Transcript Dyslipidemia update by Dr Sarma

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O ALMIGHTY
Tallee ninnu dalanchi pustakamu
chaetan boonitin neevu naa
ullambanduna nilchi jrumbhanamugaan
uktul su sabdambul
sobhillan balkumu naadu vaakkunan
sampreetin, Jaganmohinee
pullaabjaakshee Saraswatee Bhagavatee
poornaendu bimbaanana
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O! ALMIGHTY
O! Almighty, the Goddess of Wisdom!
We start this learning process, keeping
YOU in our inner hearts, please shower
Your kind blessings on all of us and ensure
What ever we speak is eloquent
What ever we discuss is pertinent
What ever we learn is relevant.
May we be blessed with the best wisdom !
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DyslipidemiasPractice Approach
Dr.Sarma RVSN, M.D., M.Sc (Canada)
Consultant in Medicine and Chest,
# 3, Jayanagar, Tiruvallur – 602 001
98940 60593, 2766 0593
Visit us at : www.drsarma.in
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CD ROM Available
The contents of my today’s presentations
are made available in a CD-ROM format
This CD, in addition, contains my talks on
Asthma, COPD, Hypertension, ECG, CAD
Dyslipidemias, Diabetes, Osteoporosis…
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The Almighty
Pardons and Grants me heaven
Even if I don't know a single letter about
Crutz Feld Jacob’s Disease
Tsutsugamushi Fever
Criggler Nazzar Syndrome
South American equine encephalitis and
Many and much more rarer topics
BUT …….
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The Almighty
Will drag me to hell and will not pardon
My ignorance of even the minute details of HT, DM
My indifference to apply the current knowledge
My negligence in screening for Lipids, DM, HT, LVH
My despondency about preventing TOD and ACS
My inadequacy in maintaining my patients
Normotensive, Euglycemic, Eulipidemic –
(This is applicable to all common diseases)
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National Cholesterol
Education Program - NCEP
Adult Treatment Panel III
(ATP III) Guidelines -2002
Updated October 2004
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The Good, Bad, Ugly and Deadly
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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 (TG)
BAD CHOLESTEROL
LDL, VLDL (TG), Lp(a)
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Lipoprotein
Lipids or Fats
(Hydrophobic)
Size < RBC
TG, EC
Phospholipids
Free Cholesterol
(Hydrophilic)
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Apoproteins
A,
B, C, E, (a)
(Amphiphatic)
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Lipoproteins
TG
EC
Apoprotein boat
Apo A I and A II for HDL
Apo B100+C+E for VLDL, IDL
Apo B100 for LDL
Apo B100+Apo(a) for Lp(a)
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Good, Bad, Ugly & Deadly
HDL
GOOD
LDL
C
TG
T
G
A I, A II
VLDL
TG
BAD
B 100
UGLY
Lp(a)
DEADLY
TG
C
B 100 + E +C
C
TG
C
B 100+ (a)
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All are the terrorists !!
Measurements
VLDL
VLDLR
TG-rich lipoproteins
Apolipoprotein B
Non-HDL-C
IDL
LDL
SDL
Highly atherogenic
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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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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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Normal Lipid Profile
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•
Total Cholesterol
TG ‘Ugly’ Lipid
‘Bad’ Cholesterols LDL
HDL ‘Good’ cholesterol
VLDL is Ugly TG ÷ 5
Lp(a) ‘Deadly’ cholesterol
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< 200
< 150
< 100
> 50
< 30
< 20
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How to interpret Lipid Profile Report?
A. Total Cholesterol
HDL Cholesterol (Soldiers) - Good
200
50
Non HDL Cholesterol (Culprits)
150
LDL Cholesterol – Bad fellows
100
Lipoprotein(a) – Deadly fellows
20
VLDL Cholesterol (1/5 of TG)- Ugly
30
B. Triglycerides
Normal Lipid Profile
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150
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Interpret this Lipid Profile Report
A. Total Cholesterol
240
HDL Cholesterol (Soldiers) - Good 50
Non HDL Cholesterol (Culprits)
190
LDL Cholesterol – Bad fellows
140
Lipoprotein(a) – Deadly fellows
20
VLDL Cholesterol (1/5 of TG)- Ugly
30
B. Triglycerides
150
Hyper cholesterolimia ↑LDL, HDL, TG, Lp(a) - N
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Interpret this Lipid Profile Report
A. Total Cholesterol
HDL Cholesterol (Soldiers) - Good
200
Non HDL Cholesterol (Culprits)
50
150
LDL Cholesterol – Bad fellows
70
Lipoprotein(a) – Deadly fellows
20
VLDL Cholesterol (1/5 of TG)- Ugly
60
300
B. Triglycerides
Hyper triglyceridemia ↑TG, HDL, LDL, Lp(a) - N
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Interpret this Lipid Profile Report
A. Total Cholesterol
HDL Cholesterol (Soldiers) - Good
160
Non HDL Cholesterol (Culprits)
25
135
LDL Cholesterol – Bad fellows
85
Lipoprotein(a) – Deadly fellows
20
VLDL Cholesterol (1/5 of TG)- Ugly
30
150
B. Triglycerides
Low HDL : ↓HDL, LDL, TG, Lp(a) - N
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Interpret this Lipid Profile Report
A. Total Cholesterol
HDL Cholesterol (Soldiers) - Good
200
Non HDL Cholesterol (Culprits)
45
155
LDL Cholesterol – Bad fellows
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Lipoprotein(a) – Deadly fellows
50
VLDL Cholesterol (1/5 of TG)- Ugly
30
150
B. Triglycerides
High Lipoprotein(a) : ↑Lp(a) , HDL, LDL, TG - N
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Interpret this Lipid Profile Report
A. Total Cholesterol
HDL Cholesterol (Soldiers) - Good
200
Non HDL Cholesterol (Culprits)
25
175
LDL Cholesterol – Bad fellows
95
Lipoprotein(a) – Deadly fellows
20
VLDL Cholesterol (1/5 of TG)- Ugly
60
300
B. Triglycerides
High Lipoprotein(a) : ↓HDL, ↑TG, LDL, Lp(a) - N
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Interpret this Lipid Profile Report
A. Total Cholesterol
260
HDL Cholesterol (Soldiers) - Good 50
Non HDL Cholesterol (Culprits)
210
LDL Cholesterol – Bad fellows
120
Lipoprotein(a) – Deadly fellows
40
VLDL Cholesterol (1/5 of TG)- Ugly
50
B. Triglycerides
250
Combined Dyslipidemia : ↑ TC↑LDL↑TG ↑Lp(a)
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Dyslipidemic Triad
A. Isolated High 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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Indian Dyslipidemic Triad
↑TG
↑Lp(a)
The Indian Triad
↓HDL
IHJ, 2000, 52: 173-177
Am J Med, 1998, vol 105(1A), 48S-56S
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Indian Dyslipidemia
• Low HDL
• High TG
• Lp(a) excess
39.2%
32.5%
28.6%
• High LDL
• Normal Lipids
10.8%
23.5%
Am J C 2001;88(suppl) 9N-13N; 22N
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Look at the risks
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•
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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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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Triglyceride Absorption
Lymph
Enterocyte
2 Fatty Acid
+
Monoglyceride
DGAT
Triglyceride
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Intestinal
Lumen
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HDL Sub types
A-I
A-I
CE
CE
The soldiers
HDL 1
The soldier-like
CE
A-II
HDL 2
APO A I
Atheroprotective
A-II
HDL 3
Alcohol increases
Athero-neutral
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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
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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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The Weapons in our hand
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Diet and Exercise (Life Style)
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
6. Selective LDL apopheresis
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Therapeutic Lifestyle Changes - TLC
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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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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
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Drug
Dose Range
Cholestyramine
4–16 g
Colestipol
5–20 g
Colesevelam
2.6–3.8 g
Treatment of ↓ HDLc
Low HDLc
Therapeutic Lifestyle Change
Drug Therapy
Therapy of Choice : Niacin
Add on drug - Finofibrate
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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%
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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
Dr.Sarma@works
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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)
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Treatment of ↑ TG
High TG
Therapeutic Lifestyle Change
Drug Therapy
Therapy of Choice : Fibrate
Add on drug – Statin, Niacin
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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 2004 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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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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How do we treat ?
•
•
•
•
•
•
•
Increased LDL
Increased TG
Decreased HDL
Increased Lp(a)
Increased LDL + TG
↑ LDL + ↓HDL
↑TG + ↓HDL
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Statins +/- EZ
Fibrates
Niacin
Niacin
Statin + Fibrate
Statin + Niacin
Fibrate + Niacin
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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.
85
Homocysteine
• Normal value is up to 10 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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86
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
87
Some Brand Names
Drug class
Brand name
Atorvastatin
TG-TOR, Storvas, Avastin, Atcor
Simvastatin
Sim, Simvotin, Simcard, Simvas
Atorvastatin + Ezetimibe
TG -Tor EZ, Storvas EZ,
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
89
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 B / Apo 1 > 2
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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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91
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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Web Resources on Lipids
www.lipidsonline.org
www.hypertensiononline.org
www.ncbi.nlm.nih.gov
www.univbaylore.org
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Announcements
1. Purpose, Men behind
2. Our emphasis and topics
3. Frequency, timings
4. Very informal - Interactive
5. Funds, sponsors, venues
6. Let us know you correctly
7. Feed back, make friends
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CD ROM Available
The contents of my today’s presentations
are made available in a CD-ROM format
This CD, in addition, contains my talks on
Asthma, COPD, Hypertension, ECG, CAD
Dyslipidemias, Diabetes, Osteoporosis…
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Visit us at: www.drsarma.in
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It is time for
Coffee Break
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