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 lowdensity 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
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
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.
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 LDLC <100 mg/dL targeted to achieve the optional goal of <70 mg/dL.8
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.
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 lipidlowering therapy is related to the degree of LDL reduction,13 which suggests a limited influence of a non-LDLC– 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
Fibric acid derivatives, or fibrates, such as gemfibrozil and fenofibrate, are agonists of the peroxisomeactivated receptor-a 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 LDLC. 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
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.
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.
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.
Dr Moe is on the Speakers' Bureau for Pfizer, BMS, Novartis, Abbott, and GlaxoSmithKline. Drs Burns Schaiff and Krichbaum are employees of Pfizer, Inc. Limited editorial support was provided by Paul Lane, PhD, at Envision Pharma, Ltd, and was funded by Pfizer, Inc.
- Mensah GA, Brown DW. An overview of cardiovascular disease burden in the United States. Health Aff (Millwood). 2007;26:38-48.
- Rosamond W, Flegal K, Furie K, et al. Heart disease and stroke statistics— 2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2008;117:e25-146.
- The Lipid Research Clinics Coronary Primary Prevention Trial Results. I. Reduction in incidence of coronary heart disease. JAMA. 1984;251:351-364.
- Brown G, Albers JJ, Fisher LD, et al. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med. 1990;323:1289-1298.
- Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003;349:523-534.
- Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl JMed. 2007;357:2109-2122.
- 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;285:2486-2497.
- Grundy SM, Cleeman JI, Bailey Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227-239.
- National Kidney Foundation. K/DOQI Clinical practice guidelines for managing dyslipidemias in chronic kidney disease. Part 3: treating dyslipidemias. Am J Kidney Dis. 2003;41(4 suppl 3):S39-S58.
- Adams RJ, Albers G, Alberts MJ, et al. Update to the AHA/ASA recommendations for the prevention of stroke in patients with stroke and transient ischemic attack. Stroke. 2008;39:1647-1652.
- American College of Cardiology. ACC Statement on ENHANCE Trial. January 15, 2008. http://www.acc.org/enhance_statement.htm. Accessed October 10, 2008.
- Libby P. Current concepts of the pathogenesis of atherosclerosis. Circulation. 2001;104:365-372.
- Kinlay S. Low density lipoprotein-dependent and independent effects of cholesterol lowering therapies on C-reactive protein: a metaanalysis. J Am Coll Cardiol. 2007;49:2003-2009.
- Cohen DE, Anania FA, Chalasani N; National Lipid Association Statin Safety Task Force Liver Expert Panel. An assessment of statin safety by hepatologists. Am J Cardiol. 2006;97(8A):77C-81C.
- Canner PL, Furberg CD, Terrin ML, McGovern ME. Benefits of niacin by glycemic status in patients with healed myocardial infarction (from the Coronary Drug Project). Am J Cardiol. 2005;95:254-257.
- Ferenchick G, Rovner D. Hepatitis and hematemesis complicating nicotinic acid use. Am J Med Sci. 1989;298:191-193.
- Guay DR. Micronized fenofibrate: a new fibric acid hypolipidemic agent. Ann Pharmacother. 1999;33:1083-1103.
- No√© J, Portmann R, Brun ME, Funk C. Substrate-dependent drugdrug interactions between gemfibrozil, fluvastatin and other organic anion-transporting peptide (OATP) substrates on OATP1B1, OATP2B1, and OATP1B3. Drug Metab Dispos. 2007;35:1308-1314.
- Garcia-Calvo M, Lisnock J, Bull HG, et al. The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1). Proc Natl Acad Sci. 2005;102: 8132-8137.
- Kastelein JP, Akdim F, Stroes ES, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. NEngl JMed. 2008;358: 1431-1443.
- Rossebo AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008; 359:1343-1356.
- Peto R, Emberson J, Landray M, et al. Analysis of cancer data from three ezetimibe trials. N Engl J Med. 2008;359:1357-1366.
- Kris-Etherton PM, Harris WS, Appel LJ; American Heart Association. Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation. 2002;106:2747-2757.