLS and Asians from the STATT study. RESULTS: After 14 weeks of simvastatin treatment, 87.1% of GOALLS non-Asians, 85.7% of GOALLS Asians, and 78.2% of STATT patients attained the NCEP LDL-C target. At Week 14, 94.4%, 92.9%, and 91.7% of the GOALLS non-Asians, GOALLS Asians, and STATT patients achieved the European LDL-C target, respectively. The average treatment doses to attain NCEP and European targets were comparable among groups. The percentage reductions in lipid parameters from baseline to week 14 were similar among groups except, changes in high density lipoprotein cholesterol and apolipoprotein A-I favored Asian subjects. There was also a greater reduction in TG in the STATT study, but this was not consistent with TG reductions experienced by Asians in the GOALLS study. In both studies, simvastatin was generally well tolerated by all patients across the dosage range of 20 mg-80 mg. No cases of rhabdomyolysis or myopathy were reported in either study. CONCLUSIONS: A great majority of CHD patients is able to achieve LDL-C treatment goals (up to 90%) on simvastatin regardless of racial background. Simvastatin treatment at doses of 20 mg-80 mg is well-tolerated in Asian and non-Asian CHD patients. This side-by-side comparison provides evidence that Asian and non-Asian CHD populations respond similarly to comparable doses of simvastatin.

Asia↗
PubMed2004

Effect of short term treatment with simvastatin and atorvastatin on lipids and paraoxonase activity in patients with hyperlipoproteinaemia.

OBJECTIVE: High-density lipoprotein (HDL)-associated paraoxonase (PON) activity may play an important role in the inhibition of low-density lipoprotein (LDL) oxidation. Previous studies have demonstrated that serum PON activity is decreased in patients with hyperlipoproteinaemia and coronary heart disease. The study presented here examined the effect of short-term treatment with simvastatin and atorvastatin on lipids and PON activity in patients with hyperlipoproteinaemia. RESEARCH DESIGN AND METHODS: A prospective, non-blinded, single-group, cross-over, comparative trial was performed. Following an 8-week dietary run-in period, 49 patients (23 men and 26 women, mean age: 59.8 +/- 7.9 years) with Fredrickson type IIa. and IIb. hyperlipoproteinaemias were randomized to receive either simvastatin 20 mg/day or atorvastatin 10 mg/day for 3 months. Following an 8-week washout period, patients were crossed-over to receive the other drug for a further 3 months. Serum lipids were measured and serum PON activity was determined spectrophotometrically using paraoxon as a substrate. RESULTS: Simvastatin treatment significantly reduced serum cholesterol, LDL-cholesterol (LDL-C) and apolipoprotein (apo) B levels (p < 0.001). Atorvastatin had a more pronounced cholesterol, LDL-C- and apo B-lowering effect (p < 0.001) compared with simvastatin. Both statins also significantly reduced serum triglyceride levels (p < 0.01). Simvastatin and atorvastatin caused no significant change in the levels of HDL-cholesterol (HDL-C) and apo A1. HDL-associated PON activity did not change significantly after simvastatin therapy, but significantly increased after atorvastatin treatment (p < 0.05). CONCLUSIONS: Short-term administration of simvastatin did not increase PON activity. Atorvastatin treatment had a favourable effect on lipid profile and increased the activity of HDL-associated PON.

Adult↗
PubMed1991

The influence of simvastatin on adrenal corticosteroid production and urinary mevalonate during adrenocorticotropin stimulation in patients with heterozygous familial hypercholesterolemia.

The adrenal gland requires a continuous supply of cholesterol for the biosynthesis of adrenal corticosteroids, which can be supplied by low density lipoprotein receptor-mediated uptake or local synthesis. The present study examined whether hypolipidemic therapy with a potent HMG CoA reductase inhibitor, simvastatin, compromises the adrenal response to ACTH stimulation in adult patients with heterozygous familial hypercholesterolemia. The adrenal response to a 36-h continuous ACTH infusion was determined at baseline and after 2 months of simvastatin treatment (40 mg, twice daily) in eight patients. Simvastatin reduced total and low density lipoprotein cholesterol levels by 36% and 45%, respectively. The time course of the increase in serum cortisol concentrations with continuous ACTH infusion was the same before and during simvastatin therapy, as were the rates of urinary excretion of free cortisol, 17-hydroxycorticosteroids, and 17-ketosteroids. Urinary excretion of mevalonate, which correlates with rates of whole body cholesterol synthesis, decreased from 3.8 +/- 0.42 (+/- SEM) mu,ol/24 h at baseline to 2.75 +/- 0.56 on simvastatin; no significant changes were seen in the urinary mevalonate levels before and after simvastatin therapy during ACTH stimulation. We conclude that the hypolipidemic effects of simvastatin in patients with heterozygous familial hypercholesterolemia are paralleled by a decrease in urinary mevalonate, but that the drug does not adversely affect ACTH-stimulated adrenal corticosteroid production.

Adrenal Cortex↗
PubMed2005

The changes in the endothelial expression of cell adhesion molecules and iNOS in the vessel wall after the short-term administration of simvastatin in rabbit model of atherosclerosis.

Cell adhesion molecules P-selectin, VCAM-1 and ICAM-1 play an important role in the pathogenesis of atherosclerosis. High levels of nitric oxide (NO) produced by inducible NO synthase (iNOS) have been associated with atherosclerotic processes. Simvastatin is an HMG-CoA reductase inhibitor responsible for many clinical benefits. The aim of this study was to detect and quantify changes in endothelial expression of P-selectin, VCAM-1, ICAM-1 and iNOS in the vessel wall after the shortterm administration of simvastatin in a rabbit model of atherosclerosis. Eighteen New Zealand White rabbits were randomly divided into three groups (n=6). In the cholesterol group, rabbits consumed an atherogenic diet (0.4% cholesterol) for eight weeks. In the simvastatin group, rabbits consumed an atherogenic diet for six weeks and then consumed an atherogenic diet supplemented with simvastatin (10 mg kg(-1)) for two weeks. Biochemical analysis showed that administration of simvastatin led to an almost two-fold lowering of the total serum cholesterol, VLDL, LDL and HDL, but not triglycerides, compared with the cholesterol-fed rabbits only. Stereological analysis of the immunohistochemical staining revealed that administration of simvastatin (10 mg kg(-1) daily) in an atherogenic diet decreased the endothelial expression of P-selectin, ICAM-1 and iNOS in both aortic arch and carotid artery compared with the cholesterol fed-rabbits only. We conclude that simvastatin has beneficial effects on endothelial function by decreasing expression of P-selectin, ICAM-1 and iNOS in endothelial cells in the very early stages of atherogenesis.

Animals↗
PubMed2006

Systemic administration of simvastatin after the onset of experimental subarachnoid hemorrhage attenuates cerebral vasospasm.

OBJECTIVE: Experimental evidence suggests that intercellular adhesion molecule-1 mediated leukocyte extravasation contributes to the pathogenesis of cerebral vasospasm. Simvastatin, an HMG-CoA reductase inhibitor, decreases intercellular adhesion molecule-1 expression and competitively inhibits leukocyte intercellular adhesion molecule-1 binding. We hypothesized that administration of simvastatin after the onset of subarachnoid hemorrhage (SAH) would attenuate perivascular granulocyte migration and ameliorate cerebral vasospasm in a rabbit model of SAH. METHODS: New Zealand white rabbits (n = 15) underwent injection of autologous blood into the cisterna magna or sham surgery followed by subcutaneous injection of simvastatin (40 mg/kg) or vehicle 30 minutes, 24 hours, and 48 hours after SAH or sham surgery. Seventy-two hours later, basilar artery lumen diameter was measured by in situ perfusion/fixation and image analysis. CD-18 monoclonal antibody stained perivascular granulocytes and macrophages were counted under light microscopy. RESULTS: In vehicle treated rabbits, mean +/- standard deviation basilar artery diameter was reduced 3 days after SAH (n = 5) versus sham (n = 5) rabbits (0.49 +/- 0.08 mm versus 0.75 +/- 0.03 mm, P < 0.01). After SAH, mean +/- standard deviation basilar artery diameter was greater in simvastatin (n = 5) treated rabbits versus vehicle (n = 5) (0.63 +/- 0.04 mm versus 0.49 +/- 0.08 mm, P < 0.01). In vehicle treated rabbits, SAH resulted in an increase in the mean +/- standard deviation perivascular CD18 cell count (sham-vehicle, 2.8 +/- 2; SAH-vehicle 90 +/- 27; P < 0.01). Subcutaneous administration of simvastatin attenuated this increase in perivascular CD18-positive cells after SAH (SAH statin, 41.6 +/- 13; SAH vehicle, 90 +/- 27; P < 0.001). CONCLUSION: Subcutaneous administration of simvastatin after the onset of SAH attenuates perivascular granulocyte migration and ameliorates basilar artery vasospasm after experimental SAH in rabbits. 5-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, such as simvastatin, may potentially serve as agents in the prevention of cerebral vasospasm after SAH.

Animals↗
PubMed2003

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

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

Anticholesteremic Agents↗
PubMed2004

More Western hypercholesterolemic patients achieve Japan Atherosclerosis Society LDL-C goals with rosuvastatin therapy than with atorvastatin, pravastatin, or simvastatin therapy.

BACKGROUND: Data from Western comparative trials suggest that rosuvastatin is more effective than atorvastatin, simvastatin, and pravastatin in helping hypercholesterolemic patients achieve US and European lipid-lowering guidelines. The purpose of this analysis was to assess the comparative efficacy of rosuvastatin in reducing low-density lipoprotein cholesterol (LDL-C) to levels recommended by the Japan Atherosclerosis Society (JAS). METHODS AND RESULTS: A post hoc analysis of data from 6 randomized, double-blind, active-controlled trials was conducted to evaluate the relative efficacy of rosuvastatin and comparator statins in helping patients achieve the LDL-C goals established by the JAS. The first 5 trials, prospectively designed for pooling, were originally conducted to compare the effects of rosuvastatin with either atorvastatin, simvastatin, or pravastatin in reducing lipid levels and helping patients achieve the LDL-C goals established by the National Cholesterol Education Program. The 6th trial was conducted with similar objectives, but in patients with heterozygous familial hypercholesterolemia (HeFH). Data from 2,139 hypercholesterolemic patients in the first 5 trials were pooled for analysis: rosuvastatin 5 mg (n=390) or 10 mg (n=389) vs atorvastatin 10 mg (n=393); rosuvastatin 5 mg (n=240) or 10 mg (n=226) vs simvastatin 20 mg (n=249) or pravastatin 20 mg (n=252). In the studies with atorvastatin as the comparator, JAS-defined LDL-C goals were reached by 67.2% of the rosuvastatin 5-mg group, 82.3% of the rosuvastatin 10-mg group, and 58.0% of the atorvastatin 10-mg group (p<0.001 for both rosuvastatin groups vs atorvastatin) at 12 weeks. Similarly, in the trials with pravastatin and simvastatin as comparators, the JAS LDL-C goals were reached by 77.5% of the rosuvastatin 5-mg group, 86.7% of the rosuvastatin 10-mg group, 45.2% of the pravastatin 20-mg group and 65.5% of the simvastatin 20-mg group (p<0.001 for both rosuvastatin groups vs pravastatin and simvastatin). In the trial of HeFH patients (n=433 for rosuvastatin, n=187 for atorvastatin), 31.9% of patients treated with rosuvastatin 20 mg achieved JAS LDL-C goals, compared with 17.6% of patients treated with atorvastatin 20 mg (p<0.001). CONCLUSIONS: Rosuvastatin has demonstrated clinical superiority over atorvastatin, pravastatin, and simvastatin in reducing LDL-C levels and in enabling patients to reach goals established by the JAS.

Aged↗
PubMed2005

Interaction between amlodipine and simvastatin in patients with hypercholesterolemia and hypertension.

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are often prescribed in association with antihypertensive agents, including calcium antagonists. Simvastatin is an HMG-CoA reductase inhibitor that is metabolized by the cytochrome P450 (CYP) 3A4. The calcium antagonist amlodipine is also metabolized by CYP3A4. The purpose of this study was to investigate drug interactions between amlodipine and simvastatin. Eight patients with hypercholesterolemia and hypertension were enrolled. They were given 4 weeks of oral simvastatin (5 mg/day), followed by 4 weeks of oral amlodipine (5 mg/day) co-administered with simvastatin (5 mg/day). Combined treatment with simvastatin and amlodipine increased the peak concentration (C(max)) of HMG-CoA reductase inhibitors from 9.6 +/- 3.7 ng/ml to 13.7 +/- 4.7 ng/ml (p < 0.05) and the area under the concentration-time curve (AUC) from 34.3 +/- 16.5 ng h/ml to 43.9 +/- 16.6 ng h/ml (p < 0.05) without affecting the cholesterol-lowering effect of simvastatin. This study is the first to determine prospectively the pharmacokinetic and pharmacodynamic interaction between amlodipine and simvastatin.

Administration, Oral↗
PubMed2001

Simvastatin induces apoptosis of cultured rat cardiomyocytes.

Considering the therapeutic effect of statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) and simvastatin in patients with coronary heart disease, our first hypothesis was that simvastatin should inhibit apoptosis (programmed cell death) in angiotensin II-treated cultured myocytes. But after realizing that simvastatin stimulates apoptosis, we changed our hypothesis and began to study its apoptotic effect in primary cultured rat cardiomyocytes. We found that simvastatin induced apoptosis in a dose-dependent manner (0.1 to 3 micromol/L), as evidenced by the appearance of increased DNA fragmentation in agarose gels and characteristic apoptotic patterns in nuclei labeled with Hoechst 33342, as well as increased activity of caspase 3. FACS analysis of simvastatin-treated cardiomyocytes showing annexin V binding and propidium iodide exclusion ruled out the possibility of necrosis. Increased intracellular enzymatic activity of creatine phosphokinase, aldolase, and lactic dehydrogenase, markers for normal cell function, could reflect the hypertrophic effect of simvastatin. The results indicate that simvastatin-induced apoptosis in cultured heart cells is concentration-dependent and additive to the apoptotic effect of angiotensin II.

Angiotensin II↗
PubMed2001

Pharmacology and clinical experience with simvastatin.

Simvastatin (Zocortrade mark, Merck) is a safe and effective 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. Simvastatin potently lowers total and low density lipoprotein (LDL) cholesterol. Simvastatin was the first cholesterol-lowering agent that reduced total mortality in a randomised clinical trial. Simvastatin is effective at reducing total mortality, myocardial infarction, coronary mortality and the incidence of stroke or transient ischemic attack in patients with coronary heart disease and hypercholesterolemia. Simvastatin, like other statins, also has non-lipid mechanisms of action. These include anti-inflammatory effects, antiproliferative effects on smooth muscle cells and an upregulation of endothelial nitric oxide synthase. Overall, simvastatin has an excellent safety profile. Simvastatin, along with other statins, has made a significant impact on the morbidity and mortality from coronary heart disease.

Aged↗
PubMed2004

Simvastatin: a review.

Simvastatin is a long-established hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, first introduced in 1988. At the maximal recommended dose of 80 mg/day, it produces an average reduction in low-density lipoprotein cholesterol (LDL-C) of 47%, accompanied by reductions in very LDL-C, triglycerides and apolipoprotein B, and a modest increase in high-density lipoprotein cholesterol. The only important, although rare, adverse effect of simvastatin is myopathy, an effect shared by all members of the class; when severe, this can take the form of rhabdomyolysis, which may lead to acute renal failure. The mechanism of the myopathy is not understood. The risk is increased by certain concomitant drugs, including gemfibrozil and potent inhibitors of cytochrome P450 3A4. Simvastatin has been studied in two large outcome trials, the Scandinavian Simvastatin Survival Study (4S), and the Heart Protection Study (HPS), both of which demonstrated strikingly beneficial effects on a variety of cardiovascular outcomes, with minimal adverse effects. 4S was the first study with a cholesterol-lowering agent to demonstrate an unequivocal reduction in all-cause mortality (30%; p = 0.0003). HPS showed that the beneficial effects of simvastatin were obtainable in a broad array of patients with, or at high risk of, coronary heart disease (CHD) in categories previously little studied, including women, the elderly, patients with diabetes without known CHD, and, perhaps most importantly, patients with LDL-C well below the UK population average. Simvastatin has recently become available in many countries as a combination product with the cholesterol absorption inhibitor, ezetimibe. Because of its long record of safety and demonstrated ability to reduce cardiovascular risk, simvastatin has recently become available without a prescription in the UK at the 10 mg dosage level.

Clinical Trials as Topic↗
PubMed2005

Clinical and economic outcomes of conversion of simvastatin to lovastatin in a group-model health maintenance organization.

OBJECTIVE: To (a) determine if converting patients on simvastatin to lovastatin affects whether they meet their low-density lipoprotein cholesterol (LDL-C) goals as defined by the National Cholesterol Education Program Adult Treatment Panel III (ATP III) clinical practice guidelines and (b) assess the change in health care expenditures associated with such a conversion. METHODS: Primary and secondary prevention patients receiving simvastatin 10 mg to 40 mg daily between September 1, 2001, and February 28, 2002, were offered lovastatin at a therapeutically equivalent dose. Fasting lipid profiles and alanine aminotransferase (ALT) levels were measured and recorded at least 6 weeks after starting lovastatin. A clinical pharmacy staff member, in collaboration with the subject's primary care provider, subsequently adjusted lipid-lowering therapy as needed to attain target LDL-C goals, as determined by the ATP III clinical practice guidelines. RESULTS: Of 5,286 patients converted to lovastatin and for whom follow-up laboratory tests were drawn, 5,046 (95.5%) were converted successfully, and 240 (4.5%) had to be converted back to simvastatin due to intolerance (N=164, 3.1%) or failure to achieve LDL-C goal (N=76, 1.4%). The proportion of patients with LDL-C at or less than their target goal increased from 75.9% before the intervention to 79.1% after conversion to lovastatin (P <0.001). ALT levels did not change significantly. The mean ALT value, a proxy measure of safety before and after conversion for all patients, was 26.9 IU/L and 26.4 IU/L, respectively (P=0.134). For the 2,235 patients converted from lovastatin 80 mg to simvastatin 40 mg, the mean pre-ALT and post-ALT values were 26.9 IU/L and 26.5 IU/L (P=0.498). The annualized cost savings due to the conversions, expressed across the entire membership of this health maintenance organization (HMO), was 4.14 US dollars per member per year (PMPY), with no change in ALT levels. Patient savings in reduced copayments in the conversion from brand simvastatin to generic lovastatin were an average of 145.29 US dollars (62%) per patient (95% confidence interval, 143-149 US dollars, P <0.001). CONCLUSION: A clinical pharmacy-directed program designed to convert patients from simvastatin to lovastatin resulted in substantial expenditure reductions for this HMO and 62% copayment savings for members, without compromise in clinical outcomes as measured by lipid control (effectiveness) and ALT levels (safety). The proportion of patients at or less than their LDL-C goal increased coincident with the conversion from simvastatin to lovastatin.

Aged↗
PubMed1997

Simvastatin. A reappraisal of its cost effectiveness in dyslipidaemia and coronary heart disease.

The Scandinavian Simvastatin Survival Study (4S) has confirmed the link between the cholesterol-reducing effects of simvastatin and improved survival in patients with hypercholesterolaemia and pre-existing coronary heart disease (CHD). Pharmacoeconomic analyses of the 4S trial, using prospectively collected data for cost-generating events, demonstrate that the cost per year of life saved for simvastatin in such patients falls within the range considered cost effective. Reductions in resource utilisation costs (numbers of hospitalisations and revascularisation procedures) largely offset the acquisition cost of long term simvastatin treatment in the US. Models of primary prevention incorporating epidemiological data to predict CHD events generally suffer from deficiencies in the methods and assumptions used, and no firm conclusions can be made at present regarding relative cost effectiveness of the drugs studied, including simvastatin. It is generally agreed that cost effectiveness will improve in patients with higher absolute risk of CHD. In summary, simvastatin has been shown in a major clinical trial and its companion economic analyses to reduce mortality and to be cost effective in patients with hypercholesterolaemia and existing CHD. As is the case for others of its class, its cost-effectiveness ratio in primary prevention remains to be ascertained. This issue aside, simvastatin is a rational choice of cholesterol-lowering agent in secondary prevention whose use can be justified on an economic basis.

Coronary Disease↗
PubMed1999

Simvastatin after orthotopic heart transplantation. Costs and consequences.

OBJECTIVE: Recent data indicate that the combination of a low cholesterol diet and simvastatin following heart transplantation is associated with significant reduction of serum cholesterol levels, lower incidence of graft vessel disease (GVD) and significantly superior 4-year survival rates than dietary treatment alone. On the basis of this first randomised long term study evaluating survival as the clinical end-point, we investigated the cost effectiveness of the above regimens as well as the long term consequences for the patient and for heart transplantation as a high-tech procedure. DESIGN AND SETTING: The perspective of the economic analysis was that of the German health insurance fund. Life-years gained were calculated on the basis of the Kaplan-Meier survival curves from the 4-year clinical trial and from the International Society for Heart and Lung Transplantation (ISHLT) overall survival statistics. Incremental costs and incremental cost-effectiveness ratios were determined using various sources of data, and both costs and consequences were discounted by 3% per year. Sensitivity analyses using alternative assumptions were conducted in addition to the base-case analysis. PATIENTS AND PARTICIPANTS: As in the original clinical trial, the target population of the economic evaluation comprised all heart transplant recipients on standard triple immunosuppression consisting of cyclosporin, azathioprine and prednisolone, regardless of the postoperative serum lipid profile. INTERVENTIONS: The therapeutic regimens investigated in the analysis were the American Heart Association (AHA) step II diet plus simvastatin (titrated to a maximum dosage of 20 mg/day) and AHA step II diet alone. MAIN OUTCOME MEASURES AND RESULTS: Four years of treatment with simvastatin (mean dosage 8.11 mg/day) translated into an undiscounted survival benefit per patient of 2.27 life-years; 0.64 life-years within the trial period and 1.63 life-years thereafter. Discounted costs per year of life gained were $US1050 (sensitivity analyses $US800 to $US15,400) for simvastatin plus diet versus diet alone and $US18,010 (sensitivity analyses $US17,130 to $US21,090) for heart transplantation plus simvastatin versus no transplantation (all costs reflect 1997 values; $US1 = 1.747 Deutschmarks). CONCLUSIONS: Prevention of GVD with simvastatin after heart transplantation was cost effective in all the scenarios examined with impressive prolongation of life expectancy for the heart recipient. Simvastatin also achieved an internationally robust 21% improvement in the cost effectiveness of heart transplantation compared with historical cost-effectiveness data.

Anticholesteremic Agents↗