Table of Contents
Chapter 1. Epidemiology of Dyslipidemia in Koreans
Current status of cardiovascular disease in Korea
Risk factors and risk evaluation of cardiovascular disease in
Distribution of serum lipid profile in Koreans
Chapter 2. Criteria for the Diagnosis and Treatment of Dyslipidemia
Evaluation of laboratory lipid and diagnostic criteria
Monitoring of lipids and enzymes
Chapter 3. Lifestyle Modifications for Dyslipidemia
Chapter 4. Pharmacological Therapy for Dyslipidemia
Selection of drugs
Characteristics of lipid-lowering agents
Chapter 5. Dyslipidemia in Different Clinical Settings
Stroke (cerebrovascular diseases)
Chronic kidney diseases
Children and adolescents
Although cardiovascular disease (CVD) has been one of the leading causes of death
in most developed countries, the rates of morbidity and mortality associated with
CVD have been steadily decreasing during the recent decades. On the contrary, the
rates of morbidity and mortality related to CVD have been rapidly increasing in Korea.1)
2) Considering that the rates of other risk factors are being reduced and more controlled
than before, this might be mainly due to the unhealthy lifestyle of Koreans and the
associated disease of dyslipidemia. For Koreans, therefore, lifestyle modification
and the management of dyslipidemia are very important in order to prevent CVD or its
The Korean Society of Lipidology and Atherosclerosis and other related societies and
organizations came together and formed the Committee for the Guidelines for the Management
of Dyslipidemia, to provide opinions for the proper management of dyslipidemia with
the aim of preventing CVDs in Korea. We published the first edition of the Guidelines
for the Management of Dyslipidemia in 1996 and the second edition in 2003. New guidelines
for dyslipidemia management were published in Europe (2011) and in the United States
(2013), on the basis of the most recent research results.3)
4) In this regard, 18 related societies and organizations in Korea gathered to suggest
new guidelines for dyslipidemia management.
Appropriate guidelines should be established on the basis of individual evaluations
of the future risks of CVD and death. This risk evaluation is possible only if the
potential risk factors can be accurately estimated in a representative Korean population
followed up for a long term and, at the same time, if the rates of CVD and death are
precisely recorded. Although several studies have been published in Korea, it might
be difficult to apply the results to actual clinical practice owing to the lack of
the above-mentioned elements.5) In addition, it is not possible to quote Western risk
evaluation criteria, as the mortality of ischemic heart disease in Korea is among
the lowest worldwide.
In this background, we adopted the previous approach, instead of following the trends
of overseas treatment guidelines. There is a desperate need, at this time, for a study
to evaluate the risk of CVD in Koreans. In addition, almost all studies on the management
of dyslipidemia are from Western countries, and a review of those studies is necessary
to determine whether such results can be applicable to Koreans. The grade of recommendation
and the evidence level in this treatment guideline were quoted from the treatment
guidelines of the American College of Cardiology and the American Heart Association
(ACC/AHA).4) For more details, it would be helpful to see the full text, which will
be published along with a summary.
Korean guidelines for management of dyslipidemia were made in full text and in executive
summary. And this is the English translation version of the executive summary. This
treatment guideline was based on observatory studies that investigated the preventive
effects of dyslipidemia management. Therefore, it does not mean that this guideline
should be applied to all patients with dyslipidemia. Instead, physicians should make
their final decision about how to treat their patients on the basis of the clinical
Chapter 1. Epidemiology of Dyslipidemia in Koreans
1. Current status of cardiovascular disease in Korea
Annually, 17000000 people die of CVD worldwide, which accounts for 30% of all deaths.6)
In Korea as well, CVD is one of the leading causes of death, where the mortality of
coronary artery disease (CAD) was 31 per 100000 males and 27 per 100000 females in
2012 (Fig. 1-1), whereas the mortality of cerebrovascular diseases was 49 per 100000
males and 53 per 100000 females in the same year (Fig. 1-2). Nevertheless, mortality
from cerebrovascular diseases has greatly decreased since the 1990s, whereas that
from coronary artery disease (CAD) has recently begun to slightly decrease when adjusted
for age (Fig. 1-1).
For cerebrovascular diseases, whereas more people died of cerebral hemorrhage (nontraumatic
intracerebral hemorrhage and subarachnoid hemorrhage) before 2002, death due to cerebral
infarction (ischemic stroke) predominated since 2002 (Fig. 1-3). This might be due
to the improved management of blood pressure, thereby reducing events of cerebral
hemorrhage, and the better treatment for cerebral hemorrhage.
Compared with the mortality data, it is difficult to identify such changes in the
prevalence and incidence rate of CVD, owing to the lack of nation-wide statistics.
The Korea National Health and Nutritional Examination Survey (KNHANES) reported that
3% of the population ≥30 years old experience stroke. Concerning CAD, the prevalence
rate of <1% in 1998 has increased up to 2.5% in 2010.7) I t is d ifficult to note
changes in the incidence rate of CVD owing to the lack of a nation-wide continuous
monitoring system, however, recent research estimated that the annual incidence rate
of acute myocardial infarction (AMI) was about 50 cases per 100000 males and about
20 cases per 100000 females.8) The incidence rate of cerebrovascular diseases depends
on the type (i.e., cerebral infarction or cerebral hemorrhage), such that the incidence
rate of cerebral hemorrhage is expected to decline rapidly, whereas that of cerebral
infarction is expected to gradually increase. Therefore, the number of patients with
cerebral infarction is expected to be greater than the number of patients with cerebral
hemorrhage. The difference in the incidence of CVD according to the geographic region
and year is predominantly explained by the change in the distribution of cardiovascular
risk factors. The prevalences of diabetes and dyslipidemia are increasing, whereas
there has not been much change in the prevalence of hypertension and the rate of smoking
cessation in Korea. Therefore, CAD is expected to be the most prevalent type of CVD
2. Risk factors and risk evaluation of cardiovascular disease in Korea
Knowing a person's cardiovascular risk factors is very important in terms of both
prevention and management; however, each method of risk factor evaluation is different
depending on the country-specific treatment guidelines. In 2009, the presence of a
history of existing CAD or its equivalent risk factors, including carotid artery disease,
peripheral artery disease (PAD), abdominal aneurysm, and diabetes, was defined as
high risk, according to the revised Korean Guidelines for the Management of Dyslipidemia.
Moreover, according to the revised National Cholesterol Education Program Adult Treatment
Panel III (NCEP-ATP III) guidelines of treatment in 2004, risks were scored on the
basis of the number of cardiovascular risk factors such as nonsmoking rate, hypertension,
low high-density lipoprotein (HDL) cholesterol, age, and family history of premature
CAD. Persons with two or more risk factors were classified as the intermediate risk
group, whereas those with none or only one risk factor were classified as the low-risk
From 1996 through to 2004 in Korea, the Korean Heart Study, on 430920 male and female
subjects who participated in nationwide health check-ups in 18 health promotion centers,
was conducted. In this study, the observation of the incidence and risk factors for
cerebrovascular diseases was followed for 10 years. The study results showed that
the most influential risk factors on cerebrovascular diseases were hypertension, nonsmoking
status, and dyslipidemia in male patients, and hypertension, dyslipidemia, diabetes,
and nonsmoking status in female patients.5) In addition, the relative risk, which
describes the risk of incident CVD or cerebrovascular diseases, of each risk factor
was analyzed. The results showed that the association of smoking and dyslipidemia
with CAD was stronger than that with cerebrovascular diseases, whereas the association
of hypertension with cerebrovascular diseases was greater than that with CADs. Total
cholesterol levels ≥200 mg/dL increased the risk of CAD, compared with levels <200
mg/dL, and increased the levels of HDL cholesterol, resulting in the risk of both
CVD and cerebrovascular diseases. Overall, the Korean-specific risk factors for CVD
included hypertension, smoking, dyslipidemia, and diabetes, all of which are similar
to those from other countries, and a Korea-specific, 10-year CAD risk-scoring system
based on these established risk factors is also currently available. However, validation
of this scoring system and the indication for lipid-lowering medications according
to the scored risks, as well as further study are needed to provide appropriate treatments
for the Korean population.
3. Distribution of serum lipid profile in Koreans
The average serum levels of total cholesterol in Korean male adults (age, ≥20 years)
were 183 mg/dL in 2005, 188 mg/dL in 2010–2012, 183 mg/dL in 2005, and 189 mg/dL between
2010 and 2012. The levels have been increasing by about 5–6 mg/dL for the last 7 years
between 2005 and 2012.
By contrast, between 2010 and 2012, the average triglyceride levels were 153 mg/dL
in males and 112 mg/dL in females, exhibiting much less variability compared with
the total cholesterol levels. During this period, the serum levels of low-density
lipoprotein (LDL) cholesterol averaged 112 mg/dL in males and 115 mg/dL in females,
whereas the levels of HDL cholesterol averaged 47 mg/dL in males and 52 mg/dL in females,
thereby making the increment approximately 1 mg/dL for both LDL and HDL cholesterol
levels, compared with the period between 2007 and 2009 (Table 1-1).1)
For adults older than 30 years, the prevalence of hypercholesterolemia (2010–2012)
was 12.6% in males and 14.9% in females, which increased by 5.4% in males and by 6.5%
in females during a 7-year period since 2005. By age group, the prevalence rate was
highest in males in their 50s and females in their 60s (16.9% and 32.2%, respectively).
The prevalence rates of hypertriglyceridemia, defined by a total cholesterol level
of ≥240 mg/dL or taking lipid-lowering agents (2010–2012), were 22.9% in males and
10.4% in females, with no significance difference from those in 2005. However, when
specified by sex, the prevalence rate was two-fold higher in males than in females.
By age, the highest prevalence rates were observed in males in their 50s (28.3%) and
females in their 60s (17.5%).1)
From 2010 through to 2012, the awareness rate of hypercholesterolemia was 45.2% in
males and 49.1% in females, whereas the treatment rate was 35.8% in males and 38.4%
in females, both of which increased by approximately 20% compared with those in 2005.
The proportion of controlled hypercholesterolemia was about 30%, whereas that of treated
patients was approximately 80%, which increased by ≥15% compared with that in 2005.
In comparison by sex, the awareness and treatment rates of female patients were slightly
higher than those of male patients. By age group, the awareness rate and treatment
rate in subjects in their 30s–40s were 25% and 15%, respectively, which were much
lower than those in the other age groups (Table 1-2).1)
Chapter 2. Criteria for the Diagnosis and Treatment of Dyslipidemia
1. Evaluation of laboratory lipid and diagnostic criteria
For the screening of dyslipidemia in persons ≥20 years old, testing of fasting serum
lipid levels (total cholesterol, triglycerides, HDL cholesterol, and LDL cholesterol)
is recommended every 4–6 years.10)
To acquire the triglyceride and LDL cholesterol levels among the lipid profiles, fasting
for at least 9–12 h before venous sampling is required. The subject should be relaxed
in the sitting position for at least 5 min before venous sampling, to avoid hemoconcentration
due to excessive movement. Collecting tubes without an anticoagulant is recommended
for serum samples, and EDTA tubes are recommended for plasma samples. When plasma
samples are used for analyses, the results are generally lower by approximately 3%
than those for serum samples.11)
Generally, the LDL cholesterol levels can be mathematically estimated, by using the
fasting levels of total cholesterol, triglycerides and HDL cholesterol. If the triglyceride
level is ≤400 mg/dL, it can be divided by 5 to estimate the level of very low density
lipoprotein (VLDL) cholesterol. As the total cholesterol is the sum of LDL cholesterol,
HDL cholesterol, and VLDL cholesterol, the value of LDL cholesterol concentration
can be calculated according to the following Friedewald formula: LDL cholesterol=Total
cholesterol–HDL cholesterol–Triglyceride/5 (unit of concentration for each item: mg/dL)
However, if a subject has a triglyceride level of >400 mg/dL, the mathematically estimated
level of LDL cholesterol with the formula suggested above will be significantly lower
than its actual value. Therefore, in this case, direct assay of LDL cholesterol levels
can be used. In addition, direct assay of LDL cholesterol should also be used in subjects
who had not fasted for at least 9 h.
A recent study, however, reported that the value of LDL cholesterol concentration
calculated by using the Friedewald formula is significantly lower than the results
obtained from direct assays,12) and this discrepancy should be accounted for in the
diagnosis and treatment of dyslipidemia. Therefore, clinicians should ensure to use
the same method to evaluate and longitudinally monitor the LDL cholesterol levels.
In addition, because variabilities in the accuracy of test results among different
manufacturers have been observed, this should also be accounted for when diagnosing
To establish the guidelines for the treatment of dyslipidemia, lipid levels should
be tested at least twice, at different time points. If there is a significant difference
between the results from the first and second tests, then a third test should be conducted
to decide the treatment goals according to the finally verified lipid level.11)
The criteria for the diagnosis of dyslipidemia according to KNHANES are shown in Table
The US NCEP criteria for lipid and lipoprotein levels can be used to evaluate the
performance of a clinical laboratory for testing of the blood lipid level that is
required for the diagnosis and treatment of dyslipidemia.14)
2. Treatment target
The ACC/AHA guidelines on the treatment of blood cholesterol were published in 2013,
after the revised ATP III guidelines were announced in 2004.4) Without the criteria
for LDL cholesterol goal, the 2013 ACC/AHA guidelines recommended to administer high-intensity
statins (expected to lower LDL cholesterol concentration by ≥50%) or moderate-intensity
statins (expected to lower LDL cholesterol concentration by about 30–50%), depending
on the risk levels. However, the degree of decrement in lipid levels per administration
intensity greatly varies among patients, and thus, administering moderate-or high-intensity
statins to all patients without certain therapeutic goals does not seem to be supported
by sufficient evidence. Considering the fact that the results from Asian studies were
not included in the establishment of the 2013 ACC/AHA guidelines, a study on the benefits
and adverse effects of high-intensity administration in Asia, including Korea, is
necessary. In addition, the 2013 ACC/AHA guidelines recommend the administration of
statins for primary prevention in patients with a 10-year risk of atherosclerotic
CVD (ASCVD) of ≥7.5%. However, this recommendation has been reported to overestimate
the risk of ASCVD in Europeans and Asians,15)
16) thereby making it not generally applicable to Asians. This has aroused the need
for the establishment of new criteria generally applicable to the Korean population.
However, owing to the insufficient data on cardiovascular risk from large-scale Korean
cohort studies, the criteria should be established on the basis of currently existing
Korean and international guidelines, and further be validated.
2) New Korean criteria for treatment
New Korean treatment guidelines, as in the previous Korean guidelines of treatment,
determines the presence of cardiovascular risk factors and maintains the same structure,
in which the goal of LDL cholesterol concentration is graded according to the risk
level. However, they were further modified and revised according to Korean and foreign
research results, as well as 2013 ACC/AHA guidelines (Table 2-2, 2-3, and 2-4).
(1) Very high risk
Patients with CVD (CAD, ischemic stroke, transient ischemic attack [TIA], or PAD)
are classified as very high risk, and targeting LDL cholesterol <70 mg/dL or reducing
≥50% of the baseline value is indicated for secondary prevention (class of recommendation
I, level of evidence A).
This recommendation is based on the results from multiple studies with subjects with
a recent history of angina,17) ischemic stroke, TIA,18) and peripheral vascular diseases,19)
in which the maximal preventive effect against CVD was seen when the level of LDL
cholesterol was lowered to <70 mg/dL or <50% of the baseline levels with statin therapy.
However, there is a need to conduct a nationwide study in the future, in order to
establish the Korean-specific goal of LDL cholesterol levels. In consideration of
previous Korean and global research results,20)
21) immediate statin therapy is recommended to be started in patients with AMI, regardless
of the baseline LDL cholesterol concentration (I, A).
(2) High risk
Although classified as high risk in the previous guideline, patients with a history
of CVD are separately classified as very high risk in the revised version of the guideline.
Meanwhile, patients with carotid artery disease (carotid artery stenosis >50%), abdominal
aneurysm, or diabetes, which are risk factors equivalent to CAD, are classified as
having a high risk, as in the previous treatment guidelines. Therefore, treatment
is recommended to be started for primary prevention if the LDL cholesterol level is
≥100 mg/dL (I, A). Some previous studies reported that carotid artery diseases result
in the increased risk for CVD,22) whereas studies on patients without CVD but with
carotid artery stenosis reported that the decrease in LDL cholesterol levels after
statin therapy helped reduce major cardiovascular events and mortality rates.23) Likewise,
the presence of an abdominal aortic aneurysm increases the cardiovascular mortality
by approximately 1.9%, even without accompanying CVD,24) and the administration of
statins resulted in a significant improvement in the size of the aortic aneurysm and
postoperative mortality in both the short term and the long term.25)
27) In addition, administration of statins in subjects with type 1 and type 2 diabetes
decreased the all-cause mortality and major cardiovascular risks.28)
30) Therefore, stains may be required for such high-risk patients.
(3) Intermediate risk
The classification of the intermediate-risk group in the new guidelines follows the
previous Korean treatment guidelines, in which moderate risk is defined as the presence
of two or more major risk factors (Table 2-4), except for the LDL cholesterol criteria.
Likewise, starting statin therapy should be considered in patients with LDL cholesterol
levels ≥130 mg/dL even after appropriate lifestyle modification for weeks and months
(II, B). Each component constituting major risk factors is established according to
the preexisting ATP-III guidelines and current Korean guidelines. Previous studies
showed that a nonsmoking status, hypertension, low HDL cholesterol, and a family history
of CVDs are associated with increased incidence of CVD.31)
34) Moreover, it was reported that increasing age leads to increased cardiovascular
risk; however, females show similar risks of CVD to those of males after 10–15 years.35)
However, it was reported that such major risk factors can predict only half of the
actual risk of CVD.11) Therefore, other risk factors such as obesity, physical activity,
dietary habits, triglycerides, high-sensitivity C-reactive protein, lipoprotein (a),
apolipoprotein, fibrinogen, homocysteine, apolipoprotein B, anklebrachial blood pressure
index, carotid intima-media thickness (clinically suspected progression even with
<50% stenosis or the presence of atherosclerotic plaques), and coronary calcium score
should be considered to establish an individualized therapeutic goal.11)
(4) Low risk
Patients with one or few major risk factors (Table 2-4), except for LDL cholesterol,
are classified in the low-risk category. For this group, it is reasonable to start
statins, as in the previous treatment guidelines, if the LDL cholesterol concentration
is ≥160 mg/dL even after modifying lifestyle for weeks or months (II, B).
Although the revised guidelines defined the LDL cholesterol goal as <160 mg/dL as
in the previous treatment guidelines, a more intensified treatment goal also is reasonable
for low-risk patients depending on the case, as other risk factors can be considered
other than the major risk factors in the intermediate-risk group, as mentioned above
In particular, if LDL cholesterol is ≥190 mg/dL, it is necessary to check if there
are other causes of dyslipidemia (biliary obstruction, nephrotic syndrome, hypothyroidism,
pregnancy, and history of taking medicines such as glucocorticoid and cyclosporine)
before any treatment.4) If LDL cholesterol is found to be ≥190 mg/dL without any secondary
causes, starting statin therapy is recommended regardless of risk levels, which also
complies with the 2004 ATP III revision9) and the 2013 ACC/AHA treatment guidelines
(5) Guidelines of treatment for hypertriglyceridemia
For the treatment guidelines for hypertriglyceridemia, if the blood triglyceride concentration
is elevated to ≥500 mg/dL, it is recommended to determine if there is any secondary
cause: weight gain, drinking, carbohydrate intake, chronic renal failure, diabetes,
hypothyroidism, pregnancy, estrogen therapy, history of taking medicines such as tamoxifen
or glucocorticoid, and/or genetic issues (I, A).4) In addition, if the blood triglyceride
concentration is elevated to ≥500 mg/dL, it is known that there is a risk of acute
pancreatitis.36) Therefore, if the triglyceride concentration is continuously found
to be ≥500 mg/dL even after the above-mentioned causes have been corrected, starting
medication with fibrate, nicotinic acid, or omega-3 fatty acid should be considered
(II, A), which also complies with the ATP III11) and the ESC/EAS guidelines.3)
If the triglyceride concentration is between 200 and 500 mg/dL, it is recommended
to prescribe statin therapy, as the first treatment, according to the calculated cardiovascular
risk level (I, A).
As the secondary goal, adjusting the non-HDL cholesterol level may be considered.
As previously mentioned, the treatment goal should be adjusted according to the criteria
in Table 2-3, by calculating the non-HDL cholesterol concentration (=Total cholesterol–HDL
cholesterol) (II, B). The target concentration of non-HDL cholesterol can be acquired
by adding 30 to the existing LDL cholesterol target. When the triglyceride (TG) level
is ≥200 mg/dL in a patient with hypertriglyceridemia even after lifestyle modifications
and statin therapy, it is reasonable to prescribe triglyceride lowering agents (e.g.,
fibrate, nicotinic acid and omega-3 fatty acid) in addition to statins for those patients
that belong to a very high-risk or high-risk group in order to prevent CVD (II, B);
however, there is a need for a future study on the usefulness of such combination
therapy because it is still a controversial issue.37)
In conclusion, although there would be many issues in applying the 2013 ACC/AHA guidelines
to Koreans, the goal of the revised treatment guidelines is to prevent delays in the
treatment by separating the very high-risk patient group and stratifying the criteria,
in consideration of the fact that statin should be started immediately for those with
CVDs or with the equivalent risk factors. Still, there will be a need for an additional
study on the domestic population, with respect to the statin dosage and LDL cholesterol
goal appropriate to Korea as well as hypertriglyceridemia control goal for primary
3. Monitoring of lipids and enzymes
In the revised guidelines, the recommendation levels consider both the existing domestic
guidelines and the global guidelines.3)
4) It is recommended to evaluate the response to treatment and the patient compliance
by conducting the lipid test before treatment, and to repeat the same test again in
6–12 weeks after starting medication, and then at intervals of 3–12 months depending
on the degree of lipid lowering and the patient's cardiovascular risk level (I, A).
Liver function test should be conducted before the initiation of statin therapy, and
then the follow-up test should be conducted together with the lipid test after statin
therapy. It is indicated that statin should be discontinued when the hepatic enzyme
levels are elevated to ≥3 times the normal levels (I, A). In addition, if a patient
complains of muscular pain and weakness, and if creatine kinase (CK) is ≥10 times
the normal level after taking statins, it is reasonable to stop the administration
owing to the diagnosis of myopathy (II, A).
In addition, as previous studies reported slight elevation of blood creatinine after
fibrate therapy, the domestic guidelines also suggest checking the creatinine level
before and after 1–3 months of fibrate therapy. If there is no further abnormal findings
afterwards, it is reasonable to perform follow-up on a regular basis (II, B).3)
Chapter 3. Lifestyle Modifications for Dyslipidemia
In the prevention and treatment of dyslipidemia, lifestyle modifications are very
important. To lower the risk levels of dyslipidemia, cessation of smoking is very
important, whereas improvement of eating and exercise habits is also important in
order to reduce the risk levels of dyslipidemia and for treatment purposes.
Obesity and weight gain are associated with the onset of dyslipidemia. Many studies
with obese or overweight subjects have reported that the levels of total cholesterol,
LDL cholesterol, and triglycerides in blood decreased after weight reduction.38) Therefore,
maintaining weight at the approximate level requires controlling the energy intake.3)
4) Generally, a body mass index (BMI) of ≥30 kg/m2 is classified as obesity. However,
there is an opinion in Korea that any BMI ≥25 kg/m2 should be classified as obesity.
Patients with obesity can improve their cholesterol and triglyceride levels by losing
weight by about 5–10%, despite failing to achieve a normal body weight. It is generally
known that a low-calorie diet with an energy intake reduced by about 500 kcal than
normal causes no special harm to a person's health and is easy to follow.
It has been traditionally recommended to limit fat intake for dyslipidemia treatment.
Indeed, some reports showed that reduced fat intake improves blood LDL cholesterol
level; however, in most cases these are compound reduction effects of losing weight,
both for reduced saturated fat and trans fat intake. In addition, it is difficult
to determine the effect of reducing the total fat intake. Moreover, fat limitation
relatively increases carbohydrate intake, and it is found that increasing carbohydrate
intake elevates the blood triglyceride level.39) However, a high fat intake may have
a negative impact on blood lipid levels by increasing the intake of saturated fat
and energy, and thus fat intake should be maintained at an appropriate level.
The ESC/EAS guidelines recommended not to increase fat intake in excess of 35% of
the total calories.3) The fat intake in Koreans is about 20% of the total calorie
intake. The Dietary Reference Intake for Koreans recommends that the appropriate fat
intake should be 15–25% of the total calories. Fat intake in Korea is lower than that
in Western countries40); however, there is a wide variation depending on each person,
with increasing fat intake in recent years. It is well known that the types of lipid
have more impact on blood lipid levels rather than the amount of total fat intake,
and it is necessary to ensure that fat intake does not exceed 30%.
Rather than limiting the amount of total fat intake, the influence of the type of
fatty acids on the blood lipid levels should be taken into account. It was found that
if saturated fatty acids were replaced with unsaturated fatty acids, the level of
blood LDL cholesterol can be lowered, and that there is a positive influence on the
levels of blood triglycerides and HDL cholesterol if trans fatty acids were replaced
with unsaturated fat.41) Therefore, for the treatment of dyslipidemia, there is a
need to limit the intake of saturated fatty acids and trans fatty acids. The ATP III
and ESC/EAS guidelines recommend limiting the intake of saturated fatty acids to <7%
of the total energy,3)
11) whereas the ATP III and 2013 ACC/AHA guidelines recommend minimizing the intake
of trans fatty acids.4)
11) Saturated fatty acids are mainly found in meat fat, poultry skin, butter, and
palm oil. The major sources of trans-fatty acids are hydrogenated oil, including margarine
and shortening, and high amounts of trans fatty acids are also contained in oils treated
for a long time at a high temperature.
Omega-3 fatty acids have no positive effect on blood cholesterol levels; however,
hypertriglyceridemia can be lowered if 2–4 g is taken daily.42)
Replacement of saturated fatty acids with polyunsaturated fatty acids is effective
in improving the blood cholesterol and triglyceride levels; however, it is recommended
to take <10% of the total energy in order to prevent lipid peroxidation of plasma
Cholesterol intake has less influence on the blood LDL cholesterol level, and there
are wide individual variations in both saturated fat and trans fat. However, it is
desirable to avoid excessive cholesterol intake. The ESC/EAS guidelines recommend
an intake of <300 mg daily.3)
Excessive carbohydrate intake, especially excessive monosaccharide intake, increases
the blood triglyceride level. Soluble dietary fiber is effective in improving blood
cholesterol and triglyceride levels.43) Therefore, it is recommended to reduce monosaccharide
intake and to consume mixed grains, marine algae, and vegetables that contain large
amounts of soluble dietary fiber.
ATP III recommends 10–25 g of soluble dietary fiber daily, whereas the ESC/EAS guidelines
recommend 5–15 g of soluble dietary fiber daily (25–40 g of the total dietary fiber).11)
Sufficient amount of food rich in dietary fiber should be taken so as to reach a fiber
intake of ≥25 g.
Excessive alcohol intake (≥10–30 g/day) should be avoided because it affects the blood
triglyceride level.44) Hypertriglyceridemia caused by alcohol intake is associated
with decreased activity of lipoprotein lipase, which results in the inhibition of
chylomicron catabolism. The ESC/EAS guidelines recommend that alcohol consumption
should be limited to 1–2 glasses/day (males: <20–30 g, females: <10–20 g), and even
to stop drinking especially in patients with hypertriglyceridemia.3)
5) Dietary pattern
More recently, there are many studies being conducted not on the respective nutrients
but on the relations between diet pattern and diseases. Eating habits are classified
according to the types food or their combination. In Western countries, there are
studies currently being conducted on the effects of eating habits such as the Dietary
Approaches to Stop Hypertension (DASH) diet and the Mediterranean diet on blood lipid
levels. On the basis of such studies, the 2013 ACC/AHA guidelines recommend applying
diet plans such as the DASH diet, US Department of Agriculture food pattern, and AHA
diet.4) In Korea, there are only a few studies on the relationship between dyslipidemia
and eating habits. However, it will be helpful to have a diet that includes a higher
portion of whole grains such as mixed grains, brown rice, and whole wheat, with foods
such as vegetable, beans, fish, fruit, and dairy products.45) On the basis of many
previous studies, it is helpful to sufficiently consume fruit and vegetables, in order
to prevent and treat dyslipidemia. However, carbohydrate accounts for a relatively
higher portion of the Korean diet with fruit consumed as dessert and eating between
meals rather than as a regular diet. Extra care should be paid because extra consumption
of fruit may increase the monosaccharide intake. The ESC/EAS guidelines recommend
taking about 200 g of fruits daily.3)
Table 3-1 shows how to select foods appropriately.
< Examples of rough estimates per fruit type, equivalent to 200 g >
1 small apple, 2 tangerines, 1 orange, 1 small oriental melon, 1 tomato, 2 kiwis,
or 1 persimmon
*1. Please use this only as reference because the actual size of the fruit may vary
according to the subjective point of view.
2. Consider as medium size any fruit whose size is not indicated herein.
1) Exercise and its effects on lipid metabolism
Whether or not regular exercise leads to any changes in blood lipid levels is controversial
because various results have been reported depending not only on the subjects' sex,
age, race, and lipid concentration but also on the type, amount, intensity, duration,
and frequency of exercise, as well as on whether lifestyle and body weight changed
with regular exercise habits.46) Moreover, regular exercise does not have a great
impact on lipid levels. Exercise is classified as either aerobic exercise or anaerobic
exercise. It was reported that there are some differences in the change of cholesterol
level according to exercise types.
Aerobic exercises increase physical oxygen consumption; these exercises include walking
at a rapid pace, jogging, swimming, and bicycling that can be maintained for ≥30 min,
enhancing cardiovascular endurance. Meanwhile, anaerobic exercises include short-distance
running, push-ups, throwing, and jumping within 10 s, which are good for strengthening
muscles by using instant power.
In general, aerobic exercises help reduce triglycerides and increase HDL cholesterol
level, with minor changes in LDL cholesterol.47)
48) Exercise therapy undoubtedly prevents CVD; however, such effects are not very
clearly observed. The goal of controlling lipid metabolism is to prevent CVD, and
exercise therapy is important for a patient with dyslipidemia.46)
The effects of anaerobic exercises on lipids is more controversial.50)
51) For other CVDs, their effect of controlling risk factors are lower than those
of aerobic exercises. However, anaerobic exercises increase muscle mass and muscle
strength, increasing physical activities and improving daily performance especially
for older persons.46)
Healthy adults may start aerobic exercises with moderate or less intensity, whereas
elderly persons or those with multiple risk factors or CVD need medical consultation
before starting exercise, and are subjected to a cardiovascular stress test by using
a treadmill or a bicycle, if needed.46) Medical assessment is required before a patient
starts performing anaerobic exercises. Therefore, not only exercises but also increasing
physical activities are recommended because these are both associated with the prevention
2) Exercise prescription
There are no special exercise prescriptions for controlling dyslipidemia; however,
the same methods are used to prevent CVD.46)
The types of recommended aerobic exercises include walking at a quick pace, jogging,
swimming, or bicycling. The appropriate frequency is 4–6 days/week, whereas the intensity
is 55–75% of the maximum heart rate (=220–age). However, the target heart rate should
not be applied to a patient with CVD who is taking a β-blocker or nondihydropyridine
calcium-channel blockers. When the intensity of the exercise starts to feel "moderate,"
it is good to intensify the exercise and maintain it at the level of "a little tough".
Warm-ups should start with light stretching and walking for 5–10 min, followed by
30–60 min of aerobic exercises as the main workout. It is possible not only to do
continuous exercises but also to do them in 10-min sets. Then, complete it with some
light walking and stretching for 5–10 min. Table 3-2 summarizes the exercise therapy
for patients with dyslipidemia.
Chapter 4. Pharmacological Therapy for Dyslipidemia
1. Selection of drugs
It is important to combine lifestyle modification together with medication. Lifestyle
modification includes diet therapy, exercise therapy, or abstaining from smoking.
To determine whether to start drug therapy, a comprehensive consideration should be
given to both the risk level of CVD and the LDL cholesterol levels. The risk level
for CVD should be classified as one of the following: low, intermediate, high, or
The treatment with drugs can be initiated according to whether the patients have CAD,
PAD, ischemic cerebral infarction, atherosclerotic artery disease (aortic aneurysm,
TIA, severe carotid artery stenosis), or diabetes, as well as on the number of CAD
risk factors (smoking, hypertension, low HDL cholesterol level, family history of
premature CAD, and age).
Statin is the first-choice drug for the treatment of hypercholesterolemia. The dosage
is recommended to be adjusted to reach the target LDL cholesterol level according
to the cardiovascular risk level (class of recommendation I, level of evidence A).3)
The first goal for drug therapy is to lower the LDL cholesterol to the target level
or below (I, A), whereas the secondary goal is to lower the non-HDL cholesterol to
target level or below (IIa, B).11)
Secondary causes of hypercholesterolemia should be considered and corrected before
starting any medication (Table 4-1).
1) Low density lipoprotein cholesterol
Very high-risk group: This group includes patients with CAD, PAD, and/or ischemic
stroke. The goal is to reduce LDL cholesterol concentration to <70 mg/dL or to reduce
it by ≥50% than the baseline value (I, A). Statin treatment can be considered regardless
of the baseline LDL cholesterol level.3)
4) There are some reports on additional beneficial effects on clinical prognosis for
patients with acute coronary syndrome (ACS), when LDL cholesterol is lowered down
to 54 mg/dL.
For patients with AMI, statins is indicated to be administered immediately regardless
of the baseline LDL cholesterol concentration (I, A).20)
High-risk group: This group includes patients with atherosclerotic artery disease
(aortic aneurysm, TIA, or carotid artery stenosis >50%) or diabetes. If the LDL cholesterol
is ≥100 mg/dL, statin medication should be started (I, A), and can be considered in
selected patients whose LDL cholesterol level is <100 mg/dL.28)
Intermediate-risk group: This group includes patients with two or more cardiovascular
risk factors (smoking, hypertension, low HDL cholesterol, and family history of premature
CAD). Starting statin medication should be considered if the LDL cholesterol level
is ≥130 mg/dL (IIa, B). It can also be initiated in patients with multiple risk factors
when their LDL cholesterol level is 100–129 mg/dL.
Low-risk group: This group includes patients with one or few cardiovascular risk factors
(smoking, hypertension, low HDL cholesterol, and family history of premature CAD).
If the LDL cholesterol level is ≥160 mg/dL, statin medication should be considered
If the triglyceride concentration is high, it is recommended to first determine whether
there are other factors increasing triglycerides and then to establish the treatment
plan by evaluating the cardiovascular risk level (Table 4-1).
As about 10% of acute pancreatitis is known to be caused by hypertriglyceridemia,
it is important to modify lifestyle and medication should be started immediately to
prevention acute pancreatitis, when the triglyceride concentration is ≥500 mg/dL (I,
A). Lifestyle modification with a low-fat diet (reduced to 10–15% of the caloric intake)
and cessation of drinking are required. Combined with lifestyle modification, medication
should be started first by using fibric acid derivatives (I, B), nicotinic acid (IIa,
B), or omega-3 fatty acids (IIa, B), which mainly lower triglycerides. For a diabetic
patient, it will be helpful to strictly control blood glucose by using insulin, whereas
apheresis can be helpful if there is a need to achieve rapid reduction.54)
When the triglyceride level is between 200 and 499 mg/dL, the first treatment goal
is to lower the LDL cholesterol to the target level based on the calculated cardiovascular
risk level (I, A). Therapeutic lifestyle modification and statin medication can be
considered to achieve the goal. After achieving the LDL cholesterol goal, when triglycerides
are still ≥200 mg/dL, it is reasonable to use triglyceride-lowering agents especially
for the high-risk and very high-risk groups (IIa, B). Fibric acid derivatives (I,
B), nicotinic acid (IIa, B), and omega-3 fatty acids (IIa, B) are used to control
57) When the triglyceride level fails to reach the target level with a single agent,
combination therapy should also be considered (IIa, C).
(1) Treatment goal
(4) Low HDL cholesterolemia
2. Characteristics of lipid-lowering agents
1) Statins: 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors
Statins are first recommended for the treatment of dyslipidemia among currently available
drugs because it has a relatively low risk profile and proven effects of decreasing
CVD by lowering LDL cholesterol.58)
(1) Action mechanism
All types of statins reduce cholesterol synthesis by competitively inhibiting 3-hydroxy-3-methylglutaryl
coenzyme A reductase, which is a cholesterol precursor.59) In hypercholesterolemia,
to maintain homeostasis in the cellular level, the expression of LDL receptors should
increase and the synthesis of cholesteryl ester should decrease.
As a result, more blood LDL cholesterol is removed and production of VLDL cholesterol
decreases in the liver, resulting in the decrease of LDL cholesterol. Statins not
only block such synthesis but also inhibit the synthesis of lipid intermediates, which
have important biological effects. Metabolites such as geranylgeranyl pyrophosphate
and farnesyl pyrophosphate prenylate proteins. Through this process, the molecules
are attached to the cell membrane, enhancing their biological activities. The geranylgeranylation
of Rho A and the inhibition of phosphorylation of peroxisome proliferator-activated
receptor alpha, which regulates the transcription of apo A1, are considered as the
mechanisms of how statin raises the HDL cholesterol level. Alteration of protein prenylation
seems to mediate some effects of statins other than their LDL cholesterol-lowering
(2) Types of statin
The currently available statins include lovastatin, pravastatin, simvastatin, fluvastatin,
atorvastatin, rosuvastatin and pitavastatin.
(3) Effects on lipid level
Each statin is different in terms of absorption, blood protein binding, excretion,
and solubility, with variable LDL cholesterol-lowering effects per dosage (Table 4-2).60)
63)) When the statin dosage is doubled, the LDL cholesterol level additionally decreases
by 6% in general. In addition, when statins are used in patients with hypertriglyceridemia,
the triglyceride level also decreases by 22–45% because the VLDL cholesterol secretion
in the liver is inhibited. HDL cholesterol slightly decreases by 5–10%. Many studies
on Koreans have been reported concerning the lipid-lowering effect of each statin.
Some domestic studies reported the tendency of higher LDL cholesterol-lowering effects
with the same dosage in Koreans compared with Western people (Table 4-3, Fig. 4-1).64)
(4) Cardiovascular diseases prevention research and indications
①Secondary prevention effect of cardiovascular disease: It is widely known that patients
with CVD (angina, ACS, AMI, stroke, or TIA) have increasing risks of cardiovascular
events or death.17)
19) For such patients, it is recommended to use statins because these drugs prevent
the recurrence of cardiovascular events (I, A). The goal for these patients, classified
as the very high-risk group, is to reduce LDL cholesterol to <70 mg/dL or ≥50% of
the baseline level for secondary prevention.
In case of AMI, statins are indicated to be prescribed immediately regardless of the
baseline LDL cholesterol level (I, A).20)
Although there are not many large-scale studies in Asians,65) there is a report on
better preventive outcomes in patients ≤75 years old with CVD when they took statins
to reduce LDL cholesterol by ≥30–50% from baseline levels. Therefore, it is reasonable
to use moderate-dose/moderate-intensity or high-dose/high-intensity statin that can
reduce the LDL cholesterol level by ≥30–50% from the baseline levels (IIa, A).
For patients aged >75 years with cardiovascular diseases, it is reasonable to start
statin after considering comorbidities and possible drug-drug interactions (IIa, B).66)
②Primary prevention of cardiovascular disease in the general population: Adults with
a blood LDL cholesterol level of ≥190 mg/dL have an increased possibility of having
CVD during their lifetime. Therefore, statins should be prescribed if the blood LDL
cholesterol concentration is ≥190 mg/dL even after lifestyle modification (I, A).3)
For an adult with a blood LDL cholesterol level of 160–190 mg/dL, it is reasonable
to use statin if the blood LDL cholesterol is ≥160 mg/dL even after lifestyle modification
for 4–8 weeks (IIa, B).
Meanwhile, for an adult with a blood LDL cholesterol of 130–160 mg/dL, lifestyle should
be properly modified, and then it may be decided whether to start statins in consideration
of cardiovascular risk level (IIb, C).
③Primary prevention in patients with diabetes: For the high-risk group, such as patients
with diabetes, carotid artery disease (stenosis >50%), or aortic aneurysm, if the
LDL cholesterol is ≥100 mg/dL, statin should be started (I, A).28)
④Patients with heart failure or undergoing dialysis: For patients with heart failure
or undergoing dialysis, statin is not indicated owing to the lack of evidence for
a preventive effect (III, B).67)
(5) Dosage and administration
Lovastatin: 20–80 mg/day, recommended to be administered with dinner
Pravastatin: 10–40 mg/day, more effective to be administered in the evening
Simvastatin: 20–40 mg/day, more effective to be administered in the evening
Fluvastatin: 20–80 mg/day, more effective to be administered in the evening
Atorvastatin: 10–80 mg/day, less influenced by the time of medication
Rosuvastatin: 5–20 mg/day, less influenced by the time of medication
Pitavastatin: 1–4 mg/day, less influenced by the time of medication
Pitavastatin: 1–4 mg/day, less influenced by the time of medication
(6) Follow-up test before/after statin medication
①Blood test before statin treatment: Before starting any statin treatment, the transaminase
(aspartate transaminase [AST] and alanine transaminase [ALT]) concentrations should
be measured (I, B). If the ALT concentration is ≥3 times than the normal range before
medication, it is reasonable to first evaluate and treat liver diseases instead of
immediately starting statins, and then to proceed with the statin medication after
the liver function has normalized (IIa, C). If the baseline muscle enzyme (CK) is
≥3 times than the normal range, it is reasonable to identify the causes before starting
any statin (IIa, C).
②Follow-up test after statin treatment: After the initiation of statin treatment,
the cholesterol, triglyceride, and HDL cholesterol levels should be evaluated after
4–12 weeks (I, B). If LDL cholesterol is ≤40 mg/dL after two consecutive measurements,
the statin dose may be reduced (IIb, C). Evaluation of liver function should be considered
at 4–12 weeks after treatment. Thereafter, it is reasonable to repeat the test every
3–12 months to check the efficacy and hepatotoxicity of statins (IIa, C). Regular
tests for muscle enzyme are not indicated (III, A).
(7) Adverse effect
The most common adverse effects that occur in about 4% of statin-treated patients
include gastrointestinal disorder, heartburn, and stomachache; moreover, rare and
fatal adverse events such as hepatotoxicity and muscle toxicity can also occur.58)
In patients >75 years old, as well as in patients who are taking multiple drugs or
taking drugs with same metabolic pathway as statins, or those with conditions that
require complex medication (e.g., heart transplant or AIDS), statin should be considered
in low dosage (IIa, C).
①Hepatotoxicity: If there is a slight increase in transaminase, there is no need to
stop statin. Statins should be stopped when liver enzymes are elevated by ≥3 times
the normal range. Restarting statins may be considered from a low dose after the normalization
of liver enzymes (IIb, C). If there are any symptoms suggesting liver damage, such
as fatigue, appetite decrease, stomachache, dark-colored urine, and jaundice, during
statin treatment, it should be considered to immediately perform a liver function
test including AST/ALT measurement (IIa, C).
②Muscle toxicity: The most common adverse effect during statin medication is muscle
pain. About 10% of patients taking statins are reported to have muscle pain and, consequently,
to stop taking statins. Many patients discontinue statin use because of muscle pain
or weakness. However, it is not clear whether these symptoms are caused by statins.
The frequency of muscle damage due to statin is known to be higher by 0.01% in patients
who are taking statins than that in a control group.
The elevation of muscle enzyme due to muscle damage, resulting in rhabdomyolysis,
hemoglobinuria, and acute renal failure, is known to occur in only a very small portion
of patients. Muscle damage after statin treatment occurs more often in patients with
multiple comorbid diseases or those with the concomitant use of cyclosporine, fibrate
derivatives, macrolide antibiotics, or several antifungal drugs. Taking fibrate derivatives
such as gemfibrozil with statin increases the risk of muscle damage, whereas fenofibrate
is known to have a relatively low risk. The measurement of muscle enzyme in asymptomatic
patients on a regular basis is not recommended (III, A). However, if there is muscle
pain, weakness, or general fatigue, it is reasonable to measure the muscle enzymes
to check if there is any muscle damage (IIa, C).
③Diabetes: Recently, some studies reported that statins increase the incidence of
diabetes.70) In most cases, new-onset diabetes was diagnosed in persons with glucose
intolerance before taking statins or in those who are taking high-dose statins. Therefore,
measurement of the fasting blood glucose before taking statins is recommended (I,
B). Even when diabetes occurs after statin use, it is recommended to continue taking
statins in order to prevent CVD, in addition to lifestyle modifications such as regular
exercise, weight control, and smoking cessation (I, B).
④Cognitive impairment: There is a report on the deterioration of cognitive function
in patients taking statins. However, the adverse effects of concomitant neuropsychological
drugs may be considered first, rather than those of statins (IIb, C).71)
Statins are absolutely contraindicated for pregnant or lactating women and for patients
with active or chronic liver disease. Statins are relatively contraindicated for patients
taking cyclosporine, macrolide antibiotics, antifungal drugs, and cytochrome P-450
2) Fibric acid derivatives
Fibric acid derivatives are recommended in patients with hypertriglyceridemia (I,
B), and reasonable to combine with statins in patients with mixed dyslipidemia in
whom both LDL cholesterol and triglycerides are increased (IIa, A).73)
74) In addition, there are a number evidences showing that fibric acid derivatives
reduce cardiovascular risk if prescribed to patients with high triglycerides and with
low HDL cholesterol. However, it is not recommended as the first-line treatment in
case of only a high LDL cholesterol level.
(2) Dosage and administration
Bezafibrate: 400–600 mg/day, 1–3 times a day, after meals
Fenofibrate: 160–200 mg/day, once a day, immediately after a meal
Gemfibrozil: 600–1200 mg/day, twice a day, 30 min before meals
(3) Follow-up test before and after treatment
The baseline lipid profile, liver function, renal function, and muscle enzymes (if
there is unexplainable muscular pain or muscle weakness) should be checked.3)
(4) Adverse effect
The most common adverse effect is gastrointestinal disorder, and there may be increases
in the prevalence of cholesterol gallstones. Myopathy may occur, but with a low frequency.
If renal function is impaired, blood drug concentration increases, with higher risks
of adverse events. In particular, when gemfibrozil is prescribed together with statins,
the risk of myopathy increases, whereas fenofibrate is preferred in combination with
statins owing to the low risk of myopathy. Fibric acid derivatives bind with albumin,
thereby increasing the blood level of warfarin, with subsequent increase in bleeding
tendency; moreover, fibric acid derivatives may increase the effect of hypoglycemic
agents. Fibric acid derivatives increase blood creatinine concentration but do not
cause renal failure.
Fibric acid derivatives are absolutely contraindicated for patients with severe liver
disorder, gall bladder disease, hypersensitivity reaction to fibric acid derivatives,
and renal dysfunction.
3) Nicotinic acid (niacin)
Niacin can be used for all types of dyslipidemia. For hypertriglyceridemia, it should
be considered as the first-line medication (IIa, B), whereas nicotinic acid is effective
for patients with low HDL cholesterol (IIa, A).76) For patients with high LDL cholesterol
or mixed-type dyslipidemia, it may be considered to use nicotinic acid in combination
with statins, if not treated with statin therapy alone; however, care should be taken
because of the risk of increasing the adverse effects, including liver function disorder,
myopathy, and increasing the incidence of diabetes (IIb, A).
(2) Dosage and administration
Regular-release nicotinic acid: Divide 1.5–3 g into three times a day and take with
a meal or after meals
Sustained-release nicotinic acid: Not used owing to hepatotoxic effects
Extended-release nicotinic acid: Take 1–2 g once a day before going to bed
(3) Follow-up test
The baseline lipid profile, liver-function, and uric acid should be checked
(4) Adverse effects
Skin flushing is a common adverse effect, which can be very severe in some patients.
Skin flushing could be reduced with long-term continuation of medication, and the
adverse effects could be reduced with the administration of the drug with a meal or
by taking aspirin. Gastrointestinal disorder is frequently observed. Other important
adverse effects include hepatotoxicity, gout, and elevation of blood glucose levels,
in proportion with dosage and the duration of therapy. The risk of hepatotoxicity
increases with sustained-release nicotinic acid, and cases of fulminant hepatic failure
have been reported. The frequency of facial flushing is known to be reduced with the
use of recently developed drugs.
Nicotinic acid is absolutely contraindicated for patients with chronic liver disease
or severe gout. Nicotinic acid is relatively contraindicated for patients with diabetes,
hyperuricemia, and peptic ulcer.
If the LDL cholesterol target level has not been reached with statin, ezetimibe should
be considered in combination (IIa, B).68)
(2) Dosage and administration
Take 10 mg of the drug once.
(3) Follow-up test
Lipid profile should be tested every 3-6 months.
(4) Adverse effects
The common adverse effects include stomachache, diarrhea, flatulence, and gastrointestinal
symptoms, whereas the relatively uncommon adverse effects include indigestion, gastroesophageal
reflux, appetite decrease, arthralgia, muscle spasm, and chest pain. Increases in
transaminase, γ-glutamyltransferase, and muscle enzymes have been reported.
This drug is not recommended if there is a hypersensitivity reaction (III, C). For
pregnant and lactating women, it is not recommended to use this drug owing to safety
issues (III, C). It is also not indicated for use in patients with acute liver disease
or those with moderate or severe chronic liver dysfunction (III, C).
5) Omega-3 fatty acids
Omega-3 fatty acid alone should be considered for hypertriglyceridemia (IIa, B), or
is reasonable to use for complex-type hyperlipidemia in combination with statin (IIa,
(2) Dosage and administration
Take 2–4 g once or twice a day.
(3) Follow-up test
Blood lipid profile and liver-function test should be conducted at every 3–6 months.
(4) Adverse effects
Some of the reported adverse effects include hemorrhagic stroke, elevation of blood
sugar levels, immunosuppressive effect, and dyslipidemia. Moreover, there are reports
on gastrointestinal symptoms such as nausea, vomiting, burping, and burping with a
fishy smell or taste, as well as on liver enzyme elevation, headache, itching, or
There are no absolute contraindications for this drug, except for a hypersensitivity
reaction. This drug belongs to pregnancy category C, and omega-3 fatty acids should
be considered only if there are great benefits of using the drug (II, C). An animal
study reported on fatal outcomes with excessive administration. There are no well-established
safety issues yet concerning use on humans during pregnancy. It is also not known
if this drug is secreted in breast milk.
Chapter 5. Dyslipidemia in Different Clinical Settings
1. Stroke (cerebrovascular diseases)
Dyslipidemia is one of the important risk factors of CVD; however, there is no clear
association between dyslipidemia and stroke in general. Although stroke considerably
contributes to the pathological mechanism of CVD, the association with dyslipidemia
is not clear because of the various subtypes of cerebrovascular disease. Many cohort
studies reported that low cholesterol levels are associated with the incidence and
mortality rate of cerebral hemorrhage. Therefore, a more careful approach is needed
in Korea, where the incidence and mortality rate of cerebral hemorrhage is relatively
higher than those in Western countries. However, dyslipidemia is an important risk
factor in cerebral infarction, especially in atherosclerotic cerebral infarction,
and many clinical studies revealed that the risk of stroke could be decreased through
1) Primary prevention
Statin therapy in adults with CVD or in those with a high risk for CVD is effective
for the primary prevention of cerebral infarction.80) The effects of other lipid-lowering
agents on the primary prevention of stroke are still uncertain.
2) Secondary prevention
Stroke patients have increased risk not only of recurrent stroke events but also of
the development of CVDs such as myocardial infarction. The subtype of stroke plays
an important role in statin therapy for the secondary prevention of stroke. Statin
therapy is the most effective treatment for atherosclerotic cerebral infarction; however
it might be harmful in those with cerebral hemorrhage.
If there are CVDs or equivalent risk factors (carotid artery disease, PAD, abdominal
aneurysm, diabetes, etc.), statins should be used for the primary prevention of stroke.
The LDL cholesterol target level can be determined according to general recommendations.
High-intensity statin therapy is recommended to prevent the recurrence of stroke in
patients with atherosclerotic cerebral infarction or TIA and in those with an LDL
cholesterol level of ≥100 mg/dL.18)
Even if the LDL cholesterol is <100 mg/dL without atherosclerotic cerebrovascular
diseases, statin therapy is strongly recommended to improve dyslipidemia in patients
with atherosclerotic cerebral infarction or TIA.
There are no sufficient data on the effects of other lipid-lowering agents on the
secondary prevention of stroke.
2. Chronic kidney diseases
1) Approach to dyslipidemia in patients with chronic kidney disease
It is evident that the CVD risk is increased in all patients with chronic kidney disease
(CKD) regardless of the severity of renal dysfunction.82) However, there are insufficient
studies on the usefulness of measuring lipid concentration, how to select the patients
for treatment, and its effects.
It is less useful to measure the lipid concentration in evaluating the cardiovascular
risk in patients with CKD. In general, higher LDL cholesterol is associated with a
higher risk for CVD even in patients with CKD; however, in patients with advanced
CKD, who are at a very high risk for CVD, the LDL cholesterol level could be rather
low owing to coexisting inflammation or malnutrition. Therefore, there are limitations
in determining whether to start treatment on the basis of the LDL cholesterol level.
For an adult with a newly diagnosed CKD (including those with dialysis and transplantation),
lipid profiling should be conducted, including total cholesterol, HDL cholesterol,
triglycerides, and LDL cholesterol, whereas the follow-up test timing, interval, and
method should be determined according to the patient's status.
2) Cholesterol-lowering medication in patients with chronic kidney disease
CKD is considered to have an equivalent risk to CAD, and LDL reduction is the primary
target of therapy.3)
As subgroup analyses of large clinical studies reported a preventive effect,83)
85) statin monotherapy or statin/ezetimibe combination therapy is recommended in patients
with CKD who are not currently subject to chronic dialysis therapy or those without
As there was no preventive effect reported in patients with CKD requiring chronic
87) statin or statin/ezetimibe combination therapy should not be newly started in
If patients with CKD requiring chronic dialysis therapy already have received statin
or statin/ezetimibe combination therapy at the time of starting dialysis, such treatment
can be maintained because a significant beneficial effect was observed in study subjects
who did not receive dialysis therapy at the time of research enrollment but started
dialysis during the research period, from a subgroup analysis of a large-scale study.85)
There is insufficient data about the safety of high-dose statin therapy in patients
with CKD and a glomerular filtration rate of <60 mL/min/1.73 m2. It is recommended
to treat with the same dosage as that used in clinical studies, as these patients
are at a high risk for potential adverse effects. As decrease in LDL cholesterol and
better clinical outcomes were observed in some Asian studies even with relatively
lower dosage, lower-dose treatment should be considered.
3) Triglyceride-lowering medication in patients with chronic kidney disease
To improve hypertriglyceridemia in adults with CKD, including patients requiring chronic
dialysis therapy and those who had undergone renal transplantation, therapeutic lifestyle
modification is recommended. It was reported that fibric acid treatment is associated
with an increase in serum creatinine level, related hospitalizations, and nephrologist
consultations.88) On the basis of those evidences, it is not currently recommended
to use fibric acid in patients with CKD for the purpose of lowering cardiovascular
In reality, there is no consistent answer yet with respect to the effects of statin
in patients with CKD. Such controversy is directly due to the shortage of high-quality
large-scale studies in patients with CKD. Since the mid-2000s, several large-scale
research results have been announced, based on which the guidelines on dyslipidemia
in patients with CKD were published in 2013 by the Kidney Disease: Improving Global
Patients with type 2 diabetes have a 2–3-fold increased risk for cardiovascular mortality
than those without diabetes. Therefore, dyslipidemia should be aggressively treated
in patients with type 2 diabetes.90)
91) The typical pattern of diabetic dyslipidemia is hypertriglyceridemia and reduced
HDL cholesterol levels. In addition, even though LDL cholesterol level is not elevated,
it is more susceptible to atherosclerosis with more small dense LDL particles. Therefore,
it is recommended to measure the blood lipid profile in patients with diabetes at
the time of the first diagnosis and annually thereafter. Besides lipid profile (total
cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides), it is helpful to
evaluate diabetic dyslipidemia by measuring the non-HDL cholesterol or apo B level.
The representative study on whether to use statins for primary prevention in patients
with type 2 diabetes is Collaborative Atorvastatin Diabetes Study.92) As a result
of administering 10 mg atorvastatin to patients with type 2 diabetes aged 40–75 years
and with one or more cardiovascular risk factors, the average LDL cholesterol was
72 mg/dL, which was reduced by 39% compared with the baseline, whereas the risk of
CVD was reduced by 37%. The meta-analysis also reported that statins decreased CVD
by up to 20% in patients with type 2 diabetes when LDL cholesterol was reduced by
1 mmol/L (38 mg/dL), regardless of the baseline LDL cholesterol level.30)
In patients with type 2 diabetes, the first priority of dyslipidemia treatment is
to lower LDL cholesterol to <100 mg/dL. In addition, it is recommended to maintain
HDL cholesterol at ≥40 mg/dL in men and at ≥50 mg/dL in women, and triglycerides at
This guideline for the management of dyslipidemia classifies patients with CVD as
very high-risk patients regardless of diabetes, and recommends more aggressive treatments
to control LDL cholesterol. For patients with diabetes without CVD, it is recommended
to lower LDL cholesterol to <100 mg/dL.
Patients with diabetes and dyslipidemia should be educated about intensive lifestyle
Statins are recommended first, not only for secondary prevention but also for the
primary prevention of CVD in patients with type 2 diabetes.
There is a lack of evidence on the effect of dyslipidemia medications other than statins
(omega-3 fatty acids and niacin), owing to insufficient data, especially in domestic
4. The elderly
The prevalence and mortality of CVD are expected to continuously increase because
of the increase in the population of elderly persons, especially the very elderly.
In particular, the prevalence of dyslipidemia increases in the elderly, who are a
high-risk group for CAD, and for whom lipid-lowering therapy will provide many benefits.
The 2013 ACC/AHA guidelines recommend using statins continuously if a person >75 years
old has already used it without adverse effects. Use of moderate-intensity statin
is recommended, but for secondary prevention. High-intensity statin therapy might
not be applicable to the elderly, owing to limited data.4) Statin therapy for primary
prevention among the elderly should be determined after considering the comorbidities,
safety issues, and priorities of care.
Meanwhile, the ESC/EAS guidelines recommended using statins for the young and the
elderly because there was no difference in risk reduction both for primary and secondary
prevention. It also recommended to exercise care concerning drug interactions and
the adverse effects of statins, because many patients have concomitant diseases or
take multiple other drugs.3)
1) Primary prevention
Statins can be beneficial for primary prevention in the elderly people because it
was reported to significantly reduce the incidence of CVD and the cardiovascular mortality.66)
2) Secondary prevention
Statin therapy is known to be useful in elderly patients with CVD, with fewer adverse
effects than those in young adults.93) The use of statins in elderly patients is considered
to be cost-effective.
3) Safety and drug interaction
For elderly patients, the risk of adverse drug reactions caused by statin should be
considered. No significant increase in adverse drug reactions has been reported in
elderly patients, including rhabdomyolysis and elevated hepatic enzymes; thus, statin
can be used safely also in elderly patients.
Statin tends to be less used in elderly patients who require statin therapy owing
to concerns about safety and efficacy issues. There are many studies supporting the
effect of statins on the primary and second prevention of CVD in the elderly. In particular,
the cost-effectiveness of statin therapy is more prominent in elderly patients as
they have a higher risk of CVD than young adults.
There are insufficient data on the usefulness and safety issues in the very elderly
(≥80 years old), and on whether aggressive lipid-lowering therapy with high-dose statins
is helpful in the elderly.
5. Children and adolescents
The definitions of dyslipidemia in children and adolescents are showed in Table 5-1.
2) Blood lipid screening test
If a blood lipid screening test is conducted in children who have a history of premature
CAD or dyslipidemia, it will lead to missing 30–60% of children with dyslipidemia.
Therefore, the blood lipid profile should be routinely screened even when there is
no clinical or family history.
As total cholesterol and LDL cholesterol decrease by 10–20% during adolescence, the
blood lipid profile should be screened routinely in children aged 9–11 years. Non-HDL
cholesterol is used for screening the blood lipid profile in children and adolescents.
If children or adolescents have a family history of premature CAD or cardiovascular
risk factors, they are considered to have a high risk of developing dyslipidemia,
and their blood lipid profile should be screened, as shown in Table 5-2.
3) Treatment of dyslipidemia
Dyslipidemia treatments consist of nonpharmacological and pharmacological therapy,
with the priority placed on aggressive nonpharmacological therapy and lifestyle modification.
Lifestyle modifications include diet therapy, smoking cessation, and exercise; moreover,
education should be aggressively provided to children and their family.
For step 1 (diet therapy), fat should be maintained at about 30% of the total calorie
for normal growth and development, whereas the saturated fat intake should be limited
to <10% and the total cholesterol intake should be limited to <300 mg (CHILD1 diet).
If the goal is not reached, step 2 diet therapy (saturated fat intake <7%, total cholesterol
intake <200 mg daily, trans fat intake <1%, unsaturated fat intake of about 10%) should
be conducted (CHILD2-LDL diet).
If the triglycerides increase, monosaccharide intake should be reduced and weight
should be reduced. CHILD2-TG diet therapy should be conducted.
(2) Lifestyle modifications
It is recommended to perform exercises with an appropriate intensity on a regular
basis, to maintain the proper BMI, as well as to quit smoking with the establishment
of an environment for smoking prevention.
(3) Pharmacological therapy96)
If lifestyle modification has been tried for at least 6 months but failed in children
and adolescents with dyslipidemia, it is possible to consider medication after evaluating
the LDL cholesterol level and the cardiovascular risk level. The fasting blood lipid
profile is tested at least twice or at 2 weeks to 3 months interval, to evaluate the
need for medication. Medication can be started in children aged 10 years or older
in general, except for special cases. The LDL cholesterol goal is at least ≤130 mg/dL
in children and adolescents.
Medication should be started under the following conditions:
①If LDL cholesterol is ≥190 mg/dL in children aged 10 years or older who conducted
lifestyle modification for >6 months;
②If LDL cholesterol is 160-189 mg/dL in children aged 10 years or older who conducted
lifestyle modification for >6 months and have a risk for CVD (if there is a family
history of premature CAD, or at least two or more risk factors of CVD).
If the LDL cholesterol is 130-190 mg/dL in children ≥10 years old and not at a risk
for CVD, lifestyle modification and controlling BMI under the 85th percentile are
For medication, adverse effects should be evaluated on a regular basis. The safety
issue about long-term statin therapy in children and adolescents has not been well
Medication may be considered according to the level of LDL cholesterol, presence of
CVD risk factors or family history of premature CAD. Medication may be started with
statins or fibrate in patients with the TG level >500mg/dL (Fig. 5-1).
6. Familial hypercholesterolemia
The incidence of heterozygous familial hypercholesterolemia (FH) is reported to be
1 per 500 people in Western studies. The most common cause is a mutation of LDL receptor
genes, rarely caused by apo B or PCSK9 gene mutation. The LDL cholesterol level is
about 200–400 mg/dL in adulthood, whereas the triglyceride level is usually normal,
or elevated in some cases. If not treated, half of the male patients and 15% of the
female patients might die at the age of about 60 years; however, there is no difference
in life expectancy with early treatment.3)
FH should be suspected in a patient with a family history of premature CAD in <50
year-old males or in f<60 year-old female or those with a history of FH. Secondary
causes of hypercholesterolemia should be ruled out. For the diagnosis, the clinical
criteria or DNA analysis is used, and the clinical criteria for diagnosis include
the Simon Broome criteria (Table 5-3),98) Dutch criteria,99) and MED/PED criteria.100)
It might be identified even in patients without clinical signs such as tendon xanthoma.
If a patient has been found to have heterozygous FH, cascade family screening is recommended.
General considerations: Heterozygous FH management includes the lifestyle modifications,
lipid-lowering medication, and tests for atherosclerotic disease. Diet therapy and
avoidance of smoking are important lifestyle modifications. Aggressive medication
therapy is needed but should be administered with caution in women with a childbearing
potential. To decide medication, combined drugs, comorbidities, and adverse effects
should be considered, and patients and their family members should be informed of
the fact that medication must be continued lifelong. High-dose statin is recommended
first, and then ezetimibe can be used in combination or alone when LDL cholesterol
level fails to reach the target level
with statin alone or when adverse effects occur.
Target goal of treatment: The goal of LDL cholesterol is same as that in patients
with a high risk for CVD. However, a maximal reduction of LDL cholesterol that can
be achieved without adverse effects should be the target because it is usually difficult
to lower the level to <70 mg/dL in FH, even with the maximum dosage of medication.
It is reasonable to lower the LDL cholesterol by ≥50% from the baseline.3)
1) Lipid metabolism during pregnancy
(1) Changes in lipid metabolism during pregnancy
Lipids in plasma during pregnancy decrease at the first stage, and then begin to increase
after 8 weeks of pregnancy. In the first and second trimesters, fat accumulates owing
to increased appetite and lipogenesis; however, fat accumulation decreases during
the third trimester owing to the increase in lipolysis and decrease in lipoprotein
In the later period of pregnancy, insulin resistance increases lipolysis, glyconeogenesis,
and ketogenesis in the fasting state in pregnant women. Insulin increases the activity
of lipoprotein lipase in adipose tissue and reduces the activity of hormone-sensitive
lipase, which is a lipolytic enzyme. In addition, insulin inhibits hepatic gluconeogenesis
and ketogenesis. Peripheral insulin resistance develops in women with gestational
diabetes and plays a role in increasing blood nonessential fatty acids and ketone
(2) Hyperlipidemia during pregnancy
In the later period of pregnancy, triglycerides, phospholipids, and cholesterol increase.
In particular, the increase of triglycerides is most prominent. Whereas HDL cholesterol
increases in the 12th week of pregnancy due to the increase of estrogen, the total
cholesterol and LDL cholesterol increase in the second and third trimesters. Triglycerides
increase in VLDL. During pregnancy, hepatic lipase decreases the size of triglyceride-rich
LDL cholesterol and increases its density. Such changes damage endothelial cells and
cause atheroma formation.
2) Treatment of dyslipidemia during pregnancy
(1) Lifestyle modifications
Physical activity is effective in preventing gestational diabetes and gestational
hypertension. The average triglyceride level, of any kind, is lower in women who are
physically active. For diet therapy, it is difficult to make a clear conclusion yet,
and additional studies are required.
(2) Omega-3 fatty acid
Omega-3 fatty acids belong to the elements of diet, and they are not considered to
increase the adverse effects during pregnancy. There are insufficient data to recommend
omega-3 fatty acid supplements instead of fish intake to normal pregnant women. However,
supplementation of docosahexaenoic acid is recommended in pregnant women who do not
usually eat fish at all.
Statins are contraindicated during pregnancy. Statins are not thought to increase
fetal anomalies during pregnancy. Statin therapy is not recommended during pregnancy
because there is no evidence that dyslipidemia treatment is beneficial to pregnant
women or that cholesterol is required for the growth of embryo during pregnancy. A
woman who is planning pregnancy or is already pregnant, should stop statins, if she
is taking statins.