Transcript Dyslipidemia Dx. Rx. by Dr Sarma

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Welcome to You
All
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Dyslipidemias
Dx. and Rx.
Dr.Sarma RVSN, M.D., M.Sc (Canada)
Consultant in Medicine and Chest,
President IMA – Tiruvallur Branch
# 3, Jayanagar, Tiruvallur – 602 001
+91 98940 60593, (4116) 260593
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CD ROM Available
The contents of today’s presentation
are available in a CD-ROM format
for computer and VCD player use.
This CD, in addition, contains our talks on
ECG, Asthma, COPD, Hypertension Rx. also
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National Cholesterol
Education Program - NCEP
Adult Treatment Panel III
(ATP III) Guidelines -2002
Updated October 2004
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Guidelines that aren’t
implemented never work
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CHD Risk Factors ranking - PROCAM Study
Risk factor
Smoking
LDL cholesterol (mg%)
> 100 but < 160
> 160
Hypertension (SBP > 140; DBP > 90)
HDL cholesterol (mg%)
40 to 55
< 40
Triglycerides (mg%)
105- 167
>167
Fasting blood glucose (mg%)
110 - 126
> 126
Family history of MI
Relative risk
P Value
2.3
0.001
1.9
4.3
1.8
0.01
0.001
0.001
1.7
2.7
0.01
0.001
1.6
2.6
0.01
0.001
1.4
1.9
1.4
0.05
0.01
0.05
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Emerging Risk Factors
1. Lipoprotein (a)
2. Homocysteine
3. Prothrombotic factors
4. Pro-inflammatory factors
5. Metabolic syndrome
6. Sub-clinical atherosclerosis
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CHD Risk Equivalents
1.
Diabetes Mellitus
2.
Peripheral Vascular Disease
3.
> 20% in Framingham risk score
4.
Carotid atheroma
5.
Reno-vascular Disease
All forms of AVD
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AVD – Clinical Manifestations
Organ
Condition
Impairment
Clinical Presentation
Heart
Coronary Heart
Disease (CHD)
Ischemia
Infarction
Angina Pectoris
Myocardial Infarction
Brain
Cerebro vascular
Disease (CVD)
Ischemia
Infarction
Transient Ischemia attack
Stroke
Kidney
Reno vascular
Disease (RVD)
Ischemia
Infarction
Renal HT, Renal impairment
Renal Failure
Ischemia
Infarction
Intermittent Claudication
Gangrene
Leg
Peripheral Vascular
Muscles Disease (PVD)
For every thing the common denominator is ED
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Progression of Atherosclerosis
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Lipid Peroxidation
LDL, IDL
Not normally taken up by the vessel wall
ROS – Free radicals and Pro-oxidants
Oxidized
LDL, IDL
Freely enters the vessel wall
Endothelium
Scavenger
pathway
Foam Cells
Atherosclerosis
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Macrophages
Cytokines, GF
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The Havoc by LDL at the endothelium
Vessel Lumen
Monocyte
LDL
Adhesion
Molecules
Cytokines
Macrophage
MCP-1
LDL
Modified
LDL
Foam Cell
Endothelium
Intima
Growth Factors
Metalloproteinases
Cell Proliferation
Matrix Degradation
Ross R. N Engl J Med 1999;340:115-126.
Pathogenesis of ACS
Non-Vulnerable
Atherosclerotic
Plaque
Vulnerable
Atherosclerotic
Plaque
Plaque Rupture with Thrombus
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Lipid Transport
TG
EC
Apoprotein boat
Apo A I and A II for HDL
Apo B100+C+E – VLDL, IDL
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Apo B100 for LDL, Lp(a)
Apo B48+C+A+E – Chy. microns
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Lipoproteins
HDL
LDL
C
T
G
A I, A II
TG
C
B 100
VLDL
CM
TG
C
B 100 + E +C
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TG
B 48+E+C
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Cholesterols and Apoproteins
• Total Cholesterol
• ‘Bad’ Cholesterols
– LDLc, IDLc
– VLDLc, VLDLr
– Lp(a), small LDL
< 200
Apoprotein
Apo B type
< 100
< 30
< 20
B100 or B100 +E
B100 + E + C
B100 + (a)
• ‘Good’ Cholesterols
– HDL 1, HDL 2, HDL 3
Apo A type
> 50
A I and A II
HDL 1 and HDL 2 are protective
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Particle size & Density
Chylomicrons
VLDL
IDL
<< 1.006
< 1.006
< 1.019
LDL
Small LDL
HDL
< 1.063
< 1.085
< 1.210
Atherogenicity increases as density increases
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Atherogenic Particles
Measurements
VLDL
VLDLR
Apolipoprotein B
Non-HDL-C
IDL
LDL
SDL
TG-rich lipoproteins
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Two Types of Lipids
LIPIDS IN BLOOD
TOTAL CHOLESTEROL
GOOD CHOLESTEROL
HDL 1 and HDL 2
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TRIGLYCERIDES
BAD CHOLESTEROL
LDL, ( IDL, VLDL, Lp(a))
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Lipid Profile Report
LIPIDS ESTIMATED
TOTAL CHOLESTEROL (TC)
HDLc
LDLc
VLDLc
TRIGLYCERIDES (TG)
Chylomicrons
PP
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VLDL
Fasting
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Lipid Calculations
A. Total Cholesterol
200
HDL Cholesterol
50
LDL Cholesterol (TC –(HDL+VLDL))
VLDL Cholesterol (1/5 of TG)
B. Triglycerides
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120
30
150
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The Good and Bad
• Total Cholesterol
• ‘Good’ Cholesterols
– HDL 1, HDL 2, HDL 3
• ‘Bad’ Cholesterols (Non HDLc)
– LDLc, IDLc
– VLDLc, VLDLr
– Lp(a), small LDL
< 200
> 50
< 150
< 100
< 30
< 20
HDL 1 and HDL 2 are protective
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How it should be reported ?
Lipid type tested
Patient
Normal
260
200
HDLc (athero-protective)
55
55
LDLc + other atherogenic
155
100
Non-HDLc (atherogenic)
205
130
Ratio of TC ÷ HDLc
4.73
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Triglycerides (TG)
250
150
Total Cholesterol (TC)
Interpretation
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HDL – N, LDL – High , TG - HIGH
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Today’s Safer Values
•
•
•
•
•
•
•
•
•
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Total Cholesterol < 200
Triglycerides < 150
LDL Cholesterol < 100
HDL Cholesterol > 50 (for women 55)
Bad Cholesterols the lower the better
Good Cholesterols the higher the better
Non HDL Cholesterol < 130
Lp(a) values < 20
Homocysteine < 14 μ mols per liter
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Indian Specialty
A. Isolated low LDL
B. Isolated low HDL
C. Isolated high TG
32.90%
21.35%
10.45%
↑TG
↑LDL
The Triad
IHJ, 2000, 52: 173-177
Am J Med, 1998, vol 105(1A), 48S-56S
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↓HDL
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Look at the risks
•
•
•
•
•
•
•
•
Low HDL + High LDL
LP(a) excess > 30 mg%
LP(a) excess > 30 mg% + LDL high
LP(a) excess > 30 mg% + low HDL
LP(a) excess > 30 mg% + Incr. tHCy
LP(a) excess + Incr. tHCy + low HDL
Circulating lipids are one aspects
Tissue lipid content is more important
+
+
++
+++
++++
+++++
J. Atherosclerosis : Hopkins PN, 1997 – 17, 2792
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Relative risk of CHD
Additive Effect
Smoking
4.5
16
1.6
3
SBP >160
5
6
4
Dyslipidemia
With DM all risks are doubled
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Intestinal Cholesterol Absorption
Through
lymphatic
system to
the liver
Intestinal
epithelial cell
MTP
CM
Cholesteryl esters
ACAT
(esterification)
Free
cholesterol
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Biliary
cholesterol
excretion
ABCG5
ABCG8
Dietary
cholesterol
Luminal
cholesterol
Bile
acid
Micellar
cholesterol
uptake
Bays H et al. Expert Opin Pharmacother 2003;4:779-790.
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Cholesterol Absorption
Lymph
Enterocyte
Ezetimibe
Cholesterol
ACAT
Avasimibe
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NPC1L1
Cholesteryl
ABCG5/G8
Ester
Intestinal
Lumen
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Fat Absorption
Liver
Duodenum
Biliary
Transport
and Storage
Jejunum
Ileum
Colon
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Triglyceride Absorption
Lymph
Enterocyte
2 Fatty Acid
+
Monoglyceride
DGAT
Triglyceride
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Intestinal
Lumen
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Chylomicron Formation
Lymph
CM
apoB48
Enterocyte
Triglyceride
Cholesteryl
Ester
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Intestinal
Lumen
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Structure of HDL Particle
A-I
A-I
CE
TG
A-II
A-I, A-II = apolipoprotein A-I, A-II;
CE = cholesterol ester; TG = triglycerides
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HDL Types
A-I
A-I
CE
CE
CE
A-II
HDL 1
HDL 2
APO A I Protective
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A-II
HDL 3
Alcohol increases
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Reverse Cholesterol Transport
MF in Vascular
Endothelium
LIVER
EC
Free Chol.
UEC
HDL
L CAT
Enzyme
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HDL Metabolism and
Reverse Cholesterol Transport
Bile
A-I
F
C
CE
LCAT
SR-BI
Liver
A-I
CE
CE
FC ABC1 FC
Nascent
Macrophage
HDL
Mature HDL
ABC1 = ATP-binding cassette protein 1; A-I = apolipoprotein A-I;
CE = cholesteryl ester; FC = free cholesterol;
LCAT = lecithin:cholesterol acyltransferase;
SR-BI = scavenger receptor class BI
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Role of CETP in HDL Metabolism
Bile
Nascent HDL
A-I
Mature HDL
FC
CE
SR-BI
Liver
A-I
LDLR
Macrophage
LCAT
CE
FC
CETP
ABC1
FC
CE
SRA
X
CE
B
VLDL/LDL
Torcitrapib
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CETP = cholesteryl ester transfer protein
LDL = low-density lipoprotein
LDLR = low-density lipoprotein receptor
VLDL = very-low-density lipoprotein
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Hyperlipidemias
Primary 5%
Familial & genetic
Secondary 95%
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Secondary Hyperlipidemia
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↑ LDL Cholesterol
Nephrotic syndrome.
Hypothyroidism
Obstr. liver disease
Anorexia nervosa
Acute Int. Porphyria
Progestogens
↑ TG
Obesity
Diabetes
Uremia
Alcoholism, Smoking
Oral contraceptives
Beta blockers
Thiazides
Anabolic steroids
Pregnancy
Steroids, Thiazides
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Clinical Action
• Presence of secondary causes of Hyperlipidemia
– Order for full lipid profile (LP) – HT also
• Presence of hyperlipidemia – increased TG or EC
– Investigate for all secondary causes
• For all above 20 years once in every 5 years
• For those above 45 yrs – once in 2 years
• For those with already known lipid abnormality
follow-up every 3-6 months
• Extended Lipid profile includes Homocysteine,
LP(a), SD-LDL, ALP, Apo A and Apo B, HS-CRP
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Clinical Photoes
Tuberous xanthoma.
Flat-topped, yellow, firm tumor
Xanthelasma. Multiple, longitudinal, creamyorange, slightly elevated papules on eyelids .
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Clinical Photoes
Tendinous xanthomas. Large subcutaneous tumors adherent to the
Achilles tendons.
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Papular eruptive xanthomas. Multiple,
discrete, red-to-yellow confluent papules
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Evaluation
1. History of eruptive xanthomas, Abd. pain
2. H/o wt. gain, DM, estrogens, Alcohol, Ex.
3. Fasting Lipid profile (TC, LDL, HDL, TG)
4. OGTT, TSH, Liver & Renal Function tests
5. CHD assessment by ECG, TMT, Angio
6. Risk factor assessment, Family H/o P.CHD
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Treatment Strategy
Lipid Profile, Risk Assessment
LDL > 100
Look For Sec. Causes
Treat the cause, if found
Treatment
NO CHD
CHD +
Primary Prevention
Sec. Prevention
2 or more RF
LDL > 100
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High Risk
< 2 RF
Low Risk
LDL < 130
LDL <160
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Treatment Plan - LDLc
Clinical Status
Goal
Diet
Drugs
No CHD
< 2 RF
<160
>160
>190
No CHD
2 or more RF
<130
>130
>160
CHD Present
<100
>100
>130
For Indians all the values must be 20 mg less
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Treatment Options
•
•
Diet – Two step approach
Drug therapy
1. HMG¢ co A Reductase Inhibitors
2. Fibric Acid derivatives
3. Nicotinic Acid
4. Ezetimibe
5. Bile Acid binding Resins (BAR)
6. Probucol
¢
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HMG is Hydroxy Methyl Glutaryl
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New Treatments
Drug therapy
1. Colesevelam (BAR)
2. Phytosterols
3. Avasimibe – ACAT inhibitor
4. Torcetrapib – CETP inhibitor
5. Drugs decreasing Apo B synthesis
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Therapeutic Lifestyle Changes - TLC
•
•
•
•
•
•
•
•
Nutrient
Saturated fat
PUFA fat
MUFA fat
Total fat
Carbohydrate
Fiber
Protein
Cholesterol
Recommended Intake
< 7% of calories
Up to 10% of calories
Up to 20% of calories
25–35% of calories
50–60% of calories
20–30 grams per day
Approx. 15% of calories
Less than 200 mg/day
DIETARY THERAPY
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Our dietary fats
• SFA (saturated) – meet and diary products,
coconut oil, Kernel, Ghee, Butter, Palm oil,
• Trans fatty acids in vanaspati, chocolates
confectionaries, baked, deep fat fried food
• MUFA (N1) – Olive oil, Gingili oil
• PUFA (N6) – Soya, Sun Flower oil, GN oil
• PUFA (N3) – Fish oils – Twice a wk ↓ 76% CAD
• Legumes, fruits, olive oil – ↓ all cause mortality
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Treatment of ↑ LDLc
High LDLc
Therapeutic Lifestyle Change
Drug Therapy
Therapy of Choice: Statin
Add on drug - EZ , Niacin, BAR
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Statins – Mechanism of Action
Cholesterol
synthesis
HMGCoA
Intracellular
Cholesterol
VLDL
LDL receptor VLDL Apo B
R
Apo E
(B–E receptor)
synthesis
Apo B
LDL
LDL receptor–mediated
hepatic uptake of LDL
and VLDL remnants
Serum LDL-C
Serum VLDL remnants
Serum IDL
Hepatocyte
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1.
2.
3.
4.
Systemic Circulation
Reduce hepatic cholesterol synthesis (HMG CoA),
lowering intracellular cholesterol,
Upregulation of LDL receptor and
↑ the uptake of non-HDL from circulation.
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CHD Risk Reduction – Statin Therapy
Endpoints
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Relative Risk Reduction (%)
+20 0 –5 –10–15–20–25–30–35–40–45–50
Major coronary events
Coronary deaths
Cardiovascular deaths
Noncardiovascular events
Total mortality
Strokes
Intermittent claudication
Angina
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La Rosa JC et al. JAMA 1999;282:2340-2346.
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Time course of Statin effects
LDL-C
lowered*
Inflammation
reduced
Endothelial
function
restored
Days
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Vulnerable
plaques
stabilized
Ischemic
episodes
reduced
* Time course established
Cardiac events
reduced*
Years
HMG CoA Reductase
Inhibitors (Statins)
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Statin
Dose Range
Lovastatin
20–80 mg
Pravastatin
20–40 mg
Fluvastatin
20–80 mg
Simvastatin
20–80 mg
Atorvastatin
10–80 mg
Rosuvastatin
5–20 mg
Cerivastatin
0.4–0.8 mg
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LDL-C Lowering - Statin Dose
Atorvastatin
211 mg/dl*
Simvastatin
219 mg/dl*
Daily Dose
0%
-10%
-20%
38%
20 mg
-30%
-40%
46%
-50%
51%
54%
-60%
10 mg
28%
35%
41%
16% with
3 Titrations
13
%
40 mg
80 mg
Adapted from Jones P et al. Am J Cardiol 1998;81:582-587.
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HMG CoA Reductase Inhibitors (Statins)
 Common side effects
 Headache, Myalgia, Fatigue, GI intol. Flu-like symptoms
 Increase in liver enzymes – serious problems are very rare
 Occurs in 0.5 to 2.5% of cases in dose-dependent manner
 Myopathy occurs in 0.2 to 0.4% of patients
 Rare cases of Rhabdomyolysis
 We can reduce this risk by
 Cautiously using statins in impaired renal function
 Using the lowest effective dose
 Cautiously combining statins with fibrates
 Muscle toxicity requires the discontinuation of statin
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Short falls of Statins
 Effectiveness and community impact are to be improved
 Rebound increase in lipids and ↑ of events after
withdrawal of statin Rx.
 High rate of discontinuation by patients
 Differences in the efficacy of different statins
 They reduce only endogenous lipids – Individual variation
 Modest effect on TG and HDL, No effect on Lp(a)
 No effect on chylomicrons; escape phenomenon
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Ezetimibe
Lymph
Enterocyte
Cholesterol
ACAT
Intestinal
Lumen
X
NPC1L1
Cholesteryl
ABCG5/G8
Ester
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Ezetimibe
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Dual Inhibition
LDL
apoB100
Liver
Statin
Duodenum
X
VLDL
apoB100
X
Ezetimibe
Jejunum
Ileum
CM
Remnant
apoB48
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CM
apoB48
Colon
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Ezetimibe Efficacy (“10 + 10 = 80”)
0%
Ezt + Ator
10+10 mg
(n=65)
Atorvastatin
10 mg
(n=60)
20 mg
(n=60)
40 mg
(n=66)
80 mg
(n=62)
-10%
-20%
-30%
–37%
-40%
-50%
–42%
–53%
–45%
–54%
-60%
P < 0.01
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Ballantyne CM et al. Circulation 2003;107:2409-2415.
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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
Reabsorption of
bile acids
Net Effect -  LDL-C
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Liver
 LDL Receptors
 VLDL and LDL removal
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Bile Acid Resins (BAR)
Major actions
• Reduce LDLc by 15–30%
• Raise HDLc by 3–5%
• May increase TG
Side effects
• GI distress / constipation / nausea
• Decreased absorption of other drugs
Contra indications
• Dysbetalipoproteinemia,
• Biliary Obstruction
• Raised TG (especially >400 mg/dL)
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Bile Acid Resins
Drug
Dose Range
Cholestyramine
4–16 g
Colestipol
5–20 g
Colesevelam
2.6–3.8 g
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Treatment of ↓ HDLc
Low HDLc
Therapeutic Lifestyle Change
Drug Therapy
Therapy of Choice : Niacin
Add on drug - Finofibrate
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The CADI study [Coronary Artery Disease in Asian Indians]
14% of Asian Indian males & 5% of females have Optimal HDL
Prevalence of coronary heart disease and its risk factors in Asian Indians
Atherosclerosis , Rosemount , IL Oct 6-11 , 1991
120
100
80
60
40
20
0
86
95
14
5
Asian Indian
females
Asian Indian
males
% with < optimal level of HDL-C
% with an optimal HDL-C levels
In Indian patients with CAD, High TG levels are
found more often than high cholesterol levels.
Journal, Ind. Acad. clin. med vol 2 Jul-Sept 2001
Causes of Low HDL
Smoking
 Obesity (visceral fat), Physical inactivity
 Very high Carbohydrate diet
 Type II Diabetes
 Hyper-triglyceridemia
 Drugs like beta-blockers, androgenic steroids
and androgenic progestins
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Nicotinic Acid – Mechanism of Action
Mobilization of FFA
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
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Effect of Niacin on Lipoproteins
35%
69
HDL-C with crystalline niacin
25%
HDL-C with Niaspan®
12.5%
Baseline
LDL-C with Niaspan®
LDL-C with crystalline niacin
-15%
TG with Niaspan®
-30%
TG with crystalline niacin
0
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1g/d
2g/d
3g/d
Adapted from Knopp RH. N Engl J Med 1999;341:498-511..
Nicotinic Acid

Products available

Immediate-release, 2–4 g/d, Sustained Release 3 g /d

Extended-release (Niaspan®) 1–2 g/d

Best agent to raise HDL-C

Reduces coronary events

Adverse effects


Flushing, itching, headache (immediate-release, Niaspan®)

Hepatotoxicity, GI (sustained-release)

Activation of peptic ulcer

Hyperglycemia and reduced insulin sensitivity
Contraindications

Active liver disease or unexplained LFT elevations

Peptic ulcer disease
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Coronary heart disease and HDL-C
Framingham Heart Study
200
Rate/1000
150
100
Women
50
Men
0
<25
25–34
35–44
45–54
55–64
65–74
75+
HDL-C (mg/dl)
Gordon, Castelli et al. Am J Med 1977; 62: 707–714
Relative risks of MI
The Physicians Health Study
3.78
3.21
2.41
1.00
Low total cholesterol
<212 mg/dl
Low HDL cholesterol
<47 mg/dl
High HDL cholesterol
47 mg/dl
High total cholesterol
212 mg/dl
Stampfer, Sacks et al. N Engl J Med 1991; 325: 373–381
HDL-C vs LDL-C
as a predictor of CHD risk
CHD RR
Risk of CAD over 4
years of follow-up*
3
2.5
2
HDL-C
1.5
25 mg/dl
45 mg/dl
65 mg/dl
85 mg/dl
1
0.5
0
100 mg/dl
160 mg/dl
220 mg/dl
LDL-C
*Men aged 50–70
Gordon, Castelli et al. Am J Med 1977; 62: 707–714
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Management of Low HDLc
 LDL cholesterol is primary target of therapy
 Weight reduction and increased physical activity
(if the metabolic syndrome is present)
 Non-HDL cholesterol is secondary target of
therapy (if triglycerides 200 mg/dL)
 Consider nicotinic acid or fibrates
(for patients with CHD or CHD risk equivalents)
Dr.Sarma@works
Treatment of ↑ TG
High TG
Therapeutic Lifestyle Change
Drug Therapy
Therapy of Choice : Fibrate
Add on drug – Statin, Niacin
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Treatment Strategy
Fasting TG Level
↑Fasting TG Level
TG >150, No CHD
TG > 150, CHD +
TG > 500, CHD +/-
TG < 150
Normal
< 2 RF
Diet Modify
2 or > RF
Diet + Fibrate
Diet + Fibrate + Niacin
Diet + Fibrate + Statin
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Triglycerides
TG Level
Classification
Treatment
< 150 mg%
Normal TG
No Rx.
150 to 200 mg%
Borderline high
Diet alone
201 to 500 mg%
High
Diet + drugs
> 500 mg%
Very high
Diet + Intensive Rx
NCEP 2002 Guidelines by expert panel on TG
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Fenofibrate
Mode of Action

Enhances the activity of lipoprotein lipase

Reduces hepatic fatty acid synthesis

Inhibits HMG co-enzyme A reductase activity

Reduces the CETP activity

Increases the LCAT activity

Increases the production of Apo AI and Apo A II
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Fibric Acid Derivatives
• Major actions
– Lower TG 20–50%,↓VLDL synthesis
– Raise HDL-C 10–20%
– ↓ LDL (TG is N), ↑ LDL (TG is ↑)
– Increase the SDL particle size (less athero)
• Side effects
Dyspepsia, gallstones, myopathy, Abn. LFT
• Contraindications
Severe renal or hepatic / biliary disease
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Fibric Acid Derivatives
Drug
Clofibrate
Bezafibrate
Gemfibrozil
Fenofibrate
Fenofibrate micronized
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Dose
1000 mg BID
200 mg BID
600 mg BID
200 mg OD
160 mg OD
Treatment of ↑ LDL + ↑ TG
Combined
Therapeutic Lifestyle Change
Drug Therapy
Therapy of Choice : Statin + Fibrate
Add on drug – Niacin, BAR
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82
Statin + Fibrate
Simva +
Gemfibrozil
Percent Change
30
20
10
16%
230
332
0
-10
-20
-30
-40
-50
-60
Ator or Simva +
Fenofibrate
HDL
166
191
38
LDL
22%
HDL
34
LDL
TG
–39%
–28%
TG
–41%
–50%
Da Col PG et al. Curr Ther Res Clin Exp 1973;53:473-482.
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Statin + Fibrate – Precautions

Use statin alone for non-HDL-C goals

Use fish oils or niacin rather than fibrates

Keep the doses of the statin and fibrate low

Dose the fibrate in the AM and the statin in the PM

Avoid (or cautiously use) combo in renal impairment

Teach the patient to recognize muscle symptoms

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Discontinue therapy if muscle symptoms are present
and CK is >10 times the upper limit of normal
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Probucol
1.
Probucol (Lorelco) 500mg b.i.d with food
2.
Third line drug – erratic effect on LDL & HDL
3.
Lowers Cholesterol and the only drug which
regresses xanthomas
4.
It is an antioxidant of LDL
5.
Diarrohea, flatulence, nausea, increases QTc
6.
Can be combined with BAR
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The Three Canons
DYSLIPIDEMIA
↑ LDL - STATIN
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Summary of Drug choice
Lipid abnormality type First choice
Additional
Remarks
↑ LDL
Statin
Ezetimibe
Myopathy ↑
↑ TG
Fibrate
Niacin
↓ CHO intake
↓ HDL
Niacin
Fibrate
Exercise
↑ LDL + ↑ TG
Statin + Fibrate Niacin
Myo risk ↑ ↑
↑ LDL + ↓ HDL
Statin + Niacin
Exercise
↑ TG + ↓ HDL
Fibrate + Niacin Statin
↑ LDL + ↑ TG + ↓ HDL
Statin + Fibrate E, N, BA, FO Myo risk ↑ ↑ ↑
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Fibrate
Exercise
Atherogenecity of small, dense LDL
SDL is highly atherogenic. It

Generates free radicals

Increases trans endothelial filtration

Increases susceptibility to oxidation

Reduces affinity for the LDL receptor

Increased binding to intimal proteoglycan

↑ Formation of pro-aggregators / vasoconstrictors

Impaired in vivo ED independent of HDL, LDL, TG
Circulation, 2000, 102: 716-721
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Lp(a) or Little‘a’
•
•
•
•
•
Similar to LDL molecule
Apo B + additional Apo ‘a’ attached by S=S bond
Primary determinant is genetic
Normal value 20 mg %, > 30 high risk
It competes with plasminogen because of its
structural similarity and so interferes with
plasmin synthesis and thrombolytic pathway
• Nicotinic acid, ? Bezafibrate, Estrogens ↓it
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Phenotype B or ALP
 This ALP or phenotype B is present and
seen in most often
• Insulin resistant individuals
• Diabetics
• Obese persons
• Sedentary life style
 More prevalent in India
 Apo A I ÷ Apo B will be < 1
Cumulative Distribution of TG Levels
Phenotypes A and B
100
90
80
70
% Cumulative60
frequency 50
40
Phenotype A
Phenotype B
30
20
10
0
20 40 60 80 100 120 140 160 180 200 220 240 260 280 300
500
TG (mg/dL)
Austin M et al. Circulation. 1990;82:495-506.
Cumulative Distribution of HDL levels
Phenotypes A and B
100
90
80
70
% Cumulative60
frequency 50
Phenotype A
Phenotype B
40
30
20
20
25
30
35
40
45
50
55
60
65
70
75
80
HDL-C (mg/dL)
Austin M et al. Circulation. 1990;82:495-506.
Metabolic Syndrome - Characteristics





Hypertriglyceridemia
Low HDL-cholesterol
Elevated apolipoprotein B
Small, dense LDL particles
Inflammatory profile





Insulin resistance
Hyperinsulinemia
Glucose intolerance
Impaired fibrinolysis
Endothelial dysfunction
These features can lead to
type 2 diabetes,
hypertension and
cardiovascular disease
The interaction between our current genotype and
our present day life style and eating habits places us
at very high risk of having this phenotype B that
makes us highly susceptible to Atherosclerosis.
Journal of Internal Medicine 2003:254(2):114-25
ATP-III Criteria for Metabolic Syndrome
 Abdominal obesity (waist circumference): men
>100 cm (40 in); women >88 cm (35 in)
 Triglycerides > 150 mg/dl
 HDL cholesterol: men < 40 mg/dl; women < 50 mg/dl
 Blood pressure > 130/ 85 mmHg.
 Fasting glucose > 110 mg/dl
Diagnosis of metabolic syndrome is made when 3 or
more of the risk determinants shown above are present.
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Homocysteine
• Normal value is up to 15 μ mols./L
• Folic acid, Vitamin B6 and B12 are essential for
the normal transulfuration and remethylation
cycles
• Excess of homocystine generates oxidative
stress on the cell membranes. DNA and protein
denaturation through ROS formation
• Folic acid 5 mg/ day + Vit. B6 and B12 are to be
given on regular basis
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Summary of Drug choice
Lipid abnormality type Advised Rx.
Remarks
↑ Homocysteine
Folic acid
B6 + B12 helps
↑ Small dense LDL
Statin + Fibrate Aggressive Rx.
↑ Little ‘a’ or LP(a)
Niacin
↑ Phenotype B
Under research DM, Obesity ↓
↓ in Phenotype A
Under research Aerobic exercise
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Statin no effect
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Some Brand Names
Drug class
Brand name
Atorvastatin
TG-TOR, Storvas, Avastin, Atcor
Simvastatin
Sim, Simvotin, Simcard, Simvas
Atorvastatin + Ezetimibe
TG tor Z, Storvas Z,
Ezetimibe
Ezedoc, Ezee, Ezet
Fenofibrate
Lipicard, Fibrate, Finolip, Stanlip
Gemfibrozyl
Lopid, Lipizyl, Normolip, Losterol
Niacin
Niasyn, Nialip, Nicocin
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Atherosclerosis and IR and DM
Hypertension
Obesity
Hyperinsulinemia
Insulin
Resistance
Diabetes
Hypertriglyceridemia
Small, dense LDL
Low HDL
Hypercoagulability
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Atherosclerosis
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Dyslipidemia in IR and DM
 Elevated TG
 Elevated VLDL

Reduced
HDL-C
All Diabetics must be given STATIN
 Increase in SD-LDL
 Decrease in Apo A I
 Increase in Apo B
 Ratio of Apo A I / Apo B < 1
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Diabetes Treatment and Lipids
Type Rx used
Effect on lipids
1.
Insulin
Favourable
2.
Metformin
Mildly favourable
3.
Sulfonylureas
Not favourable
4.
Glitazones
Favourable
5.
Acarbose
No effect
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Hypertension Treatment and Lipids
Type Rx used
Effect on lipids
1.
Diuretics
Unfavourable
2.
Indapamide
Mildly favourable
3.
ACEi and ARB
Very favourable
4.
Betablockers
Unfavourable
5.
Ca channel blockers
No effect
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Who is to be blamed ??
We do not care at all to
We soon end up having
Restrict diet, over eat CHO, sweet toothed Over weight and obesity
Eat more fruits, fiber, vegetables
Atherosclerosis and AVD
Avoid fatty, crunchy, munchy tasty food
Dyslipidemia and CHD
Avoid salty, savory, preserved food, NV
Hypertension, CVA
Do the minimum required exercise
Diabetes, IR, ↓ HDL, OA
Take enough milk and milk products, Ca
Osteoporosis & fractures
Quit smoking and abstain from alcohol
What not !
Control worry, anger, vengeance, jealousy Mental & physical illness
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Where are we heading ? ?
20000 B.C.
2004
Paleolithic sup. age
Neolithic age
19th century
21st century
Technology has changedProcessed
a lot in the way we live
Hunting-gathering
subsistence
High level of
physical activity
But, we have not
Thrifty genotype
foods
Animal fats
and glucides
¯ Dietary fibre
Sedentary
altered our
life
life style
Susceptibility genotype
Journal of internal medicine 2003:254(2):114-25
We have to pay the very heavy price !!
What could be prevented, we treat or leave
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Web Resources on Lipids
www.lipidsonline.org
www.hypertensiononline.org
www.ncbi.nlm.nih.gov
www.univ baylor.org
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CD ROM Available
The contents of today’s presentation
are available in a CD-ROM format
for computer and VCD player use.
This CD, in addition, contains our talks on
ECG, Asthma, COPD, Hypertension Rx. also
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Wishing YOU all
A HAPPAY NEW YEAR
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