Professional Documents
Culture Documents
II
STATEMENT OF INTENT
This guideline was developed to be a guide for best clinical practice
in the management of dyslipidaemia. It is based on the best
available evidence at the time of development. Adherence to this
guideline does not necessarily lead to the best clinical outcome
in individual patient care. Thus, every health care provider is
responsible for the management of his/her unique patient based
on the clinical presentation and management options available
locally.
REVIEW OF THE GUIDELINE
This guideline was issued in 2011 and will be reviewed in 2016 or
earlier if important new evidence becomes available.
CPG Secretariat
Health Technology Assessment Unit
Medical Development Division
Level 4, Block EI, Parcel E
Government Offices Complex
62590 Putrajaya, Malaysia
Available on the following websites:
http://www.malaysianheart.org
http://www.moh.gov.my
http://www.acadmed.org.my
SUMMARY
Total cholesterol (TC) and High Density Cholesterol (HDL-C)
can be measured in the fasting and non fasting states.
Triglycerides (TG) is best measured in a fasting sample. Low
Density Cholesterol (LDL-C) is calculated using the Friedwalds
equation. When TG > 2.3mmol/l, non HDL-C is a better
indicator of total atherogenic burden.
Dyslipidaemias may be primary or secondary.
Target of therapy:
LDL-C should be the primary target of therapy I,A
Non HDL-C should be an alternative primary target of
therapy in patients with TG > 4.5 mmol/l I,A
Individuals should be risk stratified. I,C (See Table 1, pg 3 and Fig
1A & B, 2A & B, pg 30-31)
Diabetes is a Coronary Heart Disease (CHD) risk equivalent. I,A
Target lipids levels will depend upon the individuals global
risk.
CVD and CHD risk equivalents
LDL-C < 2.6 mmol/L with
(High Risk):
an option of <2.0 mmol/L1,A
Individuals with a 10 year risk score
of 10 20% (Intermediate Risk): LDL-C < 3.4 mmol/L1,A
Individuals with a 10 year risk score
of < 10% (Low Risk):
LDL-C < 4.1 mmol/lL IIa,C
Therapeutic Lifestyle Changes (TLC) should be an integral
component of lipid management in all patients.1,B (Table 3, pg
4)
Individuals with Cardiovascular Disease (CVD) and CHD risk
equivalents should be treated aggressively with drug therapy
from the outset.1,A (Table 1&2, pg 3; Flowcharts I-IV, pg5-8)
Statins are the drug of choice for reducing LDL-C.1,A
Fibrates and nicotinic acid may be considered for increasing
HDL-C and reducing TG after LDL-C treatment goal has been
achieved. IIa, B
Some individuals may require combination therapy to
achieve lipid target goals.
Control of glycaemia alone is inadequate in preventing
cardiovascular (CV) events.1,A Concomitant treatment
of dyslipidaemia, hypertension and other metabolic
abnormalities are also important. 1,A
2
Table 1: Major Risk Factors for CVD (other than LDL Cholesterol)
Positive Risk Factors
Male 45 years of age
Female 55 years of age or premature menopause
without hormonal replacement therapy
Hypertension
Current cigarette smoking
Family history of myocardial infarction or sudden death
prior to age 55 in a male parent or male first degree
relative and prior to age 65 in a female parent or other
female first degree relative
HDL-C < 1.0 mmol/L
Negative Risk Factors
HDL > 1.6 mmol/L
Table 2 : Recommendations for Drug Therapy for Dyslipidaemia
Medications
Statins
Ezetimibe
Grades of
recommendation/
Levels of evidence
I, A
Comments
IIa, B
IIa, C
Fibrates
IIa,B
IIa, B
Nicotinic
Acid
IIa,B
IIa, B
Comments
Diet
Saturated Fats and
Trans-fatty acids
I, B
Cholesterol
I,B
Monounsaturated
fats
I,B
Up to 10% of calories
Polyunsaturated fats
I,B
Up to 20% of calories
Dietary Fiber
I,B
20-30 gm/day
Plant stanols
IIb, B
2-3 gm /day
Soy protein
IIb, B
25-50 gm/day
IIa, B
IIb,B
Total fats
I,B
25-35% of calories
Carbohydrates
I,B
50-60% of calories
Proteins
I,B
Anti-oxidants
III,A
Avoid
Weight Reduction
Goal:
BMI : 18.5- <23 kg/
m2
Waist circumference
>90 cm in males and
< 80 cm in females
I,C
I,B
Exercise
Goal:
30-45 min per session, at least 5 times
a week
I,B
Smoking
Goal:
Complete cessation
I,B
I,C
LDL-C 2.6mmol/L
3 months
LDL-C 2.6mmol/L
LDL-C 3.4mmol/L
TLC
3 months
LDL-C 3.4mmol/L
LDL-C 3.4mmol/L
TLC
3 months
LDL-C 4.1mmol/L
LDL-C 4.1mmol/L
TLC
3 months
LDL-C 4.9mmol/L
Patients at low risk of CVD with 0 to 1 risk factor but with evidence of subclinical
atherosclerosis should be considered for a lower LDL-C target < 2.6 mmol/L.
Reference:
1. Ford ES, Ajani UA, Croft JB et al Explaining the Decrease in U.S. Deaths
from Coronary Disease, 1980-2000. N Engl J Med 2007;356:23882398.
10
Consultant Cardiologist,
Institute Jantung Negara,
Kuala Lumpur
Consultant Cardiologist,
Sime Darby Medical Center,
Subang Jaya, Selangor
Consultant Endocrinologist,
Sime Darby Medical Center,
Subang Jaya, Selangor
Consultant Cardiologist
Pantai Medical Center
Consultant Cardiologist
Institute Jantung Negara,
Kuala Lumpur
Dr Sree Raman
Consultant Physician,
Hospital Tuanku Jaafar, Seremban
(HTA trained)
Dr Sim Kui Hian
Consultant Cardiologist,
Sarawak General
Hospital, Kuching
Dr Wan Azman
Consultant Cardiologist,
University Malaya Medical Center
Dr Zanariah Hussein
Consultant Endocrinologist,
Hospital Putrajaya, Putrajaya
11
Pharmacist
Universiti Malaya Medical Centre
Consultant Nephrologist
Hospital Kuala Lumpur
Dr Hashim Noh
General Practitioner,
Klinik Young, Newton and Partners
Kuala Lumpur/Petaling Jaya
Consultant Cardiologist
Hospital Sultanah Aminah Johor
Consultant Geriatrician
Hospital Kuala Lumpur,
Kuala Lumpur
Dr Santha Kumari
Consultant Physician
Hospital Sultanah Rahimah, Klang
Dr V Paranthaman
Dr Wan Mohamad
Wan Bebakar
Consultant Endocrinologist
Hospital Universiti Sains Malaysia,
Kota Baru, Kelantan
General Practitioner,
LW Medical Associates
Kuala Lumpur
Dr Zurkarnai Yusof
Consultant Cardiologist
Hospital Universiti Sains Malaysia,
Kota Baru, Kelantan
12
14
II-b
III
Conditions for which there is evidence and/or general agreement that a procedure/therapy is not useful/effective and in
some cases may be harmful.
LEVELS OF EVIDENCE
Data derived from multiple randomized clinical trials or meta
A
analyses
Data derived from a single randomized clinical trial or large
B
non randomized studies
Only consensus of opinions of experts, case studies or standard
C
of care
Adapted from the American Heart Association/American College of
Cardiology (AHA/ACC) and the European Society of Cardiology (ESC)
15
TABLE OF CONTENTS
Statement of Intent
1
Summary 2
Flowcharts I,II,III and IV
5-8
Message from Director General of Health
9
Members of the Expert Panel
11
External Reviewers
12
Rationale and Process of Guideline Development
13-15
Grades of Recommendation and Levels of Evidence
15
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
Introduction
Measurement of Lipids and Apoproteins
Classification of Dyslipidaemias
Dyslipidaemia as a Risk factor for CVD
Other Risk Factors for CVD
Global Cardiovascular Risk Assessment
6.1 Risk Stratification
6.2 Diabetes mellitus and Dysglycaemia as CHD
risk equivalents
6.3 Targets of therapy
Prevention of CVD
Management of Dyslipidaemia
8.1 Therapeutic Lifestyle Changes
8.2 Lipid lowering Drug Therapy
8.3 LDL Apheresis
Management in Specific Conditions
9.1 Specific Lipid Disorders
9.2 Diabetes Mellitus
9.3 Coronary Heart Disease
9.4 Hypertension
9.5 Stroke
9.6 Renal Disease
Management in Specific Groups
10.1 Women
10.2 Children and Adolescents
10.3 Elderly
Adherence, Compliance and Quality Assurance
References
Appendixes
Acknowledgement
Disclosure Statements
Source of Funding
16
17
17-19
19-22
22-24
24-27
27-34
27-32
32-34
34
35
36-47
36-39
40-47
47
47-60
47-52
52-54
54-56
56-57
57
58-60
61-63
61
61-62
62-63
63-64
65-79
80-84
85
85
85
1. INTRODUCTION
In 2009, cardiovascular disease (CVD) was the leading cause of
death in both men and women1. CVD includes coronary heart
disease (CHD), cerebrovascular disease and peripheral arterial
disease. CHD is a spectrum ranging from stable angina to acute
coronary syndromes (ACS).
The peak incidence of ACS in Malaysia was in the 51-60 year age
group and the male to female ratio was 3:12. The mean age in the
local NCVD-ACS Registry 2006 was 58.1 years.3 This is younger
than that noted in neighbouring countries such as Thailand (65
years) 4, China (63 years) 5 and in the western population (GRACE
Registry- 66 years6, Canada- 68 years7).
In the NCVD-ACS Registry, most patients (96.8%) had at least one
established cardiovascular risk factor hypertension (72.6%),
dyslipidaemia (55.9%) and/or diabetes (55%)3.
In the prevention of CVD, efforts should be aimed at reducing
global risks. This guideline emphasizes:
a multifactorial approach that addresses all risk factors.
This is because the benefits of modifying several risk factors
simultaneously are synergistic.
that preventing CVD should be directed at global CVD burden
rather than CHD alone.
In the management of dyslipidaemia the following changes have
been made:
identification of those at high risk this includes individuals
with established CVD, diabetes, multiple risk factors and
established renal disease.
emphasizes the importance of a family history of premature
CVD and familial dyslipidaemia
treatment targets.
The objectives of this CPG is to:
provide guidance on the best treatment strategies for
managing dyslipidemia utilizing and optimizing existing
health resources.
17
18
Lipoprotein
LDL
LDL + VLDL
Hypertriglyceridemia
VLDL
HDL
19
Serum Lipid
T C
TC and TG
TG and
or HDL-C
TC and
or TG
Risk of
Pancreatitis
Plasma
Cholesterol
Plasma
Triglyceride
Serum Physical
signs
(if present)
Common
(polygenic)
Hypercholesterolemia
Corneal Arcus
Xanthelasma
Familial
Combined
Hyperlipidemia
or
or
Corneal Arcus
Xanthelasma
Tendon
xanthomata,
(finger extensor,
Achilles tendons)
Corneal Arcus,
Xanthelasma,
Aortic stenosis
Tuberous
xanthomata,
(elbows), striae
xanthomata,
(palm creases)
tendon
xanthomata
Eruptive
xanthomata,
(buttocks, elbows)
retinal lipemia,
hepatosplenomegaly
Eruptive
xanthomata,
(buttocks, elbows)
retinal lipemia,
hepatosplenomegaly
Familial
Hypercholesterolemia
Remnant
Hypercholesterolemia
Chylomicronemia
Syndrome
or
Familial
Hypertriglyceridemia
High HDL-C
Low HDL-C
or
20
CHOLESTEROL
TRIGLYCERIDES
HDLCHOLESTEROL
Metabolic / Endocrine
Hypothyroidism
T2DM
Metabolic Syndrome
Cushings Syndrome
Renal
End stage renal disease
Nephrotic syndrome
or
Hepatic
Obstructive liver
disease
Primary biliary cirrhosis
Drugs
Alcohol
Thiazide diuretics
Beta blockers
21
Key messages:
Dyslipidaemias may be primary or secondary to
nephrotic syndrome, obstructive liver disease,
hypothyroidism,
Cushings
syndrome,
drugs,
alcoholism and insulin resistance states such as T2DM
and metabolic syndrome.
4. DYSLIPIDAEMIA AS A RISK FACTOR FOR CVD
Dyslipidaemia has been identified as one of the main risk factors
for CVD. Our local NCVD ACS Registry showed that dyslipidaemia
was present in 55% of our patients3. Specific lipid abnormalities
implicated are:
4.1. Elevated LDL-C levels
LDL-C has been shown to be atherogenic in epidemiological
studies. There is a direct relationship between levels of LDL-C
(or TC) and the rate of new onset CHD in men and women who
were initially free from CHD.18-21 In people with established CHD,
elevated LDL-C correlates with recurrent cardiac events.22,23 There
is a near absence of clinical CHD in populations with very low
levels of serum cholesterol throughout their life (TC<3.9mmol/L
or LDL-C< 2.6 mmol/L).24,25 The risk for CHD appears to increase
progressively above these levels. At levels of LDL-C above 3.4
mmol/L, atherogenesis proceeds at a significant rate particularly
in the presence of other major risk factors.26
Randomized controlled trials have repeatedly shown that lowering
of LDL-C reduces CVD events in both primary and secondary
prevention.27-34 Studies have also shown that LDL-C particle
concentration and size are important predictors of CVD.34,35,36
However measurement of these are not widely available and are
not standardized.
Thus LDL-C should be the primary target for cholesterol therapy.
Meta- analysis have shown that reducing LDL-C by 1% reduces
CHD risk by 1%.37
22
23
Key messages:
LDL-C should be the primary target of therapy I,A
Non HDL-C should be an alternative primary target of
therapy in patients with TG > 4.5 mol/L I,A
5. OTHER RISK FACTORS FOR CVD
More than 90% of CVD can be explained by 9 to 10 modifiable
risk factors dyslipidaemia, hypertension, smoking, diabetes,
abdominal obesity, psychosocial stress, low intake of fruits and
vegetables, alcohol intake and physical inactivity.56,57(Appendix II,
pg 80)
5.1. Age
The incidence of CVD increases with age.18 This is due to the
combined effects of age related changes in the vascular system as
well the duration of exposure to adverse risk factors.
5.2. Gender
The incidence of CVD is about 3-4 times higher in men than
women in the middle decades of life and approximately twice as
high in the elderly.18
5.3. Hypertension
Both elevated systolic and diastolic blood pressures are linked
with increased CVD risk.58,59,60 From epidemiological data, elevated
systolic blood pressure appears to be more important when
compared to diastolic blood pressure as a risk factor especially
in middle aged and elderly individuals.61-64 The presence of left
ventricular hypertrophy is associated with increased CV risk.
5.4. Smoking
This is an important CV risk factor and cause of mortality in both
men and women.65,66,67 The incidence and mortality of CVD is 2-3
times as high in cigarette smokers compared to non smokers.68,69
24
5.6 Others
Other risk factors include:
5.6.1 Lifestyle Risk Factors
- Abdominal obesity:
Risk for CVD is increased although a recent analysis seems
to indicate that abdominal obesity just helps to identify
high risk individuals with metabolic abnormalities. In
Asians, a waist circumference of > 90 cm in men and >
80 cm in women has been found to be associated with
increased CV risk.80-84 (Appendix III, pg 81)
25
- Physical Inactivity:
Numerous studies have shown that physical inactivity is
associated with increased mortality and CVD.85,86,87
- Intake of fruits and vegetables:
Low intake (less than 5 servings a day) increases CV
risk.88
5.6.2.: Risk Markers
The following risk markers maybe helpful in intermediate risk
patients to determine the intensity of therapeutic targets.
- Inflammatory markers (hs-CRP)
Pathological studies strongly support a role for
inflammation in the pathogenesis of the early stages
of atherosclerosis, plaque progression and rupture.
One such acute phase reactant is high sensitivity
C-reactive protein (hs-CRP). Data show that an elevated
level of hs-CRP identifies healthy individuals who are
at an increased risk of an initial and recurrent cardiac
events.89-93 Results of a recent trial indicated that healthy
persons with LDL-C levels in the normal range but with
elevated hs-CRP benefited from statins.94
- Hemostatic markers
An elevated level of fibrinogen has been associated with
an increased risk for coronary events.95,96
- Subclinical atherosclerosis Individuals with subclinical atherosclerotic disease are
at increased risk for major coronary events.97 Subclinical
atherosclerosis may be identified by the:
presence of abnormalities in the resting and / or
stress ECG
measurement of the ankle / brachial blood pressure
(ABI) (a level of less than 0.9 is significant)
measurement of carotid intima-medial thickness
(IMT) by ultrasound (more than 75th percentile for
age and sex)
measurement of coronary calcium score by computed
tomography (CT)
non invasive imaging of the coronary arteries by CT
angiography.
26
These tests may be used for risk stratification in individuals at intermediate risk. Patients with subclinical atherosclerotic disease may warrant a more aggressive preventive treatment strategy.
Key messages:
Increasing age, male gender, hypertension, smoking
and a family history of premature CVD are major
independent risk factors for CVD.
Diabetes is a CHD risk equivalent I,A
6. GLOBAL CARDIOVASCULAR RISK ASSESSMENT
Based on the Malaysian National Health and Morbidity Survey
2006, the prevalence of dyslipidaemia in Malaysians above the age
of 40 years was 28%98. All adults above the age of 40 years should
have a complete fasting lipid profile (TC, LDL-C, HDL-C, TG). If the
levels are normal, then screening should be done annually.
Individuals who already have evidence of atherosclerosis or are at
high risk of developing CVD, should have a complete lipoprotein
profile earlier in life. This includes individuals with a family history
of premature CVD, genetic dyslipidaemias, metabolic syndrome,
T2DM and abdominal obesity.
6. 1 Risk Stratification
Individuals with CVD and CHD risk equivalents belong to the
highest risk category.
The CHD risk equivalents are:
Other clinical forms of atherosclerotic disease (atherosclerosis
in any vascular bed - aorta including abdominal aortic
aneurysm, carotid, cerebral and peripheral vessels)
T2DM
Multiple risk factors that confer a 10 year risk for CVD > 20%
These individuals are at high risk of developing CVD . They should be
screened for the traditional risk factors and treated appropriately.
27
28
Other risk factors not included in the general risk profile that
should be taken into account in evaluating risk include:
Clinical features of insulin resistance such as abdominal
obesity, elevated triglycerides, and dysglycaemia (See Section
6.2)
ECG evidence of left ventricular hypertrophy
hs-CRP levels
Evidence of subclinical atherosclerosis
Chronic kidney disease (GFR<60ml/min)
Chronic autoimmune inflammatory disorders such as
systemic lupus erythematosis and rheumatoid arthritis
Chronic HIV infection
These individuals are at high risk of developing CVD. They
should be screened for the traditional risk factors and treated
appropriately.
Individuals with 0-1 risk factor almost always have a 10 year CVD
risk <10%.
Individuals with 2 or more risk factors can fall into one of the
following risk categories for developing CVD over 10 years:
> 20%
10-20 %
< 10%
Those individuals with a 10-year risk of developing CVD of > 20%
have a very high risk and are therefore considered as CHD risk
equivalents. (see 6.1)
Determining an individuals global CVD risk will guide LDL-C target
goal and management strategies. (Table 8, pg 34)
The 10 year risk calculation is to be performed at the outset to help
guide the intensity of cholesterol lowering therapy. It cannot be
used to track changes in risk over time as risk factors are modified.
In calculating the risk scores (Figures 1A & B, 2A & B, pg 30-31), the
TC and HDL-C should be the average of at least 2 measurements.
The average baseline blood pressure (BP) must be obtained from
an average of several readings. A smoker means any cigarette
smoking in the past month.
29
Age,y
HDL-C
-2
1.6+
-1
1.3-1.6
30-34
1
2
35-39
TC
SBP
(not
treated)
SBP
(treated)
Smoker
Diabetes
<120
No
No
<120
1.2-<1.3
<4.2
120-129
0.9-<1.2
4.2-<5.2
130-139
<0.9
5.2-<6.3
140-159
120-129
6.3-<7.4
160+
130-139
>7.4
40-44
45-49
140-159
Yes
Yes
160+
7
8
50-54
9
10
55-59
11
60-64
12
65-69
13
14
70-74
15
75+
Points
allotted
10 year Risk %
<1
1.1
1.4
1.6
1.9
2.3
2.8
3.3
3.9
4.7
5.6
30
Total Points
8
9
10
11
12
13
14
15
16
17
18+
10 year Risk %
6.7
7.9
9.4
11.2
13.2
15.6
18.4
21.6
25.3
29.4
>30
Age,y
HDL-C
TC
-3
Smoker Diabetes
<120
-2
1.6+
-1
1.3-1.6
30-34 1.2-<1.3
0.9-<1.2
SBP (not
SBP
treated) (treated)
35-39
<120
<4.2
120-129
4.2-<5.2
130-139
<0.9
140-149
5.2-<6.3
No
120-129
130-139
40-44
6.3-<7.4
150-159
45-49
>7.4
160+
No
Yes
Yes
140-149
150-159
50-54
55-59
60-64
10
65-69
11
70-74
12
75+
160+
Points
allotted
10 year Risk %
<1
1.0
1.2
1.5
1.7
2.0
2.4
2.8
3.3
3.9
4.5
5.3
Total Points
10
11
12
13
14
15
16
17
18
19
20
21+
31
10 year Risk %
6.3
7.3
8.6
10.0
11.7
13.7
15.9
18.5
21.5
24.8
28.5
>30
Heart age, y
<0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
>17
<30
30
32
34
36
38
40
42
45
48
51
54
57
60
64
68
72
76
>80
Heart age, y
<1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15+
<30
31
34
36
39
42
45
48
51
55
59
64
68
73
79
>80
32
I,A
I,A
I,A
The target LDL-C level will depend on the individuals global risk.
(see Table 8)
Table 8: Target LDL-C levels
Global Risk
0-1 risk factor a
2 or more risk
factors b
CVD and CVD risk
Equivalents
LDL-C levels to
initiate Drug therapy
Target LDLC
levels (mmol/l)
4.9 c
3.4 c
2.6
2.0 to < 2.6
< 4.1
3.4d
< 2.6e
< 2.0f
a Almost all individuals with 0-1 risk factor have a 10 year risk < 10%, thus 10 year risk
assessment in individuals with 0-1 risk factor is not necessary.
b These include individuals with multiple risk factors but a 10 year risk of CVD of < 20%.
c After 8-12 weeks of TLC.
d An optional target of <2.6mmol/L in certain high risk individuals. See flowchart II & III,
pg 4
e The lower the LDL-C achieved, the greater the CV benefits seen.
f Consider LDL-C target goal < 2.0 mmol/LI,A in very high risk individuals eg individuals
with ACS, recurrent cardiac events, CHD with T2DM and those with multiple poorly
controlled risk factors
See Flowcharts I-IV, pg 5-8.
Key messages:
Individuals should be risk categorized I,C (Table 7, pg 28,
Fig 1A & B, 2A & B, pg 30-31).
Target lipids levels will depend upon the individuals
global risk.
Individuals with CVD and CHD risk equivalents should be
treated aggressively with drug therapy I,A (Table 8, pg 34;
Flowcharts I-IV, pg 5-8).
34
7. PREVENTION OF CVD
Prevention can be divided into:
35
8. MANAGEMENT OF DYSLIPIDAEMIA
8.1. THERAPEUTIC LIFESTYLE CHANGES
Introduction
Therapeutic lifestyle changes (TLC) refer to dietary modification,
weight reduction, regular physical activity, cessation of smoking
and alcohol restriction. TLC is an integral component of the
treatment of dyslipidaemia. It should precede or be initiated
together with drug therapy and is directed especially at individuals
who are obese, who smoke and who seldom exercise. For patients
without CVD or CVD risk equivalents, emphasis should be placed
on TLC.
8.1.1. Dietary Modification
I,B
I,B
I,B
IIa,B
36
IIb,B
IIb,B
High intake of soy protein (25-50 gm/day) can cause small reductions in LDL-C.106
8.1.2. Weight Reduction
I,B
I,B
I,B
I,A
I,B
I,A
8.1.5. Alcohol
Restriction of alcohol is advised in patients with dyslipidaemia as it
increases plasma TG levels.121,122
Moderate alcohol consumption (not more than 14 units for males
and 7 units for female per week) increases HDL-C and apo A-I and
is associated with a reduction in all cause mortality.123-127
Over-consumption is however associated with a higher mortality
rate. High intake of alcohol elevates BP and can precipitate acute
pancreatitis in individuals with high TG levels. Nondrinkers should
therefore not be encouraged to start alcohol consumption to
improve their dyslipidaemia.
(1 unit of alcohol is equivalent to 250 ml of beer, 100 ml of wine
and 30 ml of whisky)
IIa,B
IIb,B
8.1.6. Miscellaneous
Omega3 polyunsaturated fatty acids are useful in individuals with
high TG and can be considered in addition to fibrates or nicotinic
acid. For lowering TG, a dose of 3-9 gm/day of omega-3 fatty acids
is required
In patients with CVD, omega-3 fatty acids (dose of 0.75 gm-1
gm/day) has been shown to reduce sudden cardiac death, CHD
mortality and total mortality although a recent trial showed no
benefit.128,129,130
It is recommended to increase intake of omega-3-fatty acids
by eating more fish, walnuts, flaxseed oil and green, leafy
vegetables.128,131
III,B
III,A
III,B
39
I,A
Statins are inhibitors of HMG CoA reductase , the rate limiting enzyme in hepatic cholesterol synthesis. They are the most effective
drug class and the treatment of choice in reducing LDL-C. They
are suitable first-line agents in familial hypercholesterolemia, for
primary prevention of CVD, secondary prevention of CVD and CHD
equivalents.
They have moderate effect in lowering TG and in elevating HDL-C.
Treatment is initiated at the recommended starting dose with the
evening meal or at bed time except for long-acting statins that
can be taken at any time. The dose is then adjusted accordingly to
achieve target levels. Serum lipids and alanine aminotransferase
should be measured at 6-8 weeks after starting treatment and
thereafter as necessary especially when doses are increased.
III,C
40
Lipid Effects
Side Effects
Contraindications
HMG-CoA
Reductase
Inhibitors
(statins)
LDL-C 18-55%
HDL-C 5-15%
TG
7-30%
-Myopathy
-Increased liver
Enzymes
Absolute:
-Active or chronic liver
disease
Relative:
-Concomitant use of
certain
drugs*
Fibric-Acid
Derivatives
(Fibrates)
LDL-C 5-20%
HDL-C 10-35%
TG
20-50%
-Dyspepsia
-Gallstones
-Myopathy
Absolute:
-Severe hepatic
disease
-Severe renal disease
Relative:
-Concomitant use of
certain drugs**
Bile-Acid
Sequestrants
(Resins)
LDL-C 15-30%
HDL-C 3-5%
TG
/
-GIT distress
-Constipation
-***Decreased
absorption of
certain drugs
Absolute:
-Dysbetalipoproteinemia
-Tg > 4.5 mmol/l
Relative:
-Tg > 2.3 mmol/l
Nicotinic Acid
(Niacin)
LDL-C 5-25%
HDL-C 15-35%
TG
20-50%
-Flushing
-Hyperglycemia
-Hyperuricemia
(or gout)
-Upper-GIT
distress
-Hepatotoxicity
Absolute:
-Chronic-liver disease
-Severe Gout
Relative:
-Diabetes (high doses
only)
-Hyperuricemia
-Peptic-Ulcer Disease
Cholesterol
Absorption
Inhibitors****
LDL-C 18-25%
HDL-C 3-5%
TG
8-14%
-Headache
-Abdominal pain
-Diarrhea
cyclosporin, macrolide antibiotics, various anti fungal agents and cytochrome P-450
inhibitors (fibrates and nicotinic acid should be used with appropriate caution)
**
gemfibrozil and repaglinide140
*** Paracetamol, NSAIDs, anticoagulant, valproate, digitalis, thiazides, thyroxine,
raloxifene, propranolol and tricyclic antidepressants.
**** usually used in combination with statins.
These data are derived from short-term clinical trials meant for
drug registration. In real life long term use, the amount of lipid
change achieved may be less than this.
41
Recent concern about statin and new onset diabetes has not been
substantiated. In fact statins have been proven to prevent CV
events in diabetics with no overt CVD.137,138 There is no evidence
that patients on statins have increased risk of cancer, poor memory
and renal toxicity.
The routine use of Co enzyme Q 10 to prevent muscle toxicity is
unproven and therefore not recommended.
Recommended Dosages for Statins*
Drug
Recommended
initiating dose
Lovastatin
20 mg
Pravastatin
20 mg
10-40 mg daily
Simvastatin
20 mg
Fluvastatin
20 mg
Atorvastatin
10 mg
Rosuvastatin
10 mg
* As stated in MIMS,Malaysia
In men with established CHD with low LDL-C and HDL-C, fibrates
have been shown to improve CV outcome. In individuals with
T2DM, fibrates reduced the composite endpoint of CV death, CV
events and the need for coronary and carotid revascularization.43,47
42
IIa,B
Recommended Dosage
Bezafibrate
Fenofibrate
Gemfibrozil
Ciprofibrate
100 mg daily
* As stated in MIMS,Malaysia
IIa,B
Nicotinic acid decrease mobilization of free fatty acids from adipose tissues. It is very effective in increasing HDL-C and also effectively lowers both TC and TG levels. It is also the first to show
mortality reduction in individuals with CHD.48
43
44
Initial Drug
Suggested Addition
(in order of preference)
Statins
Resin
Ezetimibe
Fibrates
Nicotinic Acid
Statins
Fibrates
Nicotinic Acid
If:
LDL-C < 2.6 mmol/l
Statins
If:
LDL-C > 2.6 mmol/l
Fibrates
Nicotinic Acid
Statins
Fibrates
Nicotinic Acid
TG
Fibrates
Nicotinic Acid
Statins
Omega 3 FA
I,A
IIa, B
Key messages:
Statins are the drug of choice for reducing LDL-C in a
wide range of dyslipidaemic patients. I,A
Fibrates and nicotinic acid may be considered
for increasing HDL-C and reducing TG after LDL-C
treatment goal has been achieved. IIa,B
Some individuals may require combination therapy to
achieve lipid target goals
8.3 LDL-C APHERESIS
IIa,B
IIa,B
47
In individuals with elevated TG, the primary target of therapy remains achieving LDL-C goal depending upon the individuals global
risk. (Table 8, pg 34)
I,A
In individuals where the TG > 2.3 mmol/L, non HDL-C is more representative of all atherogenic lipoproteins than LDL-C. (see also
section 2 and 4.4) In these individuals, the secondary target of
therapy is non HDL-C as listed in Table 11, pg 48.
Another secondary target of therapy is TG < 1.7 mmol/L.
Table 11: Targets of LDL-C and non HDL-C
Global Risk
Target LDLC
levels
(mmol/L)
< 4.1
< 4.9
2 or more risk
factors*
< 3.4**
< 4.1
< 3.4
< 2.6
These include individuals with multiple risk factors but a 10 year risk of CVD of
< 20%
Optional target <2.6mmol/L in certain high risk individuals. See Flowchart II &
III
I,A
IIa,B
Causes of elevated TG
Clinical significance
Borderline
High TG
(1.7-2.3
mmol/L)
Acquired causes
- Overweight and obesity
- Physical inactivity
- cigarette smoking
- excess alcohol intake
- high carbohydrate intake
(> 60% of total energy)
Secondary causes
Genetic causes
various genetic
polymorphism
High TG
(2.3-5.7
mmol/L)
Acquired causes
- same as for borderline
high TG (usually combined
with foregoing causes)
Secondary causes
Genetic causes
- familial combined
hyperlipidemia
-familial
hypertriglyceridemia
-polygeneic
hypertriglyceridemia
- familial
dysbetalipoproteinemia
Elevated atherogenicremnant
lipoproteins
Marker for other
components of
atherogenic
dyslipidemia (see above)
Marker for the
metabolic syndrome (see
above)
Very high TG
(
5.7mmol/L)
Normal TG
(< 1.7
mmol/L)
50
I,B
I,B
I,B
IIa,B
Treatment include:
Start with a fibrate or nicotinic acid
- Gemfibrozil and Fenofibrate lower TG by about 70%.43,47,160,161
- Nicotinic acid is effective at doses of above 2gm per day.139,162
very low fat diets (< 15% of calorie intake) and lifestyle
changes (See Section 8.1)106,111,139
Severe hypertriglyceridaemia associated with uncontrolled
diabetes warrants initiation of insulin therapy. The TG level
will improve but may not normalize.
Fish oils which contain long chain omega-3 polyunsaturated
fatty acids can also lower TG. Doses of 3 to 9 gm per day can
lower TG by up to 50%.139,163 They can be considered as an
addition to fibrate or nicotinic acid.
Statins are not useful as a first line therapy in this situation.
In these individuals, it is difficult to achieve target values of TG
(< 1.7mmol/L).
Levels of TG < 2.3 mmol/L are acceptable.
9.1.2. Low HDL-C and High TG:
Low HDL-C and high TG are seen in insulin resistance states and
very high carbohydrate intakes.
I,A
IIa,B
I,A
51
IIa,B
52
I,A
Primary target :
- LDL-C < 2.6 mmol/L (<1.8 mmol/L for DM with established
CVD)
Secondary target:
- Non-HDL-C < 3.4 mmol/L (when TG > 2.3 mmol/L)
- HDL-C > 1.0 mmol/L (male) and > 1.2 mmol/L (female)
- TG < 1.7 mmol/L
Initial Drug
Suggested Addition
In order of preference
Statins
Fibrates
Ezetimibe
Resins
Increase HDL-C
Fibrates* or,
Nicotinic Acid**
Statins***
Lower TG
Fibrates
Treat Combined
Hyperlipidemia
Statins***
Lower LDLC
Fibrates
Nicotinic Acid
*
statins should be the initial drug if LDL-C goal is not achieved.
** with careful monitoring and keeping the dose < 1.5 gm / day.
*** high doses may be required.
I,A
I,A
53
I,B
If drug-treated patients do not reach targets on maximal tolerated statin therapy, a reduction in LDL cholesterol of 3040% from
baseline is an alternative therapeutic goal.170
I,B
IIa,B
I,A
I,C
I,A
I,A
IIa,B
IIa,B
IIa,B
IIa,A
I,A
Individuals with stable CAD should be treated with optimal medical therapy using a combination of antiplatelet agents, statins,
-blockers and angiotensin converting enzymes inhibitors.190
I,A
I,A
I,A
Key messages:
Hypertension and elevated cholesterol levels often
coexist and synergistically increase the risk of
developing CVD and treatment of both conditions
reduces CVD events.
Statins should be considered in high risk hypertensive
individuals. I,A
9.5 Stroke
Recent studies have shown an association between raised serum
lipids and risk of ischaemic stroke.193
I,B
I,B
I,A
57
IIa,B
IIa,B
58
I,B
IIa,B
IIb,B
A third of these patients were on dialysis and they did not show any
benefit, a finding consistent with that of previous studies.141,222,223
The immunosuppresive drugs used post renal transplants or
for underlying renal disease are associated with dyslipidaemia.
Individuals receiving statins and fibrates in combination with
cyclosporin should be closely monitored for myositis.
The initiating dose of anti lipid drugs in patients with CKD should
be lower. (Table 14, pg 60).
Key messages:
Individuals with CKD have high CV Risk.
Statins have been found to be beneficial in individuals
with CHD and mild to moderate CKD.I,B
In individuals on dialysis, the benefits of lipid lowering
therapy are doubtful.IIb,B
Statins are safe in CKD.I,B
Fibrates should be used cautiously in individuals with
CKD and very high TG.IIb,B
59
Mild
GFR
6090
ml/
min/1.73
m2
Moderate
GFR
1559 ml/
min/1.73 m2
Severe
GFR
<15 ml/
min/1.73
m2
Notes
STATINS
Atorvastatin
No
No
No
Fluvastatin
No
Not defined
Not
defined
dose to one-half
at GFR <30 ml/
min/1.73 m2
Lovastatin
No
to 50%
to 50%
dose to one-half
at GFR <30 ml/
min/1.73 m2
Pravastatin
No
No
No
Start at 10 mg/day
for GFR <60 ml/
min/1.73 m2
Rosuvastatin
No
510 mg
Avoid
Contraindicated
for GFR <30 ml/
min/1.73 m2, max
dose 10 mg/day
Simvastatin
No
No
to 50%
Start at 5 mg if GFR
<10 ml/min/1.73
m2
Nicotinic acid
No
No
to 50%
34% kidney
excretion
Cholestyramine
No
No
No
Not absorbed
Colesevelam
No
No
No
Not absorbed
Ezetimibe
No
No
No
Fenofibrate
to 50%
to 25%
Avoid
Gemfibrozil
No
No
No
NONSTATINS
60
May serum
creatinine
NLA recommends
a dose of 600 mg/
day for GFR 1559
ml/min/1.73 m2
and avoiding use
for GFR <15 ml/
min/1.73 m2
III,C
IIb,B
I,B
IIa,C
IIa,B
These risk factors have been shown to persist into adult life and
lead to premature CVD.
Screening begins with an assessment of family history for CVD
or genetic dyslipidaemia.239 In addition, obese and overweight
children and those with the risk factors mentioned above should
also have a full lipoprotein profile, BP measurement and a fasting
glucose assessment.
Children whose lipid levels are significantly elevated should be
referred to specialists interested in this field.
I,B
I,A
IIb,B
There has been limited data on the use of niacin, fibric acid
derivatives and ezetimibe in children.
When prescribing drugs in children, the need for life long
therapy and its associated health risks and drug exposure during
unplanned pregnancy in individuals of child bearing age need to
be considered. Patients should be extensively counseled prior to
initiation of drug therapy.
I,A
62
Patient factors
- Simplify medication regimens using wherever possible
drugs with a single daily or twice daily dosing
- Give clear instructions
- Encourage the support of the family
- Involve patients in their care through self-monitoring
- Remind patients that lipid lowering drugs are not a
substitute for dietary and lifestyle interventions
Physician Factors
- Teach physicians to implement lipid treatment guidelines
- Educate patients to prompt preventive care
- Remind patients of appointments and follow-up missed
appointments
64
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79
SUBCLASSES/ISOFORMS
apo A-I, apo-II, apo A-IV, apo A- V
apo B-48, apo B-100
apo C-I, apo C-II, apo C-III, apo C-IV
apo E-2, apo E-3, apo E-4
Hypertension
INTERSTOKE
(all stroke; 3000
cases, 3000
controls)*
34.6% (30.4-39.1)
INTERHEART
(acute myocardial
infarction; 15152
cases, 14820 controls)**
17.9% (15.7-20.4)
Smoking
18.95 (15.3-23.1)
35.7% (32.5-39.1)
Waist-to-hip
(abdominal obesity)
26.5% (18.8-36.0)
20.1% (15.3-26.0)
18.8% (11.2-29.7)
..
13.7% (9.9-18.6)
28.5% (14.5-48.5)
12.2% (5.5-25.1)
5.0% (2.6-9.5)
9.9% (8.5-11.5)
3.8% (0.9-14.4)
6.7% (2.0-20.2)
..
4.6% (2.1-9.6)
5.2% (2.7-9.8)
32.5% (25.1-40.8)
..
..
6.7% (4.8-9.2)
24.9% (15.7-37.1)
..
49.2% (43.8-54.5)
Diet
Diet risk score
Fruits and vegetables
daily
Regular physical activity
Diabetes
Alcohol intake
Psychosocial factors
All psychosocial
factor
Psychosocial stress
Depression
Cardiac causes
Ratio of apolipoproteins
B to A1
80
Risk of co-morbidities
Underweight
< 18.5
Normal range
18.5-22.9
Average
Overweight
> 23.0
Pre-Obese
23.0-27.4
Increased
Obese I
27.5-34.9
Moderate
Obese II
35.0-39.9
Severe
Obese III
> 40.0
Very Severe
81
82
Sample size
Fatal CHD
http://www.
heartscore.
org/pages/
welcome.aspx
http://hp2010.
nhlbihin.net/
atpiii/calculator.
asp?usertype=prof
Endpoints
Age, sex,
total-HDL
cholesterol
ratio, smoking,
systolic blood
pressure
13
Mean : 46
12
Mean: 49
205,178
19 to 80;
30 to 74;
5,345
SCORE
Risk factors
considered
Mean follow-up ,y
Age (y)
Framingham
http://www.chdtaskforce.com/
coronary_risk_
assessment.html
Fatal/nonfatal MI
or sudden cardiac
death (CHD and
CVD combined)
Age, LDL
cholesterol, HDL
cholesterol,
smoking, systolic
blood pressure,
family history,
diabetes,
triglycerides
10
Mean: 47
35 to 65;
5,389
PROCAM (Men)
http://www.
reynoldsriskscore.org/
MI, ischemic
stroke, coronary
revascularization,
cardiovascular
death (CHD and CVD
combined)
10.2
Mean: 52
>45;
24,558
Reynolds (Women)
http://www.
reynoldsriskscore.org/
10.8
Mean: 63
>50;
10,724
Reynolds (Men)
AMOUNT
COMMENT
Decrease
dietary
cholesterol
Decrease
total fat/oil
Types:
a) saturated
fat
7-10% (not
more than 10%
of total calorie
intake)
b)mononunsaturated
and polyunsaturated
oils/margarine
Not more
than 6
teaspoonsfuls
per day to be
used in cooking
or as a spread
Increase
intake of
complex
carbohydrate
/ grains and
fiber
20-25 gm fiber
/ day. Include
2-3 servings
of fruit and
3-4 servings of
vegetables and
5 -7 servings
per day of
grains
Choose food
high in
protein but
low in
saturated fat
2-3 servings
per day
Consuming an egg a day does not substantially increase CVD risk.246,247 The method of cooking the egg is important.
*Adapted and modified from Lichtenstein AH, Appel LJ, Brands M et al. Diet and Lifestyle
Recommendations Revision 2006. A Scientific Statement From the American Heart Association Nutrition Committee Circulation 2006;114:82-96.
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(<1.14mmol/L) (<1.7mmol/L)
(1.7-2.3mmol/L)
(2.3-5.7mmol/L)
(5.7mmol/L)
*Adapted from Miller M, Stone NJ, Ballantyne C et al Triglycerides and Cardiovascular Disease: A Scientific Statement from the American Heart Association. Circulation 2011; 123:
2292-2333
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ACKNOWLEDGMENTS
The committee of this guideline would like to express their gratitude and appreciation to the following for their contribution:
Technical Advisory Committee, Clinical Practice Guidelines,
Ministry of Health for their valuable input and feedback
Panel of external reviewers who reviewed the draft
DISCLOSURE STATEMENT
The panel members have no potential conflict of interest to disclose.
SOURCES OF FUNDING
This CPG was made possible by an unrestricted educational grant
to NHAM from Pfizer (M) Sdn Bhd. There was total editorial independence and the funding body did not influence the content of
this guideline.
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