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At least 847 records · Page 47Linked to original sources
PubMed2007

Optimal low-density lipoprotein cholesterol lowering--morning versus evening statin administration.

OBJECTIVE: To determine the best time to administer statins for optimal lowering of low-density lipoprotein cholesterol (LDL-C) by reviewing the clinical evidence evaluating the chronobiologic effects of morning versus evening statin administration. DATA SOURCES: Using the MeSH terms HMG-CoA reductase inhibitors, statins, morning and evening dosing, and clinical trials, a literature review was conducted to identify articles in MEDLINE (1966-December 2006), International Pharmaceutical Abstracts (1970-December 2006), and IOWA Drug Information Systems (1985-December 2006). DATA SYNTHESIS: Seven English-language studies evaluating morning and evening statin administration were identified and evaluated. Based on the available data, simvastatin demonstrated a pronounced LDL-C percentage reduction with evening dosing. Although not statistically significant, a trend in the LDL-C percentage reduction favoring evening statin administration was noted with lovastatin, pravastatin, and rosuvastatin. Atorvastatin demonstrated similar LDL-C reduction regardless of administration time. With the exception of simvastatin, the trials comparing morning versus evening effects of statins on LDL-C have several significant methodologic shortcomings, including small sample size, lack of statistical power, and inappropriate exclusion criteria that did not include or did not mention drug-induced effects on lipids. CONCLUSIONS: There are sufficient data to support evening administration of simvastatin to achieve optimal lowering of LDL-C levels. Rigorous and robust trials are necessary to determine the best administration time to achieve optimal LDL-C lowering for lovastatin, pravastatin, rosuvastatin, atorvastatin, and fluvastatin.

Anticholesteremic Agents↗
PubMed2006

Pleiotropic effects of statins and related pharmacological experimental approaches.

Statins, the most widely prescribed cholesterol-lowering drugs, are considered to be first-line therapeutics for the prevention of coronary heart disease and atherosclerosis. Statins act by inhibiting the enzyme 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme in endogenous cholesterol biosynthesis, which catalyzes the reduction of HMG-CoA to mevalonic acid. Inhibition of this enzyme has proven to be effective for lowering plasma total cholesterol, low-density lipoprotein-cholesterol, and triglyceride levels in humans and can therefore be useful to treat atherosclerotic and dyslipidemic disorders. However, the clinical benefits of statins appear to extend beyond their lipid-lowering effects. Besides reducing cholesterol biosynthesis, inhibition of mevalonate by statins also leads to a reduction in the synthesis of important intermediates, such as the isoprenoids farnesyl pyrophosphate and geranylgeranyl pyrophosphate. These intermediates are involved in the posttranslational prenylation of several proteins (e.g., Ras, Rho, Rac) that modulate a variety of cellular processes including cellular signaling, differentiation, and proliferation. Given the central role of these isoprenylated proteins in endothelial function, atherosclerotic plaque stability, platelet activity, coagulation, oxidation, and inflammatory and immunologic responses, it could be anticipated that these compounds may exert multiple beneficial effects in a broad spectrum of disorders including cardiovascular disease, osteoporosis, Alzheimer's disease and related vascular dementia, viral and bacterial infection, etc. This article summarizes these cholesterol-lowering-independent effects of statins, termed "pleiotropic effects", and the underlying mechanisms, as well as the preclinical experimental approaches that would be useful to evaluate the effects of statins.

Animals↗
PubMed2006

A systems biology strategy reveals biological pathways and plasma biomarker candidates for potentially toxic statin-induced changes in muscle.

BACKGROUND: Aggressive lipid lowering with high doses of statins increases the risk of statin-induced myopathy. However, the cellular mechanisms leading to muscle damage are not known and sensitive biomarkers are needed to identify patients at risk of developing statin-induced serious side effects. METHODOLOGY: We performed bioinformatics analysis of whole genome expression profiling of muscle specimens and UPLC/MS based lipidomics analyses of plasma samples obtained in an earlier randomized trial from patients either on high dose simvastatin (80 mg), atorvastatin (40 mg), or placebo. PRINCIPAL FINDINGS: High dose simvastatin treatment resulted in 111 differentially expressed genes (1.5-fold change and p-value<0.05), while expression of only one and five genes was altered in the placebo and atorvastatin groups, respectively. The Gene Set Enrichment Analysis identified several affected pathways (23 gene lists with False Discovery Rate q-value<0.1) in muscle following high dose simvastatin, including eicosanoid synthesis and Phospholipase C pathways. Using lipidomic analysis we identified previously uncharacterized drug-specific changes in the plasma lipid profile despite similar statin-induced changes in plasma LDL-cholesterol. We also found that the plasma lipidomic changes following simvastatin treatment correlate with the muscle expression of the arachidonate 5-lipoxygenase-activating protein. CONCLUSIONS: High dose simvastatin affects multiple metabolic and signaling pathways in skeletal muscle, including the pro-inflammatory pathways. Thus, our results demonstrate that clinically used high statin dosages may lead to unexpected metabolic effects in non-hepatic tissues. The lipidomic profiles may serve as highly sensitive biomarkers of statin-induced metabolic alterations in muscle and may thus allow us to identify patients who should be treated with a lower dose to prevent a possible toxicity.

Atorvastatin↗
PubMed2005

In-hospital initiation of statin therapy in acute coronary syndromes: maximizing the early and long-term benefits.

Patients with acute coronary syndrome (ACS) are at high risk for recurrent coronary events, sudden death, and all-cause mortality. Conventional revascularization therapies reduce the risk of further ischemia but do not affect the underlying atherosclerotic disease. Statins have a proven record in the secondary prevention of coronary heart disease. Furthermore, statins have been shown to exert varying degrees of pleiotropic effects, which may stabilize vulnerable atherosclerotic plaques. A compelling body of evidence from randomized controlled trials demonstrates that high-dose, potent statin therapy initiated immediately after an acute coronary event can significantly reduce early as well as longer-term morbidity and mortality. Furthermore, high-dose, potent statin therapy displays a reasonable safety profile. National guidelines now recommend that in patients with ACS, statin therapy should be initiated in hospital prior to discharge, irrespective of baseline low-density lipoprotein cholesterol levels, to improve clinical outcomes. Every effort should be made to ensure all eligible patients with ACS are initiated and maintained on statin therapy.

Angina, Unstable↗
PubMed2002

Effect of HMG-CoA reductase inhibitors (statins) on bone mineral density.

Recent studies have suggested that 3-hydroxy-3-methylglutaryl - coenzyme A (HMG-CoA) reductase inhibitors (statins) can increase the bone mineral density (BMD). Our objective was to determine if patients on statin drugs were more likely to have a greater bone mineral density and lower risk of osteoporosis than patients not taking these drugs. A computerized pharmacy system provided complete medication dispensing records for the 983 patients (697 men and 286 women) referred for bone mineral density testing at a single Veterans Affairs Medical Center. In an analysis of covariance model that adjusted for age, body mass index, race, and vitamin use, men using statin drugs were more likely to have a greater BMD of the spine (p < 0.005). The mean difference (effect size) was 0.05 g/cm2 (95% confidence interval of [CL] 0.02-0.09), about 5.3% greater BMD. In women, the association was not significant. The risk of osteoporosis (defined as a T-score < or = -2.5) was determined using logistic regression analysis after adjustment for potential confounding variables. Although not statistically significant, men who received statin drugs for more than 2 yr were approximately half as likely to develop osteoporosis (odds ratio [OR] =.55, 95% CI = 0.28-1.08). A similar effect was observed in women taking statins for any length of time (OR = 0.36, 95% CI = 0.12-1.07). This study suggests that statin drugs may decrease osteoporosis risk, warranting a randomized controlled trial.

Aged↗
PubMed2001

Statins: new drugs for treating osteoporosis?

Statins are widely used lipid-lowering drugs that reduce cholesterol synthesis by inhibiting 3-hydroxy-3-glutaryl-coenzyme A (HMG-CoA) reductase activity. They also strongly stimulate bone formation in rodents. If the drugs' potent bone-building activity results directly from inhibition of HMG-CoA reductase, there should be less bone fracturing in humans who have taken statins to lower their serum cholesterol and prevent heart attacks, but the data gleaned from several databases are contradictory. According to some reports the lipid-lowering doses of oral statins increased bone mineral density and more than halved the risk of fracturing various bones, while according to others, including the very large Women's Health Initiative Observational Study (WHI-OS), the drugs did not significantly affect the fracturing risk. Such contradictory data could be due in part to one of the commonly used statins, pravastatin which only targets hepatocytes, or due to bone growth being stimulated by something other than inhibition of HMG-CoA reductase. Therefore, different doses of statins may be needed to build bone or optimally lower serum cholesterol. To be able to answer the question posed by the title of this editorial, it will be necessary to carry out a controlled trial using designer statins that are less liver-oriented and thus better for assessing the optimal doses needed, specifically for osteogenicity rather than for their cholesterol-lowering ability.

Animals↗
PubMed2004

Statins: can the new generation make an impression?

Although large-scale statin trials have demonstrated significant reductions in cardiovascular risk, there are many patients who have a cardiovascular event despite receiving statin therapy. There is increasing evidence that larger reductions in low-density lipoprotein cholesterol (LDL-C) are associated with greater improvements in cardiovascular morbidity and mortality, which highlights the need for more efficacious statins. This article will review the lipid-altering effects of two new statins, rosuvastatin and pitavastatin. Rosuvastatin represents an advance in the pharmacological and clinical properties of other available agents. The large LDL-C reductions observed with rosuvastatin, even at the start dose of 10 mg and in patients switched from other statins to rosuvastatin 10 mg, should help to improve goal attainment, while reducing the need for dose titration. The ability of rosuvastatin to improve other elements of the lipid profile, such as high-density lipoprotein cholesterol (HDL-C), triglycerides and non-HDL-C, may be of utility in patients with diabetes and the metabolic syndrome. Increases in HDL-C, along with the greater efficacy of rosuvastatin for reducing LDL-C and non-HDL-C, may obviate the need for combination therapy. Results of a number of outcome studies with rosuvastatin are expected over the next 5 years, which will contribute to the evidence base for statin therapy and cardiovascular disease prevention.

Cholesterol, HDL↗
PubMed2006

Statins and breast cancer: a smoking gun or guilt by association?

Statins are widely prescribed, effective cholesterol-lowering drugs. Indeed, atorvastatin and simvastatin were the most commonly prescribed drugs in the US in 2004, with > 70 million prescriptions written for atorvastatin alone. Statins are pleiotropic agents and, after an early study of patients with coronary heart disease showed a lower than expected incidence of cancers, preclinical studies were carried out that have supported the potential anticancer activity of these compounds. However, clinical reports on the relationship between statin use and breast cancer risk have yielded mixed results, with no association and both positive and negative associations being observed. Because breast cancer is the most frequent cancer in women, any link between statin use and breast cancer risk would have major public health implications. The current evidence suggests that statins are safe and effective agents in treating hyperlipidaemia and no evidence of increase or decrease risk of breast cancer. Indeed, more research is needed to define whether long-term statin therapy may decrease or increase the risk of breast cancer.

Breast Neoplasms↗
PubMed2006

Lipid changes and statins in chronic renal insufficiency.

It has been known for a long time that chronic kidney disease (CKD) is associated with dyslipidemia, but the full extent of abnormalities has been appreciated only recently, because routine laboratory tests fail to disclose the entire spectrum of lipid abnormalities. Lipids, particularly HDL cholesterol, are predictive of cardiovascular events, but a paradoxic inverse relation between cholesterol concentration and cardiovascular death has been noted in uremic patients. This currently is thought to be explained by the confounding effect of microinflammation and possibly calcification, but this is not definitely proved. Several retrospective analyses that included patients with mild or moderate CKD documented benefit from lowering of cholesterol by statins. In contrast, the Die Deutsche Diabetes Dialyse (4D) study and a small Scandinavian study failed to show a benefit from lowering of cholesterol by statins in ESRD. Pathomechanistically, it is possible that nonclassical pathomechanisms override statin-sensitive mechanisms as also suggested by the observation that statins fail to reduce carotid intima-media thickening. Although, experimentally, exposure to lipids (particularly oxidized lipids) aggravates progression, data on the effect of statins on progression in patients with CKD are not definite. The most likely explanation is that the impact of numerous confounders obscures their effect on progression. The increase in urinary protein excretion of patients who are treated with statins had been a cause of concern, but the underlying mechanism (i.e. interference with proximal tubular reabsorption of protein) meanwhile has been well documented.

Atherosclerosis↗
PubMed2003

Statin therapy in the elderly: does it make good clinical and economic sense?

HMG-CoA reductase inhibitors (statins) have been established as the dominant treatment for coronary heart disease (CHD). This dominance is based on an impressive body of clinical trial evidence showing significant benefits in primary prevention of cardiovascular events in individuals at risk for CHD and in secondary prevention of such events in patients with CHD and high or normal plasma cholesterol levels. There is, however, significant room for improvement in the treatment of CHD with respect both to drug efficacy and to the disparity between evidence-based medicine and actual clinical practice particularly in relation to treatment strategies for the elderly. Current statins fall short of requirements for 'ideal' lipid-lowering treatment in several respects; 'super' statins and other agents currently in development may satisfy more of these requirements. Moreover, available therapies are not applied optimally, because of physician nonacceptance and/or patient noncompliance; thus, the majority of patients with CHD or its risk factors still have cholesterol levels that exceed guideline targets. There is also evidence that older patients with CHD, or at high risk of CHD, are undertreated - possibly because of concerns regarding the increased likelihood of adverse events or drug interactions or doubts regarding the cost effectiveness of statin therapy in this population. This group is of particular clinical relevance, since it is showing a proportionate rapid expansion in most national populations. To address their potential healthcare needs, the ongoing Pravastatin in the Elderly at Risk (PROSPER) study is assessing the effects of pravastatin in elderly patients (5804 men and women aged 70-82 years) who either have pre-existing vascular disease or are at significant risk for developing it, with the central hypothesis that statin therapy (pravastatin 40 mg/day) will diminish the risk of subsequent major vascular events compared with placebo. After a 3.2-year treatment period, a primary assessment will be made of the influence of statin treatment on major cardiovascular events (a combination of CHD death, nonfatal myocardial infarction, and fatal or nonfatal stroke). Optimal deployment of the currently available agents and of newer agents (no matter how well they satisfy requirements for ideal treatment) ultimately depends on the establishment of an evidence base and may require far-reaching educational programmes that change the way risk factor management is viewed by caregivers and patients alike.

Aged↗
PubMed2003

Statin treatment and progression of atherosclerotic plaque burden.

Atherosclerosis is a progressive systemic disorder that, in the initial stages, is often asymptomatic. The measurement of atherosclerotic burden using imaging techniques enables the clinical benefits of lipid-modifying therapies to be assessed in early atherosclerosis and facilitates more rapid evaluation of interventions in clinical trials compared with the measurement of clinical outcome. The effect of HMG-CoA reductase inhibitors, commonly referred to as 'statins', on disease progression has been assessed in a number of imaging studies both in patients with established coronary heart disease (CHD) and in those with subclinical atherosclerosis. Statins slow plaque progression and, in early atherosclerosis, they have been demonstrated to promote regression of atherosclerotic lesions. The benefits of statin therapy on soft atherosclerotic plaques that are still developing support the use of vascular measures to detect subclinical atherosclerosis, and the subsequent early intervention with statin therapy. Moreover, given that the effects of statins on atherosclerosis progression are evident even in normocholesterolaemic patients at increased risk of developing CHD, early intervention with statin therapy may be effective in preventing CHD, irrespective of lipid level.

Arteriosclerosis↗
PubMed2002

Clinical significance of pleiotropic effects of statins: lipid reduction and beyond.

Statins significantly reduce cardiovascular-related morbidity and mortality in patients with and without coronary artery disease. The potential of this drug class has yet to be fully explored. Accumulating evidence from basic research and clinical trials indicates that statins have pleiotropic effects that may largely account for the clinical benefits observed. Potential beneficial effects of these agents include enhancement of nitric oxide production in vasculature and the kidney. Statins have been shown to stabilize unstable plaques, improve vascular relaxation, and promote new vessel formation. Clinical trials and animal studies have shown that these agents reduce cardiovascular disease (CVD) risks and events, progression of nephropathy, development of diabetes, and fracture rates; these are benefits that go beyond lipid lowering alone. Potential beneficial effects are due to the positive impact on vascular and glomerular nitric oxide (NO) production and attenuation of vascular inflammation. Effects on bone, including fracture reduction, are thought to be mediated by direct action on bone formation. Moreover, potential reduction in the development of diabetes as observed in the West of Scotland Coronary Prevention Study (WOSCOPS) may relate to the improvement in insulin sensitivity. These actions are mediated, in part, by the effects on small G-proteins, modulation of signaling cascades, transcription, and gene expression. In particular, the inhibition of small GTP-binding proteins, Rho, Ras, and Rac, whose proper membrane localization and function are dependent on isoprenylation, may play an important role in mediating the direct cellular effects of statins on the vascular wall. The clinical relevance of these effects is beginning to be recognized, and ongoing studies will be able to answer these many questions in the near future. Actions of statins on vascular, glomerular, bone, and insulin-sensitive tissue as well as effects of statins on cognitive function and oncoprotection will be discussed in this review.

Anticholesteremic Agents↗
PubMed2006

Statin therapy-evidence beyond lipid lowering contributing to plaque stability.

Primarily statin drugs inhibit hepatic 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase, which is responsible for the reduction in circulating low-density lipoprotein (LDL) cholesterol. Several findings from recent research studies indicate that statins have multiple actions that favorably influence key factors involved in the atherogenic process. These so-called pleiotropic properties affect various aspects of cell function, inflammation, coagulation, and vasomotor activity. These effects are mediated either indirectly through LDL cholesterol reduction or via a direct effect on cellular functions. Such actions may contribute to the early cardiovascular benefit observed in several outcome trials with statin drugs therapy. Although many of the pleiotropic properties of statins may be a class effect, some may be unique to certain agents and account for differences in their pharmacological activity. This review summarise the results of the major outcome trials of statins and non-statins therapy and the possible mechanisms beyond lipid lowering contributing to plaque stability.

Arteriosclerosis↗
PubMed2004

Insights into early and rapid effects of statin therapy after coronary interventions.

Recent trials provide a wealth of data documenting the benefit of cholesterol-lowering therapy with statins in both primary and secondary prevention. A growing body of evidence indicates that statins possess pleiotropic effects - independent of, or at least in addition to their lipid-lowering capacity, including inhibition of smooth muscle cell proliferation and subsequently neointimal proliferation, platelet aggregation as well as antiinflammatory and direct beneficial effects on endothelial function. The current review summarizes recent findings in non-randomized and randomized trials assessing the efficacy of statin therapy following coronary interventions with or without stent implantation. It highlights the efficacy of statins in the settings of acute coronary syndromes. Current management of acute coronary syndromes requires early administration in combination with acute interventions. High risk patients which receive the greatest benefit could be identified by measuring serum markers such as preprocedural C-reactive protein levels. The present article also describes important novel actions of statins supporting the early initiation of statins post intervention, such as the stimulation of reendothelialization - a crucial step in the healing process of the vascular wall - which is mediated at least in part by mobilization of bone-marrow derived endothelial progenitor cells.

Angioplasty, Balloon, Coronary↗
PubMed2006

Novel concepts of statin therapy for cardiovascular risk reduction in hypertension.

Hypertension is associated with an increase in cardiovascular events. Pathophysiological mechanisms of this include endothelial damage/dysfunction, inflammatory activation, insulin resistance, platelet activation and alterations in the coagulation cascade leading to a prothrombotic state. Dyslipidaemia acts synergistically with hypertension in increasing cardiovascular risk. HMG CoA reductase inhibitors (statins) are lipid-lowering drugs and more recently have been shown to have a significant pleiotropic effect on endothelial function, inflammation, platelet activation and coagulation. Statins affect the whole pathophysiology of atherogenesis from deposition to plaque rupture and thrombogenesis because of its pleiotropic effects. Therefore it is intuitive that statins may be of benefit in hypertensive patients with conventionally normal lipid levels by preventing the pathological effects of hypertension. There is an increasing clinical evidence base for statins use in patients with hypertension. In this article, the novel pleiotropic and conventional mechanisms of statins, and clinical data of statin therapy in patients with hypertension are reviewed.

Blood Coagulation↗
PubMed2005

Statins ameliorate endothelial barrier permeability changes in the cerebral tissue of streptozotocin-induced diabetic rats.

Statins may have favorable effects on endothelial barrier function. The effect of rosuvastatin and simvastatin therapy (10 mg/kg) for 5 weeks on blood-brain barrier (BBB), blood-retinal barrier (BRB), and cardiac muscle permeability of streptozotocin-induced diabetic rats was studied. The size-selective permeability of different vascular beds to a group of fluorescein isothiocyanate dextrans of varying molecular weights was measured. The volume of distribution of 250-, 70-, and 40-kDa dextrans in the cerebral tissue of diabetic rats were significantly increased. The volume of distribution of these dextrans in cerebral tissue was normalized by both statins. Diabetes did not significantly alter the BRB, but both statins decreased the volume of distribution of 70- and 40-kDa dextrans in the retina. The volume of distribution of 40 kDa in cardiac muscle was increased in diabetes, and this change was prevented with statin treatment. Treatment with rosuvastatin and mevalonate (150 mg/kg in drinking water for 5 weeks) did not alter the volume of distribution measurements. We concluded that 1) diabetes in rats is associated with significant changes in the BBB permeability; 2) statin treatment improves the endothelial barrier function in cerebral tissue, retina, and cardiac muscle; and 3) this statin effect could not be attributed to HMGCoA reductase inhibition.

Animals↗
PubMed2004

Two-year statin therapy does not alter the progression of intima-media thickness in patients with type 2 diabetes without manifest cardiovascular disease.

OBJECTIVE: Cardiovascular disease (CVD) is the most important cause of mortality in patients with type 2 diabetes. We aimed to determine the effect of statin therapy versus placebo on the progression of carotid intima-media thickness (IMT) in type 2 diabetic patients without manifest CVD. RESEARCH DESIGN AND METHODS: A randomized, placebo-controlled, double-blind clinical trial was performed in 250 patients with type 2 diabetes. Patients were given either 0.4 mg cerivastatin or placebo daily. In August 2001, when cerivastatin was withdrawn from the market, 0.4 mg cerivastatin was replaced by 20 mg simvastatin without deblinding the study. The primary end point was the change of mean common carotid IMT, as measured by B-mode ultrasound, over 2 years. RESULTS: Common carotid IMT at baseline was 0.780 mm in the placebo group and 0.763 mm in the statin group and did not change significantly after 2 years. There was no significant difference in IMT change in any carotid segment between the groups. LDL cholesterol was reduced by 25% in the statin group and increased by 8% in the placebo group (P <0.001). Cardiovascular events occurred in 12 patients in the placebo group and two patients in the statin group (P=0.006). CONCLUSIONS: There was no effect of 2 years' statin therapy on carotid IMT in type 2 diabetic subjects. The natural history of IMT in our patients was milder than anticipated. In contrast, we observed a significantly lower cardiovascular event rate on statin therapy. Prognostic tools other than IMT should be explored in this patient group.

Body Mass Index↗
PubMedDate not supplied

Skeletal effects of statins.

OBJECTIVE: To review the skeletal effects of hydroxy-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) and evaluate the use and potential benefit of statins in the management of osteoporosis. METHODS: Background information on the topic of the effect of statins on bone and fracture risk is presented, and the pertinent published literature is reviewed. RESULTS: Osteoporosis is the most common bone disease, affecting millions of people worldwide and leading to considerable morbidity, especially when it is not adequately managed. Although statins have primarily been known for their lipid-lowering effects, recent data have documented a potential association between statin use and improvement in fracture risk profile. Some statins have been shown to decrease bone-specific alkaline phosphatase or serum osteocalcin concentrations, but other studies have failed to demonstrate the beneficial effects of these agents. Therefore, additional studies should be undertaken to clarify the mechanism of action. CONCLUSION: Observational studies suggest an association between HMG-CoA reductase inhibitors and reduction in fracture risk. Large randomized controlled clinical trials must be performed to confirm this association.

Bone Remodeling↗