Chuong 28

CMDT 2013

Lipid Disorders Robert B. Baron, MD, MS

For patients with known cardiovascular disease (secondary prevention), cholesterol lowering leads to a consistent reduction in total mortality and recurrent cardiovascular events in men and women and in middle-aged and older patients. Among patients without cardiovascular disease (primary prevention), the data are less conclusive, with rates of cardiovascular events, heart disease mortality, and all-cause mortality differing among studies. Nonetheless, treatment algorithms have been designed to assist clinicians in selecting patients for cholesterol-lowering therapy based on their lipid levels and their overall risk of developing cardiovascular disease.

Lipoproteins & Atherogenesis The plaques in the arterial walls of patients with atherosclerosis contain large amounts of cholesterol. The higher the level of low-density lipoproteins (LDL) cholesterol, the greater the risk of atherosclerotic heart disease; conversely, the higher the high-density lipoproteins (HDL) cholesterol, the lower the risk of coronary heart disease (CHD). This is true in men and women, in different racial and ethnic groups, and at all ages up to age 75 years. Because most cholesterol in serum is LDL, high total cholesterol levels are also associated with an increased risk of CHD. Middle-aged men whose serum cholesterol levels are in the highest quintile for age (above about 230 mg/dL or 5.95 mmol/L) have a risk of coronary death before age 65 years of about 10%; men in the lowest quintile (below about 170 mg/dL or 4.40 mmol/L) have a 3% risk. Death from CHD before age 65 years is less common in women, with equivalent risks one-third those of men. In men, each 10-mg/dL or 0.26-mmol/L increase in cholesterol (or LDL cholesterol) increases the risk of CHD by about 10%; each 5-mg/dL or 0.13-mmol/L increase in HDL reduces the risk by about 10%. The effect of HDL cholesterol is greater in women, whereas the effects of total and LDL cholesterol are smaller.

There are several genetic disorders that provide insight into the pathogenesis of lipid-related diseases. Familial hypercholesterolemia, rare in the homozygous state (about one per million) is a condition in which the cell-surface receptors for the LDL molecule are absent or defective,

1245

28

resulting in unregulated synthesis of LDL. Patients with two abnormal genes (homozygotes) have extremely high ­levels—up to eight times normal—and present with atherosclerotic disease in childhood. Homozygotes may require liver transplantation to correct their severe lipid abnormalities. Those with one defective gene (heterozygotes) have LDL concentrations twice normal; persons with this condition may develop CHD in their 30s or 40s.

Another rare condition is caused by an abnormality of lipoprotein lipase, the enzyme that enables peripheral tissues to take up triglyceride from chylomicrons and verylow-density lipoproteins (VLDL) particles. Patients with this condition, one cause of familial hyperchylomicronemia, have marked hypertriglyceridemia with recurrent pancreatitis and hepatosplenomegaly in childhood.

Numerous other genetic abnormalities of lipid metabolism are named for the abnormality noted when serum is electrophoresed (eg, dysbetalipoproteinemia) or from combinations of lipid abnormalities in families (eg, familial combined hyperlipidemia). Thus, family members of patients with severe lipid disorders are appropriately studied. Other patients have abnormalities in the production of apoproteins, such as increased apoprotein B and its affiliated lipoproteins, LDL and VLDL; reduced apoprotein AII and its affiliated particle; or excess lipoprotein(a).

Other mutations occur in lipoprotein lipase and in the gene encoding for cholesterol efflux regulatory protein.

Genome-wide association studies have identified additional genetic variants responsible for differences in serum lipids.

``When to Refer • Known genetic lipid disorders.

• Striking family history of hyperlipidemia or premature atherosclerosis.

• Extremely high serum LDL cholesterol or triglyceride, or extremely low serum HDL cholesterol.

Alwaili K et al. High-density lipoproteins and cardiovascular disease: 2010 update. Expert Rev Cardiovasc Ther. 2010 Mar;8(3):413–23. [PMID: 20222819]

1246

CMDT 2013

Chapter 28

Kathiresan S et al. Polymorphisms associated with cholesterol and risk of cardiovascular events. N Engl J Med. 2008 Mar 20;358(12):1240–9. [PMID: 18354102] Pencina MJ et al. Predicting the 30-year risk of cardiovascular disease: the Framingham Heart Study. Circulation. 2009 Jun 23;119(24):3078–84. [PMID: 19506114] Pirruccello J et al. Genetics of lipid disorders. Curr Opin Cardiol.

2010 May;25(3):238–42. [PMID: 20224388]

Lipid Fractions & the Risk of Coronary Heart Disease In fasting serum, cholesterol is carried primarily on three different lipoproteins—the VLDL, LDL, and HDL molecules. Total cholesterol equals the sum of these three ­components: Total cholesterol = HDL cholesterol + VLDL cho lesterol + LDL cholesterol Most clinical laboratories measure the total cholesterol, the total triglycerides, and the amount of cholesterol found in the HDL fraction, which is easily precipitated from serum. Most triglyceride is found in VLDL particles, which contain five times as much triglyceride by weight as cholesterol. The amount of cholesterol found in the VLDL fraction can be estimated by dividing the triglyceride by 5: VLDL cholesterol =

Triglycerides 5

Because the triglyceride level is used as a proxy for the amount of VLDL, this formula works only in fasting samples and when the triglyceride level is < 400 mg/dL or < 4.52 mmol/L. At higher triglyceride levels, LDL and VLDL cholesterol levels can be determined after ultracentrifugation or by direct chemical measurement.

The total cholesterol is reasonably stable over time; however, measurements of HDL and especially triglycerides may vary considerably because of analytic error in the laboratory and biologic variation in a patient’s lipid level.

Thus, the LDL should always be estimated as the mean of at least two determinations; if those two estimates differ by more than 10%, a third lipid profile is obtained. The LDL is estimated as follows: LDL Total HD L Triglycerides choles- = cholesterol − cholesterol − (mg/d L) terol (mg/dL) (mg/dL) 5 When using SI units, the formula becomes LDL Total HDL choles- = cholesterol − cholesterol − terol (mmol/L ) (mmol/L )

Triglycerides (mmol/L ) 2. 2

Understanding the relationships of the different lipid fractions leads to a more accurate understanding of a

patient’s lipid-related coronary risk than the total cholesterol. Two persons with the same total cholesterol of 275 mg/dL (7.11 mmol/L) may have very different lipid profiles. One may have an HDL cholesterol of 110 mg/dL (2.84 mmol/L) with a triglyceride of 150 mg/dL (1.69 mmol/L), giving an estimated LDL cholesterol of 135 mg/dL (3.49 mmol/L); the other may have an HDL cholesterol of 25 mg/dL (0.65 mmol/L) with a triglyceride of 200 mg/dL (2.26 mmol/L) and an LDL cholesterol of 210 mg/dL (5.43 mmol/L). The second would have more than a tenfold higher CHD risk than the first, assuming no differences in other factors. Because of high HDL cholesterol levels in women, many with apparently high total cholesterol levels have favorable lipid profiles.

Thus, evaluation of the lipid fractions is essential before therapy is initiated.

Some authorities use the ratio of the total to HDL cholesterol as an indicator of lipid-related coronary risk: the lower this ratio is, the better. Although ratios are useful predictors within populations of patients, they may obscure important information in individual patients. (A total cholesterol of 300 mg/dL [7.76 mmol/L] and an HDL of 60 mg/dL [1.56 mmol/L] result in the same ratio as a total cholesterol of 150 mg/dL [3.88 mmol/L] with an HDL of 30 mg/dL [0.78 mmol/L].) Moreover, the total cholesterolto-HDL cholesterol ratio will magnify the importance of variations in HDL measurement.

There is no true “normal” range for serum lipids. In Western populations, cholesterol values are about 20% higher than in Asian populations and exceed 300 mg/dL (7.76 mmol/L) in nearly 5% of adults. About 10% of adults have LDL cholesterol levels above 200 mg/dL (5.17 mmol/L).

Total and LDL cholesterol levels tend to rise with age in persons who are otherwise in good health.

Declines are seen in acute illness, and lipid studies in such patients are of little value with the exception of the serum triglyceride level in a patient with pancreatitis.

Cholesterol levels (even when expressed as an age-matched percentile rank, such as the highest 20%) do not remain constant over time, especially from childhood through adolescence and young adulthood. Thus, children and young adults with relatively high cholesterol may have lower levels later in life, whereas those with low cholesterol may show increases.

Therapeutic Effects of Lowering Cholesterol Reducing cholesterol levels in healthy middle-aged men without CHD (primary prevention) reduces their risk in proportion to the reduction in LDL cholesterol and the increase in HDL cholesterol. Treated patients have statistically significant and clinically important reductions in the rates of myocardial infarctions, new cases of angina, and need for coronary artery bypass procedures. The West of Scotland Study showed a 31% decrease in myocardial infarctions in middle-aged men treated with pravastatin compared with placebo. The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) study showed similar results with lovastatin. As with any

Lipid Disorders primary prevention interventions, large numbers of healthy patients need to be treated to prevent a single event. The numbers of patients needed to treat (NNT) to prevent a nonfatal myocardial infarction or a coronary artery disease death in these two studies were 46 and 50, respectively. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) study of atorvastatin in subjects with hypertension and other risk factors but without CHD also demonstrated a convincing 36% reduction in CHD events. The Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) showed a 44% reduction in a combined end point of myocardial infarction, stroke, revascularization, hospitalization for unstable angina, or death from cardiovascular causes. The NNT for 1 year to prevent one event was 169.

Primary prevention studies have found a less consistent effect on total mortality. The West of Scotland study found a 20% decrease in total mortality, tending toward statistical significance. The AFCAPS/TexCAPS study with lovastatin showed no difference in total mortality. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT) also showed no reduction either in all-cause mortality or in CHD events when pravastatin was compared with usual care.

Subjects treated with atorvastatin in the ASCOT study had a 13% reduction in mortality, but the result was not statistically significant. This study, however, was stopped early due to the marked reduction in CHD events. The JUPITER trial demonstrated a statistically significant 20% reduction in death from any cause. The NNT for 1 year was 400.

In patients with CHD, the benefits of cholesterol lowering are clearer. Major studies with statins have shown significant reductions in cardiovascular events, cardiovascular deaths, and all-cause mortality in men and women with coronary artery disease. The NNT to prevent a non­ fatal myocardial infarction or a coronary artery disease death in these three studies were between 12 and 34. Aggressive cholesterol lowering with these agents causes regression of atherosclerotic plaques in some patients, reduces the progression of atherosclerosis in saphenous vein grafts, and can slow or reverse carotid artery atherosclerosis. Metaanalysis suggests that this latter effect results in a significant decrease in strokes. Results with other classes of medications have been less consistent. For example, gemfibrozil treatment subjects had fewer cardiovascular events, but there was no benefit in all-cause mortality when compared with placebo.

The disparities in results between primary and secondary prevention studies highlight several important points.

The benefits and adverse effects of cholesterol lowering may be specific to each type of drug; the clinician cannot assume that the effects will generalize to other classes of medication. Second, the net benefits from cholesterol lowering depend on the underlying risk of CHD and of other disease. In patients with atherosclerosis, morbidity and mortality rates associated with CHD are high, and measures that reduce it are more likely to be beneficial even if they have no effect—or even slightly harmful effects—on other diseases.

CMDT 2013

1247

Baigent C et al; SHARP Investigators. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet.

2011 Jun 25;377(9784):2181–92. [PMID: 21663949] Bayturan O et al. The metabolic syndrome, its component risk factors, and progression of coronary atherosclerosis. Arch Intern Med. 2010 Mar 8;170(5):478–84. [PMID: 20212186] Brugts JJ et al. The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials. BMJ. 2009;338:b2376. [PMID: 19567909] Cholesterol Treatment Trialists’ (CTT) Collaboration; Collings R et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010 Nov 13;376(9753): 1670–81. [PMID: 21067804] Cooney MT et al; SCORE investigators. HDL cholesterol protects against cardiovascular disease in both genders, at all ages and at all levels of risk. Atherosclerosis. 2009 Oct;206(2):611–6.

[PMID: 19375079] Cui Y et al. Effects of increasing high-density lipoprotein cholesterol and decreasing low-density lipoprotein cholesterol on the incidence of first acute coronary events (from the Air Force/Texas Coronary Atherosclerosis Prevention Study). Am J Cardiol. 2009 Sep 15;104(6):829–34. [PMID: 19733719] Pletcher MJ et al. Comparing impact and cost-effectiveness of primary prevention strategies for lipid-lowering. Ann Intern Med. 2009 Feb 17;150(4):243–54. [PMID: 19221376]

Secondary Conditions That Affect Lipid Metabolism Several factors, including drugs, can influence serum lipids (Table 28–1). These are important for two reasons: abnormal lipid levels (or changes in lipid levels) may be the presenting sign of some of these conditions, and correction of the underlying condition may obviate the need to treat an apparent lipid disorder. Diabetes and alcohol use, in particular, are commonly associated with high triglyceride levels that decline with improvements in glycemic control or reduction in alcohol use, respectively. Thus, secondary causes of high blood lipids should be considered in each patient with a lipid disorder before lipid-lowering therapy is started. In most instances, special testing is not needed: a history and physical examination are sufficient. However, screening for hypothyroidism in patients with hyperlipidemia is cost effective.

Clinical Presentations Most patients with high cholesterol levels have no specific symptoms or signs. The vast majority of patients with lipid abnormalities are detected by the laboratory, either as part of the workup of a patient with cardiovascular disease or as part of a preventive screening strategy. Extremely high levels of chylomicrons or VLDL particles (triglyceride level above 1000 mg/dL or 10 mmol/L) result in the formation of eruptive xanthomas (Figure 28–1) (red-yellow papules, especially on the buttocks). High LDL concentrations result in tendinous xanthomas on certain tendons (Achilles,

1248

CMDT 2013

Chapter 28

Table 28–1. Secondary causes of lipid abnormalities.

Cause

Associated Lipid Abnormality

Obesity

Increased triglycerides, decreased HDL cholesterol

Sedentary lifestyle

Decreased HDL cholesterol

Diabetes mellitus

Increased triglycerides, increased total cholesterol

Alcohol use

Increased triglycerides, increased HDL cholesterol

Hypothyroidism

Increased total cholesterol

Hyperthyroidism

Decreased total cholesterol

Nephrotic syndrome

Increased total cholesterol

Chronic kidney disease

Increased total cholesterol, increased triglycerides

Cirrhosis

Decreased total cholesterol

Obstructive liver disease

Increased total cholesterol

Malignancy

Decreased total cholesterol

Cushing disease (or corticosteroid use)

Increased total cholesterol

Oral contraceptives

Increased triglycerides, increased total cholesterol

Diuretics1

Increased total cholesterol, increased triglycerides

β-Blockers1,2

Increased total cholesterol, decreased HDL

1

Short-term effects only. β-Blockers with intrinsic sympathomimetic activity, such as pindolol and acebutolol, do not affect lipid levels.

2

s Figure 28–1. Eruptive xanthoma on the arm of a man with untreated hyperlipidemia and diabetes mellitus. (Courtesy of Richard P. Usatine, MD; used, with permission, from Usatine RP, Smith MA, Mayeaux EJ Jr, Chumley H, Tysinger J. The Color Atlas of Family Medicine. McGraw-Hill, 2009.)

patella, back of the hand). Such xanthomas usually indicate one of the underlying genetic hyperlipidemias. Lipemia retinalis (cream-colored blood vessels in the fundus) is seen with extremely high triglyceride levels (above 2000 mg/ dL or 20 mmol/L).

Screening For High Blood Cholesterol All patients with CHD or CHD risk equivalents (other clinical forms of atherosclerosis such as peripheral artery disease, abdominal aortic aneurysm, and symptomatic carotid artery disease; patients with diabetes mellitus; and patients with multiple risk factors that confer a > 20% 10-year risk for developing CHD [Table 28–2]) should be screened for elevated lipids. The only exceptions are patients in whom lipid lowering is not indicated or desirable for other reasons.

Patients who already have evidence of atherosclerosis are the group at highest risk of suffering additional manifestations in the near term and thus have the most to gain from reduction of blood lipids. Additional risk reduction measures for atherosclerosis are discussed in Chapter 10; lipid lowering should be just one aspect of a program to reduce the progression and effects of the disease.

In patients with cardiovascular disease, a complete lipid profile (total cholesterol, HDL cholesterol, and triglyceride levels) after an overnight fast should be obtained as a screening test. Those whose estimated LDL cholesterol level is high should have at least one repeat measurement.

Specific treatments for high LDL cholesterol levels are discussed below. The goal of therapy should be to reduce the LDL cholesterol to below 100 mg/dL (2.59 mmol/L) or optimally to below 70 mg/dL (1.81 mmol/L). Evidence suggests that treatment with a statin is effective even if the starting LDL cholesterol is below 100 mg/dL (2.59 mmol/L).

These data suggest that most patients with CHD or CHD risk equivalents should be treated with statin therapy.

The best screening and treatment strategy for adults who do not have atherosclerotic cardiovascular disease is less clear. Several algorithms have been developed to guide the clinician in treatment decisions, but management decisions are individualized based on the patient’s risk.

Although the National Cholesterol Education Program (NCEP) recommends screening of all adults aged 20 years or older for high blood cholesterol, the United States Preventive Services Task Force (USPSTF) suggests beginning at age 20 years only if there is increased risk of CHD. For men without increased risk, screening is recommended beginning at age 35 years. For women and for men aged 20 to 35 without increased risk, the USPSTF makes no recommendation for or against routine screening for lipid disorders. Although there is no established interval for screening, screening can be repeated every 5 years for those with average or low risk and more often for those whose levels are close to therapeutic thresholds. This strategy focuses cholesterol screening on those at the greatest risk of coronary artery disease and increases the cost effectiveness of cholesterol screening.

Individuals without cardiovascular disease can then be stratified according to risk factors as defined by the NCEP. Those with two or more risk factors are considered

1249

CMDT 2013

Lipid Disorders

Table 28–2. Framingham 10-year coronary heart disease risk projections. Calculate the number of points for each risk factor. Sum the total risk score and estimate the 10-year risk.

MEN Age

WOMEN Points -9 -4 0 3 6 8 10 11 12 13

20–34 35–39 40–44 45–49 50–54 55–59 60–64 65–69 70–74 75–79

Age

Points

20–34 35–39 40–44 45–49 50–54 55–59 60–64 65–69 70–74 75–79

-7 -3 0 3 6 8 10 12 14 16

Points

Points

Total Cholesterol

Age 20–39

Age 40–49

Age 50–59

Age 60–69

Age 70–79

Total Cholesterol

Age 20–39

Age 40–49

Age 50–59

Age 60–69

Age 70–79

< 160 160–199 200–239 240–279 ≥ 280

0 4 7 9 11

0 3 5 6 8

0 2 3 4 5

0 1 1 2 3

0 0 0 1 1

< 160 160–199 200–239 240–279 ≥ 280

0 4 8 11 13

0 3 6 8 10

0 2 4 5 7

0 1 2 3 4

0 0 1 2 2

Points

Points

Age

20–39

40–49

50–59

60–69

70–79

Age

20–39

40–49

50–59

60–69

70–79

Nonsmoker Smoker

0 8

0 5

0 3

0 1

0 1

Nonsmoker Smoker

0 9

0 7

0 4

0 2

0 1

HDL (mg/dL)

Points

HDL (mg/dL)

Points

≥ 60 50–59 40–49 < 40

-1 0 1 2

≥ 60 50–59 40–49 < 40

-1 0 1 2

Systolic BP (mm Hg)

Points if Untreated

Points if Treated

Systolic BP (mm Hg)

Points if Untreated

Points if Treated

< 120 120–129 130–139 140–159 ≥ 160

0 0 1 1 2

0 1 2 2 3

< 120 120–129 130–139 140–159 ≥ 160

0 1 2 3 4

0 3 4 5 6

(continued )

1250

CMDT 2013

Chapter 28

Table 28–2. Framingham 10-year coronary heart disease risk projections. Calculate the number of points for each risk factor. Sum the total risk score and estimate the 10-year risk. (continued) MEN Point Total < 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 ≥ 17

WOMEN

10-Year Risk % < 1 1 1 1 1 1 2 2 3 4 5 6 8 10 12 16 20 25 ≥ 30

Point Total < 9 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 ≥ 25

Ten-Year Risk

%

to be at intermediate risk of coronary artery disease, and those with less than two are at low risk. These risks include age and gender (men aged 45 years or older, women aged 55 years or older), a family history of premature CHD (myocardial infarction or sudden cardiac death before age 55 years in a first-degree male relative or before age 65 years in a first-degree female relative), hyper­tension (whether treated or not), current cigarette smoking (10 or more cigarettes per day), and low HDL cholesterol (< 40 mg/dL). Because HDL cholesterol is protective against CHD, a risk factor is subtracted if the level is > 60 mg/dL. Patients with two or more risk factors are then further stratified by evaluating their 10-year risk of developing CHD using Framingham projections of 10-year risk (Table 28–2). Because risk factors alone are an imprecise measure of CHD risk, estimating the 10-year risk using Framingham data is helpful even in patients with one or no risk factors.

Numerous other risk factors have been studied in an attempt to better predict future CHD events. These include high-sensitivity C-reactive protein (hs-CRP), electron beam computed tomography (EBCT), homocysteine, fibrinogen, lipoprotein a, LDL subfractions, ankle-brachial index, and others. Several of these, particularly hs-CRP and EBCT, may add additional prognostic ability after accounting for traditional risk factors, but no clinical trials have yet examined the effect of these on health outcomes. Clinical guidelines suggest limiting the use of additional risk factors such as hs-CRP to patients at intermediate risk (by Framingham projections) if additional data is likely to change a therapeutic decision.

Several strategies for obtaining the initial cholesterol measurement have been proposed, including: (1)

10-Year Risk % < 1 1 1 1 1 2 2 3 4 5 6 8 11 14 17 22 27 ≥ 30

Ten-Year Risk

%

measuring total cholesterol alone, (2) measuring total cholesterol and HDL cholesterol, or (3) measuring LDL and HDL cholesterol. Each is acceptable, but treatment decisions are based on the LDL and HDL cholesterol levels. Measurement of the total cholesterol alone is the least expensive strategy and is adequate for low-risk individuals; those with total cholesterol > 200 mg/dL (> 6.0 mmol/L) should then be reevaluated with a fasting LDL and HDL cholesterol measurement. Measure­ ment of the total cholesterol and HDL cholesterol allows for better characterization of the risk factor profile but also requires reevaluation if the total cholesterol is > 200 mg/dL (> 5.17 mmol/L) as recommended by the USPSTF. Initial measurement of the LDL and HDL cholesterol is least likely to lead to patient misinformation and misclassification and is the strategy recommended by the NCEP. Treatment decisions are based on the LDL cholesterol, and the patient’s risk factor profile (including the HDL cholesterol level) and estimated 10-year risk. Patients in the intermediate-risk group (two or more risk factors) are selected for diet therapy (therapeutic lifestyle changes) if LDL cholesterol is > 130 mg/dL (> 3.36 mmol/L). If the 10-year risk of CHD is < 10%, drug treatment is recommended if LDL is > 160 mg/dL (> 4.14 mmol/L); if the 10-year CHD risk is between 10% and 20%, drug ­treatment is recommended if LDL is > 130 mg/dL (> 3.36 mmol/L). Low-risk individuals with one or no risk factors and estimated 10-year CHD risk < 10% are selected for diet therapy if LDL cholesterol is > 160 mg/dL (> 4.14 mmol/L) and for drug therapy if it is > 190 mg/dL (> 4.91 mmol/L) (Table 28–3).

Lipid Disorders

CMDT 2013

1251

Table 28–3. LDL goals and treatment cutpoints: Recommendations of the NCEP Adult Treatment Panel III. Risk Category High risk: CHD2 or CHD risk equivalents3 (10-year risk > 20%)

LDL Goal (mg/dL)

LDL Level at Which to Initiate Lifestyle Changes (mg/dL)

LDL Level at Which to Consider Drug Therapy1 (mg/dL)

< 100 (optional goal: < 70 mg/dL)4

≥ 1005

≥ 100 (< 100: consider drug options)6

< 1309

≥ 1305

≥ 130 (100–129; consider drug options)10

Moderately high risk: 2+ risk factors7 (10-year risk 10% to 20%)8 Moderate risk: 2+ risk factors7 (10-year risk < 10%)8

< 130

≥ 130

≥ 160

Low risk: 0–1 risk factors11

< 160

≥ 160

≥ 190 (160–189: LDL-lowering drug optional)

1 When LDL-lowering drug therapy is used, it is advised that intensity of therapy be sufficient to achieve at least a 30–40% reduction in LDL cholesterol levels.

2 CHD includes history of myocardial infarction, unstable angina, coronary artery procedures (angioplasty or bypass surgery), or evidence of clinically significant myocardial ischemia.

3 CHD risk equivalents include clinical manifestations of noncoronary forms of atherosclerotic disease (peripheral arterial disease, abdominal aortic aneurysm, and carotid artery disease [transient ischemic attacks or stroke of carotid origin with > 50% obstruction of a carotid artery]), diabetes mellitus, and ≥ 2 risk factors with 10-year risk for CHD > 20%.

4 Very high risk favors the optional LDL cholesterol goal of < 70 mg/dL, or in patients with high triglycerides, non-high density lipoprotein (HDL) cholesterol < 100 mg/dL. 5 Any person at high risk or moderately high risk who has lifestyle-related risk factors (eg, obesity, physical inactivity, elevated triglyceride, low HDL cholesterol, or metabolic syndrome) is a candidate for therapeutic lifestyle changes to modify these risk factors regardless of LDL cholesterol.

6 If baseline LDL cholesterol is < 100 mg/dL, institution of an LDL-lowering drug is a therapeutic option on the basis of available clinical trial results. If a high-risk person has high triglycerides or low HDL cholesterol, combining a fibrate or nicotinic acid with an LDL-lowering drug can be considered.

7 Risk factors include cigarette smoking, hypertension (blood pressure ≥ 140/90 mm Hg or on antihypertensive medication), low HDL cholesterol (< 40 mg/dL), family history of premature CHD (CHD in male first-degree relative < 55 years of age; CHD in female first-degree relative < 65 years of age), and age (men ≥ 45 years; women ≥ 55 years).

8 Electronic 10-year risk calculators are available at www.nhlbi.nih.gov/guidelines/cholesterol.

9 Optional LDL cholesterol goal < 100 mg/dL. 10 For moderately high-risk persons, when the LDL cholesterol level is 100–129 mg/dL at baseline or on lifestyle therapy, initiation of an LDL-lowering drug to achieve an LDL cholesterol level < 100 mg/dL is a therapeutic option on the basis of available clinical trial results.

11 Almost all people with zero or one risk factor have a 10-year CHD risk < 10%, and 10-year risk assessment in these people is thus not necessary.

LDL, low-density lipoprotein; NCEP, National Cholesterol Education Program; CHD, coronary heart disease.

Reproduced, with permission, from Grundy SM et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004 Jul 13;110(2):227–39.

``Screening in Women The foregoing screening and treatment guidelines, based largely on LDL cholesterol levels, are designed for both men and women. Yet several observational studies suggest that a low HDL cholesterol is a more important risk factor for CHD in women than a high LDL cholesterol. Metaanalysis of studies including women with known heart disease, however, has found that medications that primarily lower LDL cholesterol do prevent recurrent myocardial infarctions in women. There is insufficient evidence to be certain of a similar effect from LDL-lowering therapy in women without evidence of CHD. Although most experts recommend application of the same primary prevention guidelines for women as for men, clinicians should be aware of the uncertainty in this area. Using estimates of 10-year CHD risk may be particularly helpful in women since a larger percentage of women than men will have

estimated 10-year CHD risks below 10% per year and thus women are less likely to benefit from therapy unless their LDL cholesterol is extremely high (> 190 mg/dL or 4.91 mmol/L).

``Screening in Older Patients Meta-analysis of evidence relating cholesterol to CHD in the elderly suggests that cholesterol is not a risk factor for CHD for persons over age 75 years. Clinical trials have rarely included such individuals. One exception is the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). In this study, elderly patients with cardiovascular disease (secondary prevention) benefited from statin therapy, whereas those without cardiovascular disease ­(primary prevention) did not. Although the NCEP recommends continuing treatment in the elderly, many clinicians will prefer to stop screening and treatment in patients age

1252

CMDT 2013

Chapter 28

75 years or older who do not have CHD. In patients age 75 years or older who have CHD, LDL-lowering therapy can be continued as recommended for younger patients with the disease. Decisions to discontinue therapy should be based on overall functional status and life expectancy, comorbidities, and patient preference and should be made in context with overall therapeutic goals and end-of-life decisions.

Bonow RO. Clinical practice. Should coronary calcium screening be used in cardiovascular prevention strategies? N Engl J Med. 2009 Sep 3;361(10):990–7. [PMID: 19726773] Emerging Risk Factors Collaboration. Major lipids, apolipoproteins, and risk of vascular disease. JAMA. 2009 Nov 11;302(18):1993–2000. [PMID: 19903920] Helfand M et al. Screening for lipid disorders in adults: selective up­date of 2001 US Preventive Services Task Force Review [Internet].

Rockville (MD): Agency for Healthcare Research and Quality (US); 2008 Jun. Report No.: 08-05114-EF-1. [PMID: 20722146] Kuklina EV et al. Prevalence of coronary heart disease risk factors and screening for high cholesterol levels among young adults, United States, 1999–2006. Ann Fam Med. 2010 Jul– Aug;8(4):327–33. [PMID: 20644187]

Treatment of High LOW-Density Lipoprotein Cholesterol Reduction of LDL cholesterol is just one part of a pro­ gram to reduce the risk of cardiovascular disease. Other ­measures—including smoking cessation, hypertension control, and aspirin—are also of central importance. Less well studied but of potential value is raising the HDL cholesterol level. Quitting smoking reduces the effect of other cardiovascular risk factors (such as a high cholesterol level); it may also increase the HDL cholesterol level. Exercise (and weight loss) may reduce the LDL cholesterol and increase the HDL. Modest alcohol use (1–2 ounces a day) also raises HDL levels and appears to have a salutary effect on CHD rates.

Several classes of medications are being actively tested to raise HDL cholesterol levels. One such class of these medications, the cholesteryl ester transfer protein inhibitors, raises HDL cholesterol levels. However, studies to date of one agent in this class, torcetrapib, have shown adverse effects on cardiovascular outcomes. A second drug, anacetrapib, is in clinical trials. Results show reductions of LDL cholesterol as well as increases in HDL cholesterol and no significant adverse experiences compared with placebo.

Larger and longer trials are planned to assess the impact of this drug on clinical outcomes.

``Diet Therapy Studies of nonhospitalized adults have reported only modest cholesterol-lowering benefits of dietary therapy, typically in the range of a 5–10% decrease in LDL cholesterol, with even less in the long term. The effect of diet therapy, however, varies considerably among individuals, as some patients will have striking reductions in LDL ­cholesterol— up to a 25–30% decrease—whereas others will have clinically important increases. Thus, the results of diet therapy should be assessed about 4 weeks after initiation.

Cholesterol-lowering diets may also have a variable effect on lipid fractions. Diets very low in total fat or in

saturated fat may lower HDL cholesterol as much as LDL cholesterol. It is not known how these diet-induced changes affect coronary risk.

Several nutritional approaches to diet therapy are available. Most Americans currently eat over 35% of calories as fat, of which 15% is saturated fat. Dietary cholesterol intake averages 400 mg/d. A cholesterol-lowering diet recommends reducing total fat to 25–30% and saturated fat to < 7% of calories. Dietary cholesterol should be limited to < 200 mg/d.

These diets replace fat, particularly saturated fat, with carbohydrate. In most instances, this approach will also result in fewer total calories consumed and will facilitate weight loss in overweight patients. Other diet plans, including the Dean Ornish Diet, the Pritikin Diet, and most vegetarian diets, restrict fat even further. Low-fat, high-carbohydrate diets may, however, result in reductions in HDL cholesterol.

An alternative strategy is the “Mediterranean diet,” which maintains total fat at approximately 35–40% of total calories but replaces saturated fat with monounsaturated fat such as that found in canola oil and in olives, peanuts, avocados, and their oils. This diet is equally effective at lowering LDL cholesterol but is less likely to lead to reductions in HDL cholesterol. Several studies have suggested that this approach may also be associated with reductions in endothelial dysfunction, insulin resistance, and markers of vascular inflammation and may result in better resolution of the metabolic syndrome than traditional cholesterol-lowering diets.

Other dietary changes may also result in beneficial changes in blood lipids. Soluble fiber, such as that found in oat bran or psyllium, may reduce LDL cholesterol by 5–10%.

Garlic, soy protein, vitamin C, pecans, and plant sterols may also result in reduction of LDL cholesterol. Because oxidation of LDL cholesterol is a potential initiating event in atherogenesis, diets rich in antioxidants, found primarily in fruits and vegetables, may be helpful (see Chapter 29).

Studies have suggested that when all of these elements are combined into a single dietary prescription, the impact of diet on LDL cholesterol may approach that of statin medications, lowering LDL cholesterol by close to 30%.

Cannon CP et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med. 2010 Dec 16;363(25):2406–15. [PMID: 21082868] Ferdowsian HR et al. Effects of plant-based diets on plasma lipids.

Am J Cardiol. 2009 Oct 1;104(7):947–56. [PMID: 19766762] Kelley GA et al. Comparison of aerobic exercise, diet or both on lipids and lipoproteins in adults: a meta-analysis of randomized controlled trials. Clin Nutr. 2011 Dec 9. [Epub ahead of print] [PMID: 22154987] Nordmann AJ et al. Meta-analysis comparing Mediterranean to low-fat diets for modification of cardiovascular risk factors.

Am J Med. 2011 Sep;124(9):841–51. [PMID: 21854893] Rumawas ME et al. Mediterranean-style dietary pattern, reduced risk of metabolic syndrome traits, and incidence in the Framingham Offspring Cohort. Am J Clin Nutr. 2009 Dec; 90(6):1608–14. [PMID: 19828705] Talati R et al. The comparative efficacy of plant sterols and stanols on serum lipids: a systematic review and meta-analysis. J Am Diet Assoc. 2010 May;110(5):719–26. [PMID: 20430133] Walker C et al. Diets for cardiovascular disease prevention: what is the evidence? Am Fam Physician. 2009 Apr 1;79(7):571–8.

[PMID: 19378874]

Lipid Disorders

``Pharmacologic Therapy Most patients whose risk from CHD is considered high enough to warrant pharmacologic therapy of an elevated LDL cholesterol should be given aspirin prophylaxis at a dose of 81 mg/d unless there are contraindications such as aspirin sensitivity, bleeding diatheses, or active peptic ulcer disease. The benefit of aspirin in reducing the risk of CHD in men is equivalent to that of cholesterol lowering. Other CHD risk factors, such as hypertension and smoking, should also be controlled.

If the decision to treat a patient with an LDL-lowering drug is made, a goal for treatment is set. The National Cholesterol Education Program’s Adult Treatment Panel III (NCEP ATP III) guidelines remain the mainstay of clinical practice. For patients with CHD or CHD risk equivalents, the goal is LDL < 100 mg/dL (< 2.59 mmol/L), but for patients with very high risk, a goal of LDL < 70 mg/dL (< 1.81 mmol/L) is a therapeutic option (see Table 28–3).

This goal may also be appropriate for patients with very high risk who have a baseline LDL < 100 mg/dL (< 2.59 mmol/L). For patients with two or more risk factors and a 10-year CHD risk of 10–20%, the recommended goal is LDL < 130 mg/dL (< 3.36 mmol/L), but a goal of < 100 mg/dL (< 2.59 mmol/L is optional. For those with two or more risk factors and a 10-year CHD risk of < 10%, the goal is < 130 mg/dL (< 3.36 mmol/L). For those with zero or one risk factor, the goal is LDL < 160 mg/dL (< 4.14 mmol/L) (see Table 28–3). In most instances, intensity of therapy should be sufficient to achieve a 30–40% reduction in LDL cholesterol. Once the goal is reached, the lipid profile should be monitored periodically (every 6–12 months), with consideration given to periodic reductions in drug dose.

A. Niacin (Nicotinic Acid) Niacin was the first lipid-lowering agent that was associated with a reduction in total mortality. Long-term follow-up of a secondary prevention trial of middle-aged men with previous myocardial infarction disclosed that about half of those who had been previously treated with niacin had died, compared with nearly 60% of the placebo group. This favorable effect on mortality was not seen during the trial itself, though there was a reduction in the incidence of recurrent coronary events.

Niacin reduces the production of VLDL particles, with secondary reduction in LDL and increases in HDL cholesterol levels. The average effect of full-dose niacin therapy, 3–4.5 g/d, is a 15–25% reduction in LDL cholesterol and a 25–35% increase in HDL cholesterol. Full doses are required to obtain the LDL effect, but the HDL effect is observed at lower doses, eg, 1 g/d. Niacin will also reduce triglycerides by half and will lower lipoprotein(a) (Lp[a]) levels and will increase plasma homocysteine levels. Intolerance to niacin is common; only 50–60% of patients can take full doses.

Niacin causes a prostaglandin-mediated flushing that patients may describe as “hot flashes” or pruritus and that can be decreased with aspirin (81–325 mg/d) or other nonsteroidal anti-inflammatory agents taken during the same day. Flushing may also be decreased by initiating niacin therapy with a very small dose, eg, 100 mg with the evening

CMDT 2013

1253

meal. The dose can be doubled each week until 1.5 g/d is tolerated. After rechecking blood lipids, the dose is increased and divided over three meals until the goal of 3–4.5 g/d is reached (eg, 1 g with each meal). Extended-release niacin is better tolerated by most patients. It is not known whether routine monitoring of liver enzymes results in early detection and thus reduced severity of this side effect. Niacin can also exacerbate gout and peptic ulcer disease. Although niacin may increase blood sugar in some patients, clinical trials have shown that niacin can be safely used in diabetic patients.

B. Bile Acid–Binding Resins The bile acid–binding resins include cholestyramine, colesevelam, and colestipol. Treatment with these agents reduces the incidence of coronary events in middle-aged men by about 20%, with no significant effect on total mortality. The resins work by binding bile acids in the intestine.

The resultant reduction in the enterohepatic circulation causes the liver to increase its production of bile acids, using hepatic cholesterol to do so. Thus, hepatic LDL receptor activity increases, with a decline in plasma LDL levels. The triglyceride level tends to increase slightly in some patients treated with bile acid–binding resins; they should be used with caution in those with elevated triglycerides and probably not at all in patients who have triglyceride levels above 500 mg/dL. The clinician can anticipate a reduction of 15–25% in the LDL cholesterol level, with insignificant effects on the HDL level.

The usual dose of cholestyramine is 12–36 g of resin per day in divided doses with meals, mixed in water or, more palatably, juice. Doses of colestipol are 20% higher (each packet contains 5 g of resin). The dose of colesevelam is 625 mg, 6–7 tablets per day.

These agents often cause gastrointestinal symptoms, such as constipation and gas. They may interfere with the absorption of fat-soluble vitamins (thereby complicating the management of patients receiving warfarin) and may bind other drugs in the intestine. Concurrent use of psyllium may ameliorate the gastrointestinal side effects.

C. Hydroxymethylglutaryl-Coenzyme A (HMG-CoA) Reductase Inhibitors (Statins) The HMG-CoA reductase inhibitors (statins) include atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. These agents work by inhibiting the rate-limiting enzyme in the formation of cholesterol. They reduce myocardial infarctions and total mortality in secondary prevention, as well as in older middle-aged men free of CHD. A meta-analysis has demonstrated significant reduction in risk of stroke. Cholesterol synthesis in the liver is reduced, with a compensatory increase in hepatic LDL receptors (presumably so that the liver can take more of the cholesterol that it needs from the blood) and a reduction in the circulating LDL cholesterol level by up to 35%. There are also modest increases in HDL levels and decreases in triglyceride levels.

Oral doses are as follows: atorvastatin, 10–80 mg/d; fluvastatin, 20–40 mg/d; lovastatin, 10–80 mg/d; pitavastatin

1254

CMDT 2013

Chapter 28

2-4 mg/d; pravastatin, 10–40 mg/d; rosuvastatin, 5–40 mg/d; and simvastatin, 5–40 mg/d. There is no clear superiority of one HMG-CoA reductase inhibitor over others.

These agents are given once daily. The most common side effects are muscle aches, occurring in up to 10% of patients, and mild gastrointestinal effects. More serious, but extremely uncommon, side effects include liver failure and muscle disease including myositis and rhabdomyolysis. Liver disease is more common in patients also taking fibrates or niacin. Muscle disease is more common with statins and fibrates and niacin as well as with erythromycin, antifungal medications, nefazadone, and cyclosporine. Manufac­ turers of HMG-CoA reductase inhibitors recommend regular monitoring of liver and muscle enzymes.

D. Fibric Acid Derivatives The fibrates are peroxisome proliferative-activated receptor-α (PPAR-α) agonists that result in potent reductions of plasma triglycerides and increases in HDL cholesterol. They reduce LDL levels by about 10–15%, although the result is quite variable, and triglyceride levels by about 40% and raise HDL levels by about 15–20%. The fibric acid derivatives or fibrates approved for use in the United States are gemfibrozil and fenofibrate. Ciprofibrate and bezafibrate are also available for use internationally.

Gemfibrozil reduced CHD rates in hypercholesterolemic middle-aged men free of coronary disease in the Helsinki Heart Study. The effect was observed only among those who also had lower HDL cholesterol levels and high triglyceride levels. In a VA study, gemfibrozil was also shown to reduce cardiovascular events in men with existing CHD whose primary lipid abnormality was a low HDL cholesterol. There was no effect on all-cause mortality.

The usual dose of gemfibrozil is 600 mg once or twice a day. Side effects include cholelithiasis, hepatitis, and myositis. The incidence of the latter two conditions may be higher among patients also taking other lipid-lowering agents. In the largest clinical trial that used clofibrate, there were significantly more deaths—especially due to cancer—in the treatment group; it should not be used.

E. Ezetimibe Ezetimibe is a lipid-lowering drug that inhibits the intestinal absorption of dietary and biliary cholesterol by blocking passage across the intestinal wall by inhibiting a cholesterol transporter. The usual dose of ezetimibe is 10 mg/d orally. Ezetimibe reduces LDL cholesterol between 15% and 20% when used as monotherapy and can further reduce LDL in patients taking statins who are not yet at therapeutic goal.

However, the effects of ezetimide on CHD and its longterm safety are not yet known. Results from one small clinical trial, ENHANCE (a study of 720 persons with heterozygous familial hypercholesterolemia), showed no significant difference of intimal media thickness with ezetimibe plus an HMG-CoA reductase inhibitor compared with an HMG-CoA reductase inhibitor alone. A second study compared a statin plus ezetimibe with a statin plus extended-release niacin. The statin plus niacin

caused a significant regression of carotid intima-media thickness and was superior to the statin plus ezetimibe combination.

``Initial Selection of Medication At present there are no absolute guidelines for selection of available lipid-modifying medications in particular patients. Nonetheless, clinical trials provide guidance (Table 28–4). For most patients who require a lipid-­ modifying medication, an HMG-CoA reductase inhibitor is preferred. Although niacin will also have beneficial effects on lipids in both men and women with CHD, there is less evidence demonstrating the desired effects on CHD and all-cause mortality. Resins are the only lipidmodifying medication considered safe in pregnancy.

Combination therapy may be used to meet lipid targets in some patients or to achieve other therapeutic goals. For example, low-dose niacin (0.5–1 g/d), will substantially increase the HDL cholesterol when added to an HMG-CoA reductase inhibitor. Despite improvements in the lipid profile, however, there are few data demonstrating improved clinical outcomes of combination therapy when compared with HMG-CoA reductase inhibitors alone. Combinations may also increase the risk of complications of drug therapy.

The combination of gemfibrozil and HMG-CoA reductase inhibitors increases the risk of muscle and liver disease more than either drug alone.

Abourbih S et al. Effect of fibrates on lipid profiles and cardiovascular outcomes: a systematic review. Am J Med. 2009 Oct; 122(10):962.e1–8. [PMID: 19698935] ACCORD Study Group et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010 Apr 29;362(17):1563–74. [PMID: 20228404] AIM-HIGH Investigators; Boden WE et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011 Dec 15;365(24):2255–67. [PMID: 22085343] Athyros VG et al. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis. Lancet. 2010 Dec 4;376(9756):1916–22.

[PMID: 21109302] Hsia J et al. Cardiovascular event reduction and adverse events among subjects attaining low-density lipoprotein cholesterol <50 mg/dl with rosuvastatin. The JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin). J Am Coll Cardiol. 2011 Apr 19;57(16):1666–75. [PMID: 21492764] Jun M et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet. 2010 May 29;375(9729):1875–84. [PMID: 20462635] Karalis DG. Intensive lowering of low-density lipoprotein cholesterol levels for primary prevention of coronary artery disease.

Mayo Clin Proc. 2009 Apr;84(4):345–52. [PMID: 19339653] Ladenson PW. Use of the thyroid hormone analogue eprotirome in statin-treated dyslipidemia. N Engl J Med. 2010 Mar 11; 362(10):906–16. [PMID: 20220185] Mikhailidis DP et al. Comparative efficacy of the addition of ezetimibe to statin vs statin titration in patients with hypercholesterolaemia: systematic review and meta-analysis. Curr Med Res Opin. 2011 Jun;27(6):1191–210. [PMID: 21473671]

Lipid Disorders

CMDT 2013

1255

Table 28–4. Effects of selected lipid-modifying drugs.

Lipid-Modifying Effects Drug

LDL

HDL

Atorvastatin (Lipitor)

−25 to −40%

+5 to 10%

Cholestyramine (Questran, others)

−15 to −25%

+5%

Colesevelam (WelChol)

−10 to −20%

Colestipol (Colestid) Ezetimibe (Zetia)

Triglyceride

↓↓

Initial Daily Dose

Maximum Daily Dose

Cost for 30 Days Treatment with Dose Listed1

10 mg once

80 mg once

$158.04 (20 mg once)

±

4 g twice a day

24 g divided

$127.00 (8 g divided)

+10%

±

625 mg, 6–7 tablets once

625 mg, 6–7 tablets once

$270.00 (6 tablets once)

−15 to −25%

+5%

±

5 g twice a day

30 g divided

$150.00 (10 g divided)

−20%

+5%

±

10 mg once

10 mg once

$146.10 (10 mg once)

Fenofibrate (Tricor, others)

−10 to −15%

+15 to 25%

↓↓

48 mg once

145 mg once

$180.00 (145 mg once)

Fenofibric Acid (Trilipix)

−10 to −15%

+15 to 25%

↓↓

45 mg once

135 mg once

$171.60 (135 mg once)

Fluvastatin (Lescol)

−20 to −30%

+5 to 10%

↓

20 mg once

40 mg once

$126.00 (20 mg once)

Gemfibrozil (Lopid, others)

−10 to −15%

+15 to 20%

↓↓

600 mg once

1200 mg divided

$73.20 (600 mg twice a day)

Lovastatin (Mevacor, others)

−25 to −40%

+5 to 10%

↓

10 mg once

80 mg divided

$71.10 (20 mg once)

Niacin (OTC, Niaspan)

−15 to −25%

+25 to 35%

↓↓

100 mg once

3–4.5 g divided

$9.00 (1.5 g twice a day, OTC) $320.40 (2 g Niaspan)

Pitavastatin (Livalo)

−30 to 40%

+10 to 25%

↓↓

2 mg once

4 mg once

$128.40 (2 mg once)

Pravastatin (Pravachol)

−25 to −40%

+5 to 10%

↓

20 mg once

40 mg once

$98.10 (20 mg once)

Rosuvastatin (Crestor)

−40 to −50%

+10 to 15%

↓↓

10 mg once

40 mg once

$169.50 (20 mg once)

Simvastatin (Zocor, others)

−25 to −40%

+5 to 10%

↓↓

5 mg once

80 mg once

$84.60 (10 mg once)

1

Average wholesale price (AWP, for AB-rated generic when available) for quantity listed. Source: Red Book Online, 2012, Thomson Reuters (Healthcare) Inc. AWP may not accurately represent the actual pharmacy cost because wide contractual variations exist among institutions.

LDL, low-density lipoprotein; HDL, high-density lipoprotein; ± variable, if any; others, indicates availability of less expensive generic preparations; OTC, over the counter.

Nicholls SJ et al. Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med. 2011 Dec 1;365 (22):2078–87. [PMID: 22085316] Raal FJ et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet. 2010 Mar 20;375(9719):998–1006. [PMID: 20227758] Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet. 2010 Nov 13;376 (9753):1658–69. [PMID: 21067805] Taylor AJ et al. Extended-release niacin or ezetimibe and carotidmedia thickness. N Engl J Med. 2009 Nov 26;361(22):2113–22.

[PMID: 19915217]

High Blood Triglycerides Patients with very high levels of serum triglycerides (> 1000 mg/dL) are at risk for pancreatitis. The pathophysiology is not certain, since pancreatitis never develops in some

patients with very high triglyceride levels. Most patients with congenital abnormalities in triglyceride metabolism present in childhood; hypertriglyceridemia-induced pancreatitis first presenting in adults is more commonly due to an acquired problem in lipid metabolism.

Although there are no clear triglyceride levels that predict pancreatitis, most clinicians treat fasting levels above 500 mg/dL (5 mmol/L). The risk of pancreatitis may be more related to the triglyceride level following consumption of a fatty meal. Because postprandial increases in triglyc­eride are inevitable if fat-containing foods are eaten, fasting triglyceride levels in persons prone to pancreatitis should be kept well below that level.

The primary therapy for high triglyceride levels is dietary, avoiding alcohol, simple sugars, refined starches, saturated and trans fatty acids, and restricting total ­calories. Control of secondary causes of high triglyceride levels (see Table 28–1) may also be helpful. In patients with fasting triglycerides ≥ 500 mg/dL (≥ 5 mmol/L) despite adequate dietary compliance—and certainly in those with a previous episode of pancreatitis—therapy with a ­triglyceride-lowering drug (eg, niacin, a fibric acid

1256

CMDT 2013

Chapter 28

­ erivative, omega-3-acid ethyl esters, or an HMG-CoA d reductase inhibitor) is indicated. Combinations of these medications may also be used.

Whether patients with elevated triglycerides (> 150 mg/ dL or 1.5 mmol/L) should be treated to prevent CHD is not known. Meta-analysis of 17 observational studies suggests that after adjustment for other risk factors, elevated triglycerides increased CHD risk in men by 14% and in women by 37%. Triglyceride-rich lipoproteins have been found in human atheromas, and elevated triglycerides are associated with small dense LDL in most instances. Elevated triglycerides are also an important feature of the metabolic syndrome, found in an estimated 25% of Americans—defined by three or more of the following five abnormalities: waist circumference > 102 cm in men or > 88 cm in women, serum triglyceride level of at least 150 mg/dL, HDL level of < 40 mg/dL in men or < 50 mg/dL in women, blood pressure of at least 130/85 mm Hg, and serum glucose level of at least 110 mg/dL. Other data, however, suggest that triglyceride measurements do not improve discrimination between those with and without CHD events, and clinical trial data are not available to support the routine treatment of high triglycerides in all patients.

The NCEP ATP III guidelines, however, recommend an aggressive approach to triglyceride management. For those with borderline levels (150–199 mg/dL or 1.5–1.99 mmol/L), emphasis is placed on calorie restriction and exercise. For patients with high triglycerides (> 200 mg/dL), the nonHDL cholesterol should be measured (total cholesterol – HDL cholesterol). The ATP III report recommends that non-HDL cholesterol should be treated with diet and

medications to result in levels 30 mg/dL higher than the LDL goal. The ATP III report does not differentiate between primary and secondary prevention. It is reasonable to use this approach for patients with CHD and risk equivalents for that disease but not for lower-risk patients.

AbouRjaili G et al. Current concepts in triglyceride metabolism, pathophysiology, and treatment. Metabolism. 2010 Aug;59(8): 1210–20. [PMID: 20060141] Ballantyne CM et al. Long-term efficacy of adding fenofibric acid to moderate-dose statin therapy in patients with persistent elevated triglycerides. Cardiovasc Drugs Ther. 2011 Feb;25(1):59–67. [PMID: 21416219] Bays HE et al. Long-term up to 24-month efficacy and safety of concomitant prescription omega-3-acid ethyl esters and simvastatin in hypertriglyceridemic patients. Curr Med Res Opin.

2010 Apr;26(4):907–15. [PMID: 20156032] Faergeman O et al; Steering Committees of IDEAL and TNT Trials. Plasma triglycerides and cardiovascular events in the Treating to New Targets and Incremental Decrease in EndPoints through Aggressive Lipid Lowering trials of statins in patients with coronary artery disease. Am J Cardiol. 2009 Aug 15;104(4):459–63. [PMID: 19660594] Roth EM et al. Efficacy and safety of rosuvastatin and fenofibric acid combination therapy versus simvastatin monotherapy in patients with hypercholesterolemia and hypertriglyceridemia: a randomized, double-blind study. Am J Cardiovasc Drugs.

2010;10(3):175–86. [PMID: 20524719] Watts GF et al. Triglycerides and atherogenic dyslipidaemia: extending treatment beyond statins in the high-risk cardiovascular patient. Heart. 2011 Mar;97(5):350–6. [PMID: 21296781]