Overview

Deposition of cholesterol in the subintimal regions of the arterial wall causes atherosclerosis, which is enhanced in the presence of hypercholesterolemia. Lipid alteration, therefore, is crucial to the treatment and prevention of coronary atherosclerosis. Drugs such as bile acid sequestrants, nicotinic acid, and fibrates are effective in reducing lipids; however, statins (also known as beta-hydroxy-beta-methylglutaryl-coenzyme A [HMG CoA] reductase inhibitors) have become the safest and most effective lipid-modifying agents and are currently recommended by the National Cholesterol Education Program (NCEP) as the first-line pharmacotherapy for dyslipidemia.

INTRODUCTION

Coronary artery disease (CAD) and stroke accounted for approximately two thirds of cardiovascular mortality in the United States in 2000. CAD is the number one killer of Americans, while stroke is the third leading cause of death, cancer being the second leading cause. In fact, cardiovascular disease (CVD) claims more lives than the next seven leading causes of death combined. Deposition and retention of atherogenic, cholesterol-rich lipoproteins in the subendothelial space within the arterial wall are central to the pathogenesis of atherosclerosis that leads to CAD and stroke.

Scientific studies have demonstrated beyond doubt that a causal relationship exists between dyslipidemia and the development of atherosclerosis and have shown through many randomized trials that cholesterol reduction leads to significant reduction in the incidence of CAD and stroke. In fact, in a review of primary- and secondary-prevention lipid reduction studies, a 1% decrease in cholesterol was associated with a 2% decrease in risk of CAD. According to the NCEP Adult Treatment Panel III (ATP III) guidelines, an elevated low-density lipoprotein cholesterol (LDL) level is the main target for dyslipidemia therapy.

Toward this end, the statins constitute a group of hypolipidemic agents that lower cholesterol by promoting reduction in plasma levels of LDL cholesterol. Numerous randomized primary and secondary prevention trials have confirmed clinical benefits with this class of agents. The principal mechanism involved includes the ability of the statins to inhibit cholesterol biosynthesis, leading to upregulation of hepatic LDL receptors causing reductions in circulating levels of LDL and very low-density lipoprotein (VLDL) particles by augmenting catabolism. A modest increase in high-density lipoprotein (HDL) is also achieved. Some of the clinical benefits of statins may be attributed to mechanisms other than their cholesterol-lowering effects. Such effects include antiinflammatory and antioxidant actions, the ability to provide plaque stability and a favorable coagulation profile by preventing platelet aggregation, and antiproliferative and immunosuppressive actions. (Tandon, 2005)

HISTORICAL PERSPECTIVE

While many drugs have been discovered by accident, statins were discovered after extensive research and evaluation of over 6000 different molecules by many researchers in the early 1970s. Finally, Akira Endo and Masao Kuroda of Tokyo, Japan, along with support from Merck pharmaceuticals, isolated lovastatin (mevinolin, MK803), the first commercially marketed statin, which was derived from a fungus, Aspergillus terreus (Endo, 1992). Many compounds have since been discovered. The potency of the drug could be increased through modification of the molecular structure of the mevastatin molecule. Simvastatin, thus produced, was found to be nearly twice as strong as pravastatin and lovastatin, while mevastatin is the least potent. As the profile of the active molecule is altered, the frequency and severity of side effects also were noted to change; as an example, the risk of myopathy increased with lovastatin as compared with pravastatin.

PHARMACOKINETICS AND PHARMACODYNAMICS

Mechanisms of action

Circulating plasma cholesterol is generated by two main sources: exogenously from the diet through absorption from the gut or endogenously through synthesis. This synthesis occurs primarily in the liver (82%) and secondarily in the intestines (11%).

Competitive inhibition of HMG CoA receptors

The crucial chemical reaction in the cholesterol synthesis pathway involves production of mevalonic acid. In this step, the substrate, HMG CoA, binds to the enzyme beta-hydroxy-beta-methylglutaryl-CoA-reductase (HMG CoA reductase), and is reduced to mevalonic acid in the presence of nicotinamide adenine dinucleotide phosphate (NADPH), which binds to the enzyme/substrate and gets oxidized to NADP CoA. This rate-limiting step, catalyzed by HMG CoA reductase, is pivotal in the synthesis of cholesterol. This competitive inhibition by the statin molecule exerts its effect by binding to the enzyme HMG CoA reductase. In the presence of the statin molecule, HMG CoA reductase exhibits 10,000-fold greater propensity to bind to the statin molecule rather than the intended substrate (HMG CoA) and, thus, makes the enzyme unavailable to catalyze the production of mevalonic acid. Since this inhibition is competitive, the effect of statin tends to be dose-dependent, with higher doses occupying greater numbers of HMG CoA reductase molecules and exhibiting greater effect in a relatively proportionate manner. Further increase in dose tends to show a plateau effect or flattened response curve.

Compensatory response and LDL-receptor upregulation

In order to compensate for this inhibition, hepatic cells begin to produce more and more LDL receptors (this is called receptor upregulation). These receptors bind to circulating LDL particles and clear them with greater efficiency, thereby reducing LDL levels by 30-55%, depending on the type and dose of statins used.

Limitations of statin effect

Patients with homozygous familial hypercholesterolemia present a difficult problem. These patients inherited recessive and ineffective alleles for LDL receptor production from both parents. Since their hepatocytes genetically do not produce LDL receptors, statins would theoretically fail to promote receptor upregulation and would not reduce LDL levels in the blood. In clinical trials, only atorvastatin has shown some effectiveness in this group of patients.

Statins also show limited effectiveness against triglycerides. Fibric acid derivatives show a more pronounced effect. Despite these limitations, NCEP guidelines place statins as the cornerstone of therapy in the treatment of dyslipidemia to prevent atherosclerosis.

Clinical lipid effects of statins

The bulk of the reduction in CAD risk by statins, is ascribable to reductions in the levels of total cholesterol (TC) and LDL-C, with less pronounced effects on increasing HDL levels and decreasing triglyceride (TG) levels.

Effect on LDL and TC levels

Hypercholesterolemia triggers and accelerates certain steps in the development of atherosclerosis, including the following:

• Passage and propagation of smooth muscle cells (SMCs) and macrophages into the subintimal areas of arterial wall
• Subsequent SMC-induced generation of a connective tissue matrix within the subendothelial area
• Migration and accrual of oxidized LDL, which is produced because of the presence of free radicals liberated by SMC and the endothelium
• Integration of oxidized LDL by macrophages to produce lipid- and cholesteryl-ester-rich foam cells in the subendothelial space

Effect on HDL levels

As noted in the NCEP ATP III report, currently available statins raise HDL levels only modestly, anywhere from 5-15%. This effect is comparable to that observed with fibrates (10%-20%), is somewhat less than that seen with nicotinic acid (15%-35%), and is clearly better than that due to bile acid sequestrants (3%-5%).

Effect on TG levels

Isolated high TG levels are occasionally encountered without other associated lipid abnormalities and are considered atherogenic. However, raised TG levels are more often observed in persons who have low HDL levels, features of metabolic syndrome, or both. Raising HDL levels can frequently reduce the impact of elevated TG levels on CAD risk. As noted in the NCEP ATP III report, currently available statins lower TG levels by 7-30%, while nicotinic acid and fibrates reduce them by 20-40%. Bile acid sequestrants affect no change in TG levels and may even bring about a paradoxical increase.

Clinical pleiotropic effect of statins

Since treatment with statins results not only in reduction of plasma LDL levels but also in amelioration of additional functional abnormalities, distinguishing which statin effects are secondary to LDL reduction and which ones are independent of LDL-lowering can be difficult. Nevertheless, many of these pleiotropic effects appear to contribute to the overall efficacy of statin therapy in preventing CAD.

Antiinflammatory effects

Generation of atherosclerosis involves migration of oxidized LDL into subintima that subsequently draws in platelets and inflammatory cells, such as macrophages. This conglomeration of cells induces the formation of adhesion molecules that form a significant component of inflammation. Statins thwart the production of oxidized LDL by a mechanism independent of their lipid-lowering properties. They also modify the capability of macrophages to absorb LDL, prevent them from changing into foam cells, and attenuate the risk of plaque vulnerability and rupture.

Improvement in endothelial function and stabilization of plaques

Endothelial dysfunction and injury, caused by elevated LDL levels and other coexistent risk factors for CAD, lead to induction of vasoactive molecules, such as cytokines, and growth factors that instigate migration and proliferation of smooth muscle cells into the subintimal region through the site of injury. This leads to thickening of the arterial wall, which usually positively remodels by gradually dilating outward to compensate for developing atherosclerosis in the subendothelial space. Recruitment of monocytes and lymphocytes also occurs, causing additional release of inflammatory chemicals. Further enlargement and restructuring of the atheromatous lesion follows, with the creation of a fibrous cap surrounding a central core of lipid and necrotic tissue. Plaques with thinner fibrous caps tend to contain greater amounts of inflammatory infiltrates (“vulnerable” plaques) and exhibit increased propensity to rupture, as compared with “stable” plaques with thicker fibrous caps and a smaller lipid core. Over the past decade, great emphasis has been given to stabilization of vulnerable plaques in order to reduce acute cardiovascular events. Restricting the inflammatory processes within the vascular wall improves the functional state of the atheromatous plaques and stabilizes them, thus lessening their atherogenicity. Hypercholesterolemia is also associated with impaired nitric oxide synthesis in the endothelial cells. The improvements in endothelial function seen with statin therapy may also be the result of upregulation of endothelial nitric oxide synthase, which leads to normal levels of this endothelial function regulator molecule. These qualities of statins are supported by some of the recent large randomized clinical trials. Data from the Cholesterol And Recurrent Events (CARE) trial and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) have, in fact, verified that statins reduce the level of the inflammatory marker C-reactive protein (CRP), which is not related to the extent of LDL reduction alone. Reduction in CRP levels results in improvement in endothelial function, vascular reactivity, and coronary perfusion.

Antiplatelet effects

In an animal study, atorvastatin caused a further reduction in platelet deposition on damaged vessel walls than did controls, and, in another study, the animals receiving simvastatin demonstrated a smaller extent of aortic fatty streak surface area and thickening in the intima of the thoracic aorta, as compared with controls. In a study, fluvastatin given for 6 months reduced platelet aggregation by 13%, normalized platelet lipid composition, and was associated with a 29% reduction in LDL levels. Thus, drug binding had a direct effect on platelet function and a hypolipemic action on the cholesterol content of the platelet cell membrane.

Antithrombotic effects

Thrombin causes stimulation of platelets, leukocytes, endothelial cells, and smooth muscle cells by inducing expression of integrins and excretion of multiple active molecules. These actions result in platelet deformation, proliferation of smooth muscle cells, angiogenesis, and enhanced inflammation. Statins act at the cellular level by downregulating thrombin-induced reactions that would otherwise continue to generate additional thrombin. In addition, in the endothelial cells and smooth muscle cells, statins favorably alter the expression of type-1 plasminogen activator inhibitor (PAI-1; procoagulant, prothrombotic) and tissue plasminogen activator (TPA; anticoagulant, fibrinolytic), the main determinants of fibrinolytic balance. In a study involving 12-week treatment with atorvastatin, pravastatin, and simvastatin, beneficial effects on fibrinogen and von Willebrand factor antigen were observed.

Anti-ischemic effects

Statins also appear to have anti-ischemic properties. In a 2-year study of pravastatin therapy (40 mg/d), a statistically significant reduction (32%) in the number of patients experiencing transient ischemia was observed (15% increase in the placebo group). In another study of lovastatin and diet vs placebo and diet in 40 patients, the lovastatin group exhibited significant reduction in the number of episodes of ST-segment depression compared with patients receiving placebo. On the contrary, the 4-month follow up of the Fluvastatin On Risk Diminishing after Acute Myocardial Infarction (FLORIDA) study demonstrated lack of effect on ischemic events.

ABSORPTION AND BIOAVAILABILITY OF STATINS

Statins are administered as oral medications and are primarily absorbed from the intestines. The tissue distribution of statins, however, varies markedly, particularly with respect to their volume distribution in the liver and in the peripheral tissues.

The administration of lovastatin with a meal increases its plasma concentration by 50%. On the contrary, dietary fiber reduces its absorption. The administration of fluvastatin with meals reduces its plasma concentration by approximately one third. The pro-drugs lovastatin and simvastatin have much lower rates (<5%) of bioavailability than do atorvastatin, pravastatin, rosuvastatin, and fluvastatin (12-29%). If pravastatin and rosuvastatin are timed with meals, their bioavailability is reduced by 35%.

Absorption rates also vary between statins. The highest absorption rate (98%) is with fluvastatin. Simvastatin and rosuvastatin have medium absorption rates (40-80%). Atorvastatin, lovastatin, and pravastatin have the lowest rates (30-40%).

Simvastatin has a significant hepatic first-pass metabolism rate of 50-60%. Rates are moderate (40-70%) for fluvastatin, pravastatin, and rosuvastatin; and lowest (20-30%) for atorvastatin and lovastatin.

METABOLISM OF STATINS

Lovastatin, simvastatin, and atorvastatin are metabolized via the cytochrome P450 (CYP) 3A4 pathway. Fluvastatin and rosuvastatin are metabolized via the CYP2C9 pathway. Pravastatin is metabolized through sulfation.

PHARMACOLOGIC PROPERTIES OF STATINS

Statins reduce LDL-C levels in a nonlinear dose-dependent manner. They are usually administered orally once daily. Their pharmacokinetic profiles are described in Table 1.

ADVERSE EFFECTS OF STATINS

Statins have excellent safety and adverse-effect profiles. The most common adverse effects include gastrointestinal symptoms and muscle aches (myalgia occurs in 5%).

Additional side effects occur rarely with the use of statins. Such side effects include rash, peripheral neuropathy, insomnia, unusual dreams, and sleep or concentration problems. Myopathy has also occurred, defined as muscle pain or weakness in the presence of a serum kinase level at least 10 times the upper limit of normal. Elevated hepatic transaminase levels occur infrequently with all lipid-lowering drugs, including the statins, and are usually mild and asymptomatic. Liver toxicity, including hepatitis, has occurred with moderate elevations of serum aminotransferase concentrations in less than 1% of patients receiving statins at high doses.

Very rarely, rhabdomyolysis (striated muscle disintegration and release of muscle cell constituents into the extracellular fluid and circulation) may lead to renal obstruction and dysfunction and is occasionally observed with statin-combination therapy. One of the agents, cerivastatin (Baycal), was removed from the market in 2001 because of a disproportionate number of cases of rhabdomyolysis.

Absolute contraindications to treatment with statins include active or chronic liver disease, active liver or muscle disease, untreated hypothyroidism or hyperthyroidism, immunosuppressive therapy, and childbearing potential (in women, because of the risk of fetal malformations).

DRUG INTERACTIONS

Drug interactions can be described in terms of whether a particular drug is an inhibitor or an inducer of the hepatic enzyme cytochrome P450 (CYP) system (as listed in Table 2). Inhibitors compete with a drug at the binding site on the enzyme so that statins have fewer binding sites available for catabolism. Essentially, this increases bioavailability and the risk of toxicity (eg, rhabdomyolysis). Inducers decrease the efficacy of statins by increasing enzyme activity. This leads to increased statin metabolism and a resultant reduction of circulating statin.

Since many drugs, including a number of cardiovascular agents, are metabolized by CYP isoenzymes (the common pathway for statins), a high likelihood for drug interactions with statins exists. Concomitant intake of other lipid-lowering drugs may change the bioavailability of statins, as well. Cholestyramine and colestipol, given within 1 hour of taking fluvastatin, pravastatin, or atorvastatin, cause a 20-90% reduction in the bioavailability of these statin medications. Myopathy, which occurs in only 0.1-0.2% of patients taking statins alone, increases in incidence more than 10-fold when administered with gemfibrozil, niacin, erythromycin, itraconazole, cyclosporine, diltiazem, or other drugs. The interaction between statins and fibrates (particularly gemfibrozil) that increases the risk of myopathy does not involve the CYP system but appears to result from the effects of fibrates on skeletal myocytes. To date, 5 cases of severe interaction between simvastatin and amiodarone have been reported with the major mechanism of inhibition of CYP3A4 by amiodarone. Interactions have also been noted between statins and diltiazem and statins and warfarin.

CLINICAL APPLICATIONS

Despite the availability of various statins and other lipid-lowering drugs, many patients with dyslipidemia do not reach the NCEP goal levels for LDL levels. The Lipid Treatment Assessment Project (L-TAP) showed that only 38.4% of patients treated with pharmacotherapy achieved LDL goals. Possible reasons for such dismal lipid control may include the following:

• Almost exclusive use of low drug doses
• Infrequent use of high or maximal doses
• Use of the wrong drug
• Limited efficacy of the drug used
• Poor tolerability
• Other drug limitations
• Lack of patient compliance

As a result, the following recommendations were made to strive for:

• Greater use of drug therapy after dietary measures fail to lower LDL levels sufficiently
• Greater use of statins relative to other lipid-lowering agents
• Greater use of higher drug doses
• Consideration of combination therapy when appropriate

The potential importance of combination therapy has also been demonstrated in a retrospective cohort study of 244 patients with CAD, peripheral arterial disease (PAD), and hyperlipidemia. Even after treatment with lipid-lowering agents, fewer than 50% of patients with baseline LDL levels above 160 mg/dL achieved the study goal of a LDL level lower than 130 mg/dL.

Much more aggressive LDL reduction has been tested in several trials. The Treating to New Targets (TNT) study compared the LDL level–lowering effects of 80 mg of atorvastatin (LDL level goal = 75 m/dL) and 10 mg of atorvastatin (LDL level goal = 100 mg/dL) in over 10,000 patients with CAD. The Incremental Decrease in Endpoints through Aggressive Lipid Lowering (IDEAL) trial compared the TC level–lowering effects of 80 mg of atorvastatin and 20-40 mg of simvastatin in 7,600 patients. The PROVE-IT study compared LDL level reduction all the way down to 65 mg/dL in patients following acute coronary syndrome. All of these studies have now clearly demonstrated the advantages of more aggressive therapy, reducing LDL levels to 65-75 mg/dL. These findings have led to revision of the NCEP ATP III guidelines, recommending stricter LDL level control in patients at high risk for CAD.

The results of phase III trials comparing rosuvastatin with other statins have established atorvastatin and, now, rosuvastatin as providing much more potent LDL reduction. For example, in a study involving patients with primary hypercholesterolemia, 5 mg of rosuvastatin was significantly superior to both 20 mg of simvastatin and 20 mg of pravastatin in reducing LDL levels (42%, 28%, and 37%, respectively). The availability of potent statins with excellent safety profiles and data supporting increasingly lower LDL goals for risk reduction necessitate the institution of even more aggressive dyslipidemia therapy. This is particularly true for those patients at high risk for CAD, those with diabetes or metabolic syndrome, and those who belong to certain ethnic groups, such as South Asians.

SPECIAL POPULATIONS

Some populations, living in the United States or abroad, exhibit more aggressive atherosclerosis and should be targeted for more aggressive lipid reduction with stricter goals. These populations include persons of African, Hispanic, and South Asian origin. Intuitively, these persons would require higher statin dosages for achieving the stricter therapeutic goals. Some of the newer trials (eg, ARIES [in African Americans], STARSHIP [in Hispanics], IRIS [in South Asians]) are beginning to support such conjectures.

However, statin metabolism in South Asians is slower than in other populations. Therefore, authorities suggest starting the therapy with somewhat smaller doses in these persons. A population pharmacokinetic analysis of rosuvastatin revealed no clinically relevant difference in pharmacokinetics among caucasian, Hispanic, black, or Afro-Caribbean groups. However, pharmacokinetic studies of rosuvastatin, including one in the United States, have demonstrated approximately a 2-fold elevation in median exposure time in Asian subjects when compared with a caucasian control group. Therefore, as far as rosuvastatin is concerned, initiation of therapy with the smallest dose (5 mg/d) should be considered for Asian patients.

The potential for increased systemic exposure relative to caucasians is relevant when considering escalation of dose in cases where hypercholesterolemia is not adequately controlled at daily doses of 5, 10, or 20 mg.

CONCLUSIONS

CAD is a major cause of morbidity and mortality in the United States. Since the introduction of statins, the HMG CoA reductase inhibitors, in the late 1980s, several large-scale, randomized, placebo-controlled clinical trials have demonstrated the efficacy, safety, and tolerability of these agents in reducing LDL and CAD morbidity and mortality rates in both primary and secondary prevention. Pharmacodynamic effects include plaque stabilization and a variety of nonlipid effects that may contribute to the reduction in coronary events. The knowledge of the pharmacokinetics and pharmacodynamics of statins is essential, and that should make the use of statins even safer and their clinical impact even greater in our relentless pursuit to eliminate the CAD epidemic.

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