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Lipid-lowering drugs

Atherosclerosis and lipoprotein metabolism


Atheromatous disease is ubiquitous and underlies the commonest causes
of death (e.g. myocardial infarction) and disability (e.g. stroke) in industrial
countries
Hypertension and dyslipidemia are ones of the most important risk factors,
amenable to drug therapy
ATHEROMA is a focal disease of the intima of large and medium-sized
arteries
A t h e r o g e n e s i s involves several stages:
- endothelial dysfunction with altered PGI2 and NO synthesis
- monocyte attachment
- endothelial cells bind LDL
- oxidatively modified LDL is taken up by macrophages
- having taken up oxidised LDL, these macrophages (now foam cells) migrate
subendothelially
- atheromatous plaque formation
- rupture of the plaque

Atherosclerosis and lipoprotein metabolism


LIPIDS,
LIPIDS including CHOLESTEROL (CHO) and TRIGLYCERIDES (TG), are
transported in the plasma as lipoproteins, of which there are four
classes:

- chylomicrons transport TG and CHO from the GIT to the tissues,


where
they are split by lipase, releasing free fatty acids.There are taken up in
muscle and adipose tissue. Chylomicron remnants are taken up in the
liver
- very low density lipoproteins (VLDL), which transport CHO and newly
synthetised TG to the tissues, where TGs are removed as before,
leaving:
- low density lipoproteins (LDL) with a large component of CHO, some of
which is taken up by the tissues and some by the liver, by endocytosis
via specific
LDL receptors
- high density lipoproteins (HDL).which absorb CHO derived from cell
breakdown in tissues and transfer it to VLDL and LDL

Atherosclerosis and lipoprotein metabolism


There are two different pathways for exogenous and
endogenous lipids:
THE EXOGENOUS PATHWAY: CHO + TG absorbed from the GIT are
transported in the lymph and than in the plasma as
CHYLOMICRONS to capillaries in muscle and adipose tissues.
Here the core TG are hydrolysed by lipoprotein lipase, and
the tissues take up the resulting FREE FATTY ACIDS
CHO is liberated within the liver cells and may be
stored, oxidised to bile aids or secreted in the bile
unaltered . Alternatively it may enter the endogenous
pathway of lipid transpor in VLDL

Atherosclerosis and lipoprotein metabolism


EXOGENOUS
PATHWAY
CHO
ENDOGENOUS
PATHWAY

may be
stored

oxidised
to
bile acids

secreted
in
the bile
unaltered

EXOGENOUS
PATHWAY for lipids

ENDOGENOUS
PATHWAY for lipids

HEPATOCYTE

CHO

Fig.1a

GIT

bile acids

Bile duct

CHO

bile acids

v.portae

Fat
+ CHO
+ fatty acids
ENDOGENOUS
PARTHWAY

chylomicr
remn
CHO TG

chylomicr
TG CHO

Peripheral tissues
Fatty acids

(According to Rang, Dale 1999)

Atherosclerosis and lipoprotein metabolism


THE ENDOGENOUS PATHWAY
CHO and newly synthetised TG are transported from the liver as VLDL to
muscle and adipose tissue, there TG are hydrolysed and the resulting
FATTY ACIDS enter the tissues
The lipoprotein particles become smaller and ultimetaly become LDL ,
which provides the source of CHO for incorporation into cell membranes,
for synthesis of steroids, and bile acids
Cells take up LDL by endocytosis via LDL receptors that recognise LDL apolipoproteins

CHO can return to plasma from the tissues in HDL particles and the
resulting cholesteryl esters are subsequently transferred to VLDL or LDL
One species of LDL lipoprotein - is associated with atherosclerosis
(localised in atherosclerotic lesions). LDL can also activate platelets,
constituting a further thrombogenic effect

ENDOGENOUS
PATHWAY for lipids

Fig.1b

EXOGENOUS
PATHWAY for lipids

GIT

HEPATOCYTE
ACoA
MVA

CHO

bile acids

Bile duct
bile acids

CHO

v.portae
CHO

LDL
receptors

CHO

HDL
CHO

CHO

from cells

CHO

VLDL
TG CHO

LDL
CHO

Uptake
of CHO

lipase

Fatty
acids

Peripheral tissues

(According to Rang, Dale 1999)

Dyslipidemia
Dyslipidemia can be primary or secondary.
The primary forms are genetically determined
Secondary forms are a consequence of other
conditions
such as diabetes mellitus, alcoholism, nephrotic
syndrome, chronic renal failure, administration
of drug

Lipid-lowering drugs

Several drugs are used to decrease


plasma LDL-CHO
Drug therapy to lower plasma lipids is
only one approach to treatment
and is used in addition to dietary
management
and correction of other modifiable
cardiovascular risk factors

Statins

Fibrates

LIPID-LOWERING
DRUGS

Others

Resins

ENDOGENOUS
PATHWAY for lipids

EXOGENOUS
PATHWAY for lipids

Fig.1c
GIT
GIT

HEPATOCYTE

STATINS

ACoA
Bile duct

MVA

STATINS
FIBRATES

CHO

bile acids

bile acids

CHO

v.portae
FIBRATES

CHO

HDL
CHO

CHO

from cells

CHO

LDL
receptors

VLDL

Chylomikr remn
TG CHO
FIBRATES CHO TG

LDL
CHO

RESINS
fat
+ CHO
+ fatty
acids

Chylomikr
TG CHO

lipase

Uptake
of CHO

Fatty
acids

Fatty
acids

Peripheral tissues

(According to Rang, Dale 1999)

LIPID-LOWERING DRUGS

Statins
HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A)
reductase inhibitors. The reductase catalyses the conversion
of HMG-CoA to mevalonic acid
Rosuvastatin>atorvastatin>simvastatin=lovastatin>pravastatin>fluvastatin

decrease hepatic CHO synthesis


increase in synthesis of CHO receptors
+ increased clearance of LDL
Several studies demonstrated positive effects on morbidity and mortality

Statins

Promising pharmacodynamic actions:


improved endothelial function
reduced vascular inflammation and platelet aggregability
antithrombotic action
stabilisation of atherosclerotic plaques
increased neovascularisation of ischaemic tissue
enhanced fibrinolysis
immune suppression
osteoclast apoptosis and increased synthetic activity in
osteoblasts

Statins

Pharmacokinetics
- well absorbed when given orally
- extracted by the liver (target tissue), undergo
extensive presystemic biotransformation
Simvastatin is an inactive pro-drug

Statins

A d v e r s e e f f e c t s:
-

mild gastrointestinal disturbances

increased plasma activities in liver


enzymes

severe myositis (rhabdomyolysis)


and angio-oedema (rare)

LIPID-LOWERING DRUGS

Fibrates
stimulate the beta-oxidative degradation of fatty acids
- liberate free fatty acids for storage in fat or for metabolism in
-

striated muscle
- increase the activity of lipoprotein lipase,
hence increasing hydrolysis of triglyceride in chylomicrons
and VLDL particles
- reduce hepatic VLDL production and increase hepatic LDL
uptake

Fibrates
Other effects:
improve glucose tolerance
inhibit vascular smooth muscle inflammation

fenofibrate clofibrate
gemfibrozil ciprofibrate

Fibrates

A d v e r s e e f f e c t s:
in patients with renal impairment myositis (rhabdomyolysis)
myoglobulinuria, acute renal failure
Fibrates should be avoided in such patients and also in alcoholics)
mild GIT symptoms

LIPID-LOWERING DRUGS

Bile acid binding resins


sequester bile acids in the GIT
prevent their reabsorption
and enterohepatic recirculation
The r e s u l t is:
decreased absorption of exogenous CHO and increased metabolism of
endogenous CHO into bile acid acids
increased expression of LDL receptors on liver cells
increased removal of LDL from the blood
reduced concentration of LDL CHO in plasma
(while an unwanted increase in TG)

Bile acid binding resins

A d v e r s e e f f e c t s:
GIT symptoms - nauzea, abdominal bloating,
constipation or diarrhea
resins are unappetising. This can be minimized by
suspending them in fruit juice
interfere with the absorption of fat-soluble vitamins
and drugs (chlorothiazide, digoxin, warfarin)
These drugs should be given at last 1 hour before or 4-6 hours after a resin

LIPID-LOWERING DRUGS

Others
Nicotinic acid inhibits hepatic TG production and VLDL
secretion
modest reduction in LDL and increase in HDL

A d v e r s e e f f e c t s:
flushing, palpitations , GIT disturbances

LIPID-LOWERING DRUGS

Others
Fish oil (rich in highly unsaturated fatty acids)
the omega-3 marine TG
- reduce plasma TG but increase CHO (CHO is more strongly
associated wih coronary artery disease)
-the effects on cardiac morbidity or mortality is unproven
( although there is epidemiological evidence that eating fish
regularly does reduce ischemic heart disease)
Reduced VLDL, reduced TG. May increased LDL in some
patient.

Lipid lowering drugs


Selective cholesterola absorbtion inhibitor
Ezetimibe is prodrug activated form to
glucoronide, inhibit cholesterol from
dietary and biliary sources, doesnt effect
on fat soluable Vit and TG

How to asses patient with


dislipidemia/suspect dislipidemia?

STEP ONE: SCREENING


ATP III Classification of LDL, Total, and HDL
Cholesterol (mg/dL)
LDL Cholesterol Primary Target of Therapy
<100 Optimal
100-129 Near optimal/above optimal
130-159 Borderline high
160-189 High
190 Very high
Total Cholesterol
<200 Desirable
200-239 Borderline high
240 High
HDL Cholesterol
<40 Low
60 High

STEP TWO: ASSESSMENT FOR PRESENCE OF HIGH RISK


CORONARY HEART DISEASE EQUIVALENTS

Identify presence of clinical atherosclerotic disease


that confers high risk
for coronary heart disease (CHD) events (CHD risk
equivalent):
Clinical CHD
Symptomatic carotid artery disease
Peripheral arterial disease
Abdominal aortic aneurysm
Diabetes is considered a CHD risk equivalent in ATP III

STEP THREE: ASSESSMENT OF MAJOR RISK


FACTORS
Determine presence of major risk factors (other
than LDL) That Modify LDL Goals:
Cigarette smoking
Hypertension (BP >140/90 mmHg or on
antihypertensive medication)
Low HDL cholesterol (<40 mg/dL)*
Family history of premature CHD (CHD in male
first degree relative <55 years; CHD in female
first degree relative <65 years)
Age (men >45 years; women >55 years)

STEP FOUR: IF 2 OR MORE MAJOR RISK FACTORS OTHER THAN


LDL ARE PRESENT THEN ASSESS 10-YEAR CHD RISK

If 2+ risk factors (other than LDL) are present without CHD


or CHD risk equivalent, assess 10-year (short-term) CHD risk
(see Framingham tables).
Three levels of 10-year risk are:
a. >20% this is considered a CHD risk equivalent
b. 10-20%
c. <10%
A 10 year risk factor >20% means that 20 out of 100
individuals will develop coronary heart disease or a coronary
event within 10 years.

STEP FIVE: DETERMINE THE RISK CATEGORY

Determine risk category by:


Establishing LDL goal of therapy
Determining need for therapeutic
lifestyle changes (TLC)
Determining level for drug
consideration

STEP FIVE: DETERMINE THE RISK CATEGORY


LDL Cholesterol Goals and Cutoff Points for
Therapeutic Lifestyle Changes (TLC) and Drug Therapy in Different Risk
Categories
Risk Category LDL Goal
LDL level at
LDL level at which to consider
which to initiate
drug therapy
TLC
100>
CHD or CHD
mg/dL 100
mg/dL 130
mg/dL
Risk Equivalents
*(100-129 mg/dL: drug optional)
(10 year risk
factor >20%)
130>
Risk Factors+ 2
mg/dL 130
year risk 10-20%:-10
mg/dL
(10 year risk
130 mg/dL
factor 20%)
year risk <10%:-10
160 mg/dL
160>
Risk Factor 0-1
mg/dL 160
mg/dL 190
mg/dL
(160-189 mg/dL: LDL-lowering
drug optional)
Some authorities recommend use of LDL-lowering drugs in this category if an *
LDL cholesterol <100 mg/dL cannot be achieved by therapeutic lifestyle
changes. Others prefer use of drugs that primarily modify triglycerides and
HDL, e.g., nicotinic acid or fibrate. Clinical judgment also may call for deferring
.drug therapy in this subcategory
Almost all people with 0-1 risk factor have a 10-year risk <10%, thus 10-year
.risk assessment in people with 0-1 risk factor is not necessary

STEP SIX: THERAPEUTIC LIFESTYLE CHANGES

TLC Diet:
Saturated fat <7% of calories, cholesterol <200 mg/day
Consider increased viscous (soluble) fiber (10-25 g/day)
and plant stanols/sterols (2g/day) as therapeutic options
to enhance LDL lowering
Weight management
Increased physical activity

STEP SEVEN: CONSIDER DRUG THERAPY

Consider drug simultaneously with


TLC for CHD and CHD equivalents
Consider adding drug to TLC after 3
months for other risk categories.

STEP SEVEN: CONSIDER DRUG THERAPY

CARDINAL POINT OF
TREATMENT
Decreased LDL is primary target
Statin are the preferred initial treatment choice, shuld be used at
sufficient to lower LDL by 30%-40%.
If maximal dose of statin is unable to achieve goal of LDL, then
statin + ezetimibe or statin + bile acid sequester are useful
combination
If TG are 200 to 499 mg/dl after LDL goal has been reached,
consider adding niacin or fibrate.
If TG > 500 mg/dl, use fibrate or niacin to lower TG and prevent
pancreatitis
If HDL ow after LDL goal reached, consider adding niacin or fibrate

Case One:
Mark Guttman is a 39 year old white
male living in Stamford, Connecticut.
Mr. Guttman is here to see you for a
follow up to an initial routine health
care maintenance exam.

Past Medical History


None
Not on any medications
No known allergies
Social History
Smokes tobacco pack a day
Occasional EtOH at social functions only
No drug use
Works as a teacher in a middle school
Was born in Westchester County, NY and lived in Connecticut is
entire life
Single, Not sexually active currently
Family History
Father is alive and healthy, Age 60
Mother has diabetes, Age 59
No siblings or children

Pertinent Physical Exam


BP 135/80
BMI 28.1
Waist Circumference 38 inches
Fasting Cholesterol Panel
Total Cholesterol (220 mg/dl/5.6 mmol/L)
LDL 162 mg/dl/4.2mmol/L
HDL 38 mg/dl/0.98 mmol/L
Triglycerides 165 mg/dl/1.8 mmol/L

Case One:
What treatment strategies for hyperlipidemia
should be offered to Mr. Guttman?
1.?
2.?
3.?
4.?
5.?
6.?

Case 2
Maria De Los Santos is a 67 year old
Dominican female living in Washington
Heights. She has been your patient for 8
years and is here to discuss the results of
her fasting lipid panel.

Past Medical History


Diabetes, Hypertension
Meds Metformin, Ramipril only
No known allergies
Social History
Has never smoked tobacco
No alcohol use
No drug use
Worked as an office administrator and retired 2 years ago
Was born in Santiago, Dominican Republic and moved to New York City 37 years
ago
Married, and sexually active currently in monogamous relationship
Family History
Father is alive and has diabetes, hypertension, and peripheral vascular disease,
age 87
Mother has diabetes, age 88
Brother has diabetes, age 65
She has 3 adult children that are all healthy

Pertinent Physical Exam


BP 145/81
Weight 210 lbs
Height 5 8 inch
BMI 31.9
Waist Circumference 42 inch
Fasting Cholesterol Panel
Total Cholesterol 189
LDL 115
HDL 56
Triglycerides 179

Aside from theraupetic lifestyle change,


should LDL lowering drug therapy offers to
Mrs.De Los santos?

Case 3
Nelson Nguyen is a 43 year old Vietnamese
male living in Castro Valley, CA. He has been
your patient for 5 years and is here to discuss
the results of his fasting lipid panel. He had been
lost to follow up to your practice for 2 years. He
was taking only hydrochlorathizide (was buying it
on own over past 2 years you added a second
hypertension med at the last visit)

Past Medical History


Hypertension
Meds Now taking hydrochlorathizide and a beta blocker
Allergies - Penicillin
Social History
Smokes tobacco 1 pack a day
No alcohol use
No drug use
Works as a coffee shop manager
Was born in Quy Nhon, Vietnam and immigrated to the United States at age 23
Married, and sexually active currently in monogamous relationship
Family History
Father died at age 47 of unknown causes
Mother is alive and healthy in Vietnam, age 65
Older brother died of a myocardial infarction at age 45
Has 2 sons that are healthy and in college

Pertinent Physical Exam


BP 160/90
Weight 200
Height 5 6
BMI 32.3
Waist Circumference 39 inches
Fasting Cholesterol Panel
Total Cholesterol 272
LDL 188
HDL 42
Triglycerides 202

Case 3
What treatment strategies for
hyperlipidemia should be offered to Mr.
Nguyen?

Step 8
Identify metabolic syndrome and treat, if
present, after 3 months of TLC.
Clinical Identification of the Metabolic
Syndrome Any 3 of the following must
be present:

Treat underlying causes (overweight/obesity and physical inactivity):


Intensify weight management
Increase physical activity.
Treat lipid and non-lipid risk factors if they persist despite these
lifestyle therapies:
Treat hypertension
Use aspirin for CHD patients to reduce pro-thrombotic state
Treat elevated triglycerides and/or low HDL

STEP NINE: TREAT ELEVATED


TRIGLYCERIDES
Treatment of elevated triglycerides (150
mg/dL)
Primary aim of therapy is to reach LDL goal
Intensify weight management
Increase physical activity
If triglycerides are >200 mg/dL after LDL
goal is reached, set secondary goal for nonHDL cholesterol (total HDL) 30 mg/dL
higher than LDL goal.

Comparison of LDL Cholesterol and Non-HDL Cholesterol


Goals for Three Risk Categories
Risk Category

LDL Goal
(mg/dL)
100>

Non-HDL Goal (mg/dL)

Multiple (2+) Risk


Factors and 10-year risk
20%

130>

160>

Risk Factor 0-1

160>

190>

CHD and CHD Risk


Equivalent (10-year risk
for CHD >20%)

130>

Treat hiperTG
If triglycerides 200-499 mg/dL after LDL goal is reached, consider
adding drug if needed to reach non-HDL goal:
intensify therapy with LDL-lowering drug, or
add nicotinic acid or fibrate to further lower VLDL.
If triglycerides 500 mg/dL, first lower triglycerides to prevent
pancreatitis:
very low-fat diet (15% of calories from fat)
weight management and physical activity
fibrate or nicotinic acid
when triglycerides >500 mg/dL, turn to LDL-lowering therapy.

Treat lower HDL


Treatment of low HDL cholesterol (>40 mg/dL)
First reach LDL goal, then:
Intensify weight management and increase physical
activity
If triglycerides 200-499 mg/dL, achieve non-HDL goal
If triglycerides >200 mg/dL (isolated low HDL) in CHD or
CHD equivalent consider nicotinic acid or fibrate.