Expanding The Orbit of Statin

Therapy
Dr. Tang Sie Hing
Consultant Interventional
Cardiologist
Chief, Cardiology Department
Normah Medical Specialist Centre,
 JUPITER
Justification for the Use of
statins in Primary prevention: an
Intervention Trial Evaluating
Rosuvastatin

Ridker P et al. N Eng J Med 2008;359: 2195-2207

 JUPITER
 JUPITER is the first large-scale, prospective study to examine
the role of statin therapy in individuals with low to normal
LDL-C levels, but with increased cardiovascular risk identified
by elevated CRP

 It assessed the long-term impact of rosuvastatin (CRESTOR™)

in individuals potentially at increased cardiovascular (CV) risk
due to elevated CRP levels who do not qualify for lipid-
lowering treatment according to current guidelines

Ridker P et al. N Eng J Med 2008;359: 2195-2207

 JUPITER - Rationale
 Nearly half of all cardiovascular events occur in patients who
are apparently healthy and who have low or normal levels of
LDL-C

 hsCRP predicts cardiovascular disease independent of LDL-C

levels

 Along with improved screening there is a need to examine the

use of lipid-lowering agents as a method of reducing the risk
of cardiovascular events

Ridker PM. New Engl J Med 2002; 347: 1557–1565

 Prevalence of conventional risk
factors† in patients with CHD
Four
(0.9%)
Three
None
8.9%
19.4%

27.8%
Two

43.0% One

Total patients=87 869

CHD=coronary heart disease
†smoking, hypertension, hypercholesterolaemia and diabetes mellitus

Khot UN et al. JAMA 2003; 290: 898–904

 CRP is a strong independent
predictor of CV events in women
Lp(a)
Homocysteine
IL-6
TC
LDL-C
sICAM-1
SAA
ApoB
TC/HDL-C
CRP
CRP + TC/HDL-C

0 1.0 2.0 4.0 6.0

Relative risk of future CV

Apo=apolipoprotein; CRP=C-reactive protein; CV=cardiovascular; HDL-C=high-density lipoprotein cholesterol; IL=interleukin;

LDL-C=low-density lipoprotein cholesterol; Lp(a)=lipoprotein (a); SAA=serum amyloid A; sICAM-1=soluble intercellular adhesion
molecule 1; TC=total cholesterol

Blake GJ, Ridker PM. Circ Res 2001; 89: 763–771

 CRP predicts risk of MI and stroke
in apparently healthy men
3.5 2.0 *

3.0 ***

1.5
2.5
Relative 2.0 Relative
risk of 1.0
1.5 ischaemi
risk
c
1.0 stroke 0.5
0.5

0 0
1 2 3 4 1 2 3 4

Quartile of Quartile of
CRP CRP

CRP=C-reactive protein; MI=myocardial infarction

*p=0.02 versus quartile 1; ***p<0.001 versus quartile 1

Ridker PM et al. N Engl J Med 1997; 336: 973–979

 CV event-free survival in women using
combined
1.00 LDL-C and hsCRP measures
Low LDL-C, low hsCRP
0.99
Probability
of event- High LDL-C, low hsCRP
free 0.98
survival Low LDL-C, high hsCRP

0.97

0.96 High LDL-C, high

hsCRP
0

CV=cardiovascular; hsCRP=high-sensitivity C-reactive protein; LDL-C=low-density lipoprotein cholesterol

Median LDL-C=3.2 mmol/L (124 mg/dL)

Ridker PM et al. N Engl J Med 2002; 347: 1557–1565
 Efficacy of Lovastatin in
AFCAPS/TexCAPS subgroups by

Median LDL-C=3.9 mmol/L (149 mg/dL). Median hsCRP=1.6 mg/L

AFCAPS/TexCAPS=Air Force/Texas Coronary Atherosclerosis Prevention Study; hsCRP=high-sensitivity C-reactive protein; LDL-
C=low-density lipoprotein cholesterol; N/A=not applicable; NNT=number needed to treat to prevent one coronary event

Ridker PM et al. N Engl J Med 2001; 344: 1959–1965

 JUPITER - Objective
• The primary objective was to investigate
whether long-term treatment with rosuvastatin
20 mg decreases the rate of first major
cardiovascular events compared with placebo
in patients with low to normal LDL-C but at
increased cardiovascular risk as identified by
elevated CRP levels

Ridker PM. Circulation 2003; 108: 2292–2297

 JUPITER – study design
No history of CAD Rosuvastatin 20 mg (n=8901)
men ≥50 yrs Placeb
women ≥60 yrs o
LDL-C <130 mg/dL run-in
CRP ≥2.0 mg/L Placebo (n=8901)

Visit: 1 2 3 4
Week: –6 –4 0 13 6-monthly Final

Lead-in/ Randomisation Lipids Lipids Lipids

eligibility CRP CRP CRP
Tolerability Tolerability Tolerability
HbA1C
Median follow-up 1.9 years

CAD=coronary artery disease; LDL-C=low-density lipoprotein cholesterol; CRP=C-reactive protein; HbA1c=glycated

haemoglobin

Ridker P et al. N Eng J Med 2008;359: 2195-2207

 JUPITER - Study Endpoints
 Primary Endpoint
 Time to the first occurrence of a major cardiovascular event,
composite of:
 cardiovascular death
 Stroke
 MI
 unstable angina
 arterial revascularisation
 Secondary Endpoints
 total mortality
 non-cardiovascular mortality
 development of diabetes mellitus
 development of venous thromboembolic events
 bone fractures
 discontinuation of study medication due to adverse effects.

Ridker PM. Circulation 2003; 108: 2292–2297

 JUPITER - Major inclusion
Men aged ≥50 years; women aged ≥60 years
Fasting LDL-C levels 130 mg/dL3.4 mmol/L),
CRP levels ≥2.0 mg/L and TG levels 500
mg/dL(5.7 mmol/L) on initial screening.

Ridker PM. Circulation 2003; 108: 2292–2297

 JUPITER - Major exclusion
 Current use of statins or other lipid-lowering therapies
 Current use of hormone replacement therapy
 Prior history of cardiovascular or cerebrovascular events, such as MI,
unstable angina, prior arterial revascularisation or stroke, or CHD-risk
equivalents
 Chronic inflammatory condition, such as severe arthritis, lupus or
inflammatory bowel disease and/or treatment with immunosuppressants
 Uncontrolled:
 hypertension: SBP > 190 mmHg or DBP > 100 mmHg
 hypothyroidism: TSH > 1.5 x ULN

 CK 3 x ULN
 Serum creatinine > 2.0 mg/dL
 Evidence of hepatic dysfunction (ALT > 2 x ULN)
 History of prior malignancy, alcohol or drug abuse
Ridker PM. Circulation 2003; 108: 2292–2297 CHD = coronary heart disease; CK = creatinine kinase; ULN = upper limit of
normal; SBP = systolic blood pressure; DBP = diastolic blood pressure
Ridker P et al. N Eng J Med 2008;359: 2195-2207
 JUPITER - Patient Flow
89,890 subjects screened
17,802 randomized

Rosuvastatin 20mg Placebo

n=8,901 n=8,901

Lost to follow up Lost to follow up

n=44 n=37

Completed study Completed study

n=8,857 n=8,864

Ridker P et al. N Eng J Med 2008;359: 2195-2207

 JUPITER - Baseline characteristics*
Rosuvastatin Placebo
n=8901 n=8901
Age (years) 66 (60-71) 66 (60-71)
Male sex (%) 61.5 62.1
Race (%)
White 71.4 71.1
Black 12.4 12.6
Hispanic 12.6 12.8
Other 3.6 3.5
BMI (kg/m2) 28.3 (25.3-32.0) 28.4 (25.3-32.0)
Systolic BP (mmHg) 134 (124-145) 134 (124-145)
Diastolic BP (mmHg) 80 (75-87) 80 (75-87)

*All values are median (interquartile range) or N (%).

Ridker P et al. N Eng J Med 2008;359: 2195-2207

 JUPITER - Baseline laboratory
Rosuvastatin Placebo
n=8901 n=8901

Total cholesterol (mg/dL) 186 (168-200) 185 (169-199)

LDL cholesterol (mg/dL) 108 (94-119) 108 (94-119)

HDL cholesterol (mg/dL) 49 (40-60) 49 (40-60)
Triglycerides (mg/dL) 118 (85-169) 118 (86-169)
hsCRP (mg/L) 4.2 (2.8-7.1) 4.3 (2.8-7.2)
Glucose (mg/dL) 94 (87-102) 94 (88-102)
HbA1c(%) 5.7 (5.4-5.9) 5.7 (5.5-5.9)
Glomerular filtration rate,
(ml/min/1.73m2) 73.3 (64.6-83.7) 73.6 (64.6-84.1)

For hsCRP, values are the average of the values obtained at two screening and visits

*All values are median (interquartile range) or N (%).

Ridker P et al. N Eng J Med 2008;359: 2195-2207
 JUPITER - Medical History
Medical History Rosuvastatin
Placebo

Current smoker (%) 15.7 16.0

Family history CHD† (%) 11.2 11.8
Metabolic syndrome‡ (%) 41.0 41.8
Aspirin use (%) 16.6 16.6

†Family history of premature CHD defined as first degree relative with CHD at age < 55 yrs (male), < 65 yrs
(female); ‡ Metabolic syndrome defined according to consensus criteria of AHA/NHLBI
Ridker P et al. N Eng J Med 2008;359: 2195-2207
JUPITER population compared with previous
trials in patients without established CHD

CVD=cardiovascular disease; CHD=coronary heart disease; LDL-C=low-density lipoprotein cholesterol; HDL-C=high-

density lipoprotein cholesterol; hsCRP=high sensitivity C-reactive protein; *Baseline lipid levels are mean values.
Ridker PM et al. Am J Cardiol 2007; 100: 1659–1664 Ridker PM et al. N Engl J Med. 2001 344: 1959-65
 JUPITER - Primary Endpoint
Time to first occurrence of a CV death, non-fatal
stroke, non-fatal MI, unstable angina or arterial
.08 Placeb
Hazard Ratio 0.56
0

o
(95% CI 0.46-0.69)
P<0.00001
Cumulative Incidence

.06
0

Rosuvastatin 20 mg
.04
0

NNT for 2y = 95
.02

4y = 31
0

5y* = 25
.00
0

0 1 2 3 4

Number at Risk Follow-up

Rosuvastati 8,90 8,63 8,41 6,54 (years) 1,95
3,89 1,35 98 54 15
n
Placeb 1
8,90 1
8,62 2
8,35 0
6,50 3
3,87 8
1,96 3
1,33 3
95 4
53 7
17
o 1 1 3 8 2 3 3 5 4 4
*Extrapolated figure based on Altman and Andersen method Ridker P et al. N Eng J Med 2008;359: 2195-2207
 JUPITER - Primary Endpoint
Placebo
Rosuvastatin HR 95% CI p-
value [n=8901] [n=8901]

Primary Endpoint 251 (1.36) 142 (0.77) 0.56

0.46-0.69 <0.001*
Non-fatal MI 62 (0.33) 22 (0.12) 0.35
0.22-0.58 <0.001*
Fatal or non-fatal MI 68(0.37) 31 (0.17) 0.46 0.30-
0.70 0.0002
Non-fatal stroke 58 (0.31) 30 (0.16) 0.52
0.33-0.80 0.003
Fatal or non-fatal stroke 64 (0.34) 33 (0.18) 0.52
0.34-0.79 0.002
Arterial Revascularization 131 (0.71) 71 (0.38) 0.54
0.41-0.72 <0.0001
Unstable angina† 27 (0.14) 16 (0.09) 0.59
0.32-1.10 0.09
CV death, stroke, MI 157 (0.85) 83 (0.45) 0.53
** Rates are per 100 person years; † Hospitalisation due to*unstable angina; *Actual p-value was < 0.00001
0.40-0.69 <0.001
HR – Hazard Ratio; CI – Confidence Limit Ridker P et al. N Eng J Med 2008;359: 2195-2207
JUPITER – Subgroup analysis
Rosuvastatin better Placebo
better

2
0.

4
0.

6
0.

8
0.

2
1.
0

1
Hazard ratio (95% CI)

Ridker P et al. N Eng J Med 2008;359: 2195-2207

 JUPITER - Total Mortality
.06
Death from any cause
0

Hazard Ratio 0.80

(95% CI 0.67-0.97) Placeb
p=0.02 o
.05
0
Cumulative Incidence

Rosuvastatin 20mg
.04
0
.03
0
.02
0
.01
0
.00
0

0 1 2 3 4

Number at Risk Follow-up

Rosuvastati 8,90 8,84 8,78 6,99 (years)
4,31 2,26 1,60 1,19 68 22
n
Placeb 1
8,90 7
8,85 7
8,77 9
6,98 2
4,31 8
2,29 2
1,61 2
1,19 3
68 7
24
o 1 2 5 7 9 5 4 6 4 6
Ridker P et al. N Eng J Med 2008;359: 2195-2207
 JUPITER
Effects on LDL-C, HDL-C, TG and hsCRP at 12 months;
Percentage change between rosuvastatin and placebo

10 LDL-C HDL-C TG hsCR

P
4%
0
Percentage change
from baseline (%)

p<0.001*
-10
17%
-20 p<0.00

-30
37%
-40 p<0.00

50%
-50
p<0.00
-60

*P-value at study completion (48 months) = 0.34

Ridker P et al. N Eng J Med 2008;359: 2195-2207
 JUPITER Tolerability and
Safety data
Placebo Rosuvastatin p-
value [n=8901] [n=8901]

Adverse Events, (%)

Any serious adverse event 15.5 15.2 0.60
Muscle weakness, stiffness, pain 15.4 16.0 0.34
Myopathy 0.1 0.1 0.82
Rhabdomyolysis 0.0 <0.1*
----
Newly diagnosed cancer 3.5 3.4
0.51
Death from cancer 0.7 0.4
0.02
Gastrointestinal disorders 19.2 19.7
0.43
Renal disorders 5.4 6.0
0.08
Bleeding 3.1 2.9
0.45
Hepatic disorders 2.1 2.4
0.13
*Occurred after trial completion; **physician reported newly diagnosed diabetes Ridker P et al. N Eng J Med 2008;359: 2195-2207
JUPITER Laboratory Safety Data
Placebo Rosuvastatin p-
value
[n=8901] [n=8901]

Laboratory Values, N (%)

Serum creatinine‡ 10 (0.10) 16 (0.20)
0.24
ALT > 3 x ULN# 17 (0.20) 23 (0.30)
0.34
Glycosuria† 32 (0.40) 36 (0.50)
0.64

Laboratory Values, median values (IQR)

GFR*, (mL/min/1.73m2) 66.6 (58.8-76.2) 66.8 (59.1-76.5)
0.02
% HbA1c** 5.8 (5.6-6.1) 5.9 (5.7-6.1)
0.00
Fasting plasma glucose**, (mg/dL) 98 (90-106) 98 (91-107)

GFR = Glomerular filtration rate, HbA1c = Haemoglobin A1c

# on consecutive visits, ‡ >100% increase from baseline, *at 12 months, **at 24 months, †>trace at 12 months
Ridker P et al. N Eng J Med 2008;359: 2195-2207
 JUPITER – summary and
perspectives
 The JUPITER study included patients with low to normal LDL-C who
were at increased CV risk as identified by elevated CRP levels and
who did not require statin treatment based on current treatment
guidelines.
 A 44% reduction in the primary endpoint of major cardiovascular
events (composite of: CV death, MI, stroke, unstable angina, arterial
revascularisation) was observed in patients who received rosuvastatin
20 mg compared with placebo (p< 0.00001).

 A 20% reduction in total mortality was observed in patients who

received rosuvastatin 20 mg compared with placebo (p=0.02), a
unique finding for statins in a population without established CHD.

 In JUPITER, long-term treatment with rosuvastatin 20 mg was well

tolerated in nearly 9000 study participants.
 There was no difference between treatment groups for muscle
weakness, cancer, haematological disorders, gastrointestinal, hepatic
or renal systems.

 The results from JUPITER highlight the importance

Ridker P et al.of highly
N Eng effective
J Med 2008;359: 2195-2207
THANK YOU