Beruflich Dokumente
Kultur Dokumente
Dyslipidaemia and
Diabetes
Section 2 -
Section 3 -
Section 4 -
Section 5 -
Section 6 -
Section 7 -
Section 8 -
Section 9 -
Section 1
CVD deaths
CHD deaths
500
an
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p
w
ed
N
en
et
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er
la
n
ds
A
us
tr
al
ia
m
an
G
er
U
S
om
an
ia
P
ol
an
d
S
co
tl
an
d
1000
150
125
100
75
50
25
0
<204
205234
235
264
265294
>295
35
Northern Europe
30
25
United States
20
15
Southern Europe, Inland
10
5
Serbia
0
2.60
3.25
3.90
4.50
5.15
5.80
6.45
7.10
7.75
8.40
9.05
Cholesterol: A Modifiable
Risk Factor
In the USA, 37% (102 million) have elevated
total cholesterol (>200 mg/dL, 5.2 mmol/L)1
In EUROASPIRE II, 58% of patients with
established CHD had elevated cholesterol
(5 mmol/L, 190 mg/dL)2
10% reduction in total cholesterol results in:
15% reduction in CHD mortality (p<0.001)
Modifiable
Non-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
x3
x9
x4.5
x16
Smoking
x1.6
x6
x4
Serum cholesterol level
(8.5 mmol/L, 330 mg/dL)
Section 2
Classification of Dyslipidaemias:
Fredrickson (WHO) Classification
Phenotype Lipoprotein
Serum
Serum Atherogenicity Prevalence
elevated
cholesterol triglyceride
I
Chylomicrons Normal to
None seen
Rare
+++
Common
IIa
LDL
IIb
+++
Common
III
IDL
+++
Intermediate
IV
VLDL
Normal to
Common
VLDL and
Normal to
chylomicrons
Rare
Normal
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 attach 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
attracts monocytes
and T lymphocytes
which adhere to
endothelial cells
CELLULAR
ADHESION
MOLECULES
induces cell
proliferation and a
prothrombic state
Endothelial Dysfunction in
Atherosclerosis
Upregulation of
endothelial
adhesion molecules
Leukocyte
adhesion
Increased
endothelial
permeability
Migration of
leukocytes
into the
artery wall
Migration of
smooth
muscle cells
Formation
of foam cells
Activation of T cells
Adherence and aggregation of
platelets
Adapted from Ross R. N Engl J Med 1999;362:115126
Accumulation of
macrophages
Formation of
necrotic core
Thinning of the
fibrous cap
Haemorrhage from
plaque
microvessels
Rupture of
the
fibrous cap
Adapted from Ross R. N Engl J Med 1999;362:115126
Growth of thrombus
Blood Flow
Intraplaque thrombus
Lipid pool
Clinical Manifestations of
Atherosclerosis
Coronary heart disease
Angina pectoris, myocardial infarction,
sudden cardiac death
Cerebrovascular disease
Transient ischaemic attacks, stroke
Peripheral vascular disease
Section 3
Structure of Lipoproteins
Free cholesterol
Phospholipid
Apolipoprotein
Triglyceride
Cholesteryl ester
Classification of Lipoproteins
Based on density:
Chylomicrons
Very low-density lipoprotein (VLDL)
LDL-Cholesterol
Strongly associated with atherosclerosis
and CHD events
10% increase results in a 20% increase
in CHD risk
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
highly atherogenic forms of LDL-cholesterol
hyperinsulinaemia/insulin resistance
procoagulation state
hypertension
abdominal obesity
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
Apolipoproteins
Main protein content of lipoproteins
Functions include:
Facilitation of lipid transport
Activation of three enzymes in lipid
metabolism
lecithin cholesterol acyltransferase
(LCAT)
Dietary
Dietary
triglycerides
triglycerides
and
and cholesterol
cholesterol
Chylomicron
Chylomicron
LP
LP lipase
lipase
Liver
Liver
Skeletal
Skeletal muscle
muscle
FFA
Chylomicron
Chylomicron
remnant
remnant
Remnant
Remnant
receptor
receptor
to
to atheroma
atheroma
Adipose
Adipose
tissue
tissue
LPL
LPL Lipoprotein
Lipoprotein lipase
lipase
HL
HL
LDL
LDL
LDL
LDL
receptor
receptor
LPL
HL
IDL
IDL
HL
LPL
Small
Small
VLDL
VLDL LPL
HL
Liver
Liver
Large
Large
VLDL
VLDL
Hepatic
Hepatic lipase
lipase
Reverse Cholesterol
Transport
cholesterol transport
Cell
membrane
SRB1
CE
CE
ABCA1
Liver
FC
LCAT
HDL
CETP
HDL3
LDL
receptor
VLDL, IDL, LDL
TG
Peripheral
tissues
FC
TG
CE
LCAT
CETP
Free cholesterol
Triglycerides
Cholesterol esters
Lecithin cholesterol acyl transferase
Cholesteryl ester transfer protein
Section 4
Lifestyle advice
Aim: TC<5 mmol/L and
LDL-C <3.0 mmol/L
Follow-up at 5-year intervals
TC 5 mmol/L and/or
LDL-C 3 mmol/L
Maintain lifestyle
advice with drug
therapy
National Cholesterol Education Program, Adult Treatment Panel III, 2001. JAMA 2001:285;24862497
Patients with
Initiate TLC*
Drug therapy
if LDL-C
considered if LDL-C
160 mg/dL
2 risk factors
(10-year risk 20%)
130 mg/dL
100 mg/dL
190 mg/dL
(160 189 mg/dL:
drug optional)
10- year risk 10
20%: 130 mg/dL
LDL-C
treatment
goal
<160 mg/dL
<130 mg/dL
<100 mg/dL
100 mg/dL = 2.6 mmol/L; 130 mg/dL = 3.4 mmol/L; 160 mg/dL = 4.1 mmol/L
LDL-cholesterol level
CHD or
CHD risk
equivalents
2 risk
factors
190 -
<2 risk
factors
Target
160
mg/dL
160 -
Target
130
mg/dL
130 -
Target
100
mg/dL
100 100 mg/dL = 2.6 mmol/L; 130 mg/dL = 3.4 mmol/L; 160 mg/dL = 4.1 mmol/L
National Cholesterol Education Program, Adult Treatment Panel III, 2001. JAMA 2001:285;24862497
NCEP
NCEP
ATP II
ATP III
8,612
14,713
71
19,555
23,663
21
Low
1,264
1,264
Total
29,431
39,640
35
High
Moderate
% increase in
drug-eligible
patients
Percentage of patients
100
of patients
received lipidmodifying therapy
80
39%
60
of patients receiving
lipid-modifying
therapy reached
NCEP ATP II
LDL-C goal
40
20
<20%
of CHD patients
who receiving
lipid-modifying
therapy reached
NCEP ATP II
LDL-C goal*
(n=4888)
(n=4137)
(n=1352)
Percentage of patients
100
80
60
61%
of high-risk
patients* received
lipid-modifying
therapy
51%
of patients
reached Joint
European TC
goal**
40
20
Section 5
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
Statins*
Down
1530%
Down
2450%
Up
612%
Down
1029%
Good
Down
1520%
Up
49%
Ezetimibe
Good
Adapted from Yeshurun D, Gotto AM. Southern Med J 1995;88(4):379391, Knopp RH. N
Engl J Med 1999;341:498511, Gupta EK, Ito MK. Heart Dis 2002;4:399409
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)
rosuvastatin
No
~90%
No
~19
atorvastatin
Yes
>98%
Yes
~15
simvastatin
Yes
958%
Yes
~3
pravastatin
No
~50%
No
~2
fluvastatin
Yes
>98%
No
~3
LDL-C
% change
HDL-C
% change
-52
+14
-10
-39
+6
-19
-38
+8
-19
-32
+2
-11
-22
+3
-12
TG
% change
Adapted from Takemoto M, Liao JK. Arterioscler Thromb Vasc Biol 2001;21:17121719
Section 6
WOSCOPS2
CARE3
LIPID4
AFCAPS/
TexCAPS5
HPS6
Existing
CHD
Patients
simvastatin
20 mg od
Yes
4444 male
and female,
aged 3570
pravastatin
40 mg od
No MI,
angina
(5%)
pravastatin
40 mg od
Yes
4159 male
and female,
aged 2175
pravastatin
40 mg od
Yes
9014 male
and female,
aged 3175
lovastatin
40 mg od
No
6605 male
and female,
aged 4573
simvastatin
40 mg od
Yes
Statin
ASCOT-LLA7 atorvastatin
10 mg od
In some
patients
6595 male,
aged 4564
20536 male
and female,
aged 4080
10305 male
and female,
aged 4079
Cholesterol
Raised
Follow-up
(years)
5.4
Raised
4.9
Average
5.0
Average
6.1
Average
5.2
Low/average
5.0
Low/average
3.3
4S1
Increasing
absolute CHD risk
CHD/high cholesterol
LIPID2
HPS3
CHD/average to high
cholesterol
CHD*/average to high cholesterol
CARE4
ASCOT-LLA5
WOSCOPS6
AFCAPS/TexCAPS7
*CHD or CHD risk equivalent, e.g. diabetes
CHD/average cholesterol
Some patients with CHD/
average cholesterol
No MI/high cholesterol
No CHD/average
cholesterol
4S Cardiovascular Endpoints
Number of events
Outcomes
placebo
(n=2223)
Risk
p-value
simvastatin
(n=2221) reduction (%)
Total mortality*
256
182
30
<0.001
Coronary death
189
111
42
<0.001
431
34
<0.001
PCTA/CABG
252
37
<0.001
383
* primary endpoint
Proportion alive
1.00
0.95
0.90
0.85
simvastatin
placebo
0.80
0.00
0.0
This
improvement
in survival is
accounted for
by the 42%
reduction in
coronary
death.
Outcomes
Non-fatal MI/CHD
death*
CHD death
Non-fatal MI
PCTA/CABG
Stroke
All cardiovascular
deaths
Total mortality#
placebo
(n=3293)
pravastatin
Risk
p-value
(n=3302) reduction (%)
248
174
31
<0.001
52
204
80
51
73
38
143
51
46
50
28
31
37
0
32
ns
<0.001
0.009
ns
0.033
135
106
22
0.051
* primary endpoint
# study not powered to detect differences in this endpoint
Shepherd J et al. N Engl J Med 1995;333:13011307
12
placebo (n=3293)
pravastatin (n=3302)
10
31%
relative
risk
reduction
p<0.001
8
6
4
2
0
3
Years
Outcomes
Non-fatal MI/CHD
death*
CHD death
Non-fatal MI
PCTA/CABG
Unstable angina
Stroke
placebo
(n=2078)
pravastatin
Risk
p-value
(n=2081) reduction (%)
274
212
24
0.003
119
173
391
359
78
96
135
294
317
54
20
23
27
13
31
ns
0.02
0.009
0.07
0.03
* primary endpoint
Sacks FM et al. N Engl J Med 1996;335:10011009
Incidence %
15
placebo
pravastatin
Change in risk,
24% reduction
p=0.003
10
0
0.0
Years
Outcomes
CHD death*
CVD death
All-cause mortality
CHD death or nonfatal MI
Any MI
PCTA or CABG
Hosp. for unstable
angina
Stroke
placebo
(n=4502)
pravastatin
(n=4512)
Risk
reduction (%)
p-value
373
433
633
715
287
331
498
557
24
25
22
24
<0.001
<0.001
<0.001
<0.001
463
708
1106
336
585
1005
29
20
12
<0.001
<0.001
0.005
204
169
19
0.048
* primary endpoint
LIPID. N Engl J Med 1998;339:13491357
10
24% risk
reduction
p<0.001
placebo
pravastatin
0
0
Outcomes
placebo
(n=3301)
Risk
lovastatin
p-value
(n=3304) reduction (%)
Fatal or non-fatal
MI + unstable
angina + sudden
cardiac death*
183
116
37
<0.001
Revascularisations
157
95
106
57
33
40
<0.001
0.002
87
60
32
0.02
Fatal and
non-fatal MI
Unstable angina
* primary endpoint
Cumulative incidence
0.07
0.06
placebo
lovastatin
37% risk
reduction
p<0.001
0.05
0.04
0.03
0.02
0.01
0.00
0.0
>5
Years of follow-up
Downs JR et al. J Am Med Assoc 1998;279:16151622
-0.0
-0.2
-0.4
-0.6
-0.8
-1.0
12
16
20
24
28
32
36 40
44 48
52
% in cholesterol reduction
Adapted from Gould AL et al. Circulation. 1998;97:946952
Incidence %
30
20
p<0.0001
placebo (n=10,267)
simvastatin
(n=10,269)
-13% RR
P=0.0003
-25% RR
10
p<0.0001
0
All-cause
mortality
Major vascular
events
All stroke
Outcomes
placebo
(n=5137)
atorvastatin
(n=5168)
154
100
0.64
0.0005
486
389
0.79
0.0005
247
178
0.71
0.0005
Non-fatal MI plus
fatal CHD
137
86
0.62
0.0005
121
89
0.73
0.0236
* primary endpoint,
Hazard
ratio
p-value
excludes silent MI
Section 7
Diabetes Mellitus
One of the most common non-communicable
diseases
Microvascular complications:
Retinopathy
Leading cause of adult blindness
Nephropathy
Accounts for 43% of new cases of ESRD
Neuropathy
6070% of patients with diabetes have nervous
system damage
Adapted from National Diabetes Statistics US 2000
Women
5.8
5.6
3.8
Men
DM
no
DM
DM
no
DM
3.2
3
1.6
Women
p<0.001
1.4
no
DM
DM
DM
no
DM
LDL-cholesterol (mmol/L)
2
1.8
Men
Women
p<0.001
p<0.001
1.6
Men
Men
3.4
5.2
1.2
p<0.001
3.6
5.4
1.4
p<0.001
DM
no
DM
DM
no
DM
HDL-cholesterol (mmol/L)
1.2
1
DM
no DM DM
no
DM
Triglycerides (mmol/L)
120
100
80
60
40
20
Prevalence (%):
54.9
22.9
2.6
2.3
9.4
8.0
30
25
20
15
10
5
0
No diabetes
Diabetes
CABG
PTCA
% change in mortality
10
0
-10
Men
Women
-20
-30
-40
-50
Diabetes
No diabetes
Adapted from Gu K et al. JAMA;281:12911297
Section 8
Insulin
Resistance
Atherosclerosis
Diabetes
Hypercoagulability
Dyslipidaemia
high TGs
small dense LDL
low HDL-C
Endothelial
Dysfunction
Defining Level
Abdominal obesity
(Waist circumference)
Men
Women
TG
HDL-C
Men
Women
Blood pressure
130/85 mm Hg
Fasting glucose
National Cholesterol Education Program, Adult Treatment Panel III, 2001. JAMA 2001:285;24862497
Insulin resistance
Central obesity
27
p<0.001
26.5
26
25.5
25
p<0.001
4
n=6055
n=690
G <140
mg/dL
IGT
n=158
G 200
mg/dL
Newly
diagnosed
diabetes
n=135
Known
diabetes
G - glucose
Section 9
Effect
75%
p-value
Comment
ns
Primary prevention;
post-hoc subgroup analysis
events
SENDCAP
65%
(bezafibrate)
events
VA-HIT
24%
(gemfibrozil)
events
DAIS
40-42%
(fenofibrate)
focal angio
changes
0.01
Specifically conducted in
Type 2 diabetes; post-hoc
analysis for IHD
0.05
Secondary intervention;
pre-planned subgroup
analysis
0.02
Specifically conducted in
Type 2 diabetes; mixed
primary and secondary
intervention; angio study
Frick MH et al. N Engl J Med 1987;317:12371245, Koskinen P et al. Diabetes Care 1992;15:820825,
Elkeles RS, Diamond JR, Poulter C et al. Diabetes Care 1998;21(4):641648, Rubins HB et al. N Engl
J Med 1999;341:410418, DAIS Investigators. Lancet 2001;357:905910
% LDL-C
lowering
% CHD risk
reduction
(overall)
% CHD risk
reduction
(diabetes)
25
37 (p<0.001)
43
28
23 (p<0.001)
25 (p=0.05)
4S3
(simvastatin; n=202)
36
32 (p<0.001)
55 (p=0.002)
LIPID4
(pravastatin; n=782)
25*
25
19
Primary prevention
AFCAPS/TexCAPS1
(lovastatin; n=239)
Secondary prevention
Patients
developing
diabetes
% risk
reduction
p-value
5974
139
30
0.042