Drugs used in the treatment of
hyperlipidemias
By
S.Bohlooli, PhD
Introduction
 Introduction
Used to prevent or slow progression of atherosclerosis
to reduce the risk of coronary artery disease and
prolong life
 Cholesterol
Advantages
 Serves as a component of cell membranes and
intracellular organelle membranes
 Is involved in the synthesis of certain hormones including
estrogen, progesterone, testosterone, adrenal
corticosteroids
 Needed for the synthesis of bile salts which are needed
for digestion and absorption of fats.
Introduction
Cholesterol
Advantages
Is deposited in the stratum corneum of the skin to
help ↓ evaporation of water and create
impermeability to water soluble compounds (helps
keep moisture in skin)
Origin
Is synthesized in the liver. Acetyl CoA is converted
to mevalonic acid and ultimately to cholesterol by
hydroxymethyl glutaryl coenzyme A (HMG-CoA)
reductase.
Introduction
Cholesterol
Origin
Endogenous synthesis of cholesterol increases at
night
An increase in dietary cholesterol produces only a
small ↑ in blood levels of cholesterol because
ingestion inhibits endogenous synthesis
Dietary saturated fats ↑ blood cholesterol levels
because they are converted to cholesterol in the
body.
Introduction
Lipoproteins
Serve as carriers for transporting lipids
(cholesterol and triglycerides) in the blood.
Apolipoproteins
Embedded in the lipoprotein shell
Three functions
• 1. Serve as recognition sites for cell-surface receptors;
allowing cells to bind and ingest the lipoprotein.
• 2. Activate enzymes that will metabolize the lipoprotein
• 3. ↑ structural stability of the lipoprotein
Introduction
Lipoproteins
Apolipoproteins
All lipoproteins that deliver lipids to peripheral tissues
(nonhepatic tissues) contain apolipoprotein B-100
(Ex: VLDL, LDL)
All lipoproteins that transport lipids from peripheral
tissues back to the liver contain apolipoprotein A-I
(Ex: HDL)
Introduction
Lipoproteins
Lipoproteins of importance
VLDL (very low density lipoprotein)
•
•
•
•
Contain triglycerides (TGs) and some cholesterol
Account for nearly all TGs in the blood
Contain B-100
Deliver triglycerides from the liver to adipose tissues and
muscles.
Introduction
Lipoproteins
Lipoproteins of importance
VLDL (very low density lipoprotein)
• Remnants of hydrolysis are IDL (intermediate density
lipoproteins), which can be transported to liver or
converted to LDL
Introduction
Lipoproteins
Lipoproteins of importance
LDL (low density lipoprotein)
•
•
•
•
•
“Bad cholesterol”
Contain cholesterol
Account for 60-70% of cholesterol in the blood
Contains B-100
Delivers cholesterol to peripheral tissues
Introduction
Lipoproteins
Lipoproteins of importance
LDL (low density lipoprotein)
• Formed from IDL, the remnants of VLDL
• Makes the greatest contribution to coronary
atherosclerosis
 Oxidized LDL contributes to atherosclerotic plaque
• Removed from plasma via endocytosis by liver
converting it to bile acids excreted in GI
Introduction
Lipoproteins
Lipoproteins of importance
HDL (high density lipoprotein)
•
•
•
•
•
•
“Good cholesterol”
Contain cholesterol
Account for 20-30% of cholesterol in the blood
Some contain Apo A-I and Apo A-II
Apo A-I is cardioprotective
Transports cholesterol from the peripheral tissues back
to the liver – promotes cholesterol removal
• Antiatherogenic
Characteristics of Plasma Lipoproteins
LIPOPROTEIN
CLASS
DENSITY OF
FLOTATION,
g/ml
SIGNIFICANT
APOPROTEINS
SITE OF
SYNTHESIS
MECHANISM(S) OF
CATABOLISM
Chylomicrons and
remnants
<<1.006
B-48, E, A-I, A-IV,
C-I, C-II, C-III
Intestine
Triglyceride hydrolysis by LPL
ApoE-mediated remnant
uptake by liver
VLDL
<1.006
B-100, E, C-I, C-II,
C-III
Liver
Triglyceride hydrolysis by LPL
IDL
1.006-1.019
B-100, E, C-II, CIII
Product of
VLDL
catabolism
50% converted to LDL
mediated by HL, 50% apoEmediated uptake by liver
50% apoE-mediated uptake by
liver
LDL
1.019-1.063
B-100
Product of
VLDL
catabolism
ApoB-100-mediated uptake by
LDL receptor (~75% in liver)
HDL
1.063-1.21
A-I, A-II, E, C-I, CII, C-III
Intestine, liver,
plasma
Complex:
Transfer of cholesteryl ester to
VLDL and LDL
Uptake of HDL cholesterol by
hepatocytes
The major pathways involved in the metabolism of chylomicrons
synthesized by the intestine and VLDL synthesized by the liver
Classification of Plasma Lipid Levels
Total cholesterol
<200 mg/dl
Desirable
200-239 mg/dl
Borderline high
≥240 mg/dl
High
HDL-C
<40 mg/dl
Low (consider <50 mg/dl as low for women)
>60 mg/dl
High
LDL-C
<70 mg/dl
Optimal for very high risk (minimal goal for CHD equivalent patients)
<100 mg/dl
Optimal
100-129 mg/dl
Near optimal
130-159 mg/dl
Borderline high
160-189 mg/dl
High
≥190 mg/dl
Very high
Triglycerides
<150 mg/dl
Normal
150-199 mg/dl
Borderline high
200-499 mg/dl
High
≥500 mg/dl
Very high
Secondary Causes of Dyslipidemia
DISORDER
Diabetes mellitus
MAJOR LIPID EFFECT
Nephrotic syndrome
Triglycerides usually > cholesterol
Alcohol use
Contraceptive use
Estrogen use
Glucocorticoid excess
Triglycerides > cholesterol
Triglycerides > cholesterol; low HDL-C
Triglycerides > cholesterol
Triglycerides > cholesterol
Triglycerides > cholesterol
Cholesterol > triglycerides
Hypothyroidism
Obstructive liver disease Cholesterol > triglycerides
Treatment of hyperlipidemia
Treatment (tx)
Non-Pharmacological Therapy – 1st line tx
1. Diet modification
•
•
•
•
•
Decrease intake of total fat and especially saturated fat
Increase fiber intake
Increase Omega-3-fatty acids (found in fish)
↑ fruits and vegetables (antioxidants)
↓ simple sugars (sucrose)
Sites of action
of drugs used
for treatment
of dislypidemia
Treatment of hyperlipidemia
 Treatment
Non-Pharmacological Therapy – 1st line tx
 2. Exercise (will ↑ HDL levels)
 3. Reduce risk factors if possible
Drug Therapy
 Niacin (vitamin B3)
• Decreases VLDL and LDL and significantly ↑ HDL
• MOA
 1. Inhibits VLDL secretion into the blood thereby
preventing production of LDL
 2. Increases clearance of VLDL via lipoprotein lipase
pathway
Niacin: chmeistry
Antilipemic agents
Niacin
MOA
3. Inhibits FFA release from adipose tissues by
inhibiting the intracellular lipase system
4. Reduces circulating fibrinogen (contributes to clot
formation) and ↑ tissue plasminogen activator (clot
dissolver)
5. HDL catabolic rate is decreased
6. Reduces the plasma level of Lp(a) lipoprotein,
which can increase risk of CAD
Antilipemic agents
Niacin
Indications
Drug of choice for ↓ levels of TG (VLDL) in pts at risk
for pancreatitis
Mixed elevation of LDL and VLDL (alone or in
combination with reductase inh.)
Elevation of TG (VLDL) and low levels of HDL
(Niaspan® - approved for elevating HDL levels)
Start with low dose and gradually increase
Given 1-3g/day in divided doses or once daily with
extended release. Give at night with food.
Antilipemic agents
Niacin - Adverse effects
Flushing
Harmless cutaneous vasodilation
Uncomfortable sensation of warmth
Occurs after drug is started or ↑ dose
Lasts for the first several weeks
Can give 325mg aspirin 30 minutes before each dose
(prevents prostaglandin synthesis). Can also take
ibuprofen QD in place of ASA
Antilipemic agents
Niacin - Adverse effects
Pruritis, rashes, dry skin
acanthosis nigricans (eruption of velvet warty
benign growths and hyperpigmentation)
Associated with insulin resistance
Will have to d/c drug if occurs
Nausea and abdominal discomfort
Reduce dosage and may need to use inhibitors of
gastric acid secretion or antacids (not containing
aluminum)
Avoid in pts with severe peptic disease
Antilipemic agents
Niacin - Adverse effects
Hepatotoxicity
Severe is rare, and reversible
Occurs mostly with older sustained release forms
Monitor liver fx regularly
Liver injury is less likely with Niaspan® (given once
daily) the new extended release formulation
Carbohydrate tolerance may be moderately
impaired (hyperglycemia)
Reversible
Can still be given to diabetics receiving insulin
Antilipemic agents
Niacin - Adverse effects
Hyperuricemia
Occurs in about 1/5 of pts
Occasionally precipitates gout
Hypotension
Especially seen in pts on antihypertensive meds
Can ↑ homocysteine levels which ↑ risk of CAD
(give folic acid to ↓ homocysteine levels)
Fibrates: chemistry
Hepatic and
peripheral effects of
fibrates
Antilipemic agents
Fibrates (gemfibrozil, fenofibrate,
clofibrate, bezafibrate)
Little or no effect on LDL
↓ VLDL (TG)
moderate ↑ of HDL
MOA
Ligand for the nuclear transcription regulator,
peroxisome proliferator-activated receptor-α (PPARα)
MOA mostly unknown
Antilipemic agents
Fibrates
MOA
↑ activity of lipoprotein lipase for lipolysis of
triglyceride (↑ clearance)
↓ lipolysis in adipose tissue, ↓ FFA release
↓ secretion of VLDL by liver
↓ uptake of FFA by liver
↑ HDL levels moderately
Antilipemic agents
Fibrates
Indication: Hypertriglyceridemia
Gemfibrozil – 600mg QD-BID (half life 1.5hrs)
Fenofibrate – 1-3 67mg tablets QD (half life 20hrs)
Taken with food - ↑ absorption
Max reduction of VLDL is achieved within 3-4 weeks
of treatment
Adverse Effects
Rashes
GI disturbances (nausea, abdominal pain, diarrhea)
Antilipemic agents
Fibrates - Adverse Effects
Gallstones (upper abdominal discomfort,
intolerance of fried food, bloating)
Gemfibrozil ↑ biliary cholesterol saturation
Use with caution in pts with biliary tract ds, women,
obese pts, and Native Americans
Myopathy (muscle injury)
Tenderness, weakness, or unusual muscle pain
Will increase risk of statin-induced myopathy when
used together (rhabdomyolysis has occurred rarely)
Antilipemic agents
Fibrates - Adverse Effects
Hepatoxicity
Arrythmias
Hypokalemia
Displaces warfarin from plasma albumin since
drug is highly protein bound. Need to ↓ warfarin
dose
Bile Acid-Binding Resins :chemistry
Antilipemic agents
Bile Acid-Binding Resins (colestipol and
cholestyramine)
Will ↓ LDL, may ↑ VLDL (would require niacin
combo if ↑ TG prior to tx)
MOA
Bile acids, the metabolites of cholesterol, are
normally reabsorbed in the jejunum and ileum. When
resins are given, they bind to bile acids in the
intestinal lumen, prevent their reabsorption and
increase their excretion.
Antilipemic agents
Bile Acid-Binding Resins
MOA
↑ excretion creates a demand for ↑ synthesis of bile
acid. Liver cells must have an ↑ cholesterol supply
(provided by LDL) to synthesize bile acid. Liver cells
will ↑ their LDL receptors, ↑ing uptake of LDL from
plasma.
Indication
Used alone to ↓ LDL (by 15-20%)
Normally used as adjuncts to the statins to ↓ LDL (by
50%)
Antilipemic agents
 Bile Acid-Binding Resins
Indication
 Can be used to relieve pruitis in pts who have cholestasis
 Can be used for severe digitalis toxicity
 Dispensed in powder form (must be mixed with fluid).
Cholestyramine 4-12g BID. Colestipol 5-30g/day in
divided doses and also in 1g tablets (2-16g/day) taken w/
fluid
Adverse Effects
 Max reductions of LDL occur in one month
 Must be taken with meals
Antilipemic agents
 Bile Acid-Binding Resins
Adverse Effects
 Constipation
 Bloating, indigestion, nausea
 Large doses may impair absorption of fats or fat soluble
vitamins (A, D, E, and K)
Drug Interactions
 Resins bind digoxin, warfarin, thiazide diuretics,
tetracycline, thyroxine, iron salts, pravastatin, fluvastatin,
folic acid, phenylbutazone, aspirin, ascorbic acid (these
agents should be given 1 hour before the resin or 4 hours
after)
chemistry
Antilipemic agents
HMG COA Reductase Inhibitors
(“statins”) (lovastatin, fluvastatin,
pravastatin, simvastatin, atorvastatin,
cerivastatin)
Most Effective for ↓ LDL
Will ↑ HDL and ↓ VLDL
Fewest adverse effects and tolerated best
Inhibition of HMG-CoA
reductase
Antilipemic agents
(“statins”)
MOA
Inhibits hepatic HMG CoA reductase
Inhibition of cholesterol synthesis causes
hepatocytes to synthesize more LDL receptors
Hepatocytes are able to remove more LDLs from the
blood
Decrease production of apolipoprotein B-100,
thereby ↓ production of VLDL
↓ plaque cholesterol content
Antilipemic agents
(“statins”)
MOA
↓ inflammation at the plaque site
Improve abnormal endothelial function
Enhance the ability of blood vessels to dilate
↓ risk of thrombosis (inhibits platelet aggregation and
blocks thrombin synthesis)
Statins have high first pass extraction by liver (only a
small fraction of each dose reaches the general
circulation)
Prodrugs – lovastatin and simvastatin
Antilipemic agents
(“statins”) – Indications
Used alone to ↓ LDL
Used with bile acid – binding resins to ↓ LDL
Used with niacin to ↓ LDL, ↓ VLDL, and ↑ HDL
Enhanced if taken with food (except for
pravastatin – taken without food)
Give in the evening
Half life is 1-3 hours (except atorvastatin – 14
hours)
Antilipemic agents
(“statins”) – Indications
Atorvastatin is most efficacious agent for use in
severe hypercholesterolemia
High potency (>40-50% LDL lowering) –
atorvastatin, simvastatin, cerivastatin
Low potency (20-40% LDL lowering) –
lovastatin, fluvastatin, pravastatin
↓ LDL within 2 weeks; max reduction in 4-6
weeks
Antilipemic agents
(“statins”) – Indications
New Drug: Altocor®
Extended release lovastatin
Slightly more effective than regular lovastatin
Take without food
Antilipemic agents
(“statins”) – Adverse Effects
Since LDL cholesterol levels will return to
pretreatment values if drugs are withdrawn,
treatment must continue lifelong
Statins are pregnancy category X
rash, GI disturbances (dyspepsia, cramps,
flatulence, constipation, abdominal pain)
Antilipemic agents
(“statins”) – Adverse Effects
Hepatotoxicity
Myopathy (0.5% of pts)
Risk highest with lovastatin and especially in
combination with Fibrates
Cyp3A4 drug interactions with all statins
excepts for pravastatin and fluvastatin
Ezetimibe:chemistry
Antilipemic agents
Ezetimibe
ezetimibe reduced cholesterol absorption by
54%
Cholesterol lowering agent
Will challenge the statins
Approved for monotherapy or in combo with
statins
reduction of 60% with simvastatin for LDL-C
Inhibitors of Cholesteryl Ester Transfer
Protein
a plasma glycoprotein synthesized by the
liver
mediates the transfer of cholesteryl esters
In animal models
inhibition of CETP result in:
higher HDL levels
decreased LDL levels
resistance to developing atherosclerosis
JTT-705 and torcetrapib