Prof. Dr.

Sarma VSN Rachakonda

M.D., M.Sc., (Canada), FCGP, FICP, FIMSA, FRCP (G), FCCP (USA)
Visiting Professor of Internal Medicine, SBMC, FLL, iDRF
Sr. Consultant Physician & Cardio-metabolic Specialist

website: www.drsarma.in
YouTube: drsarmaji channel
1
Consensus Development
Conference in July 2009
2
www.lipidsonline.org
www.ccmdweb.org
www.ncbi.nlm.nih.gov
www.univbaylor.org
www.hypertensiononline.org
www.drsarma.in

3
LDL
CMR
Statins
Optimization
NHDL
control
Non Lipid
Effects
2
1
4
3
4
DM
MS
HT
Lipids
CVD
DM
HT
Lipids
CVD
5
CMR
CAD
Stroke
PAD
CKD
CAD Stroke
CKD PAD
6
1
2
3
COST
75 %
25 %
EVENTS
7
REGRESS
Target organ damage
Asymptomatic
Target organ damage
Symptomatic
Death
CVD
New risk factors
Risk factors
Cardiometabolic risk

Atherosclerosis
CVD
8
REGRESS
Target organ damage
Asymptomatic
CVD
New risk factors
Risk factors
Cardiometabolic risk

Target organ damage
Symptomatic
Death
Atherosclerosis
CVD
9
1. Ester. Cholesterol (EC)
2. Triglycerides (TG)
What are the important
components (two) of
lipids in the plasma ?
What are the other two
components in lipids in
their outer layer ?
1. Free Cholesterol (FC)
2. Phospholipids (PL)
What are Apoproteins ?
Why are they needed in
the lipid molecules ?
1. The outer protein coat is
made of Apoproteins
2. To make lipids soluble and
thus help transport
10
Free fatty acids (FFA) to Triglyceride (TG)
Source of energy to the tissues
Stored as TG; Metabolized to CO
2
and H
2
O
Exogenous (diet) and De novo synthesis
Free Cholesterol (FC) to Esterified (EC)
Cell membrane integrity
Bile acids synthesis
Steroid hormones synthesis; Vitamin D in skin
Can not be broken down
Exogenous (diet) and De novo synthesis


11
TG, EC
Phospholipids
Free Cholesterol
(Hydrophilic)
Apolipoproteins
A, B, C, E, (a)
(Amphiphatic)
Lipids or Fats
(Hydrophobic)
Size < RBC
12
EC TG
Apoprotein boat
1. Make the lipids soluble and transportable
2. Structural Integrity of the lipoprotein
3. Act as ligands for cell receptors
4. Activate enzymes such as LPL, LCAT as cofactors
13
Apolipoprotein B
Non-HDL-C
Measurements
TG-rich lipoproteins
VLDL VLDLr IDL LDL SLDL
The smaller the particle
The greater is the danger
Lp(a) CM
14
A-I
A-I
A-II
A-I, A-II = Apo lipoprotein A-I, A-II;
CE = cholesterol ester; TG = triglycerides
CE
TG
15
CE
A-I
CE
A-I
CE
A-II A-II
HDL 1 HDL 2 HDL 3
APO A I Protective Alcohol increases
16
Synthesized
HDL
VLDL
Lp(a)
Chylomicrons
Generated
LDL
IDL (VLDL R)
Chylomicron R

17
Duodenum
Jejunum
Ileum
Colon
Biliary
Transport
and Storage
Fecal
excretion
(1.6 g/d)
Dietary
Cholesterol
(0.4 g/d)
Absorption
~50%
CM
apoB48
Liver
Biliary
Cholesterol
(2.4 g/d)
18
Synthesis
(1.2 g/d)
Cholesterol
(1.2 g/d) +
Bile Salts
(0.4 g/d)
Bays H et al. Expert Opin Pharmacother 2003;4:779-790.
Intestinal
epithelial cell
Biliary
cholesterol
Dietary
cholesterol
Luminal
cholesterol
Micellar
cholesterol
Bile
acid
Cholesteryl esters
Free
cholesterol
excretion
uptake
ACAT
ABCG5
ABCG8
(esterification)
MTP
CM
Through
lymphatic
system to
the liver
NPC1L1
19
Free Cholesterol
NPC1L1
Cholesterol
Ester
ABCG5/G8
ACAT
Ezetimibe
Avasimibe
Pancreatic Esterase
20
Sterol/Stanol Dietary
Cholesterol
21
Lymph Enterocyte
Intestinal
Lumen
Cholesterol
Cholesteryl
Ester
ABCG5/G8
ACAT
NPC1L1
22
23
Similar LDL-C
Larger LDL (phenotype A)
More cholesterol/particle
24
Lymph Enterocyte Intestinal
Lumen
2 Fatty Acids
+
Mono glyceride
DGAT
Triglyceride
Intestinal Lipase
APO
B48
Chylomicrons
25
Lymph Enterocyte Intestinal
Lumen
Cholesteryl
Ester
CM
apoB48
Triglyceride
26
27
Sinusoidal Membrane
Blood Hepatocyte
Canalicular Membrane
Bile Salt
ABCG5/G8
Cholesterol
ABCB4
Phospholipid
ABCB11
Bile
28
29
30
Intestine
Peripheral
Cells
Kidney
PLTP
LCAT
ABC1
Particle
Uptake
Liver
TGRL
Selective
Uptake
Surface
Remnants
Cubilin
apo A1
HDL
3
HDL
2
Pre-|-
HDL
CETP
SR-BI
HL, EL
LPL
Reprinted from von Eckardstein A, Assmann G. Curr Opin Lipidol.
2000;11:627637, with permission from Lippincott Williams & Wilkins.
Nascent HDL (lipid-poor apo lipoprotein A1
is produced by the liver and intestine
31
LIVER
MF in Vascular
Endothelium
Free Cholesterol
L CAT Enzyme
UEC
EC
HDL
32
Liver
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
Mature HDL
CE
A-I
CE
CE
FC
FC
LCAT
FC
Bile
SR-BI
A-I
ABC1
Macrophage
Nascent
HDL
33
B
SRA
Mature HDL
A-I
Liver
CE
CE
FC
FC
LCAT
FC
Bile
SR-BI
A-I
ABC1
Macrophage
CE
CETP = cholesteryl ester transfer protein
LDL = low-density lipoprotein
LDLR = low-density lipoprotein receptor
VLDL = very-low-density lipoprotein
LDLR
VLDL/LDL
CETP
Nascent HDL
CE
Torcitrapib
X
34
Lipoprotein Lipase : LPL
Capillary endothelium muscle, heart, adipose
tissue, TG hydrolysis to FFA & Glycerol
Converts CM and VLDL to their remnants
Apo CII is the cofactor, Insulin stimulates LPL
Hepatic Lipase : HL
Present in hepatic sinusoids
Hydrolysis of TG to FFA and glycerol
IDL converted to LDL
HDL converted to small lipid poor HDL
35
Endothelial Lipase : EL
Member of LPL family
Made by endothelial cells
Hydrolyses the phospholipid in HDL
Lecithin Cholesterol Acyl Transferase : LCAT
Produced in the liver
In the plasma catalyzes FC to EC in HDL
Cholesterol Ester Transfer Protein : CETP
Plasma protein bound to HDL, from the liver
Transfers EC to CM, VLDL, IDL, LDL from HDL
Transfers TG from CM, VLDL, IDL , LDL to HDL
36
LDL
LDL
Endothelium
Vessel Lumen
Monocyte
Macrophage
Adhesion
Molecules
Foam Cell
Intima
Modified
LDL
Cytokines
Cell Proliferation
Matrix Degradation
Growth Factors
Metalloproteinases
Ross R. N Engl J Med 1999;340:115-126.
MCP-1
37
LDL, IDL Not normally taken up by the vessel wall
ROS Free radicals and Pro-oxidants
Oxidized
LDL, IDL
Freely enters the vessel wall
Scavenger
pathway
Endothelium Macrophages
Foam Cells Cytokines, GF
Atherosclerosis
38
LIPIDS ESTIMATED
TOTAL CHOLESTEROL (TC) TRIGLYCERIDES (TG)
HDLc LDLc VLDLc Chylomicrons VLDL
PP Fasting
39
A. Isolated High LDL 32.90%
B. Isolated low HDL 21.35%
C. Isolated high TG 10.45%

IHJ, 2000, 52: 173-177
Am J Med, 1998, vol 105(1A), 48S-56S
LDL
HDL
TG
The Triad
40
IHJ, 2000, 52: 173-177
Am J Med, 1998, vol 105(1A), 48S-56S
Lp(a)
HDL
TG
The Indian Triad
41
Low HDL 39.2%
High TG 32.5%
Lp(a) excess 28.6%
High LDL 10.8%
Normal Lipids 23.5%
Am J C 2001;88(suppl) 9N-13N; 22N
42
NHDL
75%
HDL
25%
Total Cholesterol
LDL
120 mg
TG/5
30 mg
HDL
50 mg
Total Cholesterol = 200 mg
43
Total Cholesterol HDL = N-HDL
LDL + (TG/5) = N-HDL
N-HDL goal is 30 mg above the LDL goal
Because TG should be kept at 150 (150/5 = 30)
Significance of N-HDL
It includes all known atherogenic particles
Correlates closely with visceral adiposity, obesity
It is a stronger predictor of CVD than LDLc
44
LDL
NHDL
HDL 100 mg
130 mg
50+ mg
45
Level of Risk LDL Cholesterol NHDL Cholesterol Apo B 100
Highest < 70 mg /dl < 100 mg /dl < 80 mg /dl
High < 100 mg /dl < 130 mg /dl < 90 mg /dl
Low < 130 mg /dl < 160 mg /dl < 100 mg /dl
Highest: 1) Known CVD or 2) DM plus one or more major CV RF
High: 1) No DM or Known CVD but two or more additional major
CVD risk factors or 2) DM but no other major CVD risk factors
Low: No DM, No CVD, s 1 RF, Framing Score < 10% for 10 yrs
Beyond dyslipoproteinemia, smoking, HT, F H/o premature CAD
46
Name SAFA % MUFA % PUFA % Chol. mg%
Canola oil 6 55 28 0
Safflower 8 11 67 0
Sunflower 10 18 60 0
Olive oil 12 66 7 0
Sesame oil 13 36 38 0
Groundnut 15 41 29 0
Palm oil 45 33 3 0
Red meat 46 38 10 93 mg%
Butter/Ghee 48 27 4 207 mg%
Coconut oil 79 5 1 0
47
Nutrient Recommended Intake
Saturated fat < 7% of calories
PUFA fat Up to 10% of calories
MUFA fat Up to 20% of calories
Total fat 2535% of calories
Carbohydrate 5060% of calories
Fiber 2030 grams per day
Protein Approx. 15% of calories
Cholesterol Less than 200 mg/day
Two Step Dietary Therapy
48
1. Heart Healthy eating habits
2. Medical Nutrition Therapy
3. Increasing Physical Activity
4. Therapeutic Lifestyle Change (TLC)
5. Cessation of Smoking
The problem is we never implement them,
come what may!! Both as patients and as
physicians!
49
1. Use higher dose of statin that keeps LDL low
2. If not tolerated Combine Ezetamibe or BAR
3. Statin + Fibrate Good Be aware of myositis
4. No combination of Gemfibrozil + Statin please
5. Statin + Omega 3 fatty acids for NHDL
6. Statin + Niacin ideal for all lipid components
7. Niacin with Aspirin, after meal, ERN, LPR

50
Type Rx used Effect on lipids
1. Insulin Favourable
2. Metformin Mildly Favourable
3. Sulfonylurea Not Favourable
4. Glitazone Favourable
5. Acarbose No effect
51
Type Rx used Effect on lipids
1. Diuretics Unfavourable
2. Indapamide Mildly Favourable
3. ACEi and ARB Very Favourable
4. Beta Blockers Unfavourable
5. Ca Channel blockers No effect
52
LDL Cholesterol
NHDL
HDL
53
CVD 70 mg 3
o
DM 70 mg 2
o
2 RF 100mg 2
o
1RF 130mg 1
o
54
The role of LDL as an important CVD risk factor is beyond
dispute and is the primary target for lipid Rx. For every 30 mg
of in LDL, there is a 30% reduction in CAD Risk.
55
High LDLc
Therapeutic Lifestyle Change
Add on drug - EZ, Niacin, BAR
Therapy of Choice: Statin
Drug Therapy
56
HMG-
CoA
Cholesterol
Ras
protein
Geranylgeranylated
proteins
57
58
59
1. Reduce hepatic cholesterol synthesis (HMG CoA),
2. Lowering intracellular cholesterol,
3. Up regulation of LDL receptor and
4. the uptake of non-HDL from circulation.
LDL receptormediated
hepatic uptake of LDL and
VLDL remnants
Serum VLDL remnants
Serum LDL-C
Cholesterol
synthesis
LLDL receptor
(BE receptor)
synthesis
Intracellular
Cholesterol
Apo B
Apo E
Apo B
Systemic Circulation Hepatocyte
LDL
Serum IDL
VLDL
R

VLDL
HMG CoA
60
61
LDL
Receptor
Acetate
LDL
HMG-CoA
Reductase
Cholesterol
Hepatocyte
62
Secondary
Primary
LaRosa JC, et al. JAMA. 1999;282:23402346.
-50
-40
-30
-20
-10
0
R
i
s
k

R
e
d
u
c
t
i
o
n

i
n

M
a
j
o
r

C
o
r
o
n
a
r
y

E
v
e
n
t
s

(
%
)

38
P<0.001
31
P<0.001
38
P<0.001
25
P<0.001
25
P=0.002
CARE

4159

28%
LIPID

9014

25%
4S

4444

36%
WOSCOPS

6595

26%
AFCAPS/
TexCAPS

6605

27%
N

LDL-C +
LDLC = low-density lipoprotein cholesterol
63
15 25 35 45 50 40 30 20 LDL %
.
.
.
.
.
.
.
.
64
45
La Rosa JC et al. JAMA 1999;282:2340-2346.
Endpoints
+20 35 30 25 0 5 10 15 20
Relative Risk Reduction (%)
40 50
Major coronary events

Coronary deaths

Cardiovascular deaths

Non CV events


Total mortality

Strokes

Intermittent claudication

Angina
65
* Time course established
Days Years
LDL-C
lowered*
Inflammation
reduced
Vulnerable
plaques
stabilized
Endothelial
function
restored
Ischemic
episodes
reduced
Cardiac events
reduced*
66
Statin Dose Range
Lovastatin 2080 mg
Pravastatin 2040 mg
Fluvastatin 2080 mg
Simvastatin 2080 mg
Atorvastatin 1080 mg
Rosuvastatin 520 mg
Cerivastatin 0.40.8 mg
Pregnancy category Category X drugs
67
Atorvastatin
LDL 211 mg/dl
Simvastatin
LDL 219 mg/dl
Adapted from Jones P et al. Am J Cardiol 1998;81:582-587.
Daily Dose
10 mg
20 mg
40 mg
80 mg
16% with
3 Titrations
13%
38%
46%
51%
54%
28%
35%
41%
68
Jones PH, et al. Am J Cardiol. 2003;92:152160.
-60%
-50%
-40%
-30%
-20%
-10%
0%
M
e
a
n

%

C
h
a
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g
e

i
n

L
D
L
-
C

f
r
o
m

U
n
t
r
e
a
t
e
d

B
a
s
e
l
i
n
e

V
a
l
u
e

Atorvastatin Rosuvastatin Simvastatin
14% with
3 titrations
9% with
2 titrations
18% with
3 titrations
10 mg 20 mg 30 mg 40 mg
28
7
4
7
46
6*
3*
37
6
5
3
69
Duodenum
Jejunum
Ileum
CM
apoB48
Liver
CM
Remnant
apoB48
VLDL
apoB100
Ezetimibe
X
LDL
apoB100
X
Statin
Colon
70
Ballantyne CM et al. Circulation 2003;107:2409-2415.
Atorvastatin
40 mg
(n=66)
20 mg
(n=60)
10 mg
(n=60)
53%
37%
42%
45%
54%
P < 0.01
80 mg
(n=62)
-60%
-50%
-40%
-30%
-20%
-10%
0%
Ezt + Ator
10+10 mg
(n=65)
EZ In Pregnancy Category C drug
71
1-STEP
Co administer
3-STEP
TITRATION
Statin at starting dose 1st 2nd 3rd
Statin at starting dose
1518%
Doubling
+ Ezetimibe
% Reduction in LDL-C
56% 56% 56%
Bays HE et al. Expert Opin Pharmacother 2003;4:779-790.
72
Presence of Triglycerides
ApoB
Cholesterol
Dietary/Biliary Synthesis
Ezetimibe
X X
Statin
MTP MTP
Cholesterol Esters
73
Baseline LDL-C 160 mg/dL
Target LDL-C <70 mg/dL
Needed LDL-C reduction 160 70 = 90 mg/dL
To achieve the target LDL-C, this patient needs a:
57% LDL-C reduction = (16070 mg/dL)/160 mg/dL 100
Medications and doses that will achieve this reduction are:
Atorvastatin 80 mg
Rosuvastatin 20 mg
Ezetimibe/Atorvastatin 10/20 mg

Patients may need more than the initial starting dose
74
1. Increase endothelial NO and improves ED
2. Regresses atheroma and plaque burden
3. Increase expression of (tissue) tPA-1
4. expression of Endothelin-1 (vasoconstrictor)
5. Stabilizes plaque via lipid, MF, MMPs
6. Reduce oxidative stress CH independent
7. hs-CRP, TNF-o, IL-6 - inflammatory markers
8. Anti inflammatory at the site of plaque
9. Inhibits platelet aggregation, anti thrombotic
All these occur before the lowering of cholesterol.

75
Excellent patient acceptance
Few drug-drug interactions
Fewer side effects
Most common GI mild to moderate
Monitor 6-8 weeks; then every 6 months
At high doses elevated ALT/AST in 1-2%
Myopathy in 0.1 to 0.2% (CK >10 x UNL)
Rare cases of toxicity warranting Rx stopping
No increase in total or non CAD mortality
76
Headache or Dyspepsia
Initially
68 weeks after
starting therapy
At each
follow-up visit
Muscle Soreness, Tenderness, or Pain
Initially
612 weeks after
starting therapy
At each
follow-up visit
Pasternak RC, et al. J Am Coll Cardiol. 2002;40:567572.
77
Pasternak RC, et al. J Am Coll Cardiol. 2002;40:567572.
McKenney JM, et al. Am J Cardiol. 2006;97:89C94C.
Lipid Panel
Baseline 6 weeks 3 months Every 6 months
Liver Function Tests
Baseline
12 weeks after
starting/increasing
therapy
Annually, as needed
(when the patient reports
liver symptoms)
Creatine Kinase Test
Baseline
As needed (when patient reports muscle
soreness, tenderness, or pain)
78
Statins reduce the incidence of MACE
Reduce the need for PTCA, CABG, CIMT
Reduce the incidence of stroke, Amputations
The potential of statins is not fully realized
Statins are very safe in a vast majority
The strongest evidence base is established
Innumerable number of studies >200 RCTs
Caution in only a selected patients groups
Under used, under dosed in many a practice
79
CARE
62%
69%
ALDL -25% -29% -27%
80
Elevations in liver transaminases:
Increases are<3 times the upper limits of normal
Occur in 0.5% to 2.0% of statin users
Are dose-dependent
Are usually reversed with a lowered statin dose
Usually do not recur with reuse of another statin
Rarely progress to liver failure
Chronic Liver Disease; NAFLD, NASH
Pasternak RC, et al. J Am Coll Cardiol. 2002;40:567572.
McKenney JM, et al. Am J Cardiol. 2006;97:89C94C.
81
Myopathy
Patient reports muscle pain, soreness, weakness,
and/or cramps with CK of>10 the ULN)
Rhabdomyolysis
Creatine Kinase >10,000 IU/L, or
Creatine Kinase >10 ULN with an in serum
creatinine or requiring IV hydration therapy
The risk of myopathy increases with respect to:
Age (>80 years; especially in women)
Multisystem diseases, DM with CKD, Multiple
myeloma, Surgery, Alcohol, Medications
Reprinted from McKenney JM, et al. Am J Cardiol. 2006;
97:89C94C, with permission from Elsevier.
82
Assess renal function before initiating Rx. Statin can
be used in patients with CKD
No routinely monitor Sr. Creatinine, U Albumin
Some statins need dose adjustment
Routine neurologic monitoring is not needed
With symptoms of peripheral neuropathy, rule out
common causes DM, CKD, Ca, Hypo thyroid, B
12
Stop statin Rx. for 1 to 3 months and restart Rx.
Rule out common causes

Reprinted from McKenney JM, et al. Am J Cardiol 2006;
97:89C94C, with permission from Elsevier.
83
High TG
Therapeutic Lifestyle Change
Add on drug Statin, Niacin
Therapy of Choice : Fibrate
Drug Therapy
84
Mode of Action PPAR -o Agonists
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 & Apo A II
85
Fasting TG Level TG < 150
Fasting TG Level
Normal
< 2 RF
TG >150, No CHD
TG > 150, CHD +
TG > 500, CHD +/-
Diet Modify
Diet + Fibrate
2 or > RF
Diet + Fibrate + Niacin
Diet + Fibrate + Statin
86
1. Wierzbicki AS et al. QJM 1997;90:631634
2. Wiklund O et al. Am J Med 1993;94:1320
M
e
a
n

%

c
h
a
n
g
e

f
r
o
m

b
a
s
e
l
i
n
e

-41
20
-17
-37
17
-42
-50
-40
-30
-20
-10
0
10
20
30
LDL-C HDL-C TG LDL-C HDL-C TG
Simvastatin + Fenofibrate Pravastatin + Gemfibrozil
87

88
Major actions
Lower TG 2050%,VLDL synthesis
Raise HDL-C 1020%
LDL (TG is N), LDL (TG is )
Increase the SDL particle size (less AVD)
Side effects
Dyspepsia, gallstones, myopathy, Abn. LFT
Contraindications
Severe renal or hepatic / biliary disease
89
Drug Dose
Clofibrate 1000 mg BID
Benzfibrate 200 mg BID
Gemfibrozil 600 mg BID
Fenofibrate 200 mg OD
Fenofibrate micronized 160 mg OD
In Pregnancy Category C drugs
90
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 (cautiously use) combo in renal impairment
Teach the patient to recognize muscle symptoms
Discontinue therapy if muscle symptoms are
present and CK is >10 times the UNL
91
Low HDLc
Therapeutic Lifestyle Change
Add on drug - Fenofibrate
Therapy of Choice : Niacin
Drug Therapy
92
Prevalence of coronary heart disease and its risk factors in Asian Indians
Atherosclerosis , Rosemount , IL Oct 6-11 , 1991
120
86
100
80
60
40
20
0
14
95
5
Asian Indian
males
Asian Indian
females
% 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
Journal, Ind. Acad. clin. med vol 2 Jul-Sept 2001
Only 14% of Asian Indian males & 5% of females have Optimal HDL
93
Smoking
Obesity (visceral fat), Physical inactivity
Very high Carbohydrate diet
Type II Diabetes
Hypertriglyceridemia
Drugs : -blockers, Androgenic steroids
and androgenic progestins
94
HDL
Serum VLDL
results in reduced
lipolysis to LDL
Serum LDL
VLDL
Decreases hepatic production of VLDL and of Apo B
VLDL
secretion
Apo B
Hepatocyte Systemic Circulation
Mobilization of FFA
TG
synthesis
VLDL
LDL
95
Adapted from Knopp RH. N Engl J Med 1999;341:498-511..
0 1 g / d 2 g / d 3 g / d
Baseline
-15%
12.5%
25%
-30%
HDL-C with Niaspan

TG with Niaspan

TG with crystalline niacin
LDL-C with Niaspan

LDL-C with crystalline niacin
35%
HDL-C with crystalline niacin
96
Products available
Immediate-release, 14 g/d, Sustained Release 3 g/d
Extended-release (Niaspan

) 12 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
97
3.21
3.78
1.00
2.41
Low HDL cholesterol
<47 mg/dl
High HDL cholesterol
>47 mg/dl
Low total cholesterol
<212 mg/dl
High total cholesterol
>212 mg/dl
The Physicians Health Study
98
Reprinted from Castelli WP. Can J Cardiol. 1988;4:
5A10A, with permission from Pulsus Group Inc.
0
1
2
3
220 160 100 mg/dL
85
65
45
25
LDL Cholesterol (LDL-C)
C
o
r
o
n
a
r
y

A
r
t
e
r
y

D
i
s
e
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e












(
C
A
D
)


R
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R
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99
Less than 45 mg of HDLc is a low value
Majority of Indians (90%) have low HDL
Targets of therapy
Achieve LDL goal
Waist and weight reduction (in pts with MS)
N-HDL goal (30+ LDL goal) should be achieved
Consider Niacin and Fibrate
Increase Physical activity
Smoking cessation
In Pregnancy Category C drug
100
1. Guyton JR, Capuzzi DM. Am J Cardiol 1998;82:82U84U
2. Jacobson TA et al. Am J Cardiol 1994;74:149154
-39
31
-36
-40
28
-30
-50
-40
-30
-20
-10
0
10
20
30
40
LDL-C HDL-C TG LDL-C HDL-C TG
Simvastatin + Niacin Fluvastatin + Niacin
M
e
a
n

%

c
h
a
n
g
e

f
r
o
m

b
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101
-30%
-20%
-10%
0%
10%
20%
30%
-40%
-30%
-20%
-10%
0%
10%
20%
30%
Wolfe ML et al. Am J Cardiol 2001;87:476-479.
% Change
1 gram daily 2 grams daily
LDL-C HDL-C TG LDL-C HDL-C TG
27%
23%
30%
-8%
24%
24%
102
103
104
Placebo S + N + AV S + N
0
5
10
15
20
25
Brown BG et al. N Engl J Med 2001;345:1583-1592.
AV
Coronary Death, MI, Stroke, or Revascularization
89%
Reduction
21.4
2.6*
14.3
*P<0.05
vs Placebo
23.7
105
Liver
CE
A1
CE
CE
FC
FC
LCAT
FC
Bile
SR-BI
A1
Macrophage
FC
ABCA1
CE,TG
LDLR
B
CETP
VLDL/LDL
A1=apolipoprotein A1
ABCA1=ATP-binding cassette transporter A1
CE=cholesterol ester
CETP=cholesterol ester transfer protein
FC=free cholesterol
LCAT=lecithin cholesterol acyltransferase
LDL=low-density lipoprotein
LDLR=LDL receptor
SR-BI=scavenger receptor class-B, type I
TG=triglyceride
VLDL=very low density lipoprotein
106
Adapted from Brewer HB et al. Am J Cardiol 2003;
92:10K-16K, with permission from Elsevier.
LCAT
LCAT
LPL
LPL
LPL
HL
Oxidation
Macrophage
CD36
SR-A
Arterial Wall
Nascent
HDL
ABCA1
CETP
Recycling
HL
107
Reproduced from Bays H. Expert Rev Cardiovasc Ther
2004;2:89-105, with permission from Future Drugs Ltd.
Adiposopathy
TG
TG
Renal clearance
Fatty liver
CETP
CETP
Small
dense LDL
| FFA
Lipases
TG
Cholesterol
Cholesterol
TG
Lipases
TG
Small
dense HDL
108
HDL-C LDL-C
-80
-60
-40
-20
0
20
40
60
80
C
h
a
n
g
e

%

Bays H et al. Expert Opin Pharmacother 2003;4:1901-1938.
Torcetrapib 120 mg/d
monotherapy
Torcetrapib 90 mg/d +
atorvastatin 1080 mg/d
109
Acute (parenteral) therapies
Apo A1 Milano/phospholipid complexes
Apo A1 mimetic peptides
Large unilamellar vesicles (LUVs)
Delipidated HDL
Apo A1 isolated from human plasma and
phosphatidylcholine derived from soybean
Potential Strategies
110
Net Effect - + LDL-C
Gall Bladder
LDL Receptors
VLDL and LDL removal
| Cholesterol 7-o hydroxylase
Conversion of cholesterol to BA
BA Secretion
Liver
BA Excretion
Terminal Ileum
Bile Acid
Entero hepatic Recirculation
Reabsorption of
bile acids
111
Major actions
Reduce LDL by 1530%
Raise HDL by 35%
May increase TG
Side effects
GI distress / constipation / nausea
Decreased absorption of other drugs
Contra indications
Dysbeta Lipoproteinemia,
Biliary Obstruction
TG (Specially >400 mg/dL)
112
Drug Dose Range
Cholestyramine 416 g
Colestipol 520 g
Colesevelam 2.63.8 g

In Pregnancy Category B drugs
113
114
Reverse Cholesterol Transport
Anti-oxidant effects
Anti-inflammatory effects
Anti-coagulant effects
Improve endothelial function

115
Nicotinic acid receptor HM74A
Niacin effects the reduction of FFA mobilization
from adipocytes
Niacin activates cutaneous receptors
Prostaglandin D
2
, which results in flushing
A selective prostaglandin D
2
antagonist
Laropiprant inhibit niacin-induced flushing
Niacin + Laropiprant (Tredaptive [1000+20])

Pike NB. J Clin Invest. 2005;115:34003403.
116
Statins
Erythromycin
Clarithromycin
Itraconazole
Cyclosporine
Diltiazem
Gemfibrozil
HIV Antivirals
Grapefruit Juice
Fibrates
Statins
Ezetimibe
Cyclosporine
Colchicine
Loparamide
Warfarin
Niacin
OHA
Sitagliptin
Amlodipine
Ethanol
HIV Antivirals
117
Colesevelam (BAR)
Phytosterols (Stanols)
Niacin + Laropiprant to reduce flushing
Torcetrapib CETP inhibitor to HDL
Avasimibe ACAT inhibitor
Mevinolin mRNA inducers LDL-R
Squalene synthase inhibitors Better than Statins
Drugs decreasing Apo B synthesis
Dual PPAR o and agonist Ragaglitazar



118
Parameter Rosuvastatin Atorvastatin
LDL Reduction More Moderate
HDL Increase More Moderate
TG Reduction More Moderate
Survival years post MI Same Same
CMIT Reduction More Moderate
Dosage 10 mg 20 to 80 mg
Reno protection Not proved Proven
Safety and ADR Same Same
Muscle penetration Less More
STELLAR , ARTMAP , PLANET I and II , URANUS, LUNAR trials
119
Generic Name Brand Name
Rosuvastatin Rosutec, Turbovas, Restolip
Atorvastatin TG-TOR, CAD, Aztor

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, Niaspan, Nicovas
120
1. CAD, CKD, PAD, CVD are all one and the same ASCVD
2. Dyslipidemia must prompt us for evaluating total CMR
3. 95% of dyslipidemia cases secondary Look for them
4. Dyslipidemia teams up with DM, HT, MS to cause havoc
5. LDL is the primary target 100 preferably < 70 mg%
6. Statins are the wonder drugs Be aggressive - Prevent
7. The sheet anchor of Rx is any Statin and TLC is a must
8. There is a lot beyond LDL reduction and beyond statins
9. Fibrates and Niacin are good add on for the residual risk
10. Dyslipidemia drugs are very safe Risks are over blown
121
Now, we have an unparalleled
opportunity to prevent ASCVD
122
123