CM-1

Role of Rosuvastatin in the Treatment of Dyslipidemia

Daniel J. Rader, MDAssociate Professor of Medicine

Director, Preventive Cardiology and Lipid ClinicUniversity of Pennsylvania School of Medicine

CM-2Evolution of Lipid Management Guidelines:The National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP)

ATP I (1988) ATP II (1993) ATP III (2001)

Diet; low-dose,nonstatin

monotherapy

High-dose statin, combination therapy

Low- to moderate-dose statin monotherapy

Increasing aggressiveness of cholesterol-lowering therapy

CM-3

Most Patients Failed to Achieve ATP II LDL-C Goals With Lipid-Lowering Therapy

68

37

18

73

30

17

39

25

0

10

20

30

40

50

60

70

80

Low risk Medium risk CHD

Pat

ien

ts,

% a

t g

oal

L-TAP (n = 4888) Jacobson (n = 6796)

Sloan (n = 13,891) Sueta (n = 21,378)

< 160 mg/dL < 130 mg/dL ≤ 100 mg/dL

Pearson TA, et al. Arch Intern Med. 2000;160:459-467;Jacobson TA, et al. Arch Intern Med. 2000;160:1361-1369;Sloan KL, et al. Am J Cardiol. 2001;88:1143-1146; Sueta CA, et al. Am J Cardiol. 1999;83:1303-1307.

CM-4

Many Patients With CHD Do Not Come Close to Achieving ATP II LDL-C Goal: L-TAP

17.5

9.9

1314.4

11.19.4

7.9

16.6

02468

101214161820

≤ 100 101-110 111-120 121-130 131-140 141-150 151-160 > 160

LDL-C, mg/dL

Pat

ien

ts,

%

Pearson TA, et al. Arch Intern Med. 2000;160:459-467.

n = 1,460

CM-5

Many High Risk Patients Are Not Titrated or Do Not Reach LDL-C Goal Even After Titration

2,989 high-risk patients2,989 high-risk patients††

(with known NCEP(with known NCEPLDL-C goal)LDL-C goal)

53% not at goal53% not at goalon starting doseon starting dose

(n = 1575)(n = 1575)

47% at goal47% at goalon starting doseon starting dose

(n = 1414)(n = 1414)

53%53%Not titratedNot titrated

(n = 838)(n = 838)

47%47%TitratedTitrated(n = 737)(n = 737)

31%31%Not at goalNot at goal(n = 478)(n = 478)

16%16%at goalat goal

(n = 259)(n = 259)

†CHD and/or diabetes mellitus with high-density lipoprotein cholesterol (HDL-C) ≤ 45 mg/dL.Simpson RJ Jr. Circulation 2001.

CM-6

Cholesterol Treatment in NHANES (1999-2000)

Only 47% of hypercholesterolemic patients treated with drug therapy are adequately controlled.

Ford et al. Circulation. 2003;107:5185.

CM-7Many Patients With CHD Fail to Achieve LDL-C and Non-HDL-C Goals Even With Dose TitrationACCESS

0

10

20

30

40

50

60

70

80

90

100

LDL-C Non–HDL-C

Pat

ien

ts,

% a

t g

oal

Atorvastatin 10 - 80 mg

Simvastatin 10 - 40 mg

Lovastatin 20 - 80 mg

Fluvastatin 20 - 80 mg

Pravastatin 10 - 40 mg

†Patients in CHD risk category. Ballantyne CM, et al. Am J Cardiol. 2001;88:265-269.

n = 2,543†

At Wk 54At Wk 54

CM-8

On-Treatment LDL-C Is Closely Related to CHD Events in Statin Trials

HPS-Rx

HPS-placCARE-Rx

4S-plac

4S-Rx

LIPID-plac

CARE-placLIPID-Rx

WOSCOPS-plac

WOSCOPS-Rx

AFCAPS-plac

ASCOT-plac

AFCAPS-Rx

ASCOT-Rx

2° prevention

1° prevention

0

5

10

15

20

25

30

80 100 120 140 160 180 200

Mean on-treatment LDL-C level at follow-up (mg/dL)

% w

ith

CH

D e

ven

tCHD + revasc + stroke

CHD

pIac = Placebo; Rx = Treatment.Adapted from Ballantyne CM. Am J Cardiol. 1998;82:3Q-12Q.

CM-9HPS: Major Vascular Events in Highest and Lowest LDL-C Tertiles and Effect of Therapy

1012141618202224262830

40 60 80 100 120 140 160

Mean LDL-C, mg/dL

Vas

cula

r ev

ents

, %

Lowest LDL-C tertile

Highest LDL-C tertile

Placebo

Simvastatin

www.hpsinfo.org

8

CM-10

Medical Need in the Treatment of Dyslipidemia

A need exists for more efficacious therapy to achieve

– Greater LDL-C and non-HDL-C lowering at start dose

CM-11

% of Patients Achieving Both LDL-C and Non-HDL-C ATP III Goals

66

32

0

20

40

60

80

100

Achievement of both LDL-Cand non-HDL-C goals

Pat

ien

ts,

%

Rosuvastatin 10 mgAtorvastatin 10 mg

*

*P < .05 vs comparators. Baseline TG ≥ 200 mg/dL.

80

54

20

0

20

40

60

80

100

Achievement of both LDL-Cand non-HDL-C goals

Pat

ien

ts,

%

Rosuvastatin 10 mgSimvastatin 20 mgPravastatin 20 mg

Trials 24 - 26 Trials 27 - 28

CM-12

Medical Need in the Treatment of Dyslipidemia

A need exists for more efficacious therapy to achieve

– Greater LDL-C and non-HDL-C lowering at start dose

– Greater LDL-C and non-HDL-C lowering at maximal dose

CM-13

Familial Hypercholesterolemia (FH)

FH is common– There are 500,000 patients in the US

(frequency, 1 person in 500) FH causes early CHD– Average age of CHD onset is 45 to 50 yr in

men, 55 to 60 yr in women FH is difficult to treat–Most FH patients cannot be adequately

treated to NCEP LDL-C goal

CM-14% of High-Risk FH Patients Achieving NCEP ATP III LDL-C Goal in 2 Different Studies

17

4.5

17

4

0

10

20

30

40

50

% a

chie

vin

g g

oal

Rosuvastatin 40 mg

Atorvastatin 80 mgAtorvastatin 40 mg + Ezetimibe 10 mg

Atorvastatin 80 mg

Note: no statistical analyses were performed.LDL-C: < 100 mg/dL (2.59 mmol/L). Stein et al. J Am Col Cardiol 2003.

CM-15

Low HDL-C Is Common and Represents an Important Medical Need

Low HDL-C is one of the most common risk factors in patients with premature CHD

ATP III placed new emphasis on low HDL-C as a risk factor and potential target for intervention

Modest increases in HDL-C may translate into substantial cardiovascular risk reduction

Expert Panel on Detection, Evaluation, and Treatment ofHigh Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

CM-16

Medical Need in the Treatment of Dyslipidemia

A need exists for more efficacious therapy to achieve

– Greater LDL-C and non-HDL-C lowering at start dose

– Greater LDL-C and non-HDL-C lowering at maximal dose

– Improved HDL-C raising

CM-17HDL-C: % Change From Baseline Rosuvastatin: Baseline HDL-C < 40 mg/dL or ≥ 40 mg/dLTrial 65 – STELLAR (Wk 6)

12

20

14

7 8 9

0

5

10

15

20

25

10 mg 20 mg 40 mg 10 mg 20 mg 40 mg

Rosuvastatin

% c

han

ge

fro

m b

asel

ine

Data presented as LS mean.

HDL-C < 40 mg/dL HDL-C ≥ 40 mg/dL

CM-18

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% decrease1% decreasein LDL-C reduces in LDL-C reduces

CHD risk byCHD risk by1%1%

1% increase1% increasein HDL-C reduces in HDL-C reduces

CHD risk byCHD risk by3%3%

CM-19

Role of Rosuvastatin in the Treatment of Dyslipidemia

Greater LDL-C and non-HDL-C lowering at start dose

Greater LDL-C and non-HDL-C lowering at maximal dose

Improved HDL-C raising