New Insights Into the New Insights Into the Management of Management of Dyslipidaemia 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 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 Hypercholesterolaemia

x1.6 x4

x3

x6

x16x4.5 x9

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)

SmokingSmoking

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 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.

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 treatmentEuro Heart J 2001;22:554-772

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§391506605AFCAPS321.5501936595WOSCOPS

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

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

CHD <2≥2LD

L ch

oles

tero

l lev

el (m

g/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/dl100 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)

×

Major Risk Factors (Exclusive of LDL Major Risk Factors (Exclusive of LDL Cholesterol) That Modify LDL GoalsCholesterol) 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 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

StatinsStatinsMechanismInhibit 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

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

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)

Rosuvastatin

is the most effective statin at lowering LDL-Cand produces a significant increase in HDL-C

LS m

ean

% c

hang

e fr

om b

asel

ine

-60-50-40-30-20-10

010 20 40 80

Dose (mg)

rosuvastatin atorvastatin simvastatin pravastatin

Log scale

45.8%

55.0%

36.8%

51.1%

28.3%

45.8%

29.7%

20.1%

Rosuvastatinthe 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%)

RosuvastatinAtorvastatinSimvastatinPravastatin

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

0102030405060708090

100

Pati

ents

ach

ievi

ng L

DL-

C go

al (

%)

P<0.01p<0.0001

Dose (mg/day)

7463

80

10 10 20n=535 n=528 n=923

Rosuvastatinatorvastatin

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

Baseline mean LDL-C values (mg/dL)CRESTOR 10 mg: 165.1 (4.28 mmol/L)atorvastatin 10 mg: 162.6 (4.21)atorvastatin 20 mg: 167.1 (4.33)

Rosuvastatin 10 mgRosuvastatin 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

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

02468

1012

10 20 40 80Dose (mg)

LS m

ean

% c

hang

e fr

om b

asel

ine

Rosuvastatin 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

RosuvastinRosuvastin 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

-50

Mea

n ch

ange

from

ba

selin

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

Statins Statins –– Therapeutic Ratio Therapeutic Ratio

Therapeutic Effects

Adverse Effects

Cardiovascular protection

MuscleLiver

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

enta

ge o

f pat

ient

s

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

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

VariableLovastatin Pravastatin Simvastatin Fluvastatin Atorvastatin Cerivasta

tinRosuvastati

n*

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)

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 P450interactions with

rosuvastatin

JUPITERACC March 29, 2009

A Randomized Trial of Rosuvastatin in the Preventionof Venous Thromboembolism:

The JUPITER TrialRobert Glynn*, Eleanor Danielson, Francisco Fonseca*, Jacques Genest*,

Antonio Gotto*, John Kastelein*, Wolfgang Koenig*, Peter Libby*,Alberto Lorenzatti*, Jean MacFadyen, Børge Nordestgaard*,

James Shepherd*, James Willerson, and Paul Ridker* on behalf of the JUPITER Trial Study Group

JUPITERInclusion and Exclusion Criteria, Study Flow

89,863 Screened

17,802 Randomized

8,901 Assigned to Rosuvastatin 20 mg

8,901 Assigned toPlacebo

Reason for Exclusion (%)

LDL-C > 130 mg/dL 53hsCRP < 2.0 mg/L 37Withdrew Consent 4

Diabetes 1Hypothyroid <1Liver Disease <1TG > 500 mg/dL <1Age out of range <1Current Use of HRT <1Cancer <1

Poor Compliance/Other 3

8,600 Completed Study120 Lost to follow-up

8,600 Completed Study120 Lost to follow-up

8,901 Included in Efficacy and Safety Analyses

8,901 Included in Efficacy and Safety Analyses

89,890 Screened

Men > 50 yearsWomen > 60 years

No CVD, No DMLDL < 130 mg/dLhsCRP > 2 mg/L

17,802 Randomized

Reason for Exclusion (%)

LDL > 130 mg/dL 52hsCRP < 2.0 mg/L 36Withdrew Consent 5Diabetes 1Hypothyroid <1Liver Disease <1TG > 500 mg/dL <1Age out of range <1Current Use of HRT <1Cancer <1Poor Compliance/Other 3

4 weekPlaceboRun-In

8,857 Completed Study44 Lost to follow-up

8,901 Assigned to Rosuvastatin 20 mg

8,901 Assigned toPlacebo

8,864 Completed Study37 Lost to follow-up

8,901 Included in Efficacy and Safety Analyses

8,901 Included in Efficacy and Safety Analyses

Ridker et al NEJM 2008

JUPITERTotal Venous Thromboembolism

0 1 2 3 4

0.00

00.

005

0.01

00.

015

0.02

00.

025

Cum

ulat

ive

Inci

denc

e

Number at Risk Follow-up (years)

RosuvastatinPlacebo

8,901 8,648 8,447 6,575 3,927 1,986 1,376 1,003 548 1618,901 8,652 8,417 6,574 3,943 2,012 1,381 993 556 182

HR 0.57, 95%CI 0.37-0.86P= 0.007 Placebo 60 /

8901

Rosuvastatin 34 / 8901

- 43 %

Glynn et al NEJM 2009

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

Placebo 251 / 8901

Rosuvastatin 142 / 8901

HR 0.56, 95% CI 0.46-0.69P < 0.00001

0 1 2 3 4

0.00

0.02

0.04

0.06

0.08

Cum

ulat

ive

Inci

denc

e

Number at Risk Follow-up (years)RosuvastatinPlacebo

8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 1578,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174

109 Fewer Events

JUPITERVTE 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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