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6632 PDF
6632 PDF
II
STATEMENT OF INTENT
CPG Secretariat
Health Technology Assessment Unit
Medical Development Division
Level 4, Block EI, Parcel E
Government Offices Complex
62590 Putrajaya, Malaysia
http://www.malaysianheart.org
http://www.moh.gov.my
http://www.acadmed.org.my
1
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
3
Table 3 : Recommendations for Therapeutic Lifestyle Changes
Grade of Comments
Recommendation
Level of Evidence
Diet
Saturated Fats and I, B < 7% of calorie intake
Trans-fatty acids
4
FLOWCHART I: HIGH RISK INDIVIDUALS
LIPID MANAGEMENT OF PERSONS WITH CVD OR CHD RISK
EQUIVALENTS (Adapted and modified from ATPIII)139
In these high risk individuals the recommended LDL-C goal is <
2.61,A mmol/L with an optional goal < 2.0 mmol/L1,A
CVD + CHD
Risk Equivalents
5
FLOWCHART II: INTERMEDIATE RISK INDIVIDUALS
LIPID MANAGEMENT OF PERSONS WITH
MULTIPLE RISK FACTORS,
10-YEAR RISK 10-20 PERCENT
(Adapted and modified from ATPIII)139
The LDL-C goal is < 3.4 mmol/L. I,A Drugs can be considered after
a trial of TLC if the LDL-C level is 3.4 mmol/L.
6
FLOWCHART III: LOW RISK INDIVIDUALS
LIPID MANAGEMENT OF PERSONS WITH MULTIPLE (2+) RISK
FACTORS, 10-YEAR RISK < 10 PERCENT
(Adapted and modified from ATPIII)139
7
FLOWCHART IV: LOW RISK INDIVIDUALS
LIPID MANAGEMENT OF PERSONS WITH 0-1 RISK FACTOR
(Adapted and modified from ATPIII)139
In these individuals, the LDL-C goal is < 4.1 mmol/L. Drug therapy
can be considered if the LDL-C level is 4.9 mmol/L after a
trial of TLC. If LDL-C is 4.1-4.9 mmol/L, drug therapy is optional
depending on clinical judgment.
* 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.
8
9
MESSAGE FROM THE AMERICAN COLLEGE OF CARDIOLOGY
Sincerely,
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;356:2388-
2398.
10
Members of the Expert Panel
Chairperson:
Dr Robayaah Zambahari Consultant Cardiologist,
Institute Jantung Negara,
Kuala Lumpur
Secretary :
Dr R. Jeyamalar Consultant Cardiologist,
Sime Darby Medical Center,
Subang Jaya, Selangor
11
External Reviewers (in alphabetical order):
12
RATIONALE AND PROCESS OF GUIDELINE DEVELOPMENT
Rationale:
In Malaysia, cardiovascular disease (CVD) is 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).
Malaysians develop ACS at a younger age when compared to
people in Thailand, mainland China and western countries. Our
local NCVD-ACS Registry, showed that most patients (96.8%) had
at least one established cardiovascular risk factorhypertension
(72.6%), dyslipidaemia (55.9%) and /or diabetes (55%)3.
In preventing CVD, efforts should be aimed at reducing global
risks. The Clinical Practice Guideline (CPG) is on management of
dyslipidaemia. The last CPG (3rd edition) was published in 2004.
Thus the need for an update.
Objectives:
The objective of this CPG is to:
provide guidance on the best treatment strategies for
managing dyslipidemia utilizing and optimizing existing
health resources.
This CPG has been drawn up by a committee appointed by the
National Heart Association of Malaysia, Ministry of Health and the
Academy of Medicine. It comprises cardiologists, endocrinologists
and general physicians from the government and private sectors
as well as from the Universities.
Process:
Evidence was obtained by systematic review of current medical
literature on dyslipidaemia using the usual search engines
PubMed, Medscape and Ovid. The other international guidelines
(American and European) on the subject were also studied. After
much discussion, the draft was then drawn up by the members
of the Expert Panel and submitted to the Technical Advisory
Committee for Clinical Practice Guidelines, Ministry of Health
Malaysia and key health personnel in the major hospitals of the
Ministry Of Health and the Private Sector for review and feedback.
The clinical questions were divided into major subgroups and
members of the Expert Panel were assigned individual topics. The
13
group members met several times throughout the development of
the guideline. All retrieved literature were appraised by individual
members and subsequently presented for discussion during group
meetings. All statements and recommendations formulated were
agreed collectively by members of the Expert Panel. Where the
evidence was insufficient the recommendations were derived by
consensus of the Panel. The draft was then sent to local external
reviewers for comments. It was also sent to the American College
of Cardiology and the European Society of Cardiology for feedback.
The level of recommendation and the grading of evidence used in
this guideline was adapted from the American Heart Association
and the European Society of Cardiology (ACC/ESC) and outlined
on page 15. In the text, this is written in black on the left hand
margin. In the Summary and Key Recommendations, it is written
as a superscript immediately after the therapeutic agent or at the
end of the statement as applicable.
Clinical Questions Addressed:
What is the current evidence on the management of patients
with dyslipidaemia?
Which management and recommendations are most
applicable to our local setting?
Target Group:
This guideline is directed at healthcare providers including general
practitioners, medical officers, pharmacists, general and family
physicians, cardiologists and endocrinologists.
Target Population: All individuals.
Period of Validity of the Guidelines:
This guideline needs to be revised at least every 5 years to keep
abreast with recent developments and knowledge.
Applicability of the Guidelines:
This guideline was developed taking into account our local health
resources. Blood chemistry for lipid profiles, liver and renal
function tests can be done in all government health facilities. The
medications recommended are approved for use in Malaysia.
This guideline aims to educate health care professional on
strategies to optimize existing resources in the management of
dyslipidemia.
14
Implementation of the Guidelines:
The implementation of the recommendations of a CPG is part of
good clinical governance. To ensure successful implementation of
this CPG we suggest:
increasing public awareness of CVD and its prevention
continuing medical education and training of healthcare
providers.
monitoring lipid levels in the population through National
health surveys which will now be conducted every 5 years
and through the NCVD ACS/PCI registry.
clinical audit at hospital level- documentation of target LDL-C
levels.
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. Introduction 17
2. Measurement of Lipids and Apoproteins 17-19
3. Classification of Dyslipidaemias 19-22
4. Dyslipidaemia as a Risk factor for CVD 22-24
5. Other Risk Factors for CVD 24-27
6. Global Cardiovascular Risk Assessment 27-34
6.1 Risk Stratification 27-32
6.2 Diabetes mellitus and Dysglycaemia as CHD 32-34
risk equivalents
6.3 Targets of therapy 34
7. Prevention of CVD 35
8. Management of Dyslipidaemia 36-47
8.1 Therapeutic Lifestyle Changes 36-39
8.2 Lipid lowering Drug Therapy 40-47
8.3 LDL Apheresis 47
9. Management in Specific Conditions 47-60
9.1 Specific Lipid Disorders 47-52
9.2 Diabetes Mellitus 52-54
9.3 Coronary Heart Disease 54-56
9.4 Hypertension 56-57
9.5 Stroke 57
9.6 Renal Disease 58-60
10. Management in Specific Groups 61-63
10.1 Women 61
10.2 Children and Adolescents 61-62
10.3 Elderly 62-63
11. Adherence, Compliance and Quality Assurance 63-64
12. References 65-79
13. Appendixes 80-84
14. Acknowledgement 85
15. Disclosure Statements 85
16. Source of Funding 85
16
1. INTRODUCTION
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).
17
2. MEASUREMENT OF LIPIDS AND APOLIPOPROTEINS
Non-HDL-C(mmol/l) = TC HDL-C
18
Measurements made from whole blood differs slightly from that
obtained from plasma or serum. TC, TG and HDL-C measured using
desktop machines are acceptable when performed according to
specifications.
Key messages:
TC and HDL-C can be measured in the fasting and non
fasting states. TG is best measured in a fasting sample.
LDL-C is calculated using the Friedwalds equation.
When TG > 2.3mmol/l, non HDL-C is a better indicator
of total atherogenic burden.I,A
3. CLASSIFICATION OF DYSLIPIDAEMIAS
Dyslipidaemia is defined as lipid values outside the norm. Based
on therapeutic considerations, dyslipidaemias may be classified as
follows (Table 4):
19
Table 5: Primary Dyslipidaemia
Common
(polygenic) Corneal Arcus
N
Hypercholes- Xanthelasma
terolemia
Familial
Corneal Arcus
Combined
or or Xanthelasma
Hyper-
lipidemia
Tendon
xanthomata,
Familial (finger extensor,
Hypercholes- Achilles tendons)
terolemia Corneal Arcus,
Xanthelasma,
Aortic stenosis
Tuberous
xanthomata,
Remnant (elbows), striae
Hypercholes- xanthomata,
terolemia (palm creases)
tendon
xanthomata
Eruptive
xanthomata,
Chylomic-
or (buttocks, elbows)
ronemia
retinal lipemia,
Syndrome
hepatospleno-
megaly
Eruptive
xanthomata,
Familial
(buttocks, elbows)
Hypertrigly-
retinal lipemia,
ceridemia
hepatospleno-
megaly
High HDL-C -
Low HDL-C or -
20
Dyslipidaemias may be primary or secondary in etiology. (Tables
5 & 6).
In the following situations, secondary causes of dyslipidaemia
should be considered:
When TC exceeds 7.0 mmol/l, exclude conditions such as
primary hypothyroidism, nephrosis, obstructive liver disease.
Cushings syndrome (including subclinical disease) can
lead to lipid abnormalities in 40-70% of patients.15 Patients
on exogenous steroids may also develop secondary
dyslipidemias. Hypothyroidism is another important cause.16
It is more prevalent in the elderly in whom a high index of
suspicion may be necessary for diagnosis.17
When TG exceeds 4.5 mmol/l, exclude secondary causes such
as alcoholism.
When there is high TG with low HDL-C, insulin resistance
states such as type 2 Diabetes (T2DM) and metabolic
syndrome have to be considered
Failure to respond to anti-lipid therapy.
In patients with a family history of T2DM or a past history of
thyroid disease.
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.
22
4.2. Low HDL-C levels
There is substantial data linking a low HDL-C level (< 1.0 mmol/L)
with increased risk of CHD.18,38,39,40 A 1% decrease in HDL-C, in
epidemiological studies, has been associated with 2-3% increase
in CHD risk.40 Clinical trials using pharmacotherapy to increase
HDL-C levels have, however, showed mixed results. 41,42,43
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
5.1. Age
5.2. Gender
5.3. Hypertension
5.4. Smoking
24
The risk of developing CVD is directly related to the number of
cigarettes smoked.70,71 The relative risk of CV events is greater
in younger than in older patients although the absolute excess
mortality related to smoking increases with age.68,70
5.6 Others
Other risk factors include:
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
- 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 individu-
als at intermediate risk. Patients with subclinical athero-
sclerotic disease may warrant a more aggressive preven-
tive 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. 1 Risk Stratification
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
29
Figure 1A: Estimation of 10 year CVD Points for MEN
(Framingham Point Scores) 100
Points Age,y HDL-C TC SBP SBP Smoker Diabetes
(not (treated)
treated)
-2 1.6+ <120
-1 1.3-1.6
0 30-34 1.2-<1.3 <4.2 120-129 <120 No No
1 0.9-<1.2 4.2-<5.2 130-139
2 35-39 <0.9 5.2-<6.3 140-159 120-129
3 6.3-<7.4 160+ 130-139 Yes
4 >7.4 140-159 Yes
5 40-44 160+
6 45-49
7
8 50-54
9
10 55-59
11 60-64
12 65-69
13
14 70-74
15 75+
Points
allotted
31
Figure 1C : Heart Age/ Vascular Age for Men100
32
6.2. Diabetes mellitus and Dysglycaemia as CHD risk equivalents
Patients with type 2 diabetes mellitus (T2DM) and impaired
glucose tolerance
(IGT) have an increased risk of cardiovascular events.101,102 These
patients have higher mortality and a higher incidence of recurrent
cardiac events.103
The two main types of DM (type 1 and type 2) have different
patterns of dyslipidaemia. Type 2 diabetes (T2DM) may be
associated with insulin resistance, as in some individuals with the
metabolic syndrome.
The current definition of metabolic syndrome (2009) includes any
3 or more of the following (including those on treatment)*:
Elevated Waist circumference (Asian cut-off) :
- females >80cm
- males >90cm
Elevated TG > 1.7 mmol/L
Reduced HDL-C < 1.3 mmol/L (female) or
< 1.0 mmol/L (male)
Elevated blood pressure (BP):
- Systolic BP > 130 and / or diastolic BP > 85 mmHg
Disorders of glycaemia:
- T2DM, or
- impaired glucose tolerance (IGT)
[Fasting plasma sugar < 7.0 mmol/L and
2 hours after 75 gm glucose load: 7.8 11.1 mmol/L], or
- impaired fasting glucose (IFG)
[Fasting plasma sugar: 6.1 7.0 mmol/L]
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
35
8. MANAGEMENT OF DYSLIPIDAEMIA
Introduction
I,B A high intake of carbohydrate (> 60% of total caloric intake) results
in a reduction of HDL-C and a rise in TG levels.112,113 In individu-
als with the metabolic syndrome a lower carbohydrate intake is
important.
IIa,B The use of viscous (soluble) forms of dietary fibre (oats, pectin,
guar and psyllium) of at least 510 gm per day is encouraged as
they have been shown to reduce LDL-C levels.114,115,116
36
IIb,B Plant stanol/sterol esters (23 gm/day) also have a LDL-C lowering
effect117 which is dose related but there is inter-individual varia-
tion in their response. Plant sterols and stanols are not routinely
recommended for the prevention of CVD since there are no CV
outcome data.
IIb,B High intake of soy protein (25-50 gm/day) can cause small reduc-
tions in LDL-C.106
37
8.1.5. Alcohol
I,B Restriction of alcohol is advised in patients with dyslipidaemia as it
increases plasma TG levels.121,122
I,A 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
8.1.6. Miscellaneous
IIa,B 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
IIb,B 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
When a decision has been made to start drug therapy, TLC must
still be continued indefinitely because it provides substantial
additive LDL-C lowering effects.136
Key messages:
A multifactorial lifestyle approach is recommended to
reduce the risk of CVD. I,B
In patients without CVD or CHD risk equivalents, a
period of at least 6-12 weeks is given to assess the
effectiveness of TLC before considering drug therapy. I,C
39
8.2. DRUG THERAPY
Statins are inhibitors of HMG CoA reductase , the rate limiting en-
zyme 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
I,A primary prevention of CVD, secondary prevention of CVD and CHD
equivalents.
40
Table 9: Major Anti Lipid Drug Classes (Adapted from ATPIII)139
Drug Class Lipid Effects Side Effects Contraindications
HMG-CoA LDL-C 18-55% -Myopathy Absolute:
Reductase HDL-C 5-15% -Increased liver -Active or chronic liver
Inhibitors TG 7-30% Enzymes disease
(statins) Relative:
-Concomitant use of
certain
drugs*
Fibric-Acid LDL-C 5-20% -Dyspepsia Absolute:
Derivatives HDL-C 10-35% -Gallstones -Severe hepatic
(Fibrates) TG 20-50% -Myopathy disease
-Severe renal disease
Relative:
-Concomitant use of
certain drugs**
* 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.
Recommended
Drug Usual dose range
initiating dose
10-80 mg/day in single
Lovastatin 20 mg
or divided doses
Pravastatin 20 mg 10-40 mg daily
Simvastatin 20 mg 5-80 mg once daily
20-80 mg/day single
Fluvastatin 20 mg
or divided doses
Atorvastatin 10 mg 10-80 mg once daily
Rosuvastatin 10 mg 10-20 mg once daily
* As stated in MIMS,Malaysia
IIa,B 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 Doses of fibrates need to be adjusted in the presence of CKD.
Serum alanine aminotransferase should be monitored when
starting therapy or when doses are increased.
IIa,B Bile acid sequestrants bind to bile acids to promote their secretion
into the intestines. They are effective in lowering LDL-C. Resins may
increase TG and HDL-C slightly. Monotherapy has a modest effect
on CHD in primary prevention. Resins are therefore not suitable as
monotherapy in combined hyperlipidaemia. Combination with a
statin may be necessary in severe hypercholesterolaemia.
43
However its side effects (particularly flushing and gastrointestinal
side effects) tend to limit compliance. Acipimox is a derivative
of nicotinic acid which produces fewer side effects (especially
less cutaneous flushing) and does not worsen glucose tolerance.
Tredaptive is a combination of modified release nicotinic acid
and laropiprant (a prostaglandin inhibitor) which will reduce the
flushing caused by nicotinic acid.
Recommended Dosages:
Recommended Dose:
Ezetimibe 10 mg daily
44
Table 10: Suggested Drug Therapy for Dyslipidaemia
If:
LDL-C < 2.6 mmol/l Statins Fibrates
Nicotinic Acid
If:
LDL-C > 2.6 mmol/l Statins Fibrates
Nicotinic Acid
45
ie. in terms of response to treatment and to look out for possible
side-effects related to the drugs. After starting drug therapy, LDL-C
level should be measured at 6-8 weeks and drug doses titrated
if necessary. Once target lipid levels are achieved, a 4-6 monthly
follow up is recommended.
Cost effective analysis of major lipid lowering trials have shown that
although direct short term cost may be higher, the incremental
cost effectiveness ratio (derived from the ratio of cost over Quality
Adjusted Life Years) is favorable even for patented statins.144
9.1.1. Elevated TG
There is evidence of a strong association between TG levels and
CVD.44,45,46 This may in part be due to its association with the
other CV risk factors found in the metabolic syndrome. Very high
serum TG (> 5.7 mmol/L) can give rise to acute pancreatitis and
needs urgent and definitive treatment. High (2.3-5.7 mmol/L)
and borderline high levels (1.7-2.3mmol/L) of TG are a common
association with low HDL cholesterol, small dense LDL particles
and insulin resistance.
47
9.1.1.1. Targets of therapy
I,A In individuals with elevated TG, the primary target of therapy re-
mains 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 rep-
resentative 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.
* 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
48
Genetic disorders associated with high TG (familial combined
hyperlipidaemia, familial hypertriglyceridaemia and familial
dysbetalipoproteinaemia)
Once LDL-C target has been achieved, the next step is to target TG
< 1.7 mmol/L.
49
Table 12: Classification of TG (Adapted from ATPIII)139
50
There are no clinical trial evidence that show a reduction in CVD
events with drug therapy in individuals with only elevated TG both
in primary and secondary prevention. (Appendix VI, pg 84)
Treatment include:
Start with a fibrate or nicotinic acid
I,B - Gemfibrozil and Fenofibrate lower TG by about 70%.43,47,160,161
I,B - Nicotinic acid is effective at doses of above 2gm per day.139,162
I,B 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.
IIa,B 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.
Low HDL-C and high TG are seen in insulin resistance states and
very high carbohydrate intakes.
51
9.1.3. Isolated Low HDL-C
Individuals with isolated low HDLC have HDL-C < 1.0 mmol/L and
TG < 1.7 mmol/L. Low HDL-C is an independent major risk factor
for CVD.18,38,39 The major causes are obesity, physical inactivity,
cigarette smoking and genetic factors. There are however no large
outcome studies to date showing that increasing HDL-C improves
CVD outcomes. 164
I,A Statin is still the mainstay of treatment even in patients with low
LDL-C (<2.6 mmol/L). Statin trials have showed that lowering LDL-
C in persons with isolated low HDL-C, significantly reduces CVD
risk.166
IIa,B Fibrates have also been shown to reduce major CVD events in
persons with isolated low HDL-C.43,47,160,161 This benefit has been
attributed in part to the HDL-C raising effects of fibrates.
Key messages:
In patients with isolated hypertriglyceridemia, isolated
low HDL-C or its combination, the primary goal of
treatment is lowering LDL-C to target.I,A
The other targets of therapy are lowering non HDL-C
(if TG > 2.3mmol/L) to target, maintaining TG < 1.7
mmol/L and HDL-C > 1.0 mmol/L.
52
Optimal Lipid values in individuals with diabetes are:
Primary target :
I,A - 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
Lower TG Fibrates
I,A Statins should be initiated for all individuals above the age of 40
years with T2DM regardless of baseline LDL-C.170
53
I,B If drug-treated patients do not reach targets on maximal toler-
ated statin therapy, a reduction in LDL cholesterol of 3040% from
baseline is an alternative therapeutic goal.170
Key messages:
Control of glycaemia alone is inadequate in preventing
CV events. Concomitant treatment of dyslipidaemia,
hypertension and other metabolic abnormalities are
also important.I,A
Target LDL-C goal in individuals with diabetes is <2.6
mmol/L. I,A In the presence of established CVD, LDL-C
should be <1.8 mmo/L. I,A
I,A Early initiation of statin therapy soon after admission for ACS is
safe and improves outcome regardless of baseline LDL-C levels in
patient with ACS.32,171-175 These benefits are independent of the
lipid lowering effects of statins.
I,A Patient with ACS should be treated with a higher intensity statins.
More aggressive lipid lowering further lowers cardiovascular event
rates.32,171,172,176-179
54
Lipid management includes:
I,C Assessment of a fasting lipid profile for all patients, within 24
hours of hospitalization.
IIa,B Pre-treatment with statins 7 days prior to elective PCI has been
shown to reduce post-procedure MI.183
I,A Irrespective of the baseline LDL-C level, statin therapy reduces the
risk of major CV events by 24%.29
I,A Individuals with stable CAD should be treated with optimal medi-
cal therapy using a combination of antiplatelet agents, statins,
-blockers and angiotensin converting enzymes inhibitors.190
Key messages:
Statins should be started early in individuals with
ACS, and on all post revascularisation individuals
irrespective of their baseline cholesterol levels.I,A
In high risk individuals, high intensity statin treatment
confers more benefit. I,A
Statins are an integral component of optimal medical
therapy in CAD individuals. I,A
9.4. Hypertension
9.5 Stroke
I,B Statins have been shown to prevent ischaemic stroke in high risk
individuals.29,194
Key messages:
Statins have been shown to reduce the incidence of
ischaemic strokes when used in high risk individuals. I,B
Lipid lowering therapy with statins should be
considered in all individuals with previous ischaemic
stroke or transient ischaemic attack. I,B
57
9.6. Renal disease
Chronic Kidney Disease (CKD) is associated with significant CV
morbidity and mortality.200,201 Mortality increases progressively
with worsening renal function. The risk of death from CVD is
higher than the risk of eventually requiring renal replacement
therapy.202,203 Currently, there are differing views about recognizing
CKD as a CHD Risk Equivalent although all stages of CKD including
individuals with asymptomatic microalbuminuria are at increased
CVD risk. 139,200,204-209 They should be screened for traditional risk
factors and treated according to their determined risk.
IIb,B In individuals with very high TG levels (more than 5.7 mmol/L),
low dose fibrates may be initiated cautiously to prevent
pancreatitis.43,47,160,161
IIa,B Omega 3 Fish oils (at a dose of 4 gm/day) may also be used.219
IIa,B Statins have been shown to have differential effects on the kidney.
Some statins reduce proteinuria and slow the rate of progression
of renal disease while others have been neutral.220,221
58
I,B In individuals with CHD and mild to moderate CKD, statins have
been shown to be beneficial.29,218
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 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
Table 14. Dosing Modifications for Lipid-Lowering Drugs in CKD224
Ezetimibe No No No
60
10. MANAGEMENT IN SPECIAL GROUPS
10.1. Women
III,C Statins should not be used in women who are pregnant, intend to
become pregnant or who are breast feeding.
IIb,B In women who have normal LDL-C but low HDL-C and high TG,
fibrates may be used.47
I,B In primary prevention, the cornerstone of management is lifestyle
modification with advice on a healthy diet and physical activity.
IIa,C Women at high risk who do not achieve their target levels should
be considered for pharmacological intervention although there is
little data on the effect of lipid lowering therapy on CVD events for
primary prevention in women. Current practice is to treat these
women in the same manner as men based on extrapolation of
benefit in men at similar risk.232
IIa,B Women with genetic dyslipidaemias such as familial hypercholes-
terolemia with very high levels of TC or LDL-C may be considered
for lipid lowering therapy from the outset.
61
obesity and the metabolic syndrome238
T2DM
post organ transplantation
systemic lupus erythematosis
nephrotic syndrome
HIV infections
These risk factors have been shown to persist into adult life and
lead to premature CVD.
I,A In children with elevated cholesterol levels, statins are the drug
of choice.240
IIb,B There has been limited data on the use of niacin, fibric acid
derivatives and ezetimibe in children.
62
Thus, they should not be deprived from lipid lowering therapy
solely on the basis of their age although there is limited clinical
trial data in patients over the age of 80 years.
Key messages:
Women and the elderly with CHD and CHD risk
equivalent should be treated in the same manner as
man. I,A
Children with very high cholesterol levels benefit from
statin therapy. I,A
63
To improve adherence and compliance the following are
recommended:
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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APPENDIX I: APOLIPOPROTEINS : MAJOR CATEGORIES
MAJOR CLASSES SUBCLASSES/ISOFORMS
Apo A apo A-I, apo-II, apo A-IV, apo A- V
Apo B apo B-48, apo B-100
Apo C apo C-I, apo C-II, apo C-III, apo C-IV
Apo D
Apo E apo E-2, apo E-3, apo E-4
Apo H
80
APPENDIX III: BODY MASS INDEX
81
APPENDIX IV: COMPARISON OF GLOBAL CORONARY AND CARDIOVASCULAR RISK SCORES94
Framingham SCORE PROCAM (Men) Reynolds (Women) Reynolds (Men)
Sample size 5,345 205,178 5,389 24,558 10,724
Age (y) 30 to 74; 19 to 80; 35 to 65; >45; >50;
82
antihypertensive pressure family history, parental history of MI at of MI at <60 y of age
medications diabetes, <60 y of age
triglycerides
Endpoints CHD (MI and CHD Fatal CHD Fatal/nonfatal MI MI, ischemic MI, stroke, coronary
death) or sudden cardiac stroke, coronary revascularization,
death (CHD and revascularization, cardiovascular
CVD combined) cardiovascular death (CHD and CVD
death (CHD and CVD combined)
combined)
URLs for risk http://hp2010. http://www. http://www.chd- http://www. http://www.
calculators nhlbihin.net/ heartscore. taskforce.com/ reynoldsriskscore.org/ reynoldsriskscore.org/
atpiii/calculator. org/pages/ coronary_risk_
asp?usertype=prof welcome.aspx assessment.html
APPENDIX V: LIPID LOWERING DIET
PRINCIPLE AMOUNT COMMENT
Decrease < 200 mg / day Reduce intake of organ meat (offal) eg
dietary liver, heart, brains, kidney. Limit to 3
cholesterol oz once fortnightly. A small amount of
prawn / crab / oysters / cockles may be
taken once or twice a week if desired.
Decrease < 30% of total Modify cooking methods grill /steam
total fat/oil energy / boil / bake / microwave to reduce use
of oils and fats. Avoid oily / fatty food eg
deep fat fried foods.
Types: 7-10% (not Minimize the use of following butter,
a) saturated more than 10% hard margarine, full cream milk (including
fat of total calorie condensed milk) cream, high fat cheese,
intake) fatty meats, bacon and sausages,
coconut oil, santan, products containing
hydrogenated oil and some non dairy
creamers.
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APPENDIX VI: CONVERSION TABLE
*Adapted from Miller M, Stone NJ, Ballantyne C et al Triglycerides and Cardiovascular Dis-
ease: A Scientific Statement from the American Heart Association. Circulation 2011; 123:
2292-2333
84
ACKNOWLEDGMENTS
DISCLOSURE STATEMENT
SOURCES OF FUNDING
85