MEDICUSS GROUP EDUCATION

TEAM
Dyslipidemia
Lipoproteins
Chylomicrons
VLDL Very low density lipoprotein
IDL Intermediate density lipoprotein
LDL Low density lipoprotein
HDL High density lipoprotein
Distinguished by size and
density
Each contains different
kinds and amounts of
lipids and proteins
The more lipid, the lower
the density
The more protein, the
higher the density
Lipoproteins
The Origins & Major
Functions of Lipoproteins

Fig 25.5 Transport of lipids
Endogenous Lipid Transport
7
Intestine
Intestine
Skeletal muscle
Skeletal muscle
Adipose
tissue
Adipose
tissue
Chylomicron
Chylomicron
Chylomicron
remnant
Chylomicron
remnant
Remnant
receptor
Remnant
receptor
Liver
Liver
Dietary
triglycerides
and cholesterol
Dietary
triglycerides
and cholesterol
LP lipase LP lipase
Metabolism
Exogenous Pathway of Lipid
Metabolism
Metabolism
to atheroma
to atheroma
FFA
Foam
Cells
Fatty
Streak
Intermediate
Lesion
Atheroma
Fibrous
Plaque
Complicated
Lesion/Rupture
Endothelial Dysfunction
Smooth muscle
and collagen
From first decade From third decade From fourth decade
Growth mainly by lipid accumulation
Thrombosis,
hematoma
Adapted from Stary HC et al. Circulation 1995;92:1355-1374.
Atherosclerosis Timeline
NATIONAL CHOLESTEROL
EDUCATION PROGRAM (NCEP)
PERIODIK MENGHASILKAN :


SESUAI DENGAN KEMAMPUAN KLINIS
DALAM PENGELOLAAN CHOLESTEROL

ATP ( ADULT TREATMENT PANEL)
1970s
Framingham
MRFIT
LRC-CPPT
Coronary drug Project
Helsinki hean
CLAS (angio)
NCEP
Guidelines
1993
NCEP
ATP III
Guidelines
2001
Angiographic Trials
LEATS, POSCH,
SCOR,
STARS, Ornish, MARS
Meta-Analysis
(Hane, Rossauw)
AS, WOSCOPS,
CARE, LIPID
AFCAPS/TEXCAPS
VAHIT, Others


NCEP
ATP I
Guidelines
1988
EVALUATION OF THE LIPID TREATMENT APPROACH
NCEP: Major Risk Factors Identified in Risk Factor Counting
Positive risk factor Definition
Cigarette smoking Any in the past month
Hypertension 140/90 mm Hg or on medication
Low HDL-C* < 40 mg/dl
Fam. history of premature CHD
Clinical CHD or sudden death in 1
st

degree relatives < 55 y (male) or < 65
y (female)
Age Men 45 y; women 55 y
Grundy SM, et al. NCEP Report. Circulation 2004;110:227-239
* Negative (protective) risk factor: high HDL-C (60 mg/dl)
NCEP: CHD as A Risk Indicator
Stable angina
Unstable angina
Myocardial infarction
Clinically significant myocardial ischemia
Coronary artery procedures (angioplasty or CABG)
Grundy SM, et al. NCEP Report. Circulation 2004;110:227-239
NCEP: Coronary Heart Disease Risk Equivalent*
Non-coronary forms of
atherosclerotic disease
Peripheral arterial disease
Abdominal aortic aneurysm
carotid artery disease (TIA or stroke of carotid
origin or 50% obstruction of a carotid artery)
Diabetes
Fasting blood glucose of 126 mg/dL or greater
2+ risk factors with 10-year risk for hard CHD 20%
Grundy SM, et al. NCEP Report. Circulation 2004;110:227-239
Chronic kidney disease has been identified by the ACC/AHA as CHD risk
equivalent.
Anderson JL, et al. J Am Coll Cardiol 2007;50:e1157
NCEP: Emerging Risk Factors
Lipid risk factors
Triglycerides; VLDL; Lp(a); small LDL
particles; HDL subspecies; apolipoproteins;
total cholesterol/HDL-C ratio
Non-lipid risk factors
Homocystein; thrombogenic/hemostatic
factors; hs-CRP; impaired fasting glucose
Subclinical atherosclerosis
ABI; test for myocardial ischemia; test for
atherosclerotic plaque burden
Grundy SM, et al. NCEP Report. Circulation 2004;110:227-239
Framingham Risk Score for Women
Framingham Risk Score for Men
10-Year CHD Risk for Men
10-Year CHD Risk for Women
Risk Category 10-year risk Identification
Low risk < 10% 0-1 risk factor
Moderate risk < 10% 2+ risk factors
Moderately high risk 10% to 20% 2+ risk factors
High risk > 20% CHD or CHD risk equivalent
CHD Risk Assessment Based On NCEP
Grundy SM, et al. NCEP Report. Circulation 2004;110:227-239
VERY HIGH RISK GROUPS
CVD plus:
1. Multiple major risk factors (especially diabetes)
2. Severe and poorly controlled risk factors (especially
continued cigarette smoking)
3. Multiple risk factors of the metabolic syndrome
(especially high TG 200 mg/dl plus non-HDL-C 130
mg/dl with low HDL-C <40 mg/dl.
4. Acute coronary syndrome
Grundy SM, et al. NCEP Report. Circulation 2004;110:227-239
Effect of lipid-modifying therapies on lipids

Therapy


Bile acid
sequestrants

Nicotinic acid


Fibrates
(gemfibrozil)

Probucol


Statins*


Ezetimibe
TCtotal cholesterol, LDLlow density lipoprotein, HDLhigh density lipoprotein,
TGtriglyceride. * Daily dose of 40mg of each drug, excluding rosuvastatin.
TC


Down
20%

Down
25%

Down
15%

Down
25%

Down
1530%



LDL


Down
1530%

Down
25%

Down
515%

Down
1015%

Down
2450%

Down
1520%
HDL


Up
35%

Up
1530%

Up
20%

Down
2030%

Up
612%

Up
49%
TG


Neutral or up


Down
2050%

Down
2050%

Neutral


Down
1029%


Patient
tolerability

Poor


Poor to
reasonable

Good


Reasonable


Good


Good
Adapted from Yeshurun D, Gotto AM. Southern Med J 1995;88(4):379391, Knopp RH. N Engl J Med
1999;341:498511, Gupta EK, Ito MK. Heart Dis 2002;4:399409
Risk Category LDL-C
0-1 < 160 mg/dl
2 (10-year risk <10%) < 130 mg/dl
2 (10-year risk 10-20%) < 130 mg/dl
(Optional goal: < 100 mg/dl)
CHD and CHD risk equivalent
< 100 mg/dl
(optional goal: 70 mg/dl)
Grundy SM, et al. NCEP Report. Circulation 2004;110:227-239
Target of LDL-C: NCEP-ATP III
Lifestyle to be modified Clinical approach
Diet
Individualized diet counseling that provides
acceptable substitutions for favorite foods
Physical activity
Recommend 30 minutes of regular moderate
intensity activity on most, if not all, days of the week
Body Weight
Discuss 10% weight loss goals for persons who are
overweight
Cholesterol
Follow ATP III guidelines for detection, evaluation,
and treatment of persons with lipid disorders.
Blood Pressure Follow BP guidelines
Smoking Cessation
Promote smoking cessation
Adaptation from Grundy SM, et al. NCEP Report. Circulation 2004;110:227-239
Therapeutic Lifestyle Changes (TLC)
Visit 1
Check lipid profile
Start TLC
Visit 2
LDL goal not achieved
Intensify TLC
6 weeks
Visit 3
LDL goal not achieved
Drug therapy
6 weeks
Visit 3
LDL goal achieved
Continue TLC
Monitor adherence every 4-6 months
Risk Category LDL-C Goal Initiate TLC Consider Drug Therapy
High risk:
CHD or CHD risk equivalents
*
(10-year risk >20%)
<100 mg/dL
(optional:
<70 mg/dL)

100 mg/dL

100 mg/dL
(<100 mg/dL: consider drug
options)
Moderately
high risk:
2 risk factors
(10-year risk
10%20%)
<130 mg/dL
(optional:
<100 mg/dL)
130 mg/dL

130 mg/dL
(100129 mg/dL:
consider drug options)
Moderate risk:
2 risk factors
(10-year risk <10%)
<130 mg/dL 130 mg/dL 160 mg/dL
Lower risk:
01 risk factor
<160 mg/dL 160 mg/dL 190 mg/dL
(160189 mg/dL:
LDL-Clowering drug
optional)
Treatment

The optional LDL-C goal of <70

mg/dL is favored in those at
very high risk (eg, people with
diabetes, smokers) as well as
those with metabolic syndrome,
acute coronary syndrome, high
TG, and/or nonHDL-C <100
mg/dL.
Therapeutic Lifestyle Changes (TLC)
Start Drug Therapy
LDL Goal not achieve
Increased Dose of statin or
start combine drug therapy
6 weeks
LDL goal not achieved
Intensify Drug therapy or refer
to lipid specialist
6 weeks
LDL Goal Achieved
Continue Therapy
Monitor adherence every 4-6 months
HMG CoA reductase inhibitors (statins)
Evidence statements:
HMG CoA reductase inhibitors (statins) are powerful LDL-
lowering drugs (A1).
Statin therapy reduces risk for acute coronary syndromes,
coronary procedures, and other coronary outcomes in both
primary and secondary prevention (A1).
It also reduces risk for stroke in secondary prevention (A1).
Treatment with statins is generally safe, although rarely persons
experience
myopathy (D1).
Myopathy is more likely in persons with complex medical
problems or in those who are taking multiple medications (D1).

Recommendation: Statins should be considered as first-line drugs
when LDL-lowering drugs are indicated to achieve LDL treatment
goals.
50
Evidence statements:
Bile acid sequestrants produce moderate reductions in LDL cholesterol (A1).
Sequestrant therapy reduces risk for CHD (A1).
They are additive in LDL-cholesterol lowering in combination with other
cholesterol-lowering drugs (C1).
They lack systemic toxicity (A1).

Recommendation: Bile acid sequestrants should be considered as LDL-lowering
therapy for persons with moderate elevations in LDL cholesterol, for younger
persons with elevated LDL cholesterol, for women with elevated LDL cholesterol
who are considering pregnancy, for persons needing only
modest reductions in LDL cholesterol to achieve target goals, and for combination
therapy with statins in persons with very high LDL-cholesterol levels.
Bile acid sequestrants
51
Evidence statements:
Nicotinic acid effectively modifies atherogenic dyslipidemia by reducing TGRLP, raising
HDL cholesterol, and transforming small LDL into normal-sized LDL (C1).
Among lipid-lowering agents, nicotinic acid is the most effective HDL-raising drug (C1).
Nicotinic acid usually causes a moderate reduction in LDLcholesterol levels (C1),
and it is the most effective drug for reducing Lp(a) levels (C1).

Evidence statements: Nicotinic acid therapy is
commonly accompanied by a variety of side effects, including flushing and itching of the
skin, gastrointestinal distress, glucose intolerance, hepatotoxicity, hyperuricemia, and
other rarer side effects (C1).
Hepatotoxicity is more common with sustained release preparations (D1).

Evidence statement: Nicotinic acid therapy produces a moderate reduction in CHD risk,
either when used alone or in combination with other lipid-lowering drugs (A2, B2).
Nicotinic acid
52
Recommendation:
Nicotinic acid should be considered as a therapeutic option for higher-risk
persons with atherogenic dyslipidemia.
It should be considered as a single agent in higher-risk persons with atherogenic
dyslipidemia who do not have a substantial increase in LDL-cholesterol levels,
and in combination therapy with other cholesterol-lowering drugs in higher-risk
persons with atherogenic dyslipidemia combined with elevated LDL-cholesterol
levels.

Recommendation:
Nicotinic acid should be used with caution in persons with active liver disease,
recent peptic ulcer, hyperuricemia and gout, and type 2 diabetes.
High doses of nicotinic acid (>3 g/day) generally should be avoided in persons
with type 2 diabetes, although lower doses may effectively treat diabetic
dyslipidemia without significantly worsening hyperglycemia.
Nicotinic acid
53
Evidence statements:
Fibrates are effective for modifying atherogenic dyslipidemia, and
particularly for lowering serum triglycerides (C1).
They produce moderate elevations of HDL cholesterol (C1). Fibrates also are
effective for treatment of dysbetalipoproteinemia (elevated beta-VLDL) (C1).
They also can produce some lowering of LDL, the degree of which may vary
among different fibrate preparations (C1).
Fibrates also can be combined with LDL-lowering drugs in treatment of
combined hyperlipidemia to improve the lipoprotein profile, although there is
no clinical-trial evidence of efficacy for CHD risk reduction with combined
drug therapy (C1, D1).
Some fibrate are metabolite by CYP3A4, CYP2C8
Evidence statements:
Fibrate therapy moderately reduces risk for CHD (A2, B1).
It may also reduce risk for stroke in secondary prevention (A2).
Fibrates
Evidence statements:
Evidence for an increase in total mortality due to an increased non-
CHD mortality, observed in the first large primary prevention trial with
clofibrate, has not been substantiated in subsequent primary or
secondary prevention trials with other fibrates (gemfibrozil or
bezafibrate) (A2, B1).
Nonetheless, fibrates have the potential to produce some side effects.
Fibrate therapy alone carries an increased risk for cholesterol gallstones
(A2),
and the combination of fibrate and statin imparts an increased risk for
myopathy (B2).
Gemfibrozil may inhibit glucoronidation pathway
Gemfibrozil interact with statin > other fibrate
Interaction may lead to sarcolemmal fluidity and muscle membrane
destabilization

Fibrates
55
Recommendations:

Fibrates can be recommended for persons with very high
triglycerides to reduce risk for acute pancreatitis. They
also can be recommended for persons with
dysbetalipoproteinemia (elevated beta-VLDL).
Fibrate therapy should be considered an option for
treatment of persons with established CHD who have low
levels of LDL cholesterol and atherogenic dyslipidemia.
They also should be considered in combination with statin
therapy in persons who have elevated LDL cholesterol and
atherogenic dyslipidemia.
Fibrates
Ezetimibe
Menghambat absorbsi cholesterol di usus yang akan
menurunkan jumlah kolesterol yang bersirkulasi dengan
cara menghambat transport kolesterol di brush border usus .
Transporter dikenal sebagai Niemann-Pick type C1-like 1
(NPC1L1). Inhibisi dari transporter NPC1L1, mempunyai
efek untuk keadaan metabolic syndrome, seperti obesity,
insulin resistance, dan fatty liver, dan mencegah
atherosclerosis. Ezetimibe biasanya digunakan untuk pasien
yang tidak bisa menggunakan statin. Terdapat kontroversi
mengenai efikasi ezetimibe untuk menurunkan serum
kolesterol dan mengurangi plak pada dinding arteri. Terapi
kombinasi antara ezetimibe dengan simvastatin
menunjukan hasil yang hampir sama dalam menurunkan
kolesterol dari pada menggunakan atorvastatin sebagai
monoterapi.
Obat terbaru :
Menghambat enzim CETP (cholesterol ester
transport protein) : anacetrapib, torcetrapib,
dan dalcetrapib
Dimana CETP ini akan menurunkan kadar
HDL dengan memecah HDL.
Management High
Triglycerid
TG level
> 200 mg/dl
Optional
LDL-C target
< 70 mg/dl
In patients with CVD
+ non-HDL-C 130 mg/dl
+ HDL-C < 40 mg/dl
In high-risk patients
+ non-HDL-C < 100 mg/dl
Grundy SM, et al. NCEP Report. Circulation 2004;110:227-239
In moderately-high risk
+ non-HDL-C 160 mg/dl
+ HDL-C < 40 mg/dl
Optional
LDL-C target
< 100 mg/dl
TG 200 mg/dl
Tingkat risiko PJK 10 tahun ke depan tinggi
atau sangat tinggi
TG 500 mg/dl
TPGH
Terapi segera dengan
fibrat tanpa memandang
kadar kol-LDL dan
tingkat risiko PJK
Ya Tidak
Kol-LDL di atas target
NCEP
TPGH dan terapi statin
Target kol-LDL tercapai
tetapi TG 200 mg/dl
Pertimbangkan
menambahkan fibrat
Kol-LDL di atas target
NCEP
TPGH dan terapi statin
Treatment Scheme for Patients with Low-HDL-C
HDL-C 40 mg/dl
Lifestyle modification
LDL > NCEP target Isolated low HDL
Statin
Titrate statin but HDL
remains 40 mg/dl
Add niacin
Strong family history of CAD or Framingham
Risk > 20% over 10 years
Statin
Titrate statin but HDL
remains 40 mg/dl
Add niacin
Torh PP. Circulation 2004;109:1809-12