Matthew K. Ito
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Identify the major components within each lipoprotein and their role in lipoprotein metabolism and the development of atherosclerosis.
2. Identify the common types of lipid disorders.
3. Determine a patient’s coronary heart disease risk and corresponding treatment goals according to the National Cholesterol Education Program Adult Treatment Panel III guidelines.
4. Recommend appropriate therapeutic lifestyle changes (TLC) and pharmacotherapy interventions for patients with dyslipidemia.
5. Identify the diagnostic criteria and treatment strategies for the metabolic syndrome.
6. Describe the components of a monitoring plan to assess effectiveness and adverse effects of pharmacotherapy for dyslipidemias.
7. Educate patients about the disease state, appropriate TLC, and drug therapy required for effective treatment.
KEY CONCEPTS
The risk of atherosclerosis is directly related to increasing levels of serum cholesterol.
The National Cholesterol Education Program Adult Treatment Panel III guidelines have set the “optimal” level for low-density lipoprotein (LDL) cholesterol for all adults as less than 100 mg/dL (2.59 mmol/L).
All adults greater than 20 years of age should be screened at least every 5 years using a fasting blood sample.
The benefits of lowering LDL cholesterol to as low as 70 mg/dL (1.81 mmol/L) have been demonstrated in clinical trials; however, the lowest level at which to treat LDL cholesterol where there are no further benefits in coronary heart disease (CHD) risk has not yet been determined.
An adequate trial of therapeutic lifestyle changes (TLC) should be employed in all patients, but pharmacotherapy should be instituted concurrently in higher-risk patients.
Typically, statins are the medications of choice to treat high LDL cholesterol because of their ability to substantially reduce LDL cholesterol, ability to reduce morbidity and mortality from atherosclerotic disease, convenient once-daily dosing, and low risk of side effects.
Patients with metabolic syndrome have an additional lipid parameter that needs to be assessed, namely non-high-density lipoprotein (non-HDL) cholesterol (total cholesterol minus HDL cholesterol). The target for non-HDL cholesterol is less than the patient’s LDL cholesterol target plus 30 mg/dL (0.78 mmol/L).
After assessment and control of LDL cholesterol, patients with serum triglycerides of 200 to 499 mg/dL (2.26-5.64 mmol/L) should be assessed for atherogenic dyslipidemia (low HDL cholesterol and increased small-dense LDL particles) and the metabolic syndrome.
Combination drug therapy is an effective means to achieve greater reductions in LDL cholesterol (statin + ezetimibe or bile acid resin, bile acid resin + ezetimibe, or three-drug combinations) as well as raising HDL cholesterol and lowering serum triglycerides (statin + niacin or fibrate).
Reducing LDL cholesterol while substantially raising HDL cholesterol (statin + niacin) appears to reduce the risk of atherosclerotic disease progression to a greater degree than statin monotherapy
INTRODUCTION
The risk of atherosclerosis is directly related to increasing levels of serum cholesterol. Hypercholesterolemia (elevation in serum cholesterol) and other abnormalities in serum lipids play a major role in plaque formation leading to coronary heart disease (CHD) as well as other forms of atherosclerosis, such as carotid and peripheral artery disease (atherosclerosis of the peripheral arteries). This predictive relationship has been demonstrated from large epidemiologic,1 animal, and genetic studies. CHD is the leading cause of death in both men and women in the United States and most industrialized nations. It is also the chief cause of premature, permanent disability in the U.S. workforce. Annually, approximately 700,000 Americans will suffer a new heart attack and 500,000 will have a recurrent event. The average age of a first heart attack is 66 years for American men and 70 years for women. The direct and indirect cost of CHD to the U.S. economy in 2007 was almost $151.6 billion.2 Clinical trials have consistently demonstrated that lowering serum cholesterol reduces atherosclerotic progression and mortality from CHD.
The development of CHD is a lifelong process. Except in rare cases of severely elevated serum cholesterol levels, years of poor dietary habits, sedentary lifestyle, and life-habit risk factors (e.g., smoking and obesity) contribute to the development of atherosclerosis.3 Unfortunately, many individuals at risk for CHD do not receive lipid-lowering therapy or are not optimally treated. This chapter will help identify individuals at risk, assess treatment goals based on the level of CHD risk, and implement optimal treatment strategies and monitoring plans.
PATHOPHYSIOLOGY
Lipid and Lipoprotein Metabolism
Cholesterol is an essential substance manufactured by most cells in the body. Cholesterol is used to maintain cell wall integrity and for the biosynthesis of bile acids and steroid hormones. Other major lipids in our body are triglycerides and phospholipids. Since cholesterol is a relatively water-insoluble molecule, it is unable to circulate through the blood alone. Cholesterol along with triglycerides and phospholipids are packaged in a large carrier-protein called a lipoprotein (Fig. 12–1). Lipoproteins are water soluble, which allows transportation of the major lipids in the blood. These lipoproteins are spherical and vary in size (approximately 1,000 to 6 nm) and density (less than 0.94 to 1.21 g/mL) (Table 12–1). The amount of cholesterol and triglycerides vary by lipoprotein size. The major lipoproteins in descending size and ascending density are chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL). When clinical laboratories measure and report serum total cholesterol, what they are measuring and reporting are the total cholesterol molecules in all the major lipoproteins. The estimated value of LDL cholesterol is found using the following equation:
LDL cholesterol = total cholesterol -(HDL cholesterol + triglyceridesβ) using traditional units of mg/dL; or
LDL cholesterol = total cholesterol -(HDL cholesterol + triglycerides/2.2) using SI units of mmol/L.
If serum triglycerides are greater than 400 mg/dL (4.52 mmol/L), chylomicrons are present, or the patient has type III hyperlipoproteinemia, this formula becomes inaccurate and LDL cholesterol must be directly measured.3
Each lipoprotein has various proteins called apolipo-proteins (Apos) embedded on the surface (Fig. 12–1). These Apos serve four main purposes, they: (a) are required for assembly and secretion of lipoproteins (such as Apos B-48 and B-100); (b) serve as major structural components of lipoproteins; (c) act as ligands (Apo B-100 and Apo E) for binding to receptors on cell surfaces (LDL receptors); and (d) can be cofactors (such as Apo C-II) for activation of enzymes (such as lipoprotein lipase [LPL]) involved in the breakdown of triglycerides from chylomicrons and VLDL.4 Apos A-I and A-II are major structural proteins on the surface of HDL. Apo A-I interacts with adenosine triphosphate (ATP) binding cassette A1 and G1 to traffic cholesterol from extrahepatic tissue (such as the arterial wall) to immature or nascent HDL.
Cholesterol from the diet as well as from bile enters the small intestine, where it is emulsified by bile salts into micelles (Fig. 12–2). These micelles interact with the duodenal and jejunal enterocyte surfaces, and cholesterol is transported from the micelles into these cells by the Niemann-Pick Cl Like 1 (NPC1L1) transporter.5 Some cholesterol and most plant sterols, which are structurally similar to cholesterol, are exported back from the enterocyte into the intestinal lumen by the ATP-binding cassette (ABC) G5/G8 transporter. Cholesterol within enterocytes is esterified and packaged into chylomicrons along with triglycerides, phospholipids, and Apo B-48 as well as Apos C and E, which are then released into the lymphatic circulation. In the circulation, chylomicrons are converted to chylomicron remnants (through loss of triglycerides by the interaction of Apo C-II and LPL). During this process, chylomicrons also interact with HDL particles (Fig. 12–3) and exchange triglyceride and cholesterol content, and HDL particles acquire Apos A and C. Chylomicron remnant particles are then taken up by LDL-related protein (LRP).
FIGURE 12–1. Lipoprotein structure. Lipoproteins are a diverse group of particles with varying size and density. They contain variable amounts of core cholesterol esters and triglycerides, and have varying numbers and types of surface apolipoproteins. The apolipoproteins function to direct the processing and removal of individual lipoprotein particles. (From LipoScience, Inc. with permission.)
Table 12–1 Physical Characteristics of Lipoproteins
FIGURE 12–2. Intestinal cholesterol absorption and transport. Cholesterol from food and bile enter the gut lumen and are emulsified by bile acids into micelles. Micelles binding to the intestinal enterocytes, and cholesterol and other sterols are transported from the micelles into the enterocytes by a sterol transporter. Triglycerides synthesized by absorbed fatty acids along with cholesterol and apolipoprotein B-48 are incorporated into chylomicrons. Chylomicrons are released into the lymphatic circulation and are converted to chylomicron remnants (through loss of triglyceride), and then taken up by the hepatic LDL receptor-related protein (LRP). (ABC G5/G8, ATP-binding cassette G5/G8; Apo, apolipoprotein; CE, cholesterol ester; FA, fattyacid; NPC1L1, Niemann-PickC1 Like 1;TG, triglyceride.)
In the liver, cholesterol and triglycerides are incorporated into VLDL along with phospholipids and Apo B-100 (Fig. 12–4). VLDL particles are released into the circulation where they acquire Apo E and Apo C-II from HDL. VLDL loses its triglyceride content through the interaction with LPL to form VLDL remnant and IDL. IDL can be cleared from the circulation by hepatic LDL receptors or further converted to LDL (by further depletion of triglycerides) through the action of hepatic lipases (HL). Approximately 50% of IDL is converted to LDL. LDL particles are cleared from the circulation primarily by hepatic LDL receptors by interaction with Apo B-100. They can also be taken up by extrahepatic tissues or enter the arterial wall, contributing to atherogenesis.6
Cholesterol is transported from the arterial wall or other extrahepatic tissues back to the liver by HDL (Fig. 12–3). Apo A-I (derived from the intestine and liver) on nascent HDL interacts with ATP-binding cassette A1 (ABCA1) and Gl transporter on extrahepatic tissue. Cholesterol in nascent HDL is esterified by lecithin-cholesterol acyltransferase (LCAT) resulting in mature HDL. The esterified cholesterol can be transferred as noted above to Apo B-containing particles in exchange for triglycerides. Triglyceride-rich HDL is hydrolyzed by HL, generating fatty acids and nascent HDL particles, or the mature HDL can bind to the scavenger receptors (SR-BI) on hepatocytes and transfer their cholesterol ester content for excretion in the bile.
A variety of genetic mutations occur in the above steps during lipoprotein synthesis and metabolism that cause lipid disorders. The major genetic disorders and their effect on serum lipids are presented in Table 12–2. Disorders that increase serum cholesterol are generally those that affect the number or affinity of LDL receptors (also known as Apo B-E receptors) known as familial hypercholesterolemia, or the ability of Apo B-100 to bind to the receptor known as familial defective Apo B-100. These patients commonly present with corneal arcus of the eye and xanthomas of extensor tendons of the hand and Achilles tendon. Elevations in triglycerides are generally associated with overproduction of VLDL, mutations in Apo E, or lack of LPL. Patients with extremely elevated serum triglycerides can develop pancreatitis and tuberoeruptive xanthomas. Most individuals have mild to moderate elevations in cholesterol caused by a polygenic disorder. Polygenic hypercholesterolemia is not as well understood as the single-gene disorders discussed above. Polygenic hypercholesterolemia is thought to be caused by various, more subtle genetic defects as well as environmental factors such as diet and lack of physical activity.3
FIGURE 12–3. Reverse cholesterol transport. Cholesterol is transported from the arterial wall or other extrahepatic tissues back to the liver by HDL. Esterified cholesterol from HDL can be transferred to apolipoprotein B-containing particles in exchange for triglycerides. Cholesterol esters transferred from HDL to VLDL and LDL are taken up by hepatic LDL receptors or delivered back to extrahepatic tissue. (ABCA1, ATP-binding cassette A1; ABCG1, ATP-binding cassette G1; Apo, apolipoprotein; C, cholesterol; CE, cholesterol ester; CETP, cholesterol ester transfer protein; CM, chylomicrons; HDL, high-density lipoprotein; HL, hepatic lipase; LCAT, lecithin-cholesterol acyltransferase; LDL, low-density lipoprotein; SR-B1, scavenger receptors; TG, triglyceride; VLDL, very low-density lipoprotein.)
Pathophysiology of CAD
The most widely accepted theory of the process of atherosclerosis is that it is a low-grade inflammatory response due to injury of the vascular endothelium induced by lipoprotein retention in the arterial wall.6The process begins when lipoproteins migrate between the endothelial cells into the arterial wall and bind to proteoglycans (Fig. 12–5). The initial lesion, known as a fatty streak, appears to form after accumulation of lipoproteins within the intima. After entering the intima, lipoproteins are then structurally modified by oxidation. Oxidized lipoproteins as well as other cytotoxic agents promote endothelial dysfunction by disturbing the production of vasoactive molecules such as nitric oxide that maintain vasomotor tone. Small, denser LDL particles migrate into the arterial wall more readily and are particularly susceptible to oxidation. The oxidized particles cause an increased expression of cell-adhesion molecules on vascular endothelial cells leading to recruitment of monocytes into the intima. The monocytes differentiate into macrophages and express scavenger receptors allowing enhanced uptake of Apo B-containing lipoproteins. The macrophages continue to accumulate lipoproteins and ultimately develop into lipid-laden foam cells. Accumulation of foam cells leads to formation of a lipid-rich core, which marks the transition to a more complicated atherosclerotic plaque. Vascular wall remodeling leading to outward growth of the wall occurs to accommodate this lipid-rich core. Thus, the vascular lumen is relatively well preserved and generally the lesion would not be detected using traditional coronary angiographic techniques. Initially, smooth muscle cells migrate and proliferate from the media to the intima forming a protective fibrous cap which separates the potentially thrombogenic lipid core from circulating blood. As the plaque matures, inflammatory cells secrete matrix metalloproteinases that degrade collagen and fibrin produced by smooth muscle cells that lead to a weakened fibrous cap. Ischemic events result when the fibrous cap of these unstable plaques rupture and produce an occlusive thrombus. In contrast, repeated wound healing secondary to less significant plaque disruption that causes no symptoms might produce a more stable plaque as a consequence of smooth muscle cell, collagen, and fibrin accumulation and a resolution of the lipid core.6 These more stable plaques usually cause luminal encroachment (detected by traditional coronary angiographic techniques) and may produce angina pectoris. Unstable lesions usually outnumber the more stable plaques, thus accounting for a majority of acute coronary syndromes.Evidence demonstrates that aggressive lipid-lowering does stabilize these vulnerable lesions and restores endothelial function.3,6,7
FIGURE 12–4. Endogenous lipoprotein metabolism. In liver cells, cholesterol and triglycerides are packaged into VLDL particles and exported into blood where VLDL is converted to IDL. Intermediate-density lipoprotein can be either cleared by hepatic LDL receptors or further metabolized to LDL. LDL can be cleared by hepatic LDL receptors or can enter the arterial wall, contributing to atherosclerosis. (Acetyl CoA, acetyl coenzyme A; Apo, apolipoprotein; CE, cholesterol ester; FA, fatty acid; HL, hepatic lipase; HMG-CoA, 3-hydroxy-3-methyglutaryl coenzyme A; IDL, intermediate-density lipoprotein; LCAT, lecithin-cholesterol acyltransferase; LDL, low-density lipoprotein; LPL, lipoprotein lipase; VLDL, very low-density lipoprotein.)
Table 12–2 Selected Characteristics of Primary (Genetic) Dyslipidemias
FIGURE 12–5. The process of atherogenesis. Atherosclerosis is initiated by the migration and retention of LDL and remnant lipoprotein particles into the vessel wall. These particles undergo oxidation and are taken up by macrophages in an unregulated fashion. The oxidized particles participate to induce endothelial cell dysfunction leading to a reduced ability of the endothelium to dilate the artery and cause a prothrombotic state. The unregulated uptake of cholesterol by macrophages leads to foam cell formation and the development of a blood clot-favoring fatty lipid core. The enlarging lipid core eventually causes an encroachment of the vessel lumen. Early in the process, smooth muscle cells are activated and recruited from the media to the intima, helping to produce a collagen matrix that covers the growing clot protecting it from circulating blood. Later, macrophages produce and secrete matrix metalloproteinases which degrade the collagen matrix, leading to unstable plaque which may cause a myocardial infarction. (IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; MMP, matrix metalloproteinases; NO, nitric oxide.)
TREATMENT
In the United States, prevention and treatment of CHD is based primarily on guidelines issued in 2001 by the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III [ATP III]).3 The ATP IV guidelines are in development and will be available in 2010.8 LDL cholesterol is the primary diagnostic and therapeutic target. The NCEP ATP III guidelines have set the “optimal” level for LDL cholesterol for all adults as less than 100 mg/dL (2.59 mmol/L). The NCEP panel issued an update in 2004 to the ATP III guidelines based on more recent clinical trial evidence.9 The update outlines additional treatment options for certain patient populations, mainly those who are at very high risk of recurrent CHD events. These treatment options emphasize the benefits of diet, exercise, and weight control and the use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (or statins) as first-line drugs. If statins or other drugs used to treat hyperlipidemia are prescribed, doses that reduce LDL cholesterol by at least 30% to 40% should be recommended.9
Most recently, the American Heart Association and American College of Cardiology issued guidelines for secondary prevention in patients with established CHD based on the results of two additional trials published after the 2004 NCEP update.10 These guidelines suggest it is reasonable to set an LDL cholesterol goal of less than 70 mg/dL (1.81 mmol/L) in all patients with CHD. If it is not possible to attain LDL cholesterol less than 70 mg/dL (1.81 mmol/L) due to a high baseline LDL cholesterol, it is generally possible to achieve an LDL cholesterol reduction of greater than 50% with more intensive LDL-lowering therapy, including combination drug therapy.
Clinical Presentation and Diagnosis of Dyslipidemias
Lipid Panel
• Patients presenting with a total cholesterol level exceeding 200 mg/dL (5.18 mmol/L) or LDL cholesterol exceeding 100 mg/dL (2.59 mmol/L) should be evaluated for high cholesterol.
• Patients with serum triglycerides from 150 to 500 mg/dL (1.70-5.65 mmol/L) and serum HDL cholesterol less than 40 mg/dL (1.04 mmol/L) may have metabolic syndrome and need to be evaluated.
Physical Findings
• Patients with genetic disorders that cause a marked increase in serum LDL cholesterol (greater than 250 mg/dL [6.48 mmol/L]) may present with corneal arcus of the eye and xanthomas of extensor tendons of the hand and Achilles tendon.
• Patients with extremely elevated serum triglycerides (greater than 1,000 mg/dL [11.3 mmol/L]) can develop pancreatitis and tuberoeruptive xanthomas.
Indications for Lipid Panel
• All adults greater than 20 years of age should be screened at least every 5 years using a fasting blood sample to obtain a lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides). A fasting lipid profile is preferred so an accurate assessment of LDL cholesterol can be performed, and fasting will allow the clearance of triglycerides carried by chylomicrons from the circulation, allowing VLDL cholesterol to be determined.
• Children between 2 and 20 years old should be screened for high cholesterol if their parents have premature CHD or if one of their parents has a total cholesterol greater than 240 mg/dL (6.22 mmol/L). Early screening will help to identify children at highest risk of developing CHD in whom early education and dietary intervention is warranted.
Indications for Other Tests
• Conditions that may produce lipid abnormalities (such as those listed in Table 12–3) should be screened for using appropriate tests. If present, these conditions should be properly addressed.
Guidelines for Treatment
Step 1: Patient Assessment
Determine lipoprotein profile after fasting for 9 to 12 hours. The NCEP guidelines recommend that all adults greater than 20 years of age should be screened at least every5 years using a fasting blood sample to obtain a lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides). A fasting lipid profile is preferred so an accurate assessment of LDL cholesterol can be performed. Fasting permits the clearance of triglycerides carried by chylomicrons from the circulation, thus allowing VLDL cholesterol to be determined. Children between 2 and 20 years old should be screened for high cholesterol if their parents have premature CHD or if one of their parents has a total cholesterol greater than 240 mg/dL (6.22 mmol/L).3 Early screening will help to identify children at highest risk of developing CHD, in whom early education and dietary intervention is warranted.
Step 2: Rule Out Secondary Causes of Dyslipidemia
Certain drugs and diseases can cause abnormalities in serum lipids and should be evaluated (Table 12–3). Every effort should be made to correct or control underlying diseases such as hypothyroidism and diabetes. Concurrent medications known to induce lipid abnormalities should be evaluated for discontinuation prior to instituting long-term lipid-lowering therapy.3
Step 3: Identify the Presence of Clinical Atherosclerotic Disease or Other Conditions That Confer High Risk for CHD Events
Individuals with established CHD, other clinical atherosclerotic disease (CAD), or diabetes have a greater than 20% risk over a 10-year period of developing CHD events.3 The ATP III guidelines set the target LDL cholesterol level at less than 100 mg/dL (2.59 mmol/L) for high-risk patients who have a history of one or more of the following:
• Myocardial infarction (MI)
• Unstable angina
• Chronic stable angina
Table 12–3 Secondary Conditions and Drugs That May Cause Hyperlipidemias
• Coronary interventions (coronary bypass, percutaneous transluminal coronary angioplasty, or stents)
• Peripheral arterial disease (claudication or ankle-brachial index less than 0.9)
• Symptomatic carotid artery disease (stroke or transient ischemic attack)
• Diabetes (types 1 and 2)
• Multiple risk factors with a Framingham calculated risk (Fig. 12–6) greater than 20%
The benefits of lowering LDL cholesterol to as low as 70 mg/dL (1.81 mmol/L) have been demonstrated in clinical trials. Thus, in patients considered very high risk, an LDL cholesterol goal of less than 70 mg/dL (1.81 mmol/L) is a therapeutic option.9,10 These individuals have established CAD or present with acute coronary syndromes. The lowest level of LDL cholesterol where there is no further reduction in CHD risk has not yet been determined.
Step 4: Determine the Presence of Major Risk Factors
In individuals who do not have established CHD or CHD risk equivalent, the next step is to count major risk factors for CHD as presented in Table 12–4. These risk factors are considered independent predictors of CHD. HDL cholesterol of greater than or equal to 60 mg/dL (1.55 mmol/L) is considered a negative risk factor and means one risk factor can be subtracted from the total count.3
Step 5: If Two or More Risk Factors Are Present Without CHD or CHD Risk Equivalent, Assess 10-Year CHD Risk
Listed in Table 12–5 are the risk groups that require risk calculations using the Framingham scoring system.3 Because individuals with two or more risk factors may carry a risk equivalent to individuals with established CHD, and therefore should be treated with the same intensity, a scoring system developed from the Framingham Coronary Heart Disease Study is used to estimate this 10-year risk (Fig. 12–6). This system assigns points to the following risk factors: age, total cholesterol level, smoking status, HDL cholesterol level, and systolic blood pressure. The score is used to determine a patient’s risk category and the intensity of treatment to lower their LDL cholesterol. To calculate a Framingham score, visit the following website: http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm.
Step 6: Determine Treatment Goals and Therapy
Treatment goals for LDL cholesterol and thresholds for the institution of therapeutic lifestyle changes (TLC) and pharmacotherapy is the next step (Table 12–6).
Step 7: Initiate TLC If LDL Is Above Goal
TLC should be the first approach tried in all patients (Table 12–7).3 An adequate trial of TLC should be employed in all patients, but pharmacotherapy should be instituted concurrently in higher-risk patients (Table 12–6). This includes dietary restrictions of cholesterol and saturated fats as well as regular exercise and weight reduction. In addition, therapeutic options to enhance LDL cholesterol lowering such as consumption of plant stanols/sterols (which competitively inhibit incorporation of cholesterol into micelles) and dietary fiber should be encouraged. These therapeutic options collectively may reduce LDL cholesterol by 20% to 25%. For a more detailed overview of lifestyle modifications, the reader should refer to the ATP III guidelines3 and the American Heart Association’s diet and lifestyle recommendations.11
Step 8: Consider Adding Drug Therapy If LDL Is Above Threshold Level
Patients unable or unlikely to achieve their LDL cholesterol goals following a reasonable trial of TLC (typically 12 weeks for patients without CHD and sooner for those at high risk or with LDL cholesterol greater than 190 mg/dL [4.92 mmol/L] at baseline) are candidates for drug therapy (Table 12–6). Typically, statins are the medications of choice to treat high LDL cholesterol because of their ability to substantially reduce LDL cholesterol, ability to reduce morbidity and mortality from atherosclerotic disease, convenient once-daily dosing, and low risk of side effects.
FIGURE 12–6. Framingham Point Scale for estimating 10-year CHD risk. The Framingham score is used to determine a patient’s CHD risk category when they are found to have two or more CHD risk factors (Table 12–4). This system assigns points to the following risk factors: age, total cholesterol level (in mg/dL), smoking status, HDL cholesterol level, and systolic blood pressure. The point total corresponds to the 10-year risk (%) of a CHD event (nonfatal myocardial infarction and coronary death), which serves as a basis for deciding how intensively to treat hypercholesterolemia and other risk factors. To calculate risk factor using the Framingham Point Scale, go to the following website: http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm. The Système International units for the corresponding conventional units in the Framingham Point Scale illustration include: (1) total cholesterol (160 mg/dL = 4.14 mmol/L; 160–199 mg/dL = 4.14-5.15 mmol/L; 200–239 mg/dL = 5.18-6.19 mmol/L; 240–279 mg/dL = 6.22-7.23 mmol/L; 280 mg/dL = 7.25 mmol/L) and (2) HDL (60 mg/dL = 1.55 mmol/L; 50–59 mg/dL = 1.3-1.53 mmol/L; 40–49 mg/dL = 1.04-1.27 mmol/L; 40 mg/dL = 1.04 mmol/L). (BP, blood pressure; CHD, coronary heart disease; HDL, high-density lipoprotein.) (From http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm).
Patient Encounter 1, Part 1
MN is a 48-year-old man with a history of hypertension and smoking who presents to the clinic for evaluation of his cholesterol. He denies having chest pain or history of myocardial infarction, stroke, or peripheral artery disease. He has no siblings and both parents are alive with no history of CHD. MN says that he smokes about one pack of cigarettes per day. He does not exercise on a regular basis. He has been fasting for approximately 11 hours.
Can MN be evaluated today for his cholesterol?
Does he have risk factors for CHD?
What additional information do you need to know for the evaluation ofMN?
Table 12–4 Risk Factors for CHD
Table 12–5 CHD Risk Factors and Needed Risk Factors for Framingham Score Calculation
Step 9: Identify Patients With the Metabolic Syndrome
Diagnosis of the metabolic syndrome is made when three or more of the following risk factors are present:3,12
• Waist circumference greater than or equal to 40 in. (102 cm) in men (35 in. [89 cm] in Asian males), or 35 in. (89 cm) in women (31 in. [79 cm] in Asian females)
• Triglycerides greater than or equal to 150 mg/dL (1.70 mmol/L) or on drug treatment for elevated triglycerides
• HDL cholesterol less than 40 mg/dL (1.04 mmol/L) in men or 50 mg/dL (1.3 mmol/L) in women or on drug treatment for reduced HDL cholesterol
• Blood pressure greater than or equal to 130/85 mm Hg or on drug treatment for hypertension
• Fasting blood glucose greater than or equal to 100 mg/dL (5.55 mmol/L) or on drug treatment for elevated glucose
Patients with the metabolic syndrome are twice as likely to develop type 2 diabetes and four times more likely to develop CHD.3,13 These individuals are usually insulin resistant, obese, have hypertension, are in a prothrombotic state, and have atherogenic dyslipidemia characterized by low HDL cholesterol and elevated triglycerides, and an increased proportion of their LDL particles are small and dense.3
NCEP ATP III identified the metabolic syndrome as an important target for further reducing CHD risk. Treatment of the metabolic syndrome starts with increased physical activity, weight reduction (which also enhances LDL cholesterol lowering and insulin sensitivity), and moderation of ethanol use and carbohydrate intake, which effectively reduce many of the associated risk factors. Each of the risk factors should be addressed independently as appropriate, including treatment of hypertension and use of aspirin in CHD patients to reduce the prothrombotic state. Patients with metabolic syndrome have an additional lipid parameter that needs to be assessed, namely non-HDL cholesterol (total cholesterol minus HDL cholesterol)3 The target for non-HDL cholesterol is less than the patient’s LDL cholesterol target plus 30 mg/dL (0.78 mmol/L). After assessment and control of LDL cholesterol, patients with serum triglycerides between 200 and 499 mg/dL (2.26 and 5.64 mmol/L) should be assessed for atherogenic dyslipidemia [low HDL cholesterol, increased small-dense LDL particles) and metabolic syndrome. Non-HDL cholesterol estimates the cholesterol carried by all Apo B-containing lipoprotein particles. Thus, non-HDL cholesterol represents the sum of LDL cholesterol, VLDL cholesterol, and other triglyceride-rich remnant particles. The non-HDL cholesterol goal is 30 mg/dL (0.78 mmol/L) higher than the LDL cholesterol goal. This is based on the premise that a VLDL cholesterol level less than or equal to 30 mg/dL (0.78 mmol/L) is normal. For example, the LDL cholesterol goal is less than 100 mg/dL (2.59 mmol/L) and the non-HDL cholesterol goal is less than 130 mg/dL (3.37 mmol/L) for a diabetic patient without a history of CHD. Two treatment approaches can be considered for achieving the non-HDL cholesterol goal: titrating existing LDL-lowering therapy or adding niacin or a fibrate to the LDL-lowering therapy.3 The reader is referred to the Ischemic Heart Disease and Diabetes Mellitus chapters for further information regarding metabolic syndrome.
Table 12–6 National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III [ATP III]) Treatment Goals for LDL Cholesterol and Thresholds for Starting TLC and Pharmacotherapy
Table 12–7 Essential Components of TLC
Step 10: Treatment of Elevated Triglycerides
Patients with serum triglycerides exceeding 500 mg/dL (5.65 mmol/L) are at increased risk of pancreatitis, especially when levels exceed 1,000 mg/dL (11.3 mmol/L).3 Reducing triglycerides in these individuals becomes the primary target for intervention. Reduction in fats, ethanol, and carbohydrates should be considered, and secondary causes (Table 12–3) should be assessed. When pharmacotherapy is instituted, the intensity of therapy should be to reduce triglycerides to less than 150 mg/dL (1.70 mmol/L). Once triglycerides are less than 500 mg/dL (5.65 mmol/L) and the risk of pancreatitis is reduced, the primary focus of intervention should once again be on LDL cholesterol. As noted above, individuals with triglycerides between 200 and 499 mg/dL (2.26 and 5.64 mmol/L) identified as having metabolic syndrome have an increase in triglyceride-rich remnant lipoproteins and small-dense LDL particles. Non-HDL cholesterol should be a secondary target in these individuals. Niacin, fibrates, and omega-3-fatty acids (03FA) are the most effective agents in patients with hypertriglyceridemia.3
Patient Encounter 1, Part 2: Medical History, Physical Exam, and Diagnostic Tests
PMH: Hypertension for 9 years; history of gout
FH: Father and mother both alive with no history of CHD or diabetes.
SH: Works as a computer programmer and sits at his desk most of the day; does not exercise on a regular basis; drinks alcohol (2 to 3 beers) mainly on the weekends while watching sports on TV
Meds: Aspirin 80 mg once daily, verapamil SR 180 mg once daily
ROS: No chest pain, shortness of breath, or dizziness
PE:
VS: BP 142/86 mm Hg, p 71 bpm, RR 16 bpm, T 37°C (98.6°F), waist circumference 38 in. (97 cm)
CV RRR, normal S17 S2; no murmurs, rubs, or gallops
Abd: Soft, nontender, nondistended; positive for bowel sounds, no hepatosplenomegaly or abdominal aortic aneurysm
Exts: Ankle-brachial index 1.1
Neck: No carotid and basilar bruits
Labs:
Total cholesterol 256 mg/dL (6.63 mmol/L), triglycerides 235 mg/dL (2.66 mmol/L), HDL cholesterol 27 mg/dL (0.70 mmol/L), glucose 115 mg/dL (6.38 mmol/L), all other labs within normal limits
Given this additional information, what is your assessment ofMN’sCHDrisk?
Identify your treatment goals for MN.
What diagnostic parameters does MN have for the metabolic syndrome?
What nonpharmacologic and pharmacologic alternatives are available for MN?
Develop a care plan for MN.
Emerging and Life-Habit Risk Factors
In addition to the five major risks, the ATP III guidelines recognize other factors that contribute to CHD risk. These are classified as life-habit risk factors and emerging risk factors. Life-habit risk factors, consisting of obesity, physical inactivity, and an atherogenic diet, require direct intervention. For example, emerging risk factors are lipoprotein(a), homocysteine, prothrombotic/proinflammatory factors, lipoprotein-associated phospholipase A2 (Lp-PLA2), and C-reactive protein (CRP). CRP is a marker of low-level inflammation and appears to help in predicting CHD risk beyond LDL cholesterol and major CHD risk factors.13 In a recent trial, rosuvastatin significantly reduced the incidence of major cardiovascular events in apparently healthy persons without hyperlipidemia (LDL cholesterol less than 130 mg/dL [3.37 mmol/L]) but with elevated high-sensitivity CRP levels.14 These results will need to be considered by the ATP IV writing committee.8 In some patients, emerging risk factors may be used to guide the intensity of risk-reduction therapy. Deciding when to consider emerging risk factors requires the use of clinical judgment.
Pharmacotherapy
Statins (HMG-CoA Reductase Inhibitors)
Statins are very effective LDL-lowering medications and are proven to reduce the risk of CHD, stroke, and death. Thus, NCEP ATP III considers statins the preferred LDL-lowering medications. Data concerning the efficacy and safety of the statins now go back nearly 25 years. Statins are effective in reducing MIs, strokes, revascularization procedures, cardiovascular deaths, and in some cases, total mortality. This effectiveness has been demonstrated in both genders, the elderly, patients with diabetes and hypertension, those with and without pre-existing CHD, and following an acute coronary syndrome.14–25 Statins inhibit conversion of HMG-CoA to L-mevalonic acid and subsequently cholesterol. Statins lower LDL cholesterol levels by approximately 25% to 62% (Table 12–8). A substantial reduction in LDL cholesterol occurs at the usual starting dose and each doubling of the daily dose only produces an additional 6% average reduction (known as the “rule of 6”). This is important when considering dose escalation versus adding on an additional LDL-lowering drug. Statins are moderately effective at reducing triglycerides and modestly raise HDL cholesterol (Table 12–8). By inhibiting the synthesis of L-mevalonic acid, statins in turn inhibit other important by-products in the cholesterol biosynthetic pathway that affect intracellular transport, membrane trafficking, and gene transcription.26 This may explain some of the cholesterol-independent benefits (so-called “pleiotropic” effects) of statins such as reducing lipoprotein oxidation, enhancing endothelial synthesis of nitric oxide, and inhibiting thrombosis. These pleiotropic effects are thought to contribute to the rapid/earlier benefits of statins on CHD risk while the decrease in serum lipids accounts for the slower late benefit.
Table 12–8 Effects of Lipid-Lowering Drugs on Serum Lipids at FDA-Approved Doses
Statins are well tolerated with less than 4% of patients in clinical trials discontinuing therapy due to adverse side effects (Table 12–9). Elevations in liver function tests (LFTs) and myopathy, including rhabdomyolysis, are important adverse effects associated with the statins. Liver toxicity, defined as LFT elevations greater than three times the upper limit of normal, is reported in less than 2% of patients; however, the incidence is higher at higher doses and the progression to liver failure is thought to be exceedingly rare. LFTs should be obtained at baseline and 6 to 12 weeks after starting therapy or any dose escalation. Annual monitoring of LFTs is usually sufficient. Myopathy, defined as muscle symptoms with creatine kinase (CK; or creatine phosphokinase [CPK]) 10 times the upper limit of normal, is reported to range from 0% to less than 0.5% for the currently marketed statins at FDA-approved doses. Rhabdomyolysis, defined as muscle symptoms with marked elevation in CK 10 times the upper limit of normal with creatinine elevation usually associated with myoglobinuria and brown urine, is very rare.27 The concern of statin-associated myopathy has increased since the voluntary removal of cerivastatin from the world market in 2001 because the reported rate of fatal rhabdomyolysis was 16 to 80 times higher than the rate for any other statin, and many of these cases were reported in patients treated with concomitant gemfibrozil.28 The American College of Cardiology/American Heart Association/National Heart, Lung and Blood Institute published a clinical advisory with a focus on myopathy.27 Listed below are the risks associated with statin-induced myopathy published in this report:
• Small body frame and frailty
• Multisystem disease (e.g., chronic renal insufficiency, especially due to diabetes)
• Multiple medications (see below)
• Perioperative periods
• Specific concomitant medications or consumptions (check specific statin package insert for warnings): fibrates (especially gemfibrozil, but other fibrates too), nicotinic acid (rarely), cyclosporine, azole antifungals such as itraconazole and ketoconazole, macrolide antibiotics such as erythromycin and clarithromycin, protease inhibitors used to treat AIDS, nefazodone (antidepressant), verapamil, amiodarone, large quantities of grapefruit juice (usually more than 1 quart [about 950 mL] per day), and alcohol abuse (independently predisposes to myopathy)
Table 12–9 Formulation, Dosing, and Common Adverse Effects of Lipid-Lowering Drugs
Baseline CK should be obtained in all patients prior to starting statin therapy. Follow-up CK should only be obtained in patients complaining of muscle pain, weakness, tenderness, or brown urine. Routine monitoring of CK is of little value in the absence of clinical signs or symptoms. Patient assessment for symptoms of myopathy should be done 6 to 12 weeks after starting therapy and at each visit. More frequent monitoring should be done in higher-risk individuals such as those identified above.
With the exception of pravastatin which is mainly metabolized by isomerization in the gut to a relatively inactive metabolite, the other statins undergo biotransformation by the cytochrome P-450 system. Therefore, drugs known to inhibit statin metabolism should be used cautiously. The time until maximum effect on lipids for statins is generally 4 to 6 weeks.
Cholesterol Absorption Inhibitors
Ezetimibe is the first drug in a new class of agents referred to as cholesterol absorption inhibitors. Ezetimibe blocks biliary and dietary cholesterol as well as phytosterol (plant sterol) absorption by interacting with the NPC1L1 transporter located in the brush border membrane of enterocytes (Fig. 12–2).5 Ezetimibe inhibits 54% of all intestinal cholesterol absorption on average. By reducing the cholesterol content within chylomicrons delivered to the liver, ezetimibe reduces liver cholesterol stores, inducing an upregulation of LDL receptors resulting in a decrease in serum cholesterol. As a result, ezetimibe also induces a compensatory increase in cholesterol biosynthesis. Since statins inhibit cholesterol biosynthesis, the compensatory increase in cholesterol biosynthesis by ezetimibe can be blocked by combining ezetimibe with a statin.
Ezetimibe reduces LDL cholesterol by an average of 18% (Table 12–8). However, larger reductions can be seen in some individuals, presumably due to higher absorption of cholesterol. These individuals appear to have a blunted response to statin therapy. Ezetimibe lowers triglycerides by 7% to 9% and modestly increases HDL cholesterol.
Once absorbed, ezetimibe undergoes extensive glucuronidation in the intestinal wall to the active metabolite (ezetimibe glucuronide). Ezetimibe and the active metabolite are enterohepatically recirculated back to the site of action, which limits systemic exposure and may explain the low incidence of adverse effects (Table 12–9). Ezetimibe alone or with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations in LFTs. Ezetimibe combined with simvastatin and simvastatin monotherapy were not associated with a reduction in carotid intima-media thickness in patients with heterozygous familial hypercholesterolemia.29 The patients studied in this trial were well managed (80% were receiving statins prior to enrollment) and had “near normal” measurements of carotid intima-media thickness at baseline which may explain the study findings. However, ezetimibe combined with simvastatin was associated with a reduced incidence of ischemic cardiovascular events in low risk patients with mild to moderate asymptomatic aortic stenosis compared to placebo.30 Other clinical trials designed to determine ezetimibe’s effects on CHD morbidity and mortality have not been completed. The time until maximum effect on lipids for ezetemibe is generally 2 weeks.
Patient Encounter 2
LC is a 51-year-old female with a history of CHD (stent placement in the left anterior descending coronary artery 3 years prior) and type 2 diabetes who is referred to you for follow-up of her cholesterol. She is taking simvastatin 20 mg once daily in the evening for her cholesterol, metformin 2,000 mg once daily in the evening, and pioglitizone 15 mg once daily for diabetes. Her diabetes is well controlled. Her laboratory test results are within normal limits, except for her fasting lipid profile: total cholesterol 215 mg/dL (5.57 mmol/L), triglycerides 135 mg/dL (1.53 mmol/L), HDL cholesterol 51 mg/dL (1.32 mmol/L), and LDL cholesterol 137 mg/dL (3.55 mmol/L).
What is your assessment ofLC’s cholesterol results?
Identify treatment goals forLC.
Assess LC’s risk for statin-induced side effects.
Design a treatment plan forLC.
Bile Acid Sequestrants
Cholestyramine, colestipol, and colesevelam are the bile acid-binding resins or sequestrants (BAS) currently available in the United States. Resins are highly charged molecules that bind to bile acids (which are produced from cholesterol) in the gut. The resin-bile acid complex is then excreted in the feces. The loss of bile causes a compensatory conversion of hepatic cholesterol to bile, reducing hepatocellular stores of cholesterol resulting in an upregulation of LDL receptors to replenish hepatocellular stores which then result in a decrease in serum cholesterol. Resins have been shown to reduce CHD events in patients without CHD.31
Resins are moderately effective in lowering LDL cholesterol but do not lower triglycerides (Table 12–8). Moreover, in patients with elevated triglycerides, the use of a resin may worsen the condition. This may be due to a compensatory increase in HMG-CoA reductase activity and results in an increase in assembly and secretion of VLDL. The increase in HMG-CoA reductase activity can be blocked with a statin, resulting in enhanced reductions in serum lipids (see section on combination therapy). Resins reduce LDL cholesterol from 15% to 30%, with a modest increase in HDL cholesterol (3%-5%) (Table 12–8). Resins are most often used as adjuncts to statins in patients who require additional lowering of LDL cholesterol. Because these drugs are not absorbed, adverse effects are limited to the GI tract (Table 12–9). About 20% of patients taking cholestyramine or colestipol report constipation and symptoms such as flatulence and bloating. A large number of patients stop therapy because of this. Resins should be started at the lowest dose and escalated slowly over weeks to months as tolerated until the desired response is obtained. Patients should be instructed to prepare the powder formulations in 6 to 8 ounces (approximately 180–240 mL) of noncarbonated fluids, usually juice (enhances palatability) or water. Fluid intake should be increased to minimize constipation. Colesevelam is better tolerated with fewer gastrointestinal side effects, although it is more expensive. All resins have the potential to prevent the absorption of other drugs such as digoxin, warfarin, thyroxine, thiazides, β-blockers, fat-soluble vitamins, and folic acid. Potential drug interactions can be avoided by taking a resin either 1 hour before or 4 hours after these other agents. Colesevelam appears less likely than the older agents to reduce drug absorption, and the manufacturer does state that colesevelam has to be dosed hours apart from other medications that have been tested in in vitro binding or in vivo drug interaction testing or with postmarketing reports to interact. Orally administered drugs that have not been tested for interaction with colesevelam, especially those with a narrow therapeutic index, should be administered at least 4 hours prior to colesevelam.32 The time until maximum effect on lipids for resins is generally 2 to 4 weeks.
Niacin
Niacin (vitamin B3) has broad applications in the treatment of lipid disorders when used at higher doses than those used as a nutritional supplement. Niacin inhibits fatty acid release from adipose tissue and inhibits fatty acid and triglyceride production in liver cells. This results in an increased intracellular degradation of Apo B, and in turn, a reduction in the number of VLDL particles secreted (Fig. 12–4). The lower VLDL levels and the lower triglyceride content in these particles leads to an overall reduction in LDL cholesterol as well as a decrease in the number of small, dense LDL particles. Niacin also reduces the uptake of HDL-Apo A1 particles and increases uptake of cholesterol esters by the liver, thus improving the efficiency of reverse cholesterol transport between HDL particles and vascular tissue (Fig. 12–4). Niacin is indicated for patients with elevated triglycerides, low HDL cholesterol, and elevated LDL cholesterol.3
Several different niacin formulations are available: niacin immediate-release (IR), niacin sustained-release (SR), and niacin extended-release (ER).33,34 These formulations differ in terms of dissolution and absorption rates, metabolism, efficacy, and side effects. Limitations of niacin IR and SR are flushing and hepatotoxicity, respectively. These differences appear related to the dissolution and absorption rates of niacin formulations and its subsequent metabolism. Niacin IR is available by prescription (Niacor) as well as a dietary supplement which is not regulated by the FDA.33 Currently, there are no FDA-approved niacin SR products; thus, all SR products are available only as dietary supplements.
Niacin IR is usually completely absorbed within 1 to 2 hours; thus, it quickly saturates a high-affinity, low-capacity metabolic pathway, and the majority of the drug is metabolized by a second low-affinity, high-capacity system with metabolites associated with flushing.35 Conversely, absorption of niacin SR may exceed 12 hours. Because niacin SR is absorbed over 12 or more hours, the high-affinity pathway metabolizes the majority of the drug, resulting in the production of metabolites associated with hepatotoxicity. Niacin ER was developed as a once-daily formulation to be taken at bedtime, with the goal of reducing the incidence of flushing without increasing the risk of hepatotoxicity. Niacin ER (Niaspan) is the only long-acting niacin product approved by the FDA for dyslipidemia. Niacin ER has an absorption rate of 8 to 12 hours, intermediate to niacin IR and SR, and therefore balances metabolism more evenly over the high-affinity, low-capacity pathway and the low-affinity, high-capacity pathway. Furthermore, taking niacin ER at bedtime can minimize the impact of flushing.
Niacin use is limited by cutaneous reactions such as flushing and pruritus of the face and body. The use of aspirin or a nonsteroidal anti-inflammatory drug (NSAID) 30 minutes prior to taking niacin can help alleviate these reactions, as they are mediated by an increase in prostaglandin D2.3 In addition, taking niacin with food and avoiding hot liquids at the time niacin is taken is helpful in minimizing flushing and pruritus.
In general, niacin reduces LDL cholesterol from 5% to 25%, reduces triglycerides by 20% to 50%, and increases HDL cholesterol by 15% to 35% (Table 12–8). Niacin has been shown to reduce CHD events and total mortality.36as well as the progression of atherosclerosis when combined with a statin.37
Niacin can raise uric acid levels, and in diabetics can raise blood glucose levels. However, several clinical trials have shown that niacin can be used safely and effectively in patients with diabetes.38 Due to the high cardiovascular risk of patients with diabetes, the benefits of improving the lipid profile appear to outweigh any adjustment in diabetic medication(s) that is needed.39
Niacin should be instituted at the lowest dose and gradually titrated to a maximum dose of 2 g daily for ER and SR products and no more than 5 g daily for IR products. FDA-approved niacin products are preferred because of product consistency. Moreover, niacin products labeled as “no flush” don’t contain nicotinic acid and therefore have no therapeutic role in the treatment of lipid disorders.33 The time until maximum effect on lipids for niacins is generally 3 to 5 weeks.
Fibrates
The predominant effects of fibrates are a decrease in triglyceride levels by 20% to 50% and an increase in HDL cholesterol levels by 9% to 30% (Table 12–8). The effect on LDL cholesterol is less predictable. In patients with high triglycerides, however, LDL cholesterol may increase. Fibrates increase the size and reduce the density of LDL particles much like niacin. Fibrates are the most effective triglyceride-lowering drugs and are used primarily in patients with elevated triglycerides and low HDL cholesterol.
Fibrates work by reducing Apos B, C-III (an inhibitor of LPL), and E, and increasing Apos A-I and A-II through activation of peroxisome proliferator-activated receptors-alpha (PPAR-α), a nuclear receptor involved in cellular function. The changes in these Apos result in a reduction in triglyceride-rich lipoproteins (VLDL and IDL) and an increase in HDL.
Clinical trials of fibrate therapy in patients with elevated cholesterol and no history of CHD demonstrated a reduction in CHD incidence, although less than the reduction attained with statin therapy.40 In addition, a large study of men with CHD, low HDL cholesterol, low LDL cholesterol, and elevated triglycerides demonstrated a 24% reduction in the risk of death from CHD, nonfatal MI, and stroke with gemfibrozil.41 Fibrates may be appropriate in the prevention of CHD events for patients with established CHD, low HDL cholesterol, and triglycerides below 200 mg/dL (2.26 mmol/L). However, LDL-lowering therapy should be the primary target if LDL cholesterol is elevated. Evidence of a reduction in CHD risk among patients with established CHD has not been demonstrated with fenofibrate.
The fibric acid derivatives are generally well tolerated. The most common adverse effects include dyspepsia, abdominal pain, diarrhea, flatulence, rash, muscle pain, and fatigue (Table 12–9). Myopathy and rhabdomyolysis can occur, and the risk appears to increase with renal insufficiency or concurrent statin therapy. If a fibrate is used with a statin, fenofibrate is preferred because it appears to inhibit the glucuronidation of the statin hydroxy and moiety less than gemfibrozil, allowing greater renal clearance of the statins.27,42 A CK level should be checked before therapy is started and if symptoms occur. Liver dysfunction has been reported, and LFTs should be monitored. Fibrates increase cholesterol in the bile and have caused gallbladder and bile duct disorders, such as cholelithiasis and cholecystitis. Unlike niacin, these agents do not increase glucose or uric acid levels. Fibrates are contraindicated in patients with gallbladder disease, liver dysfunction, or severe kidney dysfunction. The risk of bleeding is increased in patients taking both a fibrate and warfarin. The time until maximum effect on lipids is generally 2 weeks for fenofibrate and 3 to 4 weeks for gemfibrozil.
Omega-3 Fatty Acids
03FAs (eicosapentaenoic acid and docosahexaenoic acid), the predominant fatty acids in the oil of cold-water fish, lower triglycerides by as much as 35% when taken in large amounts. Fish oil supplements may be useful for patients with high triglycerides despite diet, alcohol restriction, and fibrate therapy. This effect may be modulated through PPAR-a and a reduction in Apo B-100 secretion. 03FAs reduce platelet aggregation and have antiarrhythmic properties, and therefore their use has been associated with a reduction in MI and sudden cardiac death, respectively.43
Prescription grade 03FAs are FDA approved at a dose of 4 g daily for the treatment of elevated triglycerides. Use of high-quality 03FAs free of contaminants such as mercury and organic pollutants should be encouraged when using these agents. Common side effects associated with 03FAs are diarrhea and excess bleeding. Patients taking anticoagulant or antiplatelet agents should be monitored more closely when consuming these products because excessive amounts of 03FAs (e.g., greater than 3 g daily) may lead to bleeding and may increase the risk of hemorrhagic stroke.
Combination Therapy
A large proportion of the U.S. population won’t achieve their NCEP cholesterol targets for a variety of reasons.44 These include inadequate patient adherence, adverse events, inadequate starting doses, lack of dose escalation, and lower treatment targets.3,45 Moreover, patients with concomitant elevations in triglycerides and/or low levels of HDL cholesterol may need combination drug therapy to normalize their lipid profile. Combination drug therapy is an effective means to achieve greater reductions in LDL cholesterol (statin + ezetimibe or bile acid resin, bile acid resin + ezetimibe, or three-drug combinations) as well as raising HDL cholesterol and lowering serum triglycerides (statin + niacin or fibrate).
Combination Therapy for Elevated LDL Cholesterol
For patients who don’t achieve their LDL or non-HDL cholesterol goals with statin monotherapy and lifestyle modifications including those unable to tolerate high doses due to adverse effects, combination therapy may be appropriate. Resins or ezetimibe combine effectively with statins to augment LDL cholesterol reduction. When added to a statin, ezetimibe can reduce LDL cholesterol levels by an additional 18% to 21% or up to 65% total reduction with maximum doses of the more potent statins. Ezetimibe and simvastatin are available as a combination tablet (Vytorin) and indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol, LDL cholesterol, Apo B, triglycerides, and non-HDL cholesterol, and to increase HDL cholesterol. The usual starting dose is 10 mg/20 mg, and the maximum dose is 10 mg/80 mg (Table 12–9). Adverse events are similar to those of each product taken separately; however, the percentage of patients with LFT elevations greater than three times normal is slightly higher than with a statin alone, and there appears to be a slightly higher risk of myopathy and rhabdomyolysis when statins and ezetimibe are combined. The time until maximum effect on lipids for this combination is generally 2 to 6 weeks.
A statin combined with a resin results in similar reductions in LDL cholesterol as those seen with ezetimibe. However, the magnitude of triglyceride reduction is less with a resin compared to ezetimibe, and this should be considered in patients with higher baseline triglyceride levels. In addition, gastrointestinal adverse events and potential drug interactions limit the utility of this combination.
Ezetimibe and a resin can also be combined. A study which assessed the effects of adding ezetimibe to ongoing resin therapy showed an additional 19% reduction in LDL cholesterol and an additional 14% reduction in triglycerides. This combination was well tolerated.46
Some patients, in particular those with genetic forms of hypercholesterolemia (Table 12–2), will require three or more drugs to manage their disorder. Regimens using a statin, resin, and niacin were found to reduce LDL cholesterol up to 75%.47 These early studies were conducted with lovastatin, so larger reductions would be expected with the more potent statins available today.
Combination Therapy for Elevated Cholesterol and Triglyceridemia With or Without Low HDL Cholesterol
Fibrates are the most effective triglyceride-lowering agents and also raise HDL cholesterol levels. Combination therapy with a fibrate, particularly gemfibrozil, and a statin has been found to increase the risk for myopathy. Of the 31 rhabdomyolysis deaths reported with cerivastatin use, 12 involved concomitant gemfibrozil.28 Therefore, more frequent monitoring, thorough patient education, and consideration of factors that increase the risk as reviewed previously should be considered.
Reducing LDL cholesterol while substantially raising HDL cholesterol (statin + niacin) appears to reduce the risk of atherosclerotic disease progression to a greater degree than statin monotherapy.Combining niacin with a statin augments the LDL cholesterol lowering potential of niacin while enhancing both the HDL cholesterol-raising effects and triglyceride-lowering effects of the statin. A statin combined with niacin appears to offer greater benefits for reducing atherosclerosis progression compared to a statin alone.37 Formulations combining ER niacin and lovastatin (Advicor) and ER niacin and simvastatin (Simcor) are available, and are indicated for treatment of primary hypercholesterolemia and mixed dyslipidemia in patients treated with lovastatin or simvastatin who require further triglyceride lowering or HDL cholesterol raising and may benefit from having niacin added to their regimen. The combination is also indicated for patients treated with niacin who require further LDL-cholesterol lowering and may benefit from having lovastatin or simvastatin added to their regimen. The time until maximum effect on lipids for this combination is generally 3 to 6 weeks.
Niacin can be combined with a fibrate in patients with high elevations in serum triglycerides. The combination may increase the risk of myopathy compared to either agent alone.
Compared with monotherapy, combination therapy is relatively unstudied in terms of the effects on CHD event reduction and may reduce patient compliance through increased side effects and increased costs. When used appropriately and with proper precautions, however, they are effective in normalizing lipid abnormalities, particularly in patients who cannot tolerate adequate doses of statin therapy for more severe forms of dyslipidemia.
Investigational Agents
There are numerous investigational drugs in development for the treatment of lipid disorders and prevention of atherosclerosis. Many of these will likely be used in combination with currently available lipid-modulating drugs. The most promising is an antisense drug that significantly reduced Apo B-100 and LDL cholesterol.48 Other agents in development include newer statins; bile acid transport inhibitors; phytostanol analogues; acyl coenzyme A: cholesterol acyltransferase (ACAT) inhibitors; squalene synthase inhibitors; and newer PPAR-α, -γ, and -S agonists, as well as dual PPAR-α/γ agonists. In addition, weekly infusions of genetically engineered HDL (Apo A1 Milano) in patients with atherosclerosis has been shown to cause significant reduction in atheroma volume compared to placebo after just 5 weeks of therapy.49
These novel therapies will provide opportunities for developing different combination strategies to further reduce the risk of CHD even after adequate treatment with existing agents. Well-designed studies using noninvasive imaging technology and long-term follow-up periods are needed to ensure that there is a favorable risk-to-benefit ratio.
OUTCOME EVALUATION
• The successful outcome in cholesterol management is to reduce cholesterol and triglycerides below the NCEP ATP III goals in an effort to alter the natural course of atherosclerosis and decrease future cardiovascular events.
• Employ an adequate trial ofTLC in all patients, but institute pharmacotherapy concurrently in higher-risk patients.
• When indicated, initiate drug therapy at a dose that will reduce LDL cholesterol in the range of 30% to 40%.
• Typically, statins are the medications of choice to treat high LDL cholesterol because of their ability to substantially reduce LDL cholesterol, ability to reduce morbidity and mortality from atherosclerotic disease, convenient once-daily dosing, and low risk of side effects.
• Employ an individualized patient monitoring plan in an effort to minimize side effects and maintain treatment adherence and lipid goals.
Patient Care and Monitoring
1. Assess the patient for the presence of CHD or other atherosclerosis disorders.
2. Assess major risk factors for CHD.
3. For patients without CHD or CHD risk equivalent, but two or more major CHD risk factors, perform Framingham risk assessment.
4. Obtain fasting cholesterol profile and assess any abnormal lipid levels.
5. Obtain a thorough history of prescription, nonprescription, and natural drug product use. Determine what treatments for cholesterol the patient has used in the past (if any). Assess if the patient is taking any medications that may contribute to his or her abnormal lipid levels.
6. Assess concomitant diseases that may contribute to the patient’s abnormal lipid levels.
7. Assess risk factors for metabolic syndrome.
8. Determine the treatment goal for LDL cholesterol based on the patient’s CHD risk and non-HDL cholesterol goal if patient meets criteria for metabolic syndrome.
9. Educate all patients on TLC and the importance of regular physical activity.
10. For patients exceeding their LDL cholesterol goal, initiate TLCs. Consider starting concurrent pharmacotherapy in patients in the high-risk or moderately high-risk categories. Pharmacotherapy should be initiated at a dose to reduce LDL cholesterol by 30% to 40% at a minimum.
11. TLC should be continued and intensified (consider adding plant sterols/stanols and increase fiber) after 6 weeks if not below LDL cholesterol target. For those patients above their LDL cholesterol target after adequate trial of TLC (12 to 18 weeks), pharmacotherapy should be strongly considered.
12. Institute appropriate pharmacotherapy based on lipid abnormality. Obtain appropriate baseline labs to monitor for adverse drug effects. Assess potential disease and drug interactions that may affect choice or intensity of pharmacotherapy.
13. Monitor response, safety, and adherence after a minimum of 4 to 6 weeks. Titrate therapy or add a second drug as needed.
14. Once the LDL cholesterol goal is achieved, assess non-HDL cholesterol in those with metabolic syndrome and intensify LDL-lowering therapy further or consider adding niacin or fibrate.
15. Provide patient education regarding CHD, hyperlipidemia, therapeutic lifestyle modifications, drug therapy, and therapy adherence.
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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