DYSLIPIDEMIA

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 1st

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)


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%


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


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


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

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

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%)

The optional LDL-C goal of

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


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

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DYSLIPIDEMIA