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2. 2 Hyperlipidemia Dr.Hashim Rida Fida

3. 3 Objectives The story of hyperlipidemia Causes of hyperlipidemia Screening for hyperlipidemia Classification Risk factor for CHD Goals for lipids Treatments

4. 4 The story of lipids 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.

5. 5 The story of lipids (cont.) 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

6. 6 Atherosclerosis

7. 7 LDL from the blood penetrates the arterial walls and accumulates in smooth muscle cells in the form of cholesterol esters. These smooth muscle cells along with activated macrophages are transformed into lipid-filled foam cells. These foam cells shear off with constant blood flow and pull of parts of the vessel walls along with them, exposing underlying tissue The end result is a plaque with a center consisting of  cholesterol deposits and cell components and  a “cap” consisting of aggregated platelets and fibrin. ATHEROSCLEROSIS   LDL

8. 8 High Cholesterol Stable Angina Unstable Angina Acute Myocardial Infarction Acute Heart Failure Congestive Heart Failure Cardiac Arrhythmias Formation of atherosclerotic plaques No Symptoms Partial occlusion of coronary artery Symptoms only during exertion Partial occlusion of coronary artery with sudden, intermittent vasoconstriction. Symptoms increase in frequency and begin to occur at rest Complete occlusion of coronary artery Cell death and myocardial damage Consequences of damage to the heart TYPICAL PROGRESSION OF EVENTS IN CLASSIC ANGINA PECTORIS

9. 9 Causes of Hyperlipidemia Diet Hypothyroidism Nephrotic syndrome Anorexia nervosa Obstructive liver disease Obesity Diabetes mellitus Pregnancy Obstructive liver disease Acute hepatitis Systemic lupus erythematousus AIDS (protease inhibitors)

10. 10 Hereditary Causes of Hyperlipidemia Familial Hypercholesterolemia Co dominant genetic disorder, occurs in heterozygous form Occurs in 1 in 500 individuals Mutation in LDL receptor, resulting in elevated levels of LDL at birth and throughout life High risk for atherosclerosis, tendon xanthomas (75% of patients), tuberous xanthomas and xanthelasmas of eyes. Familial Combined Hyperlipidemia Autosomal dominant Increased secretions of VLDLs Dysbetalipoproteinemia Affects 1 in 10,000 Results in apo E2, a binding-defective form of apoE (which usually plays important role in catabolism of chylomicron and VLDL) Increased risk for atherosclerosis, peripheral vascular disease Tuberous xanthomas, striae palmaris

11. 11 Dietary sources of Cholesterol Type of FatMain SourceEffect on Cholesterol levels MonounsaturatedOlives, olive oil, canola oil, peanut oil, cashews, almonds, peanuts and most other nuts; avocados Lowers LDL, Raises HDL PolyunsaturatedCorn, soybean, safflower and cottonseed oil; fish Lowers LDL, Raises HDL SaturatedWhole milk, butter, cheese, and ice cream; red meat; chocolate; coconuts, coconut milk, coconut oil, egg yolks, chicken skin Raises both LDL and HDL TransMost margarines; vegetable shortening; partially hydrogenated vegetable oil; deep- fried chips; many fast foods; most commercial baked goods Raises LDL

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15. 15 Checking lipids Nonfasting lipid panel measures HDL and total cholesterol Fasting lipid panel Measures HDL, total cholesterol and triglycerides LDL cholesterol is calculated:  LDL cholesterol = total cholesterol – (HDL + triglycerides/5)

16. 16 When to check lipid panel Two different Recommendations Adult Treatment Panel (ATP III) of the National Cholesterol Education Program (NCEP)  Beginning at age 20: obtain a fasting (9 to 12 hour) serum lipid profile consisting of total cholesterol, LDL, HDL and triglycerides  Repeat testing every 5 years for acceptable values United States Preventative Services Task Force  Women aged 45 years and older, and men ages 35 years and older undergo screening with a total and HDL cholesterol every 5 years.  If total cholesterol > 200 or HDL <40, then a fasting panel should be obtained  Cholesterol screening should begin at 20 years in patients with a history of multiple cardiovascular risk factors, diabetes, or family history of either elevated cholesterol levels or premature cardiovascular disease.

17. 17 Classification Hyperlipidemias are classified according to the Fredrickson classification which is based on the pattern of lipoproteins on electrophoresis or ultracentrifugation. It was later adopted by the World Health Organization (WHO). It does not directly account for HDL, and it does not distinguish among the different genes that may be partially responsible for some of these conditions. It remains a popular system of classification, but is considered dated by many.

18. 18 Fredrickson classification of Hyperlipidemias

19. 19 Goals for Lipids LDL < 100 →Optimal 100-129 → Near optimal 130-159 → Borderline 160-189→ High ≥ 190 → Very High Total Cholesterol < 200 → Desirable 200-239 → Borderline ≥240 → High HDL < 40 → Low ≥ 60 → High Serum Triglycerides < 150 → normal 150-199 → Borderline 200-499 → High ≥ 500 → Very High

20. 20 Determining Cholesterol Goal (LDL!) Look at JNC 7 Risk Factors Cigarette smoking Hypertension (BP ≥140/90 or on anti- hypertensive) Low HDL cholesterol (< 40 mg/dL) Family History of premature coronary heart disease (CHD) (CHD in first-degree male relative <55 or CHD in first-degree female relative < 65) Age (men ≥ 45, women ≥ 55)

21. 21 Determining Goal LDL CHD and CHD Risk Equivalents: Peripheral Vascular Disease Cerebral Vascular Accident Diabetes Mellitus

22. 22 LDL Goals 0-1 Risk Factors: LDL goal is 160 If LDL ≥ 160: Initiate TLC (therapeutic lifestyle changes) If LDL ≥ 190: Initiate pharmaceutical treatment 2 + Risk Factors LDL goal is 130 If LDL ≥ 130: Initiate TLC If LDL ≥ 160: Initiate pharmaceutical treatment CHD or CHD Risk Equivalent LDL goal is 100 (or 70) If LDL ≥ 100: Initiate TLC and pharmaceutical treatment

23. 23 TREATMENT OF HYPERLIPIDEMIA TWO BASIC STRATEGIES : 1. DECREASE THE AMOUNT OF LIPID ENTERING THE BLOOD Low-fat, low-calorie diets First line of defense; should continue through drug treatment Drugs that reduce lipoprotein synthesis 2. IMPROVE THE CLEARANCE OF LIPID FROM THE BLOOD For VLDL (triglyceride source) this involves the enzyme LIPOPROTEIN LIPASE For LDL (cholesterol source) this involves LDL RECEPTORS: the less cholesterol in the liver, the more LDL receptors will be synthesized MORE LDL RECEPTORS = MORE EFFICIENT REMOVAL OF LDL FROM THE BLOOD

24. 24 Treatment of Hyperlipidemia Lifestyle modification Low-cholesterol diet Exercise

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28. 28 Medications for Hyperlipidemia Drug ClassAgentsEffects (% change)Side Effects HMG CoA reductase inhibitors Lovastatin Pravastatin  LDL (18-55),  HDL (5-15)  Triglycerides (7-30) Myopathy, increased liver enzymes Cholesterol absorption inhibitor Ezetimibe  LDL( 14-18),  HDL (1-3)  Triglyceride (2) Headache, GI distress Nicotinic Acid  LDL (15-30),  HDL (15-35)  Triglyceride (20-50) Flushing, Hyperglycemia, Hyperuricemia, GI distress, hepatotoxicity Fibric AcidsGemfibrozil Fenofibrate  LDL (5-20),  HDL (10-20)  Triglyceride (20-50) Dyspepsia, gallstones, myopathy Bile Acid sequestrants Cholestyramine  LDL  HDL No change in triglycerides GI distress, constipation, decreased absorption of other drugs

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30. 30 DRUGS USED FOR TREATING HYPERLIPIDEMIA HYPERTRIGLYCERIDEMIA: Niacin Fibric acid derivatives HYPERCHOLESTOLEMIA: Bile-acid binding resins Statins Ezetimibe Combination therapy (e.g., ezetimibe + a statin drug) FYI: LIPITOR (generic name atorvastatin) = a statin drug

31. 31 DRUGS USED TO TREAT HYPERLIPIDEMIA: CHOLESTEROL STATIN DRUGS: HMG-CoA Reductase Inhibitors ATORVASTATIN (Lipitor) – most prescribed (Pfizer) –HMG-CoA reductase is a key liver enzyme for the synthesis of cholesterol –By inhibiting cholesterol synthesis in the liver, cellular concentrations are reduced and LDL receptors are up-regulated resulting in increased removal of LDL from the blood. HMG CoA Cholesterol HMG CoA Reductase STATIN DRUGS

32. 32 MECHANISM OF ACTION OF STATINS

33. 33 STATINS 2003: atorvastatin (Lipitor) alone = 65.5 million prescriptions; MOST FOR ANY TRADE-NAME DRUG All appear to be equally efficacious (20-60% reductions) Taken orally before bed (most cholesterol is made when you sleep) Marked first-pass metabolism SIDE EFFECTS: Usually safe with mild side effects (GI). Some side effects are more severe: NOT PRESCRIBED TO CHIDREN AND WOMEN WHO ARE PREGNANT, LACTATING, OR MAY BECOME PREGNANT LOW INCIDENCE OF LIVER TOXICITY (0.5% PATIENTS). THESE AGENTS SHOULD BE USED WITH CAUTION IN PATIENTS WITH PARENCHYMAL LIVER DISEASE, ASIANS, AND ELDERLY LOW INCIDENCE OF RHABDOMYOLYSIS Skeletal muscle cell lysis and release of muscle cell contents into the circulation, potentially resulting in kidney failure and death. SYMPTOMS: muscle pain, muscle atrophy, fatigue, dark urine, elevated blood creatine kinase levels (skeletal muscle enzyme)

34. 34 StatinFYI: Brand name AtorvastatinLipitor, Torvast Cerivastatin Lipobay, Baycol. (Withdrawn from the market in August, 2001 due to risk of rhabdomyolysis) FluvastatinLescol, Lescol XL LovastatinMevacor, Altocor PitavastatinLivalo, Pitava PravastatinPravachol, Selektine, Lipostat RosuvastatinCrestor SimvastatinZocor, Lipex STATINS

35. 35 EZETIMIBE - newest anti-cholesterol drug (FYI: Merck) Inhibitor of intestinal cholesterol absorption: 1. Selective inhibitor of intestinal cholesterol absorption 2. Reduced re-absorption of cholesterol secreted in bile Reduces LDL levels, synergistic with statins May induce rhabdomolysis by itself and/or increase the risk for statin-induced rhabdomyolysis DRUGS USED TO TREAT HYPERLIPIDEMIA: CHOLESTEROL

36. 36 NIACIN FIBRIC ACID AGENTS BILE ACID RESINS STATINS + - EZETIMIBE Mechanisms of action of lipid-lowering drugs

37. 37 VLDL = PRIMARY CARRIER OF TRIGLYCERIDES TREATMENT OF HYPERTRIGLYCERIDEMIA INVOLVES DECREASING CIRCULATING VLDL LEVELS DRUGS THAT DECREASE VLDL LEVELS: NIACIN (a.k.a., nicotinic acid); NIACIN also increases HDL levels and decreases and LDL levels FIBRIC ACID DERIVATIVES DRUGS USED TO TREAT HYPERLIPEMIA: TRIGLYCERIDES Lipoprotein Lipase LDL Liver VLDL Blood Cholesterol 1. Inhibit VLDL synthesis in liver 2. Stimulate breakdown of VLDL by lipoprotein lipase VLDL MECHANISMS: Stimulation of lipoprotein lipase also increases LDL – this is offset by decreased VLDL synthesis + Niacin: net decrease in LDL

38. 38 DRUGS USED FOR THE TREATMENT OF HYPERTRIGLYCERIDEMIA Niacin Clinical use Hypertriglyceridemia Familial hypersholesterolemia (in combination with cholesterol- lowering drugs) Mixed (multi-factorial) hyperlipidemias Adverse effects Flushing (cutaneous vasodilation and sensation of warmth) – prostaglandin-related effect Increase gastric acid secretion – may be taken with antacids or inhibitors of gastric acid secretion – is contraindicated in patients with peptic ulcer Impairment of glucose tolerance – is contraindicated in patients with insulin resistance Hepatotxicity Hyperuricemia – may precipitate gout

39. 39 DRUGS USED FOR THE TREATMENT OF HYPERTRIGLYCERIDEMIA Fibric acid derivatives: Gemfibrozil, Fenofibrate Mechanism of action Ligands of nuclear receptor, peroxisome proliferator-activated receptor-alpha (PPAR-α) Increase expression of LPL, increase lipolysis of triglycerides Intracellular lipolysis in adipose tissue is decreased LDL levels may increase, especially in patients with mixed hyperlipidemias Clinical use Hypertriglyceridemia Adverse effects May promote cholesterol gallstones Myopathy Liver toxicity

40. 40 BINDING RESINS BILE ACID-BINDING RESINS: (colestipol cholestyramine, colesevelam; all begin with chol- or col-) REDUCE LDL (CHOLESTEROL), used for isolated increase in LDL Level of VLDL may increase in patients with hypertriglyceridemia Large hydrophobic resins taken orally that bind to bile acids in the intestine and prevent bile acid re-absorption (usually 95% re-absorbed) Cholesterol is required for bile acid synthesis in the liver Reduced bile acid concentrations in the liver results in greater conversion of cholesterol to bile acids and lower liver cholesterol levels Lower cholesterol results in an up- regulation of the number of LDL receptors on liver cells which increases cholesterol uptake from the blood DRUGS USED TO TREAT HYPERLIPIDEMIA: CHOLESTEROL

41. 41 American Heart Association Guidelines for Prescribing Cholesterol Lowering Drugs Risk Category RisksStart Drug Goal LowNo CHD 1 risk factor >190 mg/dl< 160 mg/dl ModerateNo CHD 2 or more moderate risk factors >160 mg/dl<130 mg/dl Moderate High No CHD 2 or more high risk factors >130 mg/dl<130 mg/dl HighCHD>100 mg/dl<100 mg/dl CHD: coronary heart disease Risk factors: Smoking Family history Hypertension Diabetes Age (>45 for men an > 55 for women)

42. 42 Case # 1 A 55-year-old woman without symptoms of CAD seeks assessment and advice for routine health maintenance. Her blood pressure is 135/85 mm Hg. She does not smoke or have diabetes and has been postmenopausal for 3 years. Her BMI is 24. Lipoprotein analysis shows a total cholesterol level of 240 mg/dL, an HDL level of 55 mg/dL, a triglyceride level of 85 mg/dL and a LDL level is 180 mg/dL. The patient has no family history of premature CAD.

43. 43 Case # 1 (cont.) What is the goal LDL in this woman? What would you do if exercise/diet change do not improve cholesterol after 3 months? How would your management change if she complained of claudication with walking?

44. 44 Case # 2 A 40- year-old man without significant past medical history comes in for a routine annual exam. He has no complaints but is worried because his father had a “heart attack” at the age of 45. He is a current smoker and has a 23-pack year history of tobacco use. A fasting lipid panel reveals a LDL 170 mg/dL and an HDL of 35 mg/dL. Serum Triglycerides were 140 mg/dL. Serum chemistries including liver panel are all normal.

45. 45 Case # 2 (cont.) What is this patient’s goal LDL? Would you start medication, and if so, what?

46. 46 Case # 3 A 65 year-old woman with medical history of Type II diabetes, obesity, and hypertension comes to your office for the first time. She has been told her cholesterol was elevated in the past and states that she has been following a “low cholesterol diet” for the past 6 months after seeing a dietician. She had a normal exercise stress test last year prior to knee replacement surgery and has never had symptoms of CHD. A fasting lipid profile was performed and revealed a LDL 130, HDL 30 and a total triglyceride of 300. Her Hgba1c is 6.5%.

47. 47 Case # 3 (cont.) What is this patient’s goal LDL? What medication would you consider starting in this patient? What labs would you want to monitor in this patient?