Fluvastatin,HMG‐CoA Reductase Inhibitor: Antiatherogenic Profiles Through Its Lipid‐Lowering–Dependent and ‐Independent Actions

Fluvastatin, the first totally synthetic inhibitor of 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase, has the unique structure of a mevalonolactone derivative of a fluorophenyl‐substituted indole ring. Fluvastatin markedly reduces plasma lipid levels in animals and humans by inhibiting the activity of HMG‐CoA reductase following the up‐regulation of low density lipoprotein receptors, as it occurs with other HMG‐CoA reductase inhibitors. Several lines of evidence indicate that the hypolipidemic action of fluvastatin results in antiatherosclerotic effects in hyperlipidemic animal models. Recent findings have shown, however, that fluvastatin inhibits the progression of atherosclerosis independent of its lipid‐lowering effects. In addition, fluvastatin inhibits key events or factors in the initiation or progression of atherosclerosis. These effects include antioxidant and antithrombotic properties, improvement of endothelial function, inhibition of activated monocyte‐endothelial cell interaction, and inhibition of activated macrophage and smooth muscle cell function. Recent large clinical trials with fluvastatin demonstrated its beneficial effects on the incidence of clinical events and on the progression of atherosclerotic plaques in patients with hyperlipidemia. Although angiographic changes (e.g., the decrease in minimum lumen diameter) in response to therapy were modest, the accompanying clinical benefit appeared to be significant. The lipid‐lowering therapy can not fully explain the results of clinical trials. The antiatherogenic profiles of fluvastatin might contribute to the decrease in the clinical events by directly inhibiting the atherosclerotic plaque progression and stabilizing the atherosclerotic plaque lesion. Elucidation of pleiotropic effects of fluvastatin other than lipid‐lowering properties encourages the clinical use of fluvastatin not only for the reduction of plasma cholesterol levels but also for the secondary prevention of coronary heart disease in patients with hypercholesterolemia.     

Pleiotropic effects of HMG-CoA reductase inhibitors

HMG CoA reductase inhibitiors (statins) have been shown to be effective lipid lowering agents and are able to significantly reduce cardiovascular mortality and morbidity in patients at risk for cardiovascular disease. Recent clinical and experimental data suggest that the benefit of statins may extend beyond their hepatic effects on serum cholesterol levels. This review summarizes the current evidence and the molecular mechanisms of the direct effects of statins on plaque stability, inflammation, endothelial function, oxidative stress, thrombosis and stroke. Furthermore, recent data on the effects of statins on bone marrow, bone density and dementia are described. In summary, statins have emerged as a novel and powerful tool to study cardiovascular biology, including protein isoprenylation, small G protein function, leukocyte activity and endothelial progenitor cells. These pleiotropic properties of statins may have important clinical implications in addition to lowering serum cholesterol. Received: 10 October 2001, Accepted: 24 October 2001     

Isoprenoid metabolism and the pleiotropic effects of statins

Convincing evidence from basic research and animal studies shows that 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (ie, statins) exert cardiovascular protective effects beyond cholesterol lowering. Because of the central role of low-density lipoprotein (LDL) cholesterol in mediating vascular pathology and the efficacy of statins for lowering LDL cholesterol, the clinical importance of these additional nonlipid effects remains to be determined. Nevertheless, there is growing evidence from recent clinical trials that suggests that some of the beneficial effects of statins may be unrelated to changes in LDL cholesterol. 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 Heart Protection Study and Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm, the potential cholesterol-independent effects of statins have shifted the treatment strategy from numerical lipid parameters to the global assessment of cardiovascular risks.     

Statin therapy in cardiovascular diseases other than atherosclerosis

Statins are drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, thereby blocking the synthesis of cholesterol. Since being discovered in Japan in the mid 1970s, statins have been widely used to lower low-density lipoprotein cholesterol. However, analysis of cardiovascular research has revealed other important effects beyond changes in lipid parameters, referred to as pleiotropic effects. This paper focuses on the effects of statins as anti-ischemic agents with improvement in endothelial function, along with studies on valvular aortic stenosis, atrial fibrillation, heart failure, peripheral arterial disease, and cancer. As the evolution of statin research continues, there appear to be new potential benefits from statins to be found in many facets of cardiovascular disease.     

Colesevelam: Potential Uses for the Newest Bile Resin

Colesevelam is the newest bile resin with a unique chemical structure. It binds to bile acids with higher affinity than traditional bile acid sequestrants and has fewer gastrointestinal side effects and drug interactions. Colesevelam is safe and efficacious alone or in combination with HMG‐CoA reductase inhibitors (statins) in reducing low‐density lipoprotein cholesterol (LDL‐C) levels. Despite this, the role of colesevelam in the treatment of hyperlipidemia remains limited, particularly in the face of new lipid lowering agents. As guidelines for cholesterol control become more stringent, the need to maximize therapeutic benefit through combination therapy will become increasingly more important. Colesevelam has a dose‐sparing effect on statin therapy, potentially decreasing the risk of unwanted side effects or drug‐drug interactions associated with statin use. This makes colesevelam a viable option for addition to a statin regimen when goal LDL‐C levels cannot be achieved with a statin alone. Additionally, anecdotal reports indicate that colesevelam may have potential benefits in certain patient populations that cannot tolerate other lipid lowering therapies, including organ transplant recipients, cholestatic liver disesase, and end‐stage renal disease. By recognizing the potential utility of colesevelam, clinicians can better manage those patients who are not able to tolerate first‐line therapies.     

The evolving role of statins in the management of atherosclerosis

Significant advances in the management of cardiovascular disease have been made possible by the development of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors--"statins." Initial studies explored the impact of statin therapy on coronary artery disease (CAD) progression and regression. Although the angiographic changes were small, associated clinical responses appeared significant. Subsequent large prospective placebo-controlled clinical trials with statins demonstrated benefit in the secondary and primary prevention of CAD in subjects with elevated cholesterol levels. More recently, the efficacy of statins has been extended to the primary prevention of CAD in subjects with average cholesterol levels. Recent studies also suggest that statins have benefits beyond the coronary vascular bed and are capable of reducing ischemic stroke risk by approximately one-third in patients with evidence of vascular disease. In addition to lowering low-density lipoprotein (LDL) cholesterol, statin therapy appears to exhibit pleiotropic effects on many components of atherosclerosis including plaque thrombogenicity, cellular migration, endothelial function and thrombotic tendency. Growing clinical and experimental evidence indicates that the beneficial actions of statins occur rapidly and yield potentially clinically important anti-ischemic effects as early as one month after commencement of therapy. Future investigations are warranted to determine threshold LDL values in primary prevention studies, and to elucidate effects of statins other than LDL lowering. Finally, given the rapid and protean effects of statins on determinants of platelet reactivity, coagulation, and endothelial function, further research may establish a role for statin therapy in acute coronary syndromes.     

Does it matter whether or not a lipid-lowering agent inhibits Rho kinase?

Lipid-lowering agents, such as 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, also known as statins, have been shown to reduce cardiovascular events. However, evidence from recent clinical trials suggests that some of the beneficial effects of statins may be unrelated to changes in low-density lipoprotein cholesterol. 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, and in particular on statins, is not known, but it may have important clinical and therapeutic implications. This review attempts 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.     

Statins. Evidence of effectiveness in older patients

As the population ages, increasing numbers of older adults are becoming candidates for lipid-lowering therapy with HMG CoA reductase inhibitors (statins) and lifestyle modification. Available evidence shows that statins reduce cardiovascular events and invasive revascularization in older adults. Statins have not only been shown to be safe and effective for lowering LDL cholesterol, but appear to have ancillary pleiotropic effects that are beneficial in other conditions to which older adults are prone. Despite these benefits, older adults are currently undertreated for this highly treatable cardiovascular risk factor.     

Lipidapherese

Lipid apheresis is an extracorporeal elimination procedure to reduce the blood concentration of low density lipoprotein (LDL) cholesterol and lipoprotein(a). There are three indications for this therapy: it is the treatment of choice for homozygous familial hypercholesterolemia, secondly it is applied in severe hypercholesterolemia that cannot be treated by changes in lifestyle or cannot be managed pharmacologically either because of intolerance of statins or insufficient reduction of LDL cholesterol and thirdly, it is indicated if atherosclerosis is progressive even after sufficient lowering of LDL cholesterol and if the concentration of lipoprotein(a) exceeds 60 mg/dl. Together with pleiotropic effects, long-term lowering of LDL cholesterol and lipoprotein(a) by lipid apheresis has been shown to reduce the risk of cardiovascular events by approximately 80% [1].     

Statins: immunomodulators for autoimmune rheumatic disease?

Inhibitors of 3-hydroxy-3-methylgluttaryl coenzyme A (HMG-CoA) reductase, or statins, are used extensively to reduced elevated lipid levels and reduce cardiovascular risk. However, accumulated evidence suggests that stains not only act by lowering cholesterol levels, but also exert pleiotropic effects on many essential cellular functions including cell proliferation, differentiation, and survival and participate in the regulation of cell shape and motility. Thus cardiovascular benefit is provided by lowering raised cholesterol levels and by modulation of the inflammatory component of this disease. Such an anti-inflammatory effect may also benefit patients with autoimmune rheumatic disease. This overview assesses the evidence for using statins in patients with rheumatoid arthritis and systemic lupus erythematosus (SLE).     

Niacin: The Evidence,Clinical Use,and Future Directions

The use of FDA-approved niacin (nicotinic acid or vitamin B3) formulations at therapeutic doses, alone or in combination with statins or other lipid therapies, is safe, improves multiple lipid parameters, and reduces atherosclerosis progression. Niacin is unique as the most potent available lipid therapy to increase high-density lipoprotein (HDL) cholesterol and it significantly reduces lipoprotein(a). Through its action on the GPR109A receptor, niacin may also exert beneficial pleiotropic effects independent of changes in lipid levels, such as improving endothelial function and attenuating vascular inflammation. Studies evaluating the impact of niacin in statin-naïve patients on cardiovascular outcomes, or alone and in combination with statins or other lipid therapies on atherosclerosis progression, have been universally favorable. However, the widespread use of niacin to treat residual lipid abnormalities such as low HDL cholesterol, when used in combination with statins among patients achieving very low (<75 mg/dL) low-density lipoprotein cholesterol levels, is currently not supported by clinical outcome trials.     

Low density lipoprotein density and composition in hypercholesterolaemic men treated with HMG CoA reductase inhibitors and gemfibrozil

The effects of HMG CoA reductase inhibitor (lovastatin or simvastatin) and gemfibrozil treatment on low density lipoprotein (LDL) density distribution and composition were studied in male patients with heterozygous familial hypercholesterolaemia (FH) (n = 17) or non-familial hypercholesterolaemia (non-FH) (n = 14). In FH patients the HMG CoA reductase inhibitors reduced 'light' LDL particles (density 1.022-1.033 g ml-1) significantly more than 'heavy' LDL (density 1.033-1.059 g ml-1), while a more uniform reduction of 'light' and 'heavy' LDL occurred in non-FH patients. HMG CoA reductase inhibitor treatment increased the apolipoprotein B (apoB) content and decreased the cholesterol/apoB ratio of LDL in FH patients. Gemfibrozil significantly reduced 'heavy' LDL but not the 'light' LDL fraction in both FH and non-FH patients, and the mean cholesteryl ester content of LDL increased, while the Tg content decreased, in both FH and non-FH patients. The results indicate that HMG CoA reductase inhibitor and gemfibrozil treatment have distinctly different effects on the physico-chemical properties of LDL, reflecting their different modes of action on lipoprotein metabolism.     

Cholesterol levels after 3 days of high-dose simvastatin in patients at moderate to high risk for coronary events

BACKGROUND: Elevated levels of low-density lipoprotein cholesterol (LDL-C) impair vascular function by a variety of mechanisms. HMG CoA reductase inhibitors (statins) improve endothelial function by lowering LDL-C and possibly by other "pleiotropic" effects. How rapidly statins can lower LDL-C has not been thoroughly studied. METHODS: We examined the lipid response to 3 days of high-dose simvastatin in a randomized prospective double-blind placebo-controlled crossover study. Twenty-seven subjects at moderate to high risk for coronary heart disease (CHD) received either simvastatin 80 mg/day for 3 days followed by placebo for 3 days or placebo followed by simvastatin. After a washout period of 10 to 14 days, subjects received the opposite treatment. Nonfasting blood lipid levels, including total cholesterol, direct LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides, were obtained before randomization and after each 3-day treatment period. RESULTS: The mean LDL-C level at baseline was 107 mg/dl and decreased 24% in patients receiving simvastatin and 5.6% in patients receiving placebo (P < 0.001). Statistically significant reductions were also achieved in the total cholesterol and cholesterol/HDL-C ratio: 14% and 12%, respectively. Changes in HDL-C and triglyceride levels were not significant. CONCLUSION: Treatment with simvastatin for only 3 days results in a 24% drop in the LDL-C level. As defined by ATPIII, this decrease is comparable to that necessary to lower the LDL-C from one risk level to a lower one and is, therefore, both clinically and statistically significant.     

Rosuvastatin: A Highly Effective New HMG‐CoA Reductase Inhibitor

Rosuvastatin, a new statin, has been shown to possess a number of advantageous pharmacological properties, including enhanced HMG‐CoA reductase binding characteristics, relative hydrophilicity, and selective uptake into/activity in hepatic cells. Cytochrome P450 (CYP) metabolism of rosuvastatin appears to be minimal and is principally mediated by the 2C9 enzyme, with little involvement of 3A4; this finding is consistent with the absence of clinically significant pharmacokinetic drug‐drug interactions between rosuvastatin and other drugs known to inhibit CYP enzymes. Dose‐ranging studies in hypercholesterolemic patients demonstrated dose‐dependent effects in reducing low‐density lipoprotein cholesterol (LDL‐C) (up to 63%), total cholesterol, and apolipoprotein (apo) B across a 1‐ to 40‐mg dose range and a significant 8.4% additional reduction in LDL‐C, compared with atorvastatin, across the dose ranges of the two agents. Rosuvastatin has also been shown to be highly effective in reducing LDL‐C, increasing high‐density lipo‐protein cholesterol (HDL‐C), and producing favorable modifications of other elements of the atherogenic lipid profile in a wide range of dyslipidemic patients. In patients with mild to moderate hypercholesterolemia, rosuvastatin has been shown to produce large decreases in LDL‐C at starting doses, thus reducing the need for subsequent dose titration, and to allow greater percentages of patients to attain lipid goals, compared with available statins. The substantial LDL‐C reductions and improvements in other lipid measures with rosuvastatin treatment should facilitate achievement of lipid goals and reduce the requirement for combination therapy in patients with severe hypercholesterolemia. In addition, rosuvastatin's effects in reducing triglycerides, triglyceride‐containing lipoproteins, non‐HDL‐C, and LDL‐C and increasing HDL‐C in patients with mixed dyslipidemia or elevated triglycerides should be of considerable value in enabling achievement of LDL‐C and non‐HDL‐C goals in the numerous patients with combined dyslipidemias or metabolic syndrome who require lipid‐lowering therapy. Rosuvastatin is well tolerated alone, and in combination with fenofibrate, extended‐release niacin, and cholestyramine, and has a safety profile similar to that of currently marketed statins. A large, long‐term clinical trials program is under way to investigate the effects of rosuvastatin on atherosclerosis and cardiovascular morbidity and mortality.     

The role of fibric acid derivatives in the secondary prevention of coronary heart disease

Fibric acid derivatives effectively lower triglycerides and raise high-density lipoprotein (HDL) cholesterol, but their effect on low-density lipoprotein (LDL) cholesterol is weakly beneficial (small decreases) to adverse (small increases) and varies according to the triglyceride level. Early primary prevention studies of atherosclerosis using the fibric acid derivative clofibrate showed only modest effects on atherosclerosis and an alarming increase in mortality in the intervention group. Although the Helsinki Heart Study later demonstrated that gemfibrozil decreased cardiac endpoints in primary prevention without increasing total mortality, the efficacy of fibric acid derivatives in both primary and secondary prevention of atherosclerosis has remained widely in doubt. Nevertheless, many patients with atherosclerosis have normal or even low LDL cholesterol, but elevated triglyceride, and low HDL cholesterol; furthermore, even aggressive LDL cholesterol lowering with HMG Co-A (3-hydroxy 3-methylglutaryl coenzyme A) reductase inhibitors (statins) fails to prevent the majority of atherosclerotic events. These findings have kindled increased interest in the use of fibric acid derivatives in atherosclerosis prevention, especially through treatment of non-LDL dyslipidemias. Recent studies with angiographic and clinical end-points have now provided evidence for a beneficial effect of at least some drugs in this class in the secondary prevention of atherosclerosis.     

Are Canadian guidelines for cholesterol lowering in high-risk patients optimal?

Recent Canadian lipid guidelines recommend that all high-risk patients receive medication to reduce low density lipoprotein cholesterol (LDL-C) below 2.5 mmol/L. The recently published Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) and Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT) studies compared strategies of cholesterol lowering with atorvastatin 80 mg versus pravastatin 40 mg. Atorvastatin halted the progression of atherosclerosis (whereas atherosclerosis progressed in the patients receiving pravastatin), and resulted in a 16% reduction in the primary composite end point (all-cause death, myocardial infarction, unstable angina, revascularization and stroke) compared with the pravastatin-treated group. In the PROVE IT trial, LDL-C was reduced by atorvastatin to 1.6 mmol/L and by pravastatin to 2.46 mmol/L. Although lower LDL-C levels are one explanation for the improved outcomes with atorvastatin, pleiotropic differences of the two statins, such as their effects on inflammation and coagulation, cannot be excluded. Until trials are completed that compare outcomes from LDL-C lowering to different targets with the same statin, it is premature to recommend changes to the current Canadian guidelines. However, future recommendations may suggest much lower LDL-C targets than those currently recommended.     

Statins: therapeutic cascade of their effects

Concept of sequence and time of appearance of various effects of statins is presented. Apart from hypolipidemic action due to inhibition of HMG CoA reductase activity statins exert multiple pleiotropic effects. Combination of these effects makes statins a unique instrument for solution of global tasks of prevention and treatment of atherosclerosis and its consequences (ischemic heart disease etc.). Manifestations of various pleiotropic effects of statins appear after different time intervals and in most cases are not related to suppression of cholesterol synthesis in the body. First 3-4 months (first level of the statin cascade) are characterized mainly by activity of pleiotropic properties aimed at restoration of endothelial function. These properties are responsible for enhanced eNOS expression, antiischemic, antithrombotic and antiatherogenic effects. During same period of time stabilization of unstable atheromas takes place. Manifestations of second level of the cascade of statin action appear after 2 years of treatment. They are represented by retardation of progression and even partial regression of atheromatosis of coronary and peripheral arteries. Third level is signified by achievement of strategic aims of therapy with statins (in 4-5 years) -- lowering of total and cardiac mortality, reduction of number of cardiac complications. Forth level of the cascade is represented by beneficial influences on nonatherogenic cardiological phenomena and comprise hypotensive, antiarrhythmic and cardiotonic effects. And finally some other important properties of statins constitute the fifth level of the therapeutic cascade. These properties are responsible for effects directed at noncardiac pathology (prevention of diabetes, dementia, including dementia associated with Alzheimer's disease, fractures). Immunodepression, ability to reduce saturation of bile with cholesterol belong to this group of effects.     

Cholesterol and chronic hepatitis C virus infection

Cholesterol is an essential molecule for the life cycle of the hepatitis C virus (HCV). This review focuses on the roles of cholesterol in HCV infection and introduces HCV events related to cholesterol metabolism and applications for cholesterol metabolism as a therapeutic target. HCV appears to alter host lipid metabolism into its preferable state, which is clinically recognized as steatosis and hypocholesterolemia. While hepatic fatty acid and triglyceride syntheses are upregulated in chronic hepatitis C patients, no direct evidence of increased hepatic de novo cholesterol biosynthesis has been obtained. Impaired VLDL secretion from hepatocytes is suggested to increase intracellular cholesterol concentrations, which may lead to hypocholesterolemia. Clinically, lower serum cholesterol levels are associated with lower rates of sustained virological responses (SVR) to pegylated‐interferon plus ribavirin therapy, but the reason remains unclear. Clinical trials targeting HMG‐CoA reductase, the rate‐limiting enzyme in the cholesterol biosynthetic pathway, are being conducted using statins. Anti‐HCV actions by statins appear to be caused by the inhibition of geranylgeranyl pyrophosphate synthesis rather than their cholesterol lowering effects. Other compounds that block various steps of cholesterol metabolic pathways have also been studied to develop new strategies for the complete eradication of this virus.     

Statins and inflammatory markers

Inflammation is involved in the initiation and progression of atherosclerosis and the development of atherosclerotic events. Understanding of the molecular basis of inflammation has led to the identification of markers that may be important new targets in atherothrombotic disease. Inflammatory markers, such as cell adhesion molecules, cytokines, and high-sensitivity C-reactive protein, have been shown to predict future cardiovascular events in individuals with and without established disease. 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, or statins, inhibit the synthesis of cholesterol and have been demonstrated to reduce cardiovascular morbidity and mortality. Recently, statins have been shown to modulate several of the mechanisms of inflammation in atherosclerosis in vitro and in vivo, including reduction of inflammatory markers in clinical trials. In this article, we briefly review the biology, epidemiology, and clinical trial data on the effects of statins on some of the more promising inflammatory markers.     

Regulation by plasma lipoproteins of progesterone biosynthesis and 3-hydroxy-3-methyl glutaryl coenzyme a reductase activity in cultured human choriocarcinoma cells.

The regulation of both the activity of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG CoA) reductase [mevalonate-NADP+ oxidoreductase (CoA-acylating) EC 1.1.1.34] and the secretion of progesterone by human plasma lipoproteins has been investigated in human choriocarcinoma cells in culture. HMG CoA reductase activity was computed from the rate of formation of [14C]mevalonolactone from [14C]HMG CoA. The activity of HMG CoA reductase was expressed as nanomoles of mevalonolactone formed/min . mg solubilized cell protein. An inverse relationship was found between the presence of lipoprotein in the culture medium and the activity of HMG CoA reductase in these cells. In cells maintained in the presence of lipoprotein-enriched culture medium containing 840 micrograms cholesterol/ml, the average activity of HMG CoA reductase was 0.25 nmol/min . mg protein. After removal of lipoprotein, the activity of HMG CoA reductase increased to 1.3 nmol/min . mg protein. The average activity of HMG CoA reductase in cells maintained in lipoprotein-deficient culture medium was 1.5 nmol/min . mg protein but fell to 0.3 nmol/min . mg protein after addition of lipoprotein to the medium. When cells were maintained in the presence of lipoprotein, the rates of section of progesterone and pregnenolone into the culture medium were 2-8 times greater than the rates of secretion of these steroids by cells maintained in the absence of lipoprotein. On the basis of these results, it is concluded that lipoproteins control the rate of cholesterol biosynthesis in cultured choriocarcinoma cells by regulating the activity of HMG CoA reductase, and control the rate of synthesis of progesterone by providing the precursor, cholesterol. We suggest that progesterone synthesis by the trophoblast of the human placenta may also be regulated by the uptake of lipoprotein from maternal blood.