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PubMed2003

Risk for myopathy with statin therapy in high-risk patients.

Emerging data suggest that the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) offer important benefits for the large population of individuals at high risk for coronary heart disease. This population encompasses a sizable portion of individuals who are also at high risk for drug-drug interactions due to their need for multiple medications. In general, statins are associated with a very small risk for myopathy (which may progress to fatal or nonfatal rhabdomyolysis); however, the potential for drug-drug interactions is known to increase this risk in specific high-risk groups. The incidence of myopathy associated with statin therapy is dose related and is increased when statins are used in combination with agents that share common metabolic pathways. Of particular concern is the potential for interactions with other lipid-lowering agents such as fibrates and niacin (nicotinic acid), which may be used in patients with mixed lipidemia, and with immunosuppressive agents, such as cyclosporine, which are commonly used in patients after transplantation. Clinicians should be alert to the potential for drug-drug interactions to minimize the risk of myopathy during long-term statin therapy in patients at high risk for coronary heart disease.

Calcium Channel Blockers↗
PubMed2006

The effect of early, intensive statin therapy on acute coronary syndrome: a meta-analysis of randomized controlled trials.

BACKGROUND: In addition to well-established secondary prevention benefits for atherosclerotic coronary artery disease, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are hypothesized to have short-term benefit in acute coronary syndrome (ACS), yet the data are inconsistent, with some trials underpowered to demonstrate therapeutic benefit. Our objective was to determine the effects of early, intensive statin therapy for ACS. DATA SOURCES: Studies found in the PubMed, MEDLINE, EMBASE, BIOSIS, SciSearch, PASCAL, and International Pharmaceutical Abstracts (IPA) databases and the Cochrane Controlled Trials Register published between January 1974 and May 2006. STUDY SELECTION: Randomized controlled trials of statins begun within 14 days of hospitalization for ACS were included. DATA EXTRACTION: Two investigators independently abstracted study quality, characteristics, and outcomes. DATA SYNTHESIS: Thirteen randomized controlled trials published before May 2006 were available, involving 17 963 adults (median number of patients, 135; median follow-up, 6 months). Early, intensive statin therapy for ACS decreased the rate of death and cardiovascular events over 2 years of follow-up (hazard ratio, 0.81 [95% confidence interval, 0.77-0.87]) (Q(3) = 58.54; P<.001; I(2) = 95%). Survival curves revealed that this benefit begins to occur between 4 and 12 months, achieving statistical significance by 12 months. There was no evidence of publication bias, and sensitivity analyses did not identify a dominating study or study characteristic. CONCLUSIONS: Early, intensive statin therapy reduces death and cardiovascular events after 4 months of treatment. The validity of this finding would be strengthened by an analysis of individual patient data.

Humans↗
PubMed2006

Primary prevention of cardiovascular diseases with statin therapy: a meta-analysis of randomized controlled trials.

BACKGROUND: While the role of hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins) in secondary prevention of cardiovascular (CV) events and mortality is established, their value for primary prevention is less clear. To clarify the role of statins for patients without CV disease, we performed a meta-analysis of randomized controlled trials (RCTs). METHODS: MEDLINE, EMBASE, Cochrane Collaboration, and American College of Physicians Journal Club databases were searched for RCTs published between 1966 and June 2005. We included RCTs with follow-up of 1 year or longer, more than 100 major CV events, and 80% or more of the population without CV disease. From each trial, demographic data, lipid profile, CV outcomes, mortality, and adverse outcomes were recorded. Summary relative risk (RR) ratios with 95% confidence intervals (CIs) were calculated using a random effects model. RESULTS: Seven trials with 42,848 patients were included. Ninety percent had no history of CV disease. Mean follow-up was 4.3 years. Statin therapy reduced the RR of major coronary events, major cerebrovascular events, and revascularizations by 29.2% (95% CI, 16.7%-39.8%) (P<.001), 14.4% (95% CI, 2.8%-24.6%) (P = .02), and 33.8% (95% CI, 19.6%-45.5%) (P<.001), respectively. Statins produced a nonsignificant 22.6% RR reduction in coronary heart disease mortality (95% CI, 0.56-1.08) (P = .13). No significant reduction in overall mortality (RR, 0.92 [95% CI, 0.84-1.01]) (P = .09) or increases in cancer or levels of liver enzymes or creatine kinase were observed. CONCLUSION: In patients without CV disease, statin therapy decreases the incidence of major coronary and cerebrovascular events and revascularizations but not coronary heart disease or overall mortality.

Cardiovascular Diseases↗
PubMed2003

Reduction in levels of 24S-hydroxycholesterol by statin treatment in patients with Alzheimer disease.

BACKGROUND: The statin treatment of dyslipidemia is associated with a reduced risk of development of Alzheimer disease (AD). The effect may be mediated by a reduction in cholesterol biosynthesis in the brain, by lowering levels of apolipoprotein E (apo E)-containing lipoproteins, or by pleitropic effects such as reduction in beta-amyloid production. In the brain, cholesterol from damaged or dying neurons is converted to 24S-hydroxycholesterol by cholesterol 24-hydroxylase (CYP46). The oxysterol is subsequently transferred across the blood-brain barrier, transported to the liver by low-density lipoproteins (LDLs), and excreted as bile acids. Most of plasma 24S-hydroxycholesterol is derived from brain cholesterol; consequently, plasma levels of the oxysterol reflect brain cholesterol catabolism. OBJECTIVE: To examine the effect of 3 statins and a nonstatin hypolipidemic agent on plasma levels of 24S-hydroxycholesterol and apo E in patients with AD. STUDY DESIGN: The study had a sequential parallel design. It was open-labeled and involved lipoprotein and 24S-hydroxycholesterol evaluations at baseline and at 6 weeks of treatment with 40 mg of lovastatin, simvastatin, or pravastatin sodium per day, or 1 g of extended-release niacin per day. Blood samples were drawn after a 12-hour fast for measurement of plasma sterols, oxysterols, lipoprotein cholesterol, and levels of apo E, plasma transaminases, and glucose. Measurements were made at baseline and during treatment. RESULTS: Statin treatment reduced levels of plasma lathosterol by 49.5%, 24S-hydroxycholesterol by 21.4%, LDL cholesterol by 34.9%, and total cholesterol by 25%. The ratios of lathosterol-campesterol and 24S-hydroxycholesterol-LDL cholesterol were reduced significantly, but the ratio of 24S-hydroxycholesterol-total cholesterol was unchanged. Extended-release niacin also significantly reduced levels of 24S-hydroxycholesterol by 10% and LDL cholesterol by 18.1%. None of the agents lowered plasma concentration of apo E. CONCLUSIONS: Statins lowered levels of plasma 24S-hydroxycholesterol without affecting levels of apo E. The LDL lowering was more pronounced than 24S-hydroxycholesterol reductions. The effect of statins on LDL partially explains the reduction of plasma oxysterol level.

Aged↗
PubMed2004

Statins and other cholesterol-lowering medications and the presence of glaucoma.

OBJECTIVE: To explore whether oral statin and other antihyperlipidemic medications are associated with open-angle glaucoma. METHODS: The administrative clinical databases maintained at the Veterans Affairs Medical Center, Birmingham, Ala, were used to conduct a matched case-control study. Cases were all male patients aged 50 years and older with a new diagnosis of glaucoma on an outpatient or inpatient visit during the period January 1, 1997, through December 31, 2001. Ten control subjects were matched to each case according to age (within 1 year). Prescription files were assessed for statin use as well as additional medications to lower cholesterol levels. Information on comorbid medical conditions was also obtained. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Longer duration of statin use was associated with a lower risk of open-angle glaucoma (P for trend =.04) primarily among subjects with 24 months or more of use (OR, 0.60; 95% CI, 0.39-0.92). When stratified by comorbid medical condition, among those with cardiovascular disease (OR, 0.63; 95% CI, 0.42-0.97), lipid metabolism disorders (OR, 0.63; 95% CI, 0.41-0.99), and the absence of cerebrovascular disease (OR, 0.76; 95% CI, 0.58-0.99), statins demonstrated a protective effect on open-angle glaucoma. Finally, a protective association was also observed among those who used nonstatin cholesterol-lowering agents (OR, 0.59; 95% CI, 0.37-0.97). CONCLUSIONS: Initial examination of an administrative clinical database indicates the intriguing possibility that long-term use of oral statins may be associated with a reduced risk of open-angle glaucoma, particularly among those with cardiovascular and lipid diseases. Nonstatin cholesterol-lowering agents were also associated with a reduced risk of having open-angle glaucoma. Additional investigation is warranted as to whether these classes of agents may provide an additional therapeutic addition for glaucoma.

Administration, Oral↗
PubMedDate not supplied

Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials.

CONTEXT: Lowering low-density lipoprotein cholesterol (LDL-C) is known to reduce risk of recurrent coronary heart disease in middle-aged men. However, this effect has been uncertain in elderly people and women. OBJECTIVE: To estimate the risk reduction of coronary heart disease and total mortality associated with statin drug treatment, particularly in elderly individuals and women. DATA SOURCES: Trials published in English-language journals were retrieved by searching MEDLINE (1966-December 1998), bibliographies, and authors' reference files. STUDY SELECTION: Studies in which participants were randomized to statin or control treatment for at least 4 years and clinical disease or death was the primary outcome were included in the meta-analysis (5 of 182 initially identified). DATA EXTRACTION: Information on sample size, study drug duration, type and dosage of statin drug, participant characteristics at baseline, reduction in lipids during intervention, and outcomes was abstracted independently by 2 authors (J.H. and S.V.) using a standardized protocol. Disagreements were resolved by consensus. DATA SYNTHESIS: Data from the 5 trials, with 30 817 participants, were included in this meta-analysis. The mean duration of treatment was 5.4 years. Stati n drug treatment was associated with a20% reduction in total cholesterol, 28% reduction in LDL-C, 13% reduction in triglycerides, and 5% increase in high-density lipoprotein cholesterol. Overall, statin drug treatment reduced risk 31 % in major coronary events (95% confidence interval [CI], 26%-36%) and 21 % in all-cause mortality (95% CI, 14%-28%). The risk reduction in major coronary events was similar between women (29%; 95% Cl, 13 %-42 %) and men (31 %; 95% CI, 26%-35%), and between persons aged at least 65 years (32%; 95% CI, 23%-39%) and persons younger than 65 years (31 %; 95% CI, 24%-36%). CONCLUSIONS: Our meta-analysis indicates that reduction in LDL-C associated with statin drug treatment decreases the risk of coronary heart disease and all-cause mortality. The risk reduction was similar for men and women and for elderly and middle-aged persons.

Aged↗
PubMedDate not supplied

Long-term persistence in use of statin therapy in elderly patients.

CONTEXT: Knowledge of long-term persistence with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy is limited because previous studies have observed patients for short periods of time, in closely monitored clinical trials, or in other unrepresentative settings. OBJECTIVE: To describe the patterns and predictors of long-term persistence with statin therapy in an elderly US population. DESIGN, SETTING, AND PATIENTS: Retrospective cohort study including 34 501 enrollees in the New Jersey Medicaid and Pharmaceutical Assistance to the Aged and Disabled programs who were 65 years of age and older, initiated statin treatment between 1990 and 1998, and who were followed up until death, disenrollment, or December 31, 1999. MAIN OUTCOME MEASURES: Proportion of days covered (PDC) by a statin in each quarter during the first year of therapy and every 6 months thereafter; predictors of suboptimal persistence during each interval (PDC <80%) were identified using generalized linear models for repeated measures. RESULTS: The mean PDC was 79% in the first 3 months of treatment, 56% in the second quarter, and 42% after 120 months. Only 1 patient in 4 maintained a PDC of at least 80% after 5 years. The proportion of patients with a PDC less than 80% increased in a log-linear manner, comprising 40%, 61%, and 68% of the cohort after 3, 12, and 120 months, respectively. Independent predictors of poor long-term persistence included nonwhite race, lower income, older age, less cardiovascular morbidity at initiation of therapy, depression, dementia, and occurrence of coronary heart disease events after starting treatment. Patients who initiated therapy between 1996-1998 were 21% to 25% more likely to have a PDC of at least 80% than those who started in 1990. CONCLUSIONS: Persistence with statin therapy in older patients declines substantially over time, with the greatest drop occurring in the first 6 months of treatment. Despite slightly better persistence among patients who began treatment in recent years, long-term use remains low. Interventions are needed early in treatment and among high-risk groups, including those who experience coronary heart disease events after initiating treatment.

Aged↗
PubMed2006

Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial.

CONTEXT: Prior intravascular ultrasound (IVUS) trials have demonstrated slowing or halting of atherosclerosis progression with statin therapy but have not shown convincing evidence of regression using percent atheroma volume (PAV), the most rigorous IVUS measure of disease progression and regression. OBJECTIVE: To assess whether very intensive statin therapy could regress coronary atherosclerosis as determined by IVUS imaging. DESIGN AND SETTING: Prospective, open-label blinded end-points trial (A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden [ASTEROID]) was performed at 53 community and tertiary care centers in the United States, Canada, Europe, and Australia. A motorized IVUS pullback was used to assess coronary atheroma burden at baseline and after 24 months of treatment. Each pair of baseline and follow-up IVUS assessments was analyzed in a blinded fashion. PATIENTS: Between November 2002 and October 2003, 507 patients had a baseline IVUS examination and received at least 1 dose of study drug. After 24 months, 349 patients had evaluable serial IVUS examinations. INTERVENTION: All patients received intensive statin therapy with rosuvastatin, 40 mg/d. MAIN OUTCOME MEASURES: Two primary efficacy parameters were prespecified: the change in PAV and the change in nominal atheroma volume in the 10-mm subsegment with the greatest disease severity at baseline. A secondary efficacy variable, change in normalized total atheroma volume for the entire artery, was also prespecified. RESULTS: The mean (SD) baseline low-density lipoprotein cholesterol (LDL-C) level of 130.4 (34.3) mg/dL declined to 60.8 (20.0) mg/dL, a mean reduction of 53.2% (P<.001). Mean (SD) high-density lipoprotein cholesterol (HDL-C) level at baseline was 43.1 (11.1) mg/dL, increasing to 49.0 (12.6) mg/dL, an increase of 14.7% (P<.001). The mean (SD) change in PAV for the entire vessel was -0.98% (3.15%), with a median of -0.79% (97.5% CI, -1.21% to -0.53%) (P<.001 vs baseline). The mean (SD) change in atheroma volume in the most diseased 10-mm subsegment was -6.1 (10.1) mm3, with a median of -5.6 mm3 (97.5% CI, -6.8 to -4.0 mm3) (P<.001 vs baseline). Change in total atheroma volume showed a 6.8% median reduction; with a mean (SD) reduction of -14.7 (25.7) mm3, with a median of -12.5 mm3 (95% CI, -15.1 to -10.5 mm3) (P<.001 vs baseline). Adverse events were infrequent and similar to other statin trials. CONCLUSIONS: Very high-intensity statin therapy using rosuvastatin 40 mg/d achieved an average LDL-C of 60.8 mg/dL and increased HDL-C by 14.7%, resulting in significant regression of atherosclerosis for all 3 prespecified IVUS measures of disease burden. Treatment to LDL-C levels below currently accepted guidelines, when accompanied by significant HDL-C increases, can regress atherosclerosis in coronary disease patients. Further studies are needed to determine the effect of the observed changes on clinical outcome. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00240318.

Aged↗
PubMed2001

Statins prevent endothelial cell activation induced by antiphospholipid (anti-beta2-glycoprotein I) antibodies: effect on the proadhesive and proinflammatory phenotype.

OBJECTIVE: To investigate the ability of statins, the inhibitors of the hydroxymethylglutaryl-coenzyme A reductase enzyme, to affect endothelial cell activation induced by anti-beta2-glycoprotein I (anti-beta2GPI) antibodies in vitro. METHODS: Human umbilical vein endothelial cell (HUVEC) activation was evaluated as U937 monocyte adhesion, E-selectin, and intercellular adhesion molecule I (ICAM-1) expression by cell enzyme-linked immunosorbent assay and as interleukin-6 (IL-6) messenger RNA (mRNA) expression by RNA protection assay. E-selectin-specific nuclear factor kappaB (NF-kappaB) DNA-binding activity was evaluated by the gel-shift assay. HUVECs were activated by polyclonal affinity-purified IgG, human monoclonal IgM anti-beta2GPI antibodies, human recombinant IL-1beta, tumor necrosis factor alpha, or lipopolysaccharide (LPS). RESULTS: Fluvastatin reduced, in a concentration-dependent manner (1-10 microM), the adhesion of U937 to HUVECs and the expression of E-selectin and ICAM-1 induced by anti-beta2GPI antibodies as well as by cytokines or LPS. Another lipophilic statin, simvastatin, displayed similar effects but to a lesser extent than fluvastatin. The inhibition of E-selectin expression exerted by fluvastatin was related to the impairment of NF-kappaB binding to DNA. Moreover, the drug attenuated the expression of IL-6 mRNA in HUVEC exposed to anti-beta2GPI antibodies or cytokines. Incubation of HUVECs with mevalonate (100 microM), concomitantly with fluvastatin, greatly prevented the inhibitory effect of statin. CONCLUSION: Endothelial activation mediated by anti-beta2GPI antibody can be inhibited by statins. Because of the suggested role of endothelial cell activation in the pathogenesis of antiphospholipid syndrome (APS), our data provide, for the first time, a rationale for using statins as an additional therapeutic tool in APS.

Antibodies, Antiphospholipid↗
PubMed2006

In vivo and in vitro characterization of skeletal muscle metabolism in patients with statin-induced adverse effects.

OBJECTIVE: Statins (3-hydroxymethylglutaryl-coenzyme A reductase inhibitor) are widely used to treat hypercholesterolemia. They are generally well tolerated, but myotoxic effects have been reported and the corresponding mechanisms are still a matter of debate. The aim of the present study was to determine whether impairment of calcium homeostasis and/or mitochondrial impairment could account for the adverse effects of statins in skeletal muscle. METHODS: Eleven patients with increased creatine kinase levels and myalgias after statin treatment were evaluated using in vitro contracture tests (IVCTs), histology, and 31P magnetic resonance spectroscopy (31P-MRS). RESULTS: IVCT results were abnormal in 7 of the 9 patients, indicating an impaired calcium homeostasis. The 31P-MRS investigation disclosed no anomaly at rest, and the aerobic function assessed during the postexercise recovery period was normal. On the contrary, the pH recovery kinetics was significantly slowed down as indicated by a reduced proton efflux, which could be ultimately linked to a failure of calcium homeostasis. Overall, our observations indicate a normal mitochondrial function and raise the possibility that statins may unmask a latent pathology involving an impairment of calcium homeostasis such as malignant hyperthermia (MH). CONCLUSION: In case of susceptibility to MH, statins treatment must be administered with caution, and signs of adverse effects should be checked.

Aged↗
PubMed2003

Statins lower plasma and lymphocyte ubiquinol/ubiquinone without affecting other antioxidants and PUFA.

It has been shown that treating hypercholesterolemic patients (HPC) with statins leads to a decrease, at least in plasma, not only in cholesterol, but also in important non-sterol compounds such as ubiquinone (CoQ10), and possibly dolichols, that derive from the same biosynthetic pathway. Plasma CoQ10 decrease might result in impaired antioxidant protection, therefore leading to oxidative stress. In the present paper we investigated the levels in plasma, lymphocytes and erythrocytes, of ubiquinol and ubiquinone, other enzymatic and non-enzymatic lipophilic and hydrophilic antioxidants, polyunsaturated fatty acids of phosfolipids and cholesterol ester fractions, as well as unsaturated lipid and protein oxidation in 42 hypercholesterolemic patients treated for 3 months. The patients were treated with different doses of 3 different statins, i.e. atorvastatin 10 mg (n = 10) and 20 mg (n = 7), simvastatin, 10 mg (n = 5) and 20 mg (n = 10), and pravastatin, 20 mg (n = 5) and 40 mg (n = 5). Simvastatin, atorvastatin and pravastatin produced a dose dependent plasma depletion of total cholesterol (t-CH), LDL-C, CoQ10H2, and CoQ10, without affecting the CoQ10H2/CoQ10 ratio. The other lipophilic antioxidants (d-RRR-alpha-tocopherol-vit E-, gamma-tocopherol, vit A, lycopene, and beta-carotene), hydrophilic antioxidants (vit C and uric acid), as well as, TBA-RS and protein carbonyls were also unaffected. Similarly the erythrocyte concentrations of GSH and PUFA, and the activities of enzymatic antioxidants (Cu,Zn-SOD, GPx, and CAT) were not significantly different from those of the patients before therapy. In lymphocytes the reduction concerned CoQ10H2, CoQ10, and vit E; other parameters were not investigated. The observed decline of the levels of CoQ10H2 and CoQ10 in plasma and of CoQ10H2, CoQ10 and vit E in lymphocytes following a 3 month statin therapy might lead to a reduced antioxidant capacity of LDL and lymphocytes, and probably of tissues such as liver, that have an elevated HMG-CoA reductase enzymatic activity. However, this reduction did not appear to induce a significant oxidative stress in blood, since the levels of the other antioxidants, the pattern of PUFA as well as the oxidative damage to PUFA and proteins resulted unchanged. The concomitant administration of ubiquinone with statins, leading to its increase in plasma, lymphocytes and liver may cooperate in counteracting the adverse effects of statins, as already pointed out by various authors on the basis of human and animal studies.

Antioxidants↗
PubMed2002

Short- and long-term changes of flow-mediated vasodilation in patients under statin therapy.

BACKGROUND: Flow-mediated vasodilation (FMD) of the brachial artery (BA) has been shown to improve in response to lipid-lowering therapy and other therapeutic interventions, usually within 1 to 2 months. Whether FMD remains improved under therapy in the longer term is unknown. HYPOTHESIS: The aim of this study was to examine the short- and long-term changes of FMD under statin therapy. METHODS: Flow-mediated vasodilation and nitroglycerin-mediated vasodilation (NMD) of the BA were measured with high-resolution ultrasound (13 MHz) at baseline and at 4 and 10 months in 18 consecutively recruited patients with coronary artery disease (CAD), in whom statin therapy was newly established. RESULTS: The decrease of total plasma cholesterol levels after 4 and 10 months of statin therapy (243 +/- 31 vs. 186 +/- 30 vs. 191 +/- 40 mg/dl; p < 0.001) was accompanied by an increase in FMD from 4.4 +/- 3.8% at baseline to 9.6 +/- 2.7% at 4 months and to 9.5 +/- 2.6% at 10 months (p < 0.001). Nitroglycerin-mediated vasodilation showed a trend toward improvement after 4 months (14.6 +/- 7.5 vs. 19.1 +/- 3.6 vs. 19.4 +/- 5.6%; NS). The FMD/NMD ratio also rose significantly after 4 months and remained improved after 10 months of statin therapy (0.31 +/- 0.25 vs. 0.52 +/- 0.16 vs. 0.50 +/- 0.14; p < 0.01). CONCLUSION: Statin therapy is associated with sustained improvement of endothelial function up to 10 months. These data support the utility of FMD for the assessment of vascular function in response to lipid-lowering therapy or other therapeutic interventions in long-term studies.

Adult↗
PubMed2003

New dimension of statin action on ApoB atherogenicity.

Newer, more effective statins are powerful agents for reducing elevated levels of low-density lipoprotein (LDL) cholesterol and thereby lowering the risk of coronary heart disease (CHD) and related adverse events. Although LDL remains the primary target of therapy for reducing CHD risk, increased interest is focusing on apolipoprotein B (apoB)-containing lipoprotein subfractions--particularly very-low-density lipoprotein (VLDL). VLDL remnants, and intermediate-density lipoproteins (IDL)--as secondary targets of therapy. Elevated apoB is known to be an important risk factor for CHD, and dysregulation of the metabolism of apoB-containing lipoproteins is involved in the progression of atherosclerosis. Statins reduce circulating concentrations of atherogenic apoB-containing lipoproteins by decreasing the production of VLDL in the liver and, thus, the production of VLDL remnants and LDL. Statins also increase the clearance of these particles through upregulation of LDL receptors in the liver. Efforts to develop statins with enhanced lipid-modifying properties are ongoing. The optimal statin would offer a high degree of inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a prolonged duration of action, hepatic selectivity for maximal upregulation of LDL receptors, and a low potential for drug-drug interactions. Recent studies have shown that rosuvastatin, a new agent in this class, demonstrates these qualities. Rosuvastatin is a highly effective inhibitor of HMG-CoA reductase, is relatively nonlipophilic, has a half-life of approximately 20 h, exhibits hepatic selectivity, has little systemic availability, and has a low potential for drug-drug interactions because of its limited degree of metabolism by the cytochrome P450 system. A recent double-blind, crossover study revealed that treatment with rosuvastatin resulted in marked reductions in apoB-containing lipoproteins in patients with type IIa or IIb dyslipidemia. By reducing the number of atherogenic lipoprotein particles, rosuvastatin decreases the atherosclerotic burden in hyperlipidemic patients at high risk for CHD and related adverse outcomes.

Animals↗
PubMed2003

Effects of statins in reducing thrombotic risk and modulating plaque vulnerability.

A large body of evidence demonstrates that statin therapy reduces risk for coronary events. This benefit probably stems in large part from lipid lowering, but lipid-independent cellular effects may also contribute. Statin therapy may lower the risk of thrombosis by reducing tissue factor expression and increasing plasminogen activators while reducing plasminogen-activator inhibitor. The statins may also improve endothelial function and reduce inflammatory response by increasing nitric oxide activity; all statins tested can decrease levels of C-reactive protein, a systemic marker of inflammation. Indeed, limiting inflammation may prove an important mechanism of statins' clinical benefits due to both lipid lowering and direct cellular effects. For example, attenuation of inflammation probably promotes maintained integrity of the fibrous cap of the atherosclerotic lesion by inhibiting processes that degrade the collagenous structure of the cap. Rupture of the fibrous cap causes most fatal coronary thrombosis.

Animals↗
PubMed2003

The power of statins: aggressive lipid lowering.

A large body of evidence has demonstrated that reductions in low-density lipoprotein cholesterol (LDL-C) decrease the risk of coronary heart disease (CHD) and related adverse events. The greatest reductions in morbidity and mortality are attained in higher-risk patients, suggesting that targeting this group can maximize the cost-effectiveness of statins, since fewer patients need to be treated to prevent one event. High-risk individuals (those with preexisting CHD or CHD risk equivalents) require aggressive lipid lowering to achieve the stringent LDL-C goal levels established by the third report of the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP III). The hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, have assumed the central role in this setting because of their superior ability to reduce LDL-C across the spectrum of CHD risk. Rosuvastatin, a new agent in this class, reduces LDL-C to a significantly greater degree than atorvastatin, pravastatin, or simvastatin. The more aggressive goals put forward since ATP I (1987) have heightened interest in more efficacious statins. As a result, simvastatin, atorvastatin, and now rosuvastatin have been developed, adding sequentially greater LDL-C-reducing capacity for the physician. Substantially more patients, particularly high-risk patients, are thereby able to achieve NCEP ATP III target LDL-C levels with rosuvastatin. Other cholesterol-lowering drugs (bile acid sequestrants, niacin, plant stanols, and fibrates) are much less effective at lowering LDL-C and are much less well tolerated but may be useful when combined with statins. A novel class of agents, cholesterol transport inhibitors, have recently become available. These and other new agents hold promise to help achieve ATP III goals when used in combination regimens initiated with a statin.

Cholesterol, LDL↗
PubMed2005

The benefits of statin therapy--what questions remain?

Early hydroxymethylglutaryl-CoA reductase inhibitor (statin) trials provided the first evidence of the benefits of statin therapy in secondary prevention of coronary heart disease (CHD). Outcomes data from more recent trials involving atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin, have since expanded the patient population shown to benefit from statin therapy. Current studies are evaluating the benefits of lowering lipid levels with statins to below current goals, as well as examining benefits in special patient populations and evaluating the value of surrogate markers of CHD. Early trials provided a solid foundation of knowledge on the efficacy and safety of statins. Recent and ongoing trials generate new data to resolve remaining questions in the fields of CHD prevention and lipidology.

Cerebrovascular Disorders↗
PubMed2006

Different anti-HCV profiles of statins and their potential for combination therapy with interferon.

We recently developed a genome-length hepatitis C virus (HCV) RNA replication system (OR6) with luciferase as a reporter. The OR6 assay system has enabled prompt and precise quantification of HCV RNA replication. Pegylated interferon (IFN) and ribavirin combination therapy is the world standard for chronic hepatitis C, but its effectiveness is limited to about 55% of patients. Newer therapeutic approaches are needed. In the present study, we used the OR6 assay system to evaluate the anti-HCV activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, called statins, and their effects in combination with IFN-alpha. Five types of statins (atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin) were examined for their anti-HCV activities. Fluvastatin exhibited the strongest anti-HCV activity (IC50: 0.9 micromol/L), whereas atorvastatin and simvastatin showed moderate inhibitory effects. However, lovastatin, reported recently as an inhibitor of HCV replication, was shown to exhibit the weakest anti-HCV activity. The anti-HCV activities of statins were reversed by the addition of mevalonate or geranylgeraniol. Surprisingly, however, pravastatin exhibited no anti-HCV activity, although it worked as an inhibitor for HMG-CoA reductase. The combination of IFN and the statins (except for pravastatin) exhibited strong inhibitory effects on HCV RNA replication. In combination with IFN, fluvastatin also exhibited a synergistic inhibitory effect. In conclusion, statins, especially fluvastatin, could be potentially useful as new anti-HCV reagents in combination with IFN.

Antiviral Agents↗
PubMed2006

Plasma cholesterol is hyperresponsive to statin in ABCG5/ABCG8 transgenic mice.

Interindividual variation exists in response to statin therapy. It has been hypothesized that subjects with higher baseline cholesterol synthesis rates are more sensitive to statins. To directly test this hypothesis, mice overexpressing the heterodimeric ATP-binding cassette (ABC) transporter G5/G8 (G5G8(Tg) mice) were treated with lovastatin because they have a compensatory increase in cholesterol biosynthesis as a result of increased cholesterol excretion into bile and feces. As expected, lovastatin treatment did not alter plasma and hepatic cholesterol levels in wild-type mice. Interestingly, this treatment significantly reduced plasma concentration and hepatic content of cholesterol by 42% and 17.3%, respectively, in the statin-treated versus untreated G5G8(Tg) mice despite a greater feedback upregulation of genes in the pathway of cholesterol biosynthesis in the lovastatin-treated G5G8(Tg) mice. The reduced plasma cholesterol concentration is unlikely to be attributed to LDL and HDL receptors because the protein levels of both receptors remained unchanged. Surprisingly, statin treatment resulted in an increase in biliary cholesterol concentration, which was associated with an upregulation in hepatic mRNA and protein levels of ABCG5 and ABCG8, and in hepatic mRNA levels of Niemann-Pick C1-Like 1 (NPC1L1), a gene that is required for intestinal cholesterol absorption. In conclusion, mice with higher endogenous cholesterol synthesis rates are more sensitive to statin. A synergistic hypocholesterolemic effect could be potentially achieved in humans by simultaneously inhibiting cholesterol biosynthesis and promoting ABCG5/ABCG8-mediated cholesterol excretion.

ATP Binding Cassette Transporter, Subfamily G, Mem↗