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Dipiro Edisi 9 Kolestrol
Dipiro Edisi 9 Kolestrol
8 Dyslipidemia
PATHOPHYSIOLOGY
• Cholesterol, triglycerides, and phospholipids are transported in blood as complexes
of lipids and proteins (lipoproteins). Elevated total and LDL cholesterol and reduced
HDL cholesterol are associated with development of coronary heart disease (CHD).
• Risk factors such as oxidized LDL, mechanical injury to endothelium, and excessive
homocysteine can lead to endothelial dysfunction and cellular interactions culminat-
ing in atherosclerosis. Eventual clinical outcomes may include angina, myocardial
infarction (MI), arrhythmias, stroke, peripheral arterial disease, abdominal aortic
aneurysm, and sudden death.
• Atherosclerotic lesions arise from transport and retention of plasma LDL through the
endothelial cell layer into the extracellular matrix of the subendothelial space. Once
in the artery wall, LDL is chemically modified through oxidation and nonenzymatic
glycation. Mildly oxidized LDL recruits monocytes into the artery wall, which trans-
form into macrophages that accelerate LDL oxidation. Oxidized LDL provokes an
inflammatory response mediated by chemoattractants and cytokines.
• Repeated injury and repair within an atherosclerotic plaque eventually lead to a
fibrous cap protecting the underlying core of lipids, collagen, calcium, and inflam-
matory cells. Maintenance of the fibrous plaque is critical to prevent plaque rupture
and coronary thrombosis.
• Primary or genetic lipoprotein disorders are classified into six categories: I (chylomi-
crons), IIa (LDL), IIb (LDL + very-low-density lipoprotein [VLDL]), III (intermediate-
density lipoprotein), IV (VLDL), and V (VLDL + chylomicrons). Secondary forms of
dyslipidemia also exist, and several drug classes may affect lipid levels (eg, progestins,
thiazide diuretics, glucocorticoids, β-blockers, isotretinoin, protease inhibitors, cyclospo-
rine, mirtazapine, and sirolimus).
• The primary defect in familial hypercholesterolemia is inability to bind LDL to the
LDL receptor (LDL-R). This leads to a lack of LDL degradation by cells and unregu-
lated biosynthesis of cholesterol.
CLINICAL PRESENTATION
• Most patients are asymptomatic for many years. Symptomatic patients may complain
of chest pain, palpitations, sweating, anxiety, shortness of breath, abdominal pain, or
loss of consciousness or difficulty with speech or movement.
• Depending on the lipoprotein abnormality, signs on physical examination may
include cutaneous xanthomas, peripheral polyneuropathy, high blood pressure, and
increased body mass index or waist size.
DIAGNOSIS
• Measure fasting lipoprotein profile (total cholesterol, LDL, HDL, triglycerides) in all
adults 20 years of age or older at least once every 5 years.
• Measure plasma cholesterol, triglyceride, and HDL levels after a 12-hour fast because
triglycerides may be elevated in nonfasting individuals; total cholesterol is only mod-
estly affected by fasting.
• Two determinations, 1 to 8 weeks apart are recommended to minimize variability
and obtain a reliable baseline. If the total cholesterol is greater than 200 mg/dL
(>5.17 mmol/L), a second determination is recommended, and if the values are
greater than 30 mg/dL (>0.78 mmol/L) apart, use the average of three values.
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SECTION 2 | Cardiovascular Disorders
• History and physical examination should assess: (1) presence or absence of car-
diovascular risk factors or definite cardiovascular disease; (2) family history of
premature cardiovascular disease or lipid disorders; (3) presence or absence of sec-
ondary causes of dyslipidemia, including concurrent medications; and (4) presence
or absence of xanthomas, abdominal pain, or history of pancreatitis, renal or liver
disease, peripheral vascular disease, abdominal aortic aneurysm, or cerebral vascular
disease (carotid bruits, stroke, or transient ischemic attack).
• Diabetes mellitus and the metabolic syndrome are considered CHD risk equivalents;
their presence in patients without known CHD is associated with the same level of
risk as patients without them but having confirmed CHD.
• Lipoprotein electrophoresis is sometimes performed to determine which class of
lipoproteins is involved. If the triglycerides are less than 400 mg/dL (4.52 mmol/L),
and neither type III dyslipidemia nor chylomicrons are detected by electrophoresis,
then one can calculate VLDL and LDL concentrations: VLDL = triglycerides ÷ 5; LDL
= total cholesterol – (VLDL + HDL). Initial testing uses total cholesterol for case find-
ing, but subsequent management decisions should be based on LDL.
TREATMENT
• Goals of Treatment: Lower total and LDL cholesterol to reduce the risk of first or
recurrent events such as MI, angina, heart failure, ischemic stroke, or peripheral
arterial disease.
GENERAL APPROACH
• The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP
III) recommends that fasting lipoprotein profile and risk factor assessment be used
in initial classification of adults.
• If the total cholesterol is less than 200 mg/dL (>5.17 mmol/L), then the patient
has a desirable blood cholesterol level (Table 8–1). If the HDL is also greater than
40 mg/dL (>1.03 mmol/L), no further follow-up is recommended for patients with-
out known CHD and who have fewer than two risk factors (Table 8–2). In patients
with borderline-high blood cholesterol (200–239 mg/dL; 5.17–6.18 mmol/L), assess-
ment of risk factors is needed to more clearly define disease risk.
TABLE 8–1 Classification of Total, LDL, and HDL Cholesterol and Triglycerides
Total cholesterol
<200 mg/dL (<5.17 mmol/L) Desirable
200–239 mg/dL (5.17–6.20 mmol/L) Borderline high
≥240 mg/dL (≥6.21 mmol/L) High
LDL cholesterol
<100 mg/dL (<2.59 mmol/L) Optimal
100–129 mg/dL (2.59–3.35 mmol/L) Near or above optimal
130–159 mg/dL (3.36–4.13 mmol/L) Borderline high
160–189 mg/dL (4.14–4.90 mmol/L) High
≥190 mg/dL (≥4.91 mmol/L) Very high
HDL cholesterol
<40 mg/dL (<1.03 mmol/L) Low
≥60 mg/dL (≥1.55 mmol/L) High
Triglycerides
<150 mg/dL (<1.70 mmol/L) Normal
150–199 mg/dL (1.70–2.25 mmol/L) Borderline high
200–499 mg/dL (2.26–5.64 mmol/L) High
≥500 mg/dL (≥5.65 mmol/L) Very high
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Dyslipidemia | CHAPTER 8
TABLE 8–2 Major Risk Factors (Exclusive of LDL Cholesterol) That Modify LDL Goalsa
Age
Men: ≥45 years
Women: ≥55 years or premature menopause without estrogen replacement therapy
Family history of premature CHD (definite myocardial infarction or sudden death before 55
years of age
in father or other male first-degree relative or before 65 years of age in mother or other
female
first-degree relative)
Cigarette smoking
Hypertension (≥140/90 mm Hg or on antihypertensive medication)
Low HDL cholesterol (<40 mg/dL [<1.03 mmol/L])b
CHD, coronary heart disease; HDL, high-density lipoprotein; LDL, low-density lipoprotein.
a
Diabetes is regarded as a CHD risk equivalent.
b
HDL cholesterol (≥60 mg/dL [≥1.55 mmol/L]) counts as a “negative” risk factor; its presence removes
one risk factor from the total count.
• Decisions regarding classification and management are based on the LDL cholesterol
levels listed in Table 8–3.
• Four risk categories modify the goals and modalities of LDL-lowering therapy:
1. Highest risk = Known CHD or CHD risk equivalents; risk for coronary events is
at least as high as for established CHD (ie, >20% per 10 years, or 2% per year).
2. Moderately high risk = 2 or more risk factors in which 10-year risk for CHD is
10% to 20%.
TABLE 8–3 LDL Cholesterol Goals and Cutpoints for Therapeutic Lifestyle Changes (TLCs) and
Drug Therapy in Different Risk Categories
LDL Level
at Which
to Initiate LDL Level at Which to
LDL Goal, mg/ TLC, mg/dL Consider Drug Therapy,
Risk Category dL (mmol/L) (mmol/L) mg/dL (mmol/L)
High risk: CHD or CHD risk <100 (<2.59) ≥100 (≥2.59) ≥100 (≥2.59)
equivalents (10-year risk (optional goal: (<100 [<2.59]: consider
>20%) <70 [<1.81]) drug options)a
Moderately high risk: 2+ <130 (<3.36) ≥130 (≥3.36) ≥130 (≥3.36)
risk factors (10-year risk (100-129 [2.59–3.35):
10–20%) consider drug options)
Moderate risk: 2+ risk fac- <130 (<3.36) ≥130 (≥3.36) ≥160 (≥4.14)
tors (10-year risk <10%)
Lower risk: 0 or 1 risk factorb <160 (<4.14) ≥160 (≥4.14) ≥190 (≥4.91)
(160-189 [4.14–4.90]: LDL-
lowering drug optional)
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SECTION 2 | Cardiovascular Disorders
3. Moderate risk = 2 or more risk factors and a 10-year risk of 10% or less.
4. Lowest risk = 0 to 1 risk factor, which is usually associated with a 10-year CHD
risk of less than 10%.
• Note: New cholesterol treatment guidelines issued in late 2013 are not considered
here.
NONPHARMACOLOGIC THERAPY
• Begin therapeutic lifestyle changes (TLCs) on the first visit, including dietary therapy,
weight reduction, and increased physical activity. Advise overweight patients to lose
10% of body weight. Encourage physical activity of moderate intensity 30 minutes a day
for most days of the week. Assist patients with smoking cessation and control of
hypertension.
• The objectives of dietary therapy are to progressively decrease intake of total fat,
saturated fat, and cholesterol and to achieve a desirable body weight (Table 8–4).
• Increased intake of soluble fiber (oat bran, pectins, psyllium) can reduce total and
LDL cholesterol by 5% to 20%. However, they have little effect on HDL-C or triglyc-
erides. Fiber products may also be useful in managing constipation associated with
bile acid resins (BARs).
• Fish oil supplementation reduces triglycerides and VLDL-C, but it either has no
effect on total and LDL-C or may elevate these fractions. Other actions of fish oil may
account for any cardioprotective effects.
• Ingestion of 2 to 3 g daily of plant sterols reduces LDL by 6% to 15%. They are usually
available in commercial margarines.
• If all recommended dietary changes were instituted, the estimated average reduction
in LDL would range from 20% to 30%.
PHARMACOLOGIC THERAPY
• The effect of drug therapy on lipids and lipoproteins is shown in Table 8–5.
• Recommended drugs of choice for each lipoprotein phenotype are given in Table 8–6.
• Available products and their doses are provided in Table 8–7.
Bile Acid Resins
• BARs (cholestyramine, colestipol, colesevelam) bind bile acids in the intestinal
lumen, with a concurrent interruption of enterohepatic circulation of bile acids,
which decreases the bile acid pool size and stimulates hepatic synthesis of bile acids
from cholesterol. Depletion of the hepatic cholesterol pool increases cholesterol bio-
synthesis and the number of LDL-Rs on hepatocyte membranes, which enhances the
TABLE 8–4 Macronutrient Recommendations for the Therapeutic Lifestyle Change (TLC) Diet
Componenta Recommended Intake
Total fat 25–35% of total calories
Saturated fat <7% of total calories
Polyunsaturated fat Up to 10% of total calories
Monounsaturated fat Up to 20% of total calories
Carbohydratesb 50–60% of total calories
Cholesterol <200 mg/day
Dietary fiber 20–30 g/day
Plant sterols 2 g/day
Protein ~15% of total calories
Total calories To achieve and maintain desirable body weight
a
Calories from alcohol not included.
b
Carbohydrates should derive from foods rich in complex carbohydrates, such as whole grains, fruits,
and vegetables.
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Dyslipidemia | CHAPTER 8
↑, increased; ↓, decreased.
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SECTION 2 | Cardiovascular Disorders
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Dyslipidemia | CHAPTER 8
rate of catabolism from plasma and lowers LDL levels. Increased hepatic cholesterol
biosynthesis may be paralleled by increased hepatic VLDL production; consequently,
BARs may aggravate hypertriglyceridemia in patients with combined dyslipidemia.
• BARs are useful in treating primary hypercholesterolemia (familial hypercholesterol-
emia, familial combined dyslipidemia, and type IIa hyperlipoproteinemia).
• Common GI complaints include constipation, bloating, epigastric fullness, nausea,
and flatulence. They can be managed by increasing fluid intake, increasing dietary
bulk, and using stool softeners.
• The gritty texture and bulk may be minimized by mixing the powder with orange
drink or juice. Colestipol may have better palatability than cholestyramine because it
is odorless and tasteless. Tablet forms may help improve adherence.
• Other potential adverse effects include impaired absorption of fat-soluble vitamins A, D,
E, and K; hypernatremia and hyperchloremia; GI obstruction; and reduced bioavail-
ability of acidic drugs such as warfarin, nicotinic acid, thyroxine, acetaminophen,
hydrocortisone, hydrochlorothiazide, loperamide, and possibly iron. Drug interac-
tions may be avoided by alternating administration times with an interval of 6 hours
or more between the BARs and other drugs.
Niacin
• Niacin (nicotinic acid) reduces hepatic synthesis of VLDL, which in turn reduces
synthesis of LDL. Niacin also increases HDL by reducing its catabolism.
• The principal use of niacin is for mixed dyslipidemia or as a second-line agent in
combination therapy for hypercholesterolemia. It is a first-line agent or alternative
for treatment of hypertriglyceridemia and diabetic dyslipidemia.
• Cutaneous flushing and itching appear to be prostaglandin mediated and can be
reduced by taking aspirin 325 mg shortly before niacin ingestion. Taking the niacin
dose with meals and slowly titrating the dose upward may minimize these effects.
Concomitant alcohol and hot drinks may magnify the flushing and pruritus from
niacin, and they should be avoided at the time of ingestion. GI intolerance is also a
common problem.
• Laboratory abnormalities may include elevated liver function tests, hyperuricemia,
and hyperglycemia. Niacin-associated hepatitis is more common with sustained-
release preparations, and their use should be restricted to patients intolerant of reg-
ular-release products. Niacin is contraindicated in patients with active liver disease,
and it may exacerbate preexisting gout and diabetes.
• Niaspan is a prescription-only, extended-release niacin formulation with pharmaco-
kinetics intermediate between prompt- and sustained-release products. It has fewer
dermatologic reactions and a low risk of hepatotoxicity. Combination with statins can
produce large reductions in LDL and increases in HDL.
• Nicotinamide should not be used in the treatment of dyslipidemia because it does not
effectively lower cholesterol or triglyceride levels.
HMG-CoA Reductase Inhibitors
• Statins (atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin,
and simvastatin) inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reduc-
tase, interrupting conversion of HMG-CoA to mevalonate, the rate-limiting step in
cholesterol biosynthesis. Reduced LD synthesis and enhanced LDL catabolism mediated
through LDL-Rs appear to be the principal mechanisms for lipid-lowering effects.
• When used as monotherapy, statins are the most potent total and LDL cholesterol–
lowering agents and among the best tolerated. Total and LDL cholesterol are reduced
in a dose-related fashion by 30% or more when added to dietary therapy.
• Combination therapy with a statin and a BAR is rational because the numbers of LDL-Rs
are increased, leading to greater degradation of LDL cholesterol; intracellular synthesis
of cholesterol is inhibited; and enterohepatic recycling of bile acids is interrupted.
• Combination therapy with a statin and ezetimibe is also rational because ezetimibe
inhibits cholesterol absorption across the gut border and adds 12% to 20% further
reduction when combined with a statin or other drug.
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SECTION 2 | Cardiovascular Disorders
• Constipation occurs in less than 10% of patients taking statins. Other adverse effects
include elevated alanine aminotransferase, elevated creatine kinase levels, myopathy,
and, rarely, rhabdomyolysis.
Fibric Acids
• Fibrate monotherapy (gemfibrozil, fenofibrate, clofibrate) is effective in reducing
VLDL, but a reciprocal rise in LDL may occur, and total cholesterol values may
remain relatively unchanged. Plasma HDL concentrations may rise 10% to 15% or
more with fibrates.
• Gemfibrozil reduces synthesis of VLDL and, to a lesser extent, apolipoprotein B
with a concurrent increase in the rate of removal of triglyceride-rich lipoproteins
from plasma. Clofibrate is less effective than gemfibrozil or niacin in reducing VLDL
production.
• GI complaints occur in 3% to 5% of patients. Rash, dizziness, and transient elevations
in transaminase levels and alkaline phosphatase may also occur. Gemfibrozil and
probably fenofibrate enhance gallstone formation rarely.
• A myositis syndrome of myalgia, weakness, stiffness, malaise, and elevations in cre-
atine kinase and aspartate aminotransferase may occur and seems to be more com-
mon in patients with renal insufficiency.
• Fibrates may potentiate the effects of oral anticoagulants, and the international nor-
malized ratio (INR) should be monitored very closely with this combination.
Ezetimibe
• Ezetimibe interferes with absorption of cholesterol from the brush border of the
intestine, making it a good choice for adjunctive therapy. It is approved as mono-
therapy and for use with a statin. The dose is 10 mg once daily, given with or without
food. When used alone, it results in ~18% reduction in LDL cholesterol. When
added to a statin, ezetimibe lowers LDL by an additional 12% to 20%. A combina-
tion product (Vytorin) containing ezetimibe 10 mg and simvastatin 10, 20, 40, or
80 mg is available. Ezetimibe is well tolerated; ~4% of patients experience GI upset.
Because cardiovascular outcomes with ezetimibe have not been evaluated, it should
be reserved for patients unable to tolerate statin therapy or those who do not achieve
satisfactory lipid lowering with a statin alone.
Fish Oil Supplementation
• Diets high in omega-3 polyunsaturated fatty acids (from fish oil), most commonly
eicosapentaenoic acid (EPA), reduce cholesterol, triglycerides, LDL, and VLDL and
may elevate HDL cholesterol.
• Fish oil supplementation may be most useful in patients with hypertriglyceridemia,
but its role in treatment is not well defined.
• LOVAZA (omega-3-acid ethyl esters) is a prescription form of concentrated fish oil
EPA 465 mg and docosahexaenoic acid 375 mg. The daily dose is 4 g, which can be
taken as four 1-g capsules once daily or two 1-g capsules twice daily. This product
lowers triglycerides by 14% to 30% and raises HDL by ~10%.
• Complications of fish oil supplementation such as thrombocytopenia and bleeding
disorders have been noted, especially with high doses (EPA 15–30 g/day).
TREATMENT RECOMMENDATIONS
• Treatment of type I hyperlipoproteinemia is directed toward reduction of chylomi-
crons derived from dietary fat with the subsequent reduction in plasma triglycerides.
Total daily fat intake should be no more than 10 to 25 g, or ~15% of total calories.
Secondary causes of hypertriglyceridemia should be excluded, and, if present, the
underlying disorder should be treated appropriately.
• Primary hypercholesterolemia (familial hypercholesterolemia, familial combined
dyslipidemia, and type IIa hyperlipoproteinemia) is treated with BARs, statins,
niacin, or ezetimibe.
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Dyslipidemia | CHAPTER 8
See Chapter 11, Dyslipidemia, authored by Robert L. Talbert, for a more detailed discus-
sion of this topic.
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