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

Cerebral Arteries

Stroke

Peripheral Arteries

Myocardial Infarction

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

Principal carrier of endogenous Triglyceride

Major lipid is TG, also contains Cholesterol

Excess VLDL = Elevated TG
Contains Apo B100

Metabolized by lipoprotein lipase

Synthesized from carbohydrate, fatty acids and others

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%)

Derived mainly from VLDL catabolism via IDL

Contains Apo B100

to 1/3 of total cholesterol carried by LDL

Low in TG, no turbidity

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 HDL 2 particles

HDL acts in transport of cholesterol between cells and

plasma

Apo AI major protein component of HDL

Activates lecithin cholesterol acetyltransferase

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

Lecithin-Cholesterol Acetyltransferase

Located in muscle and adipose tissue

Hydrolyzes chylomicron and VLDL Triglyceride
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

Red Rice Yeast

Also as margarine product

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

Toxicity

For homozygous IIA, no effect since LDL receptors

lacking
20-25% reduction in LDL-C after 2 to 4 weeks
Increase in HDL-C
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

Hepatotoxicity

Elevated transaminase levels

Reversible upon discontinuation

Cholelithiasis
Drug interactions
Competes with highly bound drugs to albumin
Major problem with warfarin (Coumadin )

Elevated CK, AST

Patients with renal disease at greatest risk
Myopathy reported in conjunction with statins

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

Acts to decrease VLDL and LDL

Gram doses rather than mg doses used as

vitamin
Niacin, not niacinamide (nicotinamide)
Vitamin B3
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

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

Adipose tissue primary producer of FFA

FFA major precursor for TG synthesis

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

Converted to nicotinamide

Incorporated into cofactor NAD

Excreted in urine

Rapidly absorbed
Peak levels in under one hour

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

GI distress
Liver dysfunction
Hyperuricemia

Cutaneous vasodilatation in almost all

Accompanied by warmth and itching
Tolerance within one to two weeks
Blunted by use of aspirin hour earlier

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 1224 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, halflife 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 dont 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
Alzheimers 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