Drug Treatment of Hyperlipidemia

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Drug Treatment of Hyperlipidemia

• Philip Marcus, MD

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Atherosclerotic Cardiovascular Disease and
Hypercholesterolemia

• 7 Million Americans with symptomatic ASCVD
• 12 deaths in US attributed to ASCVD
• 120 billion spent to treat ASCVD
• 1/500 has genetic predisposition leading to
  premature ASCVD
• Heterozygous familial hypercholesterolemia
• Lifestyle is contributing factor in remainder
• 31 of Americans have borderline to high total
  cholesterol
• 20 of Americans have high total cholesterol

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Ischemic Heart Disease

• Plaques of atheroma in coronary arteries
• Partially occlude
• May rupture exposing subendothelium
• Focus for thromboses
• Can result in Myocardial Infarction
• Prevention of Myocardial Infarction
• Reduce progression of atheroma
• Produce regression of existing plaques

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Development of Atheromatous Plaque
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Ischemic Heart Disease Atheroma

• Coronary Arteries
• Myocardial Infarction
• Cerebral Arteries
• Stroke
• Peripheral Arteries
• Peripheral Vascular Disease (PVD)
• Renal Arteries
• Hypertension
• Renal failure

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Atheromatous Disease Risk Factors

• Family History
• Hypertension
• Cigarette Smoking
• Hyperglycemia
• Obesity
• Physical Inactivity
• High serum cholesterol (LDL)
• Hyperhomocysteinemia

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Lipoproteins and ASCVD

• Lipoproteins
• Play essential role in transporting lipids
  between tissues
• Lipids insoluble in plasma and therefore require
  lipoproteins for transport
• Composition of Lipoproteins
• Central Core
• Contains lipid (Triglyceride or cholesterol
  esters)
• Hydrophobic
• Hydrophilic Coat
• Polar
• Contains Phospholipids, Free Cholesterol,
  Apolipoproteins

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Lipoprotein Classification

• HDL
• LDL
• VLDL
• Chylomicrons

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Chylomicrons

• Largest, lightest of particles
• Synthesized in intestinal mucosa
• Carry Triglyceride of dietary origin
• Appear after a fatty meal
• Milky plasma
• Cleared in 8 to 12 hours
• Via lipoprotein lipase
• Converts TG to FFA and Glycerol
• Heparin and Apo C-II cofactors
• Type I Hyperlipoproteinemia
• Familial
• Lipoprotein Lipase Deficiency
• Delayed chylomicron clearance, elevated serum TG
• No increase in coronary artery disease

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Very Low Density Lipoprotein (VLDL)

• Smaller and denser particles
• Secreted by liver
• Synthesized from carbohydrate, fatty acids and
  others
• Principal carrier of endogenous Triglyceride
• Major lipid is TG, also contains Cholesterol
• Excess VLDL Elevated TG
• Contains Apo B100
• Metabolized by lipoprotein lipase
• TG converted to FFA (cell permeable)
• Elevated LDL results from increased VLDL
  secretion or from decrease in LDL catabolism

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Low Density Lipoprotein (LDL)

• Smaller, denser and more soluble
• Principal lipid is cholesterol (up to 75)
• ½ to 1/3 of total cholesterol carried by LDL
• Low in TG, no turbidity
• Derived mainly from VLDL catabolism via IDL
• Contains Apo B100
• Allows binding to LDL receptor
• LDL particles, on binding to LDL receptors on
  hepatocytes and peripheral cells, deliver
  cholesterol for synthesis of cell membranes and
  steroid hormones

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Low Density Lipoprotein (LDL)

• Some cholesterol, upon presentation to LDL
  receptors, undergo esterification by fatty acids
  and are reincorporated into HDL
• Half-Life 2.5 days
• Type IIA Hyperlipoproteinemia
• Familial hypercholesterolemia
• Elevated LDL with normal VLDL levels
• Due to block in LDL degradation
• Caused by decreased number of LDL receptors
• Associated with accelerated coronary artery
  disease

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High Density Lipoprotein (HDL)

• Smallest, most dense and most soluble
• Produced by liver and small intestine in nascent
  form (HDL3)
• Discoidal HDL3 acquires protein from catabolism
  of TG rich lipoproteins to become mature,
  spheroidal HDL2 particles
• Apo AI major protein component of HDL
• Activates lecithin cholesterol acetyltransferase
• HDL acts in transport of cholesterol between
  cells and plasma
• Provides mechanism for removing cholesterol from
  tissue
• Inverse relationship between HDL and coronary
  artery disease
• Protective effect via HDL2

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Major Enzymes in Lipoprotein Metabolism

• Lipoprotein Lipase
• Located in muscle and adipose tissue
• Hydrolyzes chylomicron and VLDL Triglyceride
• Lecithin-Cholesterol Acetyltransferase
• Found in plasma
• Esterifies free cholesterol on HDL surface
• Triglyceride Lipase
• Located in liver
• Hydrolyzes TG within IDL and HDL particles

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Hyperlipidemias Primary

• Type I
• Familial Hyperchylomicronemia
• Elevated TG, Mildly elevated CHOL
• Treated by LOW FAT diet
• Type IIA
• Familial Hypercholesterolemia
• Elevated CHOL, Normal TG
• Elevated LDL
• Treatment with low cholesterol and low saturated
  fat diet. Drug therapy effective.

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Hyperlipidemias Primary

• Type IIB
• Familial combined hyperlipidemia
• Similar to IIA, but elevated VLDL also
• Elevated CHOL and TG
• Caused by overproduction of VLDL by liver
• Treatment with low cholesterol and low saturated
  fat diet. Avoidance of alcohol. Low CHO.
• Type III
• Familial dysbetalipoproteinemia
• Increased levels of IDL
• Increased TG and CHOL
• Overproduction/underutilization of IDL, abnormal
  ApoE
• Accelerated coronary artery disease
• Treatment similar to IIB

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Hyperlipidemias Primary

• Type IV
• Familial hypertriglyceridemia
• Marked increase in VLDL, normal LDL
• Relatively common
• Often associated with hyperuricemia, obesity,
  diabetes
• Accelerated coronary disease noted
• Treatment with low CHO diet, weight reduction,
  avoidance of alcohol
• Type V
• Familial mixed hypertriglyceridemia
• Type I Type IV
• Elevated VLDL chylomicrons
• Low fat and low CHO diet

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Hyperlipidemia Secondary

• Disease states
• Diabetes mellitus
• Alcoholism
• Nephrotic syndrome
• Chronic renal failure
• Hypothyroidism
• Liver disease
• Drugs
• Thiazides
• Estrogens
• b-blockers
• Isotretinoin

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Drugs Used in Treatment Past and Present

• Thyroid hormones
• Dextrothyroxine
• Estrogens
• Neomycin
• Bile Acid Binding Resins
• Ezetimibe
• Fibric Acid Derivatives
• Niacin
• Probucol
• HMG-CoA-Reductase inhibitors (statins)

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Natural AlternativesDietary Supplements

• Garlic
• Plant Sterols
• Benecol
• Also as margarine product
• Red Rice Yeast
• Contains Lovastatin
• FDA attempting to regulate as drug
• Niacin

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Bile Acid Binding Resins

• Cholestyramine, Colestipol, Colesevelam
• Anion exchange resins
• Large polymeric cations
• Insoluble chloride salt
• Ion exchange sites are trimethyl-benzyl-ammonium
  groups
• Bind negatively charged bile acids and bile salts
  in small intestine
• Prevents absorption of bile acids and cholesterol
• Chloride exchanged for bile acids
• Resin itself not absorbed

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Cholestyramine (Questran, LoCHOLEST) Colestipol
(Colestid) Colesevelam (Welchol)
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Cholestyramine Bile acid effects
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Bile Acid Binding Resins

• Bile acids normally 95 reabsorbed in jejunum
• 10 fold excretion of bile acids noted
• Bile acids are metabolites of cholesterol
• Lowering bile acids causes hepatocytes to
  increase conversion of cholesterol to bile acids
• Intracellular cholesterol concentration decreases
• Activates hepatic uptake of LDL and fall in serum
  LDL
• Increased uptake mediated by up-regulation of
  cell surface LDL receptors

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Bile Acid Binding Resins

• Drugs of choice in treating IIA and IIB
• For homozygous IIA, no effect since LDL receptors
  lacking
• 25 reduction in CHOL after 2 to 4 weeks
• Toxicity
• Unpleasant texture
• Nausea, constipation, bloating, flatulence
• Need large amount of fluids, high bulk diet
• Impaired absorption of fat-soluble vitamins
• Useful also in itching associated with partial
  biliary obstruction

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Bile Acid Binding Resins

• Drug Interactions
• Interfere with intestinal absorption of anionic
  drugs
• Thiazides
• Digoxin
• Warfarin
• Thyroxin
• Tetracycline
• Drugs to be taken 2 hours before or 4 hours after
  cholestyramine or colestipol
• Large Doses needed
• Cholestyramine 8 grams three times daily
• Colesevelam 3 tablets (1875 mg) twice a day

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Ezetimibe (Zetia)

• Localizes and acts at brush border of small
  intestine
• Inhibits absorption of cholesterol
• Leads to decrease in delivery of intestinal
  cholesterol to the liver
• Causes reduction of hepatic cholesterol stores
  and increase in clearance of cholesterol from the
  blood

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Ezetimibe (Zetia)

• Mechanism of action is complementary to that of
  HMG-CoA reductase inhibitors
• Results in reductions in
• Total cholesterol
• LDL-cholesterol
• Apolipoprotein B
• Triglycerides
• Results in increase in HDL-cholesterol

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Ezetimibe (Zetia)

• Inhibits intestinal absorption of cholesterol by
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• No effect on plasma concentrations of Vitamins A,
  D or E
• No impairment of steroid hormone synthesis

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Ezetimibe (Zetia)

• Well-absorbed orally
• Extensively conjugated to pharmacologically
  active glucuronide
• Highly bound to plasma proteins
• Metabolized in liver and small bowel via
  glucuronide conjugation
• Biliary and renal excretion

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Ezetimibe (Zetia)

• Well tolerated
• Adverse reactions no different than placebo
• Antacids and cholestyramine decrease effect of
  ezetimibe
• 10 mg once daily

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Fibric Acid Derivatives

• Mechanism of action
• Stimulates lipoprotein lipase
• Results in hydrolysis of TG in chylomicrons and
  VLDL
• Accelerates removal of VLDL and chylomicrons
• Does not alter secretion of VLDL from liver
• Also lower fibrinogen levels

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Fibric Acid Derivatives
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Fibric Acid Derivatives

• Clofibrate (Atromid-S )
• First agent used in clinical practice
• Caused 22 lowering of TG, 6 lowering of
  cholesterol
• Long-term use associated with complications
• Thromboembolic disease
• Cholelithiasis and pancreatitis
• Increased malignancies
• No beneficial effects on progression of heart
  disease

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Fibric Acid Derivatives

• Gemfibrozil (Lopid )
• Same mechanism of action
• More commonly used
• Used in hypertriglyceridemia
• Useful in Type III
• Adjunct to diet in Type IV
• Completely absorbed
• Extensively bound to albumin

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Fibric Acid Derivatives

• Gemfibrozil
• Adverse effects
• GI effects
• Myositis syndrome
• Elevated CK, AST
• Patients with renal disease at greatest risk
• Myopathy reported in conjunction with statins
• Hepatotoxicity
• Elevated transaminase levels
• Reversible upon discontinuation
• Cholelithiasis
• Drug interactions
• Competes with highly bound drugs to albumin
• Major problem with warfarin (Coumadin )

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Fibric Acid Derivatives

• Fenofibrate (Tricor)
• Adjunctive therapy
• Adult patients
• Elevated serum triglycerides
• At risk of pancreatitis
• No response to dietary manipulation
• Inhibits TG synthesis
• Decreases VLDL
• Stimulates catabolism of VLDL
• Once daily administration

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Niacin (Nicotinic Acid)

• Found to lower cholesterol levels in large doses
  as early as 1955
• Gram doses rather than mg doses used as vitamin
• Niacin, not niacinamide (nicotinamide)
• Vitamin B3
• Acts to decrease VLDL and LDL
• Lowers cholesterol(10) and TG (30)
• Maximal effects in 3 to 5 weeks
• Raises HDL

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Niacin (Nicotinic Acid)

• Mechanism of Action
• Inhibits lipolysis in adipose tissue
• Adipose tissue primary producer of FFA
• FFA major precursor for TG synthesis
• Decreases esterification of TG in liver
• Increases lipoprotein lipase activity
• Inhibits VLDL secretion and synthesis in liver
• Decreases LDL production
• Increases secretion of tPA and lowers fibrinogen
• Reverses endothelial cell dysfunction
  contributing to thrombosis and atherosclerosis
• Decreases HDL catabolism

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Niacin (Nicotinic Acid)

• Pharmacokinetics
• Orally administered
• Rapidly absorbed
• Peak levels in under one hour
• Converted to nicotinamide
• Incorporated into cofactor NAD
• Excreted in urine
• 88 excreted unchanged
• Therapeutic Use
• Type IIB and Type IV
• Raises HDL (most effective agent)
• Used with bile acid resins in Type IIB
  (heterozygotes)

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Niacin (Nicotinic Acid) Toxicity

• Many untoward effects limit usefulness
• Flushing
• Cutaneous vasodilatation in almost all
• Accompanied by warmth and itching
• Tolerance within one to two weeks
• Blunted by use of aspirin ½ hour earlier
• GI distress
• Liver dysfunction
• Hyperuricemia
• Inhibits tubular secretion of uric acid
• Impaired glucose tolerance
• Acanthosis appearance associated with insulin
  resistance

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Probucol (Lorelco )

• Lowers LDL, up to 15
• Also lowers HDL, up to 30
• Mechanism of action
• Inhibits oxidation of cholesterol
• Prevents ingestion of cholesterol by macrophages
• May slow development of atherosclerosis
• Effects on cholesterol in 1 to 3 months
• Lipophilic compound
• Persists in adipose tissues for months
• Prolongs cardiac action potential
• Avoid in long QT interval
• Avoid Amiodarone, Sotalol, Quinidine, etc
• Not shown to prevent or retard atherosclerosis

Removed from Market
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In-vivo Cholesterol Synthesis
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HMG-CoA-Reductase Inhibitors

• Inhibit first step rate-limiting in sterol
  (cholesterol) synthesis
• Structural analogs of natural substrate
• 3-hydroxy-3-methyl-glutaric acid
• Block hydroxy-methyl-glutaryl-Coenzyme A
  reductase
• Reduces conversion of HMG-CoA to mevalonic acid
• Most compounds are related to compounds occurring
  naturally in fungi
• Lovastatin first agent in class
• Inhibit de novo cholesterol synthesis
• Deplete intracellular supply of cholesterol
• Increase LDL receptors

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HMG-CoA-Reductase Inhibitors

• Lovastatin (Mevacor)
• Simvastatin (Zocor)
• Pravastatin (Pravachol)
• Fluvastatin (Lescol)
• Atorvastatin (Lipitor)
• Cerivastatin (Baycol)
• Withdrawn because of toxicity
• Rosuvastatin (Crestor)

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HMG-CoA-Reductase Inhibitors

• Lovastatin and simvastatin are lactones which are
  hydrolyzed to active drug
• Pravastatin, fluvastatin, atorvastatin are active
• Agents differ primarily in bioavailability and
  half-life
• Highly protein bound (gt95)
• Biotransformed in liver
• Metabolites mostly active
• Excretion mostly through bile and feces (83)

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HMG-CoA-Reductase InhibitorsAdverse Effects

• Generally well tolerated few adverse effects
• Hepatic dysfunction
• Elevation in transaminase levels
• Muscle
• Myopathy and rhabdomyolysis (rare)
• Renal insufficiency
• Gemfibrozil, Niacin, Cyclosporine, Itraconazole
• Drug interactions
• Warfarin
• Contraindicated in pregnancy

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HMG-CoA-Reductase Inhibitors

• See dose related decrease in LDL-cholesterol
• Occurs within 3 days
• Peaks at one month
• 25 to 45 reduction in cholesterol
• Reduces Apo B
• Also causes reduction in TG (up to 25)
• Raises HDL up to 10
• Effective in all Hyperlipoproteinemias
• Less effective in familial homozygous Type IIA
• Lack LDL receptors
• Often combined with other agents to increase
  effect
• Administer once daily in the evening

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Beneficial Effects of Statins

• Angiogenic role
• Promote formation of new blood vessels
• Reduction in mortality independent of effect on
  cholesterol concentration
• Activates protein kinase Akt
• Leads to NO production
• Promotes endothelial cell survival
• Enhances revascularization of ischemic tissue
• ? Inhibits cell apoptosis rather than stimulation
  of vessel growth

Nature Med 200061004-10
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Beneficial Effects of Statins

• Individuals of 50 years and older who were
  prescribed statins had a substantially lowered
  risk of developing dementia, independent of the
  presence or absence of untreated hyperlipidemia,
  or exposure to non statin LLAs. The available
  data do not distinguish between Alzheimers
  disease and other forms of dementia. Adjusted
  relative risk for those prescribed statins was
  0.29 (0.13-0.63 p0.002)
• Nested case-control study (UK)
• Jick, et al, Lancet 2000 356 1627-31

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