Cost-effectiveness of simvastatin in people at different levels of vascular disease risk: economic analysis of a randomised trial in 20,536 individuals.

Heart Protection Study Collaborative Group.

BACKGROUND: Statin therapy reduces the rates of heart attack, stroke, and revascularisation among a wide range of individuals. Reliable assessment of its cost-effectiveness in different circumstances is needed. METHODS: 20,536 adults (aged 40-80 years) with vascular disease or diabetes were randomly allocated 40 mg simvastatin daily (10,269) or placebo (10,267) for an average of 5 years. Comparisons were made of hospitalisation and statin costs (2001 UK prices) during the scheduled treatment period between all simvastatin-allocated versus all placebo-allocated participants. Cost-effectiveness was estimated among different categories of participant. FINDINGS: Allocation to simvastatin was associated with a highly significant 22% (95% CI 16-27; p<0.0001) proportional reduction in hospitalisation costs for all vascular events, with similar proportional reductions in every subcategory of participant studied. During an average of 5 years, estimated absolute reductions in vascular event costs per person allocated 40 mg simvastatin daily ranged from UK 847 pounds sterling (SE 137) in the highest risk quintile studied to 264 pounds sterling (48) in the lowest. Mean excess cost of statin therapy among participants allocated simvastatin was 1497 pounds sterling (8), with similar absolute increases in every subcategory. Costs of preventing a major vascular event with 40 mg simvastatin daily ranged from 4500 pounds sterling (95% CI 2300-7400) among participants with a 42% 5-year major vascular event rate to 31,100 pounds sterling (22,900-42,500) among those with a 12% rate (corresponding to 5-year major coronary event rates of 22% and 4%, respectively). INTERPRETATION: Statin therapy is cost effective for a wider range of individuals with vascular disease or diabetes than previously recognised (particularly with lower-priced generics). It would be appropriate to consider reducing the estimated level of vascular event risk at which statin therapy is recommended.

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DELINEATION OF MYOTOXICITY INDUCED BY HMG-COA-REDUCTASE-INHIBITORS IN HUMAN SKELETAL MUSCLE CELLS.

Hohenegger M.

Medical University Vienna.

The 3-Hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (statins) are widely used and well tolerated cholesterol-lowering drugs. In rare cases side effects occur in skeletal muscle, including myositis or even rhabdomyolysis. However, the molecular mechanisms are not well understood that lead to these muscle-specific side effects. Here we show that statins cause apoptosis in differentiated human skeletal muscle cells. The prototypical representative of statins, simvastatin, triggered sustained intracellular Ca(2+) transients leading to calpain activation. Intracellular chelation of Ca(2+) completely abrogated cell death. Moreover, ryanodine also completely prevented the simvastatin induced calpain activation. Nevertheless, an activation of the ryanodine receptor by simvastatin could not be observed. Downstream of the calpain activation simvastatin led to a translocation of Bax to mitochondria in a caspase 8 independent manner. Consecutive activation of caspase 9 and 3 execute apoptotic cell death which was in part reversed by the co-administration of mevalonic acid. Conversely, the simvastatin induced activation of calpain was not prevented by mevalonic acid. These data delineate the signalling cascade that leads to muscle injury caused by statins. Our observations also have implications for improving the safety of this important medication and explain to some extent why physical exercise aggravates skeletal muscle side effects.

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Simvastatin reduces MMP-3 level in interleukin 1beta stimulated human chondrocyte culture.

Laghi Pasini F.

Department of Clinical Medicine and Immunological Sciences, Division of Clinical Immunology, University of Siena, Policlinico "Le Scotte", 53100 Siena, Italy.

OBJECTIVES: Matrix metalloproteinases (MMPs) produced by chondrocytes play a role in the development of cartilage degradation in joint diseases. Moreover, inhibition of MMP secretion by macrophages accumulating in arteriosclerotic plaques would account for the plaque stabilising activity of statins in cardiovascular patients. Recently, simvastatin has been shown to inhibit both developing and established collagen induced arthritis in a murine model. We thus decided to investigate the effect of simvastatin on the production of MMP-3 from cultured interleukin (IL)1 stimulated human chondrocytes. METHODS: Cells from human cartilage, obtained from eight subjects with osteoarthritis undergoing surgery for total hip prostheses, were cultured in the presence of different concentrations of simvastatin (5, 10, and 50 micromol/l) with and without IL1beta (5 ng/ml). MMP-3 level was measured in the culture medium after 48 h of incubation. RESULTS: IL1beta stimulation of chondrocytes increased MMP-3 concentration in the cultures (from 0.69 (0.09) to 1.94 (0.12) ng/microg protein). Incubation with simvastatin was associated with a dose dependent reduction in MMP-3 increase, both in the presence (-15%, -17%, and -26% with 5, 10, and 50 micromol/l, respectively) and in the absence (-32% with 50 micromol/l) of IL1beta. The inhibiting effect of simvastatin was completely reversed by the addition of mevalonate (100 micromol/l) or farnesol (10 micromol/l). CONCLUSIONS: Our data show that simvastatin, by blocking HMGCoA-reductase and interfering in the prenylation processes, is able to inhibit MMP-3 production from cultured human chondrocytes that have been either unstimulated or stimulated with IL1beta, thus suggesting a possible additional mechanism for statins in counteracting chronic joint disease related cartilage damage.

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Effects of simvastatin on cardiac performance and expression of sarcoplasmic reticular calcium regulatory proteins in rat heart.

Hu SJ.

The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China.

AIM: To investigate the effect of simvastatin on the cardiac contractile function and the alteration of gene and protein expression of the sarcoplasmic calcium regulatory proteins, including sarcoplasmic reticulum Ca2+-ATPase (SERCA), phospholamban (PLB), and ryanodine receptor 2 (RyR2) in rat hearts. METHODS: Langendorff-perfused rat hearts were subjected to 60-min perfusion with different concentrations of simvastatin (1, 3, 10, 30, or 100 microml/L), and the parameters of cardiac function such as left ventricular developed pressure (LVDP), +dp/dtmax, and -dp/dtmax were determined. The cultured neonatal rat ventricular cardiomyocytes were incubated with simvastatin (1, 3, 10, 30, and 100 micromol/L) for 1 h or 24 h. The levels of SERCA, PLB, and RyR2 expression were measured by reverse transcription-polymerase chain reaction and Western blot. Cytotoxic effect of simvastatin on ventricular cardiomyocytes was assessed by the MTT colorimetric assay. RESULTS: LVDP, +dp/dtmax, and -dp/dtmax of hearts were increased significantly after treatment with simvastatin 3, 10, and 30 micromol/L. In simvastatin-treated isolated hearts, the levels of mRNA expression of SERCA and RyR2 were elevated compared with the control (P<0.05), while the mRNA expression of PLB did not change. After the cultured neonatal rat ventricular cardiomyocytes were incubated with 3, 10, 30, and 100 mumol/L simvastatin for 1 h, SERCA and RyR2 mRNA expressions of cardiomyocytes rose, but there was no alteration in protein expressions. However, with the elongation of simvastatin treatment to 24 h, the protein expression of SERCA and RyR2 were also elevated. Additionally, simvastatin (1-30 micromol/L) had no influence on cell viability of cultured cardiac myocytes, but simvastatin 100 micromol/L inhibited the cell viability. CONCLUSION: Simvastatin improved cardiac performance accompanied by the elevation of SERCA and RyR2 gene and protein expression.

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Regulation of Vascular Tone from Spontaneously Hypertensive Rats by the HMG-CoA Reductase Inhibitor, Simvastatin.

Alvarez de Sotomayor M.

Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville, Spain.

The acute effect of simvastatin on aortic rings from spontaneously hypertensive rats (SHRs) was identified. Simvastatin-evoked relaxations of both depolarized and phenylephrine-precontracted arteries were independent of the presence of endothelium. This effect was inhibited by diltiazem and mevalonate, but not by the Rho-kinase inhibitor, Y-27632. Simvastatin prevented contraction induced by phenylephrine, calcium ionophore A-23187 and CaCl(2) in Ca(2+)-free medium. Y-27632 decreased the effect of simvastatin. On the contrary, contraction induced by noradrenaline in Ca(2+)-free medium was not affected. These results suggest that simvastatin elicited an effect on vascular smooth muscle cells from SHRs that may involve blockade of extracellular calcium entry and decrease vascular contraction by affecting Rho-kinase. Copyright (c) 2005 S. Karger AG, Basel.

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Neuroprotective Effect of Simvastatin in Stroke: A Comparison Between Adult and Neonatal Rat Models of Cerebral Ischemia.

Sironi L.

Institute of Pharmacology and Pharmacognosy, University of Urbino "Carlo Bo" Via S. Chiara, 27-61029 Urbino (PU), Italy.

Statins, the most widely used lipid lowering drugs, have been demonstrated to play a protective role in stroke. Animal studies confirmed the observations obtained in clinical trials and provided additional data on the putative mechanism/s of action underlying this beneficial effect. We have shown that simvastatin reduced the size of the infarct to a different extend, according to the animal model used. Indeed, in the rat neonatal model of hypoxia/ischemia simvastatin affords protection only when is administered before the ischemic insult. In contrast, in adult rats bearing middle cerebral artery occlusion, simvastatin exerted its beneficial effect on brain injury when injected for 3 days either before or after induction of ischemia. Studies carried out to determine the therapeutic window of simvastatin demonstrated that the protective effect is observed after a single dose and when the drug is administered within 3-6hours after ischemia. Simvastatin-dependent activation of eNOS has been claimed to be one of the main mechanisms responsible for neuroprotection. This hypothesis is confirmed in the adult animal model where eNOS is activated by either pre- or post- simvastatin treatment but is not supported by the data obtained in the neonate where eNOS activity is not affected by drug treatment. These observations suggest that the protective effect of simvastatin on stroke may be mediated by multiple mechanisms as can be expected by its pleiotropic effects.

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