An Overview of Cholesterol Management

Abstract

Cardiovascular disease is the leading cause of death worldwide. Elevated cholesterol (hypercholesterolemia) and abnormal lipid profiles (dyslipidemia) are important risk factors for the development of cardiovascular disease. This article discusses the role of cholesterol in the body and the relationship between different cholesterol fractions and the risk of cardiovascular disease. The guidelines for assessment and treatment of dyslipidemia from the National Cholesterol Education Program are outlined, and cholesterol targets and goals of therapy are discussed. The mechanism of action, place in therapy (eg, first-line, second-line, or add-on), and common side effects are also discussed for each of the available classes of drugs used in the treatment of dyslipidemia.

Cardiovascular (CV) disease (CVD) is the leading cause of mortality and one of the leading causes of disability worldwide.1 In the United States alone, more than 80 million adults have at least one type of CVD, with hypertension, coronary heart disease (CHD), stroke, and heart failure among the most common forms of the disease. Elevated levels of cholesterol (hypercholesterolemia) and abnormal lipid profiles (dyslipidemia) are important risk factors for CVD. The American Heart Association (AHA) estimates that more than 100 million Americans have elevated cholesterol levels (>200 mg/dL) and 34 million have cholesterol levels that necessitate treatment.2

Cholesterol is an essential component of cell membranes and steroid hormones. The body synthesizes most of its required cholesterol with the remainder coming from the diet. Since cholesterol is mostly insoluble in blood, it is packaged with proteins and phospholipids to form lipoprotein complexes that circulate in the bloodstream. The types of cholesterol-containing lipoproteins are high-density lipoproteins (HDL-C), low-density lipoproteins (LDL-C), very low-density lipoproteins (VLDL-C), and chylomicrons.

High levels of LDL-C are associated with increased CV risk in epidemiologic studies. In addition, numerous clinical studies using a variety of therapies have demonstrated decreased CV events and mortality with LDL reduction. Therefore, the first goal of therapy is reduction of LDL-C levels for the most common forms of dyslipidemia. Conversely, high levels of HDL-C are associated with decreased risk of CV events. However, clinical trials assessing the morbidity and mortality benefits of drug therapies that raise HDL-C levels have had varied results. HDL-C–modifying trials with niacin have demonstrated CV event reduction.3,4 Conversely, other treatments that raise HDL-C, including hormone replacement therapy5 and torcetrapib,6 have not decreased CV events. Because of this, in the absence of large clinical outcome trials, therapies that elevate HDL cannot be assumed to produce clinical event reduction.

Approach to Patient Assessment, Treatment

The National Cholesterol Education Program (NCEP) evaluates evidence and develops guidelines for lipid management. The approach to patient management provided here comes primarily from the guidelines published in 2001 and updated in 2004.7,8

Since the primary goal of lipid management is to decrease the risk of CV events and death, the first step in management is to assess the patient's overall CV risk. To make this assessment, a fasting lipoprotein analysis should be obtained to determine the patient's LDL-C. Optimal levels for LDL-C and total cholesterol are <100 mg/dL and <200 mg/dL, respectively. The NCEP guidelines recommend that a fasting lipid panel be drawn at least every 5 years in all adults older than 20 years.7

In addition to LDL-C levels, the presence or absence of CHD or CHD-equivalent conditions must be assessed. CHD-equivalent conditions listed by the NCEP include diabetes mellitus, peripheral vascular disease, abdominal aortic aneurysm, symptomatic carotid disease, and a 10-year CV risk of less than 20% calculated with the Framingham risk calculator.7 Although not addressed by the NCEP, the National Kidney Foundation also considers chronic kidney disease (glomerular filtration rate <60 mL/min) to be a high-risk state and recommends that this patient group be treated as having a CHD-equivalent disease.9 Likewise, the AHA and the American Stroke Association recommend the use of a statin with intensive lipid-lowering effects in patients with atherosclerotic stroke or transient ischemic attack, even in the absence of known CHD.10

KEY POINTS

• ▴Cholesterol is an essential component of cell membranes and steroid hormones.
• ▴Hypercholesterolemia and dyslipidemia are important risk factors for cardiovascular disease, which affects more than 80 million Americans.
• ▴Evidence shows that high levels of LDL-C are associated with increased cardiovascular risk; reducing LDL levels has been associated with significant reduction in mortality.
• ▴The first goal of therapy in hypercholesterolemia is reduction of LDL-C levels.
• ▴Statins are considered the most effective lipid-lowering agents available, both in lowering LDL levels and in the prevention of cardiovascular events.

In the absence of CHD or CHD-equivalent conditions, CVD risk factors (Table 1) should be carefully assessed using the Framingham risk score to determine the patient's 10-year risk of CV events (Table 2).7

Table 1.

Major Risk Factors (Exclusive of LDL-C) that Modify LDL Goals^*

Cigarette smoking

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

Low HDL-C (<40 mg/dL)†

Family history of premature CHD (CHD in male first-degree relative <55 y, CHD in female first-degree relative <55 y)

Age (men ≥45 y; women ≥55 y)

^*Diabetes is regarded a CHD risk equivalent.

^†HDL cholesterol ≥60 mg/dL counts as a negative risk factor; its presence removes 1 risk factor from the total count.

LDL-C indicates low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; CHD, coronary heart disease.

Reprinted with permission from Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486–2497.

Table 2.

An Overview of Cholesterol Management

HDL indicates high-density lipoprotein; BP, blood pressure.

Reprinted with permission from Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486–2497.

Goals of Therapy

For patients with CHD or CHD-equivalent disease, the NCEP recommends the LDL-C goal of ≤100 mg/dL, with <70 mg/dL a therapeutic option for patients considered at very high risk for CV events.8 For patients with 2 or more CV risk factors but with a 10-year Framingham risk of less than 20%, the LDL-C goal is <130 mg/dL, with <100 mg/dL a therapeutic option. Finally, for patients with 0 to 1 risk factors, the LDL-C target is <160 mg/dL.8

Therapeutic Lifestyle Changes

The NCEP Adult Treatment Panel III guidelines recommend that therapeutic lifestyle changes be implemented for all patients at risk for CVD.7 These changes include reducing intake of saturated fats and cholesterol while increasing soluble fiber intake and physical activity. Optimization of weight, moderation of alcohol consumption, and cessation of smoking are also encouraged. If drug therapy is needed, it should be used as an addition to, rather than a substitute for, therapeutic lifestyle changes.

Treatment Initiation

Since the clinical evidence of benefit is greatest with the statin drug class, the American College of Cardiology (ACC) recommends drug therapy begin with a statin and that titration to goal or the maximally tolerated dose of a statin be achieved before consideration of adding other agents.11 Regardless of the initial treatment chosen, it is critical that the patient be reevaluated and therapy titrated or added until the goal LDL-C is attained.

For patients with 0 to 1 risk factors and no CHD, treatment is initiated with therapeutic lifestyle changes with reassessment after 6 weeks. If goal LDL of <160 mg/dL is not reached at 6 weeks, lifestyle changes should be intensified and reinforced and a visit with a dietitian considered. If after 12 weeks of therapeutic lifestyle changes the patient is not at the LDL-C goal of <160 mg/dL, drug therapy, usually a statin, should be added.

For patients at moderate risk, with 2 or more risk factors and a 10-year CV risk of less than 20%, treatment begins with therapeutic lifestyle changes. Drug therapy, usually a statin, can be initiated concurrently if the LDL is >100 mg/dL at baseline or if LDL-C remains >100 mg/dL after a 6-week trial of lifestyle changes.

For the highest risk patients with CHD or equivalent conditions, statin therapy and therapeutic lifestyle changes should be initiated simultaneously for all patients with LDL-C >100 mg/dL. Drug therapy may also be considered in very high-risk patients with LDL-C <100 mg/dL targeted to achieve the optional goal of <70 mg/dL.8

Pharmacotherapy Options

A variety of lipid-lowering agents are available, including 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, bile acid sequestrants, cholesterol absorption inhibitors, fibrates, nicotinic acid derivatives, and omega-3 fatty acids. Dosage ranges, US Food and Drug Administration (FDA) indications, evidence of clinical outcome benefit, and side effects are highlighted in Table 3.

Table 3.

Pharmacotherapy for Lipid Disorders

Drug	Dosage range	Available doses	Indications	Populations w/demonstrated event reduction†	Primary effect on lipids	Side effects (most often reported)	Cost, 30-day supply
Questran* (cholestyramine)	8–24 g/d, 2 divided doses	Questran Light: packets and powder (each 5 g contain 4 g anhydrous cholestyramine resin) Questran: powder and packets (each 9 g contain 4 g anhydrous cholestyramine resin)	Adjuct therapy of hypercholesterolemia Pruritis due to partial biliary obstruction	Men with primary hypercholesterolemia (LRC-CTTP1)	LDL-C↓ 10%-30%	Abdominal discomfort, constipation, flatulence, nausea and vomiting, vitamin A, D deficiency	$$$$
Welchol (colesevelam)	3.75 g/d	625-mg tablets	Adjuct therapy of hypercholesterolemia Adjunct therapy to improve glycemic control in type 2 DM		LDL-C↓ 10%48%	Asthenia, constipation, indigestion, pharyngitis, myalgia	$$$$
Colestid* (colestipol)	2–16 g/d 2 divided doses	1-g tablets	Adjunct therapy for primary hypercholesterolemia		LDL-C↓ 10%-20%	Abdominal distension, abdominal pain, constipation, musculoskeletal pain, headache	$$$
Zetia (ezetimibe)	10 mg/d	10-mg tablets	Primary hyperlipidemia Mixed dyslipidemia Homozygous familial hypercholesterolemia Homozygous sitosterolemia		LDL-C↓ 10%-20%	Headache, diarrhea, abdominal pain, arthralgia, backache, myalgia, sinusitis	$$$
Antara* (fenofibrate)	43–130 mg/d	43-, 130-mg capsules	Hypertriglyceridemia Primary hyperglyceridemia Mixed dyslipidemia		TG↓ 20%-50%	Rash, diarrhea, flatulence, nausea and vomiting, myalgia, rhinitis	$$
Lipofen* (fenofibrate)	50–150 mg/d	50-, 150-mg capsules
Lofibra* (fenofibrate)	54–200 mg/d	54-, 160-mg tablets 67-,134-, 200-mg capsules
TriCor* (fenofibrate)	48–145 mg/d	48-, 145-mg tablets
Triglide (fenofibrate)	50–160 mg/d	50-, 160-mg tablets
Lopid* (gemfibrozil)	600–1200 mg/d, 2 divided doses	600-mg tablets	Reducing CHD risk in patients w/type 2b dyslipidemia and inadequate response to TLC, other drug therapy, who have high LDL, low HDL, high TG Familial type IV or V hyperlipidemia	Men w/primary dyslipidemia (Helsinki Heart Study2) Men w/CHD and low HDL-C (VA Hit3)	TG↓ 25%-45%	Rash, abdominal pain, diarrhea, flatulence, indigestion, xerostomia, myalgia	$
Lipitor (atorvastatin)	10–80 mg/d	10-, 20-, 40-, 80-mg tablets	Primary prevention of MI, stroke in patients w/type 2 DM and other CHD risk factors Primary prevention of MI, stroke, revascularization, hospitalization for heart failure and angina in patients w/clinically evident CAD Primary hypercholesterolemia or mixed dyslipidemia Hypertriglyceridemia Primary dysbetalipoproteinemia Homozygous FH in adolescents Heterozygous FH in adolescents	Patients w/hypertension and ≥3 CHD risk factors (ASCOT4) Patients w/type 2 DM and no history of CVD (CARDS5) Patients w/stable CHD (TNT,6 IDEAL,7 ALLIANCE,8 and and AVERT9) Patients w/atherosclerotic stroke or TIA w/o documented CHD (SPARCL10) Patients w/ACS (PROVE-IT,11 MIRACL12)	LDL-C↓ 39%-60%	Abdominal pain, constipation, flatulence, indigestion, increased liver enzymes, headache, myalgia	$$$
Lescol (fluvastatin)	20–80 mg/d	20-, 40-mg capsules	Reduce coronary revascularization in CHD Reduce progression of coronary atherosclerosis in CHD Hypercholesterolemia Heterozygous FH in adolescents	Patients with CHD who had coronary intervention (LIPS13)	LDL-C↓ 20%-35%	Abdominal pain, diarrhea, dyspepsia, nausea, headache, myalgia	$$$
Lescol XL (fluvastatin ER)	80-mg mg/d	80-mg extended-release tablets					$$$$
Mevacor* (lovastatin)	10–80 mg/d	10-, 20-, 40-mg tablets	Primary prevention of MI, unstable angina, coronary revascularization To slow progression of coronary atherosclerosis in CHD Hypercholesterolemia Heterozygous FH in adolescents	High risk (elevated LDL-C w/low HDL-C) patients w/o clinical CHD (AFCAPS-TexCaps14)	LDL-C↓ 25%-45%	Abdominal pain, constipation, diarrhea, nausea, headache, myalgia, increased hepatic transaminase levels	$$
Pravachol (pravastatin)	10–80 mg/d	10-, 20-, 40-, 80-mg tablets	Primary prevention of MI, revascularization, and CV mortality Reduction in total mortality by reducing coronary death, MI, revascularization, stroke, and to slow progression of coronary atherosclerosis in patients with CHD Hypercholesterolemia Heterozygous FH in adolescents	Men w/o history of MI w/elevated LDL (WOSCOPS13) Patients w/MI in preceding 3–20 mo (CARE16) Patients w/MI or unstable angina in previous 3–36 mo (LIPID17)	LDL-C↓ 25%-40%	Diarrhea, flatulence, heart-burn, nausea, vomiting, asthenia, headache, myalgia	$$
Crestor (rosuvastatin)	5–40 mg/d	5-, 10-, 20-, 40-mg tablets	Primary hyperlipidemia and mixed dyslipidemia Primary hypertriglyceridemia Homozygous familial hypercholesterolemia To slow the progression of atherosclerosis	Men ≥55 and women ≥65 w/LDL ≤130 mg/dL and CRP ≥2 mg/L (JUPITER18)	LDL-C↓ 45%-60%	Abdominal pain, constipation, nausea, arthralgia, asthenia, headache, myalgia, increased hepatic transaminase levels	$$$$
Zocor* (simvastatin)	5–80 mg/d	5-, 10-, 20- 40-, 80-mg tablets	Prevention of CHD mortality and CV events in patients w/existing CHD, history of stroke, diabetes, or peripheral artery disease Hypercholesterolemia Heterozygous FH in adolescents	Existing CHD and elevated total cholesterol (4S19) Patients at high risk of CV events from existing CHD, history of stroke, other cerebrovascular disease, peripheral artery disease, or hypertension in men ≥65 yr (HPS20)	LDL-C↓ 35%-50%	Constipation, GI irritation, headache, upper respiratory infection, myalgia, increased hepatic transaminase levels	$$
Slo-Niacin CR* (controlled-release niacin)	0.5–2 g/d	Niacin CR: 250-, 500-, 750-mg tablets	Primary hypercholesterolemia or mixed dyslipidemia (alone or with lovastatin) Severe hypertriglyceridemia To reduce risk of recurrent MI in patients w/hypercholesterolemia and history of MI W/bile acid-binding resin to slow progression or induce regression of coronary atherosclerosis in patients w/CAD and hypercholesterolemia W/bile acid–binding resin: primary hypercholesterolemia	Men w/history of MI (CDP21; immediate-release dosage form)	LDL↓ 5%-15% TG↓ 15%-30% HDL↑ 15%-20%	Constipation, flushing, pruritis, GI irritation, nausea, vomiting	$$
Niaspan (niacin ER)	0.5–2 g/d	Niacin ER: 500-, 750-, 1000-mg tablets					$$$$$
Immediate-release niacin*	0.25–6 g/d, 3 divided doses	500-mg tablets					$
Omega-3 fatty acid* (Lovaza)	2–4 g/d	Various	Hypertriglyceridemia (TG ≥500 mg/dL)	Hypercholesterolemic Japanese patients (over statin background therapy) (JELIS22) Patients w/recent MI (GISSI-Prevenzione23)	TG↓ 25%-45%	Increased bleeding/bruising, burping, indigestion, altered taste sense	$$
Advicor (niacin-ER/lovastatin)	Niacin-ER 500 mg-lovastatin 20 mg/d to niacin-ER 2000 mg-lovastatin 40 mg/d	Niacin-ER-lovastatin 500 mg-20 mg 750 mg-20 mg 1000 mg-20 mg	Hypercholesterolemia Mixed dyslipidemia		LDL↓ 30%-45% HDL↑ 20%-30% TG↓ 30%-45%	See under components	$$$$
Simcor (niacin-ER/simvastatin)	Niacin-ER 500 mgsimvastatin 20 mg/d to niacin-ER 2000 mgsimvastatin 40 mg/d	Niacin-ER-simvastatin 500 mg-20 mg 750 mg-20 mg 1000 mg-20 mg	Hypercholesterolemia Mixed dyslipidemia Hypertriglyceridemia (all when monotherapy inadequate)		LDL↓ 10%-15% HDL↑ 20%-30% TG↓ 15%-40% (from baseline treatment w/simvastatin 0–20 mg/d)		$$$
Vytorin (ezetemibe/simvastatin)	Ezetimibe 10 mgsimvastatin 10 mg/d to ezetimibe 10 mg—simvastatin 80 mg/d	Ezetimibesimvastatin 10 mg-10 mg 10 mg-20 mg 10 mg-40 mg 10 mg-80 mg	Primary hyperlipidemia or mixed hyperlipidemia Homozygous FH		LDL↓ 45%-60%		$$$$

^*Generic available. †Studies listed in this column may not be included in FDA-approved indications.

LDL-C indicates low-density lipoprotein cholesterol; DM, diabetes mellitus; TG, triglycerides; CHD, coronary heart disease; TLC, therapeutic lifestyle changes; HDL-C, high-density lipoprotein cholesterol; MI, myocardial infarction; CAD, coronary artery disease; FH, familial hypercholesterolemia; CVD, cardiovascular disease; TIA, transient ischemic attack; ACS, acute coronary syndrome; CV, cardiovascular; GI, gastrointestinal; CR, controlled release; ER, extended release.

1. Lipid Research Clinics Program: the lipid research clinics coronary primary prevention trial results. I. Reduction in incidence of coronary heart disease. JAMA. 1984;251:351–364.
2. Helsinki Heart Study. Primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia. N Erigi J Med. 1987;317:1237–1245.
3. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med. 1999;341:410–418.
4. Sever PS, Dahlöf B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003;361:1149–1158.
5. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364:685–696.
6. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425–1435.
7. Pedersen TR, Faergeman O, Kastelein JJ, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA. 2005;294:2437–2445.
8. Koren MJ, Hunninghake DB; ALLIANCE Investigators. Clinical outcomes in managed-care patients with coronary heart disease treated aggressively in lipid-lowering disease management clinics: the ALLIANCE study. J Am Coll Cardiol. 2004;44:1772–1779.
9. Pitt B, Waters D, Brown WV, et al. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. N Engl J Med. 1999;341:70–76.
10. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001;285:1711–1718.
11. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495–1504.
12. Amarenco P, Bogousslavsky J, Callahan A 3rd, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:549–559.
13. Serruys PW, De Feyter PJ, Benghozi R, et al. The Lescol(R) Intervention Prevention Study (LIPS): a double-blind, placebo-controlled, randomized trial of the long-term effects of fluvastatin after successful transcatheter therapy in patients with coronary heart disease. Int J Cardiovasc Intervent. 2001;4:165–172.
14. 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. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279:1615–1622.
15. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995;333:1301–1307.
16. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996;335:1001–1009.
17. The 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;339:1349–1357.
18. Ridker PM, Danielson MIA, Fonseca AH, et al, for the JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195–2207.
19. The Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383–1389.
20. 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.
21. Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986;8:1245–1255.
22. Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomized, open-label, blinded endpoint analysis. Lancet. 2007;369:1090–1098.
23. Marchioli R, Schweiger C, Tavazzi L, Valagussa F. Efficacy of n-3 polyunsaturated fatty acids after myocardial infarction: results of GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico. Lipids. 2001;36(suppl):S119-S126.

Cost: $ 0–25, $$ 26–50, $$$ 51–100, $$$$ 101–200, $$$$$ >200

Sources: Clinical data compiled from Micromedex website. http://www.thomsonhc.com. Accessed August 22, 2008. Cost information from www.drugstore.com. Accessed August 22, 2008.

HMG-CoA Reductase Inhibitors (Statins)

HMG-CoA reductase inhibitors, or statins, are the recommended first-line therapy for most patients. These are the most prescribed drugs in the world and are considered the most effective lipid-lowering agents available, both in lowering LDL-C levels and in the prevention of CV events. Statins are similar in structure to HMG-CoA, a precursor of cholesterol, and act as competitive inhibitors of HMG-CoA reductase, the last regulated enzymatic step in cholesterol synthesis. Therefore, statins reduce the rate of synthesis of cholesterol. The liver responds by increasing the number of LDL receptors, which increases hepatic uptake and catabolism of circulating LDL-C. Statins reduce LDL-C by 24% to 60% and decrease triglycerides (TGs) by 5% to 50% (percentages are based on the various package inserts), depending on the agent selected and the baseline lipid profile. HDL-C levels are usually increased. The effects on HDL are a class effect and are small relative to the effects on LDL-C and TGs. In addition, statins have a variety of anti-inflammatory effects that are independent of the LDL-C lowering, which may contribute to the clinical benefit in CVD, especially early in therapy.12 However, a recent meta-analysis of 23 lipid-lowering trials demonstrated that the majority (89%-98%) of the anti-inflammatory effects of lipid-lowering therapy is related to the degree of LDL reduction,13 which suggests a limited influence of a non-LDL-C–related anti-inflammatory mechanism.

Adverse events, relatively uncommon with this class, include gastrointestinal (GI) disturbances, muscle aches, and asymptomatic transaminasemia. Rare serious adverse events may include myopathy and rhabdomyolysis. FDA-approved labeling recommends assessment of liver function at baseline, after 12 weeks of therapy, after dose escalation, and twice yearly thereafter. However, the National Lipid Association has suggested that this practice does not increase the safety of statin therapy, but merely increases cost.14

Bile Acid Sequestrants

Bile acid sequestrants bind to bile acids in the intestine, reducing absorption of cholesterol and other lipids. The resultant decrease in available cholesterol causes an increase in the number of LDL receptors on hepatocytes, further promoting clearance of LDL-C from the blood. Bile acid sequestrants are recommended as second-line therapy for patients with elevated cholesterol, but not elevated TGs, as both VLDL-C and TG concentrations may increase during therapy. Agents in this class lower LDL-C by 15% to 30% and increase HDL-C by 3% to 5% on average.9 Patient adherence with these agents is frequently poor due to the need for frequent dosing, poor palatability, and frequent GI side effects. Since these drugs remain in the GI tract, systemic adverse effects are minimal; however, these agents can interfere with absorption of concomitantly administered drugs as well as fat-soluble vitamins.

Nicotinic Acid Derivatives

Niacin reduces synthesis of VLDL-C in the liver and therefore reduces LDL-C production. Pharmacologic doses of niacin (1.5–2 g/day) lower LDL-C and TGs by 15% to 20% and 30% to 40%, respectively, and increase HDL-C by 15% to 25%. Niacin is used as second-line therapy in concert with other lipid-lowering agents. The most common adverse events include vasodilation with flushing and pruritis, which frequently is dose-limiting. Other adverse events include dyspepsia, gastric ulceration, hyperuricemia, palpitations, and, rarely, peripheral neuropathy.

Niacin-induced hyperglycemia may be problematic for patients with diabetes mellitus or with impaired glucose tolerance, particularly in the first 6 months of therapy, but long-term clinical benefits have been demonstrated in these patients.15 The most serious side effect is hepatotoxicity; cases of fatal fulminant hepatic failure have been associated with niacin administration, particularly with older formulations.16

Fibrates

Fibric acid derivatives, or fibrates, such as gemfibrozil and fenofibrate, are agonists of the peroxisomeactivated receptor-α in muscle, liver, and other tissues. Fibrates can lower TG levels by up to 50% and are therefore considered the first-line agents in patients with hypertriglyceridemia (TG >400 mg/dL). However, LDL-C reduction is variable (10%-15%), with some patients exhibiting increased levels of LDL-C. HDL-C levels may be increased up to 25% in patients with very high TG levels at baseline.17 The most common adverse events are rash and dyspepsia for fenofibrate and GI disturbances for gemfibrozil. All fibrates may increase the risk of gallstones. In addition, gemfibrozil has been shown to increase plasma concentration of statins, thereby increasing the risk of muscle toxicity.18

Ezetimibe

As with bile acid sequestrants, ezetimibe inhibits the absorption of cholesterol. However, since it does not interfere with the absorption of other dietary fats, it is better tolerated. Ezetimibe localizes at the brush border of the small intestine, where it binds to a critical mediator of cholesterol absorption, the Niemann-Pick C1-like 1 protein on the GI tract epithelial cells19 and liver cells. Like the bile acid sequestrants, by reducing the availability of LDL-C, ezetimibe also induces LDL receptor upregulation leading to increased uptake of LDL-C into cells, further lowering circulating LDL-C levels. While ezetimibe effectively lowers LDL-C, studies assessing clinical event reduction are lacking. In a recent study, no additional decrease in the carotid intima-media thickness was demonstrated with ezetimibesimvastatin combination therapy compared with simvastatin alone, despite significantly greater reduction in LDL-C in the combination group.20

In addition, in another study, an increased risk of cancer death was observed in the simvastatin-ezetimibe group compared with the placebo group,21 but an analysis of more than 20,000 patients in ongoing randomized trials revealed no increase in cancer risk in patients receiving ezetimibe compared with placebo.22 However, given the lack of documented outcome benefit with this agent, the ACC recommends that it be reserved for patients who cannot reach LDL-C goal with maximal dose statins.11

Omega-3 Fatty Acids

Epidemiologic studies have demonstrated that people who have diets rich in omega-3 fatty acids have a lower risk of CV events compared with those with a typical Western diet. Studies of omega-3 fatty acid administration have demonstrated reductions in TGs of up to 45% in patients with baseline TG levels >500 mg/dL.23 Smaller reductions are expected in patients with lower baseline levels. In addition to the reduction in TGs, HDL-C levels may be increased by as much as 9%. The addition of omega-3 fatty acids to statin therapy produces further reductions in VLDL-C and TGs and further elevations in HDL-C. The putative mechanisms for TG reduction with high-dose omega-3 fats include increased beta oxidation.

Conclusion

Elevated cholesterol level is a major risk factor for CVD, the leading cause of death worldwide. Reduction of LDL-C has been shown to decrease the risk of CV events in a large number of clinical trials. Because they are the best studied, have a favorable risk/benefit profile, and have been demonstrated to produce clinical benefits in many large trials, statins are the first-line treatment for patients with hypercholesterolemia.

Stakeholder Perspective

Experts Debate Meaning of JUPITER for Clinical Practice

PHYSICIANS/PAYERS: Should the indications for statins be expanded? This was the question that had many cardiovascular (CV) experts talking, but with little consensus, in light of the findings from the JUPITER (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin) study released in November 2008 at the American Heart Association annual meeting and then published in the New England Journal of Medicine.1 The results have also created a buzz among P & T Committee members: Should they change plan benefits for statins? Will physicians begin to prescribe the drugs to a new patient population even off-label?

JUPITER showed that apparently healthy individuals with unremarkable levels of low-density lipoprotein cholesterol (LDL-C) but with elevated levels of high-sensitivity C-reactive protein (hs-CRP)—2.0 mg/L or more—had a dramatic reduction in the risk for CV events by taking rosuvastatin (Crestor) compared with placebo.

The large benefit of rosuvastatin—a 44% relative reduction in CV risk—surpassed the expectations of the lead investigator, Paul Ridker, MD, Director of the Center for Cardiovascular Disease Prevention at Brigham and Women's Hospital, who has championed the use of hs-CRP to estimate CV risk for quite some time. “Getting CRP down appears to have incremental benefit to lowering LDL cholesterol,” Dr Ridker said. “There was a large number in our study who had an elevation of CRP without other risk factors, and this group had a benefit from rosuvastatin as well.” Of those who fit the profile of the study population, 25 patients would need to be treated to prevent 1 CV event, which is “smaller than we anticipated,” said Dr Ridker.

Steve Nissen, MD, Chairman of the Department of Cardiovascular Medicine at the Cleveland Clinic, is a believer in CRP testing and is already using it to guide treatment decisions. He noted that the reduction in death and major CV events with rosuvastatin was larger than in any other trial of a statin, and he was impressed that it occurred after only an average of 1.9 years of treatment (the study had been planned to last 5 years but was terminated early because of the large benefit found).

According to Dr Nissen, applying the findings from JUPITER to the US population could add 10 million persons who could benefit from statins.

Critics point out that although the magnitude of the 44% relative reduction in risk was large, the absolute risk reduction was rather small—only 0.9% (1.8% in the placebo group had an event compared with 0.9% in the rosuvastatin group). Of note, subjects enrolled in the trial were at low risk at baseline, and this low risk accounted for the small reduction in absolute risk. Only 157 of 8901 subjects taking placebo had an event compared with 83 of 8901 randomized to rosuvastatin.

Using Crestor to prevent 1 death in persons with elevated CRP levels has been estimated at $500,000, a cost that may be too high. Some suggest that prescribing Crestor to reduce CRP could add $8.9 billion to the cost of treatment in this country. But this cost would be reduced to about $25,000 to prevent 1 death, using a generic statin, if generic statins are as effective as the brand drug at reducing CRP levels. Evidence indicates that all the statins reduce CRP, but to different degrees.

Wayne Kuznar

Medical Writer

Cholesterol Management: The Complexity of Multiple Effectives Treatments

PAYERS: High levels of serum cholesterol have long been recognized as a significant risk factor for the development and progression of atherosclerosis. Lowering cholesterol has been shown to effectively reduce mortality and morbidity associated with acute coronary syndromes and stroke—2 of the top 3 causes of death in the United States. As our understanding of the role of cholesterol has evolved, we have come to realize the individual effects that low-density lipoprotein (LDL) and high-density lipoprotein can have in risk assessment and modification.

As the authors of this article highlight, a large number of effective treatments are available. The availability of multiple agents adds to the complexity of their use: Are all these agents equal in their ability to affect lipid levels? Are they equal in their ability to influence outcomes? For an individual patient with a specific set of risk factors and a specific lipid profile, which agents will best affect their lipid panel and their overall risk of cardiovascular or cerebrovascular complications?

The availability of several effective treatments also raises questions about thresholds for screening and treatment. A number of organizations have provided such guidance, including the American Heart Association, the National Cholesterol Education Program, the United States Preventive Services Task Force (USPSTF), and the American Academy of Pediatrics. As is often the case for the clinician attempting to determine the best recommendation for a given patient, or for the patient attempting to participate in decision-making—the rapid development of new science and research and the conflicting guidance of expert panel recommendations can compound the confusion. For example, the USPSTF currently recommends screening of patients older than 20 years, citing insufficient evidence for screening younger populations. Meanwhile, a recommendation issued in 2008 by the American Academy of Pediatrics is much more aggressive with regard to screening, and even treatment, of children with certain risk factors.1

This complexity is further increased with the publicity related to the early termination of the JUPITER trial (see previous page), which was published in November 2008.2 In JUPITER, patients without a history of cardiovascular disease, with LDL levels <130 mg/dL but with high-sensitivity C-reactive protein levels of 2.0 mg/L or more, were randomized to receive rosuvastatin or placebo. The trial was ended early because patients in the treatment group showed very significant reductions in myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes. This study will raise questions regarding the thresholds that must be met to initiate therapy. It will also raise issues concerning the relative effectiveness of various agents, depending on their ability to affect “inflammation” as a separate risk factor for atherosclerosis.

Until the evidence becomes clearer, we must empower clinicians facing these decisions with as many options as possible. They must be able to personalize therapy—the best agent for the individual patient—without undue restrictions.

Thomas McCarter, MD, FACP

Chief Clinical Officer, Executive Health Resources

Biography