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New Insights Into the

Management of
Dyslipidaemia

Global Burden of Cardiovascular Disease


According to WHO estimates:
16.6 million people die of CVD worldwide
each year
CVD contributed to approximately one third
of global deaths
In 2001:
7.2 million deaths from CHD
5.5 million deaths from stroke

Adapted from International Cardiovascular Disease Statistics 2003; American Heart Association

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 >195 mmHg)

x3
x9

x4.5

x16
Smoking

x1.6

x6

x4
Serum cholesterol level
(>8.5 mmol/L, 330 mg/dL)

Adapted from Poulter N et al., 1993

Cholesterol: A Major Risk Factor


In the USA, 102 million people have elevated
total cholesterol (>200 mg/dL, 5.2 mmol/L)1
In EUROASPIRE II, 58% of patients with established
CHD had elevated total cholesterol
(5 mmol/L, 190 mg/dL)2

10% reduction in total cholesterol results in:

15% reduction in CHD mortality (P<0.001)

11% reduction in total mortality (P<0.001)3

LDL-C is the primary target to prevent CHD

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.

Many Patients in Need of Lipid Lowering


Therapy Remain Untreated
EUROASPIRE II
39% untreated

Lipid management assessed in 5226 patients with CHD at least 6


months after discharge who qualify for treatment
Euro Heart J 2001;22:554-772

LDL Cholesterol Levels and


CHD Event Rates in Major Statin Trials
Sample
size (n)

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

Relationship Between Changes in


LDL-C and HDL-C Levels and CHD Risk

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%

NCEP ATP III LDL Cholesterol Goals

LDL cholesterol level (mg/dL)

CHD

<2

160 -

130 -

100 -

Target
100
mg/dL
Target
70
mg/dL

70 Risk factors

(National Cholesterol Education Program, Adult Treatment Panel III, 2004)

2004 NCEP-ATP III Guidelines


Risk Category

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)

Major Risk Factors (Exclusive of LDL


Cholesterol) That Modify LDL Goals

Cigarette smoking

Hypertension (BP 140/90 mmHg or on


antihypertensive medication)

Low HDL cholesterol (<40 mg/dL)

Family history of premature CHD

CHD in male first degree relative <55 years

CHD in female first degree relative <65 years

Age (men 45 years; women 55 years)

HDL cholesterol 60 mg/dL counts as a negative risk factor; its


presence removes one risk factor from the total count.

Cholesterol-Lowering Drug Therapy


Cholestyramine

Colestipol

Colesevelam

Fibrates

HMG CoA Reductase


Inhibitors

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

Mechanism of Action of Statins


Cholesterol Synthesis Pathway
acetyl CoA
HMG-CoA synthase

HMG-CoA
HMG-CoA reductase X
Statins
mevalonic acid
mevalonate pyrophosphate

isopentenyl pyrophosphate
geranyl pyrophosphate
ubiquinones

farnesyl pyrophosphate

Squalene synthase

squalene
cholesterol

dolichols

Wish List of Features of New Statin

High efficacy at start dose


Potent HMG-CoA inhibition
Lowers LDL, VLDL, Lp(a), remnants

Raises HDL
Anti-inflammatory, anti-thrombotic

Good safety profile


Selective for target organ liver
Minimal potential for drug interactions

Useful in a wide range of patients

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

Adapted from Davidson., (2002)

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)

LS mean % change from baseline

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

STELLAR Study. Am J Cardiol 2003; 92: 15260.

Statin Dose Required to Achieve


4550% LDL-C Reduction
10

20

40

80

mg

Rosuva

Atorva
Simva
Prava

Not achieved with max.


authorised dose

Fluva

Not achieved with max.


authorised dose
Adapted from Jones P.H. 2003

Rosuvastatin versus Comparators:


LDL-C efficacy at 10mg Dose
Change in LDL-C from baseline (%)
0

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

The STELLAR Study

Rosuvastatin 10 mg gets more patients to


Patients achieving LDL-C goal (%)

NCEP ATP- III LDL-C Goals

100

P<0.01
p<0.0001

90
80
70

80

60

Rosuvastatin
atorvastatin

74
63

50
40

Baseline mean LDL-C values (mg/dL)


CRESTOR 10 mg: 165.1 (4.28 mmol/L)

30

atorvastatin 10 mg: 162.6 (4.21)


atorvastatin 20 mg: 167.1 (4.33)

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)

MERCURY I study; Am Heart J 2004; 147: 705-12

Rosuvastatin effectively raises


LS mean % change from baseline

HDL-C

12
10
8
6
4

2
0
10

20

40

80

Dose (mg)
Rosuvastatin

atorvastatin

simvastatin

Log scale

pravastatin

STELLAR Study. Am J Cardiol 2003; 92: 15260.

Rosuvastatin effectively reduces TG


Dose (mg)
0

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

*p<0.002 vs pravastatin 10, 20 mg


**p<0.002 vs simvastatin 40 mg; pravastatin 20, 40 mg
p<0.002 vs simvastatin 40 mg; pravastatin 40 mg
Jones PH, et al. Am J Cardiol 2003;92:152160

Rosuvastin reduces in Inflammatory Marker


C-Reactive Protein (ANDROMEDA)
8 weeks
0

RSV
10 mg

ATV
10 mg

16 weeks
RSV ATV
20 mg 20 mg

Mean change from


baseline in hsCRP (%)

-5

-10
-15
-21.2

-20

Rosuvastatin (RSV)

-25
-30

Atorvastatin (ATV)
-34.0

-33.8

-35
-40

-45

-39.8

74th EASC 17-20 April 2004, Seville, Spain

Statins Therapeutic Ratio


Adverse Effects
Therapeutic
Effects

Muscle
Cardiovascular
protection

Liver

Drug interactions

Rosuvastatin Tolerability and Safety


Withdrawals due to Adverse Events

Percentage of patients

10
9

Percentage of patients with an adverse event


leading to withdrawal

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)

Brewer HB. Am J Cardiol 2003;92(Suppl):23K-29K

(n=1457)

(n=1278)

Reported Cases of Fatal Rhabdomyolysis and


Numbers for All Statins Dispensed in the US Since
These Products Were Launched
Lovastatin

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)

Adapted from: Steffa JA, et al. N Engl J Med. 2002;346:539-540.

Potential Drug Interactions


3A4

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:

The JUPITER Trial

Robert Glynn*, Eleanor Danielson, Francisco Fonseca*, Jacques Genest*,


Antonio Gotto*, John Kastelein*, Wolfgang Koenig*, Peter Libby*,
Alberto Lorenzatti*, Jean MacFadyen, Brge Nordestgaard*,
James Shepherd*, James Willerson, and Paul Ridker*
on behalf of the JUPITER Trial Study Group

JUPITER

Ridker et al NEJM 2008

Inclusion and Exclusion Criteria, Study Flow


89,863Screened
Screened
89,890

Men > 50 years


Women > 60 years
No CVD, No DM
LDL < 130 mg/dL
hsCRP > 2 mg/L

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

HR 0.57, 95%CI 0.37-0.86


P= 0.007

0.005

0.010

- 43 %

Rosuvastatin 34 / 8901

0.000

Cumulative Incidence

Glynn et al NEJM 2009

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

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

0.06

HR 0.56, 95% CI 0.46-0.69


P < 0.00001

0.04

109 Fewer Events

Rosuvastatin 142 / 8901

0.00

0.02

Cumulative Incidence

0.08

Placebo 251 / 8901

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

VTE is a serious event that occurred about as often as MI and


stroke in the JUPITER study
Rosuvastatin was associated with a significant 43 percent
reduction in risk of VTE with no increase in bleeding.
This benefit was comparable in magnitude and independent of
the effect on arterial events

Widening the treatment target to include prevention


of VTE and death in addition to arterial thrombosis
increases the estimated benefit of statin use

Rosuvastatin has Extensive Clinical and


post-Market Experience Mar 2005
Approved in 73 countries world-wide

Over 5 million patients treated


Over 20 million prescriptions written

Over 45,000 patients have been treated with


rosuvastatin in clinical trial program

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