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:
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 Coronary Arteries
Myocardial Infarction Cerebral Arteries
Stroke Peripheral Arteries
Peripheral Vascular Disease (PVD) Renal Arteries
Hypertension Renal failure
Atheromatous Disease: Risk Factors
Family History Hypertension Cigarette Smoking Hyperglycemia Obesity Physical Inactivity High serum cholesterol (LDL) Hyperhomocysteinemia
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
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) 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): 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 (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): 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
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 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: 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: 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 Disease states
Diabetes mellitus Alcoholism Nephrotic syndrome Chronic renal failure Hypothyroidism Liver disease
Drugs Thiazides Estrogens blockers Isotretinoin
Drugs for Lipids Lipid-regulating drugs must be taken
indefinitely Plasma lipid levels return to
pretreatment levels within 2-3 weeks when stopped
Should NOT be a substitute for lifestyle changes Diet + Exercise + Lipid-lowering drugs
optimal for treatment/prevention
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
Garlic Plant Sterols
Benecol® Also as margarine product
Red Rice Yeast Contains Lovastatin FDA attempting to regulate as drug
Niacin
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®)-
hydrophilic polymer
Resins
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 Resins: Drugs of choice in treating IIA and IIB
For homozygous IIA, no effect since LDL receptors lacking
20-25% reduction in LDL-C after 2 to 4 weeks Increase in HDL-C
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 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®) 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 (Zetia®) Mechanism of action is
complementary to that of HMG-CoA reductase inhibitors
Results in reductions in: Total cholesterol LDL-C (18%) Apolipoprotein B Triglycerides
Results in increase in HDL-cholesterol
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 (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 (Zetia®) Well tolerated Adverse reactions no different than
placebo Antacids and cholestyramine
decrease effect of ezetimibe 10 mg once daily
Fibric Acid Derivatives Activate the nuclear transcription factor
peroxisome proliferator activated receptor alpha (PPAR-alpha) which relates genes that control lipid metabolism
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 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 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 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 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): 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 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 Changes LDL particles from small, dense ones to
ones that are large and buoyant
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 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
Niacin Immediate release, quickly-absorbed Extended release, absorbed over 8
hrs Sustained release, absorbed over
12-24 hours Combination of extended release
niacin and immediate release lovastatin
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 Inhibitors:
Lovastatin (Mevacor®) 1987 Simvastatin (Zocor®) 1991 Pravastatin (Pravachol®) 1991 Fluvastatin (Lescol®) 1993 Atorvastatin (Lipitor®) 1996 Cerivastatin (Baycol®)
Withdrawn because of toxicity Rosuvastatin (Crestor®) 2003
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, half-
life and metabolism Highly protein bound (>95%) Biotransformed in liver
Metabolites mostly active Excretion mostly through bile and feces (83%)
HMG-CoA-Reductase Inhibitors:Adverse Effects
Generally well tolerated; few adverse effects
Patients who don’t tolerate one statin may tolerate another
Hepatic dysfunction Elevation in transaminase levels >3x ULN increase occurs in 1-2% Symptomatic hepatitis rare
Contraindicated in pregnancy
HMG-CoA-Reductase Inhibitors:Adverse Effects
Muscle Myalgia and muscle weakness
With or without increases in CK Myopathy and rhabdomyolysis (rare)
May lead to renal failure; dose related Renal insufficiency predisposing factor Myopathy often caused by drug interactions
Concurrent use of CYP3A4 inhibitors increase levels Itraconazole, ketoconazole, erythromycin, clarithromycin,
teilithromycin, HIV antivirals Grapefruit juice Cyclosporine
Drug interactions Gemfibrozil inhibits metabolism of all statins
Inhibits statin glucuronidation Increases risk of rhabdomyolysis
Increased anticoagulant effect when used with warfarin
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
HMG-CoA-Reductase Inhibitors:
Pravastatin and atorvastatin indicated for children
Lovastatin indicated for primary prevention of coronary artery disease
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 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