DISLIPIDEMIA

Prof. Dr. WH. Sibuea, Sp.PD

Bagian Ilmu Penyakit Dalam FKUKI

Mortality from CVD and CHD in Selected Countries

Rate per 100,000 Population (men aged 3574 years)
1500

CVD deaths
CHD deaths

1000

500

0
Russia Poland Finland New England/ USA
Zealand Wales

Italy

Spain

Japan

(Adapted from 1998 World Health Statistics)

Is Lower Better? Lower Cholesterol Levels

are Associated with Lower Mortality Rates

Mortality rate per 1000 men

18
16
14
12
10
8
6
4
2
0
3.62
(140)

4.14
(160)

4.65
(180)

5.17
(200)

5.69
(220)

6.21
(240)

6.72
(260)

Serum total cholesterol, mmol/L (mg/dL)

MRFIT study. Martin et al. Lancet 1986;ii:933936.

7.24
(280)

7.75
(300)

Death rate from CHD/1000 men

Relationship of Serum Cholesterol to Mortality

(Seven Countries Study)
35
Northern Europe

30
25

United States

20
15
Southern Europe, inland

10
5

Serbia

Southern Europe, Mediterranean

Japan

0
2.60

3.25

3.90

4.50

5.15

5.80

6.45

7.10

7.75

8.40

9.05

Serum total cholesterol (mmol/l)

(Adapted from Verschuren et al., 1995)

Cholesterol A Modifiable Risk Factor ?

In the USA:
97 million people have total cholesterol
> 200mg/dl (5.2mmol/l)
38 million people have total cholesterol
> 240mg/dl (6.2mmol/l)
10% reduction in total cholesterol results in:
15% reduction in CHD mortality (p<0.001)
11% reduction in total mortality (p<0.001)
Total cholesterol is a modifiable CV risk factor
LDL-C is the primary target to prevent CHD
Intensity of intervention depends on total CV risk

Risk Factors for Cardiovascular

Disease

Modifiable
Smoking
Dyslipidaemia
raised LDL cholesterol
low HDL cholesterol
raised triglycerides
Raised blood pressure
Diabetes mellitus
Obesity
Dietary factors
Thrombogenic factors
Lack of exercise
Excess alcohol consumption

Non-modifiable

Personal history
of CHD
Family history
of CHD
Age
Gender

Levels of Risk Associated with Smoking,

Hypertension and Hypercholesterolaemia
Hypertension
(SBP 195mmHg)

x3
x9

x4.5

x16
x1.6

Smoking

x6

x4

Serum cholesterol level

(8.5mmol/l, 330mg/dl)
(Adapted from Poulter et al., 1993)

Endothelial dysfunction:
Final common pathway in CV diseases
Hypertension

DM

Dyslipidemia

Tobacco

Oxidative Stress

Endothelial Injury
Myocardial
Infarction

Stroke
Renal disease

Erectile
Dysfunction

Normal Arterial Wall

Tunica adventitia
Tunica media
Tunica intima
Endothelium
Subendothelial connective
tissue
Internal elastic membrane
Smooth muscle cell
Elastic/collagen fibres
External elastic membrane

Pathogenesis of Atherosclerotic
Plaques
Endothelial damage
Protective response results in production of
cellular adhesion molecules
Monocytes and T lymphocytes attached to
sticky surface of endothelial cells
Migrate through arterial wall to subendothelial space
Macrophages take up oxidised LDL cholesterol
Lipid-rich foam cells
Fatty streak and plaque

Vasc. Cell ad. Mol.

Necrotic center
(cell debris, cholesterol crystal,
foam cells, calcium)
FIBROUS CAP
(smooth
muscle cells,
macrophages,
foam cells
lymphocytes,
collagen,
elastin,
proteoglycans)

media

The Tight Stenosis Is Not the Active

Lesion
A

B
A

Atheroma
Lumen

Lipid Core
Images supplied by Steven E. Nissen, MD, Cleveland Clinic.

Rupture
Site

Pathophysiology of ACS:
Disrupted Plaque
Thin cap
Plaque
rupture
High
macrophage
content
Large lipid core

Complete
Incomplete
coronary
coronary
occlusion
occlusion
Spontaneous lysis,
repair, and wall remodeling

Acute
MI

Temporary resolution
Unstable angina
of instability
or nonQ-wave
Future high-risk
MI
lesion

Adapted from Yeghiazarians et al. N Engl J Med. 2000;342:101-114.

Development of Atherosclerotic
Plaques
Fatty streak
Lipid rich plaque
Normal
Foam cells

Fibrous cap

Complex plaque

Thrombus

Lipid core

Clinical Manifestations of
Atherosclerosis

Coronary heart disease

Cerebrovascular disease

Angina pectoris, myocardial infarction, sudden

cardiac death
Transient ischaemic attacks, stroke

Peripheral vascular disease

Intermittent claudication, gangrene

Lipid dalam Plasma

- Asam Lemak
- Lemak netral ( trigliserida ) : 3 AL + 1 gliserol
- Fosfolipid :

Estergliserol + 2 AL dan fosfat,

fosfat inositol, fosfat kolin dll

- Sterol

Hormon steroid, cholesterol

Lipid dalam plasma dibawa oleh :

- Asam Lemak oleh albumin
- Cholesterol
- Trigliserid
- Fosfolipid

Dibawa oleh
lipoprotein

Structure of Lipoproteins
Free cholesterol
Phospholipid

Apolipoprotein

Triglyceride

Cholesteryl ester

Lipoprotein terdiri dari : inti hidrofobik : trigliserid dan ester kolesteril,

dikelilingi oleh fosfo lipid dan protein (apolipoprotein)

LIPOPROTEIN

* Very low density lipoproteins; ** Intermediate-density lipoproteins; *** Low

density lipoproteins; **** High density lipoproteins

Peningkatan Trigliserid (TG) menyebabkan meningkatnya transfer kolesterol

ester dari HDL ke VDL dan juga dari LDL ke VDL. Hal ini menyebabkan HDL
menurun dan partikel LDL kecil padat meningkat. Kolesterol ester transfer
protein.

Classification of Lipoproteins
Based on density:
Chylomicrons
Very low-density lipoprotein (VLDL)
Intermediate-density lipoprotein (IDL)
Low-density lipoprotein (LDL)
High-density lipoprotein (HDL)

LDL Cholesterol

Strongly associated with atherosclerosis and CHD

events
10% increase results in a 20% increase in CHD risk
Modified by other risk factors
low HDL cholesterol
smoking
hypertension
diabetes

Triglycerides

Associated with increased risk of CHD events

Link with increased CHD risk is complex

may be related to low HDL levels and highly

atherogenic forms of LDL cholesterol

May have accompanying dyslipidaemias

Normal triglyceride levels <200mg/dl
(2.3mmol/l)
Very high triglycerides (>1000mg/dl,
11.3mmol/l) increased pancreatitis risk

HDL Cholesterol
HDL cholesterol has a protective effect for risk
of atherosclerosis and CHD
The lower the HDL cholesterol level, the higher
the risk for atherosclerosis and CHD

low level (<35mg/dl, 0.9mmol/l) increases risk

HDL cholesterol tends to be low when

triglycerides are high
HDL cholesterol is lowered by smoking, obesity
and physical inactivity

Apolipoproteins
Main protein content of lipoproteins
Functions include:

facilitation of lipid transport

activation of three enzymes in lipid metabolism
lecithin cholesterol acyltransferase (LCAT)
lipoprotein lipase (LPL)
hepatic triglyceride lipase (HTGL)

binding to cell surface receptors

Exogenous Pathway of Lipid

Metabolism
Dietary
triglycerides
and cholesterol

Intestine

Chylomicron

LP lipase

Bile acids + cholesterol

LP lipase

TGs
TGs
Skeletal muscle

Chylomicron
remnant
Adipose
tissue

Liver
Remnant
receptor

Endogenous Pathway of Lipid

Metabolism
LPL

Lipoprotein lipase
d
Mo
LDL

IDL

LDL
receptor

Extrahepatic
Tisue
LPL
LPL

Hepatic lipase
Hepatic lipase

Liver

Macrophage

n
o
i
t
a
ific

VLDL
HDL

Effect of Lipid-lowering Therapies on Lipids

Therapy

TC

LDL

HDL

TG

Patient
tolerability

Bile acid
sequestrants

Down
20%

Down
1530%

Up
35%

Neutral or up

Poor

Nicotinic acid

Down
25%

Down
25%

Up
1530%

Down
2050%

Poor to
reasonable

Fibrates
(gemfibrozil)

Down
15%

Down
515%

Up
20%

Down
2050%

Good

Probucol

Down
25%

Down
1015%

Down
2030%

Neutral

Reasonable

Down
1530%

Down
2450%

Up
612%

Down
1029%

Good

Statins*

TCtotal cholesterol, LDLlow density lipoprotein, HDLhigh density lipoprotein, TG

triglyceride. * Daily dose of 40mg of each drug (cerivastatin 0.3mg)
(Adapted from Yeshurun 1995, Knopp 1999)

Mechanism of Action of Statins

Cholesterol Synthesis Pathway
acetyl CoA
HMG-CoA synthase
HMG-CoA reductase

HMG-CoA

X Statins
mevalonic acid

mevalonate pyrophosphate
isopentenyl pyrophosphate
geranyl pyrophosphate
ubiquinones

farnesyl pyrophosphate

Squalene synthase

squalene
cholesterol

dolichols

Pharmacokinetics of Statins
Statin

Metabolised
by CYP450

Protein
binding (%)

Lipophilic

Halflife (h)

lovastatin

Yes

>95%

Yes

~2

pravastatin

No

~50%

No

~2

simvastatin

Yes

958%

Yes

~3

atorvastatin

Yes

>98%

Yes

~15

cerivastatin

Yes

>99%

Yes

~3

fluvastatin

Yes

>98%

No

~3

(Adapted from Horsmans 1999, Vaughan et al, 2000)

Effects of Statins on Lipids

LDL-C
% change

HDL-C
% change

Triglycerides
% change

atorvastatin

-50

+6

-29

simvastatin

-41

+12

-18

pravastatin

-34

+12

-24

lovastatin

-34

+8.6

-16

cerivastatin

-28

+10

-13

fluvastatin

-24

+8

-10

Daily dose of 40mg of each drug (cerivastatin 0.3mg)

(Adapted from Knopp 1999)

4S Cardiovascular End Points Post-MI or Angina

Patients with Raised Cholesterol
Number of events
Outcomes

placebo
(n=2223)

simvastatin
(n=2221)

Risk
reduction (%)

p-value

Total mortality*

256

182

30

<0.001

Coronary death

189

111

42

<0.001

Major coronary events

622

431

34

<0.001

PCTA/CABG

383

252

37

<0.001

* primary end point

WOSCOPS Cardiovascular End Points

Subjects with no Previous MI but Raised
Cholesterol
Number of events
Outcomes

placebo
(n=3293)

Non-fatal MI/CHD death*

CHD death
Non-fatal MI
PCTA/CABG
Stroke
All cardiovascular deaths
Total mortality#

248
52
204
80
51
73
135

pravastatin
(n=3302)

Risk
reduction (%)

p-value

174
38
143
51
46
50
106

31
28
31
37
0
32
22

<0.001
ns
<0.001
0.009
ns
0.033
0.051 ns

* primary end point

#
study not powered to detect differences in this end point