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DYSLIPIDEMIA

Dr. Md. Toufiqur Rahman


MBBS(DMC), FCPS(Medicine),
MD(Cardiology), FACC, FRCP, FESC,
FAHA, FAPSIC, FAPSC
Associate Professor of Cardiology
National Institute of Cardiovascular
Diseases(NICVD), Dhaka.

Lipoprotein Particles

Density (g/ml)

0.95

VLDL

Chylomicron

VLDL
Remnants
1.006

IDL

1.019

Chylomicron
Remnants

LDL-R

1.050
1.063

HDL2

Lp(a)

1.100

HDL3DL3

Only these lipoprotein particles


found in plaque at biopsy.

1.20

10

20

40

60

Particle Size (nm)

80

1000

High Plasma Apo B


Lipoprotein
Levels
Promote
Rationale
for therapeutic lowering
of Apo B lipoproteins:
decrease the
probability
of inflammatory response to retention
Atherogenesis
Apo B lipoprotein
particles

Blood

Monocytes bind to
adhesion molecules

Smooth muscle
Inflammatory
response

Modification
Macrophage

Foam cell

Intestinal Cholesterol
Biliary
Intestinal
Absorption
cholesterol
epithelial cell

Through
lymphatic
system to
the liver

MTP
CM

Cholesteryl esters

ACAT
(esterification)

Free
cholesterol

excretion

ABCG5
ABCG8

Dietary
cholesterol

Luminal
cholesterol
Bile
acid
Micellar
cholesterol
uptake

Bays H et al. Expert Opin Pharmacother 2003;4:779-790.

Exogenous Pathway of Lipid


Metabolism

Cholest
AA
FA
P,
glycerol

Vessel
wall

Endogenous Pathway of Lipid


Metabolism

HDL Metabolism

Key Enzymes and Cofactors in


Lipid Metabolism
HMG-CoA reductase-reduces HMG-CoA to mevalonic acid in the
rate-limiting step of cholesterol biosynthesis (mainly liver and
intestine)
Lipoprotein Lipase- digests TG core of CMC and VLDL

Hepatic Lipase-conversion of IDL to LDL


CETP-transfers cholesteryl esters from HDL to other lipoproteins in

exchange for TG
LCAT(lecithin cholesterol acyl transferase) conversion of cholesterol
to cholesterol esters
Apolipoprotein A-major protein of HDL activating many reactions
Apo-B-major protein of VLDL, IDL, and LDL

Apo-CII and Apo E obtained from HDL by CMC and VLDL for
activation of LPL and receptor recognition respectively

LDL Oxidation and


Atherosclerosis

Mechanism of Atherogenic
Dyslipidemia
Insulin resistance
increased NEFA
and glucose flux to
liver

Increased
VLDL

IR impairs
LDLR
Insulin
resistance and
decreased apoB degradation

Insulin
resistance
and
decreased
LPL

FCHL
DM II
Metabolic
syndrome

Increased Atherogenicity of
Small Dense LDL
Direct Association
Longer residence time in
plasma than normal sized LDL
due to decreased recognition
by receptors in liver
Enhanced interaction with
scavenger receptor promoting
foam cell formation
More susceptible to oxidation
due to decreased antioxidants
in the core
Enter and attach more easily
to arterial wall
Endothelial cell dysfunction

Indirect Association
Inverse relationship with
HDL
Marker for atherogenic TG
remnant accumulation
Insulin resistance

High Density Lipoprotein and


Atherosclerosis
Reverse cholesterol transport
Maintenance of endothelial function
Protection against thrombosis

With Apo A-I inhibits generation of calcium-induced


procoagulant activity on erythrocytes by stabilizing cell
membrane

Low blood viscosity via permitting red cell deformability


Anti-oxidant properties-may be related to enzymes called
paraoxonase

Lipoprotein (a)
Specialized form of LDL

(apolipoprotein (a) covalently bound to


apo B by disulfide bridge)
Structural similarity to plasminogen,
thus interfering with fibrinolysis
Macrophage binding and cholesterol
deposition
Measured by ELISA
Cross-sectional and retrospective
epidemiologic studies have shown
association between excess Lp (a) and
CHD while prospective results are
conflicting
Associated with unstable angina and
presence of complex coronary lesions
Commonly detected in premature CHD
Possible role in target organ damage
in presence of HTN

Indications for screening:

CHD and no other identifiable


dyslipidemia
Strong CHD family history and
no other dyslipidemia
HTN and early premature
target organ damage
Hypercholesterolemia
refractory to statins and bile
acid sequestrants

Treatment guidelines

Primary goal is to lower LDL to


target and lowering to <80
may reduce risk
If LDL cannot become
optimized, then Lpa loweing
with nicotinic acid (38%) shoud
be tried
Goal <20 in whites

CHOLESTEROL
A soft waxy substance found among

lipids (fats) in the bloodstream and all


cells
Needed for digesting fats, making
hormones, building cell walls
Carried in particles called lipoproteins
that act as transport vehicles
delivering cholesterol to various body
tissues to be used, stored or excreted
Excess circulating cholesterol can lead
to plaque formation- Atherosclerosis

DYSLIPIDEMIA
(A consequence of abnormal lipoprotein
metabolism)

Elevated Total Cholesterol (TC)


Elevated Low-density lipoproteins (LDL)
Elevated triglycerides (TG)
Decreased High-density lipoproteins (HDL)

PRIMARY DYSLIPIDEMIA
ETIOLOGY
SINGLE OR MULTIPLE GENE MUTATION

RESULTING IN DISTURBANCE OF LDL, HDL


AND TRIGYLCERIDE, PRODUCTION OR
CLEARANCE.

Should be suspected in patients with

premature heart disease


family hx of atherosclerotic dx.
Or serum cholesterol level >240mg/dl.
Physical signs of hyperlipidemia.

SECONDARY DYSLIPIDEMIA

(Most adult cases of dyslipidemia are secondary in nature in


western civilizations)

Sedentary lifestyle
Excessive consumption of cholesterol

saturated fats and trans-fatty acids.

Secondary Dyslipidemia
(Medical Conditions Associated
with dyslipidemia)

Diabetes
Hypothyroidism
Cholestatic liver disease.
Nephrotic syndrome
cigarette smoking

SECONDARY DYSLIPIDEMIA

(Drugs causing mild to moderate degrees of


dyslipidemia)

Beta-blockers
Thiazide diuretics
Antiretroviral drugs
Hormonal agents

Types of Cholesterol
LDL- (bad cholesterol) The major cholesterol carrier in the

blood. Excess most likely to lead to plaque formation. Goal: LOW

HDL-

(good cholesterol) Transports cholesterol away from


arteries and back to the liver to be eliminated. Removes excess
cholesterol from plaques, slowing growth. Goal: HIGH

Triglycerides-

the chemical form in which most fat exists


in foods as well as in the body. Present in blood plasma and
together with cholesterol, form the plasma lipids. Made in the
body from other energy sources like carbohydrates. Calories
ingested in a meal and not immediately used by tissues are
converted to triglycerides. Hormones regulate the release from
fat tissue to meet the bodys needs for energy between meals.

Why Do We Care?
According to the Third Report
of the National Cholesterol
Education Program Expert
Panel on Detection,
Evaluation and Treatment of
High Cholesterol in Adults
(NCEP ATP-III):
High LDL levels are a
leading cause of coronary
heart disease (CHD) and
should be the main target of
any cholesterol lowering
regimen

ATP III Lipid and Lipoprotein


Classification
LDL Cholesterol (mg/dl)
(mg/dl)
<100
Optimal
< 40 Low
100-129
Near/Above Optimal
130-159
Borderline High
160-189
High
>190
Very High

HDL Cholesterol

> 60 High (Desirable)

Categories of Risk that Modify LDL Goals


CHD and CHD risk equivalents
<100
Multiple (2+) risk factors
<130
Zero to one risk factor
<160

Major Risk Factors For CHD


That Modify LDL Goals
Cigarette smoking
Hypertension (BP >140/90 or on BP
med)
Low HDL cholesterol (<40mg/dl)
Family Hx premature CHD
- CHD in male 1st degree relative <55 years old
- CHD in female 1st degree relative <65 years old

Age (men >45 yrs. women >55 yrs)

HDL >60 counts as a negative risk factor. Its presence


removes one risk factor from the total count

Risk Assessment for CHD


DM regarded as a CHD equivalent
For patients with multiple (2+) risk factors
-Perform 10 year risk assessment
For patients with 0-1 risk factor
-Most have 10 year risk assessment <10%;
risk assessment scoring unnecessary

Framingham Heart Study 10-year


CHD Risk Prediction Score Sheet

Current ATP III Guidelines for


Treating LDL Cholesterol
Risk
Category

LDL Goal
(mg/dl)

LDL level
to initiate
TLC

CHD or
Equivalents

<100
> 100
<70 Ideal

> 130

2+ Risk
Factors

<130

> 130 (10 Year


risk 10-20%)
> 160 (Risk
<10%)

> 130

LDL level
to
consider
Rx
therapy
(100-129 Rx
optional)

A Model of Steps in Therapeutic


Lifestyle Changes (TLC)
Visit 1

Begin TLC
Emphasize
reduction in
saturated fat
& chol.
Encourage
moderate
Physical
activity
Consider
referral to
dietician

Visit 2 (6 wks)

Visit 3 (6 wks)

Eval. LDL response

Eval LDL response

Intensify Tx if not to
goal

Consider adding Rx
if not to goal

Reinforce dietary
recommendations
Consider adding
plant stanols/sterols

Evaluate for
Metabolic syndrome

Increase fiber
intake

Intensify wt mgmt &


physical activity

Consider dietician

Consider dietician

Visit N
Monitor
adherence to
TLC Q4-6
mos

Nutrient Recommendations of TLC


Diet
Nutrient
Intake

Recommended

Saturated fat
< 7% of total calories
Polyunsaturated fat
Up to 10% of total calories
Monounsaturated fat
Up to 20% of total calories
Total fat
25-30% of total calories
Carbohydrates
50-60% of total calories
Fiber
20-30 grams/day
Protein
Approx. 15% of total calories
Cholesterol <200 mg/day
Total calories
Balance energy intake and
expenditure to maintain
desirable body weight/ prevent weight gain

Specific Dyslipidemias:
Very High LDL (> 190mg/dl)
Causes and Diagnosis

Genetic disorders
Monogenic familial hypercholesterolemia
Familial defective apolipoprotein B-100
(Apo B)
Polygenic hypercholesterolemia
Family testing to detect affected relatives

Specific Dyslipidemias: Low


HDL
Causes of Low HDL (<40 mg/dl)

Elevated triglycerides
Overweight and obesity
Physical Inactivity
Type 2 diabetes
Cigarette smoking
Very high carb. intakes (>60% energy)
Medications (some beta blockers, anabolic
steroids, progestational agents)

Specific Dyslipidemias: Elevated


Triglycerides
Classification of Serum
Triglycerides
Normal
Borderline High
High
Very High

<150 mg/dl
150-199 mg/dl
200-499mg/dl
>500 mg/dl

Specific Dyslipidemias: Elevated


Triglycerides
Causes of Elevated Triglycerides

Obesity and overweight


Physical Inactivity
Cigarette smoking
Excess alcohol intake
High carb. diets
Several diseases (Type 2 DM, chronic renal failure,
nephrotic syndrome
Medications (corticosteroids, estrogens, retinoids,
higher doses of beta blockers

Specific Dyslipidemias: Elevated


Triglycerides
Management of Very High Triglycerides
(>500 mg/dl)

Goal of therapy: Prevent acute pancreatitis


Very low fat diets (< 15% of caloric intake)
Triglyceride-lowering drug usually required
(fibrate or nicotinic acid)
Reduce triglycerides before lowering LDL

Advanced Lipid Analysis:


Size Does Matter

Advanced Lipid Analysis


LDL type floats around in

the blood
Most LDL around 260
Angstroms
5% smaller diameter LDL
particle leads to a 50%
increase in rate of uptake
by the arterial wall
LDL particle <258
Angstroms more
atherogenic
Large LDL: Pattern A
Small LDL: Pattern B (bad)
Not measured in traditional
lipid profiles

Advanced Lipid Analysis:


Lp(a)
Fairly large molecule but

easily oxidized (more


toxic)
Protein tail can
stimulate blood clotting
Not affected by foods;
appears to be genetic
Not affected much by
statins or fibrates
Niacin, vitamin E combat
tendency to be oxidized
Lowering LDL to <80100 also minimizes
toxicity

Advanced Lipid Analysis


(Berkeley Heart Labs/ NMR
LipoProfile)

Who Needs
Advanced lipid
analysis?

CHD, DM, or CHD equivalent


Metabolic Syndrome
Multiple Risk Factors
Family Hx premature CHD
Isolated low HDL cholesterol

Lipid Lowering Drugs


HMG-CoA Reductase Inhibitors (Statins)

Partially block an enzyme necessary for formation of

cholesterol
Speed removal of LDL from blood
18%-60% reduction in LDL
Most effective at lowering LDL; esp. HS dosing
Liver enzymes MUST be monitored. Check baseline,
3mos., then semi-annually (D/C if > 3x normal limits)
Side effects: Myalgias (D/C if total CK >10x normal),
rhabdomyolysis
Metabolized by CP450 (watch for drug interactions)

41

Dual Inhibition
LDL
apoB100

Liver

Statin

Duodenum

X
VLDL
apoB100

Ezetimibe

Jejunum

Ileum
CM
Remnant
apoB48
Dr.Sarma@works

CM
apoB48

Colon

Statins Mechanism of
Action
Cholesterol
synthesis
HMGCoA

Intracellular
Cholesterol

VLDL
Apo B
LDL receptor VLDL
VLDLRR
Apo E
(BE receptor)

synthesis

Apo B
LDL

LDL receptormediated
hepatic uptake of LDL
and VLDL remnants
Serum LDL-C
Serum VLDL remnants
Serum IDL

Hepatocyte

Systemic Circulation

1. Reduce hepatic cholesterol synthesis (HMG CoA),


2. lowering intracellular cholesterol,
3. Upregulation of LDL receptor and

42

43

Time course of Statin


Vulnerable
effects
LDL-C
Inflammation
plaques
lowered*

reduced

Endothelial
function
restored

Days

stabilized

Ischemic
episodes
reduced

* Time course established

Cardiac events
reduced*

Years

Lipid Lowering Drugs


Bile Acid Sequestrants

Convert cholesterol to bile acids


Bind bile acids and prevent reabsorption

in the gut
May increase triglyceride levels
Most common side effects: GI-constipation
Alternative for statins

Bile Acid Resins:


Mechanism of Action
Cholesterol 7- hydroxylase

Gall Bladder
Bile Acid

Conversion of cholesterol to BA
BA Secretion

Enterohepatic Recirculation
Terminal Ileum
BA Excretion

Liver
Reabsorption of
bile acids

Net
Net Effect
Effect -- LDL-C
LDL-C

LDL Receptors
VLDL and LDL removal

Lipid Lowering Drugs


Cholesterol Absorption Inhibitor: Zetia
Monotherapy or in combination with statin
Not recommended with fibrates
Reduces LDL number : esp. Lp(a)
Lipid-Regulating Agent: Omega 3 acid ethyl esters
(Lovaza)
Omega 3 Fish oil (salmon, herring, mackerel,
swordfish, albacore tuna, sardines, lake trout)
Only FDA approved supplement for tx of dyslipidemias
Decreases hepatic production of TG and VLDL
Increases LDL size to large buoyant particles

Lipid Lowering Drugs


Nicotinic Acid/Niacin

Reduces production and release of LDL


Effective in reduction of triglycerides

(<400mg/dl)
Increases HDL
Very effective in increasing LDL particle size
Monitor liver enzymes and glucose
Most common side effect: FLUSHING (take
ASA/ibuprofen 30 min. prior and take with
light snack). Decreased with time released
formulas (Niaspan)

Nicotinic Acid Mechanism of


Mobilization of FFA
Action
Apo B

VLDL
TG
synthesis

VLDL

VLDL
secretion

Serum VLDL
results in reduced
lipolysis to LDL
Serum LDL

LDL

HDL

Liver

Circulation

Hepatocyte

Systemic Circulation

Decreases hepatic production of VLDL and of apo B


Dr.Sarma@works

48

Lipid Lowering Drugs


Fibric Acid Derivatives/Fibrates
Very effective in reducing triglycerides (>400)
Increase HDL
Containdications: Gallbladder disease, hepatic
disease, renal dysfunction
Increase LDL particle size but not quantity
Caution with statins

Comparison of Lipid
Lowering Drugs

Cholesterol Control With


Foods and Herbs
Fiber: Decreases LDL; increases HDL
Carrots/Grapefruit: Fiber and pectin (whole fruits most

beneficial)
Avocado: monounsaturated fat
Beans: High in fiber, low fat; contain lecithin
Phytosterols: sesame, safflower, spinach, okra,
strawberries, squash, tomatoes, celery, ginger.
Shiitake mushrooms: contain lentinan (25% reduction in
animal studies)
Garlic, onion oil: lowers chol. 10-33%
Omega 3 fish oils
Red Yeast Rice: a natural substance that inhibits HMGCoA reductase. Same ingredient in Lovastatin.

What Is On the Horizon?


Glabridin (licorice root/anise plants): Inhibits oxidation

of LDL
Study of genetic alterations : cholesterol medications
tailored to specific genetic profiles
Microsomal triglyceride transfer protein (MTP): the
gene for MTP provides blueprint for production of the
protein that helps assemble LDL. Those who carry 2 copies
of a variant form of the gene had LDL levels 22% lower
than those who had one or no copy of the variant. Some
drug companies have already begun looking at MTP
inhibitors to help lower LDL
Lecithin-cholesterol acetyltransferase (LCAT): an
enzyme bound to HDL acts as a powerful antioxidant
(reduce oxidation of chol.)
Thyroid hormones: Molecules similar to thyroid
hormones could assist with weight loss and cholesterol
reduction. 2 kinds of receptors that receive the hormone
and pass its signal to the body.

Cholesterol Meds in the


News
Vytorin (Zocor + Zetia)

ENHANCE trial
New England Journal of Medicine
720 FH patients over one year
Endpoint: Carotid artery intima-media thickness (CIMT)
per ultrasound
Findings: Vytorin did not reduce CIMT compared to
Zocor alone
TAKE HOME: Its NOT just about the numbers

Cholesterol Meds in the


News
Crestor

JUPITER trial
Does Crestor reduce major CV events in pts

with no existing symptoms, low-normal LDL


but higher CRP (c-reactive protein: marker of
inflammation)?
Study D/Cd: early findings confirm reduced
deaths and CV risks
The ONLY statin shown to reduce
Atherosclerotic plaque

Other Interesting
Studies
Atherosclerosis: Maternal smoking disturbs
lipid profiles in adult offspring

Children ages 5-19 years (N=350)


Total chol. in children whose mothers smoked
increased by 4.6mg/dl more each decade
than total chol. levels in other children.
Could lead to an increase of 10mg over a 30
year period

Other Interesting Studies


The American Journal of Human Genetics :
Researchers have identified a novel genetic
determinant of dyslipidemia and possibly CVD

Genotyping of 1955 volunteers with HTN


25 serum and urine biochemical tests
Compared with genome-wide data from 2 other

studies of individuals with DM


Found 2 proteins that were associated with a 6%
increase in non-fasting serum levels of LDL chol.

Other Interesting Studies


American Journal of Medicine:

Framingham Offspring Study suggests that at least


HALF of U.S. citizens will develop dyslipidemia at some
point in their lives

4701 participants who were ages 30-54 yrs in 1971


During the following 30 years, 6 in 10 developed

borderline-high (> 130) LDL and 4 in 10 developed high


(>160) LDL
Study possible suggests that over 70% of Americans
may be eligible for statin treatment at some stage of
their lives

Other Studies: The GOOD News


Nutrition,Metabolism and Cardiovascular
Diseases: Drinking moderate amounts of beer appears
to improve the lipid profile of healthy adults (esp.
women)

57 healthy Spanish volunteers (29 women)


Abstain for 30 day wash out period, then drink moderate
(330ml for women, 660ml for men) amounts of beer for
30 days
HDL increased from 60.7-66.8 mg/dl in women and from
44.2-46.5 mg/dl in men
HDL decreased during the 30 day wash out period

Other Studies: The GOOD News


Journal of Nutrition: People with dyslipidemia can
improve their lipid profiles by drinking cocoa
160 volunteers drank 10.0, 19.5 or 26 g/day of cocoa or

placebo
After 4 weeks, all groups but placebo had lower LDL levels
Most significant reductions in those with baseline LDL > 125
LDL decreased from 160 to 152
HDL increased from 57 to 62
Decrease in (apo) B and oxidized LDL cholesterol
Polyphenols in cocoa, tea, wine, fruit and vegetables may
lead to decrease in atherosclerotic disease

Case Study 1
35 YO male, a police officer. 511,
weight=258 (BMI=35, obese)
Hx: hypertension, anxiety. Has taken
testosterone supplements in past, now
uses body building shakes.
Family Hx: Father, paternal grandfatherDM
Labs: FBS=79, TSH normal

Case Study 1
Visit 1
3
TC= 167
TG=539
HDL= 18
LDL= ?
Tricor started

Visit 2
164
288
260
24
95
Niaspan
(intolerant)

Visit
158
28
88
Levaza

Case Study 2
39 YO male (hasnt been in for 2 years)
c/o frequent urination, excessive
thirst, blurred vision.
Hx: Mod. Obesity, BMI= 33
Family Hx: Mother DM
Meds: None
Non-fasting Accucheck= 297 (3 hrs PP)

Case Study 2
TC

705

252

212

195

144

Trig

6710

149

146

128

123

HDL

170

33

36

39

42

LDL

190

140

131

82

A1C

11.9

5.6

Meds

Tricor Zocor Zocor Add


and
20mg 40mg Zetia
DM tx

5.6

Case Study 3
62 YO Female with CHD s/p CABG wanted me to
manage lipids. Also has Hypertension.
Meds: Plavix, Atenolol, lisinopril, Atorvastatin
(stopped by pt.-myalgias)
Current labs:
TC= 248
Trig= 144
HDL= 41
LDL= 156

Case Study 3
Changed atenolol to Coreg
Started Pravachol 20mg
Disease management/diet counseling
Resume walking 3-4 days/week
Repeat labs:
TC=190
Increase Pravachol 178
Trig= 130 to 40mg
128
HDL= 39
41
LDL= 112
98

Framingham Risk
Prediction Score
47 YO Female
Labs: TC= 178 Trig= 133 LDL= 110 HDL=
35
BP: 162/98
Hx: Smoker, non-diabetic

What is 10 Year CHD Risk?

Framingham Risk
Prediction Score
47 YO Female
Labs: TC= 178 Trig= 133 LDL= 110 HDL= 35
BP: 162/98
Hx: Smoker, non-diabetic

What is 10 Year CHD Risk?

10% Compared to average of 5% for her


age group

Treatment of Dyslipidemias
(Medication Comparison Chart)

Which Medication(s) slows coronary


athersclerosis, lowers LDL, increases
HDL but has no effect on
triglycerides?

Treatment of Dyslipidemias
(Medication Comparison Chart)

Which Medication(s) slows coronary


athersclerosis, lowers LDL, increases
HDL but has no effect on triglycerides?
Mevacor

NCEP ATP III Lipid Goals


What is the recommended LDL goal for
a healthy normo-tensive, nonsmoking 46 year old male whose
father died of a massive MI at the
age of 52?

NCEP ATP III Lipid Goals


What is the recommended LDL goal for a
healthy normo-tensive, non-smoking 46
year old male whose father died of a
massive MI at the age of 52?
<130 for 2 risk factors
(age >45 and father with premature
CAD)

Final Question!!!!!
58 Year old Male (smoker)
Fam. Hx: Mother with NIDDM, sister died age 70 from MI
BP= 156/86 Pulse 78
Labs: TC= 310, TG= 250, HDL=29, LDL=156, FBS=88

What is Framingham 10 year Risk score?


Based on score, what is LDL goal?
Name 2 cholesterol medications (Brand) that would
be most appropriate for his treatment.

Final Question!!!!!
58 Year old Male (smoker)
Fam. Hx: Mother with NIDDM, sister died age 70 from MI
BP= 156/86 Pulse 78
Labs: TC= 310, TG= 250, HDL=29, LDL=156, FBS=88

What is Framingham 10 year Risk score? 27%


Based on score, what is LDL goal? <100
Name 2 cholesterol medications (Brand) that would
be most appropriate for his treatment. Niaspan,
any statin except Mevacor, any of the
combination meds

Thank You

Questions?

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