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PubMed2001

Inhibition of in vitro metabolism of simvastatin by itraconazole in humans and prediction of in vivo drug-drug interactions.

PURPOSE: To evaluate an interaction between simvastatin and itraconazole in in vitro studies and to attempt a quantitative prediction of in vivo interaction in humans. METHODS: The inhibitory effect of itraconazole on simvastatin metabolism was evaluated using human liver microsomes and the Ki values were calculated for the unbound drug in the reaction mixture. A physiologically-based pharmacokinetic model was used to predict the maximum in vivo drug-drug interaction. RESULTS: Itraconazole competitively inhibited the metabolism of simvastatin to M-1 and M-2 with Ki values in the nM range. The area under the curve (AUC) of simvastatin after concomitant dosing with itraconazole was predicted to increase ca. 84-101-fold compared with that without administration of itraconazole. Taking into consideration the fact that this method predicts the maximum interaction, this agrees well with the clinical observation of a 19-fold increase. A similar prediction, based on the Ki value without taking into account the drug adsorption to microsomes, led to an underevaluation of the interaction. CONCLUSIONS: It was demonstrated that the competitive inhibition of CYP3A4-mediated simvastatin metabolism by itraconazole is the main cause of the drug interaction and that a Ki value corrected for drug adsorption to microsomes is the key factor in quantitatively predicting the maximum in vivo drug interactions.

Anticholesteremic Agents↗
PubMed1998

Dissolution of gallstones with simvastatin, an HMG CoA reductase inhibitor.

The aim of this study was to determine whether 12 months of therapy with Simvastatin, an HMG CoA reductase inhibitor, would dissolve gallstones. Twenty-seven subjects entered the study, all had a fasting oral cholecystogram, ultrasound examination, and fasting serum lipids prior to therapy. In addition, 22 subjects had their gallbladder ejection fraction, after CCK, determined by radionucleotide scanning. Eleven subjects had the cholesterol saturation index (CSI) of bile calculated before and at the end of 12 months of therapy. Of the 27 subjects, 26 completed 12 months of treatment with Simvastatin 20 mg daily. There was a significant fall in the total serum cholesterol (27%, P < 0.0001), LDL cholesterol (31%, P < 0.0001), triglyceride (34%, P < 0.0001) but no change in HDL after 12 months of therapy. Simvastatin treatment resulted in a 28% fall in the CSI of bile at the end of therapy (P < 0.01). The concentrations of individual bile acids did not change with therapy, and apart from a slight but significant increase in arachidonate, there were no other significant changes in the fatty acid composition of the biliary phospholipids. After 12 months of Simvastatin therapy there was a small decrease in the gallstone diameter but complete dissolution of gallstones was not achieved in any subjects. In conclusion 12 months of therapy with Simvastatin was effective in lowering the serum lipids and the CSI of bile but was not effective in dissolving gallstones.

Adult↗
PubMed1993

Simvastatin therapy for hypercholesterolemic patients with nephrotic syndrome or significant proteinuria.

Experimental evidence suggests that lipid lowering therapy could slow the progression of renal disease in humans. We have conducted a double-blind, placebo controlled trial of the HMG CoA reductase inhibitor simvastatin in patients with the nephrotic syndrome or significant proteinuria (> 1 g/day) and hypercholesterolemia (> or = 6.5 mmol/liter). Patients were placed on a lipid lowering diet for at least 10 weeks before randomization. After a four-week placebo run-in, 30 adults were randomized to simvastatin or placebo therapy (10 mg/day, increasing to 20 to 40 mg/day as required) for 24 weeks. There were seven dropouts, none of whom were "definitely" related to drug therapy. Total and LDL cholesterol levels fell by a mean of 33 and 31%, respectively, in simvastatin treated patients, compared with only 5 and 1% in patients on placebo (P < 0.001, P = 0.002, respectively). Apolipoprotein B100 levels fell by a mean of 31% in the simvastatin group but rose 0.3% in the placebo group (P = 0.014). There were no significant changes in HDL levels. There were no significant differences between the groups in their urine protein levels, their rise in plasma creatinine, or decline in plasma inulin clearance. Simvastatin is a safe, effective therapy for hypercholesterolemia in proteinuric states. A much larger trial is needed to show if potent lipid-lowering therapy slows progression of hypercholesterolemic proteinuric diseases.

Adolescent↗
PubMed2006

Simvastatin protection against acute immune-mediated glomerulonephritis in mice.

In addition to cholesterol lowering, 3-hydroxy-3-nethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors limit inflammatory changes associated with atherosclerosis. There is also support for their use as inhibitors of progression in chronic renal disease, irrespective of cause. In this study, their capacity to limit acute renal inflammation was evaluated. For this purpose, mice were treated with Simvastatin either prior to, at the time of, or shortly after induction of nephrotoxic nephritis. The severity of disease was determined by evaluation of blood urea nitrogen (BUN), proteinuria, and renal histologic changes. The reversibility of benefit was evaluated by the administration of mevalonic acid along with nephrotoxic serum (NTS) and Simvastatin The severity of the acute nephritis, including proteinuria, elevated BUN, and histologic changes, was ameliorated in a dose-dependent manner, when Simvastatin was administered either prior to NTS injection or at the time of NTS injection. By contrast, Simvastatin did not alter the course of established nephritis. Coadministration of mevalonic acid, the immediate substrate following HMG-CoA reductase, abolished Simvastatin's renoprotective effect, indicating that the benefit is, at least in part, due to interference with HMG-CoA reductase and biosynthetic substrates downstream from the enzyme. These findings provide the rationale for the evaluation of the efficacy of HMG-CoA reductase inhibitors in patients with recurrent forms of renal inflammation, to limit the severity of acute exacerbations of disease, prevent renal scarring and slow the rate of progression.

Acute Disease↗
PubMed2001

Inhibitory effects of verapamil and diltiazem on simvastatin metabolism in human liver microsomes.

AIMS: To determine the effects of verapamil and diltiazem on simvastatin metabolism in human liver microsomes and to compare their inhibitory potencies and CYP3A4 inactivation parameters with those reported previously for mibefradil. METHODS: Simvastatin metabolism was investigated in human liver microsomes in the presence and absence of verapamil or diltiazem (0.1-250 microM). Kinetics of CYP3A4 inactivation by verapamil and diltiazem were determined using testosterone as the substrate. RESULTS: When verapamil was coincubated with simvastatin, IC50 values ranged from 23 to 26 microM for all major metabolites. The IC50 values ranged from 4.8 to 5.6 microM on preincubation of verapamil for 30 min in the presence of an NADPH-generating system. Corresponding IC50 values for diltiazem ranged from 110-127 microM and from 21-27 microM, respectively. Verapamil and diltiazem inhibited testosterone 6beta-hydroxylation in a time- and concentration-dependent manner, key features of mechanism-based inactivation. Values for the inactivation parameters kinact and KI were 0.15 +/- 0.04 min-1 (mean +/- s.d.) and 2.9 +/- 0.6 microM, respectively, for verapamil and 0.07 +/- 0.01 min-1 and 3.3 +/- 1.5 microM, respectively, for diltiazem. CONCLUSIONS: The IC50 values for coincubation of verapamil and diltiazem were 46- and 220-fold higher, respectively, than those reported previously for mibefradil, and 16- and 71-fold higher, respectively, for preincubation. Thus, the results of this study suggest that verapamil and diltiazem are less likely than mibefradil to cause acute drug interactions with simvastatin in vivo. However, verapamil and diltiazem are moderate mechanism-based inhibitors of CYP3A4 and therefore may still cause significant inhibition of simvastatin metabolism in vivo during chronic therapy.

Calcium Channel Blockers↗
PubMed1999

Rhabdomyolysis and acute renal failure due to combination therapy with simvastatin and warfarin.

Simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, is widely used to treat hyperlipidaemia. Although myalgias are recognized adverse effects, clinically significant elevations in serum creatine phosphokinase (CPK) levels are uncommon. We describe a case of rhabdomyolysis and acute renal failure associated with concomitant use of simvastatin and warfarin. Rhabdomyolysis and renal failure occurred 7 days after warfarin (5 mg day-1) was added to a chronic stable dose of simvastatin (20 mg day-1) and resolved abruptly after discontinuation of simvastatin. We recommend careful monitoring when warfarin is given to patients receiving simvastatin.

Acute Kidney Injury↗
PubMed1999

Direct inhibitory effects of simvastatin on matrix accumulation in cultured murine mesangial cells.

BACKGROUND: 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been demonstrated to suppress glomerular injuries in various renal diseases. These agents inhibit in vitro proliferation of several cell types, including mesangial cells. This effect indicates the ability to ameliorate mesangioproliferative lesions, independent of the improvement of hypercholesterolemia. On the other hand, it is not clear whether HMG-CoA reductase inhibitors directly regulate extracellular matrix (ECM) accumulation from mesangial cells. METHODS: In this study, to examine the in vitro effects of simvastatin, an HMG-CoA reductase inhibitor, on mRNA expressions of matrix proteins, growth factors, and matrix turnover proteins, we incubated cultured murine mesangial cells stimulated by fetal calf serum (FCS) with or without simvastatin for 24 hours, and Northern analysis was performed. RESULTS: Simvastatin showed a slightly suppressive effect on mRNA expression of type IV collagen and fibronectin and a slightly up-regulative effect on that of type I collagen, whereas mRNA expression of type III collagen was markedly up-regulated. mRNA expression of platelet-derived growth factor (PDGF)-B chain and PDGF receptor beta-subunit was suppressed, whereas that of transforming growth factor-beta (TGF-beta) was not affected by simvastatin. Concerning matrix turnover proteins, simvastatin markedly reduced mRNA expression of plsminogen activator inhibitor-1 (PAI-1) without affecting the expression of tissue-type plasminogen activator (tPA). CONCLUSION: These results suggest type-specific modulation of matrix protein production independent of TGF-beta and the suppressive effects of autocrine PDGF by administration of HMG-CoA reductase inhibitors in mesangial cells. Moreover, the beneficial effects of these agents on matrix protein accumulation may be through promoting ECM degradation derived from PAI-1 suppression.

Animals↗
PubMed2004

Simvastatin blunts the increase of circulating adhesion molecules after coronary artery bypass surgery with cardiopulmonary bypass.

OBJECTIVES: Endothelial dysfunction has been shown to be a critical early component of organ injury after myocardial ischemia and reperfusion. Circulating levels of adhesion molecules have been regarded as a valid index of endothelial activation. Recent reports suggest that statins, widely used in the control of hypercholesterolemia, exert a protective effect on the endothelium reflected by a reduced level of circulating adhesion molecules. In this study, the effects of preoperative simvastatin treatment, at doses equivalent to those used orally for cholesterol control, were studied on plasma levels of VCAM-1, ICAM-1, and ELAM-1. DESIGN: A case-control study. SETTING: University hospital. PARTICIPANTS: Fifteen patients taking simvastatin with good control of cholesterol levels, 15 patients not responsive to the simvastatin treatment, and 15 normocholesterolemic patients (control) undergoing elective coronary artery bypass surgery. MEASUREMENTS AND MAIN RESULTS: The plasma levels of VACM-1, ICAM-1, and ELAM-1 were evaluated at baseline; during cardiopulmonary bypass; and 6 hours, 24 hours, and 48 hours postoperatively. In the late postoperative samples, the plasma levels of ICAM-1 and ELAM-1 were lower in both simvastatin-treated patients compared with the control patients. No significant difference was found between the patients responsive to statin and those not responsive. Finally, no significant difference was found for VCAM-1 plasma levels between the control group and the 2 treatment groups. CONCLUSIONS: Pretreatment with simvastatin significantly reduces the increase of ICAM-1 and ELAM-1 after coronary artery bypass surgery, by a mechanism that seems not related to its efficacy in lowering cholesterol levels.

Anticholesteremic Agents↗
PubMed2001

Simvastatin treatment on postprandial hypertriglyceridemia in type 2 diabetes mellitus patients with combined hyperlipidemia.

Recent studies have shown that statins are effective in reducing fasting low-density lipoprotein-cholesterol (LDL-C) and triglyceride levels. However, it remains unknown if treatment with statins also lowers daily postprandial triglyceride concentrations, which may promote atherogenesis in type 2 diabetes subjects. Forty-one subjects with type 2 diabetes and combined hyperlipidemia who had stable glycemic control were randomly assigned to take simvastatin 20 mg (n = 27) or a placebo (n = 14) once daily for 12 weeks. The medication dosage was doubled after 4 weeks if a subject's LDL-C was not less than 130 mg/dL. Among these participants, 24 subjects (15 on simvastatin and 9 on placebo) agreed to take a meal tolerance test with isocaloric mixed meals (carbohydrate, 52%; fat, 33%, and protein, 15% of the daily caloric intake) and daytime hourly blood sampling from 8 AM to 4 PM. Simvastatin treatment reduced the fasting total cholesterol level from 237 +/- 5 to 178 +/- 6 mg/dL (-25%), the LDL cholesterol level from 150 +/- 6 to 87 +/- 5 mg/dL (-40%), and raised high-density lipoprotein-cholesterol (HDL-C) level from 36 +/- 2 to 40 +/- 2 mg/dL (+11%) (all P <.001). Fasting and daily ambient triglyceride concentrations from 8 AM to 4 PM decreased significantly in response to simvastatin administration (P <.001), but not to the placebo (P =.305). Simvastatin treatment not only decreased total cholesterol and LDL-C levels and increased HDL-C levels effectively, it also decreased fasting, as well as daily postprandial triglyceride concentrations, but had no effect on glycemic control in type 2 diabetes subjects with combined hyperlipidemia.

Cholesterol↗
PubMed2002

Influence of simvastatin on LDL-subtypes in patients with heterozygous familial hypercholesterolemia and in patients with diabetes mellitus and mixed hyperlipoproteinemia.

This study evaluates the influence of simvastatin on lipid concentrations and on LDL-subtype distribution in patients with heterozygous familial hypercholesterolemia and in patients with type 2 diabetes and mixed hyperlipoproteinemia. Nine patients with familial hypercholesterolemia (LDL-cholesterol: 7.1 +/- 1.1 mmol/L, triglycerides: 1.3 +/- 0.4 mmol/L) and 8 patients with type 2 diabetes mellitus and mixed hyperlipoproteinemia (HbA1c 6.8 +/- 1.1%, LDL-cholesterol: 4.8 +/- 0.7 mmol/L, triglycerides: 2.5 +/- 1.1 mmol/L) were examined. Cholesterol concentration was determined in 7 LDL-subfractions isolated by density gradient ultracentrifugation before and during simvastatin treatment (10-20 mg/d, 4 weeks). Simvastatin decreased LDL-cholesterol (-34%/-30%, all p < 0.05) and triglycerides (-2%, n.s./-25%, p < 0.05), but had little effect on HDL-cholesterol (+7%/+2%, n.s.) in patients with familial hypercholesterolemia and diabetes mellitus, respectively. In both groups a significant reduction of cholesterol in each LDL-subfraction was observed. Large-buoyant (LDL-1, LDL-2) and intermediate-dense (LDL-3, LDL-4) LDL were reduced more than small-dense (LDL-5-LDL-7) LDL-subtypes (-36%/-38%/-23%, respectively) in patients with familial hypercholesterolemia, while in diabetic patients cholesterol reduction was uniform in all LDL-subtypes (-29%/-27%/-31%, respectively). Simvastatin decreases cholesterol concentration in all LDL-subfractions in patients with familial hypercholesterolemia and in patients with diabetes mellitus with mixed hyperlipoproteinemia. However, the relative reduction of individual LDL-subtypes differed between both groups. This suggests that the effect of simvastatin on LDL-subtype distribution depends on the type of underlying hyperlipoproteinemia.

Adolescent↗
PubMed2005

Simvastatin attenuates expression of cytokine-inducible nitric-oxide synthase in embryonic cardiac myoblasts.

Cardiac stem cells or myoblasts are vulnerable to inflammatory stimulation in hearts with infarction or ischemic injury. Widely used for the prevention and treatment of atherosclerotic heart disease, the cholesterol-lowering drugs statins may exert anti-inflammatory effects. In this study, we examined the impact of inhibition of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase with simvastatin on the expression of inducible nitric-oxide synthase (iNOS) in embryonic cardiac myoblasts stimulated with the proinflammatory cytokines, interleukin-1 or tumor necrosis factor. Treatment with simvastatin significantly reduced the levels of iNOS mRNA and protein in cytokine-treated rat H9c2 cardiac embryonic myoblasts. Addition of the HMG-CoA reductase product, L-mevalonate, and the by-product of cholesterol synthesis, geranylgeranyl pyrophosphate, could reverse the statin inhibitory effect on iNOS expression. Simvastatin treatment lowered the Rho GTPase activities, whereas the Rho-associated kinase inhibitor Y27632 partially blocked the statin inhibitory effect on nitrite production in the cytokine-treated H9c2 cells. Treatment with simvastatin led to inactivation of NF-kappaB by elevation of the NF-kappaB inhibitor IkappaB and reduction of the NF-kappaB nuclear contents in the cytokine-stimulated H9c2 cells. Hence, treatment with simvastatin can attenuate iNOS expression and NO synthesis in cytokine-stimulated embryonic cardiac myoblasts. The statin inhibitory effect may occur through isoprenoid-mediated intracellular signal transduction, which involves several key signal proteins, such as Rho kinase and IkappaB/NF-kappaB. These data suggest that statin therapy may protect the cardiac myocyte progenitors against the cytotoxicity of cytokine-induced high output of NO production in infarcted or ischemic hearts with inflammation.

Animals↗
PubMed2006

Assessing lipid lowering and plasma cholesteryl ester transfer protein activity of simvastatin following administration to rabbits fed a high fat/cholesterol diet.

PURPOSE: The purpose of this study was to assess the lipid lowering and plasma cholesteryl ester transfer protein (CETP) activity following administration of simvastatin to rabbits fed a high fat/cholesterol diet. METHODS: Male New Zealand white rabbits were housed in individual cages and fed a standard diet for 7 days. After 7 days, animals were fed 10 g of a regular chow diet plus 100 g of the same diet supplemented with 0.5% (w/v) cholesterol and 14.0% (w/v) coconut oil for 28 days. Following 28 days on this diet, the animals were randomized based on plasma cholesterol and triglyceride levels, into a group of control animals and a group (n = 6) of animals fed 100 g of cholesterol/coconut diet plus 10 g regular chow diet containing simvastatin (3 mg/kg/day) for an additional 28 days. Blood samples were taken from the marginal ear vein prior to and 28 days after the initiation of drug treatment. Plasma was harvested and stored at 4 degrees C prior to lipid analysis. Plasma total cholesterol and triglyceride levels were quantified using enzymatic kits. HDL (high-density lipoproteins) cholesterol levels were determined using the dextran sulfate-Mg(2+) precipitation method. ApoB cholesterol levels were determined by subtracting total cholesterol from HDL cholesterol. Cholesteryl ester transfer protein (CETP) activity was determined by standard assay methods. RESULTS: We observed that simvastatin significantly reduced total plasma cholesterol, triglyceride, and apoB cholesterol compared to non-treated controls. Simvastatin treatment did not alter serum CETP activity compared to non-treated controls. CONCLUSIONS: These findings suggest that decreasing plasma lipid levels by treatment with simvastatin is not due to changes in serum CETP activity in rabbits fed a high fat/cholesterol diet.

Algorithms↗
PubMed1997

Simvastatin further enhances the hypocholesterolemic effect of soy protein in rabbits.

OBJECTIVE: The effects of three dietary proteins (casein, cod, soy) and low dose simvastatin, an inhibitor of hydroxymethyl-glutaryl coenzyme A (HMG-CoA) reductase, on serum lipids were investigated. METHODS: New Zealand rabbits were fed purified diet (20% protein, 11% fat and 0.06% cholesterol) for 28 days. Animals received either 1.4 mg simvastatin or placebo orally during the last 14 days. A randomized 3 x 2 factorial design was used for the administration of diet and drug treatments. RESULTS: Mean food intake and body weight of the animals in all groups were similar. In placebo groups, soy protein decreased (p = 0.06) total cholesterolemia with significantly (p = 0.009) lower high-density lipoprotein (HDL) cholesterol, and significantly (p = 0.004) higher very low-density lipoprotein (VLDL) triglycerides (TG), compared to animal proteins. Addition of low dose simvastatin to soy protein induced a further decrease of serum total cholesterol, decreased VLDL and low-density lipoprotein (LDL) cholesterol, and LDL (apolipoprotein B), as well as improved VLDL-TG and HDL cholesterol levels. No similar reduction was seen when simvastatin was combined with casein or cod protein. CONCLUSION: These results show that low dose simvastatin may enhance the hypocholesterolemic effect of soy protein compared to animal proteins in the rabbit.

Animals↗
PubMed2005

The effect of hormone replacement therapy and simvastatin on plasma homocysteine.

BACKGROUND: Homocysteine may be an independent risk factor for coronary artery disease (CAD), and the risk is at least as strong for women as for men. Homocysteine levels are lower in women compared with men, and homocysteine is lower during pregnancy and higher during menopause. PURPOSE: To investigate the effects of hormone replacement therapy (HRT), simvastatin, and their combination on plasma homocysteine levels, we treated 16 postmenopausal, hypercholesterolemic women with CAD with HRT (0.625 mg conjugated equine estrogens [CEE] combined continuously with 2.5 mg medroxyprogesterone), 20 mg simvastatin, and their combination in a randomized, placebo-controlled study. Each treatment period was 8 weeks long, with a 4-week washout interval. Plasma homocysteine levels were evaluated at the end of each treatment period. RESULTS: Only HRT, alone and in combination with simvastatin, significantly reduced homocysteine levels compared with placebo (11.82 +/- 0.74 and 12.22 +/- 0.71 vs 13.58 +/- 0.83 micromol/L, respectively, p < 0.05). Simvastatin had no effect (13.02 +/- 0.94 micromol/L), and the combination therapy was not better that monotherapy with HRT. CONCLUSIONS: Oral HRT reduces homocysteine plasma levels, whereas simvastatin has no effect. If confirmed by randomized, prospective studies with clinical end points, HRT may be considered for women with mild hypercholesterolemia and high homocysteine levels.

Aged↗
PubMed2006

Development and characterization of a hypomorphic Smith-Lemli-Opitz syndrome mouse model and efficacy of simvastatin therapy.

Smith-Lemli-Opitz syndrome (SLOS) is a genetic syndrome caused by mutations in the 3beta-hydroxysterol Delta(7)-reductase gene (DHCR7). SLOS patients have decreased cholesterol and increased 7-dehydrocholesterol (7-DHC) levels. Dietary cholesterol supplementation improves systemic biochemical abnormalities; however, because of the blood-brain barrier, the central nervous system (CNS) is not treated. Simvastatin therapy has been proposed as a means to treat the CNS. Mice homozygous for a null disruption of Dhcr7, Dhcr7(Delta3-5/Delta3-5), die soon after birth, thus they cannot be used to study postnatal development or therapy. To circumvent this problem, we produced a hypomorphic SLOS mouse model by introducing a mutation corresponding to DHCR7(T93M). Both Dhcr7(T93M/T93M) and Dhcr7(Delta3-5/T93M) mice are viable. Phenotypic findings in Dhcr7(T93M/Delta3-5) mice include CNS ventricular dilatation and two to three syndactyly. Biochemically, both Dhcr7(T93M/T93M) and Dhcr7(T93M/Delta3-5) mice have elevated tissue 7-DHC levels; however, the biochemical defect improved with age. This has not been observed in human patients, and is due to elevated Dhcr7 expression in mouse tissues. Dietary cholesterol therapy improved sterol profiles in peripheral, but not CNS tissues. However, treatment of Dhcr7(T93M/Delta3-5) mice with simvastatin decreased 7-DHC levels in both peripheral and brain tissues. Expression of Dhcr7 increased in Dhcr7(T93M/Delta3-5) tissues after simvastatin therapy, consistent with the hypothesis that simvastatin therapy improves the biochemical phenotype by increasing the expression of a Dhcr7 allele with residual enzymatic activity. We conclude that simvastatin treatment is efficacious in improving the SLOS-associated sterol abnormality found in the brain, and thus has the potential to be an effective therapeutic intervention for behavioral and learning problems associated with SLOS.

3T3 Cells↗
PubMed1997

Effect of treatment with simvastatin on serum cholesteryl ester transfer in patients on dialysis. PERFECT Study Collaborative Group.

BACKGROUND: Plasma cholesteryl ester transfer activity is increased in patients with chronic renal failure on dialysis who have elevated levels of apolipoprotein B (apoB)-containing lipoproteins. Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor, reduces levels of these lipoproteins but the effect of treatment on cholesteryl ester transfer activity in patients on dialysis remains to be determined. METHODS: We measured serum newly synthesized cholesteryl ester transfer (NCET) activity, lecithin:cholesterol acyltransferase (LCAT) activity and serum lipid, lipoprotein and apolipoprotein concentrations before and immediately after 6 months treatment with simvastatin (10 mg daily, n = 24) or placebo (n = 29) in 53 patients with chronic renal failure receiving haemodialysis or continuous ambulatory peritoneal dialysis (CAPD). RESULTS: Simvastatin therapy significantly reduced serum cholesterol, LDL cholesterol, apoB concentrations, and both NCET (P = 0.001) and LCAT (P = 0.012) rates. The decrease in NCET activity was correlated significantly with the corresponding decrease in apoB concentration (r = 0.715, P < 0.001) and LCAT activity (r = 0.715, P < 0.001) during simvastatin therapy and was no longer significant when apoB concentration (P = 0.14) or LCAT activity (P = 0.07) were controlled. CONCLUSIONS: These data show that simvastatin therapy reduces serum NCET rates, and suggest that this may be linked to the concomitant decrease in levels of apoB-containing lipoproteins which are acceptors of transferred cholesteryl esters, and to the decrease in serum LCAT rates in patients with chronic renal failure with treatment.

Adolescent↗
PubMed1997

Cholesterol lowering after participation in the Scandinavian Simvastatin Survival Study (4S) in Finland.

BACKGROUND: Patient compliance is crucial for the effectiveness of preventive medication. The aim of the study was to investigate changes in serum cholesterol levels and the use of cholesterol lowering drugs one year after the end of the Scandinavian Simvastatin Survival Study (4S), a randomized secondary prevention study of coronary heart disease with simvastatin and placebo. METHODS AND RESULTS: A questionnaire asking the current use of cholesterol lowering drugs, most recent serum cholesterol value and attitudes towards cholesterol lowering was sent to 785 surviving 4S participants in four 4S centres in Finland. The response rate was 94%. The current use of cholesterol lowering drugs and the reported mean serum cholesterol values were similar to the original simvastatin and placebo groups. In all, 74% (n = 546) reported that they had used cholesterol lowering drugs after the study, and 63% (n = 467) were currently using them, mostly simvastatin (96%) with an average dose of 14 (SD 5) mg.day-1. Cholesterol lowering was considered to be 'very important' by 53% and 'important' by 37% of the respondents. The most frequent reasons for discontinuation were 'drug costs' (38%) and 'normal cholesterol values' (30%). The reported mean serum cholesterol levels were 5.1 (SD 1.0) and 5.7 (SD 1.1) mmol-1 in the current cholesterol lowering drug users and non-users, respectively (P < 0.0001). The in-trial treatment goal of serum cholesterol (< or = 5.2 mmol-1) was not met in 38% of the users and in 68% of the non-users of cholesterol lowering drugs. CONCLUSION: One year post-trial the original simvastatin and placebo groups of the 4S had become similar with regard to the use of cholesterol lowering drugs and serum cholesterol levels. The adherence to medication, however, still remained relatively high, but there was a shift toward lower doses, and consequently toward higher post-trial serum cholesterol levels.

Anticholesteremic Agents↗
PubMed1990

Efficacy and safety of simvastatin (alone or in association with cholestyramine). A 1-year study in 66 patients with type II hyperlipoproteinaemia.

The effects and safety of simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, were investigated alone or in association with cholestyramine in 66 patients with hypercholesterolaemia, in a 1-year study. In type IIa hypercholesterolaemia (41 patients), the association was more effective than simvastatin used alone in lowering total cholesterol (37% vs 29%) and LDL-cholesterol (45% vs 37%). In type IIb hypercholesterolaemia (23 patients), the association simvastatin-cholestyramine did not appear more effective than simvastatin used alone. The decrease of apoprotein B was parallel to the LDL-cholesterol decrease. Apoprotein A1 did not change significantly. The long-term safety of simvastatin was good. No lens opacity was noted. The most serious side-effect in our study was myolysis which occurred in two patients with a marked increase in creatine phosphokinase.

Adult↗