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
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