farmakoterapi hiperlipidemia

HYPERLIPIDEMIABy

Minyahil Alebachew(Clinical Pharmacy MSc. Student

JimmanUiversity)I.D MSc.00097/03

6/13/2011

ABBREVIATIONS• BAR: Bile Acid Resin• CHD: Coronary Heart Disease• CI: Contraindicated• CK: Creatine kinase• FLP: Fasting Lipid Panel• HDL: High Density Lipoprotein• hsCRP: High Sensitivity C-reactive

Protein

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ABBREVIATIONS (CONT.)

• IDL: Intermediate Density Lipoprotein

• LDL: Low Density Lipoprotein• LFT: Liver Function Tests• MI: Myocardial Infarction• TC: Total Cholesterol• TG: Triglyceride• VLDL: Very Low Density Lipoprotein

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CONTENTS • DEFINITION• LIPOPROTEIN CLASSIFICATION AND

COMPOSITION• PATHOPHYSIOLOGY OF

HYPERLIPIDEMIA• HEREDITARY CAUSES OF

HYPERLIPIDEMIA• HYPERLIPOPROTEINEMIA

CLASSIFICATION• LIPOPROTEIN ABNORMALITIES: 2˚

CAUSES• CLINICAL PRESENTATION

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CONTENTS (CONT.)

• DIAGNOSIS• LIFESTYLE MODIFICATION• TLC DIETARY RECOMMENDATIONS• TREATMENT DESIRED OUTCOME• TREATMENT• CLINICAL CONTROVERSY• HYPERLIPIDEMIA IN CHILDREN

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CONTENTS (CONT.) • PHARMACOLOGIC THERAPY

o BARso NIACINo HMG-COA REDUCTASE INHIBITORS/STATINSo FIBRIC ACIDSo EZETIMIBEo FISH OIL SUPPLEMENTATION

• TREATMENT RECOMMENDATIONS• COMBINATION DRUG THERAPY• REFERENCES

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DEFINITION

• Although elevated low density lipoprotein cholesterol (LDL) is thought to be the best indicator of atherosclerosis risk, dyslipidemia can also be defined as: oelevated - total cholesterol, or

triglycerides; oa low - high-density

lipoprotein(HDL) cholesterol; oor a combination of these

abnormalities. 6/13/2011

DEFINITION (CONT.)

• Hyperlipoproteinemia describes an increased concentration of the lipoprotein macromolecules that transport lipids in the plasma.

• Abnormalities of plasmalipids can result in a predisposition to coronary, cerebrovascular, and peripheral vascular arterial disease.

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LIPOPROTEIN CLASSIFICATION AND COMPOSITION

• Lipoproteins are:o large macromolecular complexes

that transport hydrophobic lipids (primarily triglycerides, cholesterol, and fat-soluble vitamins) through body fluids (plasma, interstitial fluid, and lymph) to and from tissues.

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LIPOPROTEIN CLASSIFICATION AND COMPOSITION (CONT.)

• Lipoproteins play an essential role in theoabsorption of dietary cholesterol,

long-chain fatty acids, and fat-soluble vitamins;

othe transport of triglycerides, cholesterol, and fat-soluble vitamins from the liver to peripheral tissues; and

othe transport of cholesterol from peripheral tissues to the liver.

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• VLDL carries ~10 to 15 % of total serum cholesterol; carried in circulation as TG; VLDL = TG/5

• LDL carries 60 to 70% of total serum cholesterol; IDL is also included in this group

• HDL carries 20 to 30% of total serum cholesterol; reverse transportation of cholesterol

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• Chylomicrons transport fats from the intestinal mucosa to the liver.

• In the liver, the chylomicrons release triglycerides and some cholesterol and become low-density lipoproteins (LDL).

• LDL then carries fat and cholesterol to the body’s cells.

• High-density lipoproteins (HDL) carry fat and cholesterol back to the liver for excretion. 6/13/2011


• When oxidized LDL cholesterol gets high, atheroma formation in the walls of arteries occurs, which causes atherosclerosis.

• HDL cholesterol is able to go and remove cholesterol from the atheroma.

• Atherogenic cholesterol → LDL, VLDL, IDL

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• Elevated total and LDL cholesterol and reduced HDL cholesterol are associated with the development of coronary heart disease (CHD).

• ↓TC, ↓ LDL, ↑HDL reduces mortality or CHD events

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• Lipoproteins contain a core of hydrophobic lipids (triglycerides and cholesteryl esters) surrounded by hydrophilic lipids (phospholipids, unesterified cholesterol) and proteins that interact with body fluids.

• The plasma lipoproteins are divided into five major classes based on their relative density, chylomicrons, VLDLs, IDLs, LDLs, and HDLs.

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Lipoprotein Density, g/mLa Size, nmb

Chylomicrons 0.930 75–1200

Chylomicron remnants 0.930–1.006 30–80

VLDL 0.930–1.006 30–80

IDL 1.006–1.019 25–35

LDL 1.019–1.063 18–25

HDL 1.063–1.210 5–12

Lp(a) 1.050–1.120 25

Abbreviations: VLDL, very low density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; HDL, high-density lipoprotein; Lp(a), lipoprotein A;

MAJOR LIPOPROTEIN CLASSES

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• Note: All of the lipoprotein classes contain phospholipids, esterified and unesterified cholesterol, and triglycerides to varying degrees.

• a =The density of the particle is determined by ultracentrifugation.

• b=The size of the particle is measured using gel electrophoresis.

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LIPOPROTEIN CLASSIFICATION AND COMPOSITION(CONT.)

• Each lipoprotein class comprises a family of particles that vary slightly in density, size, migration during electrophoresis, and protein composition.

• The density of a lipoprotein is determined by the amount of lipid per particle.

• cholesterol is carried as cholesteryl esters in LDLs and HDLs.

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• HDL is the smallest and most dense lipoprotein, whereas chylomicrons and VLDLs are the largest and least dense lipoprotein particles.

• Most plasma triglyceride is transported in chylomicrons or VLDLs, and most plasma

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• VLDL secreted from the liver converted to IDL then LDL

• Plasma LDL taken up by receptors on liver, adrenal, & peripheral cells o Recognized as LDL apolipoprotein B-100

• LDL internalized & degraded by these cells

• Increased intracellular cholesterol levels increases HMG-CoA reductase & decreases LDL receptor synthesis

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• Decreases in LDL receptors: plasma LDL not as readily taken up & broken down by cells

• LDL also excreted in bile o joins enterohepatic pooloeliminated in stoolocan be oxidized in subendothelial

space of arteries

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• The response-to-injury hypothesis states that o risk factors such as ooxidized LDL, mechanical injury to the

endothelium, excessive homocysteine, immunologic attack, or infection-induced changes in endothelial and intimal function lead to endothelial dysfunction and a series of cellular interactions that culminate in atherosclerosis.

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PATHOPHYSIOLOGY OF HYPERLIPIDEMIA

PATHOPHYSIOLOGY(CONT.)• The eventual clinical outcomes may

includeoangina, myocardial infarction,

arrhythmias, stroke, peripheral arterial disease, abdominal aortic aneurysm, and sudden death.

• Atherosclerotic lesions are thought to arise from transport and retention of plasma LDL through the endothelial cell layer into the extracellular matrix of the subendothelial space. 6/13/2011

PATHOPHYSIOLOGY(CONT.)

• Once in the artery wall, LDL is chemically modified through oxidation and nonenzymatic glycation, Mildly oxidized LDL then recruits monocytes into the artery wall.

• These monocytes then become transformed into macrophages that accelerate LDL oxidation.

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PATHOPHYSIOLOGY(CONT.)

• Oxidized LDL provokes oan inflammatory response mediated by

a number of chemoattractants and cytokines e.g., monocyte colony-stimulating factor, intercellular adhesion molecule, platelet-derived growth factor, transforming growth factors, interleukin-1, interleukin-6

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PATHOPHYSIOLOGY(CONT.)• Repeated injury and repair within an

atherosclerotic plaque eventually lead to oa fibrous cap protecting the

underlying core of lipids, collagen, calcium, and inflammatory cells such as T lymphocytes.

• Maintenance of the fibrous plaque is critical to prevent plaque rupture and subsequent coronary thrombosis.6/13/2011

HEREDITARY CAUSES OF HYPERLIPIDEMIA

• Familial Hypercholesterolemiao Co-dominant genetic disorder, coccurs in

heterozygous formo Occurs in 1 in 500 individualso Mutation in LDL receptor, resulting in

elevated levels of LDL at birth and throughout life

o High risk for atherosclerosis, tendon xanthomas (75% of patients), tuberous xanthomas and xanthelasmas of eyes.

• Familial Combined Hyperlipidemiao Autosomal dominanto Increased secretions of VLDLs

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HEREDITARY CAUSES OF HYPERLIPIDEMIA(CONT.)

• DysbetalipoproteinemiaoAffects 1 in 10,000oResults in apo E2, a binding-

defective form of apoE (which usually plays important role in catabolism of chylomicron and VLDL)

oIncreased risk for atherosclerosis, peripheral vascular diseaseTuberous xanthomas, striae palmaris

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HYPERLIPOPROTEINEMIA CLASSIFICATION

• Primary or genetic lipoprotein disorders are classified into six categories for the phenotypic description of dyslipidemia.

• The types and corresponding lipoprotein elevations include the following: (Fredrickson-Levy-Lees)o I (chylomicrons), o IIa (LDL), o Iib (LDL + very low density lipoprotein, or VLDL), o III (intermediate-density lipoprotein), o IV (VLDL), and o V (VLDL + chylomicrons).

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LIPOPROTEIN ABNORMALITIES: 2˚ CAUSES

• Hypercholesterolemia causing disordersohypothyroidismoobstructive liver diseaseonephrotic syndromeoanorexia nervosaoacute intermittent porphyria

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LIPOPROTEIN ABNORMALITIES: 2˚ CAUSES (CONT.)

• Hypocholesterolemia (cont’d)omalnutritionomalabsorptionomyeloproliferative diseasesochronic infectious diseases

acquired immune deficiency syndrome

tuberculosisomonoclonal gammopathyochronic liver disease

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progestinsthiazide diuretics

glucocorticoidsβ-blockersisotretinoin

protease inhibitors

cyclosporinemirtazipinesirolimus

• Hypercholesterolemia causing medications

LIPOPROTEIN ABNORMALITIES: 2˚ CAUSES(CONT.)

• HypertriglyceridemiaoobesityoDMo lipodystrophyoglycogen storage

diseaseo ileal bypass

surgeryosepsisopregnancy

• monocolonal gammopathy: multiple myeloma, lymphoma

• acute hepatitis• systemic lupus

erythematous


alcoholestrogensisotretinoinβ-blockersglucocorticoidsbile acid resinsthiazides

asparaginaseinterferonsazole antifungals

mirtazipineanabolic steroids

sirolimus


• Hypertriglyceridemia medications

non-ISA β-blockers anabolic steroids

o isotretinoin o progestins

• Low high-density lipoproteino malnutritiono obesityo medications


CLINICAL PRESENTATION• The primary defect in familial

hypercholesterolemia is the inability to bind LDL to the LDL receptor (LDL-R) or, rarely, a defect of internalizing the LDL-R complex into the cell after normal binding

• This leads to lack of LDL degradation by cells and unregulated biosynthesis of cholesterol, with total cholesterol and LDL cholesterol (LDL-C) being inversely proportional to the deficit in LDL-Rs

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CLINICAL PRESENTATION (CONT.)

• Familial hypercholesterolemia is characterized by oa selective elevation in plasma LDL and odeposition of LDL-derived cholesterol in

tendons (xanthomas) and arteries (atheromas).

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CLINICAL PRESENTATION(CONT.)Hyperlipidemia signs

• Xanthoma- plaques or nodules composed of lipid-layden histiocytes (foamy cells) in the skin, especially the eyelids

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CLINICAL PRESENTATION(CONT.) Tendenous Xanthoma

Xanthoma deposits in tendon, commonly the Achilles

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www.drsarma.in

Clinical Photoes

Tuberous xanthoma. Flat-topped, yellow, firm tumor

Xanthelasma. Multiple, longitudinal, creamy-orange, slightly elevated papules on eyelids .

www.drsarma.in

Clinical Photoes

Tendinous xanthomas. Large sub-cutaneous tumors adherent to the Achilles tendons.

Papular eruptive xanthomas. Multiple, discrete, red-to-yellow confluent papules

CLINICAL PRESENTATION(CONT.)

• Familial lipoprotein lipase deficiency is characterized by a massive accumulation of chylomicrons and a corresponding increase in plasma triglycerides or a type I lipoprotein pattern

• Presenting manifestations include repeated attacks of pancreatitis and abdominal pain, eruptive cutaneous xanthomatosis, and hepatosplenomegaly beginning in childhood.

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• Symptom severity is proportional to dietary fat intake, and consequently to the elevation of chylomicrons.

• Accelerated atherosclerosis is not associated with this disease.

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Corneal arcus• Lipid deposit in cornea

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CLINICAL PRESENTATION(CONT.)• Patients with familial type III

hyperlipoproteinemia develop the following clinical features after age 20: oxanthoma striata palmaris (yellow

discolorations of the palmar and digital creases);

oTuberous or tuberoeruptive xanthomas (bulbous cutaneous xanthomas); and

osevere atherosclerosis involving the coronary arteries, internal carotids, and abdominal aorta.

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• Atheroma- plaques in blood vessels

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• Type IV hyperlipoproteinemia is common and occurs in adults, primarily in patients who are obese, diabetic, and hyperuricemic and do not have xanthomas.

• It may be secondary to alcohol ingestion and can be aggravated by stress, progestins, oral contraceptives, thiazides, or β-blockers.

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CLINICAL PRESENTATION (CONT.)• Type V is characterized by abdominal pain,

pancreatitis, eruptive xanthomas, and peripheral polyneuropathy.

• These patients are commonly obese, hyperuricemic, and diabetic; alcohol intake, exogenous estrogens, and renal insufficiency tend to be exacerbating factors.

• The risk of atherosclerosis is increased with this disorder.

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AtherosclerosisC:\Users\Minyahil\Downloads\Video\4013_309103764001_create-3681-2-2.mp4

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DIAGNOSIS• A fasting lipoprotein profile including total

cholesterol, LDL, HDL, and triglycerides should be measured in all adults 20 years of age or older at least once every 5 years.

• Measurement of plasma cholesterol (which is about 3% lower than serum determinations), triglyceride, and HDL levels after a 12-hour or longer fast is important, because triglycerides may be elevated in non-fasted individuals; total cholesterol is only modestly affected by fasting.

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DIAGNOSIS (CONT.)• Two determinations, 1 to 8 weeks

apart, with the patient on a stable diet and weight, and in the absence of acute illness, are recommended to minimize variability and to obtain a reliable baseline.

• If the total cholesterol is >200mg/dL, a second determination is recommended, and if the values are more than 30 mg/dL apart, the average of three values should be used.

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DIAGNOSIS (CONT.)• After a lipid abnormality is confirmed,

major components of the evaluation are o the history

including age, gender, and, if female, menstrual and estrogen replacement status,

ophysical examination, and o laboratory investigations.

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DIAGNOSIS (CONT.)• A complete history and physical

examination should assess o (1) presence or absence of cardiovascular

risk factors or definite cardiovascular disease in the individual;

o (2) family history of premature cardiovascular disease or lipid disorders;

o (3) presence or absence of secondary causes of hyperlipidemia, including concurrent medications; and

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DIAGNOSIS (CONT.)• (4) presence or absence of oxanthomas, abdominal pain, or

history of pancreatitis,orenal or liver disease, operipheral vascular disease, oabdominal aortic aneurysm, or

cerebral vascular disease (carotid bruits, stroke, or transient ischemic attack).

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DIAGNOSIS (CONT.)• Diabetes mellitus is regarded as a CHD

risk equivalent. o That is, the presence of diabetes in

patients without known CHD is associated with the same level of risk as patients without diabetes but having confirmed CHD.

• If the physical examination and history are insufficient to diagnose a familial disorder, then agarose-gel lipoprotein electrophoresis is useful to determine which class of lipoproteins is affected. 6/13/2011

DIAGNOSIS (CONT.)

• If the triglyceride levels are <400 mg/dL and neither type III hyperlipidemia nor chylomicrons are detected by electrophoresis, then one can calculate VLDL and LDL concentrations:

• VLDL = triglycerides ÷ 5; • LDL = total cholesterol – (VLDL+

HDL). 6/13/2011

DIAGNOSIS (CONT.)• Initial testing uses total cholesterol for

case finding, obut subsequent management

decisions should be based on LDL.• Because total cholesterol is

composed of cholesterol derived from LDL, VLDL, and HDL, determination of HDL is useful when total plasma cholesterol is elevated.

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DIAGNOSIS (CONT.)• HDL may be elevated by

omoderate alcohol ingestion (fewer than two drinks per day),

ophysical exercise, osmoking cessation, oweight loss, ooral contraceptives, ophenytoin, and o terbutaline.

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DIAGNOSIS (CONT.)

• HDL may be lowered by smoking, obesity, a sedentary lifestyle, and drugs such as β-blockers.

• Diagnosis of lipoprotein lipase deficiency is based on low or absent enzyme activity with normal human plasma or apolipoprotein C-II, a cofactor of the enzyme.

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LIFESTYLE MODIFICATION• Initial treatment for any lipoprotein

disorder is TLC (Therapeutic Lifestyle Changes)o restricted total fats, saturated fats,

cholesterol intakeo modest increase in polyunsaturated fato increased soluble fiber intakeo exercise: moderate intensity 30 min/day

most days caution in high risk patients or those with

CAD o weight reduction (initial goal of 10%) if

neededo smoking cessationo treat HTN

TLC DIETARY RECOMMENDATIONS Componenta Recommended Intake

Total fat 25% to 35% of total calories

Saturated fat Less than 7% of total calories

Polyunsaturated fat Up to 10% of total calories

Monounsaturated fat Up to 20% of total calories

Carbohydratesb 50% to 60% of total calories

Cholesterol < 200 mg/day

Dietary fiber 20 to 30 g/day

Plant sterols 2 g/day

Protein ~15% of total calories

Total calories To achieve & maintain desirable body weight

aCalories from alcohol not included. bComplex carbohydrates (whole grains, fruits, vegetables).

TREATMENT DESIRED OUTCOME

• The goals of treatment are to lower total and LDL cholesterol in order to reduce the risk of first or recurrent events such as o myocardial infarction, o angina, o heart failure, o ischemic stroke, or o other forms of peripheral arterial disease

such as carotid stenosis or abdominal aortic aneurysm 6/13/2011

TREATMENT (CONT.)

• Most patients should receive 3 month TLC trial before initiating pharmacologic therapy unless very high risk

• If patient unable to reach goals with TLC alone choose lipid-lowering drugs based on lipoprotein disorder

• Combination therapy may be necessary omonitor closely: increased risk of drug

interactions, adverse effects

TREATMENT (CONT.)• GENERAL APPROACH

• The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) recommends that a fasting lipoprotein profile and risk factor assessment be used in the initial classification of adults.

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TREATMENT (CONT.)• There are four categories of risk that

modify the goals and modalities of LDL-lowering therapy.

• The highest risk category is having known CHD or CHD risk equivalents; the risk for major coronary events is equal to or greater than that for established CHD (i.e., >20% per 10 years, or 2% per year).

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TREATMENT (CONT.)

• The next category is moderately high risk, consisting of patients with two or more risk factors in which 10-year risk for CHD is 10% to 20%.

• The lowest risk category is persons with zero to one risk factor, which is usually associated with a 10-year CHD risk of <10%.

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TREATMENT (CONT.)

• ATP III recognizes the metabolic syndrome as a secondary target of risk reduction after LDL-C has been addressed.

• This syndrome is characterized by abdominal obesity, atherogenic dyslipidemia (elevated triglycerides, small LDL particles, low HDL cholesterol), increased blood pressure, insulin resistance (with or without glucose intolerance), and prothrombotic and proinflammatory states.

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TREATMENT (CONT.)

• If the metabolic syndrome is present, the patient is considered to have a CHD risk equivalent.

• Other targets include non-HDL goals for patients with triglycerides >200mg/dL.

• Non-HDL cholesterol is calculated by subtracting HDL from total cholesterol, and the targets are 30 mg/dL greater than for LDL at each risk stratum.

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CLINICAL CONTROVERSY

• CHD events occur in healthy patients < LDL goal

• hsCRP: inflammatory biomarker, predicts future vascular events independent of LDL onot currently recommended as a

screening tool • JUPITER study (Justification for the Use

of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin)Ridker PM.docx

• JUPITERo rosuvastatin 20 mg vs placebo

(n=17,802)ohealthy patients with LDL < 130 mg/dL,

hsCRP > 2.0 mg/dLoaverage LDL & hsCRP reduction by

50% in rosuvastatin group• Patients in this study would not have

qualified for lipid-lowering therapy according to NCEP ATPIII

• Long-term safety unknown

CLINICAL CONTROVERSY(CONT.)

CLINICAL CONTROVERSY(CONT.)• JUPITER combined 1˚ endpoint: MI, stroke,

CV death, arterial revascularization, unstable angina hospitalization ocombined 1˚ endpoint met early (1.9

years; planned to last 5 years)osubstudy evaluated incidence of venous

thromboembolismopatients treated with rosuvastatin had

significantly lower incidence of CV events & symptomatic venous thromboembolism

HYPERLIPIDEMIA IN CHILDREN• Guidelines/goals of therapy different from

adults• NCEP does not provide cut points for

TGs or HDL in children & adolescents• American Heart Association considers TG

> 150 & HDL < 35 abnormal for children/adolescents

• Children should receive fasting lipid profile after age 2 but no later than 10 years if:o family history of dyslipidemia or premature

CVDo unknown family historyo overweight, DM, HTN, smoker Daniel's

SR.docx

LIPID LEVEL CLASSIFICATION IN CHILDREN

• Children & adolescents (age < 20 yrs)o acceptable

TC < 170 mg/dLLDL < 110 mg/dL

o borderline TC 170-199 mg/dLLDL 110-129 mg/dL

o elevatedTC > 200 mg/dLLDL > 130 mg/dL

HYPERLIPIDEMIA IN CHILDREN(CONT.)

• Implement healthy lifestyle/diet in all children >2yrso low-fat dairy products in children > 1 year

who are overweight or family history of obesity, dyslipidemia, CVD

• Drug therapy not recommended age < 8 yearso exception: LDL > 500 mg/dL such as seen

in homozygous familial hypercholesterolemia

• Statins safe & effective in children; BARs, absorption inhibitors may also be used

HYPERLIPIDEMIA IN CHILDREN (CONT.)

• Pharmacologic intervention considered in patients age > 8 years after failure of dietary therapy when:oLDL > 190 mg/dL if no additional risk

factorsoLDL > 160 mg/dL if family history or > 2

additional risk factorsoLDL > 130 mg/dL if patient has

diabetes mellitus

PHARMACOLOGIC THERAPYBARs

• Bile Acid Resins (Cholestyramine, Colestipol, Colesevelam)

• The primary action of BARs is to bind bile acids in the intestinal lumen, with a concurrent interruption of enterohepatic circulation of bile acids, which decreases the bile acid pool size and stimulates hepatic synthesis of bile acids from cholesterol.

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PHARMACOLOGIC THERAPY (CONT.)BARs

• Depletion of the hepatic pool of cholesterol results in an increase in cholesterol biosynthesis and an increase in the number of LDL-Rs on the hepatocyte membrane, which stimulates an enhanced rate of catabolism from plasma and lowers LDL levels.

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PHARMACOLOGIC THERAPY(CONT.)BARs

• The increase in hepatic cholesterol biosynthesis may be paralleled by increased hepatic VLDL production, and, consequently, BARs may aggravate hypertriglyceridemia in patients with combined hyperlipidemia.

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• BARs are useful in treating primary hypercholesterolemiao (familial hypercholesterolemia, familial

combined hyperlipidemia, type IIa hyperlipoproteinemia).

• • GI complaints of constipation, bloating, epigastric fullness, nausea, and flatulence are most commonly reported.

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• These adverse effects can be managed byo increasing fluid intake, omodifying the diet to increase bulk,

and ousing stool softeners.

• The gritty texture and bulk may be minimized by mixing the powder with orange drink or juice.

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• Colestipol may have better palatability than cholestyramine because it is odorless and tasteless.

• Other potential adverse effects includeo impaired absorption of fat-soluble vitamins A,

D, E, and K; o hypernatremia and hyperchloremia; o GI obstruction; and reduced bioavailability of

acidic drugs such as warfarin, nicotinic acid, thyroxine, acetaminophen, hydrocortisone, hydrochlorothiazide, loperamide, and possibly iron.

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• Drug interactions may be avoided by alternating administration times with an interval of 6 hours or greater between the BAR and other drugs.

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PHARMACOLOGIC THERAPY(CONT.) NIACIN

• Niacin (nicotinic acid) reduces the hepatic synthesis of VLDL, which in turn leads to a reduction in the synthesis of LDL.

• Niacin also increases HDL by reducing its catabolism.

• • The principal use of niacin is for mixed hyperlipidemia or as a second-line agent in combination therapy for hypercholesterolemia.

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• It is a first-line agent or alternative for the treatment of hypertriglyceridemia and diabetic dyslipidemia.

• • Niacin has many common adverse drug reactions; most of the symptoms and biochemical abnormalities seen do not require discontinuation of therapy.

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• Cutaneous flushing and itching appear to be prostaglandin mediated and can be reduced by taking aspirin 325 mg shortly before niacin ingestion.

• Taking the niacin dose with meals and slowly titrating the dose upward may minimize these effects.

• Concomitant alcohol and hot drinks may magnify the flushing and pruritus from niacin, and they should be avoided at the time of ingestion.

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• GI intolerance is also a common problem Potentially important laboratory abnormalities occurring with niacin therapy include elevated liver function tests, hyperuricemia, and hyperglycemia.

• Niacin-associated hepatitis is more common with sustained-release preparations, and their use should be restricted to patients intolerant of regular-release products.

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• Niacin is contraindicated in patients with active liver disease, and it may exacerbate preexisting gout and diabetes.

• • Nicotinamide should not be used in the treatment of hyperlipidemia because it does not effectively lower cholesterol or triglyceride levels.

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• CETP (cholesterol ester transfer protein) inhibition leads to elevation in HDL levels

• The CETP inhibitor torcetrapib substantially increased HDL & decreased LDL

• Torcetrapib resulted in increased BP & CHD events

• Unknown whether lack of efficacy due to mechanism of action or chemical specific events

• Other means of raising HDL are being researched & tested

PHARMACOLOGIC THERAPY(CONT.) HMG-COA REDUCTASE INHIBITORS/STATINS

(ATORVASTATIN, FLUVASTATIN, LOVASTATIN, PRAVASTATIN, ROSUVASTATIN,

SIMVASTATIN)

• Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, interrupting the conversion of HMG-CoA to mevalonate, the rate-limiting step in de novo cholesterol biosynthesis.

• Reduced synthesis of LDL and enhanced catabolism of LDL mediated through LDL-Rs appear to be the principal mechanisms for lipid-lowering effects.

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PHARMACOLOGIC THERAPY(CONT.) STATINS

• When used as monotherapy, statins are the most potent total and LDL cholesterol-lowering agents and among the best tolerated.

• Total and LDL cholesterol are reduced in a dose-related fashion by 30% or more when added to dietary therapy. 6/13/2011


• Combination therapy with a statin and BAR is rational because onumbers of LDL-Rs are increased,

leading to greater degradation of LDL cholesterol;

o intracellular synthesis of cholesterol is inhibited; and

oenterohepatic recycling of bile acids is interrupted.

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• Combination therapy with a statin and ezetimibe is also rational because oezetimibe inhibits cholesterol

absorption across the gut border and oadds 12% to 20% further reduction

when combined with a statin or other drugs.

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• Constipation occurs in fewer than 10% of patients taking statins.

• Other adverse effects include elevated serum aminotransferase levels (primarily alanine aminotransferase), elevated creatine kinase levels, myopathy, and rarely rhabdomyolysis. 6/13/2011

PHARMACOLOGIC THERAPY(CONT.)

FIBRIC ACIDS (GEMFIBROZIL, FENOFIBRATE, CLOFIBRATE)

• Fibrate monotherapy is effective in reducing VLDL, but a reciprocal rise in LDL may occur and total cholesterol values may remain relatively unchanged.

• Plasma HDL concentrations may rise 10% to 15% or more with fibrates.

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PHARMACOLOGIC THERAPY(CONT.) FIBRIC ACIDS

• Gemfibrozil reduces the synthesis of VLDL and, to a lesser extent, apolipoprotein B with a concurrent increase in the rate of removal of triglyceride-rich lipoproteins from plasma.

• Clofibrate is less effective than gemfibrozil or niacin in reducing VLDL production.

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PHARMACOLOGIC THERAPY(CONT.) FIBRIC ACIDS

• GI complaints occur in 3% to 5% of patients, rash in 2%, dizziness in 2.4%, and transient elevations in transaminase levels and alkaline phosphatase in 4.5% and 1.3%, respectively.

• Clofibrate and, less commonly, gemfibrozil may enhance the formation of gallstones.

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PHARMACOLOGIC THERAPY(CONT.)

FIBRIC ACIDS • A myositis syndrome of myalgia,

weakness, stiffness, malaise, and elevations in creatine kinase and aspartate aminotransferase may occur and seems to be more common in patients with renal insufficiency.

• Fibrates may potentiate the effects of oral anticoagulants, and the international normalized ratio should be monitored very closely with this combination.

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PHARMACOLOGIC THERAPY(CONT.) EZETIMIBE (absorption Inhibitor)

• Ezetimibe interferes with the absorption of cholesterol from the brush border of the intestine, a novel mechanism that makes it a good choice for adjunctive therapy.

• It is approved as both monotherapy and for use with a statin.

• The dose is 10 mg once daily, given with or without food.

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PHARMACOLOGIC THERAPY(CONT.) EZETIMIBE

• When used alone, it results in an approximate 18% reduction in LDL cholesterol.

• When added to a statin, ezetimibe lowers LDL by about an additional 12% to 20%.

• A combination product (Vytorin) containing ezetimibe 10 mg and simvastatin 10, 20, 40, or 80 mg is available.

• Ezetimibe is well tolerated; approximately 4% of patients experience GI upset.

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PHARMACOLOGIC THERAPY(CONT.) EZETIMIBE

• Because cardiovascular outcomes with ezetimibe have not been evaluated, it should be reserved for patients unable to tolerate statin therapy or those who do not achieve satisfactory lipid lowering with a statin alone

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CLINICAL CONTROVERSY• ENHANCE trial (Ezetimibe and Simvastatin

in Hypercholesterolemia Enhances Atherosclerosis Regression)

• Familial hypercholesterolemia patients o autosomal dominant LDL receptor mutationo severely elevated LDLo premature atherosclerosis

• 2 groups (n=720)o simvastatin 80 mg + placebo o simvastatin 80 mg + ezetimibe 10 mg


• ENHANCE 1˚ outcome: change in carotid intima-media thickness (CIMT) after 24 monthso no significant difference in CIMT between

groups o simvastatin + ezetimibe group: greater

decreases in LDL & C-reactive protein • No differences in elevated liver enzymes,

myopathy • Limitations: prior lipid-lowering therapy

(many patients had near normal CIMT at initiation); not designed to evaluate differences in incidence of vascular events

CLINICAL CONTROVERSY• SEAS (Simvastatin and Ezetimibe in

Aortic Stenosis)• Simvastatin 40 mg + ezetimibe 10 mg vs

placebo (n=1873)• No change in clinical course of aortic

stenosis• Simvastatin + ezetimibe: increased

incidence of cancer• SHARP & IMPROVE-IT trials in progress

o evaluating ezetimibe for vascular risk reduction

o interm analyses do not show increased cancer risk

Peto R, Emberson J, Landray M, et al. Analyses of cancer data from three ezetimibe trials. N Eng J Med 2008;359:1357-1366.

PHARMACOLOGIC THERAPY(CONT.) FISH OIL SUPPLEMENTATION

• Diets high in omega-3 polyunsaturated fatty acids (from fish oil), most commonly eicosapentaenoic acid (EPA), reduce cholesterol, triglycerides, LDL, and VLDL and may elevate HDL cholesterol.

• Fish oil supplementation may be most useful in patients with hypertriglyceridemia, but its role in treatment is not well defined.

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• Lovaza (omega-3-acid ethyl esters) is a prescription form of concentrated fish oil EPA 465 mg and docosahexaenoic acid 375 mg.

• The daily dose is 4 g/day, which can be taken as four 1-g capsules once daily or two 1-g capsules twice daily.o This product lowers triglycerides by 14% to

30% and raises HDL by about 10%.

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• • Complications of fish oil supplementation such as thrombocytopenia and bleeding disorders have been noted, especially with high doses (EPA,15 to 30 g/day).

• Treatment of type I hyperlipoproteinemia is directed toward reduction of chylomicrons derived from dietary fat with the subsequent reduction in plasma triglycerides.6/13/2011

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TREATMENT RECOMMENDATIONS

• Total daily fat intake should be no more than 10 to 25 g/day, or approximately 15% of total calories.

• Secondary causes of hypertriglyceridemia should be excluded, and, if present, the underlying disorder should be treated appropriately.

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TREATMENT RECOMMENDATIONS(CONT.)

• Primary hypercholesterolemia (familial hypercholesterolemia, familial combined hyperlipidemia, type IIa hyperlipoproteinemia) is treated with BARs, statins, niacin, or ezetimibe.

• • Combined hyperlipoproteinemia (type IIb) may be treated with statins, niacin, or gemfibrozil to lower LDL-C without elevating VLDL and triglycerides.

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• Niacin is the most effective agent and may be combined with a BAR.

• A BAR alone in this disorder may elevate VLDL and triglycerides, and their use as single agents for treating combined hyperlipoproteinemia should be avoided.

• Type III hyperlipoproteinemia may be treated with fibrates or niacin.

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• Although fibrates have been suggested as the drugs of choice, niacin is a reasonable alternative because of the lack of data supporting a cardiovascular mortality benefit from fibrates and because of their potentially serious adverse effects.

• Fish oil supplementation may be an alternative therapy. 6/13/2011


• Type V hyperlipoproteinemia requires stringent restriction of dietary fat intake.

• Drug therapy with fibrates or niacin is indicated if the response to diet alone is inadequate.

• Medium-chain triglycerides, which are absorbed without chylomicron formation, may be used as a dietary supplement for caloric intake if needed for both types I and V

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COMBINATION DRUG THERAPY

• Combination therapy may be considered after adequate trials of monotherapy and for patients documented to be adherent to the prescribed regimen.

• Two or three lipoprotein profiles at 6-week intervals should confirm lack of response prior to initiation of combination therapy. 6/13/2011

COMBINATION DRUG THERAPY(CONT.)

• Contraindications to and drug interactions with combined therapy should be screened carefully, and the extra cost of drug product and monitoring should be considered.

• In general, a statin plus a BAR or niacin plus a BAR provide the greatest reduction in total and LDL cholesterol. 6/13/2011

COMBINATION DRUG THERAPY(CONT.)

• Regimens intended to increase HDL levels should include either gemfibrozil or niacin, bearing in mind that statins combined with either of these drugs may result in a greater incidence of hepatotoxicity or myositis.

• Familial combined hyperlipidemia may respond better to a fibrate and a statin than to a fibrate and a BAR

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REFERENCES• DiPiro JT, Talbert RL, Yee GC, Matzke GR,

Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com

• Daniels SR, Greer FR and the Committee on Nutrition. Lipid Screening and Cardiovascular Health in Childhood. Pediatrics 2008;122:198–208.

• American Academy of Pediatrics. National Cholesterol Education Program: report of the expert panel on blood cholesterol levels in children and adolescents. Pediatrics. 1992;89(3 pt 2):525-584 6/13/2011

REFERENCES• Ridker PM, Danielson E, Fonseca FA, et al.

Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195-2207.

• Glynn RJ, Danielson E, Fonseca FA, et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med 2009;360:1851-61.

• Kastelein JJ, Akdim F, Stroes ES, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Eng J Med 2008;358:1431-1443.

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