Drug Treatment of Hyperlipidemia

Philip Marcus, MD MPH

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

Development of Atheromatous Plaque

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

Lipoprotein Classification:

HDL LDL VLDL Chylomicrons

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

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

In-vivo

Cholesterol

Synthesis

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

Beneficial Effects of Statins: Reduction in plasma viscosity Decrease in platelet aggregation

and thrombin formation Reduction in inflammation

Decrease in CRP Reduction in fractures