Dyslipidemia

Dyslipidemia(Hyperlipidemia)
• Dyslipidemia is elevation of plasma cholesterol, triglycerides (TGs), or both, or a low

high density lipoprotein level that contributes to the development of atherosclerosis.
Causes may be primary (genetic) or secondary. Diagnosis is by measuring plasma levels
of total cholesterol, TGs, and individual lipoproteins. Treatment is dietary changes,
exercise, and lipid-lowering drugs.
There is no natural cutoff between normal and abnormal lipid levels because lipid measurements
are continuous. A linear relation probably exists between lipid levels and cardiovascular risk, so
many people with “normal” cholesterol levels benefit from achieving still lower levels.
Consequently, there are no numeric definitions of dyslipidemia; the term is applied to lipid levels
for which treatment has proven beneficial. Proof of benefit is strongest for lowering elevated low
density lipoprotein (LDL) levels. In the overall population, evidence is less strong for a benefit
from lowering elevated TG and increasing low high density lipoprotein (HDL) levels, in part
because elevated TG and low HDL levels are more predictive of cardiovascular risk in women
than in men.
HDL levels do not always predict cardiovascular risk. For example, high HDL levels caused by
some genetic disorders may not protect against cardiovascular disorders, and low HDL levels
caused by some genetic disorders may not increase the risk of cardiovascular disorders. Although
HDL levels predict cardiovascular risk in the overall population, the increased risk may be
caused by other factors, such as accompanying lipid and metabolic abnormalities, rather than the
HDL level itself.
Classification
Dyslipidemias were traditionally classified by patterns of elevation in lipids and lipoproteins

(Fredrickson phenotype—see Table 2: Lipid Disorders: Lipoprotein Patterns (Fredrickson
Phenotypes) ). A more practical system categorizes dyslipidemias as primary or secondary and
characterizes them by increases in cholesterol only (pure or isolated hypercholesterolemia),
increases in TGs only (pure or isolated hypertriglyceridemia), or increases in both cholesterol
and TGs (mixed or combined hyperlipidemias). This system does not take into account specific
lipoprotein abnormalities (eg, low HDL or high LDL) that may contribute to disease despite
normal cholesterol and TG levels.
Table 2
Lipoprotein Patterns (Fredrickson
Phenotypes)
Phenotype Elevated Elevated
Lipoprotein(s) Lipids
I Chylomicrons TGs
IIa LDL Cholesterol
IIb LDL and TGs and
VLDL cholesterol
III VLDL and TGs and
chylomicron cholesterol
remnants
IV VLDL TGs
V Chylomicrons TGs and
and VLDL cholesterol
LDL = low density lipoprotein; TGs =
triglycerides; VLDL = very low density
lipoprotein.
Etiology
Primary (genetic) causes and secondary (lifestyle and other) causes contribute to dyslipidemias
in varying degrees. For example, in familial combined hyperlipidemia, expression may occur
only in the presence of significant secondary causes.
Primary causes: Primary causes are single or multiple gene mutations that result in either
overproduction or defective clearance of TG and LDL cholesterol, or in underproduction or
excessive clearance of HDL (see Table 3: Lipid Disorders: Genetic (Primary) Dyslipidemias ).
Primary disorders, the most common cause of dyslipidemia in children, do not cause a large
percentage of cases in adults. The names of many reflect an old nomenclature in which
lipoproteins were detected and distinguished by how they separated into α (HDL) and β (LDL)
bands on electrophoretic gels.
Table 3
Genetic (Primary) Dyslipidemias

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Secondary causes: Secondary causes contribute to most cases of dyslipidemia in adults. The most
important secondary cause in developed countries is a sedentary lifestyle with excessive dietary
intake of saturated fat, cholesterol, and trans fats. Trans fats are polyunsaturated or
monounsaturated fatty acids to which hydrogen atoms have been added; they are commonly used
in many processed foods and are as atherogenic as saturated fat. Other common secondary
causes include diabetes mellitus, alcohol overuse, chronic kidney disease, hypothyroidism,
primary biliary cirrhosis and other cholestatic liver diseases, and drugs, such as thiazides, β-
blockers, retinoids, highly active antiretroviral agents, estrogen and progestins, and
glucocorticoids.
Diabetes is an especially significant secondary cause because patients tend to have an

atherogenic combination of high TGs; high small, dense LDL fractions; and low HDL (diabetic
dyslipidemia, hypertriglyceridemic hyperapo B). Patients with type 2 diabetes are especially at
risk. The combination may be a consequence of obesity, poor control of diabetes, or both, which
may increase circulating FFAs, leading to increased hepatic VLDL production. TG-rich VLDL
then transfers TG and cholesterol to LDL and HDL, promoting formation of TG-rich, small,
dense LDL and clearance of TG-rich HDL. Diabetic dyslipidemia is often exacerbated by the
increased caloric intake and physical inactivity that characterize the lifestyles of some patients
with type 2 diabetes. Women with diabetes may be at special risk for cardiac disease from this
form.
Symptoms and Signs
Dyslipidemia itself usually causes no symptoms but can lead to symptomatic vascular disease,
including coronary artery disease (CAD) and peripheral arterial disease. High levels of TGs (>
1000 mg/dL [> 11.3 mmol/L]) can cause acute pancreatitis. High levels of LDL can cause eyelid
xanthelasmas; arcus corneae; and tendinous xanthomas at the Achilles, elbow, and knee tendons
and over metacarpophalangeal joints. Patients with the homozygous form of familial
hypercholesterolemia may have the above findings plus planar or cutaneous xanthomas. Patients
with severe elevations of TGs can have eruptive xanthomas over the trunk, back, elbows,
buttocks, knees, hands, and feet. Patients with the rare dysbetalipoproteinemia can have palmar
and tuberous xanthomas.
Severe hypertriglyceridemia (> 2000 mg/dL [> 22.6 mmol/L]) can give retinal arteries and veins
a creamy white appearance (lipemia retinalis). Extremely high lipid levels also give a lactescent
(milky) appearance to blood plasma. Symptoms can include paresthesias, dypsnea, and
confusion.
Diagnosis
• Serum lipid profile (measured total cholesterol, TG, and HDL-cholesterol and calculated
LDL-cholesterol and VLDL)
Dyslipidemia is suspected in patients with characteristic physical findings or complications of

dyslipidemia (eg, atherosclerotic disease). Primary lipid disorders are suspected when patients
have physical signs of dyslipidemia, onset of premature atherosclerotic disease (at < 60 yr), a
family history of atherosclerotic disease, or serum cholesterol > 240 mg/dL (> 6.2 mmol/L).
Dyslipidemia is diagnosed by measuring serum lipids. Routine measurements (lipid profile)
include total cholesterol (TC), TGs, HDL-cholesterol, and LDL-cholesterol.
Lipid profile measurement: TC, TGs, and HDL-cholesterol are measured directly; TC and TG
values reflect cholesterol and TGs in all circulating lipoproteins, including chylomicrons, VLDL,
IDL, LDL, and HDL. TC values vary by 10% and TGs by up to 25% day-to-day even in the
absence of a disorder. TC and HDL-cholesterol can be measured in the nonfasting state, but most
patients should have all lipids measured while fasting for maximum accuracy and consistency.
Testing should be postponed until after resolution of acute illness, because TGs increase and
cholesterol levels decrease in inflammatory states. Lipid profiles can vary for about 30 days after
an acute MI; however, results obtained within 24 h after MI are usually reliable enough to guide
initial lipid-lowering therapy.
LDL-cholesterol values are most often calculated as the amount of cholesterol not contained in
HDL and VLDL. VLDL is estimated by TG ÷ 5 because the cholesterol concentration in VLDL
particles is usually 1/5 of the total lipid in the particle. Thus, LDL-cholesterol = TC − [HDL-
cholesterol + (TGs ÷ 5)] (Friedewald formula). This calculation is valid only when TGs are <
400 mg/dL and patients are fasting, because eating increases TGs. The calculated LDL-
cholesterol value incorporates measures of all non-HDL, nonchylomicron cholesterol, including
that in IDL and Lp(a). LDL can also be measured directly using plasma ultracentrifugation,
which separates chylomicrons and VLDL fractions from HDL and LDL, and by an immunoassay
method. Direct measurement may be useful in some patients with elevated TGs, but these direct
measurements are not routinely necessary. The role of apo B testing is under study because
values reflect all non-HDL cholesterol (in VLDL, VLDL remnants, IDL, and LDL) and may be
more predictive of CAD risk than LDL alone.
Other tests: Patients with premature atherosclerotic cardiovascular disease, cardiovascular

disease with normal or near-normal lipid levels, or high LDL levels refractory to drug therapy
should probably have Lp(a) levels measured. Lp(a) levels may also be directly measured in
patients with borderline high LDL-cholesterol levels to determine whether drug therapy is
warranted. C-reactive protein and homocysteine measurement may be considered in the same
populations.
Secondary causes: Tests for secondary causes of dyslipidemia—including measurements of

fasting glucose, liver enzymes, creatinine, thyroid stimulating hormone (TSH), and urinary
protein—should be done in most patients with newly diagnosed dyslipidemia and when a
component of the lipid profile has inexplicably changed for the worse.
Screening: A fasting lipid profile (TC, TGs, HDL-cholesterol, and calculated LDL-cholesterol)
should be obtained in all adults ≥ 20 yr and should be repeated every 5 yr. Lipid measurement
should be accompanied by assessment of other cardiovascular risk factors, defined as
• Diabetes mellitus
• Cigarette use
• Hypertension
• Family history of CAD in a male 1st-degree relative before age 55 or a female 1st-degree
relative before age 65
A definite age after which patients no longer require screening has not been established, but
evidence supports screening of patients into their 80s, especially in the presence of
atherosclerotic cardiovascular disease.
Indications for screening patients < 20 yr are atherosclerotic risk factors, such as diabetes,
hypertension, cigarette smoking, and obesity; premature CAD in a parent, grandparent, or
sibling; or a cholesterol level > 240 mg/dL (> 6.2 mmol/L) or known dyslipidemia in a parent. If
information on relatives is unavailable, as in the case of adopted children, screening is at the
discretion of the health care practitioner.
Patients with an extensive family history of heart disease should also be screened by measuring
Lp(a) levels.
Treatment
• Risk assessment by explicit criteria

• Lifestyle changes (eg, exercise, dietary modification)
• For high LDL-cholesterol, statins, sometimes bile acid sequestrants, ezetimibe Some
Trade Names
ZETIA
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, and other measures
• For high TG or low HDL-cholesterol, niacin Some Trade Names
NIACOR
NIASPAN
SLO-NIACIN
, fibrates, and sometimes other measures
General principles: Treatment is indicated for all patients with cardiovascular disease (secondary
prevention) and for some without (primary prevention). The National Institutes of Health's
National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATPIII) guidelines
are the most common reference for deciding which adults should be treated (see Table 4: Lipid
Disorders: National Cholesterol Education Program Adult Treatment Panel III Approach to
Dyslipidemias and Table 5: Lipid Disorders: NCEP Adult Treatment Panel III Guidelines for
Treatment of Hyperlipidemia ). The guidelines focus primarily on reducing elevated LDL-
cholesterol levels and secondarily on treating high TGs, low HDL, and metabolic syndrome (see
Obesity and the Metabolic Syndrome: Metabolic Syndrome). An alternate treatment guide (the
Sheffield table) uses TC:HDL ratios combined with presence of CAD risk factors to predict
cardiovascular risk, but this approach probably leads to undertreatment.
Table 4
National Cholesterol Education Program Adult Treatment Panel III Approach to
Dyslipidemias
1. Measure fasting lipoproteins (in mg/dL):
TC (mmol/L)
< 200 (<5.17) Desirable
200–239 (5.17–6.18) Borderline high
≥ 240 (≥ 6.20) High
LDL-cholesterol
< 100 (<2.58) Optimal
100–129 (2.58–3.33) Near optimal/above optimal
130–159 (3.36–4.11) Borderline high
160–189 (4.13–4.88) High
≥ 190 (≥ 4.91) Very high
HDL-cholesterol
< 40 (< 1.03) Low
≥ 60 (≥ 1.55) High
TG
< 150 (< 1.695) Desirable
150–199 (1.695–2.249) Borderline high
200–499 (2.26–5.639) High
≥ 500 (≥ 5.65) Very high
2. Identify CAD or CAD equivalents (if present, see Table 5: Lipid Disorders:
NCEP Adult Treatment Panel III Guidelines for Treatment of Hyperlipidemia )
CAD equivalents
Other atherosclerotic disease:
Peripheral arterial disease
Abdominal aortic aneurysm
Symptomatic carotid artery disease
Diabetes mellitus
Additional risk factors that confer 10-yr risk of MI or CAD death > 20% (see
step #4 and see Table 6: Lipid Disorders: Framingham Risk Tables for Men
and Table 7: Lipid Disorders: Framingham Risk Tables for Women )
3. Identify major CAD risk factors
Cigarette smoking
Hypertension (BP ≥ 140/90 or on antihypertensive drug)
Low HDL (≤ 40 mg/dL [1.03 mmol/L])
Family history of premature CAD (CAD in male 1st-degree relative < 55 or in
female 1st-degree relative < 65)
Age (men ≥ 45, women ≥ 55)
4. If ≥ 2 major risk factors are present without CAD or CAD equivalent, assess
10-yr risk of MI or CAD death using Framingham risk tables (see Table 6: Lipid
Disorders: Framingham Risk Tables for Men and Table 7: Lipid Disorders:
Framingham Risk Tables for Women ).
CAD = coronary artery disease; HDL = high density lipoprotein; LDL = low
density lipoprotein; TC = total cholesterol; TG = triglyceride.
Data from the Third Report of the Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults. National Institutes of Health,
National Heart, Lung, and Blood Institute, 2001.
Table 5
NCEP Adult Treatment Panel III Guidelines for Treatment of Hyperlipidemia
Risk Category Begin Lifestyle Consider Drug Therapy LDL Goal
Changes If If
High
CAD or CAD LDL ≥ 100 mg/dL LDL ≥ 100 mg/dL (≥ < 100 mg/dL <
equivalents (10-yr risk (≥ 2.58 mmol/L) 2.58 mmol/L) 70 mg/dL
> 20%) optional
Drugs optional if LDL
< 100 mg/dL [< 2.58
mmol/L])
Moderate high
≥ 2 risk factors with LDL ≥ 130 mg/dL LDL ≥ 130 mg/dL (≥ < 130 mg/dL <
10-yr risk 10 to 20%* (≥ 3.36 mmol/L) 3.36 mmol/L) 100 mg/dL
optional
Moderate
≥ 2 risk factors with LDL ≥ 130 mg/dL LDL ≥ 160 mg/dL (≥ < 130 mg/dL <
10-yr risk < 10%* (≥ 3.36 mmol/L) 4.13 mmol/L) 100 mg/dL
optional
Lower
0–1 risk factor LDL ≥ 160 mg/dL LDL ≥ 190 mg/dL (≥ < 160 mg/dL
(≥ 4.13 mmol/L) 4.91 mmol/L)
Drug optional if LDL

160–189 mg/dL [4.13–
4.88 mmol/L])
*For 10-yr risk, see Framingham risk tables (see Table 6: Lipid Disorders:
Framingham Risk Tables for Men and Table 7: Lipid Disorders: Framingham
Risk Tables for Women ).
CAD = coronary artery disease; LDL = low density lipoprotein; NCEP =
National Cholesterol Education Program.
Data from the Third Report of the Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults. National Institutes of Health,
National Heart, Lung, and Blood Institute, 2001 and from Grundy SM, Cleeman
JI, Merz CNB, et al. Implications of recent clinical trials for the National
Cholesterol Education Program Adult Treatment Panel III guidelines.
Circulation 110:227–239, 2004.
Treatment of children is controversial; dietary changes may be difficult to implement, and no

data suggest that lowering lipid levels in childhood effectively prevents heart disease in
adulthood. Moreover, the safety and effectiveness of long-term lipid-lowering treatment are
questionable. Nevertheless, the American Academy of Pediatrics (AAP) recommends treatment
for some children who have elevated LDL-cholesterol levels.
Treatment options depend on the specific lipid abnormality, although different lipid
abnormalities often coexist. In some patients, a single abnormality may require several therapies;
in others, a single treatment may be adequate for several abnormalities. Treatment should always
include treatment of hypertension and diabetes, smoking cessation, and in patients with a 10-yr
risk of MI or death from CAD of ≥ 10% (as determined from the Framingham tables—see Table
6: Lipid Disorders: Framingham Risk Tables for Men and Table 7: Lipid Disorders:
Framingham Risk Tables for Women ), low-dose daily aspirin Some Trade Names
BUFFERIN
ECOTRIN
GENACOTE
. In general, treatment options for men and women are the same.
Table 6
Framingham Risk Tables for Men
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Table 7
Framingham Risk Tables for

Women
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Elevated LDL-cholesterol: In adults, ATPIII guidelines recommend treatment for those with any
of the following:
• Elevated LDL-cholesterol levels and a history of CAD

• Conditions that confer a risk for future cardiac events similar to that of CAD itself (CAD
equivalents, defined as diabetes mellitus, abdominal aortic aneurysm, peripheral arterial
disease, and symptomatic carotid artery disease)
• ≥ 2 CAD risk factors
ATPIII guidelines recommend that these patients have LDL-cholesterol levels lowered to < 100
mg/dL, but accumulating evidence suggests that this target may be too high and a target LDL-
cholesterol < 70 mg/dL is an option for patients at very high risk (eg, patients with known CAD
and diabetes, other poorly controlled risk factors, metabolic syndrome, or acute coronary
syndrome). When drugs are used, a dose providing at least a 30 to 40% decrease in LDL-
cholesterol is desirable (see Table 8: Lipid Disorders: Lipid–Lowering Drugs ).
Table 8
Lipid–Lowering Drugs
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For children, the AAP recommends dietary treatment for children with LDL-cholesterol > 110
mg/dL. Drug therapy is recommended for children > 8 yr and with either of the following:
• Poor response to dietary therapy, LDL-cholesterol ≥ 190 mg/dL, and no family history of
premature cardiovascular disease
• LDL-cholesterol ≥ 160 mg/dL and a family history of premature cardiovascular disease
or ≥ 2 risk factors for premature cardiovascular disease
Childhood risk factors besides family history and diabetes include cigarette smoking,
hypertension, low HDL-cholesterol (< 35 mg/dL), obesity, and physical inactivity.
Treatment options to lower LDL-cholesterol in all age groups include lifestyle changes (diet and
exercise), drugs, dietary supplements, procedural interventions, and experimental therapies.
Many of these options are also effective for treating other lipid abnormalities. Exercise lowers
LDL-cholesterol in some people; it is also essential to maintain ideal body weight. Dietary
changes and exercise should be the initial approach whenever feasible.
Lifestyle changes can involve diet and exercise. Dietary changes include decreasing intake of
saturated fats and cholesterol; increasing the proportion of dietary fiber, and complex
carbohydrates; and maintaining ideal body weight. Referral to a dietitian is often useful,
especially for older people. The length of time for which lifestyle changes should be attempted
before beginning lipid-lowering drugs is controversial. In patients at average or low
cardiovascular risk, 3 to 6 mo is reasonable. Generally, 2 to 3 visits with a patient over 2 to 3 mo
are sufficient to assess motivation and adherence.
Drugs are the next step when lifestyle changes are not effective. However, for patients with
extremely elevated LDL-cholesterol (> 200 mg/dL [> 5.2 mmol/L]) and those at high
cardiovascular risk, drug therapy should accompany diet and exercise from the start.
Statins are the drugs and possibly treatment of choice for LDL-cholesterol reduction; they
demonstrably reduce cardiovascular mortality. Statins inhibit hydroxymethylglutaryl CoA
reductase, a key enzyme in cholesterol synthesis, leading to up-regulation of LDL receptors and
increased LDL clearance. They reduce LDL-cholesterol by up to 60% and produce small
increases in HDL and modest decreases in TGs. Statins also appear to decrease intra-arterial
inflammation, systemic inflammation, or both by stimulating production of endothelial nitric
oxide and may have other beneficial effects. Adverse effects are uncommon but include liver
enzyme elevations and myositis or rhabdomyolysis. Muscle toxicity without enzyme elevation
has also been reported. Adverse effects are more common in older patients, patients with several
disorders, and patients taking several drugs. In some people, changing from one statin to another
or lowering the dose relieves the problem. Muscle toxicity seems to be most common when some
of the statins are used with drugs that inhibit cytochrome P3A4 (eg, macrolide antibiotics, azole
antifungals, cyclosporine Some Trade Names
NEORAL
SANDIMMUNE
) and with fibrates, especially gemfibrozil Some Trade Names
LOPID
. Properties of statins differ slightly by drug, and the choice of drug should be based on patient
characteristics, LDL-cholesterol level, and provider discretion (see Table 8: Lipid Disorders:
Lipid–Lowering Drugs ).
Bile acid sequestrants block intestinal bile acid reabsorption, forcing up-regulation of hepatic
LDL receptors to recruit circulating cholesterol for bile synthesis. They are proven to reduce
cardiovascular mortality. Bile acid sequestrants are usually used with statins or with nicotinic
acid (see Lipid Disorders: Low HDL) to augment LDL-cholesterol reduction and are the drugs of
choice for children and women who are or are planning to become pregnant. Bile acid
sequestrants are safe, but their use is limited by adverse effects of bloating, nausea, cramping,
and constipation. They may also increase TGs, so their use is contraindicated in patients with
hypertriglyceridemia. Cholestyramine Some Trade Names
QUESTRAN
and colestipol Some Trade Names
COLESTID
, but not colesevelam Some Trade Names
WELCHOL
, interfere with absorption of other drugs—notably thiazides, β-blockers, warfarin Some Trade
Names
COUMADIN
, digoxin Some Trade Names
DIGITEK
LANOXIN
, and thyroxine—an effect that can be decreased by administration 4 h before or 1 h after other
drugs.
Cholesterol absorption inhibitors, such as ezetimibe Some Trade Names

ZETIA
, inhibit intestinal absorption of cholesterol and phytosterol. Ezetimibe Some Trade Names
ZETIA
usually lowers LDL-cholesterol by 15 to 20% and causes small increases in HDL and a mild
decrease in TGs. Ezetimibe Some Trade Names
ZETIA
can be used as monotherapy in patients intolerant to statins or added to statins for patients on
maximum doses with persistent LDL-cholesterol elevation. Adverse effects are infrequent.
Dietary supplements that lower LDL-cholesterol levels include fiber supplements and
commercially available margarines and other products containing plant sterols (sitosterol and
campesterol) or stanols. The latter reduce LDL-cholesterol by up to 10% without affecting HDL
or TGs by competitively displacing cholesterol from intestinal micelles.
Procedural approaches are reserved for patients with severe hyperlipidemia (LDL-cholesterol >
300 mg/dL) that is refractory to conventional therapy, such as occurs with familial
hypercholesterolemia. Options include LDL apheresis (in which LDL is removed by
extracorporeal plasma exchange), ileal bypass (to block reabsorption of bile acids), liver
transplantation (which transplants LDL receptors), and portocaval shunting (which decreases
LDL production by unknown mechanisms). LDL apheresis is the procedure of choice in most
instances when maximally tolerated therapy fails to lower LDL adequately. Apheresis is also the
usual therapy in patients with the homozygous form of familial hypercholesterolemia who have
limited or no response to drug therapy.
Future therapies to reduce LDL include peroxisome proliferator–activated receptor agonists

that have thiazolidinedione-like and fibrate-like properties, LDL-receptor activators, LPL
activators, and recombinant apo E. Cholesterol vaccination (to induce anti-LDL antibodies and
hasten LDL clearance from serum) and gene transfer are conceptually appealing therapies that
are under study but years away from being available for use.
Elevated TGs: Though it is unclear if elevated TGs independently contribute to cardiovascular

disease, they are associated with multiple metabolic abnormalities that contribute to CAD (eg,
diabetes, metabolic syndrome). Consensus is emerging that lowering elevated TGs is beneficial
(see Table 4: Lipid Disorders: National Cholesterol Education Program Adult Treatment Panel
III Approach to Dyslipidemias ). No target goals exist, but levels < 150 mg/dL (< 1.7 mmol/L)
are generally considered desirable. No guidelines specifically address treatment of elevated TGs
in children.
The overall treatment strategy is to first implement lifestyle changes, including exercise,
weight loss, and avoidance of concentrated dietary sugar and alcohol. Intake of 2 to 4
servings/wk of marine fish high in ω-3 fatty acids may be effective, but the amount of ω-3 fatty
acids is often lower than needed; supplements may be helpful. In patients with diabetes, glucose
levels should be tightly controlled. If these measures are ineffective, lipid-lowering drugs should
be considered. Patients with very high TGs should begin drug therapy at diagnosis to more
quickly reduce the risk of acute pancreatitis.
Fibrates reduce TGs by about 50%. They appear to stimulate endothelial LPL, leading to
increased fatty acid oxidation in the liver and muscle and decreased hepatic VLDL synthesis.
They also increase HDL by up to 20%. Fibrates can cause GI adverse effects, including
dyspepsia, abdominal pain, and elevated liver enzymes. They uncommonly cause cholelithiasis.
Fibrates may potentiate muscle toxicity when used with statins and potentiate the effects of
warfarin Some Trade Names
COUMADIN
.
Nicotinic acid may also be useful (see Low HDL, below).
Statins can be used in patients with TGs < 500 mg/dL if LDL-cholesterol elevations are also
present; statins may reduce both LDL-cholesterol and TGs through reduction of VLDL. If only
TGs are elevated, fibrates are the drug of choice.
Omega-3 fatty acids in high doses (1 to 6 g/day of eicosapentaenoic acid [EPA] and
docosahexaenoic acid [DHA]) can be effective in reducing TGs. The ω-3 fatty acids EPA and
DHA are the active ingredients in marine fish oil or ω-3 capsules. Adverse effects include
eructation and diarrhea. These may be decreased by giving the fish oil capsules with meals in
divided doses (eg, bid or tid). Omega-3 fatty acids can be a useful adjunct to other therapies.
Low HDL: Treatment to increase HDL-cholesterol levels may decrease risk of death, but data
are limited. ATPIII guidelines define low HDL-cholesterol as < 40 mg/dL [< 1.04 mmol/L]; the
guidelines do not specify an HDL-cholesterol target level and recommend interventions to raise
HDL-cholesterol only after LDL-cholesterol targets have been reached. Treatments for LDL-
cholesterol and TG reduction often increase HDL-cholesterol, and the 3 objectives can
sometimes be achieved simultaneously. No guidelines specifically address treatment of low
HDL-cholesterol in children.
Treatment includes lifestyle changes such as an increase in exercise weight loss. Alcohol raises
HDL-cholesterol but is not routinely recommended as a therapy because of its many other
adverse effects. Drugs are useful when lifestyle changes alone are insufficient.
Nicotinic acid (niacin) is the most effective drug for increasing HDL. Its mechanism of action is
unknown, but it appears to both increase HDL production and inhibit HDL clearance; it may also
mobilize cholesterol from macrophages. Niacin Some Trade Names
NIACOR
NIASPAN
SLO-NIACIN
also decreases TGs and, in doses of 1500 to 2000 mg/day, reduces LDL-cholesterol. Niacin
Some Trade Names
NIACOR
NIASPAN
SLO-NIACIN
produces flushing, pruritus, and nausea; premedication with low-dose aspirin Some Trade Names
BUFFERIN
ECOTRIN
GENACOTE
may prevent these adverse effects. Extended-release preparations cause flushing less often.
However, most OTC slow-release preparations are not recommended; an exception is polygel
controlled-release niacin Some Trade Names
NIACOR
NIASPAN
SLO-NIACIN
. Niacin Some Trade Names
NIACOR
NIASPAN
SLO-NIACIN
can cause liver enzyme elevations and occasionally liver failure, insulin resistance, and
hyperuricemia and gout. It may also increase homocysteine levels. In patients with average LDL-
cholesterol and below-average HDL-cholesterol levels, niacin Some Trade Names
NIACOR
NIASPAN
SLO-NIACIN
combined with statin treatment may be effective in preventing cardiovascular disorders.
Fibrates increase HDL. Infusion of recombinant HDL (eg, apoprotein A-1 Milano, an HDL
variant in which a cysteine is substituted for an arginine Some Trade Names
R-GENE
at position 173 allowing for dimer formation) appears promising as a treatment for
atherosclerosis but requires further study.
Elevated Lp(a): The upper limit of normal for Lp(a) is about 30 mg/dL (0.8 mmol/L), but values
in African-Americans run higher. Few data exist to guide the treatment of elevated Lp(a) or to
establish treatment efficacy. Niacin Some Trade Names
NIACOR
NIASPAN
SLO-NIACIN
is the only drug that directly decreases Lp(a); it can lower Lp(a) by ≤ 20% at higher doses. The
usual approach in patients with elevated Lp(a) is to lower LDL-cholesterol aggressively.
Secondary causes: Treatment of diabetic dyslipidemia should always involve lifestyle changes,
with statins to reduce LDL-cholesterol, fibrates to decrease TGs, or both drugs. Metformin Some
Trade Names
GLUCOPHAGE
lowers TGs, which may be a reason to choose it over other oral antihyperglycemic drugs when
treating diabetes. Some thiazolidinediones (TZDs) increase both HDL-cholesterol and LDL-
cholesterol (probably the less atherogenic large, buoyant type of LDL). Some TZDs also
decrease TGs. These antihyperglycemic drugs should not be chosen over lipid-lowering drugs to
treat lipid abnormalities in diabetic patients but may be useful adjuncts. Patients with very high
TG levels and less than optimally controlled diabetes may have better response to insulin Some
Trade Names
HUMULIN
NOVOLIN
than to oral antihyperglycemic drugs.
Treatment of dyslipidemia in patients with hypothyroidism, renal disease, liver disease, or a
combination of these disorders involves treating the underlying disorders primarily and lipid
abnormalities secondarily. Abnormal lipid levels in patients with low-normal thyroid function
(high-normal TSH levels) improve with hormone replacement. Reducing the dosage of or
stopping drugs that cause lipid abnormalities should be considered.
Monitoring treatment: Lipid levels should be monitored periodically after starting treatment. No
data support specific monitoring intervals, but measuring lipid levels 2 to 3 mo after starting or
changing therapies and once or twice yearly after lipid levels are stabilized is common practice.
Despite the low incidence of liver and muscle toxicity with statin use (0.5 to 2% of all users),
current recommendations are for baseline measurements of liver and muscle enzyme levels at the
beginning of treatment. Many practitioners obtain at least one additional set of liver enzymes 4 to
12 wk after beginning treatment and annually thereafter. Statin therapy can be continued unless
liver enzymes increase to > 3 times the upper limit of normal. Muscle enzyme levels need not be
checked regularly unless patients develop myalgias or other muscle symptoms. If statin-induced
muscle damage is suspected, statin use is stopped and CK may be measured. When muscle
symptoms subside, a lower dose or a different statin can be tried.
Elevated High-Density Lipoprotein Levels
Elevated HDL level is HDL-cholesterol > 80 mg/dL (> 2.1 mmol/L).
Elevated HDL-cholesterol levels usually correlate with decreased cardiovascular risk; however,
high HDL-cholesterol levels caused by some genetic disorders may not protect against
cardiovascular disease, probably because of accompanying lipid and metabolic abnormalities.
Primary causes are single or multiple genetic mutations that result in overproduction or
decreased clearance of HDL. Secondary causes of high HDL-cholesterol include all of the
following:
• Chronic alcoholism without cirrhosis

• Primary biliary cirrhosis
• Hyperthyroidism
• Drugs (eg, corticosteroids, insulin Some Trade Names
HUMULIN
NOVOLIN
, phenytoin Some Trade Names
DILANTIN
).
The unexpected finding of high HDL-cholesterol in patients not taking lipid-lowering drugs
should prompt a diagnostic evaluation for a secondary cause with measurements of AST, ALT,
and TSH; a negative evaluation suggests a possible primary cause.
Cholesteryl ester transfer protein (CETP) deficiency is a rare autosomal recessive disorder
caused by a CETP gene mutation. CETP facilitates transfer of cholesterol esters from HDL to
other lipoproteins, and CETP deficiency leads to low-cholesterol LDL and slower HDL
clearance. Affected patients display no symptoms or signs but have HDL-cholesterol > 150
mg/dL. Protection from cardiovascular disorders has not been proven. No treatment is necessary.
Familial hyperalphalipoproteinemia is an autosomal dominant condition caused by various

unidentified and known genetic mutations, including those that cause apoprotein A-I
overproduction and apoprotein C-III variants. The disorder is usually diagnosed incidentally
when plasma HDL-cholesterol levels are > 80 mg/dL. Affected patients have no other symptoms
or signs. No treatment is necessary.
Last full review/revision September 2008
Choosing Drug Therapy for Patients with

Hyperlipidemia
RICHARD S. SAFEER, M.D.,
George Washington University School of Medicine and Health Sciences, Washington,
D.C.
CYNTHIA L. LACIVITA, PHARM.D.,
Shady Grove Adventist Hospital, Rockville, Maryland
Almost 13 million American adults require drug therapy to meet the low-density lipoprotein goals set by
the National Cholesterol Education Program. Attempts to achieve these goals through diet and exercise
are often unsuccessful. Major studies in recent years have demonstrated that statins decrease low-
density lipoprotein levels, coronary events and overall mortality. Statins are the most commonly
prescribed lipid-lowering agents because they are effective, well tolerated and easy to administer. Niacin
has beneficial effects on all of the main lipid components, and new extended-release tablets have fewer
adverse effects. Fibrates remain the most effective agents in lowering triglyceride levels and should be
limited to this use. Bile acid sequestrants are seldom prescribed because of their adverse gastrointestinal
effects and cumbersome administration. (Am Fam Physician 2000;61:3371-82.)
Coronary heart disease (CHD) is the most common cause of death in the United States. Each
year, 500,000 Americans die of this disease, and associated morbidity costs more than $200
billion annually.1 Even though the relationship between CHD and elevated serum cholesterol
levels is well established, the medical community has yet to fully embrace this connection as an
area of prevention. Results from a 1996 study at a major teaching hospital revealed that only 30
percent of patients with coronary artery disease and hyperlipidemia were receiving lipid-
lowering agents from their cardiologists.2 An estimated 52 million adults require dietary changes,
and 12.7 million adults need lipid-lowering drugs to meet recommended goals for low-density
lipoprotein (LDL) levels.3
Compliance with lipid-lowering
Physicians are not the only parties at fault in the fight
therapy is a significant problem;
against CHD. Patient compliance is typically poor.
one half of treated patients
Treatment of lipid abnormalities is a lifelong battle.
discontinue their medication after
Approximately one half of the patients taking lipid-
one year.
lowering drugs discontinue their medication after one
year, and 75 percent stop after two years.4 With the
advent of new drugs (e.g., "statins") and modifications
of older agents (e.g., niacin), adverse effects are no longer a major obstacle to compliance.
The National Cholesterol Education Program (NCEP) has developed guidelines to establish clear
goals for patients with lipid abnormalities (Table 1).5 Pharmacologic treatment goals are based
largely on LDL levels.
The NCEP guidelines encourage a trial of lifestyle modification (diet and exercise) before
initiation of drug treatment. Although dietary measures such as the NCEP step 2 diet succeed in
reducing fat intake, they fall short in helping most patients achieve their LDL goals.6 Numerous
studies correlate increased exercise with decreased cardiovascular mortality.7 Although aerobic
exercise may increase high-density lipoprotein (HDL) levels, its effect in lowering LDL is often
minimal (approximately 4 to 6 percent).8 Diet and exercise are helpful in meeting LDL goals, but
these steps are seldom successful without the addition of a pharmacologic agent.
TABLE 1
Determining Patient-Specific LDL Goals Through Risk Factors
Risk-factor score* LDL goal, by risk-factor score†
Age: men > 45 years; women >55 years or 0 to 1 point: <160 mg per dL (<4.15 mmol per L)
postmenopausal without ERT 2 or more points: <130 mg per dL (<3.35 mmol
Current smoker per L)
Hypertension Patients with history of CHD: <100 mg per dL
Diabetes (<2.60 mmol per L)
CHD in first-degree relative (male relative <55
years; female relative <65 years)
HDL <35 mg per dL (0.9 mmol per L); subtract 1
risk factor if HDL >60 mg per dL
LDL = low-density lipoprotein; ERT = estrogen replacement therapy; CHD = coronary heart disease; HDL = high-
density lipoprotein.
*--Score 1 point for each positive factor.
†--LDL goals established by National Cholesterol Education Program.
Information from Grundy SM, Balady GJ, Criqui MH, Fletcher G, Greenland P, Hiratzka LF, et al. Guide to
primary prevention of cardiovascular diseases. A statement for healthcare professionals from the Task Force on
Risk Reduction. American Heart Association Science Advisory and Coordinating committee. Circulation
1997;95:2330.
HMG-CoA Reductase Inhibitors (Statins)

Statins are the most commonly prescribed lipid-lowering agents in the United States. They are
generally effective, are supported by favorable outcome studies and have relatively few adverse
effects.9-13 Recent studies have helped establish practice standards for treating patients with
elevated LDL levels to reduce the risk of CHD (Table 2).9,10,12-15 Even patients who have had a
myocardial infarction but maintain normal total and LDL cholesterol levels have decreased
morbidity and mortality from recurrent myocardial infarction and stroke when treated with a
statin.11,12 The six statins currently available are atorvastatin (Lipitor), cerivastatin (Baycol),
fluvastatin (Lescol), lovastatin (Mevacor), pravastatin (Pravachol) and simvastatin (Zocor).
TABLE 2
Outcomes of Studies Involving Statins
Study Drug Outcome
Scandinavian Simvastatin Simvastatin Decreased cardiac morbidity and mortality in
Survival Study (4S)9 patients with CHD and elevated cholesterol levels
"West of Scotland" Study Pravastatin Decreased coronary morbidity and mortality in
(WOSCOPS)10 hypercholesterolemic men with no clinical evidence
of CHD
Cholesterol and Recurrent Events Pravastatin Significantly reduced incidence of subsequent MI,
(CARE) Study12 death from CHD, stroke and need for
revascularization procedure in patients with recent
MI and normal cholesterol levels
Long-Term Intervention with Pravastatin Reduced overall mortality and incidence of MI and
Pravastatin in Ischaemic Disease stroke in patients with CHD and a broad range of
(LIPID) Study13 cholesterol levels.
Lipoprotein and Coronary Fluvastatin Slowed progression of artherosclerotic lesions in
Atherosclerosis Study (LCAS)14 patients with CHD
Air Force/Texas Coronary Lovastatin Significantly reduced incidence of first acute major
Atherosclerosis Prevention Study coronary events in patients without CHD, but with
(AFCAPS/TexCAPS)15 normal to mildly elevated total and LDL cholesterol
levels and low HDL cholesterol levels
CHD = coronary heart disease; MI = myocardial infarction; LDL = low-density lipoprotein; HDL= high-density
lipoprotein.
Information from references 9 and 10, and 12 through 15.
Indications and Efficacy

As a group, statins decrease total and LDL cholesterol levels (Table 3). Although all of the
statins decrease triglyceride levels, only cerivastatin, atorvastatin and simvastatin are labeled by
the U.S. Food and Drug Administration for this use. All statins have a minimal effect in raising
HDL levels; simvastatin and atorvastatin are labeled for this indication. At least two studies
comparing the statins (all but cerivastatin) have shown that atorvastatin is the most effective in
reducing LDL levels.16,17 However, unlike the more extensively studied agents (e.g., pravastatin,
simvastatin), atorvastatin has not been proved to reduce total morbidity and mortality.
Adverse Effects
The statins have an excellent safety and side effect The most common adverse
profile (Table 4).18,19 The most common adverse effects effects of the statins are
are gastrointestinal disturbances, headache, myalgias gastrointestinal disturbances,
and rash. In studies involving simvastatin9 and headache, myalgias and rash.
pravastatin, the number of adverse events was similar
10
in both placebo and study groups. These agents were

well tolerated, as evidenced by the low dropout rate in the two studies. Despite the statins'
favorable side effect profiles, a large percentage of patients given these drugs have discontinued
them within a year.
There are no clinically appreciable differences in the safety profiles of the statins.20 However,
unlike the other statins, pravastatin is not metabolized by the cytochrome P450 system.
Therefore, it is less likely to cause a problem when given concomitantly with drugs that inhibit
the cytochrome P450 system (e.g., macrolide antibiotics, azole antifungals).21
Approximately 1 to 2 percent of patients treated with

statins are found to have elevated values on liver Approximately 1 to 2 percent of
function tests, (i.e., more than three times the reference patients who take statins have
range).22 There have even been some reports of statin- elevated results on liver function
induced hepatitis. Elevations in liver enzyme levels (and tests (more than three times
the rare case of hepatitis) resolve after the statin is normal levels).
discontinued. Liver function tests should be performed
before starting therapy with these agents and repeated
periodically as therapy continues (Table 4).18,19 Medications that are hepatotoxic or that inhibit
liver enzymes may predispose patients to hepatic dysfunction and myopathy if given
concomitantly with a statin. Patients who are taking statins should be counseled to avoid or
minimize alcohol consumption.
Monitoring
The patient should take the statin for at least four weeks before repeating lipid level tests.
However, because diet and exercise require longer periods to produce meaningful changes, it is
acceptable to recheck lipid levels in three months. Patients should be re-examined after each
dosage adjustment or therapeutic intervention.
Muscle aches are the statins' most feared adverse effect, because they may herald
rhabdomyolysis; however, this complication is rare. In the 4S study,9 only one patient developed
rhabdomyolysis. It is more liable to occur when statins are taken in combination with other
agents (Table 5).18 Some experts recommend performing a baseline creatine kinase (CK) test
before initiating statin therapy.23 Because CK levels will not rise until muscle pain starts, there is
no benefit from repeated testing in asymptomatic patients.
TABLE 3
Efficacy and Cost of Lipid-Lowering Agents
Changes in lipid components
Cost
Drug T-Chol LDL HDL TG (generic)*
HMG-CoA reductase inhibitors
(statins)
Atorvastatin (Lipitor) 29 to 39 to 6%† 19 to
45%† 60%† 37%†
Starting dosage: 10 mg at bedtime $56
Maximum dosage: 80 mg at bedtime $210
Cerivastatin (Baycol) 24%† 34%† 7% 16%†
Starting dosage: 0.4 mg at bedtime $40
Maximum dosage: 0.4 mg at bedtime $40
Lovastatin (Mevacor) 17 to 24 to 6.6 to 10 to
29%† 40%† 9.5% 19%
Maximum dosage: 40 mg twice daily $251
Fluvastatin (Lescol) NA† 25 to NA 12 to
34%† 23%
Maximum dosage: 40 mg twice daily $75
Pravastatin (Pravachol) 16 to 22 to 7 to 12% 15 to
25%† 34%† 24%
Starting dosage: 10 to 20 mg at $68
bedtime
Simvastatin (Zocor) 28 to 38 to 8%† 15 to
36%† 47%† 24%†
Niacin (Nicotinic acid)
Niacin, extended-release (Niaspan) 3 to 5 to 18 to 21 to
10%† 14%† 22% 28%†
Maximum dosage: 2,000 mg at $49
bedtime‡
Fibric acid derivatives (fibrates)
Gemfibrozil (Lopid) 10% 10% 11% 35%†
Starting dosage: 600 mg twice daily $ 82 (57 to 60)
Maximum dosage: 1,600 mg daily in $123 (85 to
divided doses 89)§
Fenofibrate (Tricor) 17 to 10 to 7 to 15% 25 to
20% 20% 45%†
Starting dosage: 67 mg daily $21
Maximum dosage: 201 mg daily $62
Bile acid sequestrants
Cholestyramine (LoCholest) 10 to 20%† 5% NA
15%†
Starting dosage: 8 g daily $ 98 (80 to 87)
Maximum dosage: 24 g daily $390 (480 to
525)
Colestipol (Colestid) 10 to 20%† 5% NA
15%†
Starting dosage: 10 g daily $100 (199)
Maximum dosage: 10 to 30 g daily $100 (598)
HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; T-Chol = total cholesterol; LDL = low-density lipoprotein;
HDL = high-density lipoprotein; TG = triglycerides; NA = not available in package inserts.
*--Estimated cost to the pharmacist based on average wholesale prices (rounded to the nearest dollar), for one
month of therapy at starting and maximum dosages, in Red book. Montvale, N.J.,: Medical Economics Data, 1999.
Cost to the patient will be greater, depending on prescription filling fee.
†--Labeled by the U.S. Food and Drug Administration for this indication.
‡--Increase by no more than 500 mg per 4-week period.
§--Cost based on 3 tablets per day.
Information based on data in package inserts.
Cost
The statins are the most expensive lipid-lowering medicines. The cost within the group of statins
varies widely, from $42 to more than $200 for a one-month supply of medication (Table 3).
Recently, atorvastatin, when compared with simvastatin, lovastatin and fluvastatin, was found to
be the most cost-effective choice to achieve NCEP goals.24 However, this study was done before
cerivastatin (one of the least expensive statins) became available. In addition, some of the statins
have not been tested in clinical outcome studies.
TABLE 4
HMG-CoA Reductase Inhibitors (Statins)
Adverse Patient
Drug Dosage effects information Monitoring
Atorvastatin Initially, 10 mg GI, myalgias, Report malaise, Obtain lipid profiles for
(Lipitor)* daily. Bedtime headaches, fever or any response at 4 weeks.
administration is elevated liver muscle Perform LFTs before initiating
suggested, but enzymes tenderness or therapy, at 12 weeks and
dose may be taken weakness. every 6 months thereafter.
any time, without Avoid Repeat LFTs after dosage
regard to meals. consumption of increase.
Increase dosage if alcohol and Discontinue drug if serum
response is grapefruit juice transaminaselevels exceed 3
inadequate at 4 while taking this times normal level or if
weeks. medicine. myopathy or myositis occurs.
Maximum dosage:
80 mg daily
Cerivastatin Initially, 0.4 mg GI, myalgias, Report malaise, Obtain lipid profiles for
(Baycol)* daily at bedtime peripheral fever or any response at 4 weeks.
without regard to edema, muscle Perform LFTs before initiating
meals. elevated liver tenderness or therapy, at 6 and 12 weeks
Start at a lower enzymes weakness. and every 6 months
dosage if patient Avoid thereafter.
has renal disease: consumption of Repeat LFTs after dosage
0.2 mg daily at alcohol and escalation.
bedtime if CrCl is grapefruit juice Discontinue drug if serum
<60 mL per minute while taking this transaminase levels exceed 3
(<1 mL per medicine. times normal level or if
second). myopathy or myositis occurs.
Maximum dosage:
0.4 mg at bedtime.
Fluvastatin Initially, 20 mg daily GI, myalgias, Report malaise, Obtain lipid profiles for
(Lescol)* at bedtime, without back pain, fever or any response at 4 weeks.
regard to meals. headaches, muscle Perform LFTs before initiating
Increase to 40 mg dizziness tenderness or therapy, at 6 and 12 weeks
daily if response is Abdominal weakness. and every 6 months
inadequate at 4 pain, insomnia, Avoid thereafter.
weeks. elevated liver consumption of Repeat LFTs after dosage
Maximum dosage: enzymes alcohol and escalation.
80 mg daily, divided grapefruit juice Discontinue drug if serum
into 2 doses. while taking this transaminase levels exceed 3
medicine. times normal level or if
myopathy or myositis occurs.
Lovastatin Initially, 20 mg with GI, myalgias, Report malaise, Obtain lipid profiles for
(Mevacor)* evening meal. arthralgias, fever or any response at 4 weeks.
If serum cholesterol headaches, muscle Perform LFTs before initiating
is >300 mg per dL, dizziness, tenderness or therapy, at 6 and 12 weeks
start with 40 mg elevated liver weakness. and every 6 months
daily. enzymes Avoid thereafter.
Increase dosage if consumption of Repeat LFTs after dosage
response is alcohol and escalation.
inadequate at 4 grapefruit juice Discontinue drug if serum
weeks. while taking this transaminase levels exceed 3
Maximum dosage: medicine. times normal level or if
80 mg daily. myopathy or myositis occurs.
If CrCl is < 30 mL
per minute (<0.5
mL per second),
daily dose should
not exceed 20 mg.
Pravastatin Initially, 10 mg daily GI, myalgias, Report malaise, Obtain lipid profiles for
(Pravachol)* at bedtime, without generalized fever or any response at 4 weeks.
regard to meals. pain, muscle Perform LFTs before initiating
Increase dosage if headaches, tenderness or therapy and at 12 weeks.
response is dizziness, weakness. Repeat LFTs after dosage
inadequate at 4 elevated liver Avoid escalation.
weeks. enzymes consumption of Discontinue drug if serum
Maximum dosage: alcohol and transaminase levels exceed 3
40 mg daily; 10 mg grapefruit juice times normal level or if
in patients with while taking this myopathy or myositis occurs.
hepatic or renal medicine.
dysfunction.
Simvastatin Initially, 20 mg daily GI, Report malaise, Obtain lipid profiles for
(Zocor)* at bedtime. headaches, fever or any response at 4 weeks.
Increase dosage if elevated liver muscle Perform LFTs before initiating
response is enzymes tenderness or therapy and every 6 months
inadequate at 4 weakness. for the first year of therapy.
weeks. Avoid Repeat LFTs every 6 months
Maximum dosage: consumption of after dosage escalation for an
40 mg twice daily alcohol and additional year. Patients
5 mg daily at grapefruit juice taking 80 mg daily should
bedtime if patient is while taking this have LFTs every 3 months.
elderly or has medicine. Discontinue drug if serum
severe renal transaminase levels exceed 3
insufficiency. times normal level or if
myopathy or myositis occurs.
Closely monitor patients with
severe renal insufficiency. Do
not exceed 10 mg daily if
given in combination with
fibrates or niacin.
HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; GI = gastrointestinal; LFTs = liver function tests; CrCl =
creatinine clearance; LDL = low-density lipoprotein.
*--Contraindicated in pregnant women and nursing mothers.
Information from Drug facts and comparisons. St. Louis: Wolters Kluwer, 1999, and American Hospital Formulary
Service. Drug information 1998. Bethesda, Md.: American Society of Health-System Pharmacists, 1999.
Niacin (Nicotinic Acid)
Niacin is the oldest lipid-lowering agent that has been proved to decrease cardiovascular
morbidity and total mortality.25,26 It reduces serum triglyceride, total cholesterol and LDL
cholesterol values (Table 3). It also has the beneficial effect of raising HDL levels.
An extended-release form of niacin (Niaspan) has the same beneficial lipid-altering effects as
standard niacin. Although it is less effective than the statins in decreasing LDL levels, extended-
release niacin can increase HDL values by 20 percent and decrease triglyceride levels by 25
percent, making it unique among the lipid-lowering agents.
TABLE 5
Drug Interactions with Statin Agents
Statins
Other Atorvastatin Cerivastatin Fluvastatin Lovastatin Pravastatin Simvastatin
medications (Lipitor) (Baycol) (Lescol) (Mevacor) (Pravachol) (Zocor)
Azole A A A A -- A
antifungals
Cimetidine -- -- A -- -- A
(Tagamet)
Ranitidine -- -- A -- -- A
(Zantac)
Warfarin B B B B B C
(Coumadin)
Digoxin D B D B B D
Erythromycin A A A A -- A
Gemfibrozil A A A A A A
(Lopid)
Niacin A A A A A A
A = May increase serum concentration of statin and therefore increase risk of rhabdomyolysis.
B = Class warning.
C = May potentiate warfarin effect.
D = May increase serum digoxin level.
-- = No interaction.
Information from Drug facts and comparisons. St. Louis: Wolters Kluwer, 1999.
Adverse Effects
Until the recent introduction of extended-release tablets, niacin therapy had been plagued by low
compliance rates. More than 40 percent of the patients treated with standard niacin discontinued
it because of adverse effects, compared with 6 percent of patients taking extended-release
tablets.27 Flushing is the most common side effect, affecting more than three quarters of patients.
Other adverse effects include abdominal pain, nausea and vomiting (all less than 8 percent).
Patients who take extended-

release niacin tend to have fewer
adverse effects than those who
use standard niacin preparations.
Flushing can be minimized by starting the patient on a low dosage of niacin and making small
increases periodically (Table 6).18,19,28 It is also helpful for the patient to take 162 mg to 325 mg of
aspirin 30 minutes before the niacin. Taking the niacin at bedtime and avoiding concomitant
ingestion of alcohol or hot beverages will further diminish flushing. Despite these helpful tips,
many patients are noncompliant with this regimen and fail to continue the drug beyond the initial
stage of flushing. Often there is relief from the flushing if the patient can tolerate it through the
first few weeks.
Monitoring
Less than 1 percent of patients with normal results on liver function tests before taking extended-
release niacin tablets have elevated liver enzyme values (more than three times the reference
range) after niacin is started. There have been case reports of fulminant liver necrosis with
nicacin therapy29,30; therefore, periodic liver function tests are mandatory. The tests should be
performed before initiation of therapy, every 12 weeks for the first year and then every six
months. The drug should be discontinued if liver enzyme values exceed three times the reference
range. Compared with regular niacin, the extended-release tablets have a similar or lesser effect
on liver function tests.31
Caution is required in administering a statin concomitantly with extended-release niacin tablets

because this combination is associated with an increased incidence of rhabdomyolysis. Niacin
may promote glucose intolerance and should be used with caution in patients with diabetes
mellitus. Niacin can also increase uric acid levels and precipitate a gout attack. Extended-release
niacin tablets are less liable than regular niacin to have these effects on glucose and uric acid.31
TABLE 6
Niacin (Nicotinic Acid)
Patient
Drug Dosage Adverse effects information Monitoring
Nonprescription 50 to 100 mg Flushing, To decrease Check lipid levels
niacin twice daily for pruritus, flushing, take in before and 4 weeks
the first week. abdominal pain, p.m.; take aspirin 30 after reaching desired
Double the nausea, vomiting, minutes before, dosage, and 4 weeks
dosage every elevated liver avoid concomitant after every dosage
week to 1,000 to enzyme levels, ingestion of alcohol increase.
1,500 mg daily, glucose or hot beverage. Perform LFTs, uric acid
in 2 or 3 divided intolerance, rare To decrease determination and
doses. reversible gastrointestinal fasting glucose test
If response is acanthosis distress, take daily before initiating therapy
inadequate after nigricans in 2 or 3 divided and 6 weeks after
4 to 8 weeks, doses; take after a target dose is reached.
increase dosage low-fat snack. Repeat LFTs every 12
slowly to weeks thereafter for
maximum of first year, then every 6
3,000 mg daily. to 12 months.
If patient Discontinue drug if
switches serum transaminase
brands, restart levels exceed 3 times
from low dosage normal level.
and titrate up to
minimize risk of
hepatic
necrosis.
Extended-release Take daily at Flushing, To decrease Check lipid levels 4
niacin tablets bedtime: pruritus, flushing, take in weeks after starting
(Niaspan)* 500 mg--weeks abdominal pain, p.m.; take aspirin 30 and 4 weeks after
1 through 4 nausea, vomiting, minutes before; every dosage increase.
1,000 mg-- elevated liver avoid concomitant Obtain uric acid level
weeks 5 through enzymes, ingestion of alcohol and fasting glucose
8 glucose or hot beverage. levels before initiating
1,500 mg--after intolerance To decrease therapy and 6 weeks
week 8 gastrointestinal after target dose is
Maximum distress, take after a reached. Perform LFTs
dosage: 2,000 low-fat snack. before initiating therapy
mg and every 12 weeks
thereafter for first year,
then every 6 to 12
months.
Discontinue if serum
transaminase levels
exceed 3 times normal
level.
LFTs = liver function tests.
*--Pregnancy category C: adverse effects in animals, no human data.
Information from references 18, 19 and 28.
Fibric Acid Derivatives (Fibrates)
Fibrates are used to treat hypertriglyceridemia. This class of drugs includes clofibrate (Atromid-
S), gemfibrozil (Lopid) and fenofibrate (Tricor). Epidemiologic studies have identified
hypertriglyceridemia as a risk factor for CHD.32
The NCEP provides intervention guidelines for patients with elevated serum triglyceride levels
(Table 7).33 Drug therapy should be considered when a patient who has hypertriglyceridemia also
has established CHD or pancreatitis. Medication is generally not used to treat
hypertriglyceridemia unless fasting serum triglyceride levels are greater than 400 mg per dL
(4.50 mmol per L). Fibrates decrease triglyceride values by 20 to 45 percent and increase HDL
levels by 7 to 15 percent. Although these agents generally lower LDL values by 10 to 20 percent,
some patients (i.e., those with type IV hyperlipoproteinemia) show an increased LDL level.
Fibrates should not be administered to patients with severe hepatic or renal dysfunction.
TABLE 7
National Cholesterol Education Program (NCEP) Guidelines: Serum
Triglyceride Action Limits
Triglyceride value Intervention
<200 mg per dL Normal value. Some recommend a lower normal value of 150 mg per dL (1.70
(<2.25 mmol per L) mmol per L).
200 to 400 mg per Primary treatment is lifestyle modification: weight control, low-fat, low-
L (2.25 to 4.50 cholesterol diet, regular exercise, smoking cessation and (in selected patients)
mmol per L) alcohol restriction. Medication may be considered in patients with established
CHD, family history of premature CHD, concomitant total cholesterol level of
>=240 mg per dL (>=6.20 mmol per L) and HDL value of <35 mg per dL (<1.0
mmol per L), genetic form of hypertriglyceridemia (e.g., dysbetalipoproteinemia
or familial combined hyperlipidemia) or multiple risk factors.
400 to 1,000 mg Treatment as in previous category but with an emphasis on controlling causes
per dL (4.50 to of secondary hypertriglyceridemia. Medication is recommended by some
11.30 mmol per L) authorities and certainly should be used if the patient has a history of acute
pancreatitis.
>1,000 mg per dL Vigorous triglyceride-lowering efforts are required because of increased risk for
(>11.30 mmol per pancreatitis. Treat causes of secondary hypertriglyceridemia (e.g., diabetes
L) mellitus). Institute very-low-fat diet, curtail alcohol; if triglyceride level of <1,000
mg per dL (<11.30 mmol per L) is not achieved, use medications.
CHD = coronary heart disease; HDL = high-density lipoprotein.
Information from National Cholesterol Education Program. Second report of the expert panel on detection,
evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel II). Circulation 1994;89:1329-
1445.
The Coronary Drug Project evaluated the efficacy of clofibrate in the prevention and treatment of
CHD. Although patients exhibited decreases in serum triglycerides (-22.3 percent) and
cholesterol (-6.5 percent), the five-year mortality difference between placebo and clofibrate was
not significant.25 Because clofibrate is associated with serious adverse effects (cholelithiasis,
pancreatitis, malignancy) and has not been proved to affect mortality rates, it is no longer
marketed in the United States.34
Adverse Effects
Gastrointestinal intolerance (abdominal pain, nausea, vomiting, diarrhea, constipation,
dyspepsia) is the most common adverse effect associated with fibrate therapy. Neuromuscular
(headache, dizziness, vertigo, arthralgias) and dermatologic reactions have also been reported to
occur with these drugs (Table 8).18,19 Monotherapy with a fibrate is rarely associated with
myalgias or rhabdomyolysis. The incidence of myalgias and rhabdomyolysis increases with
concomitant use of a statin (e.g., gemfibrozil and lovastatin). For this reason, thoughtful
consideration should precede prescribing these two drug classes together.
TABLE 8
Fibric Acid Derivatives (Fibrates)
Patient
Drug Dosage Adverse effects information Monitoring
Gemfibrozil 600 mg twice Dyspepsia, diarrhea, Take with meals. Perform LFTs before
(Lopid)* daily, 30 minutes fatigue, nausea, Report any initiating therapy and
before morning vomiting, abdominal muscle pain, repeat periodically during
and evening pain, eczema, rash, tenderness or first year of therapy.
meals. vertigo weakness.
Maximum
dosage: 600 mg
twice daily
Micronized 67 mg (1 tablet) Dyspepsia, diarrhea, Take with meals. Perform LFTs before
fenofibrate daily, taken with fatigue, headache, Report any initiating therapy and
(Tricor)* main meal. nausea, vomiting, muscle pain, repeat periodically during
Increase dosage muscle or joint pain, tenderness or first year of therapy.
at 4-week rash, vertigo weakness. Drug contraindicated in
intervals as patients with severe liver
tolerated. or renal disease.
Maximum
dosage: 201 mg
daily (may be
taken at one
time)
LFTs = liver function tests.
*--Pregnancy category C: adverse effects in animals, no human data.
Gemfibrozil has been associated with cholelithiasis in 1 percent of the patients on long-term
therapy.19 Fibrates increase gallbladder and hepatic cholesterol concentrations; therefore, therapy
with these drugs should not be started in patients who have gallstones and should be
discontinued if gallstones develop. Because the effects of insulin and glyburide may be
potentiated by fibrates, patients treated with these medications should be monitored for signs of
hypoglycemia.
The standard formulation of fenofibrate has been available for years outside the United States. A
micronized formulation that improves absorption (Tricor) was FDA labeled in 1998, permitting a
lower once-daily dose. Absorption is increased by 30 percent when fenofibrate is taken with
meals. Renal insufficiency prolongs clearance of the drug.
Fenofibrate is indicated for the treatment of hypertriglyceridemia in persons who are at risk for
developing pancreatitis (e.g., serum triglyceride levels greater than 1,000 mg per dL [11.30
mmol per L]). Studies indicate that fenofibrate may inhibit atherogenesis by decreasing platelet
aggregation.35 The effects of fenofibrate on CHD have not been evaluated. Fenofibrate is more
costly than niacin or gemfibrozil but is an option for patients who cannot tolerate these agents.
Bile Acid Sequestrants
Cholestyramine (LoCholest) and colestipol (Colestid) are the two bile acid sequestrants currently
available (Table 9).18,19 These agents lower LDL (20 percent) and raise HDL (5 percent). Rarely,
cholestyramine and colestipol increase serum triglyceride values. Maximal therapeutic effect is
evident after one month of therapy.
TABLE 9
Bile Acid Sequestrants
Drug Dosage Adverse effects Patient information Monitoring
Cholestyramine Initially, 4 g daily Constipation Take 1 hour before Check lipid profile at
(LoCholest) in 2 or 3 divided or 4 hours after other 2 to 4 weeks and
powder doses medications. monitor for
Increase dosage Take with meals. constipation.
at 4-week Mix with 3 to 6 oz of If constipation
intervals as water, fruit juice or occurs, increase
tolerated. pulpy fruit fluid and fiber
Maximum (applesauce or intake, consider
dosage: 24 g crushed pineapple). stool softener.
daily Mixing a dose the Some patients
night before and require a laxative to
refrigerating it will prevent
improve palatability. constipation.
Stir well.
Increase fluid intake
to avoid constipation.
Colestipol Initially, 5 g daily Constipation Same as above Same as above
(Colestid) in 2 or 3 divided Flavored products
granules* doses (granules) contain
or 2 g daily aspartame.
(tablets) Avoid in
Increase dosage phenyketonuric
at 4-week patients.
intervals as
tolerated.
Maximum
dosage: 30 g
daily
*--Pregnancy category B: no adverse effects in animals, no human data.
Adverse Effects
Bile acid sequestrants are seldom used as initial therapy because success is often limited by poor
patient tolerance. Gastrointestinal disturbances are common and include constipation, nausea,
indigestion, bloating, diarrhea and flatulence. Gradually increasing the dosage, along with
increasing fluid intake and taking stool softeners, helps to minimize adverse effects. These
agents are not recommended for use in patients with severe chronic constipation or bowel
disease.
Bile acid sequestrants interfere with intestinal absorption of various vitamins and minerals (e.g.,
vitamins A, D, E, K, folic acid, magnesium, iron, zinc). Bile acid sequestrants also decrease the
absorption of numerous medications, including levothyroxine, penicillin, propranolol, thiazide
diuretics and digoxin.
Combination Therapy and Compliance

Combination regimens should be considered for use in patients who fail to meet target values
and are compliant with their current therapy. Patients with moderate to severe
hypercholesterolemia generally have more difficulty reaching their goals, although considerable
reductions in LDL do occur. If further reductions in LDL are required, and the benefits outweigh
the risks, a statin in conjunction with niacin is an effective combination. More patients reach
their lipid goals with a statin and niacin than with any other combination regimen.36 When the
patent on lovastatin expires in 2001, a one-tablet combination of lovastatin with extended-release
niacin is likely. Myopathy and rhabdomyolysis are serious concerns when statins are combined
with fibrates or niacin. It is important for physicians to educate their patients about the adverse
effects of these medications and instruct them to report muscle pain or tenderness immediately.
Compliance with bile acid sequestrants is a problem. Approximately one third of the patients for
whom bile acid sequestrants are prescribed will not take the full dosage because of constipation
or poor palatability.37 Combination therapies that include a bile acid sequestrant have lower
success rates than other combinations.
The statins have the best compliance or maintenance rates, followed by niacin, gemfibrozil and
bile acid sequestrants.37 Despite the use of single or combined drug therapy to treat
hypercholesterolemia, only 50 percent of treated patients reach the lipid goals outlined in the
NCEP recommendations.37 Combination therapy increases the likelihood of reaching target
values, but poor compliance is a variable that can foil even the most aggressive therapeutic
interventions.
Cholesterol Treatment Guidelines Update
RICHARD S. SAFEER, M.D., Concentra Medical Centers, Baltimore, Maryland
PRABHA S. UGALAT, M.P.H., George Washington University School of Medicine,

Washington, D.C.
Am Fam Physician. 2002 Mar 1;65(5):871-881.
Related Editorial
Hypercholesterolemia is one of the major contributors to atherosclerosis and coronary heart

disease in our society. The National Cholesterol Education Program of the National Institutes of
Health has created a set of guidelines that standardize the clinical assessment and management of
hypercholesterolemia for practicing physicians and other professionals in the medical
community. In May 2001, the National Cholesterol Education Program released its third set of
guidelines, reflecting changes in cholesterol management since their previous report in 1993. In
addition to modifying current strategies of risk assessment, the new guidelines stress the
importance of an aggressive therapeutic approach in the management of hypercholesterolemia.
The major risk factors that modify low-density lipoprotein goals include age, smoking status,
hypertension, high-density lipoprotein levels, and family history. The concept of “CHD
equivalent” is introduced—conditions requiring the same vigilance used in patients with
coronary heart disease. Patients with diabetes and those with a 10-year cardiac event risk of 20
percent or greater are considered CHD equivalents. Once low-density lipoprotein cholesterol is
at an accepted level, physicians are advised to address the metabolic syndrome and
hypertriglyceridemia.
Coronary heart disease (CHD) is the leading cause of morbidity and mortality in the United
States, accounting for approximately 500,000 deaths per year and an associated annual morbidity
cost of more than $200 billion.1 In the past three decades, numerous clinical and epidemiologic
studies have shown repeatedly that an elevated blood cholesterol level is one of the major
modifiable risk factors associated with the development of CHD.2 In particular, these studies
have demonstrated that low-density lipoprotein (LDL) cholesterol is the primary lipoprotein
mediating atherosclerosis. Other risk factors such as cigarette smoking, hypertension, diabetes,
and a low level of high-density lipoprotein (HDL) cholesterol also have been implicated in
CHD.3
In an effort to address this public health issue, the National Institutes of Health established the
National Cholesterol Education Program in 1985. In 1988, the National Cholesterol Education
Program, Adult Treatment Panel I (NCEP–ATP I) developed its first set of guidelines,
establishing clear goals for patients with lipid abnormalities. In 1993, the NCEP–ATP II revised
its initial recommendations and developed a second set of guidelines; in addition to emphasizing
CHD risk status, this report placed even more emphasis on HDL levels, weight loss, and physical
activity. In May 2001, the NCEP–ATP III released its third set of guidelines, reflecting changes
in calculating coronary risk and in the management of hypercholesterolemia. According to the
new guidelines, the number of patients with cholesterol levels that can be classified as abnormal
has now tripled.
The NCEP–ATP III guidelines are similar to those in the second report in identifying LDL as a
primary target of cholesterol-lowering therapy. Risk stratification continues to determine LDL
goals and the intensity of LDL-lowering therapy. Dietary therapy remains the first line of
treatment, with drug therapy reserved for use in patients at high risk for CHD or patients who do
not respond to nonpharmacologic therapy. The differences between the third report and the
previous report are summarized in Table 14 and discussed throughout this article.
TABLE 1
New Aspects of ATP III Guidelines
Focus on multiple risk factors
Raises persons with diabetes but without CHD to the risk level of CHD risk equivalent
Uses Framingham projections of 10-year absolute CHD risk to identify patients with multiple (2
or more) risk factors for more intensive treatment
Identifies persons with metabolic syndrome as candidates for intensified therapeutic lifestyle
changes
Modification of lipid/lipoprotein classification
Optimal LDL cholesterol level is now <100 mg per dL (2.60 mmol per L)
Increases categorical low HDL cholesterol level to <40 mg per dL (1.05 mmol per L)
Lowers triglyceride classification cut points
Support for implementation
Recommends complete lipoprotein profile (total, LDL, HDL, triglycerides) as preferred
screening for assessing CHD risk status
Encourages use of plant sterols/stanols as a therapeutic dietary option to lower LDL cholesterol
levels
Presents strategies for adherence to therapeutic lifestyle changes and drug therapies
Recommends treatment beyond LDL lowering for triglyceride levels >200 mg per dL (2.26
mmol per L)
One diet recommended for the entire population
12-week trial of diet alone before adding pharmacotherapy
ATP = Adult Treatment Panel; CHD = coronary heart disease; LDL = low-density lipoprotein;
HDL = high-density lipoprotein.
Adapted with permission from Executive summary of the Third Report of the National
Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment
of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2487.
Risk Assessment
In accordance with the new guidelines, optimal cholesterol screening now includes a lipoprotein
profile (total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides), preferably using
blood drawn in a fasting state. Screening is still recommended for all patients 20 years or older
and every five years thereafter. The lipoprotein profile cannot be interpreted without knowledge
of the patient's risk factors. Risk factor counting remains an important part of the guidelines
(Table 2).4 In ATP III, diabetes is no longer on this risk factor list but is now included in a new
category termed “CHD risk equivalent.”
TABLE 2
Major Risk Factors That Modify LDL Goals
Positive risk factors
Age (men ≥ 45 years; women ≥ 55 years)
Low HDL cholesterol (<40 mg per dL [1.05 mmol per L])
Cigarette smoking
Hypertension (blood pressure >140/90 mm Hg or taking antihypertensive medication)
Family history of premature CHD (CHD in male first-degree relative <55 years;
CHD in female first-degree relative <65 years)
Negative risk factor
High HDL cholesterol (> 60 mg per dL [1.55 mmol per L]); presence of this risk factor removes
one risk factor from the total count
LDL = low-density lipoprotein; HDL = high-density lipoprotein; CHD = coronary heart disease.
of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2487.
As reflected in ATP III, an additional step in the determination of CHD risk involves the
calculation of the Framingham risk score (FRS) for persons with two or more risk factors. The
addition of this step, along with the identification of major risk factors, allows physicians to
recognize those patients at greatest risk for CHD.
Risk Factors
Since 1993, additional evidence for age, gender, and HDL importance has emerged, reinforcing
the need to address these factors. The NCEP stance on smoking status, hypertension, and family
history has remained essentially unchanged.
AGE AND GENDER
Recent studies have shown that the identification and treatment of dyslipidemia in patients 65
years and older can decrease the risk of first and recurrent coronary events. [Evidence level A,
randomized controlled trials (RCTs)/meta-analyses] The Scandinavian Simvastatin Survival
Study (4S), the Cholesterol and Recurrent Events (CARE) study, and the Air Force/Texas
Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) were further analyzed for the
population older than 65 years. In each treatment group, morbidity and mortality from
cardiovascular disease was decreased by at least 29 percent.5–7 Although data are limited for
patients older than 85 years, the elderly are candidates for cholesterol-lowering therapy.
Initiation of therapy should be carefully examined in the context of comorbidities and the
increased use of medications within this population.
Primary and secondary cardiovascular risk reduction is also important in women. Cardiovascular
disease is the primary cause of death among American women, far exceeding the rate of all
cancers combined.1 Women's mortality following myocardial infarction is three times that of
men,8 suggesting that women may not be active participants in cardiovascular risk reduction
strategies. By demonstrating cardiovascular event reduction through the use of statins, the 4S,
CARE, and AFCAPS/TexCAPS trials support cholesterol-lowering therapy in women.
[Evidence level A, RCTs/meta-analyses]
The recent Heart and Estrogen/progestin Replacement Study (HERS) has cast some doubt on the
use of hormone replacement therapy (HRT) in the secondary prevention of CHD risk in
postmenopausal women.9 Although several primary prevention studies support the use of HRT
to prevent heart disease, the studies that support the use of statins to prevent heart disease in
women are much stronger. Therefore, the ATP III prefers the initial use of a cholesterol-lowering
agent to HRT for CHD risk reduction in postmenopausal women.
Although women have, on average, higher HDL levels than men, the ATP III guidelines do not
distinguish between genders in regard to choosing a threshold level for HDL.
HDL CHOLESTEROL
The ATP III guidelines have been expanded to recognize the importance of HDL levels by
raising the threshold of low HDL cholesterol from less than 35 mg per dL (0.90 mmol per L) to
less than 40 mg per dL (1.05 mmol per L). [Evidence level C, consensus/expert opinion]
The “negative” risk factor (which negates one risk point from the major risk factor list) awarded
to patients with an HDL level of 60 mg per dL (1.55 mmol per L) or higher in the last set of
guidelines remains in ATP III. Since the release of the second set of guidelines in 1993, the
significance of HDL cholesterol in the evolution of coronary artery disease has become more
evident. The AFCAPS/TexCAPS study correlated a 6 percent increase in HDL cholesterol levels
with a reduction of first acute major coronary events in men and women with baseline average
LDL cholesterol levels and below-average HDL cholesterol levels. [Evidence level A,
RCTs/meta-analyses]
Similarly, The Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-
HIT) also demonstrated the benefit of raising HDL levels.10 In this study, HDL levels increased
by 6 percent, triglyceride levels decreased by 31 percent, and coronary events decreased by 22
percent with gemfibrozil therapy, compared with placebo. Analyses of the data revealed a
correlation between rising HDL levels and lower coronary event rates. [Evidence level A,
RCTs/meta-analyses] This was not consistently true across the spectrum of baseline triglyceride
levels, suggesting that HDL was the primary element responsible for the positive outcome.
Framingham Risk Score
The FRS is a risk assessment tool that has been derived from data collected in the Framingham
Heart Study.11 As mentioned previously, the new NCEP guidelines recommend that patients
with two or more risk factors have their FRS calculated. [Evidence level B, retrospective data
analysis]
The FRS consists of points that are allocated for the various degrees of risk associated with five
categories: age, total cholesterol level, HDL cholesterol level, tobacco smoking status, and
hypertension (and whether the latter condition is treated). The summation of these points results
in a percent risk of having a cardiac event in the next 10 years. Figures 1 and 2 outline FRS
assessment for men and women, respectively.4
Calculating 10-Year Risk in Men

FIGURE 1.
Framingham scoring system for estimating 10-year risk of coronary heart disease in men. (CHD
= coronary heart disease; BP = blood pressure; HDL = high-density lipoprotein; FRS =
Framingham risk scoring)
note:Risk assessment for determining the 10-year risk for developing CHD is carried out using
Framingham risk scoring. The first step is to calculate the number of risk points for each risk
factor from the table. For initial assessment, values for total cholesterol and HDL cholesterol are
required. Total cholesterol and HDL cholesterol values should be the average of at least two
measurements obtained from lipoprotein analysis. The designation smoker means cigarette
smoking in the past month. The blood pressure value used is that obtained at the time of the
assessment, regardless of whether the person is taking antihypertensive agents.
of High Blood Cholesterol in Adults (Adults Treatment Panel III). JAMA 2001;285:2486–97.
Calculating 10-Year Risk in Women

FIGURE 2.
Framingham scoring system for estimating 10-year risk of coronary heart disease in women.
(CHD = coronary heart disease; BP = blood pressure; HDL = high-density lipoprotein; FRS =
Framingham risk scoring)
note:Risk assessment for determining the 10-year risk for developing CHD is carried out using
Framingham risk scoring. The first step is to calculate the number of risk points for each risk
factor from the table. For initial assessment, values for total cholesterol and HDL cholesterol are
required. Total cholesterol and HDL cholesterol values should be the average of at least two
measurements obtained from lipoprotein analysis. The designation smoker means cigarette
smoking in the past month. The blood pressure value used is that obtained at the time of the
assessment, regardless of whether the person is taking antihypertensive agents.
of High Blood Cholesterol in Adults (Adults Treatment Panel III). JAMA 2001;285:2486–97.
CHD Equivalents
In the ATP II guidelines, risk categories were developed to separate patients with CHD (or its
equivalent, such as abdominal aortic aneurysm, intermittent claudication, symptomatic carotid
artery disease, etc.) from those without CHD. This distinction was primarily made to delineate
the establishment of new target LDL levels for patients with CHD and to provide appropriate
therapy to these patients based on their increased cardiovascular risk. In the ATP III guidelines,
the target LDL level for patients with established CHD is still 100 mg per dL or less. Patients
with diabetes and patients with an FRS of 20 percent or higher are considered CHD equivalents.
Because patients with diabetes and patients with an FRS of 20 percent or higher are in the same
risk category as CHD patients, they are also recommended to maintain an LDL level of 100 mg
per dL. [Evidence level C, consensus/expert opinion]
The interventions for reaching the LDL goal in patients with diabetes or an FRS of 20 percent or
higher are the same as those in patients with CHD.
The establishment of diabetes as a CHD risk equivalent reflects the prevalence of heart disease
as a cause of death in the diabetic population. Three fourths of patients with diabetes die from
heart disease–related illnesses compared with one half of the general population. Poor glycemic
control has repeatedly been shown to be associated with an elevated risk of cardiovascular
events.
According to the 2000 American Diabetes Association Guidelines, the primary goal of
hyperlipidemia therapy in patients with type 2 diabetes (with or without vascular disease) is to
reduce LDL cholesterol levels below 100 mg per dL.12 [Evidence level C, consensus/expert
opinion] In addition to having LDL cholesterol particles of a more atherogenic variety, persons
with diabetes have lower HDL cholesterol levels and higher triglyceride levels.13 The 4S and
CARE trials included a sufficient number of diabetic patients to prove that after LDL cholesterol
lowering, fewer cardiovascular events occurred in this patient population.
Treatment
The extent of LDL-lowering therapy depends on the patient's CHD risk. Two major modalities
for lowering the LDL level advocated by the ATP III are therapeutic lifestyle changes (TLC) and
drug therapy. Table 34 outlines LDL cholesterol goals and cut points for initiation of TLC and
prescription medication. Patients are classified in one of three categories of risk: (1) CHD and
CHD equivalents, (2) two or more risk factors (further delineated by an FRS of 10 to 20 percent
versus 10 percent or less), or (3) zero or one risk factor.
TABLE 3
LDL Cholesterol Goals and Cut Points for Therapeutic Lifestyle Changes (TLC) and Drug
Therapy in Different Risk Categories
LDL level at
which to initiateLDL level at which to consider
Risk category LDL goal TLC drug therapy
CHD or CHD risk <100 ≥ 100 mg/dL ≥ 130 mg/dL (at 100 to 129 mg/dL,
equivalent (10-year risk mg/dL(2.60 drug optional)*
>20 percent) mmol/L)
2 or more risk factors <130 mg/dL ≥ 130 mg/dL ≥ 130 mg/dL for 10-year risk of 10
(10-year risk <20 (3.35 mmol/L) to 20 percent; 160 mg/dL for 10-year
percent) risk of <10 percent
0 to 1 risk factor† <160 mg/dL ≥ 160 mg/dL ≥ 190 mg/dL (at 160 to 189 mg/dL,
(4.15 mmol/L) LDL-lowering drug optional)
LDL = low-density lipoprotein; CHD = coronary heart disease; HDL = high-density lipoprotein.
*—If an LDL cholesterol level of <100 mg per dL cannot be achieved by therapeutic lifestyle
changes, some authorities recommend use of LDL-lowering drugs in this category. Others prefer
using drugs that primarily modify triglycerides and HDL (i.e., nicotinic acid or fibrate). Clinical
judgment also may call for deferring drug therapy in this subcategory.
†—People with zero to one risk factor almost always have a 10-year risk <10 percent; thus, 10-
year risk assessment is not necessary in this group.
of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486–97.
Therapeutic Lifestyle Changes
TLC encompasses diet, physical activity, and weight loss. ATP III continues to stress the
importance of nonpharmacologic treatment but recognizes its limitations by reducing the trial of
these modalities from six months to 12 weeks before considering the use of medications to assist
in achieving recommended LDL goals. Furthermore, the composition of the diet has been
modified, as noted in Table 4.4 One diet is recommended for all patients, as opposed to the two-
step diet recommended in the previous guidelines.
TABLE 4
Nutrient Composition of the Therapeutic Lifestyle Changes Diet
Nutrient Recommended intake
Saturated fat* <7 percent of total calories
Polyunsaturated fat Up to 10 percent of total calories
Monounsaturated fatUp to 20 percent of total calories
Total fat 25 to 35 percent of total calories
Carbohydrates† 50 to 60 percent of total calories
Fiber 20 to 30 g per day
Protein Approximately 15 percent of total calories
Cholesterol <200 mg per day
Total calories‡ Balance energy intake and expenditure to maintain desirable body weight
LDL = low-density lipoprotein; HDL = high-density lipoprotein.
*—Avoid trans fatty acids as well because they increase LDL and lower HDL cholesterol levels.
†—Carbohydrates should be derived from foods rich in complex carbohydrates, including whole
grains, fruits, and vegetables.
‡—Daily energy expenditure should include at least moderate physical activity.
of High Blood Cholesterol in Adults (Adult Treatment Panel III) JAMA 2001;285:2486–97.
The distribution of the fat allowance has been altered to recognize the value of monounsaturated
and polyunsaturated fatty acids. By replacing saturated fats (cheese, whole milk, red meat) with
monounsaturated fats (olive, canola oil) and polyunsaturated fats (corn oil, peanuts), LDL is
reduced. Although replacing saturated fats with a high-carbohydrate diet results in lower LDL
levels, it has the adverse effect of raising triglycerides and lowering HDL. Saturated and trans-
unsaturated fatty acids should be avoided.
The ATP III suggests the addition of plant stanols (hydrogenated phytosterols) to the patient's
diet when initial attempts to alter the diet have not resulted in reaching the LDL goal. [Evidence
level C, consensus/expert opinion] Plant stanols interfere with small-intestine absorption of
intestinal and biliary cholesterol. While they lower LDL levels, they have no significant effect on
HDL or triglyceride levels.14 Phytosterols can be found in many products, including margarine
spreads. Other sources of phytosterols include sesame seeds and peanuts; soybeans are a natural
source of phytosterols.
Physical inactivity is an independent risk factor, raising the risk of a cardiovascular event
twofold.15 [Evidence level A, RCTs/meta-analyses] Aerobic exercise raises HDL levels and
lowers triglyceride levels. When it results in weight loss, it contributes to LDL reduction. Weight
loss also improves insulin sensitivity and serum glucose uptake, reducing the risk of diabetes.
Cigarette smoking remains a cardiovascular risk factor. Patients who stop smoking can expect an
increase of up to 30 percent in their HDL levels.16
Drug Therapy
As indicated by ATP III, failure of TLC to modify LDL cholesterol levels or the presence of high
CHD risk levels warrants the use of drug therapy. Despite its use, particular attention to TLC
should always be maintained and reinforced by the physician. Several drugs have specific effects
on lipoprotein metabolism. Table 5 lists current classes of drugs and their associated lipid-
altering effects.17
Benefits of LDL-lowering therapy initially should be monitored at six-week intervals. If the LDL
goal based on established risk is not achieved, therapy should be intensified with an increase in
drug dosage or the addition of another LDL-lowering drug. Even if the LDL goal is attained,
other lipid risk factors should always be addressed. Once LDL levels are within normal range, a
patient's lipoprotein profile should be monitored every six to 12 months. Compliance with
medication remains an obstacle in the treatment of hypercholesterolemia.
TABLE 5
Characteristics of Drugs Affecting Lipoprotein Metabolism
Agents CostEffects on LDLEffects on HDLEffects on triglycerides
Bile acid sequestrants*$$ ↓↓↓ ↑/minimal None
Fibric acids† $$$ ↓ ↑↑↑ ↓↓↓↓
Nicotinic acid‡ $ ↓↓ ↑↑↑↑ ↓↓↓
Statins§ $$$ ↓↓↓↓ ↑↑ ↓↓
$
LDL = low-density lipoprotein; HDL = high-density lipoprotein.
note :Dollar signs indicate relative costs among drugs (Red Book, Montvale, N.J. Medical
Economics Data, 1999). Arrows indicate relative effects on lipoprotein levels, with four arrows
denoting the greatest effect.
*—Cholestyramine: 4 to 16 g; colestipol: 5 to 30 g (suspension); colesevelam: 2.6 to 3.8 g.
†—Gemfibrozil: 600 mg twice daily; fenofibrate: 200 mg.
‡—Immediate-release (crystalline) nicotinic acid: 1.5 to 3 g; extended-release nicotinic acid

(Niaspan): 1 to 2 g; sustained-release nicotinic acid: 1 to 2 g.
§—Lovastatin: 20 to 80 mg; pravastatin: 10 to 40 mg; simvastatin: 20 to 80 mg; fluvastatin: 20

to 80 mg; atorvastatin: 10 to 80 mg; cerivastatin: 0.4 to 0.8 mg.
Information from Safeer RS, Lacivita CL. Choosing drug therapy for patients with
hyperlipidemia. Am Fam Physician 2000;61:3374–5.
Special Considerations
METABOLIC SYNDROME
The ATP III panel recognizes the importance of metabolic syndrome (also known as syndrome
X) as a secondary target of therapy after recommended LDL levels are achieved. Metabolic
syndrome, or insulin resistance syndrome, is defined as a cluster of abnormalities that include
obesity, hypertension, dyslipidemia, and type 2 diabetes; it is associated with insulin resistance
and compensatory hyperinsulinemia.18 It is estimated that this syndrome affects 70 to 80 million
Americans.19
In particular, insulin resistance has been found in persons with low levels of HDL cholesterol
and high levels of very low-density lipoprotein (VLDL) cholesterol and triglycerides.20 Because
insulin resistance is often a precursor to the development of this syndrome, identification and
potential treatment of insulin-resistant patients has been suggested as a means of preventing
some or all components of the syndrome. However, measurement of fasting insulin levels is not
standard practice at this time; criteria for normal and abnormal values have not yet been
established.
As discussed in the new guidelines, the diagnosis of metabolic syndrome can be made when
three or more of the risk determinants are present, as outlined in Table 6.4 These determinants
can be measured readily in clinical practice. The treatment of metabolic syndrome is twofold: (1)
reduce the underlying causes (i.e., obesity and physical inactivity), and (2) treat the associated
lipid and nonlipid risk factors.
TABLE 6
Clinical Diagnosis of Metabolic Syndrome
Risk factor Defining level
Abdominal obesity (waist circumference)
Men >102 cm (> 40 in)
Women >88 cm (> 35 in)
Triglyceride level ≥ 150 mg/dL (170
mmol/L)
HDL cholesterol
Men <40 mg/dL (1.05 mmol/L)
Women <50 mg/dL (1.30 mmol/L)
Blood pressure ≥ 130 / 85 mm Hg
Fasting glucose ≥ 110 mg/dL
HDL = high-density lipoprotein.

of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285:2486–97.
HYPERTRIGLYCERIDEMIA
The ATP III recognizes the increasing number of studies correlating elevated triglyceride levels
with increased coronary artery disease risk. By lowering the acceptable triglyceride level from
the previous set of guidelines, the ATP III encourages a more aggressive approach to
hypertriglyceridemia (Table 7).4 Diet and exercise are the primary modes of treating
hypertriglyceridemia. If indicated, nicotinic acid and fibric acid derivatives are the most
efficacious in lowering triglyceride levels. Triglyceride reduction is a secondary benefit of statins
(the primary benefit being LDL cholesterol reduction).
TABLE 7
ATP III Classification of Triglyceride Levels and Treatment Strategies
Classification Serum level Treatment strategy
Normal <150 mg/dL (170 None
mmol/L)
Borderline- 150 to 199 mg/dL Achieve target goal for LDL cholesterol; emphasize weight
high (170 to 2.25 mmol/L) reduction and physical activity
High 200 to 499 mg/dL Achieve target goal for LDL cholesterol; institute weight
(2.26 to 5.64 reduction and physical activity; use drug therapy to achieve
mmol/L) non-HDL goal*
Very high ≥ 500 mg/dL (5.65 Primary goal is triglyceride lowering followed by LDL
mmol/L) lowering†
ATP = Adult Treatment Panel; LDL = low-density lipoprotein; HDL = high-density lipoprotein;
VLDL = very low-density lipoprotein.
*—There are two approaches to drug therapy: (1) intensify therapy with LDL-lowering drug or
(2) nicotinic acid or fibrate can be added. Non-HDL = LDL + VLDL. The non-HDL goal is 30
mg per dL higher than the LDL goal.
†—The approach to triglyceride lowering is a diet very low in fat (15 percent of calorie intake),
weight reduction, increased physical activity and, usually, a triglyceride-lowering drug (fibrate or
nicotinic acid).
Information from Executive summary of the Third Report of the National Cholesterol Education
Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486–97.
The major lipid component of VLDL is the triglyceride. The NCEP mentions VLDL levels as
part of a secondary treatment goal in patients with hypertriglyceridemia. VLDL levels can be
monitored as part of the lipoprotein profile, and respond similarly to the lifestyle changes and to
the medicines used to treat triglyceride levels.

Dyslipidemia

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Dyslipidemia

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Dyslipidemia(Hyperlipidemia)

• Dyslipidemia is elevation of plasma cholesterol, triglycerides (TGs), or both, or a low

Dyslipidemias were traditionally classified by patterns of elevation in lipids and lipoproteins

Genetic (Primary) Dyslipidemias

Diabetes is an especially significant secondary cause because patients tend to have an

Symptoms and Signs

Dyslipidemia is suspected in patients with characteristic physical findings or complications of

Other tests: Patients with premature atherosclerotic cardiovascular disease, cardiovascular

Secondary causes: Tests for secondary causes of dyslipidemia—including measurements of

• Risk assessment by explicit criteria

Drug optional if LDL

Treatment of children is controversial; dietary changes may be difficult to implement, and no

Framingham Risk Tables for

• Elevated LDL-cholesterol levels and a history of CAD

Cholesterol absorption inhibitors, such as ezetimibe Some Trade Names

Future therapies to reduce LDL include peroxisome proliferator–activated receptor agonists

Elevated TGs: Though it is unclear if elevated TGs independently contribute to cardiovascular

Nicotinic acid may also be useful (see Low HDL, below).

Elevated High-Density Lipoprotein Levels

Elevated HDL level is HDL-cholesterol > 80 mg/dL (> 2.1 mmol/L).

• Chronic alcoholism without cirrhosis

Familial hyperalphalipoproteinemia is an autosomal dominant condition caused by various

Last full review/revision September 2008

Choosing Drug Therapy for Patients with

HMG-CoA Reductase Inhibitors (Statins)

Indications and Efficacy

in both placebo and study groups. These agents were

Approximately 1 to 2 percent of patients treated with

Niacin (Nicotinic Acid)

Patients who take extended-

Caution is required in administering a statin concomitantly with extended-release niacin tablets

Fibric Acid Derivatives (Fibrates)

Bile Acid Sequestrants

Combination Therapy and Compliance

Cholesterol Treatment Guidelines Update

RICHARD S. SAFEER, M.D., Concentra Medical Centers, Baltimore, Maryland

PRABHA S. UGALAT, M.P.H., George Washington University School of Medicine,

Am Fam Physician. 2002 Mar 1;65(5):871-881.

Hypercholesterolemia is one of the major contributors to atherosclerosis and coronary heart

AGE AND GENDER

Framingham Risk Score

Calculating 10-Year Risk in Men

Calculating 10-Year Risk in Women

Therapeutic Lifestyle Changes

LDL = low-density lipoprotein; HDL = high-density lipoprotein.

‡—Daily energy expenditure should include at least moderate physical activity.

LDL = low-density lipoprotein; HDL = high-density lipoprotein.

*—Cholestyramine: 4 to 16 g; colestipol: 5 to 30 g (suspension); colesevelam: 2.6 to 3.8 g.

†—Gemfibrozil: 600 mg twice daily; fenofibrate: 200 mg.

‡—Immediate-release (crystalline) nicotinic acid: 1.5 to 3 g; extended-release nicotinic acid

§—Lovastatin: 20 to 80 mg; pravastatin: 10 to 40 mg; simvastatin: 20 to 80 mg; fluvastatin: 20

HDL = high-density lipoprotein.

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