How to approach a case of hyperlipidemia

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(Therapeutics)How to approach a case of Dyslipidemia (30-31) Year II By Dr Attia JabrA)

1. Check the random level of total cholesterol (TC) as initial screening.

2. If it is increased, do a fasting level of TC, TG, and HDL.

During weight loss and MI What about Lipid profile?As regards the level of TC

a. The normal total cholesterol is < 200 mg/dl

b. If it is between 200-239..Moderate

c. If it is > 240.. Severe.

d. The ratio between TC/HDL: is more senstiveAs regards TG

a. If it is < 150 it is normal

b. If it is 150-199Mild increase

c. If it is 200-499.Moderate increase

d. If it is > 500..Severe increase.

B) Ask for a second fasting lipid profile (12h fasting)

The NCEP guidelines are:

1. LDL>160 + or other risk factors

2. LDL 130-159 +2 risk factors

3. LDL >100 + atherosclerotic disease

4. HDL< 40 How can you calculate the LDL.C?C) Assess for the number of risk factors present in the patient:NB; DM is considered now CHD equivalent The Major risk factors are:

1. Current Cigarette smoking

2. Hypertension (BP > or = 140/90 or on Anti-hypertensive therapy. > stroke3. Low HDL.C < 40 mg/dl

4. Family history of CHD (definite MI) or sudden death due to CHD in father or other first degree relatives < 55Y or before 65 y in mother or other female first degree relatives.

5. Age (men 45 y; women 55y6. Risk equivalent: DM, PVD

Minor risk factors:A. Sedentary life style: 50%B. Obesity (BMI >30) & Waist > 102 cm M & 88cm F: 50%C. Dietary: Alcohol HT, CVS riskD. Triglycerides, VLDL, IDL Contributing factors:

A. CRF

B. Radiation therapy

C. SLE.Putative factors:A. Homocyteine

B. Lpa C. Small LDL D. C-reactive protein, E. Chronic infectionNB. Some criteria that raise the suspicion of familial dyslipidemia are: 1. CHD or dyslipidemia in first degree female < 65y 2. CHD or dyslipidemia in first degree males < 55Y

3. Xanthelasma OR corneal arcus under age of 50

4. Tendon xanthomata 5. High TC at any age

Types of familial dyslipidemias (60% of cases of dyslipedimia):TypeTGTCLDL.CRaised lipoproteinsAtheroma riskAssociated

Signs

I++++NChylomicronsN

IIa 1/500N++++LDL+++Xanthomas,CA

IIb 1/200++++++LDL/VLDL+++Common

III

1/5000++++NVLDL/chylo++Obesity, DM,HT xanthomas

IV++N/+NVLDL++Obesity, DM, Hyperuricemia, alcoholic

V

1/1000000++++NVLDL/ChyloNObesity, DM

Polygenic HC+++++LDL++Family H 25%

No physical

D) Assess for presence of secondary causes of hyperlipidemia (because they can be treated) 40%. The most important secondary causes are:

1. DM type I, type II(High TG, Low HDL, High LDL) ( CHD 4times)2. Hypothyroidism (Combined or High TG)3. Pregnancy

4. Inappropriate diet

5. Alcohol abuse (TG)6. Chronic renal failure (TG)7. Renal & cardiac transplantation

8. Nephrotic syndrome (LDL-C) + corticosteroids.9. Hepatocellular disease

10. Cholestasis

11. Myeloma

12. Obesity (High TG& Low HDL-C)13. Drugs; the most important drugs are

a. Antihypertensives (Diuretics (thiazides (LDL-c, VLDL-c, TG& Loop, B. blockers TG, HDL). What are the alternatives?b. Oral contraceptives (Ht, DM)c. Androgensd. Corticosteroids (TC, LDL, TG, VLDL)e. Ciclosporines (LDL, Ht, DM) + corticosteroids.f. Progestogens (LDL, HDL)g. Vit. A derivativesh. Protease inhibitors, Tamoxifeni. Hepatic microsomal enzyme inducers (like phenytoin, rifampicin, carbamazepine, grisofulvin etc). Increase all (HDL, LDL, VLDL) But good ratio TC: HDLE) Define your goal of treatment concentrating on level of LDL as follows:Risk categoryLDL goal

Mg/dlDiet/life style indicatedDrug therapy

indicated

No CHD with 0 or 1 risk factors190

No CHD wit 2 risk factors160

DM130

CHD130

CHD + Multiple risk factors or DM100

F) The design of treatment is as follows: 1. Treat risk factors (life style changes)1. Stop smoking

2. Encourage regular excersize. Value?3. Treat secondary causes of hyperlipidemia, DM, HT.4. Obese should lose weight. (Relation?)5. Stop alcohol2. Diet (step II) (3-6%) 30% total fat (10% polyunsaturated, 15% monosaturated, < 7% saturated fat), Cholesterol 200 mg/day. Increase fiber at least 30 gm/day.NutrientStep IStep II

Total fat30%30%

Saturated fat55%>55%

Protein15%15%

Cholesterol300 mg/day200 mg/day

Dietary management of hyperlipoproteinemia

Always initiated firstly in the management.

Except patients with familial hypercholestrolemia and combined hyperlipidemia in which both drugs and diet should begin together.

Total fat restrictionhypertriglyceridemia

Cholesterol & Saturated fatHypercholestrolemia (LDL)

Decrease CHO (Sucrose & simple sugars) VLDL.

Increase dietary fibers (oat or rice bran)LDL

Increase vegetables, fresh fruit, cereals, whole grain. Stanol esters and plant sterols ( reduce Cholesterol absorption) No alcoholHypertriglyceridemia

Decrease caloric intake and stabilization of weight.

Total fat calories should be 20-25% with saturated fat < 8%, Allow monousaturated (olive oil, and polyunsaturated like sun & corn flower oil (not excess. Why?) & Cholesterol < 200 mg/day( not more than 4 eggs /w)

Take care of hydrogenated fat & prolonged heating Increase complex CHO and fiber Monosaturated fat should predominate fat allowance.

Omega 3 fatty acids found in fish oils (Cod liver oil) salmon fish can induce profound lowering of triglycemia with endogenous or mixed type. However, Omega 6 in plant oils raises these levels.

The diet should contain anti-oxidants 500 mg ascorbic acid + Mixed natural tocopherols (200-400 IU) + other natural antioxidants present in fruits and vegetables.

Reduce the total amount of proteins to reduce homocysteine

Daily supplementation with 1 mg folic acid + vit. B complex Salt: reduce the amount from 9 gm to 6 gm3. Continue on diet and life style changes for 3-6M if ineffective or unacceptable or if there is evidence of IHD, hypertension, DM, positive family history, or there is hypertriglyceridemia, lipid lowering drugs should be used.Indications of drug therapy:

1. In whom the above dietary measures are not successful

2. Who find the dietary restrictions risky

3. Who are at great risk of IHD, pancreatitis >1000 mg TG

4. For secondary prevention after IHDA) Primary prevention:

The aims of treatment of 1ry hyperlipoprotinemia are (When there is risk of CHD of 15% or more in 10Y)A) To reduce the risk of atheroma in familial hypercholesterolemia, familial hypertriglyceridemia , remnant hyperlipoprotenimia)

B) To reduce the risk of acute pancreatitis in chylomicronemia and familial hypertriglyceridemia).C) The treatment can reduce xanthomatous eruption in the skin and tendons.D) Important factors to consider in risk management in primary prevetion:1. Dietary advice

2. Smoking

3. Physical activity

4. Body weight

5. Hypertension

6. Control of diabetes7. Low dose aspirin: in high risk especially with HT8. Lowering of cholesterol by statins according to the risk factors ( 15% and Tc> 200 mg/dlLife style modification + Drug therapy e.g. statin.B) Secondary prevention:9. Statins except when the major abnormality is low HDL10. Treat other risk factors

11. Low dose aspirin

12. ACE inhibitors for left ventricular dysfunction

13. B. blockers for MI

14. Warfarin or aspirin for those over 60 y who have atrial fibrillation15. Omega 3 fatty acidsTreatment of hypertriglyceridemia:

1. Begin with non-pharmacological measures

2. Control of diet, weight diabetes, alcohol

3. If insufficient, use drugs as follows:

a. Modest TG + TCuse statins

b. Extremely high TGuse fibrates or niacin

c. High risk individuals combine statins + fibrates

The use of drugs in lowering plasma lipid concentration:

a. Statins & Resins for cholesterolb. Fibrates & Nicotinic A for TG.

c. All have side effects, see the table.d. Two drugs with mg (statins & Fibrates)

e. Two drugs with Gms (Resins & Niacin).f. Begin with small doses then increase gradually till full therapeutic doses.

g. Follow up the effect of drugs every 4-6 w until you reach your goal then every 6 months, then annually.h. Nicotinic acid increases uric acid & fenofibrates decreases it.

i. Lipid profile is done /6 W until adjustment, then annually.j. Liver function test & kidney function & creatine kinase E should be done during treatment for follow up the side effects of drugs.

k. Before therapy you may look for the secondary causes by some investigations like TSH, liver function, kidney functions, blood glucose, drugsl. It should be known that drug therapy should be continued life long. Why?Drug combinations:

4. If one drug is not effective, you can add one or more drug, the following drug combinations are possible:a. Fibrates + Resins ( familial combined hyperlipidemia)

b. Statins + Resins ( Familial hypercholesterolemia)

c. Niacin + Resins ( Familial hypercholesterolemia)

d. Niacin + Statins (Familial hypercholesterolemia)

e. Ternary combinations of (Resins + Niacin + Statins)

Never use Statins + fibrates except. Why? StatinsResinsFibratesNicotinic acid

Examples

DosesSimva, fluva,

Atorva-statin (10-80 mg)Colistipol

Choestyramine (15-30 gm)Bezafibrate

400-600 mg/dayGemfibrozil 600mg/12h1.5-6gm/day

EffectPredominantly lower CholesterolLower TG, VLDL/2ry C,LDL

MechanismHMG-COA reductase EBile acid absorptionLipoprotein lipase EAdipose tissue lipolysis

UsesFamilial hypercholestolemia(type IIa, familial combined hyperlipidemia type IIbHypertriglyceridemia (type IV, V) combined hyperlipidemia (type IIb,III)

Other usesPruritusDiarrhea

Digitalis toxicityNever combine with statins for sever myositisMay be used in combination to HC

TC45%30%20%20%

TG30%20%50%60%

VLDL10%-60%10%

LDL60%20%25%30%

HDL15%

5%20%25%

Side effects

HepatitisHepatic injury-Hepatic injuryLarge dosesSR

MyositisMuscle injuryLoss of bile saltsMuscle injuryGlucose

Uric acid

GIT

GITGIT(constipation)Gall stones & GITGIT(PU)

OthersHypersensitivityCutaneous flush & pruritus

Pregnancy and lactationNOYes NONO

Drug-drug interactionsC.P450 inducers and inhibitors (grapefruit)

Nicotinic, cyclosporineBinding drugs( digoxin, diuretics,thyroxine, statins, Vit KStatins& Oral anticoagulants & oral antidiabetics& Resins& CiclosporinDrugs of DM & Gout

Questions for revision:

Q1. What are the pathways of lipoprotein metabolism?

Q2. Enumerate the important types of lipoproteins? Their content?

Q3. Why do we say Dyslipidemia not hyperlipidemia?

Q4. What are the common familial disorders of dyslipidemia? Which is raised?

Q5. Can dyslipidemia cause MI in adolescents < 20Y? Which type?

Q6. Which of the familial disorders is not associated with atherosclerosis?

Q7. What are the common disorders known to affect adversely the lipid profile?

Q8. What is the effect of B.blockers on lipid profile?

Q9. Which B. Blockers do not affect the lipid profile? Why?Q10. What are the other antihypertensive drugs which do not affect lipids?

Q11. What are the life style changes you advise a patient to do before treatment?

Q12. What is the BMI? Formula? Scales?Q13. What is your advice as regards diet for patients with dyslipidemia?

Q14. What is your opinion in antioxidants in CHD?

Q15. For how long will you advise for diet and life style changes? 1ry& 2ryQ16. What are the general lines for primary prevention for cases of dyslipidemia?

Q17. What are the general lines for secondary prevention for cases of dyslipidemia?

Q18. What is the mechanism of action of statins?

Q19. Why statins are useful in CHD?

Q20. What are the most important side effects of statins?

Q21. What is the effect of grapefruit on statins effect and toxicity?

Q22. What is the mechanism of action of fibrates?

Q23. What are the main side effects of fibrates?

Q24. What are the drug-drug interactions of statins?

Q25. What are the drug-drug interactions of fibrates?

Q26. What is the mechanism of action of Resins?

Q27. Which drug raises the TG?

Q28. What are the precautions taken while taking resins?

Q29. What are the major adverse effects of Resins?

Q30. What is the mechanism of action of nicotinic cid?

Q31. What are the major side effects of NA?

Q32. What is your opinion about fish oil in treating hyperlipidemia?

Q33. Why statins are preferred to be taken at evening?

Q34. When do you expect the results of statins?

Q35. How can you overcome the hot flushes of nicotinic acid?

Q36. Are the accompanying statements false or true? Why?a. An individual with high HDL there is a lowering in the risk of CHD if the HDL is reduced.

b. An important contributor to the development of hypercholesrolemia is a genetic defect.

c. Anion exchange resins act by enhancing the absorption of bile acids from the gut.d. Decreased cholesterol synthesis results in increased number of HDL receptors

e. Simvastatin lowers LDL by 5%

f. Co-administration of bile acid resins and statins has no greater effect than giving each drug separately.When do you think to use drug combinations in treating dyslipidemia?Indicated in:

1. Very high VLDL during ttt of HC

2. Combined high LDL and VLDL

3. LDL and VLDL not responsive to single agent

4. Elevated level of Lpa or HDL + other dyslipidemia

The combinations are:

1. Statins + Resins or EzetimibeFHC # VLDL. (+ 20-30%)

2. Statins (25% dose) + Niacin FHC & FCH. (Myopathy)

3. Statins (25% dose) + fibratesFCH. (fenofibrate + rosuvastatin)

4. Statin + Niacin +Resins FHC & FCH ,VLDL + LDL. 70%

5. Fibric acid + ResinsFCH. #Niacin or statin

6. Statins + Ezetimibe FHC (even Homozygous)

7. Resins + niacin + statins+ Ezetimibe LDL(doses)

Case discussion

Case 1: A 42-year-old woman, has a plasma total triglyceride of 1042 mg/dl and total cholesterol of 368 mg/dl. Plasma HDL is 72 mg/dl. Electrophoresis of the plasma lipoproteins an intense pre-B-band; all others are normal or absent. Blood glucose is normal. She is not taking any medications.

Q1. What hyperprlipoproteinemia does this patient most likely have?

Q2. What is the greatest health risk to this patient based upon the provided information?

Q3. Which individual drug or combination can safely be used to produce maximum lowering of her plasma lipids?

Q4. IF the patient is given fenofirate to treat his condition, what enzyme or receptor activity will most increase?Case 2; Awatif a 45 years is an asymptomatic female. She is screened with a lipoprotein profile during an annual physical evaluation. She has non-insulin dependent DM treated with 60 U NPH. She is overweight. Her fasting lipoprotein profiles: total cholesterol 234 mg/dl, triglycerides 2300 mg/dl, HDL-24 mg/dl, LDL 160 mg/dl, fasting BG 290 mg/dl. What is your assessment of CHD risk and what treatment if any should be given?

Control DM-Fibrates-Lipid profile100 give statin.Case 3; Mr D.F is a 43-year-old man who has been relatively fit and well for the past 20 y during which he has rarely visited his GP. Two weeks ago he was admitted to hospital suffered MI. On questioning it was revealed that his brother had died in a road traffic accident at the age of 19 and his father had died from CHD aged 54Y. Examination of Mr D.F. revealed tendon xanthomas. Blood drawn within 2 h of the onset of MI revealed TC 350, HDL 40 and triglycerides 200 mg/dl

Questions

Q1. Calculate the concentration of LDL and comment on the finding?

Q2. What is the likely diagnosis and treatment of DF on discharge?

Q3. D F wants to know why he was not identified as being at high risk of CHD before he suffered his MI?Case 4; Mr P.T. is a 50-year-old man with a blood pressure of 140/85 mm Hg and type 2 DM, but no history of CHD. He smokes 10 cigarettes a day. On a routine clinic visit he is found to have a TC of 240 mg/dl, HDL 30 , and TG 150 mg/ dl.Questions:

Q1. Is PT at high risk of CHD?

Q2. What advice/ treatment would be appropriate?Case 5: Mrs Soad is a 49-year-old woman who visits her doctor complaining of menopausal symptoms including hot flushes, night sweats and irritability. She is concerned about her risk of CHD because her husband and mother have angina. Her mother developed angina at the age of 68 and 5 years later was diagnosed with breast cancer. In general Mrs Soad does not like taking medicines and would not much prefer exercise to hormone replacement therapy (HRT)? Q1. Is Mrs Soad at risk of CHD?

Q2. What advice would you give her about the relative benefits of exercise and HRT?Case 6. A 58-year-old man has recovered from anterior MI. His fasting plasma cholesterol is 210 mg/dl. You want to reduce his risk of a further MI by lowering his cholesterol.

a. What advice would you give him?

b. What drug would you recommend and why?

c. What reduction of plasma cholesterol would you expect, and when would you expect an adequate response?

d. How do statins work?

e. What target total cholesterol would you aim for?

f. What unwanted effects would you warn him about?

g. If the target cholesterol is not attained, how could you reduce cholesterol further?

h. How the additional drugs you have recommended work?

Case 7:

A 45-year- man has a plasma total triglyceride of 105 mg/dl and total cholesterol of 431 mg/dl. Plasma HDL is 53 mg/dl. Electrophoresis of his plasma lipoproteins show an intense B-band; all others are normal. He is taking itraconazole for persistent fungal infections. He had two older brothers who both died of MI at 53 and 51 years of age.

Q1. What hyperlipoproteinemia does this patient most likely have?

Q2. What is the most likely biochemical basis of this patient's hyperlipidemia?

Q3. What drugs would be contraindicated in this patient if his use of itraconazole was not discontinued?

Q4. If the patient was treated with cervistatin, what adverse effects would be of greatest potential concern?

Case 8; Essam, a 53-year-old man, has a mean LDL.c of 200 mg/dl determined on two appointments after following a step II diet, low-saturated fat diet for 6 months. His high BP is under marginal control with enalapril 10 mg/day ( BP,134/88). His glucose level is 80 mg/dl. He reports no family history of premature CHD events. He does not smoke. His HDL.c is 45 mg/dl. There are no secondary or familial causes of his hypercholesterolemia, and no evidence of atherosclerosis was found during his initial medical evaluation. He jogs 2 miles 3 times a week. Is Essam a candidate of cholesterol lowering drug therapy, and if so, Q 1; What drug (s) should be considered for lowering his LDL.c level?

Q2. According to the answer in previous question either a bile acid resin, niacin, or HMG-CoA reductase inhibitor would be acceptable? What about fibrates?Q3. Which one of these 3 major drugs would be used first to manage L.W lipid disorder? Your goal? Which drug from this group? Why? If failed, what will you do? Combinations?Q4. How can you monitor each of these drugs?A. BAR (Lipid profile /4-8 w)

B. Statins (Lipid profile, LFTs (0-3m-A), CPK((0-symptoms)C. Niacin therapy (Lipid profile, LFTS (0-6-8w for 1year, symptoms) Glucose, uric acid, BP (hypertensive & elderly patients)Q5. What are the doses of theses drugs? Time of administration?

Q6. What is the difference between colesevelam and cholestyramine?

Q7. What do you know about Ezetimibe?

Q8. What role can supplemental fibers play in the treatment of the patient? 5%Q9. Can fish oils be used to treat elevated LDL-C in patient's treatment?TG 30-60%Case 9. Asmaa is a 55-year-old recently postmenopausal woman. She has a mean LDL of 200 mg/dl after a 6-month trial of a step II diet. She has a strong family history of CHD. Her mother is 78 years complaining of fracture as a result of osteoporosis. No DM, No HT. She smokes 10 cigrettes/day. HDL 58 mg/dl. Tg 78 mg/dl. No evidence of secondary or familial dyslipidemia and no evidence of atherosclerosis. No hysterectomy. Physically active and with normal weight. She complains of hot flashes and night sweats.

Q1. Does this patient need cholesterol lipid lowering? If so. Which drug? Q2. What is your opinion for using estrogen therapy in treating this lady?

Q3. What are the adverse effects of estrogen in this lady?

Q4. How can you decrease the side effects of estrogen therapy in this lady?

Q5. What are the contraindications of estrogen?

Q6. Do you think that statins are good for the patient?

Q7. What is your opinion in using BAR or niacin?Case 10: If the Ali's BP persists after lifestyle changes are made, how should he be managed?

Q1. Which drugs Beta blockers (ISA?), alpha blockers, mixed, thiazides?, CCBs, ACEI Q2. Which diuretics do not affect blood lipids?

Q3. Are B. Blockers essential in Ali's condition?What is your opinion in anti-oxidant in management of hyperlipidemic patients especially who have developed CHD?

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