Download Consensus Statement on Management of Hyperlipidaemia

PREFACE
The necessity for a standardised consensus on clinical management of various medical
conditions cannot be overemphasized. The idea for such consensus statements was first initiated
by the Master of the Academy of Medicine of Malaysia in 1992. In collaboration with the
Ministry of Health of Malaysia, this has now become a reality.
In choosing the members of the expert panel, the Ministry placed emphasis on eligible
representatives from the Universities, the public sector and the private sector. Grateful thanks
must be given to these members for voluntarily sacrificing their valuable time in formulating the
contents of this consensus statement. The expert panel met on several occasions to prepare the
draft consensus which was then formally presented and discussed at a nationwide workshop held
in December 1993.
I would like to extend my appreciative acknowledgements also to the Academy of Medicine of
Malaysia, the Ministry of Health of Malaysia and to the numerous members of the secretarial
staff who shall, for the sake of brevity, remain nameless!
Dato' Dr Robaayah Zambahari
1
MEMBERS OF THE EXPERT PANEL
CHAIRPERSON
Dato' Dr Robaayah Zambahari
Consultant Cardiologist
Institut Jantung Negara
Kuala Lumpur
COORDINATOR/EDITOR
Dr Ridzwan Bakar
Consultant Cardiologist
Pantai Medical Centre
Kuala Lumpur
SECRETARY
Dr Rosli Mohd Ali
Consultant Cardiologist
Institut Jantung Negara
Kuala Lumpur
PANELISTS
Prof Dato' Dr Khalid Abdul Kadir
Dato’ Dr Ismail Merican
Professor of Medicine
Consultant Endocrinologist
Universiti Kebangsaan Malaysia
Kuala Lumpur
Consultant Physician
Department of Medicine
Hospital Kuala Lumpur
Kuala Lumpur
Prof Dr Amir Khir
Dr R Jeyamalar
Professor of Medicine
Consultant Endocrinologist
Universiti Malaya
Kuala Lumpur
Consultant Cardiologist
Subang Jaya Medical Centre
Subang Jaya
Datuk Dr Joseph Ong Ah Soon
Dr Khoo Kah Lin
Consultant Physician
Assunta Hospital
Petaling Jaya
Consultant Cardiologist
Pantai Medical Centre
Kuala Lumpur
Datuk Dr Tarmizi Thayaparan
Consultant Physician
Department of Medicine
Hospital Seremban
Negri Sembilan
2
CONSENSUS STATEMENT ON MANAGEMENT OF HYPERLIPIDAEMIA
1.
INTRODUCTION
Cardiovascular disease is an increasingly important health problem in Malaysia. It is
the most common cause of death reported in government hospitals.The majority of
these cases are due to coronary artery disease (CAD), of which hyperlipidaemia is one
of the main risk factors. The primary and secondary prevention of CAD should
therefore be directed against hyperlipidaemia as well as the other risk factors.
The above objective can be achieved by a two-fold strategy:
a) to promote population-wide lifestyle recommendations for risk reduction.
b) to identify individuals at high risk who require therapy.
In this context, it is important to treat the patient as a whole and not to treat the
individual risk factors in isolation - a global approach. In the light of recent studies,
there is convincing evidence that cholesterol reduction in individuals with and without
heart disease leads to a reduction in total mortality, CAD morbidity and mortality.
Dietary modification, cessation of smoking, exercise and weight reduction form the
cornerstone of any coronary prevention strategy. Where appropriate, pharmacotherapy
with lipid-modifying drugs should be instituted.
Treatment of hyperlipidaemia should be risk stratified. It is most cost effective in
individuals with highest risks i.e. those with CAD, followed by individuals without
CAD but with multiple risk factors.
2.
MEASUREMENT OF LIPID LEVELS
Measurement of plasma lipids should take into consideration various factors. The level
would be affected if measured during or immediately after acute stress or illness eg.
acute myocardial infarction, febrile illness, surgery. In acute MI the cholesterol level
may be spuriously low between 24 hours post infarction to 3 months. Certain drugs
would affect the lipid levels eg. thiazide diuretics, steroids.
The total cholesterol (TC) and high density lipoprotein cholesterol (HDL-C) can be
measured in both fasting and non-fasting states. The triglycerides (TG) should be
measured after 10-12 hours of fasting. TG levels are influenced by alcohol intake in the
preceding 24 hours and smoking during the fasting state. The low density lipoprotein
cholesterol (LDL-C) level is derived by calculation from the Friedewald formula as
follows:
LDL-C (mmol/L) = TC - HDL-C - TG / 2.3
This formula cannot be used if the TG levels exceed 4.5 mmol/L.
Plasma cholesterol is 3% lower than serum. Measurements made from whole blood
differs slightly from that obtained from plasma or serum. Fingerprick method using a
3
desktop machine for the measurement of TC, TG and HDL-C, can produce satisfactory
results. These machines however require well-trained operators, careful maintenance
and calibration.
Lipid levels especially TG show biological variability. Because of this and laboratory
variability more than one measurement are usually required, particularly in borderline
cases.
3.
CLASSIFICATION OF HYPERLIPIDAEMIA
Hyperlipidaemia can be classified based on therapeutic considerations as follows:
Table 1.
CLASSIFICATION OF HYPERLIPIDAEMIA
INCREASED CONCENTRATION
LIPOPROTEIN
SERUM LIPID
I. Hypercholesterolaemia
LDL
Cholesterol
II. Mixed Hyperlipidaemia
LDL + VLDL*
Cholesterol and Triglyceride
III. Hypertriglyceridaemia
VLDL
Triglyceride
* VLDL - very low density lipoprotein.
4
The hyperlipidaemias may be primary or secondary in origin.
Table 2.
PRIMARY HYPERLIPIDAEMIAS
Risk of
CHD
Risk of
pancreatitis
Plasma
cholesterol
Plasma
triglyceride
Physical signs
(if present)
Common ("polygenic")
hypercholesterolaemia
+
-

N
Corneal arcus,
xanthelasma
Familial combined
hyperlipidaemia
++
-
 or N
 or N
Corneal arcus,
xanthelasma
Familial
hypercholesterolaemia
+++
-

N or  N
Tendon xanthomata
(finger extensor,
Achilles' tendons),
corneal arcus,
xanthelasmas, aortic
stenosis
Remnant
hypercholesterolaemia
+++
±


Tuberous xanthomata
(elbows), striate
xanthomata (palm
creases), tendon
xanthomata
Chylomicronaemia
syndrome
-
+++


Eruptive xanthomata
(buttocks, elbows),
retinal lipaemia,
hepatosplenomegaly
Familial
hypertriglyceridaemia
?
++


Eruptive xanthomata
(buttocks, elbows),
retinal lipaemia,
hepatosplenomegaly
High HDL
-
-

N
-
5
Table 3.
CAUSES OF SECONDARY HYPERLIPIDAEMIA
CONDITIONS
MAIN LIPID ABNORMALITIES
Diabetes mellitus
 Triglyceride,  HDL
Alcohol abuse
 Triglyceride
Therapeutic drugs
(diuretics, oral contraceptives, retinoids,
corticosteroids, anabolic steroids,
progestogens related to testosterone)
 Triglyceride and/or cholesterol, 
HDL
Hypothyroidism
 Cholesterol
Chronic renal failure
 Triglyceride
Nephrotic syndrome
 Cholesterol, ±  triglyceride
Cholestasis
 Cholesterol
Bulimia
 Triglyceride
Anorexia nervosa
 Cholesterol
Pregnancy
 Triglyceride
Secondary causes of hyperlipidemia should be considered in the following situations:
1. TC exceeds 7.0 mmol/L, one should exclude primary hypothyroidism, nephrosis,
obstructive liver disease.
2. TG exceeds 4.5 mmol/L, one should exclude secondary causes such as alcoholism.
3. High TG with low HDL usually indicates insulin resistance syndrome such as
NIDDM and impaired glucose tolerance.
4. Failure to respond to therapy.
5. Special risk groups eg family history of diabetes mellitus, past history of thyroid
disease.
6
4.
HYPERLIPIDAEMIA AS A RISK FACTOR FOR CHD
From available epidemiological and scientific data, hyperlipidaemia has been identified
as one of the main risk factors of CHD. Specific lipid entities implicated are:
4.1
Elevated total cholesterol levels
In epidemiological studies, a single total cholesterol measurement appears to be
predictive of the risk of CHD. The evidence linking elevated total cholesterol
levels with increased risk for CHD comes from:
-
animal experiments,
-
nature and dynamics of human atherosclerotic plaques,
-
occurrence of elevated total cholesterol levels in groups with clinically
manifested atherosclerotic disease,
-
genetic hyperlipidaemias associated with premature CHD;
-
epidemiological studies of CHD risk in populations with differing total
cholesterol levels.
The risk for CHD appears to increase progressively with total cholesterol levels
above 3.5 mmol/L. The relationship between CHD risk and total cholesterol
levels is continuous and curvilinear. The higher the total cholesterol level, the
greater the risk. People with the lowest total cholesterol levels are however not
completely immune to the disease. The subfraction of cholesterol which
correlates best with atheroma and CHD is LDL-C. It has been shown that
reducing total cholesterol by 1% will reduce CHD risk by 2%.
4.2
Low plasma HDL-C levels
There is substantial data linking a low HDL-C level with an increased risk of
CHD. These include:
-
family studies of kindreds with familial forms of low HDL-C who have
CHD.
-
epidemiological data all seem to show an inverse relationship between
HDL-C levels and CHD risk.
-
angiographic studies of atherosclerosis regression in lipid intervention
trials in which there was an increase in HDL-C levels.
7
Epidemiological data seem to consistently show that there is a 2-3% decrease in
CHD risk for each 0.4 mmol/L rise in HDL-C levels after adjustment for other
risk factors.
4.3
Elevated TG Levels
The relationship between elevated TG levels and CHD risk is not that clear and
the evidence appears mixed. Prospective cohort studies seem to indicate a strong
positive relationship between hypertriglyceridaemia and elevated CHD risk.
When subjected to multivariate analysis, the effect of TG is however diminished.
In genetic hypertriglyceridaemias, many affected individuals do not have an
increased CHD risk while others seem to be at risk. In most angiographic
regression trials, lowering of TG levels was not associated with significant
atherosclerotic regression.
In some other studies however, the greatest benefit in terms of CHD risk
reduction was seen in individuals with high LDL-C levels, low HDL-C levels
and high TG levels. There is an inverse relationship between TG and HDL-C
levels. Elevated TG also alter the coagulation and fibrinolytic systems.
However, TG values in any one person are highly variable. The predictive value
of TG is also low when compared to total cholesterol.
At present, it would appear that there is inadequate data indicating increased risk
of CHD with elevated TG levels per se.
5.
OTHER RISK FACTORS FOR CHD
5.1
Age
The incidence of CHD increases with age.
5.2
Gender
The incidence of CHD is about 3-4 times higher in men than in women in the
middle decades of life and approximately twice as high in the elderly.
8
5.3
Hypertension
Both elevated systolic and diastolic blood pressures are linked with increased
CHD risk. From epidemiological data, elevated systolic blood pressure appears
to be more important when compared to elevated diastolic blood pressure as a
risk factor. There is no single measurement of either systolic or diastolic blood
pressure separating individuals with high risk from those who are at low risk.
5.4
Smoking
This is an important risk factor in both men and women. The incidence and
mortality of CHD is twice as high in male cigarette smokers compared to nonsmokers. The risk of developing CHD is directly related to the number of
cigarettes smoked. In individuals who discontinue smoking, the risk decreases
within a year or two of stopping although it remains slightly higher compared to
non-smokers.
5.5
Diabetes Mellitus and Impaired Glucose Tolerance
From prospective epidemiological data, the occurrence of CHD doubles in men
with impaired glucose tolerance. In women, the incidence increases 3-4 fold
particularly before the age of 50. Both insulin dependent and non-insulin
dependent diabetics have an increased risk of developing CHD. It should be
noted that in non-insulin dependent diabetes mellitus (NIDDM), there is an
associated increase in TG, decrease in HDL-C, increase in serum insulin, obesity,
high waist-to-hip ratio (WHR) and hypertension, all of which contribute to the
increased risk of CAD.
5.6
Family History of Premature CHD
Familial and genetic factors may play an important role in the determination of
some major risk factors, especially hypertension, lipid abnormalities and glucose
intolerance. In addition, there appears to be a familial predisposition to CHD
per se that is independent of other known risk factors. The presence of
premature CHD in first degree male relatives below the age of 55 years or female
relatives below the age of 65 years is a recognised independent risk factor for
CHD.
9
5.7
Others
- Obesity
- Sedentary Life-Style
- Psychosocial Factors
- Hyperinsulinaemia (features include high waist to hip ratio)
Risk factors that are implicated in CHD but whose role in current clinical
practice needs to be fully established include:
- elevated fibrinogen levels
- elevated Lipoprotein(a) [Lp(a)] levels
- homocysteinaemia
Table 4.
RISK FACTORS FOR CHD
Positive Risk Factors
- Elevated total cholesterol
- * Elevated LDL-C levels
- HDL-C < 0.9 mmol/L
- Hypertension
- Cigarette smoking
- Diabetes mellitus
- Family history of myocardial infarction or sudden death
prior to 55 years of age in a male parent or sibling and
prior to 65 years of age in a female parent or other
female first degree relative
- Male  45 years of age
- Female  55 years of age or premature menopause
without hormonal replacement therapy
HDL-C > 1.6 mmol/L is considered as a negative risk factor
* LDL-C is a derived and not a measured value.
NB.
Obesity and sedentary life-style have not been included as risk
factors because they operate through other risk factors that are
already included (hypertension, diabetes mellitus, decreased
HDL-C).
10
6.
PREVENTION OF CHD
Prevention can be divided into:
a.
Primary Prevention
 preventing the occurrence of CHD events in people without CHD.
b.
Secondary Prevention
 preventing the progression of CHD and its complications in people
with established CHD.
Evaluation and aggressive treatment for primary prevention especially for young
adults i.e. men <35 years and premenopausal women is not well established and
should be assessed on a case to case basis especially if there is a strong family
history of CHD. Secondary prevention on the other hand requires aggressive
management.
6.1
Primary Prevention
The strategy would be based on:6.1.1
Population based strategy
This strategy is aimed at educating the public concerning CHD, its
presentation and complications, cardiac risk factors and the importance of
maintaining a healthy life style. Mass screening for hyperlipidaemia is
not advocated as it is not cost-effective and there may be inadequate
follow-up and counselling.
6.1.2
Individual based strategy
The aim is to identify individuals at risk of developing CHD and modify
their risk factors. Individuals at high risk defined as those having 2 or
more risk factors, especially in those with a family history of premature
CHD, should have a full lipoprotein analysis after at least 10 hours of
fasting. If the results are in the acceptable range it should be repeated
every 3 years. If it is abnormal, a repeat analysis should be obtained in 23 weeks before deciding on further management. It should be strongly
emphasized that management is based on treating the patient as a whole,
modifying all the risk factors and not the hyperlipidaemia in isolation.
The objective is to reduce the risk of CHD in the immediate and long
term.
11
6.2
Secondary Prevention
The population involved are patients with established CHD with or without other
atherosclerotic disease, e.g. peripheral vascular disease, cerebrovascular disease.
Recent clinical trials indicate aggressive lipid lowering therapy will :
 lead to stabilisation, reduce progression and induce regression of
atherosclerotic plaques.
 decrease total and CHD mortality and morbidity.
Drug therapy should be initiated together with non-pharmacological measures
(NPM).
12
7.
LIPID LEVELS FOR INITIATING TREATMENT
The decision to initiate treatment is determined by target levels based on:
a.
b.
Presence or absence of CHD.
Presence or absence of non-lipid risk factors.
.
TARGET LEVELS FOR HYPERCHOLESTEROLAEMIA
TARGET LEVEL
GLOBAL RISK
Risk mildly increased
pretreatment total cholesterol of 5.2 7.8 mmol/L
No risk factor of CHD
Risk moderately increased
pretreatment total cholesterol of
5.2 - 7.8 mmol/L
plus 1 risk factor
High risk
presence of CHD or peripheral
vascular disease
OR
presence of familial
hypercholesterolaemia or plasma
cholesterol > 7.8 mmol/L
OR
Diabetics with CHD
OR
plasma cholesterol 5.2-7.8 mmol/L
plus 2 risk factors
REDUCE PLASMA
CHOLESTEROL TO
(mmol/L)
REDUCE LDL-C TO
(mmol/L)
5.2 - 6.5
< 4.1
<5.2
< 3.4
4.5 - 5.0
< 3.0
(Note: 1. It is preferable to aim for the lower value.
2. TG target level is not yet determined; suggested value <2.3 mmol/L)
13
8.
MANAGEMENT OF HYPERLIPIDAEMIA
8.1
Non-Pharmacological Measures
Introduction
Non-pharmacological measures (NPM) refer to dietary modification, weight reduction,
regular exercise, cessation of smoking and alcohol restriction.
NPM are the mainstay of treatment of hyperlipidaemia. They should precede or be
initiated together with drug therapy and are directed especially at individuals who are
obese, who smoke and who seldom exercise. The obvious advantages of NPM are the
absence of adverse side effects that may complicate drug therapy and the minimal costs
incurred.
For patients without CHD, peripheral vascular disease or any other risk factors, emphasis
should be placed on NPM especially dietary modification and exercise.
8.1.1
Dietary Modification
This is aimed at optimising lipid levels while maintaining a balanced diet. It
involves reducing high intake of saturated fats (SFA), cholesterol and calories.
The lipid lowering diet includes the reduction of total fat, reduction of the
proportion of SFA and increase in the proportion of mono (MUFA) and
polyunsaturated fats (PUFA) and reduction of dietary cholesterol. SFA raise
blood cholesterol levels whereas PUFA help to lower cholesterol.
Dietary therapy can lower TC by 12-15%.
8.1.2
Weight Reduction
This is of special importance in overweight and obese patients particularly those
with central obesity. Obesity has been shown to be associated with higher levels
of TG and lower levels of HDL-C and in some cases there may be a slight
increase in TC and LDL-C. Weight reduction helps to lower TG and increase
HDL-C, in addition to enhancing the cholesterol (TC and LDL-C )- lowering
effect of dietary treatment. A weight reduction of 0.5-1.0 kg per week is
recommended. The recommended BMI is <25kg/m2 and waist-to-hip ratio
(WHR) is < 0.9 for males and < 0.8 for females.
14
8.1.3
Exercise
Exercise and weight reduction will enhance the lipid-lowering effect of dietary
treatment. Such exercises include aerobic exercises (eg brisk walking, jogging,
cycling, swimming). Exercise will also increase HDL-C and decrease plasma
TG. To achieve good lipid profiles, exercise needs to be regular and adequate (at
least 30-45 minutes per session 3x a week). A regular exercise programme can
counteract the low HDL-C observed in patients on a low cholesterol diet.
8.1.4
Cigarette Smoking
Smoking is one of the major risk factors for CHD. Smoking reduces HDL-C
level and increases lipid peroxidation products which is atherogenic. Passive
smoking also decreases HDL-C levels.
8.1.5
Alcohol
Restriction of alcohol is advised in patients with hyperlipidaemia as it increases
plasma TG levels. Moderate alcohol consumption (not more than 21 units for
males and 14 units for female per week) has been associated with higher levels
of HDL-C, HDL3, apoproteins A-I and A-II. In general, alcohol consumption is
not recommended as a means of improving lipid profile.
8.2
Monitoring Therapy
The lipid profile should be measured 3-6 months after initiating NPM. Generally, NPM
may reduce lipid levels by up to 25%. If these levels are not achieved, patient
compliance should be assessed. For individuals at low risk, failure to achieve a defined
target value for reduction of cholesterol does not mean that dietary therapy be replaced
by drug therapy. Whatever reduction that is achieved will help lower the risk of CHD
especially with the concomitant adoption of a healthy lifestyle.
Drug therapy should be considered together with NPM from the outset in patients with
established coronary heart disease or in those with severe primary hyperlipideamia.
Those without CHD or who have mild to moderate hyperlipidaemia, could be managed
by NPM. Drug therapy is presently not recommended for these groups of patients
especially if they are males who are <35 years old or pre-menopausal females.
15
8.3
Miscellaneous
Omega-3 fatty acid is useful in individuals with high TG and can be considered in
addition to fibrates or nicotinic acid.
The importance of the following in treating hyperlipidemia remains uncertain :- transfatty acids, essential fatty acids (linoleic acid, linolenic acid), anti-oxidants and lecithin.
16
8.4
Drug Therapy
Non-pharmacological measures form the mainstay in the treatment of hyperlipidaemia.
In secondary hyperlipidaemia, efforts should be made to correct the underlying cause. In
those with established CHD, drug treatment will need to be initiated from the outset in
conjunction with NPM.
There are 4 major groups of drugs currently in use. They are:
8.4.1
Bile Acid Sequestrants (Resins)
Bile acid sequestrants are effective in lowering LDL-C, both in familial
hypercholesterolaemia (at full dosage) and in other forms of diet-resistant
hypercholesterolaemia (often in lower, easily tolerated dosage). Resin increases
HDL-C slightly. Combination with a statin may be necessary in severe
hypercholesterolaemia.
Resins are not suitable in combined (mixed)
hyperlipidaemia as monotherapy. TG levels may increase unless used together
with a TG-lowering drug.
Recommended Dosage
- cholestyramine (Questran) 4 - 24 g/day taken daily or twice daily with meals
Side Effects *
GIT symptoms eg. constipation (major single complaint), abdominal discomfort,
flatulence, nausea, vomiting, anorexia, diarrhoea. Bleeding tendencies (Vitamin
K deficiency), skin rash. Resins may reduce absorption of a number of oral
medication.
Contraindications *
Hypersensitivity, complete biliary obstruction.
* For more details, please look up for further reference.
17
8.4.2
HMG CoA Reductase Inhibitors (Statins)
HMG CoA reductase inhibitors are highly effective in all conditions where LDLC elevation is the predominant disorder. They are suitable first-line agents in
familial hypercholesterolaemia. They have moderate effect in lowering TG and
in elevating HDL-C. Treatment is commenced at a minimum dosage and
increased stepwise, if necessary. Serum lipids, creatinine kinase and alanine
aminotransferase are measured at 6-8 weeks interval initially and thereafter as
necessary.
In patients with very high pretreatment cholesterol levels, combination therapy
with resin may be needed. The safety of statins in pregnancy has not been
established.
8
Recommended Dosage
- lovastatin (Mevacor) 10-80 mg/day daily or
- pravastatin (Pravachol)
divided doses
10-40 mg daily or
- simvastatin (Zocor)
doses
5-40 mg daily or divided
- fluvastatin (Lescol)
divided doses
20-80 mg daily or
divided doses
Side Effects *
These drugs are generally well-tolerated. Note side effects are flatulence,
diarrhoea, constipation, nausea, myopathy, hepatitis.
The risk of myopathy and rhabomyolysis may be increased in combination
therapy with fibric acid derivatives, niacin and cyclosporin.
Contraindications *
Hypersensitivity, active liver disease, pregnancy and lactation.
* For more details, please look up for further reference.
18
8.4.3
Fibric Acid Derivatives (Fibrates)
Fibric acid derivatives are particularly useful in patients with combined (mixed)
hyperlipidaemia and hypertriglyceridaemia as they reduce serum TG effectively,
increase HDL-C substantially and can be used in mild to moderate
hypercholesterolaemia, in which LDL-C may be lowered. Treatment is usually
commenced with a recommended optimal dosage.
Serum alanine
aminotransferase should be monitored.
Recommended Dosage
- bezafibrate (Bezalip)
divided doses or
sustained release form,
- fenofibrate
(Lipanthyl)
daily
200-600 mg daily or in
400 mg daily
100-300 mg daily
or micronised form, 200 mg
- gemfibrozil 600-1200mg daily or in divided
doses
(Lopid)
- ciprofibrate
(Modalim)
100 mg daily
Side Effects *
Most commonly reported are GIT symptoms, eg. diarrhoea, abdominal pain,
nausea and flatulence. Abnormal liver function tests.
Contraindications *
Severe hepatic or renal dysfunction, gall bladder disease, hypersensitivity.
8.4.4
Nicotinic Acid and its derivatives
Nicotinic acid effectively lowers both serum cholesterol and TG levels but its
side effects tend to limit compliance, eg. cutaneous flushing and abdominal
symptoms being the most common problems. Liver disease, gout and diabetes
are relative contra-indications for its usage and therefore routine monitoring for
signs of these diseases is necessary. Acipimox is a derivative of nicotinic acid
which produces less cutaneous flushing and does not worsen glucose tolerance.
* For more details, please look up for further reference.
19
Recommended Dosage
Nicotinic acid (Niacin) is available as tablets of 50 mg or 500 mg, and sustained
release form:
- starting dose:
150-300 mg daily in divided
doses
titration of dose up to 2 - 6
g/day
Acipimox (Olbetam) 750 mg daily in divided doses
Side Effects *
Cutaneous flushing, abdominal pain.
Contraindications *
Hypersensitivity.
contraindications.
Liver disease, gout and diabetes mellitus are relative
* For more details, please look up for further reference.
20
8.5
Hypertriglyceridaemia
In severe hypertriglyceridaemia, TG > 6 mmol/L which is refractory to 8-12 weeks of
non-pharmacological therapy, drug therapy is recommended. In patients with a history
of acute pancreatitis or with levels > 10 mmol/L, drug therapy should be started
immediately.
Table 6.
RECOMMENDED DRUG THERAPY
HYPERLIPIDAEMIA
DRUG OF CHOICE
Hypercholesterolaemia
resin, statin
Mixed Type
fibrates, nicotinic acid, statin
Hypertriglyceridaemia
fibrates, nicotinic acid
21
8.6
Combination Drug Therapy
This may be necessary to achieve target levels in severe hyperlipidaemia. Acceptable
forms of combination therapy include:
Table 7.
COMBINATION DRUG THERAPY
HYPERLIPIDAEMIA
Severe
Hypercholesterolaemia
DRUG OF CHOICE
statin + resin
statin + fibrates *
statin + nicotinic acid
resin + nicotinic acid
Severe Mixed Type
statin + fibrates *
statin + nicotinic acid
resin + fibrates /nicotinic acid
* there is an increased risk of myositis and rhabdomyolysis with this combination.
8.7
Monitoring and Duration of Therapy
It should be stressed that these patients will be on long term therapy. It is therefore
important to assess them on a regular basis, ie. in terms of the response to treatment by
regular lipid measurements every 3-6 months and to look out for possible side effects
related to the drugs.
22
9.
TREATMENT OF SPECIAL GROUPS
9.1
Women
CHD in women occurs principally in later life - it lags 10 years behind CHD in men
and is the leading cause of death among women in developed countries. Management
of CHD risk in women is as important. The lipid and non-lipid risk factors in men
have similar predictive values in women. This CHD lag period in women is probably
due to such protective factors as female sex hormones accounting for the differences
in lipoprotein levels. Prior to menopause women have lower total and LDL
cholesterol levels than men and higher HDL cholesterol as well. After menopause the
TC and LDL-C increases and approaches the levels in similar aged men. Serum TG
appears to be more important in women as a risk factor for CHD.
Lipid lowering drug therapy can often be delayed in pre-menopausal women when
LDL-C does not exceed 5.7 mmol/l and other risk factors are not present. In
postmenopausal women and in premenopausal women with severe primary
hyperlipidaemia non-pharmacological therapy together with drug therapy should be
initiated. When lipid lowering trials with clinical event end-points are analysed
separately, the degree of cholesterol lowering and reductions in CHD mortality have
been about the same in men and women. If lipid lowering drugs are necessary in
women with likelihood of pregnancy, bile-acid sequestrants are preferred. The choice
of drugs for post-menopausal women is as for men.
Diabetes mellitus in women removes the protective effect and in the diabetic women
the CHD risk becomes similar to men. The threshold for treatment of lipid levels in
diabetic women should therefore be as for men.
Use of oestrogens appears to have a biphasic effect on CHD risk in women. Use of
higher dose oestrogen in OCP especially in smokers have a marked effect on
increasing the CHD risk. On the other hand the use of oestrogen replacement therapy
may confer benefit in post-menopausal women by increasing HDL and lowering LDL
cholesterol levels. Data from non-randomised studies suggest that oestrogen
replacement is associated with lesser severity of atherosclerosis as shown by
coronary angiography and a lower frequency of CHD. The effect of progestogen on
lipids has been considered but it appears that adding medroxyprogesterone does not
have adverse effects on LDL and HDL. The use of progestogen is important in those
with intact uterus to protect against endometrial carcinoma but has not been shown to
be protective against breast carcinoma. The use of the second generation selective
oestrogen receptor modulators eg. raloxifene which has agonist activity on the bone
and cholesterol metabolism but without action on the breast or uterus may offer a
safer alternative. Long-term trial results are yet to be seen.
23
9.2
Elderly
In the elderly the relative risk of CHD conferred by raised cholesterol is only
moderate or mild but the attributable risk is high. This is because the prevalence of
CHD is much higher in the elderly compared to younger groups. A high cholesterol
level leads to more CHD in the elderly and therefore the need to treat also exists in
this age group. Clinical trials in the elderly are limited but sub-group analysis of
recent trials support aggressive lipid lowering treatment in the healthy elderly. It is
important to consider functional age rather than chronological age.
In the elderly the presence of other risk factors and secondary causes of
hyperlipidaemia, eg. drugs should be actively sought and treated. Target lipid levels in
the elderly are those used for the general adult population. Dietary therapy needs to be
individualised. They should be encouraged to exercise appropriately. The elderly are
prone to adverse effects of all drugs therefore caution should be exercised. Fibrates
and the statins are generally well tolerated.
9.3
Children
Screening of children should be selective and confined to those above two years of
age whose parents have premature CHD or primary hyperlipidaemia.
Non-pharmacological measures are advocated in children between the age of 2 - 18
years but calorie levels must take into account growth and development and desirable
body weight.
Drug therapy should be started in children above the age of 12 years where LDL-C
remains very high despite lifestyle change. When indicated, the drug of choice should
be a resin. The other drugs should be avoided unless absolutely necessary as the
safety of these drugs in children have not been established.
9.4
Diabetes mellitus
Atherosclerotic disease is a major cause of mortality and morbidity in diabetics and
occurs earlier in younger individuals and in women when compared to the nondiabetic population. Diabetics especially NIDDM have lipid abnormalities especially
hypertriglyceridaemia, decreased HDL-C. They have a higher proportion of small
dense LDL as well as other atherogenic abnormalities eg. elevated Lp(a), glycated
LDL (which is more susceptible to peroxidation), increased fibrinogen and reduced
plasminogen activation inhibitor-1 (PAI-1).
Treatment by lifestyle change and glycaemic control (optimisation of body weight,
exercise and drug therapy) will have a positive impact on the lipid indices. In view of
data from recent studies, more aggressive cholesterol lowering in diabetics is
necessary as compared to non diabetics to reduce the risk of CHD events. Statins
have also been shown to beneficially influence diabetic nephropathy.
24
9.5
Renal Disease
In nephrotic syndrome elevated serum total and LDL-C occurs. Treatment of the
underlying cause for the nephrotic syndrome should be given first as the lipid problem
may resolve. In those with persistent hyperlipidaemia especially with the presence of
other risk factors anti lipid treatment should be considered. Chronic renal failure is
associated with dyslipidaemia and hypertension. It has been shown that treating
hyperlipidaemia may slow down the progression of renal impairment. Caution must
be exercised when starting statins watching out for acute deterioration in renal
function and myopathy. A lower starting and maintenance dose is recommended. In
haemodialysis patients, the main abnormalities are elevated levels of TG and lower
levels of HDL-C. In CAPD patients more severe disturbances of lipid profile can
occur. In these patients on renal replacement therapy there is inadequate data at
present to make definite recommendations regarding drug therapy. There are at
present no good control studies to show reduction of cardiac events following anti
lipid treatment.
25
10.
CONCLUSIONS

Interpretation of lipid profiles should take into consideration variability and modifying
factors including secondary causes.

Elevated TC, LDL-C, low HDL-C and the combination of high TG - low HDL-C are
proven risk factors of CHD.

Primary prevention reduces CHD events, cardiac and total mortality.

Secondary prevention will lead to stabilisation, reduce progression and induce
regression of atherosclerotic plaques. Aggressive lipid lowering therapy reduces strokes,
cardiac events, cardiac and total mortality.

The threshold for initiating therapy depends on the presence or absence of coronary risk
factors and atherosclerotic diseases.

Management of the risk factors for CHD should be global in approach including NPM
and where appropriate, drug therapy should be initiated.

For those without CHD, emphasis should be on NPM.

In those with no other risk factors, treatment should be initiated to achieve a target level
of LDL-C of less than 4.1 mmol/L.

In those with one other risk factor, treatment should be initiated to achieve a target level
of LDL-C of less than 3.4 mmol/L.

In those with two or more other risk factors, or presence of atherosclerotic disease,
treatment should be initiated to achieve a target LDL-C level of less than 3.0 mmol/L.

For those with CHD or with two or more other risk factors, drug therapy should be
initiated together with NPM.

In diabetics, aggressive lipid lowering therapy is advocated.



In post-menopausal or diabetic women, a similar treatment strategy should be followed.

In the elderly, treatment is still beneficial with similar target values as in the younger
age group.
In children, if drug treatment is necessary, it should be started after the age of 12 years
using resins.
26
APPENDIX 1
LIPID LOWERING DIET
Principle
Decreased total fat/oil.
Amount
Comment
< 30% energy.
Modify cooking methods grill/steam/boil/microwave/bake to
reduce use of oil and fats.
a) Saturated fat.
Avoid.
eg. butter, hard margarine, whole
milk, cream, high fat cheese, fatty
meals, bacon and sausages, coconut
oil, santan, products containing
hydrogenated oils eg. some coffee
whitener.
b) Mono and
polyunsaturated
oils/margarine.
Not more than 2
tablespoons per day
(including the amount
in products based on
these).
eg. olive oil, sunflower oil, corn oil,
palm oil, soyabean oil, peanut oil,
polyunsaturated margarine.
Types:
Use food high in protein but
low in saturated fat
Skinned chicken, fish, bean curd
(tofu), egg white, legumes.
Increased intake of complex
carbohydrate; increased
fruit, vegetables and
legumes for fibre
20-25gm fibre/day - half All fruits, fresh vegetables, legumes
derived from fruit and
(lentils, peas, beans) unrefined cereals
vegetables.
including oats, wholemeal flour,
tubers.
Decreased dietary
cholesterol.
< 300 mg/day
Allow up to 2 egg yolks per week.
Avoid organ meat (offal) eg. liver,
heart, brains, kidney.
Allowed a small/reduced amount of
prawn/crab/oyster/cockles once or
twice a week.
27
APPENDIX 2
BODY MASS INDEX
Calculation of body mass index (BMI) is one way of determining the ideal weight for an
individual. BMI is the relationship of body weight to height. Increased BMI is associated with
increased mortality and morbidity - predictive value of BMI is enhanced by taking waist/hip
ratio into consideration as well.
To work out BMI, use this formula (applicable to adults only).
Body Mass Index
(Weight in kg)
=
( Height in m)2
(BMI)
Classification according to BMI
BMI
CLASSIFICATION
<18.5
>19 - 25
underweight
desired weight
>25 - 30
overweight
>30 - 40
obese
> 40
morbid obesity
28
APPENDIX 3
Waist-To-Hip Ratio (WHR)
WHR is a simple measurement to indirectly quantify adipose tissue distribution. An increased
WHR indicates preferential accumulation of adipose tissue in the abdominal region (visceral
fat).
The measurement of the waist is made at the mid-level between the lowest point of the rib
cage and the upper most point of the iliac crest. The measurement of the hip is made at the
level of the greater trochanter.
Normal WHR
Males
< 0.90
Females
< 0.80
29
Bibliography
1.
American Heart Association Task Force on Risk Reduction. When To Start Cholesterol
- Lowering Therapy in Patients with Coronary Heart Disease. Circulation 1997;
95:1683-1685.
2.
Anderson K M, Castelli W P. Cholesterol and mortality: 30 years of follow-up from the
Framingham Study. JAMA, 1987; 257.
3.
Assmann G and Schutle H. PROCAM Study. Am. J. Cardiol., 1992; 70: 733-737.
4.
Burns - Cox C J, Chong V H, Gillman R. Risk Factors and the Absence of CHD in
Aborigines in West Malaysia. Br. Heart J., 1972; 34(9): 95.
5.
Chong Y H, Khoo K L. Serum Lipid Levels and Prevalence of Hyperlipidaemia in
Malaysia. Clin. Chem. Acta, 1975; 65: 143-148.
6.
Chong Y H. Serum Lipids and Lipoprotein in Healthy Malaysians. Med. J. Malaya
1964; 16: 136-138.
7.
Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in
Adults. National Cholesterol Education Program: Second Report of the Expert Panel on
Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult
Treatment Panel II). Circulation 1994; 89: 1329-1445.
8.
Frick M H, Haapa K, et al. Helsinki Heart Study. Primary Prevention Trial with
Gemfibrozil in Middle Aged Men with Dyslipidaemia. N. Eng. J. Med., 1987; 317:
1237-45.
9.
Garber AM, Browner WS. American College of Physicians Guidelines for Using Serum
Cholesterol, and Triglycerides Levels as Screening Tests for Preventing Coronary Heart
Disease in Adults. Ann. Intern. Med. 1996; 124:515-517.
10. Gould AL, Rossouw JE, et al. Cholesterol Reduction Yields Clinical Benefit. A New
Look at Old Data. Circulation 1995; 91:2274-2282.
11. Kannel W B, Neaton Y D, Wentworth D, Thomas H E, Stanler J, Hulley S B,
Kjelsberg M O for the MRFIT Research Groups. Overall and CHD Mortality Rates in
Reference to Major Risk Factors in 325,384 Men Screened for the Multiple Risk Factors
Intervention Trial. Am. Heart J., 1986; 112: 825-836.
12. Kannel W B, Castelli W P, Gordon T, McNamane P. Serum Cholesterol, Lipoprotein
and the Risk of CHD. The Framingham Study. Ann. Intern. Med., 1971; 74: 1-12.
13. Kannel W B. Lipids, Diabetes and CHD. Insight From The Framingham Study. Am.
Heart J., 1985; 110: 1100-1107.
14. Khoo K L and Chong Y H. Editorial: Diet, Drug and Hyperlipidaemia.
Progress, 1974; May: 13-14.
30
Medical
15. Khoo K L. A Study of Certain Lipid Abnormalities in Peninsular Malaysia. MD Thesis;
University of Singapore: 1979
16. Kissebah AG, Freedman DS, Peivis AN. Health Risks of Obesity. Med. Clin. North Am.
1989; 73 : 111-138.
17. Lerner D J, Kannel W B. Patterns of CHD Morbidity and Mortality in the Sexes: A 26
year Follow-Up of the Framingham Population. Am. Heart J., 1986; 111: 383-90.
18. Lipid Research Clinics Program. The lipid Research Clinic Coronary Primary
Prevention Trial Results. (I) Reduction in Incidence of CHD. (II) The Relationship of
Reduction in Incidence of CHD to Cholesterol Lowering. JAMA, 1984; 2: 351-74.
19. Manninen V, Tenkanen L, Koskinen P, et al. Joint efforts of serum triglycerides and
LDL cholesterol and HDL cholesterol concentration on CHD risk in Helsinki Heart
Study: implications for treatment. Circulation, 1992; 85 (1): 1-9.
20. Multiple Risk Factor Intervention Trial Research Group. Multiple Risk Factor
Intervention Trial. Risk Factor Changes and Mortality Results. JAMA, 1982; 248: 14651477.
21. Pooling Project Research Group. Relationships of Blood Pressure, Serum Cholesterol,
Smoking Habits, Relative Weight and ECG Abnormalities to Incidence of Major
Coronary Events. Final Report of the Pooling Project. J. Chronic Dis., 1978; 31: 201206.
22. Pyorala K, Pedersen TR, Kjekshus J, et al. Cholesterol Lowering with Simvastatin
Improves Prognosis of Diabetic Patients with Coronary Heart Disease. Diabetes Care
1997; 20:614-620.
23. Report on The National Cholesterol Education Program Expert Panel on Detection,
Evaluation and Treatment of High Blood Cholesterol in Adults. Arch. Int. Med., 1988;
148: 36-69.
24. Sacks FM, Pfeffer MA, Moye LA, et al for the Cholesterol and Recurrent Events Trial
Investigators. The Effect of Pravastatin on Coronary Events After Myocardial Infarction
in Patients with Average Cholesterol Levels. NEJM 1996; 335:1001-1009.
25. Scandinavian Simvastatin Survival Study (4S) Group. Randomized Trial of Cholesterol
Lowering in 4444 Patients with Coronary Heart Disease. Lancet 1994; 344: 1383-1389.
26. SHEP Cooperative Research Group. Prevention of Stroke by Antihypertensive Drug
Treatment in Older Person Treated for Isolated Systolic Hypertension. Results of the
SHEP. JAMA, 1991; 265: 3255-64.
27. Shepherd J, Cobbe SM, Ford I, et al for the West of Scotland Coronary Prevention Study
Group. Prevention of Coronary Heart Disease with Pravastatin in Men with
Hypercholesterolaemia . NEJM 1995; 333:1301-1307.
31
28. Summary of the Recommendations of the European Atherosclerosis Society:
"Prevention of Coronary Heart Disease - Scientific Background and New Clinical
Guidelines". Prepared for the European Atherosclerosis Society by the International
Taskforce for the Prevention of Coronary Heart Disease. 1992
29. Summary of the Second Report of the National Cholesterol Education Program (NCEP)
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in
Adults (Adult Treatment Panel II). JAMA, 1993; 269(23): 3015-3023.
30. Task Force of the European Society of Cardiology, European Atherosclerosis Society
and European Society of Hypertension. Prevention of Coronary Heart Disease in Clinical
Practice. Eur. Heart J. 1994;15:1300-1331.
31. WHO Expert Committee.
Physical Status: The Use and Interpretation of
Anthropometry. WHO Technical Report Series 1995: 854.
32