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HyperlipidemiaDr.Hashim Rida Fida

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

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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.

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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

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Atherosclerosis

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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

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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

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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)

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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

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Dietary sources of CholesterolType of Fat Main Source Effect on

Cholesterol levels

Monounsaturated Olives, olive oil, canola oil, peanut oil, cashews, almonds, peanuts and most other nuts; avocados

Lowers LDL, Raises HDL

Polyunsaturated Corn, soybean, safflower and cottonseed oil; fish

Lowers LDL, Raises HDL

Saturated Whole milk, butter, cheese, and ice cream; red meat; chocolate; coconuts, coconut milk, coconut oil , egg yolks, chicken skin

Raises both LDL and HDL

Trans Most margarines; vegetable shortening; partially hydrogenated vegetable oil; deep-fried chips; many fast foods; most commercial baked goods

Raises LDL

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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)

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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.

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ClassificationHyperlipidemias 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.

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Fredrickson classification of Hyperlipidemias

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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

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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)

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Determining Goal LDL CHD and CHD Risk Equivalents:

Peripheral Vascular Disease Cerebral Vascular Accident Diabetes Mellitus

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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

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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

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Treatment of Hyperlipidemia Lifestyle modification

Low-cholesterol diet Exercise

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Medications for HyperlipidemiaDrug Class Agents Effects (% 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 Acids Gemfibrozil

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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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

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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

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MECHANISM OF ACTION OF STATINS

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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)

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Statin FYI: Brand name

Atorvastatin Lipitor, Torvast

CerivastatinLipobay, Baycol. (Withdrawn from the market in August, 2001 due to risk of rhabdomyolysis)

Fluvastatin Lescol, Lescol XL

Lovastatin Mevacor, Altocor

Pitavastatin Livalo, Pitava

Pravastatin Pravachol, Selektine, Lipostat

Rosuvastatin Crestor

Simvastatin Zocor, Lipex

STATINS

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EZETIMIBE - newest anti-cholesterol drug (FYI: Merck)

Inhibitor of intestinal cholesterol absorption:1. Selective inhibitor of intestinal cholesterol

absorption2. Reduced re-absorption of cholesterol secreted in

bile

Reduces LDL levels, synergistic with statinsMay induce rhabdomolysis by itself and/or increase the risk for statin-induced rhabdomyolysis

DRUGS USED TO TREAT HYPERLIPIDEMIA: CHOLESTEROL

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NIACIN

FIBRIC ACID AGENTS

BILE ACIDRESINS

STATINS

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EZETIMIBE

Mechanisms of action of lipid-lowering drugs

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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. InhibitVLDL 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

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• Niacin: net decrease in LDL

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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

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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

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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

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American Heart Association Guidelines for Prescribing Cholesterol Lowering Drugs

Risk Category

Risks Start Drug

Goal

Low No CHD

1 risk factor

>190 mg/dl < 160 mg/dl

Moderate No 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

High CHD >100 mg/dl <100 mg/dl

CHD: coronary heart disease

Risk factors:SmokingFamily historyHypertensionDiabetesAge (>45 for men an > 55 for women)

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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.

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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?

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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.

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

what?

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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%.

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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?