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1.  Pleiotropic effects of statin therapy 
Trends in molecular medicine  2008;14(1):37-44.
Statins inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which is required for cholesterol biosynthesis, and are beneficial in the primary and secondary prevention of cardiovascular disease. Most of the benefits of statin therapy are owing to the lowering of serum cholesterol levels. However, by inhibiting HMG-CoA reductase, statins can also inhibit the synthesis of isoprenoids, which are important lipid attachments for intracellular signaling molecules, such as Rho, Rac and Cdc42. Therefore, it is possible that statins might exert cholesterol-independent or ‘pleiotropic’ effects through direct inhibition of these small GTP-binding proteins. Recent studies have shown that statins might have important roles in diseases that are not mediated by cholesterol. Here, we review data from recent clinical trials that support the concept of statin pleiotropy and provide a rationale for their clinical importance.
doi:10.1016/j.molmed.2007.11.004
PMCID: PMC2621332  PMID: 18068482
2.  Cholesterol and Statins in Alzheimer’s Disease 
Archives of neurology  2011;68(10):1239-1244.
Over the past twenty years, evidence has accumulated that high cholesterol levels may increase the risk of developing Alzheimer’s disease (AD). With the global use of statins to treat hypercholesterolemia, this finding has led to the hope that statins could prove useful in treating or preventing AD. However, the results of work on this topic are inconsistent: some studies find beneficial effects, others do not. In this first segment of a two-part review, we examine the complex preclinical and clinical literature on cholesterol and AD. First, we review epidemiological research on cholesterol levels and the risk of AD and discuss the relevance of discrepancies among studies as regards participants’ age and clinical status. Next, we assess studies correlating cholesterol with AD-type neuropathology. The potential molecular mechanisms for cholesterol’s apparent adverse effect on the development of AD are then discussed. Finally, we review preclinical studies of statins and AD. Thus, this first portion of our review provides the background and rationale for investigating statins as potential therapeutic agents in AD patients, the subject of the second part.
doi:10.1001/archneurol.2011.203
PMCID: PMC3211071  PMID: 21987540
3.  3-Hydroxy-3-methylglutaryl–Coenzyme A Reductase Inhibitors in the Treatment of Central Nervous System Diseases 
Archives of neurology  2010;67(9):1062-1067.
3-Hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase inhibitors (statins) are among the most prescribed medications in the United States. Statins act on the rate-limiting step in cholesterol biosynthesis (the conversion of HMG-CoA to mevalonate) and are effective in treating dyslipidemia. However, statins decrease other downstream products of the mevalonate pathway, and it is via these pathways that statins may affect inflammation, nitric oxide synthesis, the coagulation cascade, and other processes. Through these pleiotropic effects, statins may have an effect on neurologic diseases, including ischemic and hemorrhagic stroke, Alzheimer disease, Parkinson disease, and multiple sclerosis. This article reviews the basic biochemistry of statins as it relates to these pleiotropic effects, the potential role of statins in several neurologic disorders, and the results of clinical trials performed for several of these conditions.
doi:10.1001/archneurol.2010.199
PMCID: PMC3138553  PMID: 20837848
4.  Cholesterol and Cognitive Performance in Normal Controls and the Influence of Elective Statin Use after Conversion to Mild Cognitive Impairment: Results in a Clinical Trial Cohort 
Neuro-Degenerative Diseases  2010;7(1-3):183-186.
Background
We reported a significant 67% reduction in the hazard risk of incident Alzheimer's disease (AD) with elective statin use in the AD Anti-inflammatory Prevention Trial (ADAPT), without a reduction in risk of incident mild cognitive impairment (MCI).
Objective
To assess if cholesterol levels are associated with cognitive performance and determine if statin use alters cognitive performance after onset of MCI.
Design
Fractionated cholesterol levels, neurological and cognitive status were evaluated annually. Comparisons of non-LLA (lipid-lowering agent) users or statin-LLA users were performed blind to the ADAPT medication randomization. Pearson's correlations were validated using a time-dependent linear mixed model.
Results
The MMSE performance significantly declined over time in non-LLA users, and, after adjusting for this, a significant positive correlation between MMSE and HDL was identified (p = 0.0002). A negative correlation between total and LDL cholesterol, and immediate and delayed recall of the Rivermead paragraph was significant (total cholesterol, p < 0.003; LDL, p < 0.02). Pilot data suggest a positive signal on delayed recall of both the Hopkins word list and Rivermead paragraph with deterioration in the non-LLA users and improvement in the statin users after conversion to MCI.
Conclusion
Cholesterol levels may be associated with differential performance on the MMSE and measures of learning or memory. The trend for improved delayed recall in statin users with MCI compared to non-LLA users with MCI may have contributed to the reduced hazards risk of incident AD without reducing the risk of MCI.
doi:10.1159/000295660
PMCID: PMC2859238  PMID: 20224282
Alzheimer's disease; Mild cognitive impairment; Cholesterol; Lipid-lowering agents
5.  Prospects of Statins in Parkinson Disease 
Parkinson disease (PD) is second only to Alzheimer disease as the most common neurodegenerative disorder in humans. Despite intense investigations, no effective therapy is available to halt the progression of PD. Although statins are widely used cholesterol-lowering drugs throughout the world, recent studies suggest that these drugs modulate neurodegeneration-related signaling processes and may be beneficial for PD. Simvastatin is the most potent statin in crossing the blood-brain barrier, and this particular statin drug negatively correlates with the incidence of PD and shows efficacy in animal models of PD. However, PD mainly occurs in the aging population, who are more vulnerable to cholesterol or lipid-related disorders, raising questions whether this possible beneficial effect of statins in PD patients is cholesterol dependent or cholesterol independent. This article presents data on the therapeutic efficacy of simvastatin in a chronic MPTP model of PD, reviews recent literature, and discusses the pros and cons of statin therapy in PD.
doi:10.1177/1073858410385006
PMCID: PMC3132406  PMID: 21252380
Parkinson disease; statins; signal transduction; dopamine; neuroprotection
6.  Lipid lowering agents are associated with a slower cognitive decline in Alzheimer's disease 
Background: Data from epidemiological studies and animal models imply that disturbances in cholesterol metabolism are linked to Alzheimer's disease susceptibility. Lipid lowering agents (LLAs) may have implications for the prevention of Alzheimer's disease.
Objective: To investigate whether LLAs are associated with a slower cognitive decline in Alzheimer's disease.
Methods: An observational study in 342 Alzheimer patients followed in a memory clinic for 34.8 months (mean age 73.5 years, mini-mental state examination score (MMSE) 21.3 at entry); 129 were dyslipaemic treated with LLAs (47% with statins), 105 were untreated dyslipaemic, and 108 were normolipaemic. The rate of cognitive decline was calculated as the difference between the first and last MMSE score, divided by the time between the measurements, expressed by year. Patients were divided into slow and fast decliners according to their annual rate of decline (lower or higher than the median annual rate of decline in the total population).
Results: Patients treated with LLAs had a slower decline on the MMSE (1.5 point/year, p = 0.0102) than patients with untreated dyslipaemia (2.4 points/year), or normolipaemic patients (2.6 points/year). Patients with a slower decline were more likely to be treated with LLAs. Logistic regression analysis, with low annual cognitive decline as the dependent variable, showed that the independent variable LLA (treated with or not) was positively associated with the probability of lower cognitive decline (odds ratio = 0.45, p = 0.002).
Conclusions: LLAs may slow cognitive decline in Alzheimer's disease and have a neuroprotective effect. This should be confirmed by placebo controlled randomised trials in patients with Alzheimer's disease and no dyslipaemia.
doi:10.1136/jnnp.2005.063388
PMCID: PMC1739466  PMID: 16291883
7.  CHOLESTEROL-INDEPENDENT NEUROPROTECTIVE AND NEUROTOXIC ACTIVITES OF STATINS: PRESPECTIVES FOR STATIN USE IN ALZHEIMER DISEASE AND OTHER AGE-RELATED NEURODEGENERATIVE DISORDERS 
Statins, long known to be beneficial in conditions where dyslipidemia occurs by lowering serum cholesterol levels, also have been proposed for use in neurodegenerative conditions, including Alzheimer disease. However, it is not clear that the purported effectiveness of statins in neurodegenerative disorders is directly related to cholesterol-lowering effects of these agents; rather, the pleiotropic functions of statins likely play critical roles.
Moreover, it is becoming more apparent with additional studies that statins can have deleterious effects in preclinical studies and lack effectiveness in various recent clinical trials. This perspective paper outlines pros and cons of the use of statins in neurodegenerative disorders, with particular emphasis on Alzheimer disease.
doi:10.1016/j.phrs.2011.04.007
PMCID: PMC3130102  PMID: 21536132
8.  A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease 
Neurology  2011;77(6):556-563.
Background:
Lowering cholesterol is associated with reduced CNS amyloid deposition and increased dietary cholesterol increases amyloid accumulation in animal studies. Epidemiologic data suggest that use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) may decrease the risk of Alzheimer disease (AD) and a single-site trial suggested possible benefit in cognition with statin treatment in AD, supporting the hypothesis that statin therapy is useful in the treatment of AD.
Objective:
To determine if the lipid-lowering agent simvastatin slows the progression of symptoms in AD.
Methods:
This randomized, double-blind, placebo-controlled trial of simvastatin was conducted in individuals with mild to moderate AD and normal lipid levels. Participants were randomly assigned to receive simvastatin, 20 mg/day, for 6 weeks then 40 mg per day for the remainder of 18 months or identical placebo. The primary outcome was the rate of change in the Alzheimer's Disease Assessment Scale–cognitive portion (ADAS-Cog). Secondary outcomes measured clinical global change, cognition, function, and behavior.
Results:
A total of 406 individuals were randomized: 204 to simvastatin and 202 to placebo. Simvastatin lowered lipid levels but had no effect on change in ADAS-Cog score or the secondary outcome measures. There was no evidence of increased adverse events with simvastatin treatment.
Conclusion:
Simvastatin had no benefit on the progression of symptoms in individuals with mild to moderate AD despite significant lowering of cholesterol.
Classification of evidence:
This study provides Class I evidence that simvastatin 40 mg/day does not slow decline on the ADAS-Cog.
doi:10.1212/WNL.0b013e318228bf11
PMCID: PMC3149154  PMID: 21795660
9.  Statins and colorectal cancer 
The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, more commonly referred to as statins, comprise a family of lipid-lowering drugs that are prescribed on a global scale on account of their demonstrated safety and efficacy in reducing mortality from cardiovascular disease. Beyond their potent pharmacologic inhibition of cholesterol biosynthesis, statins appear to have pleiotropic effects, including modulation of cell growth, apoptosis, and inflammation. Through modulation of these pathways, statins have the potential to influence a wide range of disease processes, including cancer. Much attention has focussed on the association between statins and colorectal cancer, raising the prospect that these well-tolerated compounds could form the basis of future chemopreventive strategies. Herein we review the epidemiologic, clinical, and pre-clinical data relevant to statins and colorectal neoplasia, and discuss the current status and future potential of statins as chemopreventive agents.
doi:10.1016/j.cgh.2012.08.037
PMCID: PMC3703461  PMID: 22982096
10.  Isoprenoid Metabolism and the Pleiotropic Effects of Statins 
Current atherosclerosis reports  2003;5(5):372-378.
Convincing evidence from basic research and animal studies shows that HMG CoA reductase inhibitors or statins, exert cardiovascular protective effects beyond cholesterol-lowering. Because of the central role of LDL-C in mediating vascular pathology and the efficacy of statins for lowering LDL-C, the clinical importance of these additional non-lipid effects remains to be determined. Nevertheless, there is growing evidence from recent clinical trials, which suggests that some of the beneficial effects of statins may be unrelated to changes in LDL-C. Indeed, in animal studies, many of the cholesterol-independent or “pleiotropic” effects of statins are due predominantly to inhibition of isoprenoid, but not cholesterol synthesis. Thus, with the recent findings of the HPS and ASCOT-LLA, the potential cholesterol-independent effects of statins have shifted the treatment strategy from numerical lipid parameters to the global assessment of cardiovascular risks.
PMCID: PMC2676316  PMID: 12911847
11.  Effects of Simvastatin on Cholesterol Metabolism and Alzheimer Disease Biomarkers 
Preclinical and epidemiologic studies suggest a protective effect of statins on Alzheimer disease (AD). Experimental evidence indicates that some statins can cross the blood-brain barrier, alter brain cholesterol metabolism, and may ultimately decrease the production of amyloid-β (Aβ) peptide. Despite these promising leads, clinical trials have yielded inconsistent results regarding the benefits of statin treatment in AD. Seeking to detect a biological signal of statins effect on AD, we conducted a 12-week open-label trial with simvastatin 40 mg/d and then 80 mg/d in 12 patients with AD or amnestic mild cognitive impairment and hypercholesterolemia. We quantified cholesterol precursors and metabolites and AD biomarkers of Aβ and tau in both plasma and cerebrospinal fluid at baseline and after the 12-week treatment period. We found a modest but significant inhibition of brain cholesterol biosynthesis after simvastatin treatment, as indexed by a decrease of cerebrospinal fluid lathosterol and plasma 24S-hydroxycholesterol. Despite this effect, there were no changes in AD biomarkers. Our findings indicate that simvastatin treatment can affect brain cholesterol metabolism within 12 weeks, but did not alter molecular indices of AD pathology during this short-term treatment.
doi:10.1097/WAD.0b013e3181d61fea
PMCID: PMC3694274  PMID: 20473136
Alzheimer disease; simvastatin; cholesterol; biomarker
12.  Does it Matter Whether or Not a Lipid-Lowering Agent Inhibits Rho Kinase? 
Current atherosclerosis reports  2007;9(5):384-388.
Lipid lowering agents, such as HMG CoA reductase inhibitors or statins, have been shown to reduce cardiovascular events. However, growing evidence from recent clinical trials suggest that some of the beneficial effects of statins may be unrelated to changes in LDL-C. In animal studies, many of the cholesterol-independent or “pleiotropic” effects of statins are mediated by inhibition of Rho kinase (ROCK). Indeed, ROCK has been implicated in the regulation of vascular tone, proliferation, inflammation, and oxidative stress. To what extent ROCK activity is inhibited in patients on lipid lowering therapy, in particular, statins, is not known, but may have important clinical and therapeutic implications. This review will attempt to make the case that, in addition to lipid lowering, inhibition of ROCK contributes to some of the benefits of statin therapy in patients with cardiovascular disease.
PMCID: PMC2643375  PMID: 18001621
13.  Rho GTPases, Statins, and Nitric Oxide 
Circulation research  2005;97(12):1232-1235.
The lipid-lowering drugs, 3-hydroxy-3-methylgulutaryl-coenzyme A (HMG-CoA) reductase inhibitors or statins, are used in the prevention and treatment of cardiovascular diseases. Recent experimental and clinical studies suggest that statins may exert vascular protective effects beyond cholesterol reduction. For example, statins improve endothelial function by cholesterol-dependent and -independent mechanisms. The cholesterol-independent or “pleiotropic” effects of statins include the upregulation and activation of endothelial NO synthase (eNOS). Because statins inhibit an early step in the cholesterol biosynthetic pathway, they also inhibit the synthesis of isoprenoids such as farnesylpyrophosphate and geranylgeranylpyrophosphate, which are important posttranslational lipid attachments for intracellular signaling molecules such as the Rho GTPases. Indeed, decrease in Rho GTPase responses as a consequence of statin treatment increases the production and bioavailability of endothelium-derived NO. The mechanism involves, in part, Rho/Rho-kinase (ROCK)-mediated changes in the actin cytoskeleton, which leads to decreases in eNOS mRNA stability. The regulation of eNOS by Rho GTPases, therefore, may be an important mechanism underlying the cardiovascular protective effect of statins.
doi:10.1161/01.RES.0000196564.18314.23
PMCID: PMC2633589  PMID: 16339495
statin; Rho; Rho-kinase; endothelium; nitric oxide
14.  Perioperative use of statins in noncardiac surgery 
Background
Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) can significantly decrease cardiovascular mortality and morbidity, irrespective of the patients’ cholesterol status. This paper reviews the effects of perioperative statin therapy in patients undergoing noncardiac surgery.
Method
A systematic literature review was undertaken of all published literature on this subject using Medline and cross-referenced. All published relevant papers on the perioperative use of statins were used.
Results
Perioperative statin therapy is associated with a lower perioperative morbidity and mortality in patients undergoing elective or emergency surgery. The effects are due to a combination of lipid-lowering and pleiotropic properties of statins.
Conclusion
Ideally a large scale multi-centre randomized controlled trial of perioperative statin therapy should be performed but this may be difficult to conduct since there is already overwhelming evidence in the literature to suggest perioperative cardiovascular protective properties. Statins may still be under-prescribed in surgical patients.
PMCID: PMC2464754  PMID: 18629359
perioperative, cardiac complications; morbidity, mortality; outcome; statins; vascular; noncardiac surgery
15.  PLEIOTROPIC EFFECTS OF STATINS 
Statins are potent inhibitors of cholesterol biosynthesis. In clinical trials, statins are beneficial in the primary and secondary prevention of coronary heart disease. However, the overall benefits observed with statins appear to be greater than what might be expected from changes in lipid levels alone, suggesting effects beyond cholesterol lowering. Indeed, recent studies indicate that some of the cholesterol-independent or “pleiotropic” effects of statins involve improving endothelial function, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting the thrombogenic response. Furthermore, statins have beneficial extrahepatic effects on the immune system, CNS, and bone. Many of these pleiotropic effects are mediated by inhibition of isoprenoids, which serve as lipid attachments for intracellular signaling molecules. In particular, 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 pleiotropic effects of statins.
doi:10.1146/annurev.pharmtox.45.120403.095748
PMCID: PMC2694580  PMID: 15822172
HMG-CoA reductase inhibitor; cholesterol; isoprenoids; atherosclerosis; inflammation
16.  STATINS AND NEUROPROTECTION: A PRESCRIPTION TO MOVE THE FIELD FORWARD 
There is growing interest in the use of statins, HMG-CoA reductase inhibitors, for treating specific neurodegenerative diseases (cerebrovascular disease, Parkinson’s disease, Alzheimer’s disease, multiple sclerosis) and possibly traumatic brain injury. Neither is there is a consensus on the efficacy of statins in treating the aforementioned diseases nor are the mechanisms of the purported statin-induced neuroprotection well-understood. Part of the support for statin-induced neuroprotection comes from studies using animal models and cell culture. Important information has resulted from that work but there continues to be a lack of progress on basic issues pertaining to statins and brain which impedes advancement in understanding how statins alter brain function. For example, there are scant data on the pharmacokinetics of lipophilic and hydrophilic statins in brain, statin-induced neuroprotection versus cell death and statins and brain isoprenoids. The purpose of this mini-review will be to examine those aforementioned issues and to identify directions of future research.
doi:10.1111/j.1749-6632.2009.05359.x
PMCID: PMC2909025  PMID: 20633110
Alzheimer’s disease; Cerebrovascular disease; Cholesterol; HMG-CoA reductase; Isoprenoids; Neurodegeneration; Neuroprotection; Statins; Stroke
17.  RHOA Is a Modulator of the Cholesterol-Lowering Effects of Statin 
PLoS Genetics  2012;8(11):e1003058.
Although statin drugs are generally efficacious for lowering plasma LDL-cholesterol levels, there is considerable variability in response. To identify candidate genes that may contribute to this variation, we used an unbiased genome-wide filter approach that was applied to 10,149 genes expressed in immortalized lymphoblastoid cell lines (LCLs) derived from 480 participants of the Cholesterol and Pharmacogenomics (CAP) clinical trial of simvastatin. The criteria for identification of candidates included genes whose statin-induced changes in expression were correlated with change in expression of HMGCR, a key regulator of cellular cholesterol metabolism and the target of statin inhibition. This analysis yielded 45 genes, from which RHOA was selected for follow-up because it has been found to participate in mediating the pleiotropic but not the lipid-lowering effects of statin treatment. RHOA knock-down in hepatoma cell lines reduced HMGCR, LDLR, and SREBF2 mRNA expression and increased intracellular cholesterol ester content as well as apolipoprotein B (APOB) concentrations in the conditioned media. Furthermore, inter-individual variation in statin-induced RHOA mRNA expression measured in vitro in CAP LCLs was correlated with the changes in plasma total cholesterol, LDL-cholesterol, and APOB induced by simvastatin treatment (40 mg/d for 6 wk) of the individuals from whom these cell lines were derived. Moreover, the minor allele of rs11716445, a SNP located in a novel cryptic RHOA exon, dramatically increased inclusion of the exon in RHOA transcripts during splicing and was associated with a smaller LDL-cholesterol reduction in response to statin treatment in 1,886 participants from the CAP and Pravastatin Inflamation and CRP Evaluation (PRINCE; pravastatin 40 mg/d) statin clinical trials. Thus, an unbiased filter approach based on transcriptome-wide profiling identified RHOA as a gene contributing to variation in LDL-cholesterol response to statin, illustrating the power of this approach for identifying candidate genes involved in drug response phenotypes.
Author Summary
Statins, or HMG CoA reductase inhibitors, are widely used to lower plasma LDL-cholesterol levels as a means of reducing risk for cardiovascular disease. We performed an unbiased genome-wide survey to identify novel candidate genes that may be involved in statin response using genome-wide mRNA expression analysis in a sequential filtering strategy to identify those most likely to be relevant to cholesterol metabolism based on their gene expression characteristics. Among these, RHOA was selected for further functional study. A role for this gene in the maintenance of intracellular cholesterol homeostasis was confirmed by knock-down in hepatoma cell lines. In addition, statin-induced RHOA transcript levels measured in a panel of lymphoblastoid cell lines was correlated with statin-induced change in plasma LDL-cholesterol measured in individuals from whom the cell lines were derived. Lastly, a cis-acting splicing QTL associated with expression of a rare cryptic RHOA exon was also associated with statin-induced changes in plasma LDLC levels. This result exemplifies the power of applying biological information of well understood molecular pathways with genome-wide expression data for the identification of candidate genes that influence drug response.
doi:10.1371/journal.pgen.1003058
PMCID: PMC3499361  PMID: 23166513
18.  Statins in hypercholesterolaemia: A dose-specific meta-analysis of lipid changes in randomised, double blind trials 
BMC Family Practice  2003;4:18.
Background
Statins alter lipid concentrations. This systematic review determined the efficacy of particular statins, in terms of their ability to alter cholesterol.
Review methods
PubMed, the Cochrane Library, references lists of reports, and reviews were searched (September 2001) for randomised, double blind trials of statins for cholesterol in trials of 12 weeks or longer. Mean change in total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides was calculated using pooled data for particular statins, and for particular doses of a statin. Pre-planned sensitivity analyses were used to determine the effects of initial concentration of total cholesterol, study duration, the effects of major trials, and effects in placebo versus active controlled trials. Information was not collected on adverse events.
Results
Different statins at a range of doses reduced total cholesterol by 17–35% and LDL-cholesterol by 24–49% from baseline. Lower doses of statins generally produced less cholesterol lowering, though for most statins in trials of 12 weeks or longer there was at best only a weak relationship between dose and cholesterol reduction. Duration of treatment and baseline total cholesterol concentration did not alter the amount of the benefit attained.
Conclusions
Statins are effective medicines and confer benefit to patients in terms of primary and secondary prevention of coronary heart disease. Reductions in total cholesterol of 25% or more and LDL cholesterol of more than 30% were recorded for fixed doses of simvastatin 40 mg, atorvastatin 10 mg, and rosuvastatin 5 mg and 10 mg.
doi:10.1186/1471-2296-4-18
PMCID: PMC317299  PMID: 14969594
19.  Impact of Ezetimibe on Atherosclerosis: Is the Jury Still Out? 
Mayo Clinic Proceedings  2009;84(4):353-361.
Ezetimibe is a new lipid-lowering agent that inhibits intestinal absorption of dietary cholesterol. It substantially lowers low-density lipoprotein cholesterol levels when used alone or in combination with statins. However, its effect on cardiovascular mortality remains unknown. We reviewed peer-reviewed published literature on the effect of ezetimibe on different phases of atherosclerosis. MEDLINE, EMBASE, BIOSIS, and other Web of Knowledge databases were searched for relevant abstracts and articles published in the English language that compared ezetimibe and statins as modulators of atherosclerosis. On the basis of the available evidence, ezetimibe appears to reduce inflammation when used in combination with statins, but its effect on endothelial function is mixed and less clear. The effect of ezetimibe on coronary disease progression or prevention of cardiovascular events is currently unknown. Use of ezetimibe as a second- or third-line agent to achieve low-density lipoprotein cholesterol treatment goals seems appropriate on the basis of the available evidence.
PMCID: PMC2665981  PMID: 19339654
20.  Statin Use and Cancer Risk: A Comprehensive Review 
Expert opinion on drug safety  2010;9(4):603-621.
Importance of the Field
HMG-CoA inhibitors (statins), a class of drugs that reduce cholesterol, are used to manage and prevent coronary heart disease. They are among the most commonly prescribed drugs worldwide. Contrary to early concerns over the carcinogenicity of statins, a growing body of evidence suggests statins may in fact have a chemopreventive potential against cancer.
Areas Covered in This Review
In this paper, we review evidence on the association between statin use and cancer risk. Specifically, we report on clinical trials and observational studies that measured all cancer or site-specific cancers of the breast, colorectal, lung, prostate, and reproductive organs associated with statin use.
What the reader will gain
An understanding of the evidence, including strengths and limitations, to support an association between statins and cancer. Information on the current state of the field and future directions are also discussed.
Take Home Message
Few strong or consistent associations between statins and cancer incidence overall or for any of the sites reviewed were detected. Data is lacking for any effects of statins on cancer prognosis and secondary prevention; with the exception of consistent evidence that statins are associated with reduced risk of advanced/aggressive prostate cancer. Statins appear safe in relation to cancer risk but any chemopreventive effect in humans remains to be established and should not be recommended outside the context of clinical trials. It is encouraging that numerous trials are on-going. The prospect of reducing the incidence and burden of some of the most prevalent cancers with a safe, affordable, and tolerable medication that already reduces the risk of the leading cause of death, cardiovascular disease, warrants further exploration in clinical trials and observational studies of prognosis and survival.
doi:10.1517/14740331003662620
PMCID: PMC2910322  PMID: 20377474
statins; HMG-CoA inhibitors; cancer; prevention; treatment; drug safety
21.  Statin therapy in autoimmunity: From protein prenylation to immunomodulation 
Nature reviews. Immunology  2006;6(5):10.1038/nri1839.
Statins have been prescribed extensively for their cholesterol-lowering properties and efficacy in cardiovascular disease. Compelling evidence now exists, however, that statins also possess extensive immunomodulatory properties that operate independently of lipid lowering. Consequently, much attention has been directed towards their potential as therapeutic agents in the treatment of autoimmune disease. Modulation of post-translational protein prenylation seems to be a key mechanism by which statins alter immune function. In this article, the effect of statin therapy on immune function, and how this impacts on the pathogenesis of autoimmune disease, will be reviewed alongside current opinion of the key biological targets.
doi:10.1038/nri1839
PMCID: PMC3842637  PMID: 16639429
22.  Therapeutic potential of statins in multiple sclerosis: immune modulation, neuroprotection and neurorepair 
Future neurology  2008;3(2):153.
Statins as inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A reductase are widely used as cholesterol-lowering drugs. Recent studies provide evidence that the anti-inflammatory activity of statins, which is independent of their cholesterol-lowering effects, may have potential therapeutic implications for neuroinflammatory diseases such as multiple sclerosis (MS), Alzheimer’s disease and brain tumors, as well as traumatic spinal cord and brain injuries. Studies with animal models of MS suggest that, in addition to immunomodulatory activities similar to the ones observed with approved MS medications, statin treatment also protects the BBB, protects against neurodegeneration and may also promote neurorepair. Although the initial human studies on statin treatment for MS are encouraging, prospective randomized clinical studies will be required to evaluate their efficacy in the larger patient population.
doi:10.2217/14796708.3.2.153
PMCID: PMC2811338  PMID: 20107624
blood-brain barrier; immunomodulation; inflammation; multiple sclerosis; neurodegeneration; neuroinflammatory diseases; neurorepair; pleotropic effects; statins
23.  STATINS MAY AGGRAVATE MYASTHENIA GRAVIS 
Muscle & nerve  2008;38(3):1101-1107.
Statin-induced myopathy is well-known, but the effect of cholesterol-lowering agents on myasthenia gravis (MG) has not been studied in detail. We investigated statin use and its effects on MG among patients with this disease. Statin information was systemically obtained from 170 patients being treated at the Neuromuscular Disease Clinic at the University of Alabama at Birmingham. When a new myalgic syndrome or worsening of MG developed within 4 months after statin treatment, no other likely cause was found, and clinical improvement occurred either with or without discontinuation of the statin, we considered these symptoms to be statin-induced. Fifty-four patients (31%) were on statins. The statin group had proportionally more males, and older patients compared with the non-statin group. A myalgic syndrome was noted in 7 (13%) patients, but it resolved without any sequelae after withdrawal of the statin. MG worsening occurred in 6 (11%) patients without regard to type of MG or brand of statin. MG worsening occurred independently of myalgic syndrome and involved predominantly oculobulbar symptoms within 1-16 weeks of statin treatment. In 4 patients, additional treatment was needed to reverse MG worsening. Statins are safe in the majority of MG patients, but their use must be accompanied by close observation for possible MG worsening.
doi:10.1002/mus.21074
PMCID: PMC2670554  PMID: 18720508
drug side effect; HMG coenzyme A reductase inhibitor; myasthenia gravis; myotoxicity; statin
24.  Statins and Cardiovascular Diseases: From Cholesterol Lowering to Pleiotropy 
Current pharmaceutical design  2009;15(5):467-478.
Statins are 3-hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase inhibitors, which are prescribed extensively for cholesterol lowering in the primary and secondary prevention of cardiovascular disease. Recent compelling evidence suggests that the beneficial effects of statins may not only be due to their cholesterol lowering effects, but also, to their cholesterol-independent or pleiotropic effects. Through these so-called pleiotropic effects, statins are directly involved in restoring or improving endothelial function, attenuating vascular remodeling, inhibiting vascular inflammatory response, and perhaps, stabilizing atherosclerotic plaques. These cholesterol-independent effects of statins are due predominantly to their ability to inhibit isoprenoid synthesis, the products of which are important lipid attachments for intracellular signaling molecules, such as Rho, Rac and Cdc42. In particular, inhibition of Rho and its downstream target, Rho-associated coiled-coil containing protein kinase (ROCK), has emerged as the principle mechanisms underlying the pleiotropic effects of statins. This review provides an update of statin-mediated vascular effects beyond cholesterol lowering and highlights recent findings from bench to bedside to support the concept of statin pleiotropy.
PMCID: PMC2896785  PMID: 19199975
Statin; vascular; cholesterol; inflammation; nitric oxide; rho kinase
25.  Relationship Between Statin Use and Colon Cancer Recurrence and Survival: Results From CALGB 89803 
Background
Although preclinical and epidemiological data suggest that statins may have antineoplastic properties, the impact of statin use on patient survival after a curative resection of stage III colon cancer is unknown.
Methods
We conducted a prospective observational study of 842 patients with stage III colon cancer enrolled in a randomized adjuvant chemotherapy trial from April 1999 to May 2001 to investigate the relationship between statin use and survival. Disease-free survival (DFS), recurrence-free survival (RFS), and overall survival (OS) were investigated by Kaplan–Meier curves and log-rank tests in the overall study population and in a subset of patients stratified by KRAS mutation status (n = 394), and Cox proportional hazards regression was used to assess the simultaneous impact of confounding variables. All statistical tests were two-sided.
Results
Among 842 patients, 134 (15.9%) reported statin use after completing adjuvant chemotherapy. DFS among statin users and nonusers was similar (hazard ratio [HR] of cancer recurrence or death = 1.04, 95% confidence interval [CI] = 0.73 to 1.49). RFS and OS were also similar between statin users and nonusers (adjusted HR of cancer recurrence = 1.14, 95% CI = 0.77 to 1.69; adjusted HR of death = 1.15, 95% CI = 0.77 to 1.71). Survival outcomes were similar regardless of increasing duration of statin use before cancer diagnosis (Ptrend = .63, .63, and .59 for DFS, RFS, and OS, respectively). The impact of statin use did not differ by tumor KRAS mutation status, with similar DFS, RFS, and OS for statin use among mutant and wild-type subgroups (Pinteraction = .84, .67, and .98 for DFS, RFS, and OS, respectively).
Conclusion
Statin use during and after adjuvant chemotherapy was not associated with improved DFS, RFS, or OS in patients with stage III colon cancer, regardless of KRAS mutation status.
doi:10.1093/jnci/djr307
PMCID: PMC3196479  PMID: 21849660

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