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Drug Treatment of Hyperlipidemia. Philip Marcus, MD. Atherosclerotic Cardiovascular Disease and Hypercholesterolemia. 7 Million Americans with symptomatic ASCVD 1:2 deaths in US attributed to ASCVD $120 billion spent to treat ASCVD 1/500 has genetic predisposition leading to premature ASCVD

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atherosclerotic cardiovascular disease and hypercholesterolemia
Atherosclerotic Cardiovascular Disease and Hypercholesterolemia
  • 7 Million Americans with symptomatic ASCVD
  • 1:2 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
ischemic heart disease
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
ischemic heart disease atheroma
Ischemic Heart Disease: Atheroma
  • Coronary Arteries
    • Myocardial Infarction
  • Cerebral Arteries
    • Stroke
  • Peripheral Arteries
    • Peripheral Vascular Disease (PVD)
  • Renal Arteries
    • Hypertension
    • Renal failure
atheromatous disease risk factors
Atheromatous Disease: Risk Factors
  • Family History
  • Hypertension
  • Cigarette Smoking
  • Hyperglycemia
  • Obesity
  • Physical Inactivity
  • High serum cholesterol (LDL)
  • Hyperhomocysteinemia
lipoproteins and ascvd
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
lipoprotein classification
Lipoprotein Classification:
  • HDL
  • LDL
  • VLDL
  • 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
very low density lipoprotein vldl
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
low density lipoprotein ldl
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
low density lipoprotein ldl1
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
high density lipoprotein hdl
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
major enzymes in lipoprotein metabolism
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
hyperlipidemias primary
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.
hyperlipidemias primary1
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
hyperlipidemias primary2
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
hyperlipidemia secondary
Hyperlipidemia: Secondary
  • Disease states
    • Diabetes mellitus
    • Alcoholism
    • Nephrotic syndrome
    • Chronic renal failure
    • Hypothyroidism
    • Liver disease
  • Drugs
    • Thiazides
    • Estrogens
    • b-blockers
    • Isotretinoin
drugs used in treatment past and present
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)
natural alternatives dietary supplements
Natural “Alternatives”Dietary Supplements
  • Garlic
  • Plant Sterols
    • Benecol®
      • Also as margarine product
  • Red Rice Yeast
    • Contains Lovastatin
    • FDA attempting to regulate as drug
  • Niacin
bile acid binding resins
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
Cholestyramine (Questran®, LoCHOLEST®)

Colestipol (Colestid®)

Colesevelam (Welchol®)

bile acid binding resins1
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
bile acid binding resins2
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
bile acid binding resins3
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
ezetimibe zetia
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
ezetimibe zetia1
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
ezetimibe zetia2
Ezetimibe (Zetia®)
  • Inhibits intestinal absorption of cholesterol by 54%
  • No effect on plasma concentrations of Vitamins A, D or E
  • No impairment of steroid hormone synthesis
ezetimibe zetia3
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
ezetimibe zetia4
Ezetimibe (Zetia®)
  • Well tolerated
  • Adverse reactions no different than placebo
  • Antacids and cholestyramine decrease effect of ezetimibe
  • 10 mg once daily
fibric acid derivatives
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
fibric acid derivatives1
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
fibric acid derivatives2
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
fibric acid derivatives3
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 ®)
fibric acid derivatives4
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
niacin nicotinic acid
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
niacin nicotinic acid1
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
niacin nicotinic acid2
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)
niacin nicotinic acid toxicity
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
probucol lorelco
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

hmg coa reductase inhibitors
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
hmg coa reductase inhibitors1
HMG-CoA-Reductase Inhibitors:
  • Lovastatin (Mevacor®)
  • Simvastatin (Zocor®)
  • Pravastatin (Pravachol®)
  • Fluvastatin (Lescol®)
  • Atorvastatin (Lipitor®)
  • Cerivastatin (Baycol®)
    • Withdrawn because of toxicity
  • Rosuvastatin (Crestor®)
hmg coa reductase inhibitors2
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 (>95%)
  • Biotransformed in liver
    • Metabolites mostly active
  • Excretion mostly through bile and feces (83%)
hmg coa reductase inhibitors adverse effects
HMG-CoA-Reductase Inhibitors:Adverse 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
hmg coa reductase inhibitors3
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
beneficial effects of statins
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 2000;6:1004-10

beneficial effects of statins1
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 Alzheimer’s disease and other forms of dementia. Adjusted relative risk for those prescribed statins was 0.29 (0.13-0.63; p=0.002)
  • Nested case-control study (UK)
  • Jick, et al, Lancet 2000; 356: 1627-31