Professional Documents
Culture Documents
Management of
Dyslipidaemia
Adapted from International Cardiovascular Disease Statistics 2003; American Heart Association
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
x3
x9
x4.5
x16
Smoking
x1.6
x6
x4
Serum cholesterol level
(>8.5 mmol/L, 330 mg/dL)
Adapted from: 1. American Heart Association. Heart and Stroke Statistical Update; 2002; 2. EUROASPIRE II
Study Group. Eur Heart J 2001;22:554572; 3. Gould AL et al. Circulation 1998;97:946952.
Baseline
LDL
(mg/dL)
4S
PROSPER
CARE
LIPID
HPS
ALERT
LIPS
AFCAPS
4444
5804
4159
9014
20536
2102
1677
6605
190
147
140
150
131
158
131
150
66
39
39
35
39
39
35
39
5.2
3.8
2.6
2.6
2.3
2.0
1.8
1.0
34
19
24
24
27
35
31
37
WOSCOPS
ASCOT-LLA
6595
10305
193
131
50
39
1.5
0.9
32
36
Study
LDL-C net
CHD
CHD
change
event
risk reduction
(mg/dL)* rate/year
(%)
CHD events refers to cardiac death or nonfatal MI, unless otherwise indicated.
*Placebo-subtracted change from baseline;
for placebo treated patients;
including silent MI plus resuscitated cardiac arrest;
including unstable angina.
1mmole/L LDL = 38.6 mg/dL
1% decrease
in LDL-C reduces
CHD risk by
1%
Third Report of the NCEP Expert Panel. NIH Publication No. 01-3670 2001.
http://hin.nhlbi.nih.gov/ncep_slds/menu.htm
1% increase
in HDL-C reduces
CHD risk by
3%
CHD
<2
160 -
130 -
100 -
Target
100
mg/dL
Target
70
mg/dL
70 Risk factors
High risk:
CHD or
CHD Risk Equivalents
LDL Goal
<100 mg/dl
(Option:
<70 mg/dl)
Initiate TLC
(Therapeutic
Lifestyle Changes)
100 mg/dl
10-20% risk
<130 mg/dl
(Option: <100
mg/dl)
130 mg/dl
Moderately risk:
160 mg/dl
<10% risk
Lower risk:
0-1 Risk Factor
130 mg/dl
100 mg/dl
(<100 mg/dL: consider drug
options)
130 mg/dl
(100129 mg/dL:
consider drug options)
Moderately high
risk:
2+ Risk
Factors
Consider Drug
Therapy
<160 mg/dl
160 mg/dl
190 mg/dl
(160189 mg/dL:
LDL-Clowering drug
optional)
Cigarette smoking
Colestipol
Colesevelam
Fibrates
Lovastatin
Simvastatin
Gemfibrozil
Pravastatin
Fenofibrate
Atorvastatin
Clofibrate
Cerivastatin
(2001/8 withdrawal from market)
Nicotinic Acid
Ezetimibe
Rosuvastatin
Pitavastatin
Niacin/Lovastatin
Amlodipine/Atorvastatin
Aspirin/Pravastatin
Statins
Mechanism
Inhibit HMG CoA reductase which is the rate-limiting step
in cholesterol biosynthesis.
Pharmacodynamics
Most effective class of drugs at lowering LDL-C levels
- LDL-C by 18-55%
- HDL-C by 5-15%
- TG by 7-30%
Adverse reactions
myopathy, rhabdomyolysis, elevations of serum
aminotransferase activity
HMG-CoA
HMG-CoA reductase X
Statins
mevalonic acid
mevalonate pyrophosphate
isopentenyl pyrophosphate
geranyl pyrophosphate
ubiquinones
farnesyl pyrophosphate
Squalene synthase
squalene
cholesterol
dolichols
Raises HDL
Anti-inflammatory, anti-thrombotic
Cost effective
After Hanefeld, Int J Clin Pract 2001 55;399405
Rosuvastatin:
Well defined pharmacology
Potency on Cell selectivity
Hepatic
enzyme
log ratio
Metabolism
IC50 (nM)
by Cyt P450
3A4
Elimination
Half Life
(hours)
rosuvastatin
5.4
3.3
No
19
atorvastatin
8.2
2.2
Yes
14
cerivastatin
10.0
0.14
Yes
23
simvastatin
11.2
0.54
Yes
12
fluvastatin
27.6
0.04
No
12
pravastatin
44.1
3.3
No
12
Rosuvastatin
is the most effective statin at lowering LDL-C
and produces a significant increase in HDL-C
Rosuvastatin
the most effective statin at lowering LDL- C
Dose (mg)
10
20
40
80
Log scale
-10
-20
20.1%
-30
28.3%
-40
29.7%
36.8%
45.8%
45.8%
-50
55.0%
51.1%
-60
rosuvastatin atorvastatin
simvastatin
pravastatin
20
40
80
mg
Rosuva
Atorva
Simva
Prava
Fluva
10
15
20
25
30
35
40
45
50
20
mg
10
mg
*
10
mg
20
mg
40
mg
55
60
40
mg
80
mg
Rosuvastatin
Atorvastatin
10
mg
10
mg
20
mg
20
mg
40
mg
40
mg
80
mg
Simvastatin
Pravastatin
Rosuvastatin 10 mg (46%)
*p<0.002 vs atorvastatin 10 mg; simvastatin 10, 20, 40 mg; pravastatin 10, 20, 40 mg
p<0.002 vs atorvastatin 20, 40 mg; simvastatin 20, 40, 80 mg; pravastatin 20, 40 mg
p<0.002 vs atorvastatin 40 mg; simvastatin 40, 80 mg; pravastatin 40 mg
Adapted from Jones PH et al. Am J Cardiol 2003;92:152160
100
P<0.01
p<0.0001
90
80
70
80
60
Rosuvastatin
atorvastatin
74
63
50
40
30
20
10
n=535
10
n=528
10
Dose (mg/day)
n=923
20
high risk (with CHD or CHD risk equivalent) - Target LDL-C: <100mg/dL (2.59mmol/L)
HDL-C
12
10
8
6
4
2
0
10
20
40
80
Dose (mg)
Rosuvastatin
atorvastatin
simvastatin
Log scale
pravastatin
10 20 40
10 20 40 80
10 20 40 80
10 20 40
Change in
TG from 10
baseline
15
(%)
20
25
30
8.2
11.9
14.8
17.6
20
19.8
* 23.7
**
22.6
26.1
26.8
28.2
18.2
7.7
13.2
Rosuvastatin
Atorvastatin
Simvastatin
Pravastatin
RSV
10 mg
ATV
10 mg
16 weeks
RSV ATV
20 mg 20 mg
-5
-10
-15
-21.2
-20
Rosuvastatin (RSV)
-25
-30
Atorvastatin (ATV)
-34.0
-33.8
-35
-40
-45
-39.8
Muscle
Cardiovascular
protection
Liver
Drug interactions
Percentage of patients
10
9
8
7
6
5
4
3
2
1
2.9%
3.2%
10-40 mg
10-80 mg
2.5%
2.5%
10-80 mg
10-40 mg
simvastatin
pravastatin
0
rosuvastatin
(n=3074)
atorvastatin
(n=2899)
(n=1457)
(n=1278)
Pravastatin
Simvastatin
Fluvastatin
Atorvastatin
Cerivasta
tin
Rosuvastati
n
*
8/87
10/91
12/91
12/93
12/96
6/97
11/02#
19
14
31
99,197
81,364
116,145
37,392
140,360
9,815
10,100
0.19
0.04
0.12
0.04
3.16
Variable
Date approved
Fatal cases of
rhabdomyolysis
No. of
prescriptions
dispensed since
marketing began
(in thousands)
Reporting rate
(per 1 million
prescriptions)
*worldwide prescriptions
#Netherlands (MR ref state)
2C9
Simvastatin
Fluvastatin
Atorvastatin
Phenytoin
Lovastatin
Diltiazem
Clopidogrel
Amiodarone
Cimetidine
cytochrome P450
Ery/clarithromycin
interactions with
Ketoconazole
Carbamazepine
St Johns wort
Grapefruit juice
Fluconazole
Warfarin
Rosuvastatin
Low potential for
rosuvastatin
JUPITER
ACC March 29, 2009
A Randomized Trial of Rosuvastatin in the Prevention
of Venous Thromboembolism:
JUPITER
4 week
Placebo
Run-In
17,802 Randomized
Randomized
17,802
Reason
for Exclusion
Reason
for Exclusion(%) (%)
LDLLDL-C
> 130 >
mg/dL
130 mg/dL
hsCRP
< 2.0
mg/L
hsCRP
< 2.0
mg/L
Withdrew
Consent
Withdrew Consent
Diabetes
Diabetes
Hypothyroid
Hypothyroid
Liver
Disease
Liver
Disease
TG TG
> 500
mg/dL
> 500
mg/dL
AgeAge
outout
of range
of range
Current
UseUse
of HRT
Current
of HRT
Cancer
Cancer
Poor
Compliance/Other
Poor
Compliance/Other
8,901Assigned
Assigned to
8,901
to
Rosuvastatin
20
mg
Rosuvastatin 20 mg
8,901 Assigned
Assigned toto
8,901
Placebo
Placebo
8,600Completed
Completed Study
8,857
Study
120
Lost
to
follow-up
44 Lost to follow-up
8,864
Study
8,600 Completed
Completed Study
120Lost
Lost to
to follow-up
37
follow-up
8,901
8,901 Included in Efficacy
8,901
8,901Included
IncludedininEfficacy
Efficacy
and
andSafety
SafetyAnalyses
Analyses
and
and Safety
Safety Analyses
Analyses
52 53
36 37
5 4
11
<1 <1
<1 <1
<1 <1
<1 <1
<1 <1
<1 <1
33
0.025
JUPITER
Total Venous Thromboembolism
Placebo 60 / 8901
0.015
0.020
0.005
0.010
- 43 %
Rosuvastatin 34 / 8901
0.000
Cumulative Incidence
Follow-up (years)
Number at Risk
Rosuvastatin
Placebo
8,901
8,901
8,648
8,652
8,447
8,417
6,575
6,574
3,927
3,943
1,986
2,012
1,376
1,381
1,003
993
548
556
161
182
JUPITER
0.06
0.04
0.00
0.02
Cumulative Incidence
0.08
Follow-up (years)
Number at Risk
Rosuvastatin
Placebo
8,901
8,901
8,631
8,621
8,412
8,353
6,540
6,508
3,893
3,872
1,958
1,963
1,353
1,333
983
955
544
534
157
174
JUPITER
VTE in JUPITER: Conclusions
Ferozsons
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