Hyperlipidemia Done by Mohannad A ALShibani Pharm D

Hyperlipidemia Done by: Mohannad A. AL-Shibani Pharm. D intern 1

Main points I. Pathophsiology II. Management III. Case 2

Pathophsiology Definition: an increase plasma level of cholesterol and / or triglyceride q 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 3

Pathophsiology 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 4

Pathophsiology 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 5

Pathophsiology Risk factor: q Non – modifiable: Ø Age >45 for male , >55 for female Ø Male sex (at risk 4 -5 times more than female) Ø Family history of premature CHD (1 st-degree relative) Ø Genetic susceptibility 6

Pathophsiology Risk factor: q Modifiable Ø HTN(> 140/90 mm. Hg ) Ø DM Ø Obesity Ø Inactivity Ø Low HDL(<40 mg/dl) Ø Smoking Ø Chronic kidney disease 7

CHD INCIDENCE PER 1000 higher Cholesterol Levels Associated With CHD Risk higher 150 125 100 75 50 25 0 204 205234 235264 265294 295 SERUM CHOLESTEROL (MG/100 ML) 8

Pathophsiology 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) 9

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Pathophsiology Characteristic of plasma lipoprotein: Lipoprotein class Major lipid % of TGL % PROTIEN CONTENT APPEREANCE AFTER REREG. chylomicron TGL(Diet) 3 -7 1 -2 Cream layer VLDL TGL(Endogeno 20 -30 us) 6 -10 turbid LDL cholesterol 51 -58 18 -22 clear HDL cholesterol 18 -25 45 -55 clear 11

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Pathophsiology Classification: 1 -phenotypic (Fredrickson classification) class familial Lipoprotein in LDL excess TGL I(rare) hyperchylomicro nemia chylomicron + +++ IIa hypercholesrole mia LDL ++++ N. L. IIb Combined hyperlipedemia LDL&VLDL +++ ++ III(rare) dysbetalipoprote nimia IDL ++ +++ IV hypertriglyceride mia VLDL + ++++ V(rare) Combined hypertriglyceride mia VLDL&CHYLO MICRON ++ ++++ 13

Pathophsiology Classification: 2 -(Genetic classification) Heterozygous familial hypercholesterolemia Homozygous familial hypercholesterolemia One defect gene Two defect gene Atherosclerosis 4 th decade (40 -50 years) Atherosclerosis 1 st/2 nd decade (10 -20 years) Total cholesterol =7. 7 -12. 9 mmol/l Total cholesterol =18 -25 mmol/l AMI before age 20(if not treated) The prevalence of is approximately 1 case per 1 million persons per 500 persons in U. S 14

Pathophsiology Diagnosis: measure Serum lipid profile after 12 hr. fasting like I. total cholesterol II. TG III. HDL-cholesterol IV. calculated LDL-cholesterol and VLDL) VLDL= ( TGL / 5 ) LDL= {Total cholesterol – (HDL +VLDL)} 15

Pathophsiology Normal level of lipoprotein: National Cholesterol Education Program Adult Treatment Panel III lipoprotein mg/d. L mmol/L Total cholesterol <200 <5. 17 HDL >40 >1. 03 Triglyceride <150 <1. 7 LDL <130 <3. 33 Screening: A fasting lipid profile should be repeated every 5 yr. Lipid measurement should be accompanied by assessment of other cardiovascular risk factors 16

II-Managment 17

managment I. Life style modification II. Drug therapy like: q Bile acid sequestrants Nicotinic acid derivative Fibric acid derivative HMG-Co. A reductase inhibitor Cholesterol absorption inhibitors q q 18

managment Life style modification: q decreasing intake of saturated fats and cholesterol; increasing fiber, complex carbohydrates; stop smoking and maintaining IBW. Referral to a dietitian is often useful, q 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/d. L [> 5. 2 mmol/L]) and those at high cardiovascular risk, drug should accompany with diet and exercise from the start 19

PHARMACOTHERAPEUTIC OPTIONS cholesterol-lowering medications may be considered in addition to lifestyle changes. 20

managment Drug therapy: 1) Bile acid sequestrants o M. O. A: block intestinal bile acid reabsorption, forcing up-regulation of hepatic LDL receptors to recruit circulating cholesterol for bile synthesis 21

managment 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 2 A o Example: cholestyramine , and colestipol 22

managment § Cholestyramine available in powder form so can mix with orange drink or juice to minimize gritty texture ü Dose: 4 g QID § Colestipol have better adherence b/z its odorless and tasteless, available in tablet form ü Dose: 2 to 16 grams/day once or in divided doses 23

managment 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 2 B as first line and second line in type 2 A, may used as first line or alternative in type 4&5 24

managment S. E. : hyperglycemia , hyperurecemia , itching and cutaneous flushing may restrict its use but…. Dose: 500 mg at within meal or after to reduce the incidence and side effects which may occur and titrated dose to 2000 mg/d 25

managment 3 -fibric acid derivative: M. O. A. : Ø 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). ü Drug of choice in type 4 and may used in 2 B and in decrease HDL alone 26

managment 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) q S. E: muscle cramps and stiffness 27

managment 4 -HMG-Co. A reductase inhibitor: § M. O. A: inhibit hydroxymethylglutaryl Co. A reductase, a key enzyme in cholesterol synthesis, leading to upregulation 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 28

managment ü Drug of choice in type 2 A & 2 B b/z it mainly act on LDL Ø S. E: 1)Mylagia 2)increase liver function test Example: 1 -atorvastatin(lipitor) simvastatin(zocor) 3 -pravastatin(lipostat) 5 -rosuvastatin(crestor) 24 -fluvastatin(lescol) 29

Comparative efficiency and pharmacology of the statins. Drug Reduction in Increase in Reduction LDL-C (%) HDL-C (%) in TG (%) Reduction in TC (%) Metabolism T 1/2 (h) Atorvastatin 26 -60 3 -15 11 -53 25 -45 CYP 3 A 4 13 -30 Simvastatin 26 -47 8 -16 12 -34 19 -36 CYP 3 A 4 1 -3 Fluvastatin 22 -36 3 -11 12 -25 16 -27 CYP 2 C 9 3 -5 Rosuvastatin 45 -63 8 -14 10 -35 33 -46 CYP 2 C 9 19 Pravastatin 22 -34 2 -12 15 -24 15 -26 Sulfation 2 -3 30

NAME of drug LDL lowering & ATORVASTATIN 10 mg 39% 125 40 mg managment 50% 201 80 mg 60% 20 mg 22% 40 mg 24% 80 mg 30% 119 10 mg 22% 68 20 mg 32% 111 40 mg 34% 5 mg 45% 10 mg 52% 116 20 mg 55% 197 40 mg 63% 10 mg 30% 48 20 mg 38% 54 40 mg 41% 65 80 mg 47% 20 mg Fluvastatin Pravastatin Rosuvastatin Simvastatin Cost in SR 43% 229 31

managment 32

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managment 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 34

managment Doesn’t influence the activity of CYP-450 S. E. : abdomain pain , fatigue , diarrhea Example: Ezetemibe (Ezetrol) Dose: 10 mg OD cost: 225 SR approved in Oct. 2002 35

managment ü New combination of ezetemibe and simvastatin in saudi market called (INGEY) or (Vytorin) Ø Dose : - 10/20 mg -10/40 mg cost: 273 SR cost: 296 SR 36

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managment 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 38

managment 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 ü IF TGL high alone used first niacin or fibrate ü IF HDL low alone consider first niacin 39

Take Home points: q. LDL is the primary target of lower cholesterol & better predictor of CHD q. NCEP recommend full lipid panel every 5 years q. Dietry therapy should consider first line in tratment q. Drug therapy should combined with Life style modification q. Selection of drug is based on efficiacy , side effect &cost 40

III-case study 41

File no. : 552020 Case study HPI: 68 years Yemenian female, 82 kg, with known case of type 2 DM, and dyslipidemia. She came to family clinic complaining of fatigue , palpitation and dyspnea Vital signs: Wt : 82 Kg HR: 20 mm/hr BP: 119/77 mm Hg Temp: 37. 2 c CC: generalized fatigue from any activity , difficult in breathing and increase in its heart rate with sweating Physical examination: HEENT: normal Chest: clear CVS: S 1 + S 2+O Abd: normal and soft mities: normal 42

Case study 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 ü She took ASA 81 mg OD ü Patient note non compliance to drug due financial reason . and not adherence to her diet 43

Case study 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. 03 mmol/l (<3. 3 mmol/l) 3 - HDL=1. 32 mmol/l (>1. 03 mmol/l) 4 -TGL=1. 91 mmol/l (<3. 3 mmol/l) 5 - chol=5. 5 mmol/l (<5. 17 mmol/l) 6 - FBS= 6. 1 mmol/l (<7 mmol/l) 7 - 2 hr= 11. 4 mmol/l (<11. 0 mmol/l) 44

Case study date LDL mmol/l 9/3/06 3. 4 4/3/07 HDL mmol/l TGL mmol/l FBS mmol/l 2 hr mmol/l Hb. A 1 c% 1. 87 8. 6 11. 8 3. 6 7. 5 11. 1 13/6/07 3. 2 5. 9 10. 5 7. 2 28/10/07 3. 6 1. 43 6. 8 10. 7 7. 2 2/2/08 3. 91 1. 34 6. 1 11. 4 7. 3 5/5/08 3. 5 1. 40 2. 2 6. 8 10. 7 7. 5 11/10/08 3. 71 1. 37 1. 56 6. 2 11. 4 7. 7 16/12/08 4. 03 1. 32 1. 91 6. 10 11. 4 7. 5 45

Case study Plan: q The most common cause of therapy failure is: 1) the wrong medication, 2) the wrong dose, 3) patient non-compliance v On 5/5/2008…………………. 46

Case study atorvastatin 10 mg equivalent to 20 mg simvastatin v In case of DM : 1)advice to increase dose of glibenclamide to 5 mg TID v In case of hyperlipidemia: 1)Advice to increase dose of simvastatin to 20 mg OD 47

Recommendation: Educate the patient about his medication uses and administration Advise patient to take the medication regularly to avoid the complication in future Illustrate 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 48

, Alternative with medication Total cost per month in SR Glibenclamide (Daonil )5 mg BID 50 (Glibil) 20 Metformin (Glucophage) 500 mg BID 21 (Metfor) 9 Atorvastatin (lipitor) 10 mg OD 125 (Statin) 75 Or Simvastatin (zocor)20 mg OD 119 (Simva) 54 4 same 4 ASA (Aspirin) 81 mg. OD TOTAL cost=200 SR OR 194 SR same active constituent Total cost per month in SR Total cost=108 SR OR 87 SR 49

Refrences § Marry A. Kimble. Handbook of Applied Therapuetics. Lippincott Williams and Wilkins, MD. 8 th 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. 5 th ed. Caddo, OK, Professional Communications, Inc. , 2005. 50

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