S1. HYPERCHOLESTEROLAEMIA

7/24/2019 S1. HYPERCHOLESTEROLAEMIA

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HYPERCHOLESTROLAEMIA

BY:MUHAMMAD SYAFIQ SHARIF 012012100009

EZURYNN NATASHA MOHD HAFIZ 012012100117


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OUTLINE

RECAP metabolism of lipid

Types of Blood Lipids

Primary & Secondary Hypercholestrolaemia

Sign & Symptoms

Complications

CVD Major Risk Factors

Framingham Risk Score

What is normal level/when to treat?

Non-pharmacological treatments

Pharmacological treatments


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METABOLISM OF LIPID

What is fat? Dietary lipid comprise long-chain triglycerides, cholesterol

esters and lecithin.

Lipid are insoluble in water and undergo lipolysis andincorporation into mixed micelles before they can beabsorbed into enterocytes along with fat soluble vitamins A,D, E, and K.

The lipids are processed within enterocytes and pass vialymphatic into systemic circulation.

Fat DigestionStep 1 : Luminal

phase

Step 2 : Fat

solubilisation

Step 3 :

Digestion

Step 4 :

Absorption

Step 5 : Re-

esterification

Step 6 : Transport


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Source:

DavidsonsPrinciples andPractice ofMedicine, page452

EXOGENOUS & ENDOGENOUS LIPID

SYNTHESIS


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TYPES OF BLOOD LIPIDS

Total cholesterol (TC)

High Density Lipoprotein Cholesterol (HDL-C)

Low Density Lipoprotein Cholesterol (LDL-C)

Friedewald equation :

LDL-C (mmol/L) = TC HDL-CTG / 2.2

*the formula is not valid if TG > 4.5mmol/L

* Non HDL-C is a better indicator for atherogenic burden

if TG > 2.3 mmol/L (Non HDL-C (mmol/L) = TCHDL-C)

Triglyceride (TG)

Very Low Density Lipoprotein (VLDL)


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WHEN DO LIPID MEASUREMENTS

USUALLY PERFORMED?

Screening for primary and secondary prevention of

cardiovascular disease.

Investigation of patients with clinical feature of lipid

disorders. Monitoring of response to diet, weight control and

medication.

( Based on Davidsons Principle & Practice ofMedicine )


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CLASSIFICATION OF DYSLIPIDAEMIA

Dyslipidaemiaabnormal level of cholesterol in

blood.


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PRIMARY & SECONDARY

DYSLIPIDAEMIA

Primary

dyslipidaemia:due to

genetic factor


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PRIMARY DYSLIPIDAEMIA

Table from Clinical Practice Guideline Malaysia

Management of Dyslipidaemia 2011


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SECONDARY DYSLIPIDAEMIA

Seconday causes of dyslipidaemia should considered if:

TC > 7mmol/L, exclude conditions such as primary

hypothyroidism, nephrosis, obstructive liver disease.

TG > 4.5 mmol/L, exclude secondary causes such as

alcoholism.

High TG with low HDL-C, insulin states such as T2DM

and metabolic syndrome have to be considered.

Failure to respond to anti-lipid therapy.

Patients with a family history of T2DM or past history of

thyroid disease.


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CLINICAL MANIFESTATION OF

DYSLIPIDAEMIA

Chest pain

Xanthelasma

Corneal arcus

Extensor digitorum xanthomas

Pre-patellar xanthomas

Archilles tendon xanthomas

Aortic stenosis


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COMPLICATIONS

Atherosclerosis

Chest pain (angina)

Heart Attack

Stroke

Hypertension


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CARDIOVASCULAR MAJOR RISK

FACTORS

Age

Gender

Ethnic

Hypertension

Smoking

Positive family history

Obesity Physical inactivity

Unhealthy diets

High cholesterol


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CARDIOVASCULAR MAJOR RISK

FACTORS


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REFERENCES

Clinical Practice Guide by Ministry of Health

Malaysia 4th Edition

Davidson's Principles & Practice of Medicine 22nd

Edition


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HYPERCHOLESTEROLAEMIA( C O N T I N U A T I O N )


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FRAMINGHAM RISK SCORE

It is risk assessment tool for estimating a patients 10year risk developing cardiovascular disease.

Assessments based on:Diabetes mellitus or other heart disease equivalent

Smoking

Age

Gender

Total cholesterolHDL CholesterolSystolic Blood pressure

Hypertension treatment


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In determining cardiovascular risk the following steps are

taken:

Count the number of major risk factors for CVD

For individual with more than 2 risk factors, calculate

the 10-year CVD risk using Framingham risk score

sheets.

For individual with 0 1 risk factors, the CV risk score

need not to be calculated as the risk


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Individual with 2 or more risk factors can fall intoone the following categories for developing CVD

over 10 years:

Low risk = less than10% chance

Intermediate risk = 10% - 20% chanceHigh risk = more than 20% chance


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RECOMMENDED TREATMENT GOALS

Total cholesterol


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TARGET LIPID LEVELS

LDL-C is the primary target for therapy.

The target LDL-C level depends on the individualsglobal risk.

Consider LDL-C target goal


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Target LDL-C Levels


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Management ofDyslipidaemia

Non-pharmacological

measures

Pharmacologicalmeasures


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NON-PHARMACOLOGICAL MEASURES

Therapeuticlifestyle changes

Dietarymodification

Weight

reduction

Regularexercise

Cessation ofsmoking

Restriction of

alcohol


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PHARMACOLOGICAL MEASURES

Therapeutic Lifestyle Change forms an integralcomponent in the management of dyslipidaemia.

In secondary dyslipidaemia, efforts should bemade to correct the underlying cause.

In those with established CVD/CHD riskequivalents, drug treatment ( lipid lowering drugs )will need to be initiated in conjunction with TLC.


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There are 5 major groups of anti-lipid drugs :

HMG CoA Reductase Inhibitors ( Statins )

Fibric Acid Derivatives ( Fibrates )

Bile Acid Sequestrants ( Resins )

Cholesterol Absorption Inhibitors

Nicotinic Acid ( Niacin ) and its derivatives

Major Anti-Lipid Drug Classes ( ATPIII )


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Major Anti Lipid Drug Classes ( ATPIII )


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HMG CoA Reductase Inhibitors ( Statins )

MOA : Reduce cholesterol synthesis by inhibition ofrate limiting HMG CoA reductase enzyme.

The most effective drug class & the treatment of

choice in reducing LDL-C.

Suitable first-line agents in familialhypercholesterolemia, primary prevention of CVD,

secondary prevention of CVD and CHD.

Moderate effect in lowering TG and in elevatingHDL-C.


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Recommended Dosages for Statins (MIMS, Malaysia)

Drug

Recommended

initiating dose Usual dose range

Lovastatin 20 mg 1080 mg/day in single or

divided doses

Pravastatin 20 mg 1040 mg daily

Simvastatin 20 mg 580 mg once daily

Fluvastatin 20 mg

2080 mg/day single or

divided doses

Atorvastatin 10 mg 1080 mg once daily

Rosuvastatin 10 mg 1020 mg once daily

Fib i A id D i i ( Fib )


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Fibric Acid Derivatives ( Fibrates )

Alternative treatment in individuals with mild tomoderate hypercholesterolemia who are statin

intolerant.

MOA : Increases the activity of lipoprotein lipase,decreases the release of fatty acids fromadipose tissue.

Drug Recommended Dosage

Bezafibrate 200 mg daily increasing to a max dose of 200 mg

tds (regular) or 400 mg daily (sustained release)

Fenofibrate 300 mg daily or in divided doses (regular) or 200mg daily (mirconised) or 160 mg daily (supra)

Gemfibrozil 6001500 mg daily in divided doses (regular) or

900 mg daily (sustained release)

Ciprofibrate 100 mg daily


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Bile Acid Sequestrants ( Resins )

MOA : Bind to bile acids to promote their secretion intothe intestines (decreases bile acid absorption),Increases hepatic conversion of cholesterol tobile acids,Increases LDL receptors on hepatocytes.

Effective in lowering LDL-C.

Combination with a statin may be necessary in severehypercholesterolemia.

May interfere with bioavailability of other drugs thusother medications should be taken 1 hour before or 4hours after resin.

Currently not available in the Malaysian market.


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Nicotinic Acid ( Niacin ) and its derivatives

MOA : Decreases mobilization of free fatty acids

from adipose tissues.

Effective in increasing HDL-C and lowers both TC

and TG levels.

Its side effects (flusing, GI side effects) tend to limitcompliance.

Recommended Dosages :

Nicotinic acid (Niacin) is available as capsules of 100 mg or500mg, and sustained release form

Starting dose: 150-300 mg daily in divided doses, titration

of dose up to 2g/day (Usual dose).

It should be taken with meals to reduce GI side effects.


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Cholesterol Absorption Inhibitors

Indicated as monotherapy for primaryhypercholesterolemia in patients who cannottolerate statin or fibrate.

Can also be used in combination with statins tofurther lower LDL-C.

Recommended dose :

- Ezetimibe 10 mg daily


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LDL-C reduction with statin treatment remains thecornerstone of lipid lowering therapy to reduce risk ofCVD.

Fibrates & nicotinic acid may be considered for

increasing HDL-C and reducing TG after LDL-Ctreatment goal has been achieved.

If target goals are not achieved after 8 to 12 weeks ofoptimal monotherapy, combination therapy is suggested.

The combination of gemfibrozil (fibrate) + statin isdiscouraged due to increased incidence of adverseeffect (myositis).

If used, caution and close monitoring should be stressed.

RECOMMENDED DRUG TREATMENT


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Suggested Drug Therapy for Dyslipidaemia


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MONITORING & DURATION OF THERAPY

These individuals will be on a lifelongtherapy.

It is important to assess them on aregular basis in terms of treatment &possible side effects.

After starting drug therapy, LDL-C level

should be measured at 6-8 weeks anddrug doses titrated if necessary.

Once target lipid levels are achieved, a4-6 monthly follow up is recommended.


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Monitoring of ALT is necessary if statinsand fibrates are used for treatment.

Liver function tests should be carried outbefore & within 1-3 months of startingtreatment.

Statins should be discontinued iftransaminase levels rise to at 3 timesthe upper limit of normal.

If the levels are elevated between 2 to3 times upper limit of normal, the trendshould be monitored at monthly

intervals.


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If the levels are stable, they onlyneed be checked periodically or if

the dose of statin or fibrate isincreased.

If myositis is suspected, then creatinekinase levels should be measured.

If the level is more than 10 times theupper limit of normal, the drugshould be discontinued.


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MANAGEMENT IN SPECIAL CONDITIONS

A. Diabetes Mellitus ( T2DM )

Control of glycaemia alone is inadequate inpreventing CV events. Concomitant treatment of

dyslipidaemia, hypertension and other metabolicabnormalities are also important.

Target LDL-C goal in individuals with diabetes is


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B. Coronary Heart Disease( CHD )

Statins should be started early in individuals withACS, and on all post revascularisation individualsirrespective of their baseline cholesterol levels.

In high risk individuals, high intensity statin treatmentconfers more benefit.

Statins are an integral component of optimal

medical therapy in CAD individuals.


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C. Hypertension

Hypertension and elevated cholesterol levels oftencoexist and synergistically increase the risk ofdeveloping CVD.

Treatment of both conditions reduces CVD events.

Statins should be considered in high risk hypertensive

individuals.


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D. Stroke

Statins have been shown to reduce the incidenceof ischaemic strokes when used in high riskindividuals.

Lipid lowering therapy with statins should beconsidered in all individuals with previousischaemic stroke or transient ischaemic attack.


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E. Renal disease

Individuals with CKD have high CV Risk.

Statins have been found to be beneficial inindividuals with CHD and mild to moderate CKD.

In individuals on dialysis, the benefits of lipidlowering therapy are doubtful.

Statins are safe in CKD

Fibrates should be used cautiously in individualswith CKD and very high TG.


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MANAGEMENT IN SPECIAL GROUPS

A. Women

Statins should be the drug of choice.

Statins should not be used in women who arepregnant, intend to become pregnant or who arebreast feeding.

In women who have normal LDL-C but low HDL-Cand high TG, fibrates may be used.

Current practice is to treat these women in the samemanner as men based on extrapolation of benefit in

men at similar risk.

D li id i i P


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Dyslipidaemia in Pregnancy

Lipid & lipoprotein levels increase during pregnancy. This

includes an increase in LDL-C, which resolves post-partum.

Remnant dyslipidaemia & tryglyceridaemia may beexacerbated during pregnancy.

Dyslipidaemia is rarely thought to warrant urgenttreatment so pharmacological therapy is usuallycontraindicated when contraception or pregnancy isanticipated.

Teratogenecity has been reported with systemicallyabsorbed agents, and non-absorbed agents mayinterfere with nutrient bioavailability.

B Children and Adolescents


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B. Children and Adolescents

Children whose lipid levels are significantly elevatedshould be referred to specialists interested in this field.

The main approach is a healthy lifestyle withappropriate diet, maintenance of desirable weightand regular exercise.

In children with elevated cholesterol levels, statins arethe drug of choice.

There has been limited data on the use of niacin, fibricacid derivatives and ezetimibe in children.

C Eld l

( > 65 )


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C. Elderly( > 65 years )

Increasing age is a major risk factor for CVD &death.

For secondary prevention, the elderly derive agreater absolute benefit from lipid lowering therapy.

However, there is limited clinical trial data in patientsover the age of 80 years.

Renal function should be assessed and drug dosages

adjusted accordingly.


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REFERENCES

4th Edition of Clinical Practice Guidelines,Management of Dyslipidaemia 2011

DavidsonsPrinciples & Practice of Medicine, 22nd

Edition

MurtaghsGeneral Practice, 5th Edition


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S1. HYPERCHOLESTEROLAEMIA

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