The use of fibrates and of statins in preventing atherosclerosis in diabetes.

Atherosclerotic cardiovascular disease is the most common complication of diabetes. Recent guidelines in the USA have underlined the importance of treating lipid abnormalities in people with diabetes in order to reduce the risk of this complication. Should lifestyle approaches not be sufficient drugs will need to be added. The two most common classes of drugs to correct lipoprotein abnormalities are the statins and the fibrates. Each has a role to play and their use depends on the nature of the lipid abnormality that is present. Thus, rather than considering their use as an 'either/or' situation, this review will consider the uses of each class. In addition, as correcting the lipoprotein abnormalities may not account for all of the benefit produced by these agents, their non-lipid, pleotropic effects that may be antiatherogenic will also be reviewed.     

Aggressive lipid management for cardiovascular prevention: evidence from clinical trials

Epidemiologic evidence shows that elevated serum cholesterol, specifically low-density lipoprotein cholesterol (LDL-C), increases the risk of coronary heart disease (CHD). Moreover, large-scale intervention trials demonstrate that treatment with HMG-CoA reductase inhibitors (statins), the most effective drug class for lowering LDL-C, significantly reduces the risk of CHD events. Unfortunately, only a moderate percentage of hypercholesterolemic patients are achieving LDL-C targets specified by the National Cholesterol Education Program (NCEP), in part because clinicians are not effectively titrating medications as needed to achieve LDL-C goals. Recent evidence suggests that more aggressive LDL-C lowering may provide greater clinical benefit, even in individuals with moderately elevated serum cholesterol levels. Furthermore, recent studies suggest that statins have cardioprotective effects in many high-risk individuals, including those with baseline LDL-C <100 mg/dl. High-density lipoprotein cholesterol (HDL-C) was recognized by the NCEP-Adult Treatment Panel II (ATP II) as a negative risk factor for CHD. The NCEP-ATP III guidelines have also reaffirmed the importance of HDL-C by increasing the low HDL-C designation from <35 to <40 mg/dl as a major risk factor for CHD. Similarly, triglyceride control will play a larger role in dyslipidemia management. As more clinicians effectively treat adverse lipid and lipoprotein cardiovascular risk factors, patients will likely benefit from reductions in cardiovascular events.     

Avances en el tratamiento de la hipercolesterolemia

Numerous epidemiological and prospective studies have shown a direct relationship between total cholesterol and low-density lipoprotein cholesterol (LDL-C) and cardiovascular disease (cardiovascular morbidity and mortality). In many intervention studies with more than 100,000 subjects, statins have shown a powerful and significant reduction of cardiovascular events and a decrease in cardiovascular and overall mortality, far superior to those produced by any other lipid-lowering group.Consequently statins are considered to be safe and well tolerated and are the first choice in the treatment of hypercholesterolemia and in cardiovascular disease prevention. If targets are not reached, other pharmacological groups must be associated (resins, nicotinic acid, ezetimibe, fibrates, etc.). Moreover, when hypercholesterolemia is associated with low concentrations of high-density lipoprotein (HDL)-cholesterol and high triglyceride levels, the association of statins with nicotinic acid, fibrates or omega-3 should be considered.Some questions remain to be answered: what LDL-C levels are desirable in secondary prevention? Which individuals might benefit from treatment in primary prevention? Which lipid-lowering drug is the most suitable to combine with statins and diminish cardiovascular risk in each situation? The present article reviews these important points.     

Update for primary healthcare providers: recent statin trials and revised National Cholesterol Education Program III guidelines

Statins produce large, clinically important beneficial effects on total low-density lipoprotein (LDL) cholesterol and triglycerides while raising high-density lipoprotein (HDL) cholesterol--each of which increases the risks for cardiovascular disease (CVD). In randomized trials of secondary and primary prevention, and their meta-analyses, statins confer statistically significant, clinically important reductions in myocardial infarction, stroke, and CVD death. In 2001, the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III included LDL as the primary target, recommending optional goals of < 100 mg/dL for high-risk patients, < 130 mg/dL for moderate-risk patients, and < 160 mg/dL for low-risk patients. We conducted a search of randomized trials of statins whose results were published since May 15, 2001. We extracted overall trial results and data on adverse events, when available. We reviewed 7 published trials of statins, some of which contributed to the recent addendum to the NCEP ATP III guidelines that recommend reducing LDL goals to < 70 for very high-risk and < 100 for moderately high-risk patients via statins. Data from these trials demonstrate that greater LDL reductions produce larger CVD benefits in various categories of high- and moderate-risk patients, including a large number of primary prevention patients with metabolic syndrome who should be treated as aggressively as patients who have survived a myocardial infarction or stroke. Together, these recent statin trials and the NCEP ATP III revised guidelines, if implemented by primary healthcare providers, would result in many more patients receiving statins of proven benefit and reassuring adverse event profile.     

Role of CETP inhibitors in the treatment of dyslipidemia

PURPOSE OF REVIEW: This review summarizes novel human data on cholesteryl ester-transfer protein (CETP) and atherosclerosis and the possible use of CETP inhibitors in the treatment of dyslipidemia. In addition, it will underline that therapeutic targeting of the high-density lipoprotein (HDL) metabolism entails more than simply observing changes in cholesterol levels of this lipoprotein. RECENT FINDINGS: Two pharmacological small-molecule inhibitors of CETP, JTT-705 and torcetrapib, have recently been shown to effectively raise HDL cholesterol in humans without serious side effects when either used as a monotherapy or combined with statins that lower low-density lipoprotein cholesterol. Importantly, prospective data from the Epic-Norfolk study furthermore indicate that elevated CETP concentration in conjunction with elevated triglyceride levels are associated with increased odds for cardiovascular events. Data from the Diabetic Atherosclerosis Intervention Study furthermore show that elevated CETP concentration is associated with increased progression of coronary atherosclerosis in patients with type 2 diabetes who use fenofibrate. SUMMARY: Long-term studies will have to show whether CETP inhibition decreases the risk of atherosclerotic disease in dyslipidemic patients. Increased CETP activity might be detrimental under hypertriglyceridemic conditions which is of importance when considering that a large proportion of patients at increased risk from coronary artery disease exhibit elevated triglyceride levels. Studies into the effects of CETP inhibition in hypertriglyceridemic patients therefore seem warranted. Awaiting the first data on the effect of CETP inhibition on surrogate endpoints for atherosclerosis, this review furthermore outlines that the complexity of HDL metabolism will necessitate a wide variety of studies on many aspects of this intriguing lipoprotein.     

The dyslipidemia of chronic renal disease: effects of statin therapy

PURPOSE OF REVIEW: Dyslipidemia is a prevalent condition in patients with chronic renal disease, but is often left untreated. Statin treatment constitutes an effective way to improve lipid abnormalities. This review summarizes present studies on dyslipidemia and its treatment in patients with chronic renal disease. RECENT FINDINGS: The specific dyslipidemia in renal disease is associated with the presence of proteinuria and decreased creatinine clearance, and may even adversely affect the progression of chronic renal disease. Statin therapy may have renoprotective effects due to a combination of lipid lowering and pleiotropic effects. Statins exert several anti-inflammatory properties and lead to a decrease of proteinuria. Post-hoc analyses of large-scale lipid lowering trials have shown that the reduction of cardiovascular risk was equivalent to the reduction achieved in patients without chronic renal failure. We feel, however, that if intervention with statins is postponed until patients reach end-stage renal disease, statins have limited benefit. SUMMARY: Present studies suggest that patients with renal disease should be screened early for dyslipidemia and that statins have to be considered as the lipid lowering therapy of choice. These drugs reduce cardiovascular risk. Further studies are needed to firmly establish whether statins preserve renal function.     

Novel aspects of PCSK9 and lipoprotein receptors in renal disease-related dyslipidemia

Chronic kidney disease (CKD) is a global health problem with a profound impact on quality of life. Cardiovascular disease is established as a major cause of morbidity and mortality in patients with CKD. Dyslipidemia is frequently observed in CKD patients, suggesting a causal relation between dyslipidemia and cardiovascular disease in CKD patients. Currently, lipid-lowering drugs such as statins, are the primary choice for lipid lowering therapy in high-risk populations. Despite many studies showing CVD risk reduction with statins, CVD still remains the leading cause of the death in CKD. This underscores the need for new therapeutic approaches to reduce cardiovascular risk in CKD patients. Reduced lipoprotein lipase activity, increased very low-density lipoprotein production, increased proprotein convertase subtilisin kexin type 9 (PCSK9) expression and loss of hepatic heparan sulfate proteoglycans (HSPG) syndecan-1 have been associated with CKD-related dyslipidemia. Low-density lipoprotein receptor (LDLR), low-density lipoprotein receptor-related protein 1 (LRP-1) and syndecan-1, are the most important hepatic receptors for lipoprotein clearance. However, their contributions to the pathogenesis of dyslipidemia and cardiovascular disease in CKD remain unclear. Interestingly, in CKD, increased plasma lipid levels are associated with elevated levels of PCSK9. This promotes the proteolysis of LDLR, suggesting a role for PCSK9 in CKD-associated dyslipidemia. Fully humanized monoclonal antibodies targeting PCSK9 have been approved by the US Food and Drug Administration and the European Medicines Agency as lipid lowering treatment for patients with hypercholesterolemia. In CKD sub-group analysis, ODYSSEY COMBO I and ODYSSEY COMBO II studies demonstrated strong reduction in LDL-C by alirocumab compared to placebo and ezetimibe and when added to statins. However, their efficacy in reducing plasma TG is controversial. Therefore, further research work is need for a detailed analysis on efficacy and safety of PCSK9 antibodies in CKD groups. Interestingly, novel findings on PCSK9 interaction with HSPG might shed new insight on altered lipid metabolism in CKD. In this review, we discuss various aspects of lipoprotein metabolism and hepatic lipoprotein receptor signaling pathways along with the concept of renal disease-related dyslipidemia. Furthermore, this review highlights the drawbacks of current lipid-lowering therapies and proposes novel approaches for lipid management in CKD.     

Which is the best lipid-modifying strategy in metabolic syndrome and diabetes: fibrates, statins or both?

Although less clinical intervention studies have been performed with fibrates than with statins, there are evidences indicating that fibrates may reduce risk of cardiovascular events. The potential clinical benefit of the fenofibrate will be specified by the ongoing Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, which rationale, methods and aims have been just published. Controlled clinical trials show similar or even greater cardiovascular benefits from statins-based therapy in patient subgroups with diabetes compared with overall study populations. Therefore, statins are the drug of first choice for aggressive lipid lowering actions and reducing risk of coronary artery disease in these patients. However, current therapeutic use of statins as monotherapy is still leaving many patients with mixed atherogenic dyslipidemia at high risk for coronary events. A combination statin/fibrate therapy may be often necessary to control all lipid abnormalities in patients with metabolic syndrome and diabetes adequately, since fibrates provide additional important benefits, particularly on triglyceride and HDL-cholesterol levels. Thus, this combined therapy concentrates on all the components of the mixed dyslipidemia that often occurs in persons with diabetes or metabolic syndrome, and may be expected to reduce cardiovascular morbidity and mortality. Safety concerns about some fibrates such as gemfibrozil may lead to exaggerate precautions regarding fibrate administration and therefore diminish the use of the seagents. However, other fibrates, such as bezafibrate and fenofibrate appear to be safer and better tolerated. We believe that a proper co-administration of statins and fibrates, selected on basis of their safety, could be more effective in achieving a comprehensive lipid control as compared with monotherapy.     

Finding multiple target optimal intervention in disease‐related molecular network

Drugs against multiple targets may overcome the many limitations of single targets and achieve a more effective and safer control of the disease. Numerous high‐throughput experiments have been performed in this emerging field. However, systematic identification of multiple drug targets and their best intervention requires knowledge of the underlying disease network and calls for innovative computational methods that exploit the network structure and dynamics. Here, we develop a robust computational algorithm for finding multiple target optimal intervention (MTOI) solutions in a disease network. MTOI identifies potential drug targets and suggests optimal combinations of the target intervention that best restore the network to a normal state, which can be customer designed. We applied MTOI to an inflammation‐related network. The well‐known side effects of the traditional non‐steriodal anti‐inflammatory drugs and the recently recalled Vioxx were correctly accounted for in our network model. A number of promising MTOI solutions were found to be both effective and safer.     

Statin therapy and autoimmune disease: from protein prenylation to immunomodulation

Statins have been prescribed extensively for their cholesterol-lowering properties and efficacy in cardiovascular disease. However, compelling evidence now exists that statins also have extensive immunomodulatory properties that operate independently of lipid lowering. Consequently, much attention has been directed towards their potential as therapeutic agents for 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 Review, the effect of statin therapy on immune function, and how this relates to the pathogenesis of autoimmune disease, is reviewed alongside current opinion of what the key biological targets of statins are.     

The Association of Cardioprotective Medications with Pneumonia-Related Outcomes

Introduction

Little research has examined whether cardiovascular medications, other than statins, are associated with improved outcomes after pneumonia. Our aim was to examine the association between the use of beta-blockers, statins, angiotensin converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs) with pneumonia-related outcomes.

Materials and Methods

We conducted a retrospective population-based study on male patients ≥65 years of age hospitalized with pneumonia and who did not have pre-existing cardiac disease. Our primary analyses were multilevel regression models that examined the association between cardiovascular medication classes and either mortality or cardiovascular events.

Results

Our cohort included 21,985 patients: 22% died within 90 days of admission, and 22% had a cardiac event within 90 days. The cardiovascular medications studied that were associated with decreased 90-day mortality included: statins (OR 0.70, 95% CI 0.63–0.77), ACE inhibitors (OR 0.82, 95% CI 0.74–0.91), and ARBs (OR 0.58, 95% CI 0.44–0.77). However, none of the medications were significantly associated with decreased cardiovascular events.

Discussion

While statins, ACE inhibitors, and ARBs, were associated with decreased mortality, there was no significant association with decreased CV events. These results indicate that this decreased mortality is unlikely due to their potential cardioprotective effects.     

Pharmacogenetics and pharmacogenomics of cholesterol-lowering therapy

PURPOSE OF REVIEW: To summarize recent findings on pharmacokinetics, pharmacodynamics, drug-drug interactions and influence of lifestyle heterogeneity on adverse events in cholesterol-lowering therapy RECENT FINDINGS: The prevention of cardiovascular disease is critically dependent on lipid-lowery therapy, including statins, cholesterol absorption inhibitors, fibrates and nicotinic acid. Statins are the most prescribed drugs in lipid lowering therapy with variability in response and almost one third of the patients do not meet their treatment goals. The severe adverse effects of treatment with cerivastatin stimulated the search for new genes and gene variations affecting pharmacokinetics, drug-drug interactions and pharmacodynamics. Moreover, instead of monotherapy, combined therapy of statins with ezetemibe and niacin was considered. This led to the identification of CD13, NPC1L1 and HM74A as new targets and CYP2C8 and glucuronidation enzymes as potential targets for drug-drug interactions. Moreover multiple polymorphic sites and pleiotrophic gene targets were reinvestigated in larger cohorts and the relevant pathogenetic factors start to evolve. SUMMARY: Statin therapy is widely used and well tolerated by the majority of patients. To further reduce potential adverse effects and to increase efficacy, combined therapy concepts with ezetimibe or niacin are underway.     

Statins: a revised appraisal for potential additional future treatment indications

Beside statins'' well established positive influence on atherosclerotic vascular disease caused by hypercholesterolemia through selective competitive inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, additional effects on the immune system have been described for them. These observations have raised great hopes for additional future treatment indications, including rheumatoid arthritis and multiple sclerosis. Ten years of searching for such novel treatment indications have not led to breakthroughs and future efforts must be seen with skepticism.In the previous issue of Arthritis Research and Therapy Vandebriel and colleagues [1] report that the statins atorvastatin and pravastatin orally administered before disease induction in collagen-induced arthritis (CIA) in male DBA/lOlaHsd mice led to accelerated onset and higher disease incidence compared to controls. In addition, atorvastatin applied after induction of CIA resulted in earlier disease onset than administration before induction of CIA. Atorvastatin, but not pravastatin, administration also resulted in increased production of anti-collagen autoantibodies. In line with these novel findings in CIA, the same group recently demonstrated in a retrospective analysis of patients with rheumatoid arthritis (RA) that statins increase the risk for development of RA [2].Statins are one of the most prescribed drugs in clinical medicine at present. Their main mechanism of action is selective, competitive inhibition of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a precursor of sterols, including cholesterol.Statins are indicated in patients with significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia for reduction of mortality from coronary heart disease, non-fatal myocardial infarction and stroke and reduction of coronary and non-coronary revascularization procedures. Furthermore, statins are indicated in patients with various forms of hyperlipidemia. While statins have a clear and well established positive effect in the disease conditions named above, emerging data for additional indications is rather weak and side effects should be taken into consideration.In addition to the inhibition of HMG-CoA reductase, a multitude of additional drug-related and off-target effects with possible therapeutic value have been described. Importantly, it has also been demonstrated that statins have immunomodulatory properties. Most prominently, atorvastatin application in experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis, leads to reduced disease severity due to effects on antigen presentation and T-cell activation and phenotype [3]. Unexpectedly, clinical studies in multiple sclerosis patients could not confirm the beneficial effects of statins observed in experimental autoimmune encephalomyelitis [4]. Statins that pass the blood-brain barrier should also be used with caution for other reasons, since some experimental- data indicate that statins inhibit remyelination [5].Statins have been evaluated as a treatment of Alzheimer''s disease. There are positive trends, but the data are conflicting and further studies in patients with mild Alzheimer''s disease will possibly clarify the assumed therapeutic value [6].The findings of Vandebriel and colleagues are in contrast to previously published reports in which atorvastatin, pravastatin, simvastatin and rosuvastatin given by various routes after CIA induction in mice have been reported to reduce disease or to have no effect (summarized in [1]). The reasons for the discrepancy could be differences in disease induction, route of dosing and dose, used substrains of mice and the animal housing environment. On the other hand, there is no previously published study in which statins were given before disease induction of CIA.So far statins have also been considered of potential future therapeutic value in RA. In RA there are data indicating that atorvastatin as an add on therapy to disease-modifying antirheumatic drugs (DMARDs) has beneficial effects in patients with RA: the randomized double blind placebo-controlled Atorvastatin in Rheumatoid Arthritis (TARA) study demonstrated some modest effects on acute phase variables and swollen joints, while other parameters remained unaffected [7]. Another study equally demonstrated beneficial effects in patients with RA treated with atorvastatin and reported an increased number of regulatory T cells as a possible mechanism of action [8]. Others reported effects on inflammatory parameters and Th1/Th2 balance leading to beneficial treatment effects of simvastatin in RA [9].Recently, the US Food and Drug Administration (FDA) changed its safety label for statins and indicated that liver injury associated with statin use is rare but can occur. They also acknowledged that statin use can be associated with memory loss, forgetfulness and confusion. In addition, a small, increased risk of raised blood sugar levels and the development of type 2 diabetes have been reported. Moreover, there is a risk for muscle damage.Vandebriel and colleagues also demonstrate an influence on collagen type II autoantibody titers after treatment with atorvastatin [1]. Since this was only the case for atorvastatin and not pravastatin, the data could indicate varying effects on the immune response of different- types of statins. Possibly the B-cell arm of autoimmune diseases could be affected by statin administration, leading to increased autoantibody titers. In line with the speculation that the B-cell arm of the immune response is affected by statin administration is the increased incidence of lupus-like syndromes in patients receiving statins [10].In summary, the work by Vandebriel and colleagues [1] suggests that broad use of statins could lead to increased incidence of autoimmune disease, especially RA. Further work will be necessary to demonstrate the cell biological and immunological mechanisms explaining these findings. Future studies in rodents and humans should better delineate the differences in the properties of individual statins with regard to their modes of action. The hypothesis that statins will have additional future indications for treatment of autoimmune diseases like RA or multiple sclerosis is more unlikely. Presently, there are no convincing data for the use of statins in these indications outside of controlled clinical trials. Exceptions remain co-morbidities with cardiovascular disease, stroke and hyperlipidemia.     

HIV-associated dementia, mitochondrial dysfunction, and oxidative stress

Over the past several decades, researchers have made large advances in unraveling the pathogenesis of HIV-related neurological disease leading to substantial benefits for affected individuals. Concomitant advances in HIV-treatment have changed the landscape of HIV care, resulting in alterations in HIV neuroepidemiolgy and potentially the neuropathogenesis of cognitive disorders. Specifically, widespread ARV medications use has heightened our awareness of mitochondrial toxicity, oxidative stress, and metabolic abnormalities and stimulated more research into the related cognitive consequences. Specific sources of oxidative stress among HIV-1-infected individuals to be discussed in this article include the direct effects of HIV-1, chronic immune activation in response to HIV-1 and other pathogens, and co-morbid factors. Continued research in this area could provide novel therapeutic targets.     

Statins: are any questions unanswered?

PURPOSE OF REVIEW: To summarize recent and ongoing randomized trials of statin therapy for the prevention of major vascular events. RECENT FINDINGS: Four large-scale randomized trials have compared high-dose vs. standard doses of statin therapy among patients with coronary heart disease, and their results suggest that higher doses are more effective for preventing major vascular events, albeit with evidence of increased toxicity. There is now clear evidence that statin therapy is effective among most patients with type 2 diabetes, although uncertainty remains about the benefits in those with advanced nephropathy. Ongoing trials will assess whether statin therapy is beneficial among patients with noncoronary vascular disease (such as congestive heart failure, cerebrovascular disease, or aortic stenosis), and among people with comorbid conditions or risk factors that increase the risk of vascular disease (including chronic kidney disease and raised C-reactive protein with below average low-density lipoprotein cholesterol). SUMMARY: Statin therapy safely reduces the risk of vascular events in a wide range of patients. Uncertainties persist about the effects of higher statin doses and the role of statins among patients with specific conditions or risk factors.     

Lipid Abnormalities in Patients Infected With HumanImmunodeficiency Virus

ObjectiveTo review the types, mechanisms, clinical implications, and management of lipid abnormalities associated with human immunodeficiency virus (HIV) infection and its treatment.MethodsReview of the relevant literature using MEDLINE data sources from 1985 to February 2008, endocrinology textbooks, and hand-searching of cross-references from original articles and reviews. Clinical trials, animal studies, in vitro studies, case reports, reviews, and guidelines of major medical associations were included.ResultsAdvanced stages of HIV infection are characterized by low plasma levels of total cholesterol, highdensity lipoprotein cholesterol, low-density lipoprotein cholesterol, and elevated triglycerides. Antiretroviral agents can exert negative effects on lipids that vary substantially between different drug classes and between individual drugs within each class. Prospective studies suggest that the use of protease inhibitors may be associated with increased risk of myocardial infarction that is mediated in part by dyslipidemia. Target levels of plasma lipids and management of HIV–related dyslipidemia generally follow the same guidelines as in the general population. However, dyslipidemia in this setting is often difficult to control with a single lipid-lowering agent, and potentially serious drug interactions may exist between some statins, such as simvastatin, and protease inhibitors.ConclusionsPlasma lipids should be measured in all patients infected with HIV before and 3 to 4 months after starting antiretroviral drugs. Statins are the initial drugs of choice in most patients. The concomitant use of statins and antiretroviral drugs should take into account various interactions between these agents. (Endocr Pract. 2008;14:492-500)     

Statins,stem cells,and cancer

The statins (3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors) were proven to be effective antilipid agents against cardiovascular disease. Recent reports demonstrate an anticancer effect induced by the statins through inhibition of cell proliferation, induction of apoptosis, or inhibition of angiogenesis. These effects are due to suppression of the mevalonate pathway leading to depletion of various downstream products that play an essential role in cell cycle progression, cell signaling, and membrane integrity. Recent evidence suggests a shared genomic fingerprint between embryonic stem cells, cancer cells, and cancer stem cells. Activation targets of NANOG, OCT4, SOX2, and c‐MYC are more frequently overexpressed in certain tumors. In the absence of bona fide cancer stem cell lines, human embryonic stem cells, which have similar properties to cancer and cancer stem cells, have been an excellent model throwing light on the anticancer affects of various putative anticancer agents. It was shown that key cellular functions in karyotypically abnormal colorectal and ovarian cancer cells and human embryonic stem cells are inhibited by the statins and this is mediated via a suppression of this stemness pathway. The strategy for treatment of cancers may thus be the targeting of a putative cancer stem cell within the tumor with specific agents such as the statins with or without chemotherapy. The statins may thus play a dual prophylactic role as a lipid‐lowering drug for the prevention of heart disease and as an anticancer agent to prevent certain cancers. This review examines the relationship between the statins, stem cells, and certain cancers. J. Cell. Biochem. 106: 975–983, 2009. © 2009 Wiley‐Liss, Inc.     

Clinical pharmacology of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.

In this article, de novo cholesterol synthesis, its inhibition by HMG-CoA reductase inhibitors (statins) and clinical pharmacology aspects of the statins have been reviewed. Statins are available in both active and pro-drug forms. Their affinity to bind and subsequently to inhibit HMG-CoA reductase activity is approximately 3 orders of magnitude higher than that of natural substrate (HMG-CoA). All members of this group of lipid-lowering agents are, to a varying degree, absorbed from the gut. However, their bioavailability depends on their lipophobicity and their concomitant use with meals. The interaction between HMG-CoA reductase inhibitors and other lipid-lowering agents has been reviewed in more detail. One major side-effect of lipid-lowering combination therapy is myopathy with or without rhabdomyolysis. Combination of statins with gemfibrozil seems to increase risk of this adverse event, particularly in patients with renal impairment, more than combination with other lipid-lowering agents. Combination therapy with other agents including anticoagulants, antihypertensive, anti-inflammatory, oral hypoglycemic and antifungal agents as well as beta-blockers, H2 blockers, cyclosporine and digoxin has been also reviewed. The pleiotropic non-lipid lowering properties of statins and their effects on the quality of lipoprotein particles, the activities of cholesteryl ester transfer protein and lecithin:cholesterol acyltransferase as well as their possible synergistic effects with n-3 fatty acids, phytosterols, vitamin E and aspirin in reducing cardiovascular events warrant further investigation.