New era of New era of Dyslipidaemia treatmentDyslipidaemia treatmentRovirosRoviros (Rosuvastatin) (Rosuvastatin)

Dr Jahanzaib Sheikh

Nabi Qasim Pharma

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 AssociationAdapted 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 HypercholesterolaemiaLevels of Risk Associated with Smoking, Hypertension and Hypercholesterolaemia

x1.6x1.6 x4x4

x3x3

x6x6

x16x16

x4.5x4.5 x9x9

HypertensionHypertension(SBP >195 mmHg)(SBP >195 mmHg)

HypertensionHypertension(SBP >195 mmHg)(SBP >195 mmHg)

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

(>8.5 mmol/L, 330 mg/dL)(>8.5 mmol/L, 330 mg/dL)

SmokingSmokingSmokingSmoking

Adapted from Poulter N et al., 1993Adapted 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 Adapted from: 1. American Heart Association. Heart and Stroke Statistical Update; 2002; 2. EUROASPIRE II Study Group. Study Group. Eur Heart JEur Heart J 2001; 2001;2222:554–572; 3. Gould AL :554–572; 3. Gould AL et al. Circulationet al. Circulation 1998; 1998;9797:946–952.:946–952.

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

Adapted from: 1. American Heart Association. Heart and Stroke Statistical Update; 2002; 2. EUROASPIRE II Adapted from: 1. American Heart Association. Heart and Stroke Statistical Update; 2002; 2. EUROASPIRE II Study Group. Study Group. Eur Heart JEur Heart J 2001; 2001;2222:554–572; 3. Gould AL :554–572; 3. Gould AL et al. Circulationet al. Circulation 1998; 1998;9797:946–952.:946–952.

Meta-analysis of 38 primary and secondary prevention trials, with more than 98,000 patients in total

0 4 8 12 16 20 24 28 32 36–1.0

–0.8

–0.6

–0.4

–0.2

–0.0

Mortality in coronary heart disease, p=0.012

Total mortality, p=0.04

Lowering of cholesterol (%)

Mortality, logodds ratio

Benefit of Lowering Cholesterol

Gould AL et al. Circulation 1998;97:946–952

Relationship Between Changes in LDL-C and HDL-C Levels and CHD Risk

Third Report of the NCEP Expert Panel. NIH Publication No. 01-3670 2001. http://hin.nhlbi.nih.gov/ncep_slds/menu.htm

1% decreasein LDL-C reduces

CHD risk by1%

1% increasein HDL-C reduces

CHD risk by3%

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

Many Patients that are Treated are Still not Getting to Goal

2989 patients†

1575 (53%) not at goal on

starting dose

1414 (47%) at goal on starting

dose

838 (53%) not

titrated

737 (47%) titrated

478 (65%)not at goal

†Patients with and LDL-C goal of <100mg/dL (CHD and/or diabetes mellitus) with HDL-C ≤45 mg/dLSimpson RJ Circulation 2001;104:II–829

259 (35%) at goal

Adult Treatment Panel III Adult Treatment Panel III (ATP III) Guidelines(ATP III) Guidelines

National Cholesterol

Education Program

LDL Cholesterol Levels and LDL Cholesterol Levels and CHD Event Rates in Major Statin TrialsCHD Event Rates in Major Statin Trials

311.8351311677LIPS

242.6351509014LIPID

352.0391582102ALERT

360.93913110305ASCOT-LLA

193.8391475804PROSPER

272.33913120536HPS

242.6391404159CARE

371.0§391506605AFCAPS

321.5501936595WOSCOPS

345.2‡6619044444S

CHD risk reduction

(%)

CHD event

rate/year†

LDL-C net change

(mg/dL§§)*

Baseline LDL

(mg/dL§§)

Sample size (n)Study

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 Relationship between LDL-CLDL-C and and CV EventCV Event Rate Rate

Adapted from Ballantyne CM et al. Am J Cardiol 1998;82:3Q–12Q.

LDL-C achieved mg/dL (mmol/L)LDL-C achieved mg/dL (mmol/L)

WOSCOPS - PlWOSCOPS - Pl

AFCAPS/TexCAPS - PlAFCAPS/TexCAPS - Pl

ASCOT - PlASCOT - PlAFCAPS/TexCAPSAFCAPS/TexCAPS - Rx- Rx

WOSCOPS - RxWOSCOPS - Rx

ASCOT - RxASCOT - Rx

ALLHAT - RxALLHAT - Rx ALLHAT - PlALLHAT - Pl

44S - RxS - Rx

HPS - PlHPS - Pl

LIPID - RxLIPID - Rx

44S - PlS - Pl

CARE - RxCARE - Rx

LIPID - PlLIPID - Pl

PROSPER - PlPROSPER - PlCARE - PlCARE - Pl

HPS - RxHPS - Rx

PROSPER - RxPROSPER - Rx

00

55

1010

1515

2020

2525

3030

70 (1.8)70 (1.8) 90 (2.3)90 (2.3) 110 (2.8)110 (2.8) 130 (3.4)130 (3.4) 150 (3.9)150 (3.9) 170 (4.4)170 (4.4) 190 (5.0)190 (5.0) 210 (5.4)210 (5.4)

Even

t ra

te (

%)

Even

t ra

te (

%)

- - Secondary preventionSecondary prevention

- - Primary preventionPrimary prevention

Rx - Statin therapyRx - Statin therapy

Pl - PlaceboPl - Placebo

Update to ATP III Guidelines: Update to ATP III Guidelines: RationaleRationale

• Since ATP III completion in 2001, 5 large clinical outcome trials of statin therapy have been published– Heart Protection Study (HPS)– Prospective Study of Pravastatin in the Elderly at Risk

(PROSPER)– Antihypertensive and Lipid-Lowering Treatment to Prevent Heart

Attack Trial—Lipid-Lowering Trial (ALLHAT-LLT)– Anglo-Scandinavian Cardiac Outcomes Trial—Lipid-Lowering Arm

(ASCOT-LLA)– Pravastatin or Atorvastatin Evaluation and Infection Therapy

(PROVE-IT) trial • ATP III update incorporates information from

these trials

Grundy SM et al. Circulation. 2004;110:227-239.

NCEP ATP III LDL Cholesterol Goals NCEP ATP III LDL Cholesterol Goals

CHD <2≥2LD

L ch

oles

tero

l lev

el (

mg/

dL)

Risk factors

70 -

130 -

100 -

160 -

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

Target 70

mg/dL

Target 100

mg/dL

2004 NCEP-ATP III Guidelines2004 NCEP-ATP III Guidelines

Risk Category LDL GoalInitiate TLC

(Therapeutic Lifestyle Changes)

Consider Drug Therapy

High risk: CHD or

CHD Risk Equivalents

<100 mg/dl

(Option:

<70 mg/dl)

100 mg/dl

130 mg/dl

100 mg/dl

(<100 mg/dL: consider drug options)

2+ Risk Factors

Moderately high risk: 10-20% risk <130 mg/dl

(Option: <100 mg/dl)

130 mg/dl

130 mg/dl

(100–129 mg/dL: consider drug options)

Moderately risk: <10% risk

160 mg/dl

Lower risk: 0-1 Risk Factor

<160 mg/dl 160 mg/dl

190 mg/dl

(160–189 mg/dL:LDL-C–lowering drug

optional)

×

Cholesterol-Lowering Drug TherapyCholesterol-Lowering Drug Therapy

HMG CoA Reductase

Inhibitors Lovastatin

Simvastatin

Pravastatin

Atorvastatin

Cerivastatin

(2001/8 withdrawal from market)

Rosuvastatin

Pitavastatin

Niacin/Lovastatin

Amlodipine/Atorvastatin

Aspirin/Pravastatin

Cholestyramine Colestipol

Colesevelam

Fibrates Gemfibrozil

Fenofibrate

Clofibrate

Nicotinic Acid

Ezetimibe

CholestyramineCholestyramineMechanism of actionBind bile acids and metabolites of cholesterol in the intestine through anion exchange

PharmacodynamicsModerate reduction in LDL-C levels

- LDL-lowering potential increases when

combined w/ other agents (e.g. statins)

- May raise TG levels in some p’ts

- LDL-C by 15-30%

- HDL-C by 3-5%

Adverse effectsGI distress (constipation, bloating) 、 interfere with absorption of fat-soluble vitamins 、 triglyceridemia 、 hyperuricemia

FibratesFibratesMechanism of actionAs ligands for the nuclear transcription receptor, peroxisome

proliferator-activated receptor-apha (PPAR-). Increase

lipolysis of lipoprotein triglyceride via LPL.

PharmacodynamicsLower TG & raises HDL

- Primarily targets atherogenic dyslipidemia including

diabetic dyslipidemia

- LDL-C by 5-20% (in non-hypertriglyceridemic individuals)

- HDL-C by 10-35%; TG by 20-50%

Adverse effectsGI symptoms, headache, drowsiness, dizziness,

myopathy, gallstone rish , arrhythmias

Nicotinic AcidNicotinic AcidMechanism

Alter lipid levels by inhibiting lipoprotein synthesis & decreasing the production of VLDL particles by the liver

Pharmacodynamics

Most effective at raising HDL levels of the lipid-modifying drugs

- LDL-C by 5-25%

- HDL-C by 15-35%

- TG by 20-50%

Adverse effects

Flushing, itching, rash, GI upset

EzetimibeEzetimibeMechanism

Inhibit absorption of cholesterol from intestine.

Pharmacodynamics

A decreased delivery of cholesterol to the liver.

Reduction of hepatic cholesterol stores.

An increased clearance of cholesterol from the blood.

- total LDL-C LDL-C

- TG Apo-B

- HDL-C

Adverse effects

headache, Chest pain, arthralgia, GI distress

StatinsStatins

MechanismInhibit HMG CoA reductase which is the rate-limiting step in cholesterol biosynthesis.

PharmacodynamicsMost effective class of drugs at lowering LDL-C levels

- LDL-C by 18-55%

- HDL-C by 5-15%

- TG by 7-30%

Adverse reactionsmyopathy, rhabdomyolysis, elevations of serum aminotransferase activity

Mechanism of Action of Statins Mechanism of Action of Statins Cholesterol Synthesis PathwayCholesterol Synthesis Pathway

acetyl CoA

HMG-CoA

mevalonic acid

mevalonate pyrophosphate

isopentenyl pyrophosphate

geranyl pyrophosphate

farnesyl pyrophosphate

squalene

cholesterol

dolicholsubiquinones

HMG-CoA synthase

HMG-CoA reductase

Squalene synthase

StatinsX

Atorvastatin

Simvastatin

PravastatinB M YB M Y

Fluvastatin

Lovastatin

Cerivastatin

Rosuvastatin

19911987 1993

200019961997 2003

Only about 50% of patients with high LDL-C achieve goal on current lipid lowering therapies

– Non-compliance

– Lack of effective treatment

– Fear of high dose titration

More effective cholesterol-loweringagents are needed to attain LDL-C goals1,2

1Kotseva, K, Wood D, de Backer, G et al. 20012Pearson T et al. 2000

Why Do We Need a New Statin?Why Do We Need a New Statin?

Wish List of Features of New Statin 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;399–405

Statin PharmacophoreStatin Pharmacophore

OO

N

N

S

N

OH

OHO

O

CH3

CH3

CH3

F

CH3

Ca(3R, 5S)

Relative lipophilicityRelative lipophilicity **

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0

rosuvastatin

cerivastatinsimvastatin

fluvastatinatorvastatin

pravastatin

** log D at pH 7.4

Buckett et al., (2000); McTaggart et al., (2001)

RosuvastatinRosuvastatin::A new A new hydrophilichydrophilic statin – statin – single enantiomersingle enantiomer

Inhibition of Cholesterol Synthesis in Rat Hepatocytes and Rat Fibroblasts

Buckett et al., (2000)

Rosuvastatin:Rosuvastatin: Hepatoselective HepatoselectiveCholesterol synthesis inhibited in hepatocytes at Cholesterol synthesis inhibited in hepatocytes at 1000-fold1000-fold lower concentrations than fibroblasts lower concentrations than fibroblasts

0

20

40

60

80

100

120

140

0.1 1 10 100 1000 10000 1000000

% of Control

Mean

Concentration (nM)

Fibroblasts IC 50 = 331 nM

Hepatocytes IC 50 = 0.2 nM

Cerivastatin: Non hepatoselectiveCerivastatin: Non hepatoselectiveCholesterol synthesis inhibited in fibroblasts Cholesterol synthesis inhibited in fibroblasts

and hepatocytes at similar concentrationsand hepatocytes at similar concentrations

Buckett et al., (2000)

100 1000 10000

% of Control

0 0.01 0.1 1 10 1000000

20

40

60

80

100

120

140

Concentration (nM)

MeanFibroblasts IC 50 = 1.3 nM

Hepatocytes IC50 = 2.4 nM

Inhibition of Cholesterol Synthesis in Rat Hepatocytes and Rat Fibroblasts

binding interactionArg568 and sulphone

Istvan and Deisenhofer (2001)

Rosuvastatin:Rosuvastatin: X-Ray crystallography provides X-Ray crystallography provides molecular rationale for potent enzyme inhibitionmolecular rationale for potent enzyme inhibition

The rosuvastatin:HMG-CoA reductase complex has more bonding interactions than any other statin

*P<0.05 vs Rosuvastatin; ***P<0.001 vs Rosuvastatin

Rosuvastatin:Rosuvastatin: Potent inhibitor of Potent inhibitor of HMG-CoA reductase in human catalytic domainHMG-CoA reductase in human catalytic domain

Three determinations, IC 50

(nM) with 95% confidence limits

Rosuva5.4

100

10

Ceriva *

10.0

Atorva8.2

Fluva ***

27.6

Simva *

11.2

Prava ***

44.1

IC50 (nM)(log scale)

McTaggart et al., (2001)

Rosuvastatin:Rosuvastatin:

Well defined pharmacologyWell defined pharmacology

Potency on enzyme IC50 (nM)

Cell selectivity log ratio

Hepatic Metabolismby Cyt P450

3A4

Elimination Half Life(hours)

rosuvastatin

pravastatin

5.4

44.1

3.3

3.3 1–2

cerivastatin 10.0 –0.14 Yes 2–3

atorvastatin 8.2 2.2 Yes 14

fluvastatin 27.6 –0.04 No 1–2

simvastatin 11.2 0.54 Yes 1–2

19No

No

Adapted from Davidson., (2002)

PharmacologicPharmacologic properties of Statins

Property Rosuva Atorva Fluva Lova Prava Simva

Prodrug No No No Yes No Yes

Salt form Ca Ca Na None Na None

Single isormer

Yes Yes Yes Yes Yes Yes

Lipophilicity

(log P)-0.3 +4.1 +3.2 +4.3 -0.2 +4.7

IC50(nm)

Potency5 8 28 NA NA 11

Thomas N. Riley, PhD & Jack DeRuiter, PhD (2004)

Pharmacokinetic properties of Statins

Parameter Rosuva Atorva Fluva Lova Prava Simva

Absolute bioavailability,% 20 12 10-35 <5 18 >5

Food effect on bioavailability None 13% 15-25% 50% 30% None

Protein binding, % 90 >98 >99 95 48 95

Hepatic extraction, % dose 90 >70 68 >70 50 78-87

Metabolic enzyme

(S, substrate; I, inhibitor)(none)

2C9,2C193A4(S) 2C9(I) 3A4(S)

Sulfation

(none)3A4(S)

Half-life, h 20 14 <1 3-4 1.8 3

Elimination, %

Urine

Feces

10

90

2

96

5

95

10

70

20

70

13

80

Thomas N. Riley, PhD & Jack DeRuiter, PhD (2004)

ROVIROS®

Rosuvastatin

is the most effective statin at lowering LDL-C

and produces a significant increase in HDL-C

GALAXYGALAXY

AURORA CORONA JUPITER

ORION (MRI)METEOR

ASTEROID (IVUS)

STELLARMERCURY I/II

ORBITALDISCOVERY

COMETSLUNARPLUTO

POLARISPULSARECLIPSE

EXPLORERPLANET

GALAXY Programme studies with CRESTOR, investigating:

Atherogenic lipid profile+/- inflammatory markers Atherosclerosis

Reduction in CV morbidity & mortality

FFPC meeting October 2003: Dr Dave Kallend

LS

mean

% c

han

ge f

rom

baselin

e

-60

-50

-40

-30

-20

-10

0

10 20 40 80Dose (mg)

CRESTOR atorvastatin simvastatin pravastatin

Log scale

45.8%

55.0%

36.8%

51.1%

28.3%

45.8%

29.7%

20.1%

RosuvastatinRosuvastatin the most effective statin at lowering LDL- C

STELLAR Study. Am J Cardiol 2003; 92: 152–60.

Rosuva

Atorva

Simva

Prava

10 20 40 80

Fluva

Statin Dose Required to AchieveStatin Dose Required to Achieve45–50% 45–50% LDL-C ReductionLDL-C Reduction

mg

Not achieved with max. authorised dose

Not achieved with max. authorised dose

Adapted from Jones P.H. 2003

RosuvastatinRosuvastatin versus Comparators: versus Comparators: LDL-C efficacy at 10mg DoseLDL-C efficacy at 10mg Dose

Change in LDL-C from baseline (%)

0 –10 –20 –30 –40 –50 –60

10mg*

–5 –15 –25 –35 –45 –55

20mg†

40mg‡

10mg

20mg

80 mg

10mg

20mg

40mg

80mg

10mg

20mg

40mg Rosuvastatin 10 mg (–46%)

Rosuvastatin

Atorvastatin

Simvastatin

Pravastatin

40mg

*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;92:152–160 The STELLAR StudyThe STELLAR Study

Percentage of patients at LDL-C goal at week 61, 2

60%

20%

100%

80%

40%

atorvastatin

10 mg

n=158

10 mg

20 mg

10 mg

20 mg

simvastatin pravastatin

n=158

80 mg

40 mg

80 mg

20 mg

40 mg

40 mgn=160

CRESTOR

10 mg

n=156

*

P-values***p<0.002CRESTOR 10 mg vs. atorvastatin 10 mg pravastatin 10, 20 & 49 mg and simvastatin 10, 20, & 40 mg

10 mg10 mg

20 mg20 mg

10 mg10 mg

20 mg20 mg

Usual start dosesUsual start doses

10%

30%

50%

70%

90%

% p

ati

en

ts r

each

ing

LD

L-C

goal*

Rosuvastatin:Rosuvastatin: 10 mg gets more patients to their LDL-C goal than the start doses of the most commonly used statins1,2,3,4

References: 1. STELLAR 2. Schuster MERCURY I Am Heart J 2004; 147: 705-12. 3. Krithiades Eur Heart J Suppl 2004; 6(suppl A): A12-A18.4. Shepherd Am J Cardiol 2003; 92(suppl): 11C-19C. *2003 European goals

0

10

20

30

40

50

60

70

80

90

100

Pati

en

ts a

ch

ievin

g L

DL-C

goal (%

)

P<0.01p<0.0001

Dose (mg/day)

74

63

80

10 10 20

n=535 n=528 n=923

OMNITORatorvastatin

•high risk (with CHD or CHD risk equivalent) - Target LDL-C: <100mg/dL (2.59mmol/L)

Baseline mean LDL-C values (mg/dL)

OMNITOR 10 mg: 165.1 (4.28 mmol/L)

atorvastatin 10 mg: 162.6 (4.21)

atorvastatin 20 mg: 167.1 (4.33)

RosuvastatinRosuvastatin 10 mg 10 mg gets more patients to NCEP ATP- III LDL-C GoalsNCEP ATP- III LDL-C Goals

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

**P<0.01 vs atorvastatin; ***P<0.001 vs atorvastatin

Rosuvastatin: 10mg enables more patients with Rosuvastatin: 10mg enables more patients with hypercholesterolemia to reach their Joint European hypercholesterolemia to reach their Joint European

Societies LDL-C goals, than atorvastatin 10mgSocieties LDL-C goals, than atorvastatin 10mg

*** *****

8285

81

5149

64

0

20

40

60

80

100

10-yr CHD risk < 20% High CHD risk All Categories

Joint European Societies Cholesterol Categories

Pati

en

ts a

ch

ievin

g g

oal (%

)

rosuvastatin 10mg

atorvastatin 10mg

n=314 n=327n=75 n=66 n=389 n=393

Patients reaching European LDL-C goals by risk category at week 12Patients reaching European LDL-C goals by risk category at week 12(Pooled Data)(Pooled Data)

Shepherd et al., (2003)

0

10

20

30

40

50

60

70

80

90

100

R10 A10 A20 S20 P40

Patientsat goal (%)

**

*84

*p<0.0001 (R10 vs A10, S20 & P40) 1998 European goal <3.0 mmol/l (116 mg/dl)

88

7669

62

RosuvastatinRosuvastatin 10 mg 10 mg gets more patients to European LDL-C GoalsEuropean LDL-C Goals

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

RosuvastatinRosuvastatin 10 mg 10 mg Patients (%) achieving European LDL-C goalPatients (%) achieving European LDL-C goal

*p<0.05 A10/R10 vs A10/A10; †p<0.01 A20/R20 vs A20/A20; ‡p<0.0001 S20/R10 vs S20/S20 and P40/R10 vs P40/P40)1998 European goal <3.0 mmol/l (116 mg/dl)

MERCURY I study; Am Heart J 2004; 147: 705−712

Period 1: R10 A10 A10 A20 A20 A20 S20 S20 P40 P40 Period 2: R10 R10 A10 R10 R20 A20 R10 S20 R10 P40

Patientsat goal (%)

†

0102030405060708090

10088

8086 86 86 8890

84

7266

* ‡ ‡

Dose (mg)

RosuvastatinRosuvastatin effectively raises effectively raises HDL-C HDL-C 11

0

2

4

6

8

10

12

10 20 40 80Dose (mg)

LS

mean

% c

han

ge f

rom

baselin

e

CRESTOR atorvastatin simvastatin pravastatin

Log scale

STELLAR Study. Am J Cardiol 2003; 92: 152–60.

*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;92:152–160

–20

–22.6

–26.8–28.2

–11.9

–17.6

–14.8

–18.2

10 20 40 80

–23.7

** –26.1

†

–19.8

*

10 20 40 10 20 40 80

–8.2 –7.7

–13.2

10 20 40

–30

–25

–20

–15

–10

0

–5

Dose (mg)

RosuvastatinAtorvastatin

PravastatinSimvastatin

Change in TG from baseline(%)

RosuvastatinRosuvastatin effectively reduces effectively reduces TG

RosuvastatinRosuvastatin reduces in Inflammatory Markerreduces in Inflammatory Marker CC--RReactive eactive PProteinrotein (ANDROMEDA)(ANDROMEDA)

RSV ATV10 mg 10 mg

RSV ATV20 mg 20 mg

16 weeks8 weeks

-45

-40

-35

-30

-25

-20

-15

-10

-5

0

Mean

ch

an

ge f

rom

b

aselin

e in

hsC

RP

(%

)

Rosuvastatin (RSV)

Atorvastatin (ATV)

-34.0-34.0

-21.2-21.2

-39.8-39.8

-33.8-33.8

7474thth EASC 17-20 April 2004, Seville, Spain EASC 17-20 April 2004, Seville, Spain

Pleiotropic Effects Pleiotropic Effects ofof RosuvastatinRosuvastatinin Animal Models of Vascular Diseasein Animal Models of Vascular Disease

eNOS, NO availability leukocyte-endothelial interactions superoxide, oxidative stress Preservation of vascular function in

hypertension and insulin-resistance Protection against ischaemia-reperfusion

injury Protection of kidney function and inhibition

of renal fibrosis and glomerulosclerosis

Statins Statins –– Therapeutic Ratio Therapeutic Ratio

Therapeutic Effects

Adverse Effects

Cardiovascular protection

Muscle

Liver

Drug interactions

Benefit

Risk

RosuvastatinRosuvastatin Tolerability and Safety – Tolerability and Safety – Withdrawals due to Withdrawals due to Adverse EventsAdverse Events

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

Percentage of patients with an adverse event leading to withdrawal

10

0

2

4

6

8

rosuvastatin simvastatin pravastatin

Perc

en

tag

e o

f p

ati

en

ts

1

3

5

7

9

2.9%2.5% 2.5%

(n=3074) (n=1457) (n=1278)

3.2%

atorvastatin(n=2899)

10-40 mg10-80 mg10-80 mg10-40 mg

RosuvastatinRosuvastatin Tolerability and Safety Tolerability and Safety - Muscle Effects- Muscle Effects

As with other statins, effects on skeletal muscle, e.g. uncomplicated myalgia, myopathy and, rarely, rhabdomyolysis have been reported in patients treated with rosuvastatin

Incidence of treatment-related myopathy* in clinical trials was low in patients treated with rosuvastatin up to 40 mg (<0.1%) which is similar to that seen with other currently marketed statins1

Frequency of rhabdomyolysis with rosuvastatin is very rare (<0.01%) which is in line with that reported for other marketed statins2

*defined as CK >10 ULN plus muscle symptoms

1. Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K2. Data on File Please refer to local Prescribing Information

RosuvastatinRosuvastatin - Muscle Effects - Muscle Effects

CK >10 CK >10 xx ULN: Frequency by ULN: Frequency by LDL-C ReductionLDL-C Reduction

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

Cerivastatin (0.2–0.8 mg)

Rosuvastatin (10–40 mg)

Pravastatin (40–80 mg)

Atorvastatin (10–80 mg)

Simvastatin (40–80 mg)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

20 30 40 50 60 70LDL-C reduction (%)

CK

>10 ×

ULN

(%

)

Reported Cases ofReported Cases of Fatal Rhabdomyolysis Fatal Rhabdomyolysis and and Numbers for All Statins Dispensed in the US Since Numbers for All Statins Dispensed in the US Since

These Products Were LaunchedThese Products Were Launched

Variable

Lovastatin Pravastatin Simvastatin Fluvastatin Atorvastatin Cerivastatin

Rosuvastatin*

Date approved 8/87 10/91 12/91 12/93 12/96 6/97 11/02#

Fatal cases of rhabdomyolysis

19 3 14 0 6 31 0

No. of prescriptions dispensed since marketing began

(in thousands)

99,197 81,364 116,145 37,392 140,360 9,815 10,100

Reporting rate

(per 1 million prescriptions)

0.19 0.04 0.12 0 0.04 3.16 0

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

**worldwide prescriptionsworldwide prescriptions#Netherlands (MR ref state)#Netherlands (MR ref state)

Rosuvastatin Rosuvastatin Tolerability and Safety Tolerability and Safety - Liver Effects- Liver Effects

Elevations in liver transaminase levels are an infrequent but recognized complication of treatment with statins

Incidence of clinically significant increases in serum transaminases* with rosuvastatin 10–40 mg in clinical trials was low (0.2%) which is similar to that seen with other currently marketed statins1,2

As with other statins:

– liver function tests recommended

– caution in patients who consume excessive quantities of alcohol and/or have a history of liver disease

– contraindicated in patients with active liver disease

*ALT >3 x ULN on 2 successive occasions

1. Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K2. Shepherd J et al. Am J Cardiol 2004;94:882-888Please refer to local Prescribing Information

RosuvastatinRosuvastatin – Liver Effects – Liver Effects

Persistent ALT >3 Persistent ALT >3 ×× ULN: Frequency by ULN: Frequency by LDL-C ReductionLDL-C Reduction

Persistent elevation is elevation to >3 x ULN on 2 successive occasions

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

0.0

0.5

1.0

1.5

2.0

2.5

3.0

20 30 40 50 60 70LDL-C reduction (%)

Pers

iste

nt

ALT >

3 ×

ULN

(%

)

Fluvastatin (20–80 mg)

Rosuvastatin (10–40 mg)

Lovastatin (20–80 mg)

Atorvastatin (10–80 mg)

Simvastatin (40–80 mg)

Potential Drug InteractionsPotential Drug Interactions3A4

Simvastatin

Atorvastatin

Lovastatin

Diltiazem

Clopidogrel

Amiodarone

Cimetidine

Ery/clarithromycin

Ketoconazole

Carbamazepine

St John’s wort

Grapefruit juice

2C92C9

• FluvastatinFluvastatin

• PhenytoinPhenytoin

• FluconazoleFluconazole

• WarfarinWarfarin

• RosuvastatinRosuvastatin

Low potential for

cytochrome P450

interactions with

rosuvastatin

Rosuvastatin SafetyRosuvastatin Safety

Safety profile of rosuvastatin, including Safety profile of rosuvastatin, including effects on liver enzymes and creatine effects on liver enzymes and creatine kinase, compares favorably to those of kinase, compares favorably to those of other marketed statins from 10–40 mg other marketed statins from 10–40 mg daily in all pre-approval studiesdaily in all pre-approval studies

• Hydrophilic propertiesHydrophilic properties

• Good selectivity for target organ – liverGood selectivity for target organ – liver

• Limited metabolism by cytochrome P450 Limited metabolism by cytochrome P450

((2C92C9‚‚2C192C19))

RosuvastatinRosuvastatin: : DDrugrug InteractionsInteractions

Interactions of limited significance:Interactions of limited significance:• Oral contraceptives - Oral contraceptives - ethinyl oestradiol and norgestrelethinyl oestradiol and norgestrel• Antacid - Antacid - 50% rosuvastatin levels50% rosuvastatin levels• Erythromycin - Erythromycin - 20–30% rosuvastatin plasma levels20–30% rosuvastatin plasma levels• Warfarin – transient Warfarin – transient INR in some patientsINR in some patients

Not recommended for use with:Not recommended for use with:• Gemfibrozil – 2x increase in Gemfibrozil – 2x increase in rosuvastatinrosuvastatin plasma levels plasma levels

(Note: Fenofibrate may be co-administered)(Note: Fenofibrate may be co-administered)

Contraindication:Contraindication:• Cyclosporin – 7x increase in rosuvastatin AUCCyclosporin – 7x increase in rosuvastatin AUC

• ANY fibrate with rosuvastatin 40 mgANY fibrate with rosuvastatin 40 mg

No clinically significant interactions seen or expected with:

• Fluconazole / Ketoconazole / Itracnoazole

• Fenofibrate

• Digoxin

• Drugs mediated by cytochrome P450 metabolism

Interactions with limited clinical significance:

• Oral contraceptive pill - ethinyl oestradiol and norgestrel levels

• Antacid - 50% rosuvastatin levels

• Erythromycin - 20-30% rosuvastatin plasma levels

• Warfarin – INR

Interactions resulting in not recommended for use:

• Gemfibrozil – 2x increase in rosuvastatin plasma levels

Interactions resulting in contraindication to concomitant use:

• Cyclosporin – 7x increase in rosuvastatin plasma levels

Rosuvastatin Summary of Product Characteristics;Martin PD et al., (2001); Cooper et al., (2001); Kemp et al., (2001)

Rosuvastatin: Limited drug-drug interactionsRosuvastatin: Limited drug-drug interactions

RosuvastatinRosuvastatin 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

RosuvastatinRosuvastatin in our clinical trial programme

---- GALAXY program

Thanks for

your attention !