1. LIPIDS in primary care

4. •
•
•
•
•
•
Lipoprotein metabolism
LDL
TGL
HDL
Current guidelines
Case discussion

5. Lipoprotein metabolism

6. 
What are the important
components (two) of
lipids in the plasma ?
1. Ester. Cholesterol (EC)
2. Triglycerides (TG)

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


7. TG
EC
Apoprotein boat
1.
2.
3.
4.
Make the lipids soluble and transportable
Structural Integrity of the lipoprotein
Act as ligands for cell receptors
Activate enzymes such as LPL, LCAT as cofactors

9. Cholesterol biosynthesis

10. Structure of lipoprotein
INTEGRAL APOPROTEINS
CHOLESTEROL
ESTERS
MONOLAYER OF PHOSPHOLIPID
AND CHOLESTERLOL
CORE
TRIGLYCERIDES
PERIPHERAL APOPROTEINS

11. The Lipoprotein Particles

12. Lipemic Turbid Serum

13. The Atherogenic Particles
Measurements
Chylo M
VLDL VLDLR
TG-rich lipoproteins
Apolipoprotein B
Non-HDL-C
IDL
LDL Lp(a) SLDL
The smaller the particle
The greater is the danger

14. Fat
apo B-48
CCK
Bile salts
Duodenum
Chylomicron
Micelles
ACAT
Enterocytes
apo-C
apo-E
Lacteal
Thoracic duct
Systemic circulation

15. LDL-R
Chylomicron remnant receptor
apo-B-48
VLDL
apo-E
apo-C
Liver
apoE
Chylomicron
Adipocyte
Chylomicron remnant
When TGs < 20% remaining, they loose apoC

16. apo-B-100
Liver
VLDL
apo-B-100
TGs <50%
Remains
attached
to LPL
LPL
VLDL Remnant
TGs <30%
Cell wall
Aldosterone
Cortisol
Sex hormones
Adipocyte &
Myocyte
VLDL
LDL-R
IDL
TGs < 10% Loses apoE & apoC
LDL
apoB-100

17. Chylomicrons and VLDL

18. •
•
•
•
•
•
Lipoprotein metabolism
LDL
TGL
HDL
Current guidelines
Case discussion

21. Havoc by LDL at Endothelium
Vessel Lumen
Monocyte
LDL
Adhesion
Molecules
Cytokines
Macrophage
21
Ross R. N Engl J Med 1999;340:115-126.
MCP-1
LDL
Modified
LDL
Foam Cell
Endothelium
Intima
Growth Factors
Metalloproteinases
Cell Proliferation
Matrix Degradation

23. Statin Evolution
PROVE IT 22
CARDSTIME
AZZ
SEARC
ALLHAT
LIPID –
H
AFCAPS/TexCA
REVERSAL
IDEA
Post CABG PS MIRACL PROSPE
R
ASCOT TNT L
CARE
FLORIDA
4S
HP
MARS WOSCOPS
S
1991
1993 1994 1995
Pravastati
n
NCEP
Approved (ATP II)
Simvastati
n
Approved
1997
Atorvastatin
Approved
Cervastatin
Approved
1999
2001
20032004
Ezetimibe
Approved
NCEP
(ATP III)
Cervastatin
Withdrawn
Rosuvastati
n Approved

24. Relation Between CHD Events and
LDL-C in Recent Statin Trials
30
4S-PI
2° Prevention
25
4S-Rx
20
% with
LIPID-Rx
15
CHD event
CARE-Rx
10
LIPID-PI
CARE-PI
1° Prevention
WOSCOPS-PI
AFCAPS/TexCAPS-PI
5
AFCAPS/TexCAPS-Rx
0
90
110
130
150
WOSCOPS-Rx
170
190
Mean LDL-C level at follow-up (mg/dL)
PI=placebo; Rx=treatment
Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
4S Study Group. Lancet. 1995;345:1274-1275.
Sacks FM et al. N Engl J Med. 1996;335:1001-1009.
Downs JR et al. JAMA. 1998;279:1615-1622.
Tonkin A. Presented at AHA Scientific Sessions, 1997.
210

25. Summary of Effects of Lipid Lowering on Lipids
and Clinical Events in Recent Statin Trials
%+
Nonfatal
8
10
CHD All-cause
5
5 MI/CHD
5
death mortality
LDL-C
TC
death
0
HDL-C
-5
-10
-9
-15
-20
-20
-20 -20
-22
-25
-24
-25
-26
-30
-28
-30
-31
-35
-33
-34
-35
-40
-42
-45
WOSCOPS (N=6,595) 4S (N=4,444)
CARE (N=4,159)
1o
prevention
N=number enrolled.
2o
prevention
2o
prevention

26. Lipid Profile Report
LIPIDS ESTIMATED
TOTAL CHOLESTEROL (TC)
HDLc
LDLc
VLDLc
TRIGLYCERIDES (TG)
Chylomicrons
PP
26
VLDL
Fasting

27. Lipid profile report
• TC 200 mg/dl
• HDL 40 mg/dl
• TGL 150 mg/dl
• TC 200 mg/dl
• HDL 40 mg/dl
• TGL 450 mg/dl
• VLDL = 30 (TGL/5)
• LDL =130 (TC-HDL-VLDL)
• VLDL = 90 (TGL/5)
• LDL =70(TC-HDL-VLDL)
Non HDL

28. NON HDL C=Total Cholesterol– HDL cholesterol
VLDL
IDL
VLDL
IDL
LDL
LDL
SMALL DENSE
NON HDL GOAL: 30mg above LDL goal
NON
HDL
APO
B

29. ATP III
•
•
•
•
•
Obtain a fasting lipid profile
CHD risk factor
Major risk factors (ABC HF)
Target LDL
TLC

32. LDL mass may underestimate
atherogenic risk
Up to 70%
more particles
100 mg/dL
100 mg/dL
Cholesterol
balance
Adapted from Otvos JD, et al. Am J Cardiol 2002; 90 (suppl):22i-29i

33. Small Dense LDL and CHD:
Potential Atherogenic Mechanisms
• Increased susceptibility to oxidation
• Increased vascular permeability
• Decreased affinity for LDL receptor
• Association with insulin resistance
syndrome
• Association with high TG and low HDL
Austin MA et al. Curr Opin Lipidol 1996;7:167-171.

36. Statin Action
36

37. Time Course of Statin Effects
LDL-C
lowered*
Inflammation
reduced
Endothelial
function
restored
Days
37
Vulnerable
plaques
stabilized
Ischemic
episodes
reduced
* Time course established
Cardiac events
reduced*
Years

38. Dual Inhibition
LDL
apoB100
Liver
Statin
Duodenum
X
VLDL
apoB100
X
Ezetimibe
Jejunum
Ileum
CM
Remnant
apoB48
38
CM
apoB48
Colon

39. Statin Dose Required to Achieve
45–50% Reduction
10
20
40
Prava
Not achieved with maximum
licenced dose
Fluva
80 mg
Not achieved with maximum
licenced dose
Simva
Atorva
Rosuva
Adapted from Jones P.H. et al. Am J Cardiol 2003;92:152–160

40. Mean % Change in LDL-C from
Untreated Baseline Value
40
10 mg
40 mg
Atorvastatin
20 mg
Rosuvastatin
30 mg
Simvastatin
0%
-10%
-20% −3
-30%
7
-40% −6
−5
-50% −3
-60%
−46†
14% with
3 titrations
−6
−3
*
*
Jones PH, et al. Am J Cardiol. 2003;92:152–160.
−2
8
−7
−4
−7
9% with
2 titrations
18% with
3 titrations

41. Molecular pathway
EARLY
HIGH DOSE
Lipophylic statins better

42. Rosuvastatin: Additional binding
site with HMG-CoA
Rosuvastatin
Additional sulphone
binding site Arg568
Istvan and Deisenhofer Science 2001; 292:1160-1164

43. Liver effects - Benefit versus Risk
ALT >3 × ULN: Frequency by LDL-C reduction
Rosuvastatin (10, 20, 40 mg)
Occurrence of ALT >3×ULN (%)
Atorvastatin (10, 20, 40, 80 mg)
3.0
Simvastatin (40, 80 mg)
Lovastatin (20, 40, 80 mg)
2.5
Fluvastatin (20, 40, 80 mg)
2.0
1.5
1.0
0.5
0.0
20
30
40
50
LDL-C reduction (%)
Persistent elevation is elevation to >3 x ULN on 2 successive occasions
Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K
60
70

44. Muscle effects - Benefit versus Risk
Occurrence of CK >10 × ULN (%)
CK >10 x ULN: Frequency by LDL-C Reduction
Rosuvastatin (10, 20, 40 mg)
Atorvastatin (10, 20, 40, 80 mg)
Simvastatin (40, 80 mg)
Pravastatin (20, 40 mg)
Cerivastatin (0.2, 0.3, 0.4, 0.8 mg)
3.0
2.5
2.0
1.5
1.0
0.5
0.0
20
30
40
50
LDL-C reduction (%)
Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K
60
70

45. Inadequate Achievement of NCEP ATP III
Treatment Goals, Especially among Patients at
Highest Risk
100%
80%
70%
60%
40%
40%
39%
18%
20%
0%
Low Risk
n=
High Risk
CHD
861
1,924
1,352
All
Patients
4,137
Drug therapy included statins (fluvastatin, lovastatin, pravastatin,
simvastatin), gemfibrozil, bile acid sequestrants, niacin, psyllium fiber, and
combination drug therapy.
Adapted from Pearson TA et al. Arch Intern Med 2000;160;459-467.

46. Statin Therapy
Residual CVD Events
CTT Meta-Analysis of 14 Statin Trialsa
40
Major Vascular
Event Rateb, %
30
34.9
Control
Treatmentc
CVD Risk Higher Than Patients
With No Diabetes on Placebo
29.6
24.8
19.4
20
Residual
Risk
10
Residual
Risk
0
a4.3-year
bNonfatal
cEvent
Diabetes
No Diabetes
mean follow-up of 18 686 Diabetes
patients with diabetes; n = 71 370 patients with noNo Diabetes
diabetes
MI, CHD death, stroke, or coronary revascularization
rate per 1 mmol/L (39 mg/dL) reduction in LDL-C
CTT Collaborators. Lancet. 2008;371:117-125.

48. •
•
•
•
•
•
Lipoprotein metabolism
LDL
TGL
HDL
Current guidelines
Case discussion

49. 



Atherogenic
Dyslipidemia
Adiposity
High carbohydrate diet
Insulin resistance
Genetic predisposition
High
TG
pool
Renal clearance
TG
HL
TG
CETP
Apo
CIII
TG
CE
TG
LPL
TG TG
CE
Small
dense HDL
HL
TG TG
Apo E
CE
Apo B
TGRL
Remnants
CE
CETP
TG
TG
Small
dense LDL
HL
Bays H. Expert Rev Cardiovasc Ther 2004;2:89-105.

50. Role of Triglycerides:
PROVE IT-TIMI* Trial1
30-Day Risk Death, MI,
Or Recurrent ASC(%)
• Elevated triglyceride level ≥200 mg/dL increases the risk of death,
myocardial infarction or acute coronary syndrome significantly
LDL-C <70 mg/dL,
on statins
On – Treatment (mg/dL)
1. Fruchart JC, Sacks F, Hermans MP, et al. The Residual Risk Reduction Initiative: a call to action to reduce residual
vascular risk in patients with dyslipidemia. Am J Cardiol. 2008;102(10 Suppl):1K-34K.

55. TGL/HDL RATIO
• BELOW 3.8 FOR ASIANS 3.0
• GOOD USEFUL RATIO IN DIABETICS,
METABOLIC SYNDROME
• ABNORMAL RATIO INDICATES INCREASE
IN SMALL DENSE LDL ALTHOUGH BLOOD
LEVELS OF LDL IS NORMAL OR LOW
JACC 2005

58. •
•
•
•
•
•
Lipoprotein metabolism
LDL
TGL
HDL
Current guidelines
Case discussion

59. LDL-C & HDL-C v/s CAD Risk
Coronary Artery Disease
(CAD) Relative Risk
Framingham Heart Study
3
2
25
1
45
65
0
85
220
160
100 mg/dL
LDL Cholesterol (LDL-C)
59
Reprinted from Castelli WP. Can J Cardiol. 1988;4:
5A–10A, with permission from Pulsus Group Inc.

60. Antiatherogenic Actions of HDL-C
Reverse
Cholesterol
Transport
Cellular
Cholesterol
Efflux
Anti-infectious
Activity
Anti-inflammatory
Activity
HDL-C
Antithrombotic
Activity
Endothelial
Repair
Antiapoptotic
Activity
Antioxidative
Activity
Vasodilatory
Activity
Adapted from Chapman MJ et al. Curr Med Res Opin. 2004,20:1253-1268, with permission from LibraPharm, Ltd.
Assmann G et al. Annu Rev Med. 2003,54:321-341.

61. Relationship Between
Changes in
LDL-C and HDL-C Levels
and CHD Risk
1% decrease
in LDL-C reduces
CHD risk by
1%
1% increase
in HDL-C reduces
CHD risk by
3%
Third Report of the NCEP Expert Panel. NIH Publication No. 01-3670. 2001.
http://hin.nhlbi.nih.gov/ncep_slds/menu.htm

62. Nicotinic Acid – Mechanism of Action
Mobilization of FFA
Apo B
VLDL
TG
synthesis
VLDL
VLDL
secretion
Serum LDL
LDL
Liver
Hepatocyte
Serum VLDL
results in reduced
lipolysis to LDL
HDL
Circulation
Systemic Circulation
Decreases hepatic production of VLDL and of apo B

63. Change from Baseline (%)
Lipid Effects of Niacin
Extended-Release (ER)
30
20
10
0
-10
-20
-30
-40
-50
HDL-C
30
-22
-21
10
-3
-5
-8
-12
-13
-16
-17
-14
-21
LDL-C
Lp(a)
-25
-30
-26
-32
-39
500
•
21
16
29
24
Lipid effects
– Most potent agent for
1000
1500
mg
2000
2500
-44
TG
3000
HDL: 20%+; nonlinear
– Favorable effects on LDL-particle density
–
LDL (linear), TG, and Lp(a)
•
Tolerability with concomitant statin therapy
– No change in rate of liver adverse effects or myositis versus statin monotherapy
Capuzzi DM et al. Am J Cardiol 1998;82:74U-81U.

64. Niacin-Induced Flushing Limits
Niacin Utilization
100%
Percent Users
80%
>1500 mg
1001-1500 mg
751-1000 mg
501-750 mg
≤500 mg
60%
40%
20%
0%
4 wk
8 wk
12 wk
24 wk
1y
N=14,386
N=6,349
N=5,277
N=5,402
N=2,104
Average Daily Dose of ER Niacin Prescription Refills at Fixed Time Intervals Niaspan discontinuation rate high, adherence rate low,
dose less optimal. Only 47% of all ER niacin users reached recommended maintenance dose of 1000 mg or higher, and only 77%
reached the dose of 2000 mg during follow-up. Clinical evidence showed that nonadherence for medication leads to the prevalence
of the disease and discontinuation from medication increases patient mortality risk.
1. Retrospective cohort study using administrative claims data from 2000 to 2003 Ingenix Lab/Rx Database™. Kamal-Bahl et al. Abstract presented at
AHA 7th Scientific Forum on Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke, Washington D.C., May, 2006.
2. Ho PM, et al. Arch Intern Med. 2006;466:1836–1841. 3. Ho PM et al. Arch Intern Med. 2006;166:1842–1847.

65. AIM-HIGH
Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides
and Impact on Global Health Outcomes
3300 patients
4 year follow-up
Primary End Point
Key Secondary End Points
Composite of CHD death, nonfatal
MI, ischemic stroke, or hospitalization
for high-risk ACS with objective
evidence of ischemia
Composite of CHD death, nonfatal MI,
or ischemic stroke
ClinicalTrials.gov Identifier: NCT00120289

66. ATHEROGENIC
THROMBOGENIC
DUAL PATHOGEN
RISK:
2-4 FOLD
WTH LOW HDL:
8 FOLD
WITH HIGH LDL:
12 FOLD
ALL THREE:
25 FOLD

67. RESIDUAL RISK DUE TO
•
•
•
•
•
•
LOW HDL
HIGH TRIGLYCERIDES
SMALL DENSE LDL
NON HDL CHOLESTEROL
Hs CRP
LIPOPROTEIN (a)

68. Rosuvastatin achieves significantly
greater increase in HDL-C
Mean change in HDL-C
from baseline (%)
12
9.6%*
10
8
*
Rosuvastatin
7.7%
Pravastatin
6
5.7%
4
5.3%
2
3.2%
6.8%
Simvastatin
5.6%
Atorvastatin
2.1%
0
10
20
40
80
Dose, mg (log scale)
*P<0.002
RSV 20 mg vs ATV 20, 40 & 80 mg; RSV 40 mg vs ATV 40 & 80 mg
Jones P.H. et al. Am J Cardiol 2003;92:152–160

69. RESIDUAL RISK
THE ISSUES
• Whether treating residual risk is really
needed when LDL goal is achieved ?
• How to treat it?
• Is there evidence that treating residual
risk decreases clinical events?

71. 4 major statin benefit groups were identified for whom
the ASCVD risk reduction clearly outweighs the risk of
adverse events.
1) with clinical ASCVD,
2) primary elevations of LDL–C >190 mg/dL,
3) diabetes aged 40 to 75 years with LDL– C 70 to189
mg/dL and without clinical ASCVD, or
4) without clinical ASCVD or diabetes with LDL–C 70
to189 mg/dL and estimated 10-year ASCVD risk
>7.5%.

72. •
•
•
•
•
•
Lipoprotein metabolism
LDL
TGL
HDL
Current guidelines
Case discussion

73. Major recommendations for statin therapy for
ASCVD prevention

74. Major recommendations for statin therapy for
ASCVD prevention (Conti.... from prev. page)

76. Initiating statin therapy in individuals with
clinical ASCVD

77. Initiating statin therapy in individuals
without clinical ASCVD

78. Initiating statin therapy in individuals
without clinical ASCVD (Conti.... from prev. page)

79. Statin Therapy: Monitoring therapeutic response
and adherence

80. Now, we have an unparalleled
opportunity to prevent ASCVD
80