12. Hyperlipidemia - Lawrence M. Brown, PharmD, PhD

12-1. Introduction


• Hyperlipidemia is an elevation in the blood concentration of a lipid such as cholesterol or triglyceride (in the form of lipoprotein).

• Dyslipidemia refers to any lipid disorder.

• Lipids include cholesterol, triglycerides (TGs), and phospholipids.

• Lipoproteins are apolipoproteins + cholesterol + TGs + phospholipids.

• Major lipoproteins are chylomicrons, very-low-density lipoproteins (VLDLs), intermediate-density lipoproteins (IDLs), low-density lipoproteins (LDLs), high-density lipoproteins (HDLs), and lipoprotein (a).

• Apolipoproteins are structural components of lipoproteins.

• The Friederwald equation is a formula used to calculate LDL:

LDL = total cholesterol - (HDL + TG/5).

Classification of Lipids

Total cholesterol, LDL, HDL, and TG are measured in mg/dL. Adult Treatment Panel III (ATP III) recommendations from the National Cholesterol Education Program (NCEP) are shown in

Table 12-1.

Clinical Presentation

Hyperlipidemia can cause atherosclerosis, atheroma formation, atherothrombosis, and the subsequent consequences of the following disease processes:

• Coronary artery disease (angina and myocardial infarction)

• Cerebrovascular disease (transient ischemic attack, stroke, or both)

• Peripheral arterial disease (intermittent claudication)

A state of elevated lipids alone generally promotes no symptoms, except in some familial lipid disorders, in which there may be cutaneous manifestations of lipid deposition (e.g., tendon xanthomas, planar xanthomas, xanthelasmas, and eye manifestations [corneal arcus]).

Pathophysiology of Atherosclerosis

A progressive, systemic disease starting early in life, atherosclerosis has the following pathophysiology:

• Atheroma lesions, called fatty streaks, develop in the arterial vascular walls as a result of the accumulation of cholesterol within vessel walls.

• Atheroma lesions may lead to occlusion by thrombus or embolus formation.

• LDL cholesterol accumulates below the intimal surface of the artery. The general guideline is the higher the cholesterol elevation in the blood, the more LDL migration into the artery.

• Endothelial dysfunction occurs, which increases LDL cholesterol's permeability.

• LDL becomes oxidized and recruits monocytes.

• Monocytes are transformed into macrophages and ingest the oxidized LDL.

• This process results in lipid-filled cells called foam cells.

• Foam cells are the initial lesion of atherosclerosis. Growth factors are produced by macrophages.

• Other processes are also occurring (e.g., additional endothelial cell injury and inflammatory

[Table 12-1. Classification of Lipids]

   responses that can further accelerate the development of plaque).

• Elevated cholesterol and hyperlipidemia enhance this process.

• Plaque may continue to develop, may become stable, or may rupture.

• Plaque rupture exposes atherogenic materials in the lesion to blood.

• Platelets are activated, and a clot may form.

• Partial occlusion or obstruction can result in angina; complete occlusion results in myocardial infarction (MI).

• Other vascular beds promote similar outcomes.

Diagnostic Criteria

Lipid disorders (dyslipidemias) are classified as familial or secondary.

Familial disorders

• Familial disorders usually are caused by a defect in lipid metabolism.

• They are categorized into the hypercholesterolemias and the combined hyperlipidemias.

• Assessment of fasting lipid panels provides diagnostic information and classification of lipid disorders.

• For familial hypercholesterolemia, LDL = 250-450 mg/dL.

• Familial defective apolipoprotein B-100 may be present.

• Polygenic hypercholesterolemia is the most common form (LDL = 160-250 mg/dL).

• Combined hyperlipidemias are as follows:

• Familial combined hyperlipidemia (LDL = 160-250 mg/dL and TG = 200-800 mg/dL)

• Familial hyperapobetalipoproteinemia

• Hypoalphalipoproteinemia

• Dysbetalipoproteinemia

• Elevated lipoprotein (a)

• Familial disorders are characterized by variations in the amounts of HDL, IDL, LDL, and VLDL.

Secondary disorders

The most common secondary causes of lipid disorders are as follows:

• Diabetes mellitus

• Hypothyroidism

• Renal failure

• Obstructive liver disease

• Drugs such as β-blockers, thiazide diuretics, oral contraceptives, oral estrogens, glucocorticosteroids, and cyclosporine

Risk factors are used to assess the potential for an individual to develop coronary heart disease (CHD) or another equivalent atherosclerotic process over the next 10 years. The Framingham Global Risk Score is calculated to provide this information. The major nonlipid risk factors for CHD are counted and used to assess the 10-year risk of developing CHD.

Major nonlipid risk factors for CHD are as follows:

• Cigarette smoking

• Hypertension (patient with blood pressure ≥ 140/90 mm Hg or patient on antihypertensive medication)

• Low HDL cholesterol (< 40 mg/dL)

• Family history of premature CHD (CHD in a male first-degree relative age < 55 years and CHD in a female first-degree relative age < 65 years)

• Age (men ≥ 45 years; women ≥ 55 years)

HDL ≥ 60 mg/dL counts as a negative risk factor and acts to remove one of the other risk factors from the total count.

Treatment Principles

Treatment and target lipid goals are based on the estimation of risk for CHD using the Framingham Global Risk Score.

If a patient has a form of clinical CHD, such as angina, MI, stroke, or transient ischemic attack, he or she is considered to be at high risk for another ischemic event within the next 10 years.

Those at highest risk require the most aggressive therapy (i.e., drug therapy and achievement of the lowest possible LDL level). The major nonlipid risk factors noted previously are used in the risk analysis for those individuals who do not have CHD or a CHD risk equivalent.

Table 12-2 identifies risk categories, lipid goals, and risk of event.

Treatment consists of lifestyle changes (i.e., therapeutic lifestyle changes), which are discussed in the nonpharmacologic and pharmacotherapy sections of this chapter.

The algorithm for drug therapy in primary prevention (< 20% risk) is as follows:

• Initiate LDL-lowering drug therapy (statins, niacin, and resin) for 6 weeks.

• If the LDL goal is not met, intensify LDL-lowering therapy (higher dose or combination therapy) for 6 weeks.

• If LDL goal is still not achieved, intensify drug therapy or refer to a lipid specialist for 4-6 months.

• Monitor response and adherence.

Drug therapy in secondary prevention (> 20% risk) requires the most aggressive treatment. A large LDL reduction requires a statin and possibly a statin in combination with another agent. Follow the same algorithm as outlined in the primary prevention (< 20% risk) algorithm just listed.

Monitoring (Clinical Evaluation) of Adults

For screening, the NCEP's ATP III recommends that, starting at age 20, adults receive a fasting lipid profile (FLP). If the FLP is normal, screening is repeated in 5 years.

[Table 12-2. Risk Categories, Lipid Goals, and Risk of Event]

Monitoring and Treatment of Children and Adolescents

The American Academy of Pediatrics has historically recommended cholesterol screening of children with a family history of high cholesterol or heart disease. However, the academy now recommends screening of children age 2 to 10 if family history is unknown or if the child has other risk factors for heart disease such as obesity, hypertension, or diabetes. Screenings that result in normal range results should be repeated in 3 to 5 years.

Children age 8 and older (previously age 10 and older) with LDL levels > 190 mg/dL should be considered for medication therapy (> 160 mg/dL for children with family history of heart disease or more than two other risk factors and > 130 mg/dL for children with diabetes). First line medication options include bile acid sequestrants, cholesterol absorption inhibitors, and statins (statins previously not recommended as first-line medication option). Niacin products are not recommended for use, and fibrates should be used with caution and under the supervision of a pediatric lipid specialist.

Children age 2 and older who are overweight or obese and who have a high TG level or low HDL level should receive a recommendation of weight management and increased physical activity as the primary treatment.

Monitoring Tool

The main monitoring tool is a fasting lipid panel. The baseline FLP is done before drug or dietary interventions.

After therapeutic lifestyle changes or drug therapy is started, the patient should be monitored every 6 weeks for 12 weeks initially, again in 4-6 months, and then periodically thereafter (usually annually). Results of the FLP will show the effects of lifestyle and drug therapy interventions and help direct changes in therapy.

12-2. Drug Therapy



Tables 12-3,

12-4, and

12-5 for details on dosing, efficacy, and drug combinations.

[Table 12-3. Drug Products and Dosage]


• Conduct baseline liver function tests (LFTs) and creatine kinase (CK) before therapy is initiated. LFTs should be repeated again in 4-6 weeks, at 3 months, and then periodically (usually annually).

• CK needs to be monitored only if the patient has suspected muscle damage.

• Assess effectiveness at 6 weeks.


• Determine baseline FLP to screen for hypertriglyceridemia:

• If TG > 200 mg/dL, use resins with caution.

• If TG > 400 mg/dL, resins are contraindicated.

• Assess effectiveness at 6 weeks.

[Table 12-4. Efficacy of Drugs Used to Treat Hyperlipidemia]

Nicotinic Acid

• Determine baseline fasting glucose, conduct LFTs, and determine serum uric acid levels before initiating therapy.

• Repeat these tests 4-6 weeks after each dose level is reached.

• Sustained-release niacin requires monthly LFT readings while dosage is titrated; subsequent LFT readings should occur every 12 weeks for the first year and then periodically.

• Diabetics require routine fasting glucose tests.

• Monitor serum uric acid after the highest dose level is achieved in patients with a history of hyperuricemia or gout.

• Assess effectiveness at 6 weeks.

[Table 12-5. Pharmacotherapeutic Options for Treatment of Hyperlipidemia]

Fibric Acids

• Determine baseline FLP (total cholesterol, HDL, LDL, and TG) before therapy and again at 3 and 6 months.

• Monitor changes in TG at 3 months, and assess effectiveness.

Cholesterol Inhibitors

• Determine baseline FLP.

• Assess effectiveness at 6 weeks.

Omega-3 Fatty Acids

• Determine very high baseline TG of ≥ 500 mg/dL.

• Can be used in combination with diet therapy or with diet and statin therapy.

• Assess effectiveness at 2 months. Discontinue use if decrease in TG level is adequate.

• Periodic monitoring of alanine aminotransferase levels is recommended.

• Periodic monitoring is recommended for increase in LDL cholesterol levels.

Mechanisms of Action

HMG-CoA reductase inhibitors (statins)

These agents competitively inhibit HMG-CoA (3-hydroxy-3-methyl-glutaryl-coenzyme A) reductase, which is the enzyme responsible for conversion of HMG-CoA to mevalonate.

Mevalonate is an early precursor to and a rate-limiting step in cholesterol synthesis. This reduction in liver cholesterol synthesis results in upregulation of liver LDL receptors and increased clearance of LDL and VLDL particles in the blood. These actions induce a decrease in total cholesterol and LDL cholesterol, promote a slight increase in HDL cholesterol, and effect a modest decrease in TG.

Bile acid sequestrants (resins)

Nonabsorbable anion exchange resins exchange chloride ions for bile acids and other anions in the intestine. This action inhibits enterohepatic recycling, which results in bile excretion and a decrease in the cholesterol pool in the liver. LDL receptors are upregulated, increased LDL is cleared, and LDL is lowered.


Niacin reduces LDL cholesterol and TG and increases HDL. It may decrease VLDL synthesis, thereby leading to decreased LDL cholesterol and TG. It may inhibit metabolism of apolipoprotein A-I, which increases HDL cholesterol.

Fibric acids (fibrates)

Fibrates reduce TG by reduction of apolipoproteins B, C-III, and E. They increase HDL by increasing apolipoproteins A-I and A-II.

Cholesterol inhibitors (ezetimibe)

Cholesterol inhibitors selectively inhibit intestinal absorption of dietary and biliary cholesterol at the brush border of the small intestine, which results in a decrease in the absorption of cholesterol and a decrease in cholesterol in the blood.

Omega-3 fatty acids

The mechanism of action for omega-3 fatty acids is not completely understood. Possible mechanisms of action include the following:

• Inhibition of acyl CoA: 1,2-diacylglycerol acyltransferase

• Increased mitochondrial and peroxisomal β-oxidation in the liver

• Decreased lipogenesis in the liver

• Increased lipoprotein lipase activity

Patient Instructions and Counseling


Statins are usually administered in the evening because most hepatic cholesterol production occurs during the night. Lovastatin conventional tablets should be given with the evening meal because absorption is better with food; however, the extended-release lovastatin products should be taken at bedtime. The lovastatin plus Niaspan combination product should be taken at bedtime with a low-fat snack.

Non-extended release statins can be dosed once daily. Other regular dosage forms should be divided as the doses are raised above 40 mg/day.

Atorvastatin may be given any time of the day because of its longer half-life.

Rosuvastatin dosage adjustment is required in patients with severe renal impairment. Plasma concentrations of rosuvastatin increased to a clinically significant extent (about threefold) in patients with severe renal impairment (creatinine clearance < 30 mL/min/1.73m2) compared with healthy subjects (creatinine clearance > 80 mL/min/1.73m2). Dosage adjustment is also required in patients with liver disease.

Monitor LFTs and muscle toxicity as described earlier.

Bile acid sequestrants (resins)

Cholestyramine and colestipol should be started with one dose daily with the largest meal. They may be increased (after the patient adjusts to the resin) to two doses daily with the largest meals or divided between breakfast and dinner.

Titrate doses slowly to avoid gastrointestinal side effects.

Powdered doses can be mixed with food, such as soup, oatmeal, nonfat yogurt, applesauce, and so forth. The mixture can also be chilled overnight to improve palatability. Do not mix with carbonated beverages, because they promote increased air swallowing. Counsel the patient that drinking through a straw may also help.

Patients who suffer constipation with the resins may mix them with psyllium; however, this mixture should be ingested immediately after mixing to prevent a gel from forming.

Counsel the patient to rinse the glass and drink remains to ensure ingestion of all resin.

Colesevelam is a tablet formulation, which may be easier for some patients to self-administer. However, the tablets are large, and some patients may not be able to swallow them.

Monitor for adherence and gastrointestinal side effects for all resins.

Nicotinic acid (niacin)

Immediate-release niacin should be started at a low dose and slowly titrated upward:

• Start with 100 mg tid and adjust upward the second week to 200 mg tid; the next week, increase to 350 mg tid; and the following week, raise to 500 mg tid. When 1,500 mg/day is reached and maintained for 4 weeks, assess effectiveness before increasing the dose.

• If further titration is needed, go to 750 mg tid and assess effectiveness after 4 weeks before increasing titration. Maximum dose is 1,000 mg tid.

• Aspirin 325 mg or ibuprofen 200 mg must be given 30 minutes before the morning dose to minimize flushing and itching.

• Caution patients to avoid hot beverages and hot showers so as not to exacerbate the flushing effect.

Extended-release formulation should be taken at bedtime (500 mg) and titrated weekly to a maximum dose of 1,500 mg/day. Aspirin should be taken 30 minutes before the dose.

Sustained-release formulations are started at 250 mg bid and increased at weekly intervals to a maximum dose of 2,000 mg/day. Aspirin should be given 30 minutes before the dose.

Monitor for adherence and side effects. The titration schedule for some patients may have to be gradual because of flushing and itching.

Fibric acids (fibrates)

Gemfibrozil should be taken twice daily 30 minutes before meals.

Tricor can be taken with or without food once daily.

Reduce the dose in patients with renal insufficiency, and monitor for muscle toxicity, especially when used in combination with statins and niacin.

Cholesterol inhibitors

Cholesterol inhibitors are dosed once daily without regard to food. They can be taken simultaneously in combination with statins.

Omega-3 fatty acids

The daily dose (4 g) can be taken in single or divided dose (2 g bid). These agents should be taken with meal(s).

Use of omega-3 fatty acids does not reduce the importance of patient adhering to a diet.

Omega-3 fatty acids are not for use in patients with a history of allergy or sensitivity to fish.

Assess effectiveness at 2 months. Discontinue use if the decrease in TG level is adequate.

Adverse Drug Events

HMG-CoA reductase inhibitors (statins)

• Myopathy owing to muscle damage may occur.

• Myalgia from muscle soreness or tenderness may occur.

• Myositis occurs in 0.2% of patients:

myalgia + 足 creatine kinase

(3 - 10 times upper limit of normal)

• Rhabdomyolysis occurs rarely, but can cause acute renal failure. Stop the drug immediately.

severe myositis + creatine kinase

10 × upper limit of normal,

足 serum creatinine and urine myoglobin

• Elevated liver enzymes occur in 0.1-2.3% of patients. Obtain baseline LFTs, and repeat at 4-6 weeks, again at 6 months, and yearly thereafter.

• Flu-like symptoms and headache may occur.

• Patients may have mild gastrointestinal (GI) complaints.

• Contraindication is absolute in active or chronic liver disease.

• Contraindication is relative in combination with certain drugs (see discussion of drug interactions).

Bile acid sequestrants (resins)

• GI distress may occur.

• Patients may experience palatability problems with the resin slurry.

• Constipation may occur that increases with the dose and in the elderly.

• Decreased absorption of other drugs may occur. Dose other drugs 1 hour before or 4 hours after ingestion of resin.

• Contraindication is absolute in dysbetalipoproteinemia (highly elevated VLDL) and TG > 400 mg/dL.

• Contraindication is relative when TG > 200 mg/dL.

Nicotinic acid (niacin)

• Flushing is common. Pretreat with aspirin (325 mg) 30 minutes before the first niacin dose of the day.

• Hyperglycemia is a risk. Use with caution in diabetics.

• Hyperuricemia (or gout) may occur:

• Upper GI distress

• Hepatotoxicity

• Absolute contraindication in chronic liver disease and severe gout

• Relative contraindication in diabetes, hyperuricemia, or severe gout

Fibric acids (fibrates)

• Dyspepsia may occur.

• Gallstones may occur.

• Myopathy increases when combined with statins.

• Contraindication is absolute in severe renal or severe hepatic disease.

Cholesterol inhibitors

• Elevated liver enzymes (same as placebo) may occur.

• GI distress (less than with resins) may occur.

• Contraindication is absolute in moderate to severe hepatic disease.

Omega-3 fatty acids

• Burping

• Indigestion

• Taste sense alteration

• Backache

Drug-Drug and Drug-Disease Interactions

HMG-CoA reductase inhibitors (statins)

CYP450 (cytochrome P450) mixed-function oxidase enzymes metabolize statins, and drugs that inhibit this process can cause increases in statin concentrations, thus predisposing patients to myopathy and liver toxicity.

Common CYP450 3A4 inhibitors include amiodarone, clarithromycin, cyclosporine, danazol, delavirdine, diltiazem, erythromycin, fluoxetine, fluvoxamine, grapefruit juice, indinavir, itraconazole, ketoconazole, miconazole, nefazodone, nelfinavir, nicardipine, nifedipine, pimozide, propoxyphene, quinidine, ritonavir, saquinavir, sildenafil, tacrolimus, tamoxifen, testosterone, troleandomycin, verapamil, and zafirlukast.

Pravastatin is not metabolized by the CYP450 system; therefore, these drug-drug interactions are avoided.

Contraindication is absolute in active or chronic liver disease.

Bile acid sequestrants (resins)

Avoid concomitant use with all other drugs, especially digoxin, levothyroxine, tetracycline, warfarin, fat-soluble vitamins, and minerals.

Always separate other drugs by 1 hour before use and 4 hours after use.

Colesevelam does not appear to have these drug and nutrient interactions.

Contraindication is absolute in dysbetalipoproteinemia.

Nicotinic acid (niacin)

Use caution in combination with resins. Combination therapy with statins and gemfibrozil may cause an increased risk of myopathy.

Contraindication is absolute in chronic liver disease and severe gout.

Fibric acids (fibrates)

These agents are highly protein bound, and they are metabolized by the CYP450 3A4 enzyme system.

The effect of warfarin may be increased.

Cyclosporine may increase gemfibrozil concentrations.

Fenofibrate may have less interaction potential with warfarin and cyclosporine.

Bile acid sequestrants (resins) decrease fibrate absorption.

Combinations with statins and niacin may increase the risk of myopathy.

Contraindication is absolute in severe renal disease and severe liver disease.

Cholesterol inhibitors

Cyclosporine may increase ezetimibe concentrations.

Combination with a resin may decrease absorption. Combination with a fibric acid may predispose to gallbladder disease.

Contraindication is absolute in moderate to severe hepatic disease.

Omega-3 fatty acids

Possible prolonged bleeding time may occur when used with anticoagulants.

Landmark Clinical Trials with Statins

Primary prevention trials

West of Scotland Study

This trial with pravastatin showed decreased coronary morbidity and mortality in hypercholesterolemic men with no clinical evidence of CHD.

Air Force-Texas Coronary Atherosclerosis Prevention Study

This trial with lovastatin showed reduced incidence of first acute major coronary events in patients who did not have CHD but did have normal to mildly elevated total cholesterol and LDL with low HDL.

Secondary prevention trials

Scandinavian Simvastatin Survival Study

This trial with simvastatin showed decreased cardiac morbidity and mortality in patients with CHD and elevated cholesterol.

Cholesterol and Current Events Study

This trial with pravastatin showed reduced incidence of MI, death from CHD, stroke, and need for revascularization procedures in patients with recent MI and normal cholesterol levels.

Long-Term Intervention with Pravastatin in Ischemic Disease Study

This trial with pravastatin showed reduced mortality and incidence of MI and stroke in patients with CHD and a broad range of cholesterol.

Heart Protection Study

This trial with simvastatin is the largest single cholesterol trial (as of 2002) in patients at high risk of CHD (prior MI, diabetes, or hypertension) and LDL > 135 mg/dL. Antioxidants studied included vitamins E and C and beta-carotene. Simvastatin therapy showed a reduced incidence of CHD regardless of age (also elderly) or preexisting condition. There was no threshold for LDL at 100 mg/dL (i.e., benefits extended below this level). In addition, there was no cardiovascular protective effect from vitamins E and C and beta-carotene.

12-3. Nondrug Therapy


Nonpharmacologic therapy focuses on therapeutic lifestyle changes (TLCs), which incorporate dietary changes, physical activity, and weight reduction. "Heart healthy" nutrition is the foundation for any therapeutic interventions.

General TLC Recommendations

• Decrease the amount of high-fat foods consumed (especially foods high in saturated fat).

• Decrease intake of high-cholesterol foods.

• Replace saturated fats with monounsaturated fats and fish oils.

• Use foods high in complex carbohydrates (fiber, starch, fruits, and vegetables).

• Strive for and maintain an acceptable weight.

• Patients should be instructed on how to read a nutrition label.

• Recommended nutrient makeup of the TLC diet is shown in

Table 12-6.

Algorithm for TLCs

Begin lifestyle therapies and continue for 6 weeks. Evaluate LDL response, and if the LDL goal is not achieved, intensify LDL-lowering therapy (diet + weight management + physical activity) for 6 more weeks. Evaluate LDL response, and if LDL goal is still not achieved, consider adding drug therapy (if not already added). Monitor adherence to TLC every 4-6 months thereafter.

Other Nonpharmacologic Therapies

• Soluble fiber and plant sterols and stanols can help lower LDL.

• Viscous or soluble fiber such as psyllium or pectin in the amount of 5-10 g/d or other sources of fiber such as vegetables, fruits, and whole grains can reduce LDL by up to 8%.

• The active ingredient in fish oils is omega-3 fatty acid. Fish oils can reduce TGs as much as 30-60%. Fish oils can be added when niacin or fibrates do not control TGs.

• Recent clinical trials have shown that antioxidants; vitamins A, C, and E; and beta-carotene are not protective for cardiovascular disease.

• Light to moderate alcohol use (one drink per day for women, two drinks per day for men) has been associated with reductions in CHD rates. The benefit may be due to a rise in HDL. Use of alcohol should not be encouraged as a means of

[Table 12-6. Nutrient Makeup of the TLC Diet]

   lowering cholesterol. Excessive alcohol use can cause elevations of TGs.

• Alternative therapies such as herbal therapies have not been systematically studied in hyperlipidemia and should not be recommended for treatment of hyperlipidemia or other lipid disorders.

12-4. Key Points

• Hyperlipidemia is the elevation of the blood concentration of a lipid such as cholesterol or triglyceride (in the form of lipoprotein).

• There are four major classifications of lipids: total cholesterol, low-density lipoproteins, high-density lipoproteins, and triglycerides.

• The process of atherosclerosis begins with atheroma lesions in the arterial vascular walls resulting from the accumulation of cholesterol within vessel walls.

• Polygenic hypercholesterolemia (LDL = 160-250 mg/dL) is the most common form of familial dyslipidemia.

• Major nonlipid risk factors for coronary heart disease are cigarette smoking, hypertension, family history of premature CHD, and age (men ≥ 45 years, women ≥ 55 years).

• People with a history of CHD, such as angina, MI, stroke, or transient ischemic attack, are considered at highest risk of having another ischemic event in the next 10 years and require the most aggressive therapy and the lowest target LDL goal (< 100 mg/dL).

• Monitoring for drug therapy of hyperlipidemia includes laboratory monitoring for adverse effects (e.g., liver function tests, uric acid, and creatine kinase) and fasting lipid profiles for effectiveness.

• The mechanism of action of statin agents to treat hyperlipidemia is to competitively inhibit HMG-CoA reductase, which is the enzyme responsible for conversion of HMG-CoA into mevalonate—an early precursor to and a rate-limiting step in cholesterol synthesis.

• The statins are usually administered in the evening (except for atorvastatin, which has a longer half-life than the other agents in this class) because most hepatic cholesterol production occurs during the night.

• Lovaza is a prescription formulation of omega-3 fatty acid, and its use should be discontinued if an adequate reduction in TGs is not achieved after 2 months of use.

• The only class of agents to control hyperlipidemia that is not contraindicated in patients with active or chronic liver disease is the bile acid sequestrant (resin) type.

• Pravastatin is not metabolized by the CYP450 enzyme system and, thus, avoids most of the drug interactions with the other statin agents.

• Cholesterol screenings are now recommended for children age 2-10 years if they have a family history of high cholesterol or heart disease, if the family history is unknown, or if the child has other risk factors for heart disease such as obesity, hypertension, or diabetes.

• Advicor should not be substituted for equivalent doses of immediate-release (crystalline) niacin. For patients switching from immediate-release niacin to extended-release niacin, therapy with the latter should be initiated with low doses (i.e., 500 mg once daily at bedtime), and the dose should then be titrated to the desired therapeutic response.

• The bile acid sequestrants (resins) may decrease the absorption of digoxin, levothyroxine, tetracycline, warfarin, fat-soluble vitamins, and minerals.

• The new formulation of Tricor can be taken with or without food once daily.

• Therapeutic lifestyle changes that incorporate dietary changes, increased physical activity, and weight reduction are the first recommended therapy for hyperlipidemia for 6-12 weeks prior to addition of drug therapy.

12-5. Questions

Use the following case study to answer Questions 1-5.

J. B. is a 50-year-old man who comes to your pharmacy for cholesterol and medication monitoring. His medical history is notable for stage 1 hypertension, recent-onset type 2 diabetes, and hypercholesterolemia. Family history is noncontributory. Social history indicates he neither smokes nor uses alcohol. He has no known allergies. His medication history reveals that he occasionally takes acetaminophen for headaches and no other over-the-counter medications or herbal products. Current medications include hydrochlorothiazide 25 mg/d (for 4 years) and a new prescription today for atorvastatin 10 mg/d. Your physical assessment reveals the following: BP 144/90 mm Hg; pulse, 70 and regular; weight, 185 pounds; height, 5´9族. An FLP today reveals the following: total cholesterol = 250 mg/dL, HDL = 40 mg/dL, and triglycerides = 145 mg/dL.


What is J. B.'s LDL cholesterol?

A. 130 mg/dL

B. 153 mg/dL

C. 162 mg/dL

D. 178 mg/dL

E. 181 mg/dL



What is J. B.'s LDL goal?

A. < 100 mg/dL

B. 130-160 mg/dL

C. 160-189 mg/dL

D. < 200 mg/dL

E. > 40 mg/dL



J. B. is started on TLC and atorvastatin because of his high LDL. When should you assess the effectiveness of therapy?

A. 12 weeks

B. 6 months

C. 3 weeks

D. 6 weeks

E. Annually



J. B. is most likely to have which of the following?

A. Familial hypercholesterolemia

B. Polygenic hypercholesterolemia

C. Familial combined hyperlipidemia

D. Elevated triglycerides

E. Isolated low HDL



J. B. returns for reassessment at the appropriate time. His FLP shows that his LDL is now 115 mg/dL. What is your recommendation?

A. Stop the statin because the patient has achieved optimal LDL.

B. Increase statin dose.

C. Intensify TLC.

D. Add gemfibrozil.

E. Add cholestyramine.



The National Cholesterol Education Program Expert Panel identifies which of the following as a positive risk factor for coronary heart disease?

A. Hypertension

B. Low HDL (< 40 mg/dL)

C. Family history of premature CHD

D. Current cigarette smoking

E. All of the above



Which of the following is not a secondary cause of hyperlipidemia?

A. High LDL

B. Hypothyroidism

C. Diabetes

D. Renal disease

E. β-blockers



Cholesterol biosynthesis can be decreased by which of the following?

A. Statins

B. Oat bran

C. Bile acid sequestrants (resins)

D. Ezetimibe

E. Aspirin



Choose the medication with the greatest effect on raising HDL.

A. Lovastatin

B. Pravastatin

C. Gemfibrozil

D. Niaspan

E. Colesevelam



Choose the drug class with the most potent lowering effect on LDL.

A. Nicotinic acid

B. Fibric acids

C. Omega-3 fatty acids

D. Cholesterol inhibitors

E. HMG-CoA reductase inhibitors



The initial lesion in the development of atherosclerosis is

A. development of foam cells.

B. increase in HDL reverse transport.

C. rupture of a vulnerable plaque.

D. clot formation in the artery lumen.

E. development of a thin cap over the lipid pool.



Choose the correct statement.

A. Diabetes is an absolute contraindication to the use of nicotinic acid.

B. Aspirin is dosed three times per day to prevent flushing from niacin.

C. Gemfibrozil may reduce triglycerides by as much as 50%.

D. Colesevelam has similar patient tolerability problems as does cholestyramine.

E. Ezetimibe frequently causes muscle toxicity.



Hyperlipidemia refers to

A. elevation of apolipoproteins.

B. hypercholesterolemia.

C. high levels of white blood cells.

D. increased ingestion of protein.

E. endothelial dysfunction.



Which of the following indicates an optimal LDL?

A. > 190 mg/dL

B. < 40 mg/dL

C. > 60 mg/dL

D. < 100 mg/dL

E. < 150 mg/dL



Polygenic hypercholesterolemia is characterized by which of the following?

A. LDL = 150-450 mg/dL

B. LDL = 160-250 mg/dL

C. TG > 400 mg/dL

D. HDL = 50 mg/dL

E. LDL = 160-250 mg/dL + TG > 400 mg/dL



Identify a baseline laboratory test required before statin treatment.

A. White blood cell count

B. Complete blood cell count

C. Liver function test

D. Serum creatinine

E. Creatinine clearance



The major troublesome side effect in nicotinic acid therapy is

A. diarrhea.

B. vomiting.

C. hair growth.

D. flushing.

E. dizziness.



Which of the following medications has this warning: "For patients switching from immediate-release niacin, therapy with this drug should be initiated with a low dose and then titrated to the desired therapeutic response"?

A. Pravigard

B. Vytorin

C. Advicor

D. Atorvastatin

E. Ezetimibe



Identify the drug interaction that involves the CYP450 system.

A. Ezetimibe + niacin

B. Colestipol + simvastatin

C. Gemfibrozil + cholestyramine

D. Fenofibrate + ezetimibe

E. Lovastatin + itraconazole



A TLC diet could include

A. antioxidant therapy such as vitamin E.

B. < 7% of total calories from saturated fat.

C. 150-250 g/d of fiber.

D. 2-4 drinks of alcohol per day.

E. assessment of the effectiveness of TLC at 12-week intervals.


12-6. Answers


E. Use the Friederwald equation to calculate LDL:

LDL = total cholesterol - (HDL + TG/5)

LDL = 250 - (40 + 145/5) = 181



A. J. B. has type 2 diabetes, which is a risk equivalent for coronary heart disease. Therefore, he is at highest risk for an event in the future, and his LDL goal should be optimal or < 100 mg/dL.



D. Both TLC and drug therapy measures should be assessed at 6-week intervals.



B. J. B.'s LDL is 181 mg/dL, which falls into the range for polygenic hypercholesterolemia (160-250 mg/dL), and he does not have elevated TGs or low HDL.



C. Because J. B.'s LDL is still slightly above optimal, intensify TLC. That is, continue to decrease saturated fat in the diet and to intensify weight reduction and physical activity. If the LDL is still above 100 mg/dL at the next assessment in 6 weeks, options would be to increase the statin dose (double it) or add another agent such as niacin or ezetimibe.



E. All of the answers are positive risk factors for CHD as defined by the NCEP's Adult Treatment Panel III. The remaining positive risk factors are gender and age (i.e., males 45 years and over and females 55 years and over).



A. Causes of hyperlipidemia must be ruled out. The common secondary causes are renal failure; hypothyroidism; obstructive liver disease; diabetes; and drugs such as β-blockers, thiazide diuretics, oral contraceptives, oral estrogens, glucocorticoids, and cyclosporine.



A. Statins competitively inhibit HMG-CoA reductase, which is the enzyme responsible for converting HMG-CoA to mevalonate. Inhibition of mevalonate reduces cholesterol synthesis.



D. Nicotinic acid (Niaspan) has the most efficacy in raising HDL compared with other therapies. HDL may be raised 15-35%.



E. Statins (HMG-CoA reductase inhibitors) have the most efficacy in lowering LDL. LDL may be lowered 18-55%.



A. Foam cells represent the initial lesion of atherosclerosis and develop as a result of the ingestion of oxidized LDL by macrophages in the subintimal space of the artery.



C. Diabetes is a relative contraindication to the use of nicotinic acid. Aspirin is dosed once daily, before the first nicotinic acid dose of the day. Gemfibrozil can reduce TGs 20-50%. Colesevelam is a tablet and avoids most of the palatability problems of other resins. Ezetimibe does not cause muscle toxicity.



B. Hyperlipidemia is defined as an elevation of a lipid in the blood. The lipid can be cholesterol or triglyceride in the form of a lipoprotein.



D. Level < 100 = optimal; 100-129 = near optimal or above optimal; 130-159 = borderline high; 160-189 = high; and ≥ 190 = very high.



B. Polygenic hypercholesterolemia is the most common cause of mild to moderately elevated LDL (LDL = 160-250 mg/dL).



C. Baseline tests before statin use include liver function tests and creatine kinase.



D. The most common side effect is flushing, which may occur in many patients. To decrease flushing intensity, a patient should take aspirin 325 mg 30 minutes prior to the first dose of nicotinic acid. Itching may also occur with flushing.



C. Advicor (Niaspan + lovastatin) contains Niaspan, which is not dose equivalent to immediate-release niacin or modified-release (sustained-release or time-release) niacin preparations.



E. Lovastatin is metabolized by CYP450 3A4 enzymes, and itraconazole will inhibit this enzyme system. Inhibition causes lovastatin blood and tissue concentrations to rise, thus predisposing the patient to muscle or liver toxicity.



B. A TLC diet includes < 7% saturated fat, 20-30 g/d fiber, avoidance of alcohol, and assessment at 6 weeks. Vitamin E is not recommended for cardiovascular risk reduction.


12-7. References

Beaird SL. HMG-CoA reductase inhibitors: Assessing differences in drug interactions and safety profiles. J Am Pharm Assoc. 2000;40:6337-44.

Daniels SR, Greer FR, Committee on Nutrition. Lipid screening and cardiovascular health in childhood. Pediatrics. 2008;122:198-208.

Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: Results of AFCAPS/TexCAPS. JAMA. 1998;279: 1615-22.

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-97.

Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: A randomised placebo-controlled trial. Lancet. 2002;360:7-22.

Knopp RH. Drug treatment of lipid disorders. N Engl J Med. 1999;341:498-511.

Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349-57.

McKenney JM, Hawkins DW, eds. Handbook on the Management of Lipid Disorders. Springfield, N.J.: Scientific Therapeutics Information/National Pharmacy Cardiovascular Council; 2001.

Pasternak RC, Smith SC Jr, Bairey-Merz CN, et al. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol. 2002;40: 568-73.

Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4,444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383-89.

Sudhop T, Lutjohann D, Kodal A, et al. Inhibition of intestinal cholesterol absorption by ezetimibe in humans. Circulation. 2002;106:1943-48.

Talbert RL. Hyperlipidemia. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 5th ed. New York: McGraw-Hill; 2002:395-418.

West of Scotland Coronary Prevention Study Group. Influence of pravastatin and plasma levels on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation. 1998; 97:1440-45.

Wolf MI, Vartnian SF, Ross JL, et al. Safety and effectiveness of Niaspan when added sequentially to a statin for treatment of dyslipidemia. Am J Cardiol. 2001;87:476-79.