Chapter 31: Drug Therapy for Hypercholesterolemia and Dyslipidemia

Chylomicrons, the largest plasma lipoproteins, are the only lipoproteins that float to the top of a tube of plasma that has been allowed to stand undisturbed for 12 hours. The buoyancy of chylomicrons reflects their high fat content (98-99%), of which 85% is from fatty acids of dietary triglycerides. In chylomicrons, the ratio of triglycerides to cholesterol is ∼10 or greater. In normolipidemic individuals, chylomicrons are present in plasma for 3-6 hours after a fat-containing meal has been ingested. After a fast of 10-12 hours, no chylomicrons remain.

The apolipoproteins of chylomicrons include some that are synthesized by intestinal epithelial cells (apoB-48, apoA-I, and apoA-IV), and others acquired from HDL (apoE and apoC-I, C-II, and C-III) after chylomicrons have been secreted into the lymph and enter the plasma (Table 31–2). The apoB-48 of chylomicrons is one of two forms of apoB present in lipoproteins. ApoB-48, synthesized only by intestinal epithelial cells, is unique to chylomicrons. ApoB-100 is synthesized by the liver and incorporated into VLDL and intermediate-density lipoproteins (IDL) and LDL, which are products of VLDL catabolism. The apparent molecular weight of apoB-48 is 48% that of apoB-100, which accounts for the name "apoB-48." The amino acid sequence of apoB-48 is identical to the first 2152 of the 4536 residues of apoB-100. An RNA-editing mechanism unique to the intestine accounts for the premature termination of the translation of the apoB-100 mRNA. ApoB-48 lacks the portion of the sequence of apoB-100 that allows apoB-100 to bind to the LDL receptor, so apoB-48 functions primarily as a structural component of chylomicrons.

Another ACAT enzyme, ACAT-1, is expressed in macrophages, including foam cells, adrenocortical cells, and skin sebaceous glands. Although ACAT-1 esterifies cholesterol and promotes foam-cell development, ACAT-1 knockout mice do not have reduced susceptibility to atherosclerosis.

The plasma concentration of chylomicrons is primarily controlled by reducing dietary fat consumption. Drugs that affect chylomicron metabolism include orlistat, which inhibits hydrolysis of dietary triglycerides, insulin replacement in patients with type I diabetes mellitus (insulin has a "permissive effect" on LPL-mediated triglyceride hydrolysis), and fibrates, which enhance LPL gene expression.

In plasma lipid metabolism, the LRP is important because it is the backup receptor responsible for the uptake of apoE-enriched remnants of chylomicrons and VLDL. Cell-surface heparan sulfate proteoglycans facilitate the interaction of apoE-containing remnant lipoproteins with the LRP, which mediates uptake by hepatocytes. Inherited absence of either functional HL (very rare) or functional apoE impedes remnant clearance by the LDL receptor and the LRP, increasing triglyceride- and cholesterol-rich remnant lipoproteins in the plasma (type III hyperlipoproteinemia).

ApoA-V modulates plasma triglyceride levels, possibly by several mechanisms: inhibition of hepatic VLDL triglyceride production and secretion, promoting LPL-mediated hydrolysis of chylomicrons and VLDL triglycerides, and facilitating hepatic uptake of triglyceride-rich lipoproteins and their remnants (Wong and Ryan, 2007). ApoA-V is produced solely by the liver, and despite its very low plasma concentration (∼0.1% of the concentration of apoA-I), profoundly affects plasma triglyceride levels in mice and humans.

Without MTP, hepatic triglycerides cannot be transferred to apoB-100. As a consequence, patients with dysfunctional MTP fail to make any of the apoB-containing lipoproteins (VLDL, IDL, or LDL). MTP also plays a key role in the synthesis of chylomicrons in the intestine, and mutations of MTP that result in the inability of triglycerides to be transferred to either apoB-100 in the liver or apoB-48 in the intestine prevent VLDL and chylomicron production and cause the genetic disorder abetalipoproteinemia. Experimental compounds that interfere with MTP function reduce triglyceride levels but cause hepatic steatosis that has precluded their use in humans. New approaches to MTP inhibition are under study (Hussain and Bakillah, 2008).

ApoE plays a major role in the metabolism of triglyceride-rich lipoproteins (chylomicrons, chylomicron remnants, VLDL, and IDL). About half of the apoE in the plasma of fasting subjects is associated with triglyceride-rich lipoproteins, and the other half is a constituent of HDL. About three-fourths of the apoE in plasma is synthesized by the liver; brain and macrophages synthesize the bulk of the remainder. In transgenic mice, overexpression of apoE by macrophages inhibits hypercholesterolemia-induced atherogenesis. Three alleles of the apoE gene (designated ∊2, ∊3, and ∊4) occur with a frequency of ∼8%, 77%, and 15%, respectively, and code for the three major forms of apoE: E2, E3, and E4. Consequently, there are three homozygous apoE phenotypes (E2/2, E3/3, and E4/4) and three heterozygous phenotypes (E2/3, E2/4, and E3/4). Approximately 60% of the human population is homozygous for apoE3. Single amino acid substitutions result from genetic polymorphisms in the apoE gene. ApoE2, with a cysteine at residue 158, differs from apoE3, which has arginine at this site. ApoE3, with a cysteine at residue 112, differs from apoE4, which has arginine at this site. These single amino acid differences affect both receptor binding and lipid binding of the three apoE isoforms. Both apoE3 and apoE4 can bind to the LDL receptor, but apoE2 binds much less effectively, and as a consequence causes the remnant lipoprotein dyslipidemia of type III hyperlipoproteinemia.

ApoB-100, the primary apoprotein of LDL, is the ligand that binds LDL to its receptor. Residues 3000-3700 in the carboxyl-terminal sequence are critical for binding. Mutations in this region disrupt binding and also are a cause of autosomal dominant hypercholesterolemia (familial defective apoB-100). A third disorder causing autosomal dominant hypercholesterolemia is caused by gain of function mutations in the gene encoding PCSK9, a serine protease that destroys LDL receptors in the liver (Horton et al., 2007). Autosomal recessive hypercholesterolemia closely resembles familial hypercholesterolemia but is not caused by LDL receptor mutations.

LDL becomes atherogenic when modified by oxidation (Witztum and Steinberg, 2001), a required step for LDL uptake by the scavenger receptors of macrophages. This process leads to foam-cell formation in arterial lesions. At least two scavenger receptors (SRs) are involved (SR-AI/II and CD36). Knocking out either receptor in transgenic mice retards the uptake of oxidized LDL by macrophages. Expression of the two receptors is regulated differently: SR-AI/II appears to be expressed more in early atherogenesis, and CD36 expression is greater as foam cells form during lesion progression. Despite the large body of evidence implicating oxidation of LDL as a requisite step during atherogenesis, controlled clinical trials have not unequivocally demonstrated the efficacy of antioxidant vitamins in preventing vascular disease.

Mature HDL can be separated by ultracentrifugation into HDL₂ (d = 1.063-1.125 g/mL), which are larger, more cholesterol-rich lipoproteins (70-100 Å in diameter), and HDL₃ (d = 1.125-1.21 g/mL), which are smaller particles (50-70 Å in diameter). In addition, two major subclasses of mature HDL particles in the plasma can be differentiated by their content of the major HDL apoproteins, apoA-I and apoA-II (Movva and Rader, 2008). Epidemiologic evidence in humans suggests that apoA-II may be atheroprotective (Birjmohun et al., 2007; Movva and Rader, 2008).

Lipoprotein particles may be distinguished by their electrophoretic mobities: mature HDL particles have α mobility; LDL particles show β mobility. The precursor of most of the α-migrating plasma HDL is a discoidal particle containing apoA-I and phospholipid, called pre-β1 HDL because of its pre-β1 electrophoretic mobility. Pre-β1 HDL are synthesized by the liver and the intestine, and they also arise when surface phospholipids and apoA-I of chylomicrons and VLDL are lost as the triglycerides of these lipoproteins are hydrolyzed. Discoidal pre-β1 HDL can then acquire free unesterified cholesterol from the cell membranes of tissues, such as arterial wall macrophages. Two macrophage membrane transporters, ABCA1 and ABCG1, promote the efflux of cholesterol from macrophages of humans studied in vivo. Prior studies in vitro suggested that another transport protein, class B, type I scavenger receptor (SR-BI) facilitates cholesterol egress from macrophages to HDL, but in vivo studies in humans do not support an important role for SR-BI in this process (Wang et al., 2007). However, SR-BI in the liver facilitates the uptake of cholesteryl esters from HDL without internalizing and degrading the lipoproteins.

Epidemiological Studies. Epidemiological studies have demonstrated the importance of the relationship between excess saturated fat consumption and elevated cholesterol levels. Reducing the consumption of dietary saturated fat and cholesterol is the cornerstone of population-based approaches to the management of hypercholesterolemia. In addition, it is clearly established that the higher the cholesterol level, the higher the CHD risk. However, very high cholesterol levels (values >300 mg/dL) account for only 5-10% of CHD events. In fact, one-third of CHD events occur in persons with total cholesterol levels between 150 and 200 mg/dL (Castelli, 2001). The challenge is how to identify and treat the 20% of individuals with cholesterol levels between 150 and 200 mg/dL who will develop CHD.

Clinical Trials. Studies of the efficacy of cholesterol lowering began in the 1960s, and the results of the earliest trials showed that modest reductions in total cholesterol and LDL-C were associated with reductions in fatal and nonfatal CHD events but not total mortality. It was not until the advent of a more efficacious class of cholesterol-lowering drugs, the statins, that cholesterol-reduction therapy was finally proven to prevent CHD events and reduce total mortality. Patients benefit regardless of gender, age (above or below 75 years of age), baseline lipid values, or whether they have a prior history of vascular disease or type 2 diabetes mellitus (Cholesterol Treatment Trialists' Collaborators, 2008; Cholesterol Treatment Trialists' Collaborators, 2005). Stroke risk is reduced by statin therapy, too, despite the rather weak relationship between total cholesterol and LDL-C levels. Statin therapy is effective in preventing first and subsequent atherothrombotic strokes. Evidence of a benefit or harm of statin therapy in patients with a prior hemorrhagic stroke is sparse and requires additional studies. Available studies suggest caution when considering statin therapy for a patient with hemorrhagic stroke (Amarenco and Labreuche, 2009).

Results of the clinical trials employing statins demonstrate benefit without offsetting adverse effects, and the benefit is proportionate to the extent of the reduction of LDL-C level. Moderate doses of statins that lower LDL-C levels by about 40% reduce cardiovascular events by about one-third (Cholesterol Treatment Trialists' Collaborators, 2005). More intensive regimens that lower LDL-C by 45-50% reduce CVD events by as much as 50% (Cannon et al., 2006).

Patients at greatest risk of developing an atherothrombotic CVD event are those who have had a prior event (myocardial infarction, acute coronary syndrome, transient ischemic attack, stroke, or claudication) or who are at high risk because of type 2 diabetes mellitus. These subjects are at very high risk and require intensive management of plasma lipids (Table 31–3). Other subjects who have not had a prior CVD event require assessment of plasma lipid levels and the other major CVD risk factors to determine if treatment to reduce lipid-related risk is necessary.

Lipid levels (total cholesterol, triglycerides, LDL-C, HDL-C, and non-HDL-C) and glucose concentration should be measured following a fasting period of 10-12 hours. The LDL-C should be calculated [total cholesterol – (HDL-C) – (triglycerides/5) = LDL-C] and not measured by any of the "direct" techniques (Mora et al., 2009). Non-HDL-C is derived as follows: total cholesterol – HDL-C = non-HDL-C. The classification of plasma lipid values is shown in Table 31–4.

Measurement of apoA-I and apoB afford better risk prediction of lipid-related risk than LDL-C and HDL-C. However, lack of an established national reference laboratory for quality control of these apolipoprotein assays has precluded formal adoption of apoA-I and apoB measurements by the NCEP thus far (Contois et al., 2009; Sniderman, 2009; Sniderman and Marcovina, 2006). Despite this, targets for apoB levels have been established by the American Diabetes Association for the management of patients with type 2 diabetes mellitus (Brunzell et al., 2008).

Measurements of lipoprotein fraction concentrations, their subfractions, and lipoprotein particle diameters also are widely available, but it is not clear that these tests add to the ability to predict risk based on measurements of levels of cholesterol or apoA-I and apoB (Mora, 2009).

In addition to plasma lipid levels and a fasting glucose level, each subject requires an evaluation to assess the presence or absence of the other major CVD risk factors: age, a family history of premature CVD event, smoking, hypertension, type 2 diabetes mellitus, and obesity (Table 31–5). There are a host of additional novel risk factors that are being evaluated to determine if they will improve current risk prediction assessment schemes based on lipid levels and the established major CVD risk factors (Table 31–5). Thus far, routine use of any of these novel risk factors has not been shown to improve risk prediction (Folsom et al., 2006; Lloyd-Jones and Tian, 2006). However, in certain primary prevention patients, two of the recently described risk factors, C-reactive protein (CRP) and assessment of the extent of coronary calcification, may improve risk assessment beyond that based on the traditional major risk factors (Tables 31–3 and 31–5).

Using the values for levels of total cholesterol and HDL-C and the results of the assessment for the other major CHD risk factors, the next step is to calculate a person's risk of having a CHD event over the next 10 years. Risk prediction tables based on observational studies conducted by the Framingham Heart Study are used to calculate this 10-year risk. This approach to risk assessment was adopted by the NCEP, but in the 2001 ATP III guidelines, the risk prediction model predicted only the 10-year risk of having a fatal or nonfatal myocardial infarction. However, the same risk factors that are associated with development of myocardial infarction also promote other CVD events, including stroke, transient ischemic attack, peripheral vascular disease, and heart failure. Furthermore, many patients who develop acute coronary syndrome do not sustain a myocardial infarction because of thrombolytic therapy and revascularization procedures (angioplasty and bypass graft surgery). Because cholesterol-lowering therapy is beneficial to prevent CVD events in patients with any of these manifestations of CVD, it became apparent that it would be useful for primary care physicians to be able to predict a patient's risk of developing any one of these manifestations of CVD, not just CHD. New general CVD 10-year risk prediction tables are now available from the Framingham Heart Study (D'Agostino et al., 2008; Wickramasinghe et al., 2009) (Table 31–6). Ten-year risk calculated with the general CVD tables will exceed 10-year risk calculated using the CHD tables from the ATP III guidelines.

Once the 10-year risk has been calculated, the patient's category of risk can be assigned using Table 31–3. This establishes treatment goals for LDL-C and non-HDL-C as well as thresholds for initiating drug therapy. Because CVD, diabetes mellitus, and obesity are so prevalent, diet and exercise assessment and advice are appropriate for everyone and should not depend on an arbitrary threshold value for LDL-C for implementation. Ten-year risk assessment is recognized as the guideline-mandated method for managing dyslipidemia. Unfortunately, only about 50% of physicians correctly assess their patient's risk, and 30% of adults nationwide are not being screened (Christian et al., 2006; Kuklina et al., 2009). Many high-risk patients are not being recognized and treated prior to developing clinical CHD. Among the nearly 75,000 patients admitted to 541 U.S. hospitals between 2000 and 2006 with first-ever episodes of acute coronary syndrome, only 14% were taking a cholesterol-lowering drug (Sachdeva et al., 2009).

All patients who meet the criteria for lipid-lowering therapy should receive instruction about therapeutic lifestyle change. Dietary restrictions include <7% of calories from saturated and trans fatty acids, <200 mg of cholesterol daily, up to 20% of calories from monounsaturated fatty acids, up to 10% of calories from polyunsaturated fat, and total fat calories ranging between 25% and 35% of all calories. Two oily fish meals/week are especially important for post–myocardial infarction patients to provide a substantial reduction in the risk of sudden cardiac death. Patients with CHD or a CHD equivalent (symptomatic peripheral or carotid vascular disease, abdominal aortic aneurysm, >20% 10-year CHD risk, or diabetes mellitus) should immediately start appropriate lipid-lowering drug therapy irrespective of their baseline LDL-C level. Patients without CHD or CHD equivalent should be managed with lifestyle advice (diet, exercise, weight management) for 3-6 months before drug therapy is implemented.

Before drug therapy is initiated, secondary causes of hyperlipidemia should be excluded. Most secondary causes (Table 31–7) can be excluded by ascertaining the patient's medication history and by measuring serum creatinine, liver function tests, fasting glucose, and thyroid-stimulating hormone levels. Treatment of the disorder causing secondary dyslipidemia may preclude the necessity of treatment with hypolipidemic drugs.

Can Cholesterol Levels Be Lowered Too Much?. Are there total and LDL cholesterol levels below which adverse health consequences begin to increase? Observational studies initially were confusing. In the U.S. and western Europe, low cholesterol levels were associated with an increase in noncardiac mortality from chronic pulmonary disease, chronic liver disease, cancer (many primary sites), and hemorrhagic stroke; subsequent data indicate that it is the noncardiac diseases that cause the low plasma cholesterol levels and not the reverse. One exception may be hemorrhagic stroke. In the Multiple Risk Factor Intervention Trial (MRFIT), hemorrhagic stroke occurred more frequently in hypertensive patients with total cholesterol levels <160 mg/dL; however, the increased incidence of hemorrhagic stroke was more than offset by reduced CHD risk due to the low cholesterol levels. A recent meta-analysis of statin efficacy in preventing recurrent stroke found an increase in the risk of subsequent hemorrhagic stroke among patients with a prior hemorrhagic stroke who also received a statin. However, the risk of atherothrombotic stroke was reduced in proportion to the degree of cholesterol lowering by statin therapy (Amarenco and Labreuche, 2009).

Abetalipoproteinemia and hypobetalipoproteinemia, two rare disorders associated with extremely low total cholesterol levels, are instructive because affected individuals have reduced CHD risk and no increase in noncardiac mortality. Patients who are homozygous for the mutations that cause these disorders have total cholesterol levels <50 mg/dL and triglyceride levels <25 mg/dL. With the advent of more efficacious cholesterol-lowering agents, it has been possible to test the benefits and risks of lowering LDL-C levels <50 mg/dL (Ridker et al., 2008). Lower LDL-C levels translate into greater reductions in clinical events without any increase in adverse events.

Diabetic dyslipidemia usually is characterized by high triglycerides, low HDL-C, and moderate elevations of total cholesterol and LDL-C. In fact, diabetics without diagnosed CHD have the same level of risk as nondiabetics with established CHD. Thus, the dyslipidemia treatment guidelines for diabetic patients are the same as for patients with CHD, irrespective of whether the diabetic patient has had a CHD event (The Expert Panel, 2002). The American Diabetes Association recommends new lipid therapy targets for diabetics. In addition to targets for LDL-C and non-HDL-C, two targets for total plasma apoB were established based on the level of CVD risk (Brunzell et al., 2008).

Clinical trials with statins have clearly established that total and vascular disease mortality are reduced in diabetics as a consequence of prevention of CVD events (Cholesterol Treatment Trialists' Collaborators, 2008). A recently completed trial comparing statin therapy to statin plus fenofibrate therapy will provide the first outcome data for statin plus fibrate combination therapy in type 2 diabetes patients (Ginsberg et al., 2007).

Of the five risk factors, abdominal obesity is defined by ethnic-specific values of abdominal waist circumference (Alberti et al., 2009). An alternative to assessing the five criteria that identify the metabolic syndrome is to determine the ratio of the concentrations of fasting triglycerides divided by the HDL-C. Values >3.5 predict insulin resistance as effectively as meeting the criteria for diagnosing metabolic syndrome (McLaughlin et al., 2005). The prevalence of metabolic syndrome among patients with premature vascular disease may be as high as 50%. Treatment should focus on weight loss and increased physical activity, because being overweight or obese usually precludes optimal risk factor reduction. Specific treatment of increased LDL-C, non-HDL-C, and triglyceride levels and low HDL-C levels also should be undertaken.

In patients with low HDL-C, the total cholesterol:HDL-C ratio is a particularly useful predictor of CHD risk (Bersot, 2003). Observational studies suggest that a favorable ratio is ≤3.5 and a ratio of >4.5 is associated with increased risk (Table 31–9). However, results of a post hoc analysis of the relationship between HDL-C levels and treatment benefit of statin therapy suggest that there is substantial additional benefit associated with a total cholesterol:HDL-C ratio <3 (Barter et al., 2007). American men, who are a high-risk group, have a typical ratio of ∼4.5. Patients with low HDL-C may have what are considered to be "normal" total and LDL cholesterol levels; however, because of their low HDL-C levels, such patients may be at high risk based on the total cholesterol:HDL-C ratio (e.g., a total cholesterol, 180 mg/dL; HDL-C, 30 mg/dL; ratio, 6). A desirable total cholesterol level in low-HDL-C patients may be considerably lower than 200 mg/dL, especially because low-HDL-C patients also may have moderately elevated triglycerides, which may reflect increased levels of atherogenic remnant lipoproteins. Patients with average or low LDL-C, low HDL-C, and high total cholesterol:HDL-C ratios have benefitted from treatment (Barter et al., 2007).

The treatment of low HDL-C patients focuses on lowering LDL-C to the target level based on the patient's risk factor or CHD status (Table 31–3) and a reduction of VLDL cholesterol (estimated by dividing the plasma triglyceride level by 5) to <30 mg/dL to reach the target for non-HDL-C. Satisfactory treatment results are a ratio of total cholesterol:HDL-C ≤3.5 (Table 3–9). Patients with total cholesterol:HDL-C ratios >4.5 are at risk even if their "non-HDL-C" levels (LDL-C and VLDL cholesterol) are at the goal values recommended by the 2001 NCEP guidelines. Consequently, it is useful to base treatment of patients with low HDL-C levels on both LDL-C and non-HDL-C levels plus the total cholesterol:HDL-C ratio (Tables 31–3 and 31–8) (Bersot et al., 2003).

Multiple well-controlled clinical trials have documented the efficacy and safety of simvastatin, pravastatin, lovastatin, atorvastatin, and rosuvastatin in reducing fatal and nonfatal CHD events, strokes, and total mortality (Cholesterol Treatment Trialists' Collaborators, 2005; Ridker et al., 2008). Rates of adverse events in statin trials were the same in the placebo groups and in the groups receiving the drug.

History. Statins were isolated from a mold, Penicillium citrinum, and identified as inhibitors of cholesterol biosynthesis in 1976 by Endo and colleagues. Subsequent studies by Brown and Goldstein established that statins act by inhibiting HMG-CoA reductase. The first statin studied in humans was compactin, renamed mevastatin, which demonstrated the therapeutic potential of this class of drugs. Alberts and colleagues at Merck developed the first statin approved for use in humans, lovastatin (formerly known as mevinolin), which was isolated from Aspergillus terreus. Six other statins are also available. Pravastatin and simvastatin are chemically modified derivatives of lovastatin (Figure 31–2). Atorvastatin, fluvastatin, rosuvastatin, and pitavastatin are structurally distinct synthetic compounds.

A yeast that grows on rice, monascus purpureus, produces a series of compounds, one of which, monacolin K, is an inhibitor of HMG-CoA reductase and is chemically identical to lovastatin. OTC preparations, known as red yeast rice, contain monacolin K. As with many nutraceuticals, content of the active principle may vary, and such preparations should be used with great caution.

Chemistry. The structural formulas of the original statin (mevastatin) and the seven statins currently available in the U.S. are shown in Figure 31–2 along with the reaction (conversion of HMG-CoA to mevalonate) catalyzed by HMG-CoA reductase, the enzyme they competitively inhibit. The statins possess a side group that is structurally similar to HMG-CoA. Mevastatin, lovastatin, simvastatin, and pravastatin are fungal metabolites, and each contains a hexahydronaphthalene ring. Lovastatin differs from mevastatin in having a methyl group at carbon 3. There are two major side chains. One is a methylbutyrate ester (lovastatin and pravastatin) or a dimethylbutyrate ester (simvastatin). The other contains a hydroxy acid that forms a six-membered analog of the intermediate compound in the HMG-CoA reductase reaction. Fluvastatin, atorvastatin, rosuvastatin, and pitavastatin are entirely synthetic compounds containing a heptanoic acid side chain that forms a structural analog of the HMG-CoA intermediate. As a result of their structural similarity to HMG-CoA, statins are reversible competitive inhibitors of the enzyme's natural substrate, HMG-CoA. The inhibition constant (K_i) of the statins is ∼1nM; the dissociation constant of HMG-CoA is three orders of magnitude higher.

Lovastatin and simvastatin are lactone prodrugs that are modified in the liver to active hydroxy acid forms. Because they are lactones, they are less soluble in water than are the other statins, a difference that appears to have little if any clinical significance. Pravastatin (an acid in the active form), fluvastatin (sodium salt), and atorvastatin, rosuvastatin, and pitavastatin (calcium salts), are all administered in the active, open-ring form.

Some studies suggest that statins also can reduce LDL levels by enhancing the removal of LDL precursors (VLDL and IDL) and by decreasing hepatic VLDL production. Because VLDL remnants and IDL are enriched in apoE, a statin-induced increase in the number of LDL receptors, which recognize both apoB-100 and apoE, enhances the clearance of these LDL precursors. The reduction in hepatic VLDL production induced by statins is thought to be mediated by reduced synthesis of cholesterol, a required component of VLDL. This mechanism also likely accounts for the triglyceride-lowering effect of statins and may account for the reduction (∼25%) of LDL-C levels in patients with homozygous familial hypercholesterolemia treated with 80 mg of atorvastatin or simvastatin.

Triglyceride Reduction by Statins. Triglyceride levels >250 mg/dL are reduced substantially by statins, and the percent reduction achieved is similar to the percent reduction in LDL-C. Accordingly, hypertriglyceridemic patients taking the highest doses of the most potent statins experience a 35-45% reduction in LDL-C and a similar reduction in fasting triglyceride levels (Hunninghake et al., 2004). The efficacy of triglyceride lowering by pitavastatin in patients with baseline triglyceride levels >250 mg/dL is currently unknown.

Effect of Statins on HDL-C Levels. Most studies of patients treated with statins have systematically excluded patients with low HDL-C levels. In studies of patients with elevated LDL-C levels and gender-appropriate HDL-C levels (40-50 mg/dL for men; 50-60 mg/dL for women), an increase in HDL-C of 5-10% was observed, irrespective of the dose or statin employed. However, in patients with reduced HDL-C levels (<35 mg/dL), statins may differ in their effects on HDL-C levels. Simvastatin, at its highest dose of 80 mg, increases HDL-C and apoA-I levels more than a comparable dose of atorvastatin (Crouse et al., 2000). In preliminary studies of patients with hypertriglyceridemia and low HDL-C, rosuvastatin appears to raise HDL-C levels by as much as 15-20% (Hunninghake et al., 2004). More studies are needed to ascertain whether the effects of statins on HDL-C in patients with low HDL-C levels are clinically significant.

Effects of Statins on LDL-C Levels. Statins lower LDL-C by 20-55%, depending on the dose and statin used. In large trials comparing the effects of the various statins, equivalent doses appear to be 5 mg of simvastatin = ∼15 mg of lovastatin = ∼15 mg of pravastatin = ∼40 mg of fluvastatin (Pedersen and Tobert, 1996), 20 mg of simvastatin = ∼10 mg of atorvastatin (Jones et al., 1998) (Crouse III et al., 1999), and 20 mg of atorvastatin = 10 mg of rosuvastatin (Jones et al., 2003). Analysis of dose-response relationships for all statins demonstrates that the efficacy of LDL-C lowering is log-linear; LDL-C is reduced by ∼6% (from baseline) with each doubling of the dose (Jones et al., 1998; Pedersen and Tobert, 1996). Maximal effects on plasma cholesterol levels are achieved within 7-10 days.

Table 31–10 provides information on the statin doses required to reduce LDL-C by 20-55%. The fractional reductions achieved with the various doses are the same regardless of the absolute value of the baseline LDL-C level. The statins are effective in almost all patients with high LDL-C levels. The exception is patients with homozygous familial hypercholesterolemia, who have very attenuated responses to the usual doses of statins because both alleles of the LDL receptor gene code for dysfunctional LDL receptors; the partial response in these patients is due to a reduction in hepatic VLDL synthesis associated with the inhibition of HMG-CoA reductase–mediated cholesterol synthesis. Statin therapy does not reduce Lp(a) levels.

Statins and Endothelial Function. A variety of studies have established that the vascular endothelium plays a dynamic role in vasoconstriction/relaxation. Hypercholesterolemia adversely affects the processes by which the endothelium modulates arterial tone. Statin therapy enhances endothelial production of the vasodilator nitric oxide, leading to improved endothelial function. Statin therapy improves endothelial function independent of changes in plasma cholesterol levels.

Statins and Plaque Stability. The vulnerability of plaques to rupture and thrombosis is of greater clinical relevance than the degree of stenosis they cause (Corti et al., 2003). Statins affect plaque stability in a variety of ways. They inhibit monocyte infiltration into the artery wall and inhibit macrophage secretion of matrix metalloproteinases in vitro. The metalloproteinases degrade extracellular matrix components and thus weaken the fibrous cap of atherosclerotic plaques.

Statins also appear to modulate the cellularity of the artery wall by inhibiting proliferation of smooth muscle cells and enhancing apoptosis. It is debatable whether these effects would be beneficial or harmful if they occurred in vivo. Reduced proliferation of smooth muscle cells and enhanced apoptosis could retard initial hyperplasia and restenosis, but they also could weaken the fibrous cap and destabilize the lesion. Interestingly, statin-induced suppression of cell proliferation and the induction of apoptosis have been extended to tumor biology. The effects of statins on isoprenoid biosynthesis and protein phenylation associated with reduced synthesis of the cholesterol precursor mevalonate may alter the development of malignancies (Li et al., 2003; Wong et al., 2002).

Statins and Inflammation. Appreciation of the importance of inflammatory processes in atherogenesis is growing, and statins may have an anti-inflammatory role. Statins decreased the risk of CHD and levels of CRP (an independent marker for inflammation and high CHD risk) independently of cholesterol lowering (Libby and Aikawa, 2003; Libby and Ridker, 2004). Body weight and the metabolic syndrome are associated with elevated levels of highly sensitive CRP, leading some to suggest that the CRP may simply be a marker of obesity and insulin resistance (Pearson et al., 2003). It remains to be determined whether the CRP is simply a marker of inflammation or if it contributes to the pathogenesis of atherosclerosis. The clinical utility of measuring CRP with "highly sensitive" assays appears to be limited to those primary prevention subjects with a moderate (10-20%) 10-year risk of sustaining a CHD event. Values of highly sensitive CRP >3 mg/L suggest that such patients should be managed as secondary prevention patients (Pearson et al., 2003).

Statins and Lipoprotein Oxidation. Oxidative modification of LDL appears to play a key role in mediating the uptake of lipoprotein cholesterol by macrophages and in other processes, including cytotoxicity within lesions. Statins reduce the susceptibility of lipoproteins to oxidation both in vitro and ex vivo.

Statins and Coagulation. The most compelling evidence of a non–lipid-lowering effect of a statin is the rosuvastatin-mediated reduction in venous thromboembolic events, a prespecified endpoint, in JUPITER. This trial demonstrated a 43% reduction in venous thromboembolic events in patients treated with rosuvastatin, 20 mg daily, compared with placebo during a median follow-up period of 1.9 years (Glynn et al., 2009). Statins reduce platelet aggregation and reduce the deposition of platelet thrombi. In addition, the different statins have variable effects on fibrinogen levels. Elevated plasma fibrinogen levels are associated with an increase in the incidence of CHD.

Absorption, Metabolism, and Excretion

Absorption from the Small Intestine. After oral administration, intestinal absorption of the statins is variable (30-85%). All the statins, except simvastatin and lovastatin, are administered in the β-hydroxy acid form, which is the form that inhibits HMG-CoA reductase. Simvastatin and lovastatin are administered as inactive lactones that must be transformed in the liver to their respective β-hydroxy acids, simvastatin acid (SVA) and lovastatin acid (LVA). There is extensive first-pass hepatic uptake of all statins, mediated primarily by the organic anion transporter OATP1B1 (see Chapter 5).

Due to extensive first-pass hepatic uptake, systemic bioavailability of the statins and their hepatic metabolites varies between 5% and 30% of administered doses. The metabolites of all statins, except fluvastatin and pravastatin, have some HMG-CoA reductase inhibitory activity (Bellosta et al., 2004). Under steady-state conditions, small amounts of the parent drug and its metabolites produced in the liver can be found in the systemic circulation. After the lactones of simvastatin and lovastatin are transformed in the liver to SVA and LVA, small amounts of these active inhibitors of HMG-CoA reductase, as well as small amounts of the lactone forms, can be found in the systemic circulation. In the plasma, >95% of statins and their metabolites are protein bound, with the exception of pravastatin and its metabolites, which are only 50% bound (Schachter, 2005).

After an oral dose, plasma concentrations of statins peak in 1-4 hours. The t_1/2 of the parent compounds are 1-4 hours, except in the case of atorvastatin and rosuvastatin, which have half-lives of ∼20 hours, and simvastatin with a t_1/2 ∼12 hours (Ieiri et al., 2007). The longer t_1/2 of atorvastatin and rosuvastatin may contribute to their greater cholesterol-lowering efficacy (Corsini et al., 1999). The liver biotransforms all statins, and more than 70% of statin metabolites are excreted by the liver, with subsequent elimination in the feces (Bellosta et al., 2004). Inhibition by other drugs of OATP1B1, which transports several statins into hepatocytes, and inhibition or induction of CYP3A4 by a variety of pharmacological agents provide rationales for drug-drug interactions involving statins (Shitara and Sugiyama, 2006).

Adverse Effects and Drug Interactions

Hepatotoxicity. Initial post-marketing surveillance studies of the statins revealed an elevation in hepatic transaminase to values greater than three times the upper limit of normal, with an incidence as great as 1%. The incidence appeared to be dose related. However, in the placebo-controlled outcome trials in which 10- to 40-mg doses of simvastatin, lovastatin, fluvastatin, atorvastatin, pravastatin, or rosuvastatin were used, the incidence of 3-fold elevations in hepatic transaminases was 1-3% in the active drug treatment groups and 1.1% in placebo patients (Law et al., 2006; Ridker et al., 2008). No cases of liver failure occurred in these trials. Although serious hepatotoxicity is rare, 30 cases of liver failure associated with statin use were reported to the FDA between 1987 and 2000, a rate of about one case per million person-years of use (Law et al., 2006). It is therefore reasonable to measure alanine aminotransferase (ALT) at baseline and thereafter when clinically indicated.

Observational studies and a prospective trial suggest that transaminase elevations in patients with nonalcoholic fatty liver disease and hepatitis C are not at risk of statin-induced liver toxicity (Alqahtani and Sanchez, 2008; Chalasani et al., 2004; Lewis et al., 2007; Norris et al., 2008). This is important, as many insulin-resistant patients are affected by nonalcoholic fatty liver disease and have elevated transaminases. As insulin resistance is associated with increased CVD risk, insulin-resistant patients, especially those with type 2 diabetes mellitus, benefit from lipid-lowering therapy with statins (Cholesterol Treatment Trialists' Collaborators, 2008). It is reassuring that these patients with elevated transaminases can safely take statins.

Myopathy. The major adverse effect associated with statin use is myopathy (Wilke et al., 2007). Between 1987 and 2001, the FDA recorded 42 deaths from rhabdomyolysis induced by statins (excluding cerivastatin, which has been withdrawn from the market worldwide). This is a rate of one death per million prescriptions (30-day supply). In the statin trials described earlier (under "Hepatotoxicity"), rhabdomyolysis occurred in eight active drug recipients versus five placebo subjects. Among active drug recipients, 0.17% had CK values exceeding 10 times the upper limit of normal; among placebo-treated subjects, the incidence was 0.13%. Only 13 out of 55 drug-treated subjects and 4 out of 43 placebo subjects with greater than 10-fold elevations of CK reported any muscle symptoms (Law et al., 2006).

The risk of myopathy and rhabdomyolysis increases in proportion to statin dose and plasma concentrations. Consequently, factors inhibiting statin catabolism are associated with increased myopathy risk, including advanced age (especially >80 years of age), hepatic or renal dysfunction, perioperative periods, multi-system disease (especially in association with diabetes mellitus), small body size, and untreated hypothyroidism (Pasternak et al., 2002; Thompson et al., 2003). Concomitant use of drugs that diminish statin catabolism or interfere with hepatic uptake is associated with myopathy and rhabdomyolysis in 50-60% of all cases (Law and Rudnicka, 2006; Thompson et al., 2003). Thus, avoiding these drug interactions should reduce myopathy and rhabdomyolysis by about one-half (Law and Rudnicka, 2006). The most common statin interactions occurred with fibrates, especially gemfibrozil (38%), cyclosporine (4%), digoxin (5%), warfarin (4%), macrolide antibiotics (3%), mibefradil (2%), and azole antifungals (1%) (Thompson et al., 2003). Other drugs that increase the risk of statin-induced myopathy include niacin (rare), HIV protease inhibitors, amiodarone, and nefazodone (Pasternak et al., 2002).

There are a variety of pharmacokinetic mechanisms by which these drugs increase myopathy risk when administered concomitantly with statins. Gemfibrozil, the drug most commonly associated with statin-induced myopathy, inhibits both uptake of the active hydroxy acid forms of statins into hepatocytes by OATP1B1 and interferes with the transformation of most statins by glucuronidases (Prueksaritanont et al., 2002a; Prueksaritanont et al., 2002b; Prueksaritanont et al., 2002c). Primarily due to inhibition of OATP1B1-mediated hepatic uptake, co-administration of gemfibrozil nearly doubles the plasma concentration of the statin hydroxy acids (Neuvonen et al., 2006). Other fibrates, especially fenofibrate, do not interfere with the glucuronidation of statins and pose less risk of myopathy when used in combination with statin therapy. (For reviews of statin interactions with other drugs, see Bellosta et al., 2004 and Neuvonen et al., 2006). Concomitant therapy with simvastatin, 80 mg daily, and fenofibrate, 160 mg daily, results in no clinically significant pharmacokinetic interaction (Bergman et al., 2004). Similar results were obtained in a study of low-dose rosuvastatin, 10 mg daily, plus fenofibrate, 67 mg three times a day. When statins are administered with niacin, the myopathy probably is caused by an enhanced inhibition of skeletal muscle cholesterol synthesis (a pharmacodynamic interaction).

Drugs that interfere with statin oxidation are those metabolized primarily by CYP3A4 and include certain macrolide antibiotics (e.g., erythromycin); azole antifungals (e.g., itraconazole); cyclosporine; nefazodone, a phenylpiperazine antidepressant; HIV protease inhibitors; and amiodarone (Alsheikh-Ali and Karas, 2005; Bellosta et al., 2004; Corsini, 2003). These pharmacokinetic interactions are associated with increased plasma concentrations of statins and their active metabolites. Atorvastatin, lovastatin, and simvastatin are primarily metabolized by CYPs 3A4 and 3A5. Fluvastatin is mostly (50-80%) metabolized by CYP2C9 to inactive metabolites, but CYP3A4 and CYP2C8 also contribute to its metabolism. Pravastatin, however, is not metabolized to any appreciable extent by the CYP system and is excreted unchanged in the urine. Pravastatin, fluvastatin, and rosuvastatin are not extensively metabolized by CYP3A4. Pravastatin and fluvastatin may be less likely to cause myopathy when used with one of the predisposing drugs. However, because cases of myopathy have been reported with both drugs, the benefits of combined therapy with any statin should be carefully weighed against the risk of myopathy. Although rosuvastatin is not transformed to any appreciable extent by oxidation, cases of myopathy have been reported, particularly in association with concomitant use of gemfibrozil (Schneck et al., 2004). Experience with pitavastatin is limited. There are no data regarding myopathy and rhabdomyolysis that might be associated with its use.

Despite the rarity of 10-fold elevations of CK, many patients complain of muscle aches (myalgias) while taking statins. It is unclear if such myalgias are caused by taking a statin. In one clinical trial involving 20,000 subjects randomized to simvastatin (40 mg daily) or placebo, it was observed over the 5 years of the study that one-third of patients complained of myalgia at least once, whether the active drug or the placebo was being taken (Heart Protection Study Collaborative Group, 2002).

Replacing vitamin D in patients with a vitamin D deficiency reportedly reduces statin-associated myalgias and improves statin tolerance (Ahmed et al., 2009). The observation needs to be confirmed, but it is potentially significant because vitamin D deficiency is associated with myopathy, insulin resistance, and increased incidence of CVD (Lee et al., 2008).

Pregnancy. The safety of statins during pregnancy has not been established. Women wishing to conceive should not take statins. During their childbearing years, women taking statins should use highly effective contraception (see Chapter 40). Nursing mothers also are advised to avoid taking statins.

The initial recommended dose of lovastatin (mevacor) is 20 mg and is slightly more effective if taken with the evening meal than if it is taken at bedtime, although bedtime dosing is preferable to missing doses. The dose of lovastatin may be increased every 3-6 weeks up to a maximum of 80 mg/day. The 80-mg dose is slightly (2-3%) more effective if given as 40 mg twice daily. Lovastatin, at 20 mg, is marketed in combination with 500, 750, or 1000 mg of extended-release niacin (advicor). Few patients are appropriate candidates for this fixed-dose combination (see the section on "Nicotinic Acid," later in the chapter).

The approved starting dose of simvastatin (zocor) for most patients is 20 mg at bedtime unless the required LDL-C reduction exceeds 45% or the patient is a high-risk secondary prevention patient, in which case a 40-mg starting dose is indicated. The maximal dose is 80 mg, and the drug should be taken at bedtime. In patients taking cyclosporine, fibrates, or niacin, the daily dose should not exceed 20 mg. Simvastatin, 20 mg, is marketed in combination with 500, 750, or 1000 mg of extended-release niacin (simcor). See the section on "Nicotinic Acid."

Pravastatin (pravachol) therapy is initiated with a 20- or 40-mg dose that may be increased to 80 mg. This drug should be taken at bedtime. Because pravastatin is a hydroxy acid, bile-acid sequestrants will bind it and reduce its absorption. Practically, this is rarely a problem because the resins should be taken before meals and pravastatin should be taken at bedtime. Pravastatin also is marketed in combination with buffered aspirin (pravigard). The small advantage of combining these two drugs should be weighed against the disadvantages inherent in fixed-dose combinations.

The starting dose of fluvastatin (LESCOL) is 20 or 40 mg, and the maximum is 80 mg/day. Like pravastatin, it is administered as a hydroxy acid and should be taken at bedtime, several hours after ingesting a bile-acid sequestrant (if the combination is used).

Atorvastatin (lipitor) has a long t_1/2, which allows administration of this statin at any time of the day. The starting dose is 10 mg, and the maximum is 80 mg/day. Atorvastatin is marketed in combination with the Ca²⁺-channel blocker amlodipine (caduet) for patients with hypertension or angina as well as hypercholesterolemia. The physician should weigh any advantage of combination against the associated risks and disadvantages.

Rosuvastatin (crestor) is available in doses ranging between 5 and 40 mg. It has a t_1/2 of 20-30 hours and may be taken at any time of day. Because experience with rosuvastatin is limited, treatment should be initiated with 5-10 mg daily, increasing stepwise, if needed, until the incidence of myopathy is better defined. If the combination of gemfibrozil with rosuvastatin is used, the dose of rosuvastatin should not exceed 10 mg.

Pitavastatin (livalo) is available in doses of 1, 2, and 4 mg. There is very limited post-marketing experience with this drug. Gemfibrozil reduces clearance of pitavastatin and raises blood concentrations; consequently, gemfibrozil should be used cautiously, if at all, in combination with pitavastatin.

The choice of statins should be based on efficacy (reduction of LDL-C) and cost. Three drugs (lovastatin, simvastatin, and pravastatin) have been used safely in clinical trials involving thousands of subjects for 5 or more years. The documented safety records of these statins should be considered, especially when initiating therapy in younger patients. Once drug treatment is initiated, it is almost always lifelong. Baseline determinations of ALT and repeat testing at 3-6 months are recommended. If ALT is normal after the initial 3-6 months, then it need not be repeated more than once every 6-12 months. Measurements of CK are not routinely necessary unless the patient also is taking a drug that enhances the risk of myopathy. Because myopathy may develop months to years after the start of combined therapy, it is unlikely that routine monitoring for the accompanying rise in CK will consistently herald the onset, even if monitoring is performed every 3-4 months.

Statins in Combination with Other Lipid-Lowering Drugs. Statins, in combination with the bile acid–binding resins cholestyramine and colestipol, produce 20-30% greater reductions in LDL-C than can be achieved with statins alone. Preliminary data indicate that colesevelam hydrochloride plus a statin lowers LDL-C by 8-16% more than statins alone. Niacin also can enhance the effect of statins, but the occurrence of myopathy increases when statin doses >25% of maximum (e.g., 20 mg of simvastatin or atorvastatin) are used with niacin. The combination of a fibrate (clofibrate, gemfibrozil, or fenofibrate) with a statin is particularly useful in patients with hypertriglyceridemia and high LDL-C levels. This combination increases the risk of myopathy but usually is safe with a fibrate at its usual maximal dose and a statin at no more than 25% of its maximal dose. Fenofibrate, which is least likely to interfere with statin metabolism, appears to be the safest fibrate to use with statins (Prueksaritanont et al., 2002b). Triple therapy with resins, niacin, and statins can reduce LDL-C by up to 70%. Vytorin, a fixed combination of simvastatin (10, 20, 40, or 80 mg) and ezetimibe (10 mg), decreased LDL-C levels by up to 60% at 24 weeks.

Chemistry. Cholestyramine and colestipol (Figure 31–3) are anion-exchange resins. Cholestyramine, a polymer of styrene and divinylbenzene with active sites formed from trimethylbenzylammonium groups, is a quaternary amine. Colestipol, a copolymer of diethylenetriamine and 1-chloro-2,3-epoxypropane, is a mixture of tertiary and quaternary diamines. Cholestyramine and colestipol are hygroscopic powders administered as chloride salts and are insoluble in water. Colesevelam is a polymer, poly(allylamine hydrochloride), cross-linked with epichlorohydrin and alkylated with 1-bromodecane and (6-bromohexyl)-trimethylammonium bromide; it is a hydrophilic gel and insoluble in water.

The resin-induced increase in bile-acid production is accompanied by an increase in hepatic triglyceride synthesis, which is of consequence in patients with significant hypertriglyceridemia (baseline triglyceride level >250 mg/dL). In such patients, bile-acid sequestrant therapy may cause striking increases in triglyceride levels. Use of colesevelam to lower LDL-C levels in hypertriglyceridemic patients should be accompanied by frequent (every 1-2 weeks) monitoring of fasting triglyceride levels until the triglyceride level is stable, or the use of colesevelam in these patients should be avoided.

Effects on Lipoprotein Levels. The reduction in LDL-C by resins is dose dependent. Doses of 8-12 g of cholestyramine or 10-15 g of colestipol are associated with 12-18% reductions in LDL-C. Maximal doses (24 g of cholestyramine, 30 g of colestipol) may reduce LDL-C by as much as 25% but will cause gastrointestinal side effects that are poorly tolerated by most patients. One to two weeks is sufficient to attain maximal LDL-C reduction by a given resin dose. In patients with normal triglyceride levels, triglycerides may increase transiently and then return to baseline. HDL-C levels increase 4-5%. Statins plus resins or niacin plus resins can reduce LDL-C by as much as 40-60%. Colesevelam, in doses of 3-3.75 g, reduces LDL-C levels by 9-19%.

Adverse Effects and Drug Interactions. The resins are generally safe, as they are not systemically absorbed. Because they are administered as chloride salts, rare instances of hyperchloremic acidosis have been reported. Severe hypertriglyceridemia is a contraindication to the use of cholestyramine and colestipol because these resins increase triglyceride levels. At present, there are insufficient data on the effect of colesevelam on triglyceride levels.

Cholestyramine and colestipol both are available as a powder that must be mixed with water and drunk as a slurry. The gritty sensation is unpleasant to patients initially but can be tolerated. Colestipol is available in a tablet form that reduces the complaint of grittiness but not the gastrointestinal symptoms. Colesevelam is available as a hard capsule that absorbs water and creates a soft, gelatinous material that allegedly minimizes the potential for gastrointestinal irritation.

Patients taking cholestyramine and colestipol complain of bloating and dyspepsia. These symptoms can be substantially reduced if the drug is completely suspended in liquid several hours before ingestion (e.g., evening doses can be mixed in the morning and refrigerated; morning doses can be mixed the previous evening and refrigerated). Constipation may occur but sometimes can be prevented by adequate daily water intake and psyllium, if necessary. Colesevelam may be less likely to cause the dyspepsia, bloating, and constipation observed in patients treated with cholestyramine or colestipol.

Cholestyramine and colestipol bind and interfere with the absorption of many drugs, including some thiazides, furosemide, propranolol, L-thyroxine, digoxin, warfarin, and some of the statins. The effect of cholestyramine and colestipol on the absorption of most drugs has not been studied. For this reason, it is wise to administer all drugs either 1 hour before or 3-4 hours after a dose of cholestyramine or colestipol. Colesevelam does not appear to interfere with the absorption of fat-soluble vitamins or of drugs such as digoxin, lovastatin, warfarin, metoprolol, quinidine, and valproic acid. The maximum concentration and the AUC of sustained-release verapamil are reduced by 31% and 11%, respectively, when the drug is co-administered with colesevelam. The effect of colesevelam on the absorption of other drugs has not been tested, but it seems prudent to recommend that patients take other medications 1 hour before or 3-4 hours after a dose of colesevelam.

Preparations and Use. Cholestyramine resin (questran, others) is available in bulk (with scoops that measure a 4-g dose) or in individual packets of 4 g. Additional flavorings are added to increase palatability. The "light" preparations contain artificial sweeteners rather than sucrose. Colestipol hydrochloride (colestid, others) is available in bulk, in individual packets containing 5 g of colestipol, or as 1-g tablets.

Resins should never be taken in the dry form. The powdered forms of cholestyramine (4 g/dose) and colestipol (5 g/dose) are either mixed with a fluid (water or juice) and drunk as a slurry or mixed with crushed ice in a blender. Ideally, patients should take the resins before breakfast and before supper, starting with one scoop or packet twice daily, and increasing the dosage after several weeks or longer as needed and as tolerated. Patients generally will not take more than two doses (scoops or packets) twice a day.

Colesevelam hydrochloride (welchol) is available as a solid tablet containing 0.625 g of colesevelam and as a powder in packets of 3.75 g or 1.875 g. The starting dose is either three tablets taken twice daily with meals or all six tablets taken with a meal. The tablets should be taken with a liquid. The maximum daily dose is seven tablets (4.375 g). The powder in the packets is first suspended in 4-8 oz of water and should be taken with meals. Dosing of the packet containing 3.75 g is once daily; the packet containing 1.875 g is taken twice daily.

In the liver, niacin reduces triglyceride synthesis by inhibiting both the synthesis and esterification of fatty acids, effects that increase apoB degradation. Reduction of triglyceride synthesis reduces hepatic VLDL production, which accounts for the reduced LDL levels. Niacin also enhances LPL activity, which promotes the clearance of chylomicrons and VLDL triglycerides. Niacin raises HDL-C levels by decreasing the fractional clearance of apoA-I in HDL rather than by enhancing HDL synthesis. This effect is due to a reduction in the hepatic clearance of HDL-apoA-I, but not of cholesteryl esters, thereby increasing the apoA-I content of plasma and augmenting reverse cholesterol transport. In macrophages, niacin stimulates expression of the scavenger receptor CD36 and the cholesterol exporter ABCA1. The net effect of niacin on monocytic cells ("foam cells") is HDL-mediated reduction of cellular cholesterol content (Rubic et al., 2004).

Effects on Plasma Lipoprotein Levels. Regular or crystalline niacin in doses of 2-6 g/day reduces triglycerides by 35-50%; the maximal effect occurs within 4-7 days. Reductions of 25% in LDL-C levels are possible with doses of 4.5-6 g/day, but 3-6 weeks are required for maximal effect. HDL-C increases less in patients with low HDL-C levels (<35 mg/dL) than in those with higher levels.

Absorption, Fate, and Excretion. The pharmacological doses of regular (crystalline) niacin used to treat dyslipidemia are almost completely absorbed, and peak plasma concentrations (up to 0.24 mmol) are achieved within 30-60 minutes. The t_1/2 is about 60 minutes, which accounts for the necessity of dosing two to three times daily. At lower doses, most niacin is taken up by the liver; only the major metabolite, nicotinuric acid, is found in the urine. At higher doses, a greater proportion of the drug is excreted in the urine as unchanged nicotinic acid.

Adverse Effects. Two of niacin's side effects, flushing and dyspepsia, limit patient compliance. The cutaneous effects include flushing and pruritus of the face and upper trunk, skin rashes, and acanthosis nigricans. Flushing and associated pruritus are prostaglandin mediated. Flushing is worse when therapy is initiated or the dosage is increased but ceases in most patients after 1-2 weeks of a stable dose. Taking an aspirin each day alleviates the flushing in many patients. Flushing recurs if only one or two doses are missed, and the flushing is more likely to occur when niacin is consumed with hot beverages (coffee, tea) or with ethanol-containing beverages. Flushing is minimized if therapy is initiated with low doses (100-250 mg twice daily) and if the drug is taken after breakfast or supper. Dry skin, a frequent complaint, can be dealt with by using skin moisturizers, and acanthosis nigricans can be dealt with by using lotions or creams containing salicylic acid. Dyspepsia and rarer episodes of nausea, vomiting, and diarrhea are less likely to occur if the drug is taken after a meal. Patients with any history of peptic ulcer disease should not take niacin because it can reactivate ulcer disease.

The most common, medically serious side effects are hepatotoxicity, manifested as elevated serum transaminases, and hyperglycemia. Both regular (crystalline) niacin and sustained-release niacin, which was developed to reduce flushing and itching, have been reported to cause severe liver toxicity. An extended-release niacin (niaspan) appears to be less likely to cause severe hepatotoxicity, perhaps simply because it is administered once daily instead of more frequently. The incidence of flushing and pruritus with this preparation is not substantially different from that with regular niacin. Severe hepatotoxicity is more likely to occur when patients take more than 2 g of sustained-release, over-the-counter preparations. Affected patients experience flu-like fatigue and weakness. Usually, aspartate transaminase and ALT are elevated, serum albumin levels decline, and total cholesterol and LDL-C levels decline substantially. In fact, reductions in LDL-C of 50% or more in a patient taking niacin should be viewed as a sign of niacin toxicity.

In patients with diabetes mellitus, niacin should be used cautiously because niacin-induced insulin resistance can cause severe hyperglycemia. Niacin use in patients with diabetes mellitus often mandates a change to insulin therapy. In a study of patients with type 2 diabetes taking niaspan, 4% stopped taking the drug because of inadequate glycemic control (Grundy et al., 2002). If niacin is prescribed for patients with known or suspected diabetes, blood glucose levels should be monitored at least weekly until proven to be stable. Niacin also elevates uric acid levels and may reactivate gout. A history of gout is a relative contraindication for niacin use. Rarer reversible side effects include toxic amblyopia and toxic maculopathy. Atrial tachyarrhythmias and atrial fibrillation have been reported, more commonly in elderly patients. Niacin, at doses used in humans, has been associated with birth defects in experimental animals and should not be taken by pregnant women.

Therapeutic Use. Niacin is indicated for hypertriglyceridemia and elevated LDL-C; it is especially useful in patients with both hypertriglyceridemia and low HDL-C levels. There are two commonly available forms of niacin. Crystalline niacin (immediate-release or regular) refers to niacin tablets that dissolve quickly after ingestion. Sustained-release niacin refers to preparations that continuously release niacin for 6-8 hours after ingestion. NIASPAN is the only preparation of niacin that is FDA-approved for treating dyslipidemia and that requires a prescription.

Crystalline niacin tablets are available over the counter in a variety of strengths from 50- to 500-mg tablets. To minimize the flushing and pruritus, it is best to start with a low dose (e.g., 100 mg twice daily taken after breakfast and supper). The dose may be increased stepwise every 7 days by 100-200 mg to a total daily dose of 1.5-2 g. After 2-4 weeks at this dose, transaminases, serum albumin, fasting glucose, and uric acid levels should be measured. Lipid levels should be checked and the dose increased further until the desired effect on plasma lipids is achieved. After a stable dose is attained, blood should be drawn every 3-6 months to monitor for the various toxicities.

Because concurrent use of niacin and a statin can cause myopathy, the statin should be administered at no more than 25% of its maximal dose. Patients also should be instructed to discontinue therapy if flu-like muscle aches occur. Routine measurement of CK in patients taking niacin and statins does not assure that severe myopathy will be detected before onset of symptoms, as patients have developed myopathy after several years of concomitant use of niacin with a statin.

Over-the-counter, sustained-release niacin preparations and NIASPAN are effective up to a total daily dose of 2 g. All doses of sustained-release niacin, but particularly doses above 2 g/day, have been reported to cause hepatotoxicity, which may occur soon after beginning therapy or after several years of use (Knopp et al., 2009). The potential for severe liver damage should preclude use of OTC preparations in most patients, including those who have taken an equivalent dose of crystalline niacin safely for many years and are considering switching to a sustained-release preparation. NIASPAN may be less likely to cause hepatotoxicity.

History. In 1962, Thorp and Waring reported that ethyl chlorophenoxyisobutyrate lowered lipid levels in rats. In 1967, the ester form (clofibrate) was approved for use in the U.S. and became the most widely prescribed hypolipidemic drug. Its use declined dramatically, however, after the World Health Organization (WHO) reported that, despite a 9% reduction in cholesterol levels, clofibrate treatment did not reduce fatal cardiovascular events, although nonfatal infarcts were reduced. Total mortality was significantly greater in the clofibrate group. The increased mortality was due to multiple causes, including cholelithiasis. Interpretation of these negative results was clouded by failure to analyze the data according to the intention-to-treat principle. A later analysis demonstrated that the apparent increase in noncardiac mortality did not persist in the clofibrate-treated patients after discontinuation of the drug (Heady et al., 1992). Clofibrate use was virtually abandoned after publication of the results of the 1978 WHO trial. Clofibrate as well as two other fibrates, gemfibrozil and fenofibrate, remain available in the U.S.

Two subsequent trials involving only men have reported favorable effects of gemfibrozil therapy on fatal and nonfatal cardiac events without an increase in morbidity or mortality (Frick et al., 1987; Rubins et al., 1999). A third trial of men and women reported fewer events in a subgroup characterized by high triglyceride and low HDL-C levels (Haim et al., 1999).

Chemistry. Clofibrate, the prototype of the fibric acid derivatives, is the ethyl ester of p-chlorophenoxyisobutyrate. Gemfibrozil is a nonhalogenated phenoxypentanoic acid and thus is distinct from the halogenated fibrates. A number of fibric acid analogs (e.g., fenofibrate, bezafibrate, ciprofibrate) have been developed and are used in Europe and elsewhere (see Figure 31–4 for their structural formulas).

LDL levels rise in many patients treated with gemfibrozil, especially those with hypertriglyceridemia. However, LDL levels are unchanged or fall in others, especially those whose triglyceride levels are not elevated or who are taking a second-generation agent, such as fenofibrate, bezafibrate, or ciprofibrate. The decrease in LDL levels may be due in part to changes in the cholesterol and triglyceride contents of LDL that are mediated by CETP; such changes can alter the affinity of LDL for the LDL receptor. There also is evidence that a PPARα-mediated increase in hepatic SREBP-1 production enhances hepatic expression of LDL receptors (Kersten et al., 2000). Lastly, fibrates reduce the plasma concentration of small, dense, more easily oxidized LDL particles (Vakkilainen et al., 2003).

Most of the fibric acid agents have potential antithrombotic effects, including inhibition of coagulation and enhancement of fibrinolysis. These salutary effects also could alter cardiovascular outcomes by mechanisms unrelated to any hypolipidemic activity.

Patients with type III hyperlipoproteinemia (dysbetalipoproteinemia) are among the most sensitive responders to fibrates (Mahley and Rall, 2008). Elevated triglyceride and cholesterol levels are dramatically lowered, and tuberoeruptive and palmar xanthomas may regress completely. Angina and intermittent claudication also improve.

In patients with mild hypertriglyceridemia (e.g., triglycerides <400 mg/dL), fibrate treatment decreases triglyceride levels by up to 50% and increases HDL-C concentrations by about 15%; LDL-C levels may be unchanged or increase. The second-generation agents, such as fenofibrate, bezafibrate, and ciprofibrate, lower VLDL levels to a degree similar to that produced by gemfibrozil, but they also are more likely to decrease LDL levels by 15-20%. In patients with more marked hypertriglyceridemia (e.g., 400-1000 mg/dL), a similar fall in triglycerides occurs, but LDL increases of 10-30% are seen frequently. Normotriglyceridemic patients with heterozygous familial hypercholesterolemia usually experience little change in LDL levels with gemfibrozil; with the other fibric acid agents, reductions as great as 20% may occur in some patients.

Fibrates usually are the drugs of choice for treating severe hypertriglyceridemia and the chylomicronemia syndrome. While the primary therapy is to remove alcohol and as much fat from the diet as possible, fibrates help both by increasing triglyceride clearance and decreasing hepatic triglyceride synthesis. In patients with chylomicronemia syndrome, fibrate maintenance therapy and a low-fat diet keep triglyceride levels well below 1000 mg/dL and thus prevent episodes of pancreatitis.

In a 5-year study of hyperlipidemic men, gemfibrozil reduced total cholesterol by 10% and LDL-C by 11%, raised HDL-C levels by 11%, and decreased triglycerides by 35% (Frick et al., 1987). Overall, there was a 34% decrease in the sum of fatal plus nonfatal cardiovascular events without any effect on total mortality. No increased incidence of gallstones or cancers was observed. Subgroup analysis suggested that the greatest benefit occurred in the subjects with the highest levels of VLDL or combined VLDL and LDL and in those with the lowest HDL-C levels (<35 mg/dL). Gemfibrozil may have affected the outcome by influencing platelet function, coagulation factor synthesis, or LDL size. In a recent secondary prevention trial, gemfibrozil reduced fatal and nonfatal CHD events by 22% despite a lack of effect on LDL-C levels. HDL-C levels increased by 6%, which may have contributed to the favorable outcome.

Absorption, Fate, and Excretion. All of the fibrate drugs are absorbed rapidly and efficiently (>90%) when given with a meal but less efficiently when taken on an empty stomach. The ester bond is hydrolyzed rapidly, and peak plasma concentrations are attained within 1-4 hours. More than 95% of these drugs in plasma are bound to protein, nearly exclusively to albumin. The t_1/2 of fibrates differ significantly, ranging from 1.1 hours (gemfibrozil) to 20 hours (fenofibrate). The drugs are widely distributed throughout the body, and concentrations in liver, kidney, and intestine exceed the plasma level. Gemfibrozil is transferred across the placenta. The fibrate drugs are excreted predominantly as glucuronide conjugates; 60-90% of an oral dose is excreted in the urine, with smaller amounts appearing in the feces. Excretion of these drugs is impaired in renal failure, although excretion of gemfibrozil is less severely compromised in renal insufficiency than is excretion of other fibrates. The use of fibrates is contraindicated in patients with renal failure.

Adverse Effects and Drug Interactions. Fibric acid compounds usually are well tolerated. Side effects may occur in 5-10% of patients but most often are not sufficient to cause discontinuation of the drug. Gastrointestinal side effects occur in up to 5% of patients. Other side effects are reported infrequently and include rash, urticaria, hair loss, myalgias, fatigue, headache, impotence, and anemia. Minor increases in liver transaminases and alkaline phosphatase have been reported. Clofibrate, bezafibrate, and fenofibrate have been reported to potentiate the action of oral anticoagulants, in part by displacing them from their binding sites on albumin. Careful monitoring of the prothrombin time and reduction in dosage of the anticoagulant may be appropriate when treatment with a fibrate is begun.

A myopathy syndrome occasionally occurs in subjects taking clofibrate, gemfibrozil, or fenofibrate and may occur in up to 5% of patients treated with a combination of gemfibrozil and higher doses of statins. To diminish the risk of myopathy, statin doses should be reduced when combination therapy of a statin plus a fibrate is employed. Several drug interactions may contribute to this adverse response. Gemfibrozil inhibits hepatic uptake of statins by OATP1B1. Gemfibrozil also competes for the same glucuronosyl transferases that metabolize most statins. As a consequence, levels of both drugs may be increased when they are co-administered (Prueksaritanont et al., 2002b; Prueksaritanont et al., 2002c). Patients taking this combination should be instructed to be aware of the potential symptoms and should be followed at 3-month intervals with careful history and determination of CK values until a stable pattern is established. Patients taking fibrates with rosuvastatin should be followed especially closely even if low doses (5-10 mg) of rosuvastatin are employed until there is more experience with and knowledge of the safety of this specific combination. Fenofibrate is glucuronidated by enzymes that are not involved in statin glucuronidation. Thus, fenofibrate-statin combinations are less likely to cause myopathy than combination therapy with gemfibrozil and statins.

All of the fibrates increase the lithogenicity of bile. Clofibrate use has been associated with increased risk of gallstone formation.

Renal failure is a relative contraindication to the use of fibric acid agents, as is hepatic dysfunction. Combined statin-fibrate therapy should be avoided in patients with compromised renal function. Gemfibrozil should be used with caution and at a reduced dosage to treat the hyperlipidemia of renal failure. Fibrates should not be used by children or pregnant women.

Therapeutic Use. Clofibrate is available for oral administration. The usual dose is 2 g/day in divided doses. This compound is little used but may be useful in patients who do not tolerate gemfibrozil or fenofibrate. Gemfibrozil (lopid) usually is administered as a 600-mg dose taken twice a day, 30 minutes before the morning and evening meals. Fenofibrate is available in two different formulations. The first preparation developed is the dimethylethyl ester of fenofibric acid, which is poorly water soluble and poorly absorbed. After uptake by the liver, this compound is hydrolyzed to produce fenofibric acid, which is the active moiety. Recently, a choline salt of fenofibric acid that is highly soluble in water and readily absorbed was developed. The effects of both formulations, however, are similar with respect to changes in plasma lipid concentrations (Grundy et al., 2005; Jones et al., 2009). The dimethylethyl ester preparations of fenofibric acid include TRICOR and LOFIBRA. The tricor brand of fenofibrate is available in tablets of 48 and 145 mg. The usual daily dose is 145 mg. Generic fenofibrate (lofibra) is available in capsules containing 67, 134, and 200 mg. TRICOR, 145 mg, and LOFIBRA, 200 mg, are equivalent doses. The choline salt of fenofibric acid (trilipix) is available in capsules of 135 and 45 mg. TRILIPIX, 135 mg, is equivalent to TRICOR, 145 mg, and LOFIBRA, 200 mg. Choline fenofibrate is indicated for combination therapy with statins (Jones et al., 2009). Fibrates are the drugs of choice for treating hyperlipidemic subjects with type III hyperlipoproteinemia as well as subjects with severe hypertriglyceridemia (triglycerides >1000 mg/dL) who are at risk for pancreatitis. Fibrates appear to have an important role in subjects with high triglycerides and low HDL-C levels associated with the metabolic syndrome or type 2 diabetes mellitus (Robins, 2001). When fibrates are used in such patients, the LDL levels need to be monitored; if LDL levels rise, the addition of a low dose of a statin may be needed. Many experts now treat such patients first with a statin (Heart Protection Study Collaborative Group, 2003) and then add a fibrate, based on the reported benefit of gemfibrozil therapy. However, statin-fibrate combination therapy has not been evaluated in outcome studies (American Diabetes Association, 2004). If this combination is used, there should be careful monitoring for myopathy.

History. Ezetimibe (SCH58235) was developed by pharmaceutical chemists studying inhibition of intestinal ACAT. Several compounds were found to inhibit cholesterol absorption, but by inhibiting intestinal cholesterol transport rather than ACAT.

In wild-type mice, ezetimibe inhibits cholesterol absorption by about 70%; in NPC1L1 knockout mice, cholesterol absorption is 86% lower than in wild-type mice, and ezetimibe has no effect on cholesterol absorption (Altmann et al., 2004). Ezetimibe does not affect intestinal triglyceride absorption. In human subjects, ezetimibe reduced cholesterol absorption by 54%, precipitating a compensatory increase in cholesterol synthesis that can be inhibited with a cholesterol synthesis inhibitor such as a statin (Sudhop et al., 2002). There also is a substantial reduction of plasma levels of plant sterols (campesterol and sitosterol concentrations are reduced by 48% and 41%, respectively), indicating that ezetimibe also inhibits intestinal absorption of plant sterols.

The consequence of inhibiting intestinal cholesterol absorption is a reduction in the incorporation of cholesterol into chylomicrons. The reduced cholesterol content of chylomicrons diminishes the delivery of cholesterol to the liver by chylomicron remnants. The diminished remnant cholesterol content may decrease atherogenesis directly, as chylomicron remnants are very atherogenic lipoproteins. In experimental animal models of remnant dyslipidemia, ezetimibe profoundly diminished diet-induced atherosclerosis (Davis et al., 2001a).

Reduced delivery of intestinal cholesterol to the liver by chylomicron remnants stimulates expression of the hepatic genes regulating LDL receptor expression and cholesterol biosynthesis. The greater expression of hepatic LDL receptors enhances LDL-C clearance from the plasma. Indeed, ezetimibe reduces LDL-C levels by 15-20% (Gagné et al., 2002; Knopp et al., 2003).

Combination Therapy (Ezetimibe plus Statins). The maximal efficacy of ezetimibe for lowering LDL-C is 15-20% when used as monotherapy (Knopp et al., 2003). This reduction is equivalent to, or less than, that attained with 10- to 20-mg doses of most statins. Consequently, the role of ezetimibe as monotherapy of patients with elevated LDL-C levels appears to be limited to the small group of statin-intolerant patients.

The actions of ezetimibe are complementary to those of statins. Statins, which inhibit cholesterol biosynthesis, increase intestinal cholesterol absorption (Miettinen and Gylling, 2003). Ezetimibe, which inhibits intestinal cholesterol absorption, enhances cholesterol biosynthesis by as much as 3.5 times in experimental animals (Davis et al., 2001b). Dual therapy with these two classes of drugs prevents both the enhanced cholesterol synthesis induced by ezetimibe and the increase in cholesterol absorption induced by statins. This combination provides additive reductions in LDL-C levels irrespective of the statin employed (Ballantyne et al., 2004; Ballantyne et al., 2003; Melani et al., 2003).

A combination tablet containing ezetimibe, 10 mg, and various doses of simvastatin (10, 20, 40, and 80 mg) has been approved (vytorin). At the highest simvastatin dose (80 mg), plus ezetimibe (10 mg), average LDL-C reduction was 60%, which is greater than can be attained with any statin as monotherapy (Feldman et al., 2004). Despite the robust laboratory-based efficacy of this combination, the clinical cardiovascular benefits remain controversial when the combination is compared to effects of statins alone (Kastelein et al., 2008; Mitka, 2009).

Absorption, Fate, and Excretion. Ezetimibe is highly water insoluble, precluding studies of its bioavailability. After ingestion, it is glucuronidated in the intestinal epithelium and absorbed and then enters an enterohepatic recirculation (Patrick et al., 2002). Pharmacokinetic studies indicate that about 70% is excreted in the feces and about 10% in the urine (as a glucuronide conjugate) (Patrick et al., 2002). Bile-acid sequestrants inhibit absorption of ezetimibe, and the two agents should not be administered together. Otherwise, no significant drug interactions have been reported.

Adverse Effects and Drug Interactions. Other than rare allergic reactions, specific adverse effects have not been observed in patients taking ezetimibe. The safety of ezetimibe during pregnancy has not been established. With doses of ezetimibe sufficient to increase exposure 10-150 times compared with a 10-mg dose in humans, fetal skeletal abnormalities were noted in rats and rabbits. Since all statins are contraindicated in pregnant and nursing women, combination products containing ezetimibe and a statin should not be used by women in childbearing years in the absence of contraception.

Therapeutic Use. Ezetimibe (zetia) is available as a 10-mg tablet that may be taken at any time during the day, with or without food. Ezetimibe may be taken with any medication other than bile-acid sequestrants, which inhibit its absorption.