Atorvastatin compared with simvastatin-based therapies in the management of severe familial hyperlipidaemias.

Crook MA.

Department of Chemical Pathology, St Thomas' Hospital, London, UK. Anthony.Wierzbicki ukcl.ac.uk

We compared atorvastatin with simvastatin-based therapies in a prospective observational study of 201 patients with severe hyperlipidaemia. Atorvastatin 10 mg therapy was substituted for simvastatin 20 mg, 20 mg for 40 mg, 40 mg for simvastatin 40 mg plus resin, and 80 mg for simvastatin-fibrate-resin therapy. Lipid and safety profiles were assessed. Atorvastatin reduced total cholesterol by 31 +/- 11-40 +/- 14% vs. 25 +/- 12-31 +/- 11%; LDL by 38 +/- 16-45 +/- 18% vs. 31 +/- 18-39 +/- 18% and geometric mean triglycerides by 29.3-37.3% vs. 16.6-24.8%, but reduced HDL 11% +/- 47% at 80 mg compared with a 16% +/- 34% increase with simvastatin-based therapy. Target LDL < 3.5 mmol/l was achieved more often with atorvastatin (63% vs. 50%; p < 0.001). Atorvastatin increased geometric mean fibrinogen by 12-20% vs. a 0-6% fall with simvastatin (p << 0.001). Side effects were noted in 10-36% of patients, including one case of rhabdomyolysis, and 36% discontinued therapy. These data suggest that atorvastatin is more effective than current simvastatin-based therapies in achieving treatment targets in patients with familial hypercholesterolaemia but at the expense of a possible increase in side-effects. This issue needs further study in randomized controlled trials.

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Effects of hydroxymethylglutaryl coenzyme A reductase inhibitor simvastatin on smooth muscle cell proliferation in vitro and neointimal formation in vivo after vascular injury.

Chiariello M.

Division of Cardiology, University Federico II, Naples, Italy. Indolfi unina.it

OBJECTIVES: We sought to evaluate the effects of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors on vascular smooth muscle cell (VSMC) proliferation in vitro and neointimal formation in vivo after vascular injury. BACKGROUND: Neointimal hyperplasia after vascular injury is responsible for restenosis after arterial stenting, whereas arterial remodeling and neointimal formation are the causes of restenosis after percutaneous transluminal coronary angioplasty. METHODS: We assessed the effect of simvastatin on in vitro VSMC proliferation. To study the effects of simvastatin in vivo, balloon injury and stent deployment were performed in the common carotid artery of rats. Neointimal area was measured two weeks later in the balloon injury model and three weeks after stent deployment. RESULTS: Simvastatin markedly inhibits VSMC proliferation in vitro. In vivo, simvastatin reduced, in a dose-dependent manner, the neointimal area and the neointima-media ratio after balloon injury from 0.266 +/- 0.015 mm2 to 0.080 +/- 0.026 mm2 and from 1.271 +/- 0.074 to 0.436 +/- 0.158 (p < 0.001 vs. control rats) at the highest dose. Simvastatin also significantly reduced the neointimal formation and the neointima-media ratio after stenting from 0.508 +/- 0.035 mm2 to 0.362 +/- 0.047 mm2 (p < 0.05 vs. control rats) and from 2.000 +/- 0.136 to 1.374 +/- 0.180 (p < 0.05 vs. control rats). The vessel thrombosis rate after stent deployment was 30% in the control group and 11.1% in the treated group (p = NS). Moreover, the systemic administration of simvastatin did not affect hepatic and renal functions, blood pressure or heart rate. CONCLUSIONS: Simvastatin potently inhibits VSMC proliferation in vitro and reduces neointimal formation in a rat model of vascular injury.

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Effects of simvastatin only or in combination with continuous combined hormone replacement therapy on serum lipid levels in hypercholesterolaemic post-menopausal women.

Oktay A.

Department of Cardiology, Marmara University School of Medicine, Istanbul, Turkey.

AIMS: To evaluate the effects of simvastatin only or combined with continuous hormone replacement therapy on the serum lipid profile in hypercholesterolaemic post-menopausal women. METHODS AND RESULTS: One hundred hypercholesterolaemic post-menopausal women were given either simvastatin 10 mg daily together with oestrogen 0.625 mg and medroxyprogesterone 2.5 mg daily (HRT+simvastatin group) (n:50) or simvastatin 10 mg daily (simvastatin only group) (n:50) in a prospective manner. Serum total, low density lipoprotein, and high density lipoprotein cholesterol and triglyceride levels were measured at baseline, at 3 and 6 months. The initial mean (+/-SD) cholesterol values were as follows for the HRT+simvastatin group and the simvastatin only group, respectively: total cholesterol 240. 0+/-28.0 and 248.9+/-28.2 mg x dl(-1); low density lipoprotein cholesterol 174.7+/-25.6 and 175.1+/-25.9 mg x dl(-1); high density lipoprotein cholesterol 37.2+/-5.0 and 39.9+/-7.3 mg x dl(-1). Compared with the baseline, total and low density lipoprotein cholesterol levels decreased; and high density lipoprotein cholesterol levels increased significantly at 3 and 6 months in both groups. However, the mean percent reduction in total cholesterol and low density lipoprotein cholesterol was significantly greater in the HRT+ simvastatin group compared with the simvastatin only group both at 3 months (12.3+/-7.0% vs 8.9+/-6.2%;P<0.01; and 19.0+/-10.6% vs 13.2+/-10.4%;P< 0.005, respectively) and at 6 months (14.6+/-7.7% vs 11.3+/-7.4%;P<0.05 and 23.3+/-9.7% vs 15.8+/-12.3%;P<0.005, respectively). The mean percent increase in serum high density lipoprotein cholesterol concentrations was also significantly greater in the HRT+simvastatin group compared with the simvastatin only group at both times (14.6+/-11.8% vs 9.8+/-11.8%;P<0.005, at 3 months, and 21.3+/-15.2% vs 11.1+/-12.5;P<0.005, at 6 months, respectively). Furthermore, significantly more patients in the HRT+simvastatin group than in the simvastatin only group attained their target treatment goals dictated by the National Cholesterol Education Program Adult Treatment Panel II Guidelines. Although the mean percent decrease in triglyceride levels was significantly greater in the HRT+simvastatin group at 3 months, the significance disappeared at 6 months. CONCLUSION: The combination of simvastatin and continuous combined hormone replacement therapy seems to be more effective than simvastatin only in the treatment of hypercholesterolaemia in post-menopausal women. Copyright 2000 The European Society of Cardiology.

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Atorvastatin and simvastatin have distinct effects on hydroxy methylglutaryl-CoA reductase activity and mRNA abundance in the guinea pig.

Fernandez ML.

Department of Nutritional Sciences, University of Connecticut, Storrs 06269, USA.

The effects of atorvastatin and simvastatin on hydroxy methylglutaryl (HMG)-CoA reductase activity and mRNA abundance were studied in guinea pigs randomized to three groups: untreated animals and those treated with 20 mg/kg of atorvastatin or simvastatin. Guinea pigs were fasted for 0, 6, 12, or 18 h in an attempt to remove the drug from their systems. Reductase activity and mRNA levels were analyzed after each time point. Reductase inhibitor treatment resulted in 50-62% lower cholesterol concentrations compared to untreated guinea pigs (P < 0.0001), while plasma triacylglycerol (TAG) concentrations did not differ among groups. Plasma cholesterol and TAG were 50-70% lower after 18 h fasting in the three groups (P < 0.001). In the nonfasting state, simvastatin and atorvastatin treatment did not affect HMG-CoA reductase activity compared with untreated animals. However, after 6 h of fasting, simvastatin-treated guinea pigs had higher HMG-CoA reductase activity than untreated animals (P < 0.01), suggesting that the drug had been removed from the enzyme. In contrast, atorvastatin-treated guinea pigs maintained low enzyme activity even after 18 h of fasting. Further, HMG-CoA reductase mRNA abundance was increased by sevenfold after atorvastatin treatment and by twofold after simvastatin treatment (P < 0.01). These results suggest that simvastatin and atorvastatin have different half-lives, which may affect HMG-CoA reductase mRNA levels. The increase in reductase activity by simvastatin during fasting could be related to an effect of this statin in stabilizing the enzyme. In contrast, atorvastatin, possibly due to its longer half-life, prolonged inhibition of HMG-CoA reductase activity and resulted in a greater increase in mRNA synthesis.

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Simvastatin enhanced sodium nitroprusside-induced apoptosis of smooth muscle cells. An involvement of geranylgeraniol.

Ishikawa K.

Second Department of Internal Medicine, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, Japan.

A decrease in serum cholesterol is one of the most beneficial effects in anti-atherogenesis. Nitric oxide is also an anti-atherogenic substance, inducing vasodilation and inhibits proliferation of smooth muscle cells (SMC). Therefore, we examined sodium nitroprusside (SNP)-induced apoptosis of vascular SMC with respect to cholesterol metabolism. Cultured vascular SMC from bovine carotid arteries and rat aorta were used. Apoptosis was determined by propidium iodide assay. Treatment of the SMC with SNP(100 micromol/l-1 mmol/l ) for 6 h induced a little nuclear fragmentation. SNP (1 mmol/l ) elicited apoptosis in 4.4+/-2.2% of cells. Pretreatment of SMC with simvastatin (1 microg/ml, 2 days), a hydroxymethylglutaryl Coenzyme A (HMG CoA) reductase inhibitor, synergistically enhanced SNP-induced apoptosis (% apoptosis =15. 9+/-3.3%). Either mevalonate (100 micromol/l) or geranylgeraniol (30 micromol/l) recovered the simvastatin (1 microg/ml)-enhanced SMC apoptosis induced by SNP. Neither squalene (10 mmol/l) nor farnesol (30 micromol/l) had a recovery effect on the simvastatin-enhanced SMC apoptosis induced by SNP. Pretreatment with simvastatin (1 microg/ml) reduced total cholesterol content in SMC. Mevalonate (100 micromol/l) restored a decrease in total cholesterol content. However, incubation with LDL deficient serum did not enhance SNP-induced apoptosis of SMC, although treatment with LDL deficient serum decreased the total cholesterol content in SMC. These data suggested that decrease in HMG CoA reductase metabolites, especially geranylgeraniol might enhance the SNP-induced apoptosis of SMC, and that, apoptosis was not involved in a decrease in cholesterol of SMC.

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A Randomized Multicenter Trial Comparing and Efficacy of Simvastatin and Fluvastatin.

Tate AC.

Department of Medicine, Medical Research Laboratories, Portland, Oregon, USA

BACKGROUND: Inhibitors of hydroxymethylglutaryl co-enzyme A reductase are widely used for the treatment of hypercholesterolemia. Physicians and third-party payers need an accurate measure of their relative potency and hypolipidemic efficacy. We have therefore compared simvastatin against fluvastatin, the newest member of this class. METHODS AND RESULTS: One hundred fifty-eight hypercholesterolemic patients in seven United States lipid clinics participated in this balanced double-blind incomplete block study. After a placebo-diet run-in period, patients received treatment with active drug for three consecutive 5-week periods, with measurement of lipids in a NHLBI-CDC standardized central laboratory at the end of each period. Each patient was randomly assigned to three of the following five treatments: simvastatin 5 mg, 10 mg, and 20 mg and fluvastatin 20 mg and 40 mg. The mean percent reductions in low density lipoprotein cholesterol from baseline were 21, 27, 32, 16, and 23 respectively. The simvastatin/fluvastatin milligram potency ratio was 6.8 (95% CI, 5.3-9.3). At the same 20 mg dose, simvastatin produced an effect on LDL cholesterol approximately double that of fluvastatin and resulted in 46% of patients achieving their National Cholesterol Education Program low density lipoprotein cholesterol target levels, compared to 12% for fluvastatin. CONCLUSIONS: Fluvastatin at its maximal dose of 40 mg daily is approximately equivalent to simvastatin 5 mg daily. Higher doses of simvastatin are considerably more effective in the treatment of primary hypercholesterolemia.

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