done by: mohannad a. al-shibani pharm.d intern 1

Hyperlipidemia

Done by: Mohannad A. AL-Shibani Pharm.D intern

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Main pointsI. Pathophsiology

II. Management

III.Case

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Definition: an increase plasma level of cholesterol and / or triglyceride

Hyperlipidemia may be secondary to disorder like DM , hypothyroidism, nephrotic syndrome , obesity, high alcohol intake and some drugs

Prevalence: 20.6 million children and adults – 12.0 % of the population -- have hyperlipedemia

Pathophsiology

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Diagnosed: 14.6 million people

Undiagnosed: 6.0 million people

In KSA 22% of population have an increase in cholesterol and /or triglyceride

A leading risk factor for CV disease

Pathophsiology

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Etiology:I. Primary causes(genetic): single or multiple

gene mutations that result in either overproduction or defective clearance of TG and LDL cholesterol, or in underproduction or excessive clearance of HDL

II. Secondary causes(lifestyle &others): xss. dietary intake of saturated fat, cholesterol, and trans fats. Like polyunsaturated or monounsaturated fatty acids , diabetes mellitus, alcohol over use,CKD, hypothyroidism, biliary cirrhosis and drugs, such as thiazides, β-blockers , estrogen and progestins

Pathophsiology

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Risk factor:Non – modifiable:

Age >45 for male , >55 for femaleMale sex (at risk 4-5 times more than female)Family history of premature CHD (1st-degree

relative) Genetic susceptibility

Pathophsiology

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Risk factor:Modifiable

HTN(> 140/90 mmHg )DMObesity InactivityLow HDL(<40 mg/dl)SmokingChronic kidney disease

Pathophsiology

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higher Cholesterol Levels Associated With CHD Risk higher

0

25

50

75

100

125

150

204 205-234 235-264 265-294 295

CH

D I

NC

IDEN

CE P

ER

1000

SERUM CHOLESTEROL (MG/100 ML)

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Complication:1) Fatty streaks: its reversible process while

atherosclerosis (plaque) irreversible

2) Corneal xanthelasma: accumulation of yellow plaque underneath skin ,eyelid(irreversible)

3) Planar exanthema: appear on hand,Knee,&elbow (irreversible)

4) Irruptive exanthema : rashes due increase TG (reversible)

Pathophsiology

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Characteristic of plasma lipoprotein:

Pathophsiology

APPEREANCE AFTER REREG.

% PROTIEN CONTENT

% of TGL Major lipid Lipoprotein class

Cream layer 1-2 3-7 TGL(Diet) chylomicron

turbid 6-10 20-30 TGL(Endogenous)

VLDL

clear 18-22 51-58 cholesterol LDL

clear 45-55 18-25 cholesterol HDL

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Classification: 1-phenotypic (Fredrickson

classification)

Pathophsiology

TGL LDL Lipoprotein in excess

familial class

+++ + chylomicron hyperchylomicronemia

I(rare)

N.L. ++++ LDL hypercholesrolemia

IIa

++ +++ LDL&VLDL Combined hyperlipedemia

IIb

+++ ++ IDL dysbetalipoprotenimia

III(rare)

++++ + VLDL hypertriglyceridemia

IV

++++ ++ VLDL&CHYLOMICRON

Combined hypertriglyceridemia

V(rare)13

Classification: 2-(Genetic classification)

Pathophsiology

Homozygous familial hypercholesterolemia

Heterozygous familial hypercholesterolemia

Two defect gene One defect gene

Atherosclerosis 1 st/2nd decade (10-20 years)

Atherosclerosis 4 th decade (40-50 years)

Total cholesterol =18-25 mmol/l Total cholesterol =7.7-12.9 mmol/l

AMI before age 20(if not treated)

1 case per 1 million persons The prevalence of is approximately 1 case per 500 persons in U.S

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Diagnosis: measure Serum lipid profile after 12 hr. fasting like

I. total cholesterolII. TGIII. HDL-cholesterolIV. calculated LDL-cholesterol and VLDL)

VLDL= ( TGL / 5 )LDL= {Total cholesterol – (HDL +VLDL)}

Pathophsiology

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Normal level of lipoprotein: National Cholesterol Education Program Adult Treatment Panel III

Screening: A fasting lipid profile should be repeated every 5 yr. Lipid measurement should be accompanied by assessment of other cardiovascular risk factors

Pathophsiology

mmol/L mg/dL lipoprotein

<5.17 <200 Total cholesterol

>1.03 >40 HDL

<1.7 <150 Triglyceride

<3.33 <130 LDL

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II-Managment

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I. Life style modification

II. Drug therapy like:

Bile acid sequestrants Nicotinic acid derivative Fibric acid derivative HMG-CoA reductase inhibitor Cholesterol absorption inhibitors

managment

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Life style modification:decreasing intake of saturated fats and

cholesterol; increasing fiber, complex carbohydrates; stop smoking and maintaining IBW. Referral to a dietitian is often useful,

Drugs are the next step when lifestyle changes are not effective after 3-4 month. However, for patients with extremely elevated LDL-cholesterol (> 200 mg/dL [> 5.2 mmol/L]) and those at high cardiovascular risk, drug should accompany with diet and exercise from the start

managment

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PHARMACOTHERAPEUTIC OPTIONS

cholesterol-lowering medications may be considered in addition to lifestyle changes.

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Drug therapy:1) Bile acid sequestrantso M.O.A:block intestinal bile acid reabsorption,

forcing up-regulation of hepatic LDL receptors to recruit circulating cholesterol for bile synthesis

managment

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o usually used with statins or with nicotinic acid to augment LDL-cholesterol reduction

o their use is limited by adverse effects of bloating, nausea, cramping, and constipation. They may also increase TGL so use only in type 2A

o Example: cholestyramine ,and colestipol

managment

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Cholestyramine available in powder form so can mix with orange drink or juice to minimize gritty texture

Dose: 4 g QID Colestipol have better adherence b/z its

odorless and tasteless, available in tablet form

Dose: 2 to 16 grams/day once or in divided doses

managment

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2-Nicotinic acid derivative: M.O.A.: alters lipid profiles has not been well

defined. It may inhibition of release of free fatty acids from adipose tissue, and increased lipoprotein lipase activity, which may increase the rate of chylomicron triglyceride removal from plasma

the most effective drug for increasing HDL

Principle use in type 2B as first line and second line in type 2A,may used as first line or alternative in type4&5

managment

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S.E.: hyperglycemia , hyperurecemia ,itching and cutaneous flushing may restrict its use but….

Dose: 500mg at within meal or after to reduce the incidence and side effects which may occur and titrated dose to 2000 mg/d

managment

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3-fibric acid derivative:M.O.A.:

increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity).

Drug of choice in type 4 and may used in 2B and in decrease HDL alone

managment

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Example: 1)gemfibrozil(lopid) dose:600 mg BID

Cost: 55 SR

, 2)fenofibrate(lipanthyl) dose:200 mg OD

Cost: 49 SR

Other: 3) clofibrate(use restricted due high mortality)

4) benzofibrate(use restricted due stone formation)

S.E: muscle cramps and stiffness

managment

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4-HMG-CoA reductase inhibitor:

M.O.A: inhibit hydroxymethylglutaryl CoA reductase, a key enzyme in cholesterol synthesis, leading to up-regulation of LDL receptors and increased LDL clearance. They reduce LDL-cholesterol by up to 60%

Not only have statins improved lipid profiles, but they have in turn reduced cardiovascular morbidity and mortality

managment

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Drug of choice in type 2A & 2B b/z it mainly act on LDL

S.E: 1)Mylagia 2)increase liver function test

Example: 1-atorvastatin(lipitor) 2-simvastatin(zocor)

3-pravastatin(lipostat) 4-fluvastatin(lescol)

5-rosuvastatin(crestor)

managment

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Comparative efficiency and pharmacology of the statins.

DrugReduction in LDL-C

)%(

Increase in HDL-

C)%(

Reduction in TG)%(

Reduction in TC

)%(Metabolism T1/2 (h)

Atorvastatin 26-60 3-15 11-53 25-45 CYP3A4 13-30

Simvastatin 26-47 8-16 \12-34 19-36 CYP3A4 1-3

Fluvastatin 22-36 3-11 12-25 16-27 CYP2C9 3-5

Rosuvastatin 45-63 8-14 10-35 33-46 CYP2C9 19

Pravastatin 22-34 2-12 15-24 15-26 Sulfation 2-3

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managment

Cost in SR LDL lowering & NAME of drug

125 39% ATORVASTATIN 10mg

201 43% 20 mg

229 50% 40mg

60% 80mg

22% Fluvastatin 20mg

24% 40 mg

119 30% 80 mg

68 22% Pravastatin 10 mg

111 32% 20 mg

34% 40 mg

45% Rosuvastatin 5 mg

116 52% 10 mg

197 55% 20 mg

%63 40 mg

48 30% Simvastatin 10 mg

54 38% 20 mg

65 41% 40 mg

47% 80 mg

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managment

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5-cholesterol absorption inhibitor: M.O.A: inhibit intestinal absorption of biliary

and dietry cholesterol

Decrease LDL by 15-20% Increase HDL by 2.5-5% Decrease TGL by 0-2%

can be used as monotherapy in patients intolerant to statins or added to statins for patients on maximum doses with persistent LDL-cholesterol elevation

managment

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Doesn’t influence the activity of CYP-450

S.E.: abdomain pain ,fatigue , diarrhea

Example: Ezetemibe (Ezetrol) cost:225 SR

Dose: 10 mg OD approved in Oct.2002

managment

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New combination of ezetemibe and simvastatin in saudi market called (INGEY) or (Vytorin)

Dose : - 10/20 mg cost: 273 SR -10/40 mg cost:296 SR

managment

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Guidelines for treatment according NCEP:

1- Initiate LDL-lowering drug therapy with a statin, or bile acid sequestrant, or nicotinic acid.

2- In 6 weeks, evaluate if LDL goal is achieved. If not,Consider higher dose of statin or add bile acid sequestrant or nicotinic acid or ezetemibe

managment

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3-In 6 weeks, evaluate if LDL goal is achieved. If not, intensify drug therapy. If LDL goal is achieved, treat other lipid risk factors

4-Every 4 - 6 months, monitor response and adherence to therapy

IF TGL high alone used first niacin or fibrate

IF HDL low alone consider first niacin

managment

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LDL is the primary target of lower cholesterol & better predictor of CHD

NCEP recommend full lipid panel every 5 years

Dietry therapy should consider first line in tratment

Drug therapy should combined with Life style modification

Selection of drug is based on efficiacy ,side effect &cost

Take Home points:

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III-case study

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HPI:68 years Yemenian female, 82 kg, with known case of type 2DM, and dyslipidemia . She came to family clinic complaining of fatigue ,palpitation and dyspnea

Vital signs:

Wt : 82 Kg HR: 20 mm/hr Temp: 37.2 c

BP: 119/77 mm Hg

CC: generalized fatigue from any activity , difficult in breathing and increase in its heart rate with sweating

Physical examination:

HEENT: normal Chest: clear

CVS: S1 + S2+O Abd: normal and soft Extremities: normal

Case studyFile no.:552020

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Past medical history:1) Hyperlipidemia from 2 years treated by:

Atorvastatin (lipitor) 10 mg OD then changed ……

2)Type 2 DM from 4 years treated by: metformin (glucophage) 500 mg BID glibenclamide(daonil) 5 mg BID

She took ASA 81 mg OD Patient note non compliance to drug due financial

reason .and not adherence to her diet

Case study

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Family history: Her mother with DM type II

Social history: married, non smoker , poor education and financial proplem

Lab result: 1-Glycated haemoglobin level is 7.5%

2- LDL=4.03mmol/l (<3.3mmol/l)

3- HDL=1.32 mmol/l (>1.03mmol/l)

4-TGL=1.91 mmol/l (<3.3mmol/l)

5- chol=5.5mmol/l (<5.17mmol/l)

6- FBS= 6.1mmol/l (<7 mmol/l)

7- 2hr= 11.4mmol/l (<11.0 mmol/l)

Case study

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Case studyHbA1c%

2 hrmmol/l

FBSmmol/l

TGLmmol/l

HDLmmol/l

LDLmmol/l

date

11.8 8.6 1.87 3.4 9/3/06

11.1 7.5 3.6 4/3/07

7.2 10.5 5.9 3.2 13/6/07

7.2 10.7 6.8 1.43 3.6 28/10/07

7.3 11.4 6.1 1.34 3.91 2/2/08

7.5 10.7 6.8 2.2 1.40 3.5 5/5/08

7.7 11.4 6.2 1.56 1.37 3.71 11/10/08

7.5 11.4 6.10 1.91 1.32 4.03 16/12/0845

Plan:

The most common cause of therapy failure is:1) the wrong medication, 2) the wrong

dose,

3) patient non-compliance

On 5/5/2008………………….

Case study

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atorvastatin 10 mg equivalent to 20 mg simvastatin

In case of DM : 1)advice to increase dose of glibenclamide to

5mg TID

In case of hyperlipidemia: 1)Advice to increase dose of simvastatin to 20

mg OD

Case study

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Recommendation:Educate the patient about his medication

uses and administrationAdvise patient to take the medication

regularly to avoid the complication in futureIllustrate to the patient importance of diet Try to help the socioeconomic proplem of the

patient by shown him the cheapiest alternative of his medication availble in market

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Total cost per month in SR

Alternative with same active constituent

Total cost per month in SR

medication

20 (Glibil) 50 Glibenclamide(Daonil) 5mg

BID

9 (Metfor) 21 Metformin(Glucophage)

500mg BID

75 ((Statin 125 Atorvastatin(lipitor )10 mg

OD

54 ((Simva 119 Or Simvastatin(zocor)20 mg

OD

4 same 4 Aspirin))ASA 81 mgOD

Total cost=108 SROR 87 SR

TOTAL cost=200 SROR 194 SR

,

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Marry A. Kimble.Handbook of Applied Therapuetics.Lippincott Williams and Wilkins, MD.8th Ed, 2007; Chapter 12, page:127-143

Grundy SM, et al. Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation 2004; 110: 227-239

Stone NJ, Blum CB, Winslow E. Management of lipids in clinical practice. 5th ed. Caddo, OK, Professional Communications, Inc., 2005.

Refrences

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