Basic & Clinical Pharmacology, 10th Edition

35. Agents Used in Hyperlipidemia - Mary J. Malloy, MD, & John P. Kane, MD, PhD

INTRODUCTION

Plasma lipids are transported in complexes called lipoproteins. Metabolic disorders that involve elevations in any lipoprotein species are termed hyperlipoproteinemias or hyperlipidemias. Hyperlipemia denotes increased levels of triglycerides.

The two major clinical sequelae of hyperlipidemias are acute pancreatitis and atherosclerosis. The former occurs in patients with marked hyperlipemia. Control of triglycerides can prevent recurrent attacks of this life-threatening disease.

Atherosclerosis is the leading cause of death for both genders in the USA and other Western countries. Lipoproteins that contain apolipoprotein (apo) B-100 convey lipids into the artery wall. These are low-density (LDL), intermediate-density (IDL), very-low-density (VLDL), and lipoprotein(a) (Lp[a]).

Cellular components in atherosclerotic plaques include foam cells, which are transformed macrophages and smooth muscle cells filled with cholesteryl esters. These cellular alterations result from endocytosis of modified lipoproteins via at least four species of scavenger receptors. Chemical modification of lipoproteins by free radicals creates ligands for these receptors. The atheroma grows with the accumulation of foam cells, collagen, fibrin, and frequently calcium. Whereas such lesions can slowly occlude coronary vessels, clinical symptoms are more frequently precipitated by rupture of unstable atheromatous plaques, leading to activation of platelets and formation of occlusive thrombi.

Although treatment of hyperlipidemia can cause slow physical regression of plaques, the well-documented reduction in acute coronary events that follows vigorous lipid-lowering treatment is attributable chiefly to mitigation of the inflammatory activity of macrophages and is evident within 2-3 months after starting therapy.

High-density lipoproteins (HDL) exert several anti atherogenic effects. They participate in retrieval of cholesterol from the artery wall and inhibit the oxidation of atherogenic lipoproteins. Low levels of HDL (hypoalphalipoproteinemia) are an independent risk factor for atherosclerotic disease and thus are a target for intervention.

Acronyms

Apo Apolipoprotein

CETP Cholesteryl ester transfer protein

CK Creatine kinase

HDL High-density lipoproteins

HMG-CoA 3-Hydroxy-3-methylglutaryl-coenzyme A

IDL Intermediate-density lipoproteins

LCAT Lecithin:cholesterol acyltransferase

LDL Low-density lipoproteins

Lp(a) Lipoprotein(a)

LPL Lipoprotein lipase

PPAR-a Peroxisome proliferator-activated receptor-alpha

VLDL Very-low-density lipoproteins

Cigarette smoking is a major risk factor for coronary disease. It is associated with reduced levels of HDL, impairment of cholesterol retrieval, cytotoxic effects on the endothelium, increased oxidation of lipoproteins, and stimulation of thrombogenesis. Diabetes, also a major risk factor, is another source of oxidative stress.

Normal coronary arteries can dilate in response to ischemia, increasing delivery of oxygen to the myocardium. This process is mediated by nitric oxide, acting upon smooth muscle cells of the arterial media. This function is impaired by atherogenic lipoproteins, thus aggravating ischemia. Reducing levels of atherogenic lipoproteins and inhibiting their oxidation restores endothelial function.

Because atherogenesis is multifactorial, therapy should be directed toward all modifiable risk factors. Atherogenesis is a dynamic process. Quantitative angiographic trials have demonstrated net regression of plaques during aggressive lipid-lowering therapy. Primary and secondary prevention trials have shown significant reduction in mortality from new coronary events and in all-cause mortality.

PATHOPHYSIOLOGY OF HYPERLIPOPROTEINEMIA

NORMAL LIPOPROTEIN METABOLISM

Structure

Lipoproteins have hydrophobic core regions containing cholesteryl esters and triglycerides surrounded by unesterified cholesterol, phospholipids, and apoproteins. Certain lipoproteins contain very high-molecular-weight B proteins that exist in two forms: B-48, formed in the intestine and found in chylomicrons and their remnants; and B-100, synthesized in liver and found in VLDL, VLDL remnants (IDL), LDL (formed from VLDL), and Lp(a) lipoproteins.

Synthesis & Catabolism

A. CHYLOMICRONS
Chylomicrons are formed in the intestine and carry triglycerides of dietary origin, unesterified cholesterol, and cholesteryl esters. They transit the thoracic duct to the bloodstream.

Triglycerides are removed in extrahepatic tissues through a pathway shared with VLDL that involves hydrolysis by the lipoprotein lipase (LPL) system. Decrease in particle diameter occurs as triglycerides are depleted. Surface lipids and small apoproteins are transferred to HDL. The resultant chylomicron remnants are taken up by receptor-mediated endocytosis into hepatocytes.

B. VERY-LOW-DENSITY LIPOPROTEINS
VLDL are secreted by liver and export triglycerides to peripheral tissues (Figure 35-1). VLDL triglycerides are hydrolyzed by LPL, yielding free fatty acids for storage in adipose tissue and for oxidation in tissues such as cardiac and skeletal muscle. Depletion of triglycerides produces remnants (IDL), some of which undergo endocytosis directly by liver. The remainder is converted to LDL by further removal of triglycerides mediated by hepatic lipase. This process explains the "beta shift" phenomenon, the increase of LDL (beta-lipoprotein) in serum as hypertriglyceridemia subsides. Increased levels of LDL can also result from increased secretion of VLDL and from decreased LDL catabolism.

C. LOW-DENSITY LIPOPROTEINS
LDL is catabolized chiefly in hepatocytes and other cells by receptor-mediated endocytosis. Cholesteryl esters from LDL are hydrolyzed, yielding free cholesterol for the synthesis of cell membranes. Cells also obtain cholesterol by synthesis via a pathway involving the formation of mevalonic acid by HMG-CoA reductase. Production of this enzyme and of LDL receptors is transcriptionally regulated by the content of cholesterol in the cell. Normally, about 70% of LDL is removed from plasma by hepatocytes. Even more cholesterol is delivered to the liver via IDL and chylomicrons. Unlike other cells, hepatocytes can eliminate cholesterol by secretion in bile and by conversion to bile acids.

D. LP(A) LIPOPROTEIN
Lp(a) lipoprotein is formed from LDL and the (a) protein, linked by a disulfide bridge. The (a) protein is highly homologous with plasminogen but is not activated by tissue plasminogen activator. It occurs in a number of isoforms of different molecular weights. Levels of Lp(a) vary from nil to over 500 mg/dL and are determined chiefly by genetic factors. Lp(a) can be found in atherosclerotic plaques and may also contribute to coronary disease by inhibiting thrombolysis. Levels are elevated in nephrosis.

E. HIGH-DENSITY LIPOPROTEINS
The apoproteins of HDL are secreted by the liver and intestine. Much of the lipid comes from the surface monolayers of chylomicrons and VLDL during lipolysis. HDL also acquires cholesterol from peripheral tissues, protecting the cholesterol homeostasis of cells. Free cholesterol is transported from the cell membrane by a transporter, ABCA1, acquired by a small particle termed prebeta-1 HDL, and then esterified by lecithin: cholesterol acyltransferase (LCAT), leading to the formation of larger HDL species. Cholesterol is also exported from macrophages by the ABCG1 transporter to large HDL particles. The cholesteryl esters are transferred to VLDL, IDL, LDL, and chylomicron remnants with the aid of cholesteryl ester transfer protein (CETP). Much of the cholesteryl ester thus transferred is ultimately delivered to the liver by endocytosis of the acceptor lipoproteins. HDL can also deliver cholesteryl esters directly to the liver via a docking receptor (scavenger receptor, SR-BI) that does not cause endocytosis of the lipoproteins.

LIPOPROTEIN DISORDERS

INTRODUCTION

Lipoprotein disorders are detected by measuring lipids in serum after a 10-hour fast. Risk of heart disease increases with concentrations of the atherogenic lipoproteins, is inversely related to levels of HDL, and is modified by other risk factors (Table 35-1). Evidence from clinical trials suggests that LDL cholesterol levels of 60mg/dL may be optimal for patients with coronary disease. Ideally, triglycerides should be below 120 mg/dL. Differentiation of the disorders requires identification of the lipoproteins involved (Table 35-2). Diagnosis of a primary disorder usually requires further clinical and genetic data as well as ruling out secondary hyperlipidemias (Table 35-3).

Phenotypes of abnormal lipoprotein distribution are described in this section. Drugs mentioned for use in these conditions are described in the following section on basic and clinical pharmacology.

THE PRIMARY HYPERTRIGLYCERIDEMIAS

Introduction

Hypertriglyceridemia is associated with increased risk of coronary disease. VLDL and IDL have been found in atherosclerotic plaques. These patients tend to have cholesterol-rich VLDL of small particle diameter. Hypertriglyceridemic patients with coronary disease or risk equivalents should be treated aggressively. Patients with triglycerides above 700 mg/dL should be treated to prevent acute pancreatitis because the LPL clearance mechanism is saturated at about this level.

Primary Chylomicronemia

Chylomicrons are not present in the serum of normal individuals who have fasted 10 hours. The recessive traits of deficiency of lipoprotein lipase or its cofactor are usually associated with severe lipemia (2000-2500 mg/dL of triglycerides when the patient is consuming a typical American diet). These disorders might not be diagnosed until an attack of acute pancreatitis occurs. Patients may have eruptive xanthomas, hepatosplenomegaly, hypersplenism, and lipid-laden foam cells in bone marrow, liver, and spleen. The lipemia is aggravated by estrogens because they stimulate VLDL production, and pregnancy may cause marked increases in triglycerides despite strict dietary control. Although these patients have a predominant chylomicronemia, they may also have moderately elevated VLDL, presenting with a pattern called mixed lipemia (fasting chylomicronemia and elevated VLDL). LPL deficiency is diagnosed by assay of lipolytic activity after intravenous injection of heparin. A presumptive diagnosis is made by demonstrating a pronounced decrease in triglycerides a few days after reduction of daily fat intake below 15 g. Marked restriction of total dietary fat is the basis of effective long-term treatment. Niacin or a fibrate may be of some benefit if VLDL levels are increased.

Familial Hypertriglyceridemia

A. SEVERE (USUALLY MIXED LIPEMIA)
Mixed lipemia usually results from impaired removal of triglyceride-rich lipoproteins. Factors that increase VLDL production aggravate the lipemia because VLDL and chylomicrons are competing substrates for LPL. The primary mixed lipemias probably reflect a variety of genetic determinants. Most patients have centripetal obesity with insulin resistance. Other factors that increase secretion of VLDL also worsen the lipemia. Eruptive xanthomas, lipemia retinalis, epigastric pain, and pancreatitis are variably present depending on the severity of the lipemia. Treatment is primarily dietary, with restriction of total fat, avoidance of alcohol and exogenous estrogens, weight reduction, and exercise. Most patients also require treatment with a fibrate or niacin.

B. MODERATE
Primary increases of VLDL also reflect a genetic predisposition and are worsened by factors that increase the rate of VLDL secretion from liver, ie, obesity, alcohol, diabetes, and estrogens. Treatment includes addressing these issues and the use of fibrates or niacin as needed. Marine omega-3 fatty acids are a valuable adjuvant.

Familial Combined Hyperlipoproteinemia

In this common disorder associated with an increased incidence of coronary disease, individuals may have elevated levels of VLDL, LDL, or both, and the pattern may change with time. Familial combined hyperlipoproteinemia involves an approximate doubling in VLDL secretion and appears to be transmitted as a semidominant trait. Triglycerides can be increased by the factors noted above. Elevations of cholesterol and triglycerides are generally moderate, and xanthomas are usually absent. Diet alone does not normalize lipid levels. A reductase inhibitor alone, or in combination with niacin or fenofibrate, is usually required to treat these patients. When fenofibrate is combined with a reductase inhibitor, pravastatin or rosuvastatin are recommended because they are not metabolized via CYP3A4.

Familial Dysbetalipoproteinemia

In this disorder, remnants of chylomicrons and VLDL accumulate and levels of LDL are decreased. Because remnants are rich in cholesteryl esters, the level of cholesterol may be as high as that of triglycerides. Diagnosis is confirmed by the absence of the E3 and E4 iso-forms of apo E or the E2/E2 genotype. Patients often develop tuberous or tuberoeruptive xanthomas, or characteristic planar xanthomas of the palmar creases. They tend to be obese, and some have impaired glucose tolerance. These factors, as well as hypothyroidism, can aggravate the lipemia. Coronary and peripheral atherosclerosis occur with increased frequency. Weight loss, together with decreased fat, cholesterol, and alcohol consumption, may be sufficient, but a fibrate or niacin is usually needed to control the condition. These agents can be given together in more resistant cases, or a reductase inhibitor may be added.

THE PRIMARY HYPERCHOLESTEROLEMIAS

Familial Hypercholesterolemia

Familial hypercholesterolemia is an autosomal dominant trait. Although levels of LDL tend to increase throughout childhood, the diagnosis can often be made on the basis of elevated umbilical cord blood cholesterol. In most heterozygotes, cholesterol levels range from 260 to 500 mg/dL. Triglycerides are usually normal, tendon xanthomas are often present, and arcus corneae and xanthelasma may appear in the third decade. Coronary disease tends to occur prematurely. In homozygous familial hypercholesterolemia, which can lead to coronary disease in childhood, levels of cholesterol often exceed 1000 mg/dL and early tuberous and tendinous xanthomas occur. These patients may also develop elevated plaque-like xanthomas of the aortic valve, digital webs, buttocks, and extremities.

Defects of LDL receptors underlie familial hypercholesterolemia. Some individuals have combined heterozygosity for alleles producing nonfunctional and kinetically impaired receptors. In heterozygous patients, LDL can be normalized with combined drug regimens (Figure 35-2). Homozygotes and those with combined heterozygosity whose receptors retain even minimal function may partially respond to niacin, ezetimibe, or reductase inhibitors.

Familial Ligand-Defective Apolipoprotein B

Defects in the domain of apo B-100 that binds to the LDL receptor impair the endocytosis of LDL, leading to hypercholesterolemia of moderate severity. Tendon xanthomas may occur. These disorders are as prevalent as familial hypercholesterolemia. Response to reductase inhibitors is variable. Up-regulation of LDL receptors in liver increases endocytosis of LDL precursors but does not increase uptake of ligand-defective LDL particles. Niacin often has beneficial effects by reducing VLDL production.

Familial Combined Hyperlipoproteinemia

As described above, some persons with this disorder have only an elevation in LDL. Serum cholesterol is usually less than 350 mg/dL. Dietary and drug treatment, usually with a reductase inhibitor, is indicated. It may be necessary to add niacin or fenofibrate to normalize LDL or to reduce triglycerides.

Lp(a) Hyperlipoproteinemia

This familial disorder, which is associated with increased atherogenesis, is determined chiefly by alleles that dictate increased production of the (a) protein moiety. Niacin reduces levels of Lp(a) in many patients.

Other Disorders

Deficiency of cholesterol 7a-hydroxylase can increase LDL in the heterozygous state. Homozygotes can also have elevated triglycerides, resistance to reductase inhibitors, and increased risk of gallstones. Autosomal recessive hypercholesterolemia is due to mutations in a protein that normally assists in endocytosis of LDL. Mutations in the PCSK9 gene also cause isolated elevations of LDL. Niacin, ezetimibe, and reductase inhibitors may be useful, variably, in these disorders.

HDL Deficiency

Rare genetic disorders, including Tangier disease and LCAT deficiency, are associated with extremely low levels of HDL. Familial hypoalphalipoproteinemia is a more common disorder with levels of HDL cholesterol usually below 35 mg/dL in men and 45 mg/dL in women. These patients tend to have premature atherosclerosis, and the low HDL may be the only identified risk factor. Management should include special attention to avoidance or treatment of other risk factors. Niacin increases HDL in many of these patients. Reductase inhibitors and fibric acid derivatives exert lesser effects.

In the presence of hypertriglyceridemia, HDL cholesterol is low because of exchange of cholesteryl esters from HDL into triglyceride-rich lipoproteins. Treatment of the hypertriglyceridemia may increase or normalize the HDL level.

SECONDARY HYPERLIPOPROTEINEMIA

Before primary disorders can be diagnosed, secondary causes of the phenotype must be considered. The more common conditions are summarized in Table 35-3. The lipoprotein abnormality usually resolves if the underlying disorder can be treated successfully.

DIETARY MANAGEMENT OF HYPERLIPOPROTEINEMIA

Dietary measures are initiated first¾unless the patient has evident coronary or peripheral vascular disease¾and may obviate the need for drugs. Patients with familial hypercholesterolemia or familial combined hyperlipidemia will always require drug therapy. Cholesterol and saturated and trans fats are the principal factors that increase LDL, whereas total fat, alcohol, and excess calories increase triglycerides.

Sucrose and other simple sugars raise VLDL in hypertriglyceridemic patients. Alcohol can cause significant hypertriglyceridemia by increasing hepatic secretion of VLDL. Synthesis and secretion of VLDL are increased by excess calories. During weight loss, LDL and VLDL levels may be much lower than can be maintained during neutral caloric balance. The conclusion that diet suffices for management can only be made after weight has stabilized for at least 1 month.

General recommendations include limiting total calories from fat to 20-25% of daily intake, saturated fats to less than 8%; and cholesterol to less than 200 mg/d. Reductions in serum cholesterol range from 10% to 20% on this regimen. Use of complex carbohydrates and fiber is recommended, and cis-monounsaturated fats should predominate. Weight reduction, caloric restriction, and avoidance of alcohol are especially important for patients with elevated VLDL and IDL.

The effect of dietary fats on hypertriglyceridemia is dependent upon the disposition of double bonds in the fatty acids. Omega-3 fatty acids found in fish oils, but not those from plant sources, can induce profound reduction of triglycerides in some patients with endogenous or mixed lipemia. In contrast, the omega-6 fatty acids present in vegetable oils may cause triglycerides to increase.

Patients with primary chylomicronemia and some with mixed lipemia must consume a diet severely restricted in total fat (10-15 g/d, of which 5 g should be vegetable oils rich in essential fatty acids), and fat-soluble vitamins should be given.

Homocysteine, which initiates proatherogenic changes in endothelium, can be reduced in many patients by restriction of total protein intake to the amount required for amino acid replacement. Supplementation with up to 2 mg of folic acid plus other B vitamins is also recommended.

BASIC & CLINICAL PHARMACOLOGY OF DRUGS USED IN HYPERLIPIDEMIA

INTRODUCTION

The decision to use drug therapy is based on the specific metabolic defect and its potential for causing atherosclerosis or pancreatitis. Suggested regimens for the principal lipoprotein disorders are presented in Table 35-2. Diet should be continued to achieve the full potential of the drug regimen. Drugs should be avoided in pregnant and lactating women and those likely to become pregnant. All drugs that alter plasma lipoprotein concentrations may require adjustment of doses of warfarin and indandione anticoagulants. Children with heterozygous familial hypercholesterolemia may be treated with a resin or reductase inhibitor, usually after 7 or 8 years of age, when myelination of the central nervous system is essentially complete. The decision to treat a child should be based on the level of LDL, other risk factors, the family history, and the child's age. Drugs are rarely indicated before age 16.

COMPETITIVE INHIBITORS OF HMG-COA REDUCTASE (REDUCTASE INHIBITORS; "STATINS")

Introduction

These compounds are structural analogs of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A, Figure 35-3). Lovastatin, atorvastatin, fluvastatin, pravastatin, simvastatin, and rosuvastatin belong to this class. They are most effective in reducing LDL. Other effects include decreased oxidative stress and vascular inflammation with increased stability of atherosclerotic lesions. It has become standard practice to initiate reductase inhibitor therapy immediately after acute coronary syndromes, irrespective of lipid levels.

Chemistry & Pharmacokinetics

Lovastatin and simvastatin are inactive lactone prodrugs that are hydrolyzed in the gastrointestinal tract to the active b-hydroxyl derivatives, whereas pravastatin has an open, active lactone ring. Atorvastatin, fluvastatin, and rosuvastatin are fluorine-containing congeners that are active as given. Absorption of the ingested doses of the reductase inhibitors varies from 40% to 75% with the exception of fluvastatin, which is almost completely absorbed. All have high first-pass extraction by the liver. Most of the absorbed dose is excreted in the bile; 5-20% is excreted in the urine. Plasma half-lives of these drugs range from 1 hour to 3 hours except for atorvastatin, which has a half-life of 14 hours, and rosuvastatin, 19 hours.

Mechanism of Action

HMG-CoA reductase mediates the first committed step in sterol biosynthesis. The active forms of the reductase inhibitors are structural analogs of the HMG-CoA intermediate (Figure 35-3) that is formed by HMG-CoA reductase in the synthesis of mevalonate. These analogs cause partial inhibition of the enzyme and thus may impair the synthesis of isoprenoids such as ubiquinone and dolichol and the prenylation of proteins. It is not known whether this has biologic significance. However, the reductase inhibitors clearly induce an increase in high-affinity LDL receptors. This effect increases both the fractional catabolic rate of LDL and the liver's extraction of LDL precursors (VLDL remnants) from the blood, thus reducing LDL (Figure 35-2). Because of marked first-pass hepatic extraction, the major effect is on liver. Preferential activity in liver of some congeners appears to be attributable to tissue-specific differences in uptake. Modest decreases in plasma triglycerides and small increases in HDL also occur.

Therapeutic Uses & Dosage

Reductase inhibitors are useful alone or with resins, niacin, or ezetimibe in reducing levels of LDL. Women who are pregnant, lactating, or likely to become pregnant should not be given these agents. Use in children is restricted to those with homozygous familial hypercholesterolemia and selected patients with heterozygous familial hypercholesterolemia.

Because cholesterol synthesis occurs predominantly at night, reductase inhibitors¾except atorvastatin and rosuvastatin¾should be given in the evening if a single daily dose is used. Absorption generally (with the exception of pravastatin) is enhanced by food. Daily doses of lovastatin vary from 10 mg to 80 mg. Pravastatin is nearly as potent on a mass basis as lovastatin up to the maximum recommended daily dose, 80 mg. Simvastatin is twice as potent and is given in doses of 5-80 mg daily. Fluvastatin appears to be about half as potent as lovastatin on a mass basis and is given in doses of 10-80 mg daily. Atorvastatin is given in doses of 10-80 mg/d, and rosuvastatin, the most efficacious agent for severe hypercholesterolemia, at 5-40 mg/d. The dose-response curves of pravastatin and especially of fluvastatin tend to level off in the upper part of the dosage range in patients with moderate to severe hypercholesterolemia. Those of lovastatin, simvastatin, and atorvastatin are somewhat more linear.

Toxicity

Elevations of serum aminotransferase activity (up to three times normal) occur in some patients. This is often intermittent and usually not associated with other evidence of hepatic toxicity. Therapy may be continued in such patients in the absence of symptoms if aminotransferase levels are monitored and stable. In some patients, who may have underlying liver disease or a history of alcohol abuse, levels may exceed three times normal. This finding portends more severe hepatic toxicity. These patients may present with malaise, anorexia, and precipitous decreases in LDL. Medication should be discontinued immediately in these patients and in asymptomatic patients whose aminotransferase activity is persistently elevated to more than three times the upper limit of normal. These agents should be used with caution and in reduced dosage in patients with hepatic parenchymal disease, Asians, and the elderly. In general, aminotransferase activity should be measured at baseline, at 1-2 months, and then every 6-12 months (if stable).

Minor increases in creatine kinase (CK) activity in plasma are observed in some patients receiving reductase inhibitors, frequently associated with heavy physical activity. Rarely, patients may have marked elevations in CK activity, often accompanied by generalized discomfort or weakness in skeletal muscles. If the drug is not discontinued, rhabdomyolysis may cause myoglobinuria, leading to renal injury. Myopathy may occur with monotherapy, but there is an increased incidence in patients receiving certain other drugs.

The catabolism of lovastatin, simvastatin, and atorvastatin proceeds chiefly through CYP3A4, whereas that of fluvastatin and rosuvastatin is mediated by CYP2C9. Pravastatin is catabolized through other pathways, including sulfation. The 3A4-dependent reductase inhibitors tend to accumulate in plasma in the presence of drugs that inhibit or compete for the 3A4 cytochrome. These include the macrolide antibiotics, cyclosporine, ketoconazole and its congeners, HIV protease inhibitors, tacrolimus, nefazodone, fibrates, and others (see Chapter 4). Concomitant use of reductase inhibitors with amiodarone or verapamil also causes an increased risk of myopathy. Conversely, drugs such as phenytoin, griseofulvin, barbiturates, rifampin, and thiazolidinediones increase expression of CYP3A4 and can reduce the plasma concentrations of the 3A4-dependent reductase inhibitors. Inhibitors of CYP2C9 such as ketoconazole and its congeners, metronidazole, sulfinpyrazone, amiodarone, and cimetidine may increase plasma levels of fluvastatin and rosuvastatin. Pravastatin appears to be the drug of choice for use with verapamil, the ketoconazole group of antifungal agents, macrolides, and cyclosporine. Plasma levels of lovastatin, simvastatin, and atorvastatin may be elevated in patients ingesting more than 1 liter of grapefruit juice daily.

Creatine kinase activity should be measured in patients receiving potentially interacting drug combinations. In all patients, CK should be measured at baseline. If muscle pain, tenderness, or weakness appears, CK should be measured immediately and the drug discontinued if activity is elevated significantly over baseline. The myopathy usually reverses promptly upon cessation of therapy. If the association is unclear, the patient can be rechallenged under close surveillance. Myopathy in the absence of elevated CK has been reported. Rarely, hypersensitivity syndromes have been reported that include a lupus-like disorder and peripheral neuropathy.

These drugs should be temporarily discontinued in the event of serious illness, trauma, or major surgery.

NIACIN (NICOTINIC ACID)

Introduction

Niacin (but not niacinamide) decreases VLDL and LDL levels, and Lp(a) in most patients. It often increases HDL levels significantly.

Chemistry & Pharmacokinetics

Niacin (vitamin B₃) is converted in the body to the amide, which is incorporated into niacinamide adenine dinucleotide (NAD). It is excreted in the urine unmodified and as several metabolites.

Mechanism of Action

Niacin inhibits VLDL secretion, in turn decreasing production of LDL (Figure 35-2). Increased clearance of VLDL via the LPL pathway contributes to reduction of triglycerides. Niacin has no effect on bile acid production. Excretion of neutral sterols in the stool is increased acutely as cholesterol is mobilized from tissue pools and a new steady state is reached. The catabolic rate for HDL is decreased. Fibrinogen levels are reduced, and levels of tissue plasminogen activator appear to increase. Niacin inhibits the intracellular lipase of adipose tissue via receptor-mediated signaling, possibly reducing VLDL production by decreasing the flux of free fatty acids to the liver. Sustained inhibition of lipolysis has not been established, however.

Therapeutic Uses & Dosage

In combination with a resin or reductase inhibitor, niacin normalizes LDL in most patients with heterozygous familial hypercholesterolemia and other forms of hypercholesterolemia. These combinations are also indicated in some cases of nephrosis. In severe mixed lipemia that is incompletely responsive to diet, niacin often produces marked reduction of triglycerides, an effect enhanced by marine omega-3 fatty acids. It is useful in patients with combined hyperlipidemia and in those with dysbetalipoproteinemia. It is clearly the most effective agent for increasing HDL and the only agent that may reduce Lp(a).

For treatment of heterozygous familial hypercholesterolemia, most patients require 2-6 g of niacin daily; more than this should not be given. For other types of hypercholesterolemia and for hypertriglyceridemia, 1.5-3.5 g daily is often sufficient. Crystalline niacin should be given in divided doses with meals, starting with 100 mg two or three times daily and increasing gradually.

Toxicity

Most persons experience a harmless cutaneous vasodilation and sensation of warmth after each dose when the drug is started or the dose increased. Taking 81-325 mg of aspirin one half hour beforehand blunts this prostaglandin-mediated effect. Ibuprofen, once daily, also mitigates the flush. Tachyphylaxis to flushing usually occurs within a few days at doses above 1.5-3 g daily. Patients should be warned to expect the flush and understand that it is a harmless side effect. Pruritus, rashes, dry skin or mucous membranes, and acanthosis nigricans have been reported. The latter contraindicates use of niacin because of its association with insulin resistance. Some patients experience nausea and abdominal discomfort. Many can continue the drug at reduced dosage, with inhibitors of gastric acid secretion, or use of antacids not containing aluminum. Niacin should be avoided in most patients with severe peptic disease.

Reversible elevations in aminotransferases up to twice normal may occur, usually not associated with liver toxicity. However, liver function should be monitored at baseline and at appropriate intervals. Rarely, true hepatotoxicity may occur, and in these cases the drug should be discontinued. The association of severe hepatic dysfunction, including acute necrosis, with the use of over-the-counter sustained-release preparations of niacin has been reported. This effect has not been noted to date with one preparation, Niaspan, given at bedtime in doses of 2 g or less. Carbohydrate tolerance may be moderately impaired, but this is usually reversible except in some patients with latent diabetes. Niacin may be given to diabetics who are receiving insulin and to some receiving oral agents if insulin resistance is not increased. Hyperuricemia occurs in some patients and occasionally precipitates gout. Allopurinol can be given with niacin if needed. Rarely, niacin is associated with arrhythmias, mostly atrial, and a reversible toxic amblyopia. Patients should be instructed to report blurring of distance vision. Niacin may potentiate the action of antihypertensive agents, requiring adjustment of their dosages. Birth defects have been reported in animals given very high dosages.

FIBRIC ACID DERIVATIVES (FIBRATES)

Introduction

Gemfibrozil and fenofibrate decrease levels of VLDL and, in some patients, LDL as well. Another fibrate, bezafibrate, is not yet available in the USA.

Chemistry & Pharmacokinetics

Gemfibrozil is absorbed quantitatively from the intestine and is tightly bound to plasma proteins. It undergoes enterohepatic circulation and readily passes the placenta. The plasma half-life is 1.5 hours. Seventy percent is eliminated through the kidneys, mostly unmodified. The liver modifies some of the drug to hydroxymethyl, carboxyl, or quinol derivatives. Fenofibrate is a methylethyl ester that is hydrolyzed completely in the intestine. Its plasma half-life is 20 hours. Sixty percent is excreted in the urine as the glucuronide, and about 25% in feces.



Mechanism of Action

These agents function primarily as ligands for the nuclear transcription receptor, peroxisome proliferator-activated receptor-alpha (PPAR-a). They increase lipolysis of lipoprotein triglyceride via LPL. Intracellular lipolysis in adipose tissue is decreased. Levels of VLDL decrease, in part as a result of decreased secretion by the liver. Only modest reductions of LDL occur in most patients. In others, especially those with combined hyperlipidemia, LDL often increases as triglycerides are reduced. HDL cholesterol increases moderately. Part of this apparent increase is a consequence of decreasing triglycerides in plasma, with reduction in exchange of triglycerides into HDL in place of cholesteryl esters. Some increase in HDL protein has been reported.

Therapeutic Uses & Dosage

These drugs are useful in hypertriglyceridemias in which VLDL predominate and in dysbetalipoproteinemia. They also may be of benefit in treating the hyper-triglyceridemia that results from treatment with viral protease inhibitors. The usual dose of gemfibrozil is 600 mg orally once or twice daily. The dosage of fenofibrate (as Tricor) is one to three 48 mg tablets (or a single 145 mg tablet) daily. Absorption of gemfibrozil is improved when the drug is taken with food.

Toxicity

Rare adverse effects include rashes, gastrointestinal symptoms, myopathy, arrhythmias, hypokalemia, and high blood levels of aminotransferases or alkaline phosphatase. A few patients show decreases in white blood count or hematocrit. Both agents potentiate the action of coumarin and indanedione anticoagulants, and doses of these agents should be adjusted. Rhabdomyolysis has occurred rarely. Risk of myopathy increases when fibrates are given with reductase inhibitors. The use of fenofibrate with rosuvastatin appears to minimize this risk. Fibrates should be avoided in patients with hepatic or renal dysfunction. There appears to be a modest increase in the risk of cholesterol gallstones, reflecting an increase in the cholesterol content of bile. Therefore, fibrates should be used with caution in patients with biliary tract disease or in those at high risk such as women, obese patients, and Native Americans.

BILE ACID-BINDING RESINS

Introduction

Colestipol, cholestyramine, and colesevelam are useful only for isolated increases in LDL. In patients who also have hypertriglyceridemia, VLDL levels may be further increased during treatment with resins.

Chemistry & Pharmacokinetics

These agents are large polymeric cationic exchange resins that are insoluble in water. They bind bile acids in the intestinal lumen and prevent their reabsorption. The resin itself is not absorbed.

Mechanism of Action

The bile acids, metabolites of cholesterol, are normally efficiently reabsorbed in the jejunum and ileum (Figure 35-2). Excretion is increased up to tenfold when resins are given, resulting in enhanced conversion of cholesterol to bile acids in liver via 7a-hydroxylation, which is normally controlled by negative feedback by bile acids. Increased uptake of LDL and IDL from plasma results from up-regulation of LDL receptors, particularly in liver. Therefore, the resins are without effect in patients with homozygous familial hypercholesterolemia who have no functioning receptors but may be useful in patients with receptor-defective combined heterozygous states.

Therapeutic Uses & Dosage

The resins are used in treatment of patients with primary hypercholesterolemia, producing approximately 20% reduction in LDL cholesterol in maximal dosage. If resins are used to treat LDL elevations in persons with combined hyperlipidemia, they may cause an increase in VLDL requiring the addition of a second agent such as niacin. Resins are also used in combination with other drugs to achieve further hypocholesterolemic effect (see below). They may be helpful in relieving pruritus in patients who have cholestasis and bile salt accumulation. Because the resins bind digitalis glycosides, they may be useful in digitalis toxicity.

Colestipol and cholestyramine are available as granular preparations. A gradual increase of dosage of granules from 4 or 5 g/d to 20 g/d is recommended. Total dosages of 30-32 g/d may be needed for maximum effect. The usual dosage for a child is 10-20 g/d. Granular resins are mixed with juice or water and allowed to hydrate for 1 minute. Colestipol is also available in 1 g tablets that must be swallowed whole, with a maximum dose of 16 g daily. Colesevelam is available in 625 mg tablets. The maximum dose is six tablets daily. Resins should be taken in two or three doses with meals. They lack effect when taken between meals.

Toxicity

Common complaints are constipation and bloating, usually relieved by increasing dietary fiber or mixing psyllium seed with the resin. Resins should be avoided in patients with diverticulitis. Heartburn and diarrhea are occasionally reported. In patients who have preexisting bowel disease or cholestasis, steatorrhea may occur. Malabsorption of vitamin K occurs rarely, leading to hypoprothrombinemia. Prothrombin time should be measured frequently in patients who are taking resins and anticoagulants. Malabsorption of folic acid has been reported rarely. Increased formation of gallstones, particularly in obese persons, was an anticipated adverse effect but has rarely occurred in practice.

Absorption of certain drugs, including those with neutral or cationic charge as well as anions, may be impaired by the resins. These include digitalis glycosides, thiazides, warfarin, tetracycline, thyroxine, iron salts, pravastatin, fluvastatin, folic acid, phenylbutazone, aspirin, and ascorbic acid. Any additional medication (except niacin) should be given 1 hour before or at least 2 hours after the resin to ensure adequate absorption. Colesevelam does not bind digoxin, warfarin, or reductase inhibitors.

INHIBITORS OF INTESTINAL STEROL ABSORPTION

Introduction

Ezetimibe is the first member of a group of drugs that inhibit intestinal absorption of phytosterols and cholesterol. Its primary clinical effect is reduction of LDL levels.

Chemistry & Pharmacokinetics

Ezetimibe is readily absorbed and conjugated in the intestine to an active glucuronide, reaching peak blood levels in 12-14 hours. It undergoes enterohepatic circulation and its half-life is 22 hours. Approximately 80% of the drug is excreted in feces. Plasma concentrations are substantially increased when it is administered with fibrates and reduced when it is given with cholestyramine. Other resins may also decrease its absorption. There are no significant interactions with warfarin or digoxin.



Mechanism of Action

Ezetimibe is a selective inhibitor of intestinal absorption of cholesterol and phytosterols. A transport protein, NPC1L1, appears to be the target of the drug. It is effective even in the absence of dietary cholesterol because it inhibits reabsorption of cholesterol excreted in the bile.

Therapeutic Uses & Dosage

The effect on cholesterol absorption is constant over the dosage range of 5-20 mg/d. Therefore, a single daily dose of 10 mg is used. Average reduction in LDL cholesterol with ezetimibe alone in patients with primary hypercholesterolemia is about 18%, with minimal increases in HDL cholesterol. It is also effective in patients with phytosterolemia. Ezetimibe is synergistic with reductase inhibitors, producing decrements as great as 25% in LDL cholesterol beyond that achieved with the reductase inhibitor alone.

Toxicity

Ezetimibe does not appear to be a substrate for cytochrome P450 enzymes. Experience to date reveals a low incidence of reversible impaired hepatic function with a small increase in incidence when given with a reductase inhibitor. Myositis has been reported rarely.

TREATMENT WITH DRUG COMBINATIONS

INTRODUCTION

Combined drug therapy is useful (1) when VLDL levels are significantly increased during treatment of hypercholesterolemia with a resin; (2) when LDL and VLDL levels are both elevated initially; (3) when LDL or VLDL levels are not normalized with a single agent, or (4) when an elevated level of Lp(a) or an HDL deficiency coexists with other hyperlipidemias.

1. Fibric Acid Derivatives & Bile Acid-Binding Resins

This combination is sometimes useful in treating patients with familial combined hyperlipidemia who are intolerant of niacin or statins. However, it may increase the risk of cholelithiasis.

2. HMG-CoA Reductase Inhibitors & Bile Acid-Binding Resins

This synergistic combination is useful in the treatment of familial hypercholesterolemia but may not control levels of VLDL in some patients with familial combined hyperlipoproteinemia. Statins should be given at least 1 hour before or 4 hours after the resin to ensure their absorption.

3. Niacin & Bile Acid-Binding Resins

This combination effectively controls VLDL levels during resin therapy of familial combined hyperlipoproteinemia or other disorders involving both increased VLDL and LDL levels. When VLDL and LDL levels are both initially increased, doses of niacin as low as 1-3 g/d may be sufficient in combination with a resin. The niacin-resin combination is effective for treating heterozygous familial hypercholesterolemia.

The drugs may be taken together, because niacin does not bind to the resins. LDL levels in patients with heterozygous familial hypercholesterolemia require daily doses of up to 6 g of niacin with 24-30 g of resin.

4. Niacin & Reductase Inhibitors

This regimen is more effective than either agent alone in treating hypercholesterolemia. Experience indicates that it is an efficacious and practical combination for treatment of familial combined hyperlipoproteinemia.

5. Reductase Inhibitors & Ezetimibe

This combination is highly synergistic in treating primary hypercholesterolemia and has some use in the treatment of patients with homozygous familial hypercholesterolemia who have some receptor function.

6. Reductase Inhibitors & Fibrates

Fenofibrate appears to be complementary with rosuvastatin or pravastatin in the treatment of familial combined hyperlipoproteinemia and other conditions involving elevations of both LDL and VLDL. The combination of fenofibrate with rosuvastatin is particularly effective. Other statins may interact unfavorably due to effects on cytochrome P450 metabolism.

7. Ternary Combination of Resins, Ezetimibe, Niacin, & Reductase Inhibitors

These agents act in a complementary fashion to normalize cholesterol in patients with severe disorders involving elevated LDL. The effects are sustained, and little compound toxicity has been observed. Effective doses of the individual drugs may be lower than when each is used alone¾eg, as little as 1-2 g of niacin may substantially increase the effects of the other agents.



PREPARATIONS AVAILABLE

Atorvastatin (Lipitor)
Oral: 10, 20, 40, 80 mg tablets
Cholestyramine (generic, Questran, Questran Light)
Oral: 4 g packets anhydrous granules cholestyramine resin; 210 g (Questran Light), 378 g (Questran) cans
Colesevelam (Welchol)
Oral: 625 mg tablets
Colestipol (Colestid)
Oral: 5 g packets granules; 300, 500 g bottles; 1 g tablets
Ezetimibe (Zetia)
Oral: 10 mg tablets
Fenofibrate
Oral (Tricor): 48, 145 mg tablets; (Antara): 43, 87, 130 mg capsules; (Lofibra): 67, 134, 200 mg capsules
Fluvastatin (Lescol)
Oral: 20, 40 mg capsules; extended release (Lescol XL): 80 mg capsules
Gemfibrozil (generic, Lopid)
Oral: 600 mg tablets
Lovastatin (generic, Mevacor)
Oral: 10, 20, 40 mg tablets;; extended release (Altoprev): 10, 20, 40, 60 mg
Niacin, nicotinic acid, vitamin B₃ (generic, others)
Oral: 100, 250, 500, 1000 mg tablets; extended release (Niaspan): 500, 750, 1000 mg
Pravastatin (Pravachol)
Oral: 10, 20, 40, 80 mg tablets
Rosuvastatin (Crestor)
Oral: 5, 10, 20, 40 mg tablets
Simvastatin (Zocor)
Oral: 5, 10, 20, 40, 80 mg tablets

COMBINATION TABLETS

Advicor (sustained release niacin plus lovastatin)
Oral: 500 or 1000 mg niacin with 20 mg lovastatin tablets
Vytorin (ezetimibe plus simvastatin)
Oral: 10/10, 10/20, 10/40, 10/80 mg tablets



REFERENCES

Grundy SM et al: Diagnosis and management of the metabolic syndrome: An American Heart Association/National Heart, Lung, and Blood Institute scientific statement. Circulation 2005;112:2735.

Grundy SM et al, for the Coordinating Committee of the National Cholesterol Education Program: Implications of recent clinical trials for the National Cholesterol Education Adult Treatment Panel III guidelines. Circulation 2004;110:227.

Kromhout D et al: Prevention of coronary heart disease by diet and lifestyle. Circulation 2002;105:893.

Libby P, Ridker PM, Maseri A: Inflammation and atherosclerosis. Circulation 2002;105:1135.

Waters DD et al, for the TNT Steering Committee Members and Investigators: Treating to New Targets (TNT) Study; does lowering low density lipoprotein cholesterol levels below currently recommended guidelines yield incremental clinical benefit? Am J Cardiol 2004;93:154.