1. “An Examination of the JUPITER Trial”
Moderator
Kevin Winfield, MD
Medical Director
Clear Lake Lipid Center
Houston, TX

2. Disclosure
Disclosure of Unlabeled Use and Investigational Product Discussions:
Dr. Winfield has indicated that his presentation will not include the discussion of unlabeled uses of commercial products or products that have not yet been approved by the FDA for use in the United States for any purpose.
Disclosure of Affiliations and Significant Relationships:
Dr. Winfield has received honoraria related to speakers’ bureau activities from Novartis, AstraZeneca, and Abbott Laboratories.

3. “An Examination of the JUPITER Trial”
Paul Ridker, MD
Director
Center for Cardiovascular
Disease Prevention
Division of Preventive Medicine
Brigham and Women’s Hospital
Boston, MA

4. Disclosure Disclosure of Affiliations and Significant Relationships:
Dr. Ridker has received honoraria related to consulting activities from Schering-Plough, Sanofi-Aventis, AstraZeneca, Isis, Dade, Merck & Co., Novartis, Vascular Biogenics.
He has also received grant support from research activities from National Heart, Lung, and Blood Institute, National Cancer Institute, American Heart Association, Doris Duke Charitable Foundation, Leducq Foundation, Donald W. Reynolds Foundation, James and Polly Annenberg La Vea Charitable Trusts, AstraZeneca, Novartis, Pharmacia, Roche, Sanofi-Aventis, Abbott Laboratories, Amgen.
Equity: Co-inventor on patients held by Brigham and Women’s Hospital.

5. The JUPITER Trial JUPITER AHA November 9, 2008
A Randomized Trial of Rosuvastatin in the Prevention
of Cardiovascular Events Among 17,802 Apparently Healthy
Men and Women With Elevated Levels
of C-Reactive Protein (hsCRP):
The JUPITER Trial
Paul Ridker*, Eleanor Danielson, Francisco Fonseca*, Jacques Genest*,
Antonio Gotto*, John Kastelein*, Wolfgang Koenig*, Peter Libby*,
Alberto Lorenzatti*, Jean MacFadyen, Borge Nordestgaard*,
James Shepherd*, James Willerson, and Robert Glynn*
on behalf of the JUPITER Trial Study Group
An Investigator Initiated Trial Funded by AstraZeneca, USA
* These authors have received research grant support and/or consultation fees from one or more
statin manufacturers, including Astra-Zeneca. Dr Ridker is a co-inventor on patents held by the
Brigham and Women’s Hospital that relate to the use of inflammatory biomarkers in
cardiovascular disease that have been licensed to Dade-Behring and AstraZeneca.

6. hsCRP Adds Prognostic Information Beyond Traditional Risk Factors in All Major Cohorts Evaluated
PHS 1997
WHS 2000
UK 2000
MONICA 2004
ARIC 2004
Iceland 2004
NHS 2004
HPFUS 2004
EPIC-N 2005
Strong 2005
Kuopio 2005
FHS 2006
CHS 2005
PIMA 2005
Fully Adjusted Relative Risk
< 1 mg/L
1 to 3 mg/L
> 3 mg/L

7. What are the environmental and genetic influences on CRP?
Relative Risk of Future CV Events
“low risk”
“moderate risk”
“high risk”
hsCRP (mg/L)
Ridker et al Circulation 2004;109:

8. Inflammation, Statin Therapy, and hsCRP: Initial Observations
P Trend = 0.005
-21.6% (P=0.004) 3
0.25
0.24
Placebo 2
0.23
0.22
Relative Risk
Median hs-CRP (mg/dL)
0.21 1
0.20
Pravastatin
0.19
0.18
Pravastatin
Placebo
Pravastatin
Placebo
Baseline
5 Years
Inflammation Absent
Inflammation Present
Circulation. 1998;98:839–844.
Circulation. 1999;100:

9. Clinical Relevance of Achieved LDL and Achieved hsCRP
After Treatment with Statin Therapy
Cumulative Rate of
Recurrent Myocardial Infarction or Coronary Death (percent)
0.10
0.10
hsCRP>2 mg/L
LDLC>70 mg/dL
0.08
0.08
0.06
0.06
0.04
0.04
hsCRP<2 mg/L
LDLC<70 mg/dL
0.02
0.02
0.00
0.00
0.0
0.5
1.0
1.5
2.0
2.5
0.0
0.5
1.0
1.5
2.0
2.5
Follow-Up (years)
Ridker et al NEJM 2005;352:20-28.

10. Clinical Relevance of Achieved LDL and Achieved hsCRP
After Treatment with Statin Therapy
0.0
0.5
1.0
1.5
2.0
2.5
0.00
0.02
0.04
0.06
0.08
0.10
Recurrent Myocardial Infarction or Coronary Death
(percent)
Follow-Up (Years)
LDL > 70 mg/dL, CRP > 2 mg/L
LDL > 70 mg/dL, CRP < 2 mg/L
LDL < 70 mg/dL, CRP > 2 mg/L
LDL < 70 mg/dL, CRP < 2 mg/L
Ridker et al NEJM 2005;352:20-28.

11. JUPITER Why Consider Statins for Low LDL, high hsCRP Patients?
In 2001, in an hypothesis generating analysis of apparently healthy individuals in the AFCAPS / TexCAPS trial*, we observed that those with low levels of both LDL and hsCRP had extremely low vascular event rates and that statin therapy did not reduce events in this subgroup (N=1,448, HR 1.1, 95% CI ). Thus, a trial of statin therapy in patients with low cholesterol and low hsCRP would not only be infeasible in terms of power and sample size, but would be highly unlikely to show clinical benefit.
In contrast, we also observed within AFCAPS/TexCAPS that among those with low LDL but high hsCRP, vascular event rates were just as high as rates among those with overt hyperlipidemia, and that statin therapy significantly reduced events in this subgroup (N=1,428, HR 0.6, 95% CI ).
*Ridker et al N Engl J Med 2001;344:

12. JUPITER Why Consider Statins for Low LDL, high hsCRP Patients?
AFCAPS/TexCAPS Low LDL Subgroups
Low LDL, Low hsCRP
Low LDL, High hsCRP
Low LDL, Low hsCRP
Low LDL, High hsCRP
[A]
[B]
0.5
1.0
2.0
0.5
1.0
2.0 RR
Statin Effective
Statin Not Effective
Statin Effective
Statin Not Effective
However, while intriguing and of potential public health importance, the observation in AFCAPS/TexCAPS that statin therapy might be effective among those with elevated hsCRP but low cholesterol was made on a
post hoc basis. Thus, a large-scale randomized trial of statin therapy was needed to directly test this hypotheses.
Ridker et al, New Engl J Med 2001;344:

13. Justification for the Use of statins in Prevention:
JUPITER
Primary Objectives
Ridker et al NEJM 2008
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin
To investigate whether rosuvastatin 20 mg compared to
placebo would decrease the rate of first major cardiovascular
events among apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are nonetheless
at increased vascular risk on the basis of an enhanced
inflammatory response, as determined by hsCRP > 2 mg/L.
To enroll large numbers of women and individuals of Black or
Hispanic ethnicity, groups for whom little data on primary
prevention with statin therapy exists.

14. JUPITER
Trial Design
JUPITER Multi-National Randomized Double Blind Placebo Controlled Trial of Rosuvastatin in the Prevention of Cardiovascular Events Among Individuals With Low LDL and Elevated hsCRP MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA
Rosuvastatin 20 mg (N=8901)
No Prior CVD or DM
Men >50, Women >60
LDL <130 mg/dL
hsCRP >2 mg/L
Placebo (N=8901)
4-week run-in
Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker et al, Circulation 2003;108:

15. Baseline Clinical Characteristics
JUPITER
Baseline Clinical Characteristics
Rosuvastatin Placebo
(N = 8901) (n = 8901)
Age, years (IQR) ( ) ( )
Female, N (%) 3,426 (38.5) 3,375 (37.9)
Ethnicity, N (%)
Caucasian 6,358 (71.4) 6,325 (71.1)
Black 1,100 (12.4) 1,124 (12.6)
Hispanic 1,121 (12.6) 1,140 (12.8)
Blood pressure, mm (IQR)
Systolic ( ) 134 ( )
Diastolic (75-87) 80 (75-87)
Smoker, N (%) 1,400 (15.7) 1,420 (16.0)
Family History, N (%) 997 (11.2) 1,048 (11.8)
Metabolic Syndrome, N (%) 3,652 (41.0) 3,723 (41.8)
Aspirin Use, N (%) 1,481 (16.6) 1,477 (16.6)
All values are median (interquartile range) or N (%)

16. Baseline Blood Levels (median, interquartile range)
JUPITER
Baseline Blood Levels (median, interquartile range)
Rosuvastatin Placebo
(N = 8901) (n = 8901)
hsCRP, mg/L ( ) ( )
LDL, mg/dL ( ) 108 ( )
HDL, mg/dL (40 – 60) 49 (40 – 60)
Triglycerides, mg/L 118 ( ) ( )
Total Cholesterol, mg/dL 186 ( ) 185 ( )
Glucose, mg/dL 94 (87 – 102) 94 (88 – 102)
HbA1c, % (5.4 – 5.9) (5.5 – 5.9)
All values are median (interquartile range) [ Mean LDL = 104 mg/dL ]

17. Comparison of the JUPITER trial population to previous statin trials
of primary prevention
JUPITER WOSCOPS AFCAPS
Sample size (n) 17, , ,605
Women (n) 6,
Minority (n) 5,
Duration (yrs) (max 5)
Diabetes (%)
Baseline LDL-C (mg/dL)
Baseline HDL-C (mg/dL)
Baseline TG (mg/dL)
Baseline hsCRP (mg/L) > NA NA
Intervention Rosuvastatin Pravastatin Lovastatin
20 mg 40 mg mg
JUPITER Trial Study Group, Am J Cardiol 2007

18. JUPITER Effects of rosuvastatin 20 mg on LDL, HDL, TG, and hsCRP
LDL (mg/dL)
HDL (mg/dL)
LDL decrease 50 percent at 12 months
HDL increase 4 percent at 12 months
hsCRP (mg/L)
TG (mg/dL)
hsCRP decrease 37 percent at 12 months
TG decrease 17 percent at 12 months 12 24 36 48
Months
Months

19. JUPITER
Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death
Placebo 251 / 8901
0.08
0.06
Cumulative Incidence
0.04
Rosuvastatin 142 / 8901
0.02
0.00 1 2 3 4
Follow-up (years)
Number at Risk
Rosuvastatin
8,901
8,631
8,412
6,540
3,893
1,958
1,353
983
544
157
Placebo
8,901
8,621
8,353
6,508
3,872
1,963
1,333
955
534
174

20. JUPITER
Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death
HR 0.56, 95% CI
P <
Placebo 251 / 8901
0.08
Number Needed to Treat (NNT5) = 25
- 44 %
0.06
Cumulative Incidence
0.04
Rosuvastatin 142 / 8901
0.02
0.00 1 2 3 4
Follow-up (years)
Number at Risk
Rosuvastatin
8,901
8,631
8,412
6,540
3,893
1,958
1,353
983
544
157
Placebo
8,901
8,621
8,353
6,508
3,872
1,963
1,333
955
534
174

21. - 47 % JUPITER Myocardial Infarction, Stroke, Cardiovascular Death
HR 0.53, 95%CI
P <
0.05
Placebo (N = 157)
0.04
- 47 %
0.03
Cumulative Incidence
0.02
Rosuvastatin (N = 83)
0.01
0.00 1 2 3 4
Follow-up (years)
Number at Risk
Rosuvastatin
8,901
8,643
8,437
6,571
3,921
1,979
1,370
998
551
159
Placebo
8,901
8,633
8,381
6,542
3,918
1,992
1,365
979
550
181

22. - 47 % JUPITER Arterial Revascularization / Unstable Angina
HR 0.53, 95%CI
P <
0.06
Placebo (N = 143)
0.05
0.04
- 47 %
Cumulative Incidence
0.03
0.02
Rosuvastatin (N = 76)
0.01
0.00 1 2 3 4
Follow-up (years)
Number at Risk
Rosuvastatin
8,901
8,640
8,426
6,550
3,905
1,966
1,359
989
547
158
Placebo
8,901
8,641
8,390
6,542
3,895
1,977
1,346
963
538
176

23. Individual Components of the Primary Endpoint
JUPITER
Individual Components of the Primary Endpoint
Endpoint Rosuvastatin Placebo HR 95%CI P
Primary Endpoint* <
Non-fatal MI <
Any MI <0.0002
Non-fatal Stroke
Any Stroke
Revascularization
or Unstable Angina <
MI, Stroke, CV Death <
*Nonfatal MI, nonfatal stroke, revascularization, unstable angina, CV death

24. Primary Endpoint – Subgroup Analysis I
JUPITER
Primary Endpoint – Subgroup Analysis I N
P for Interaction
Men
11,001
0.80
Women
6,801
Age
< 65
8,541
0.32
Age > 65
9,261
Smoker
2,820
0.63
Non-Smoker
14,975
Caucasian
12,683
0.57
Non-Caucasian
5,117
USA/Canada
6,041
0.51
Rest of World
11,761
Hypertension
10,208
0.53
No Hypertension
7,586
All Participants
17,802
0.25
0.5
1.0
2.0
4.0
Rosuvastatin Superior
Rosuvastatin Inferior

25. Primary Endpoint – Subgroup Analysis II
JUPITER
Primary Endpoint – Subgroup Analysis II N
P for Interaction
Family HX of CHD
2,045
0.07
No Family HX of CHD
15,684
BMI < 25 kg/m 2
4,073
0.70
BMI kg/m
7,009 2
BMI
>
30 kg/m 2
6,675
Metabolic Syndrome
7,375
0.14
No Metabolic Syndrome
10,296
Framingham Risk
<
10%
8,882
0.99
Framingham Risk > 10%
8,895
hsCRP > 2 mg/L Only
6,375
hsCRP > 2 mg/L Only
6,375
All Participants
17,802
0.25
0.5
1.0
2.0
4.0
Rosuvastatin Superior
Rosuvastatin Inferior

26. Adverse Events and Measured Safety Parameters
JUPITER
Adverse Events and Measured Safety Parameters
Event Rosuvastatin Placebo P
Any SAE 1,352 (15.2) 1,337 (15.5) 0.60
Muscle weakness 1,421 (16.0) 1,375 (15.4) 0.34
Myopathy (0.1) (0.1) 0.82
Rhabdomyolysis (0.01)* (0.0) --
Incident Cancer (3.4) (3.5) 0.51
Cancer Deaths (0.4) (0.7) 0.02
Hemorrhagic stroke (0.1) (0.1) 0.44
GFR (ml/min/1.73m2 at 12 mth) ( ) ( ) 0.02
ALT > 3xULN (0.3) (0.2) 0.34
Fasting glucose (24 mth) (91-107) (90-106) 0.12
HbA1c (% at 24 mth) ( ) ( ) 0.01
Glucosuria (12 mth) (0.5) (0.4) 0.64
Incident Diabetes** (3.0) (2.4) 0.01
*Occurred after trial completion, trauma induced. All values are median (interquartile range) or N (%)
**Physician reported

27. Statins and the Development of Diabetes
JUPITER
Statins and the Development of Diabetes
HR (95% CI)
WOSCOPS Pravastatin
(0.50–0.98)
PROSPER Pravastatin
(1.06–1.68)
HPS Simvastatin
(0.98–1.35)
ASCOT-LLA Atorvastatin
(0.91–1.44)
PROVE-IT Atorvastatin VS Pravastatin
(0.67–1.83)
JUPITER Rosuvastatin
(1.05–1.54)
0.25
0.5
1.0 2 4
Statin Better
Statin Worse

28. Secondary Endpoint – All Cause Mortality
JUPITER
Secondary Endpoint – All Cause Mortality
HR 0.80, 95%CI
P= 0.02
Placebo 247 / 8901
0.06
- 20 %
0.05
0.04
Cumulative Incidence
0.03
Rosuvastatin 198 / 8901
0.02
0.01
0.00 1 2 3 4
Follow-up (years)
Number at Risk
Rosuvastatin
8,901
8,847
8,787
6,999
4,312
2,268
1,602
1,192
683
227
Placebo
8,901
8,852
8,775
6,987
4,319
2,295
1,614
1,196
684
246

29. JUPITER
Conclusions – Efficacy I
Among apparently healthy men and women with elevated
hsCRP but low LDL, rosuvastatin reduced by 47 percent
incident myocardial infarction, stroke, and cardiovascular
death.
Despite evaluating a population with lipid levels widely
considered to be “optimal” in almost all current prevention
algorithms, the relative benefit observed in JUPITER was
greater than in almost all prior statin trials.
In this trial of low LDL/high hsCRP individuals who do not
currently qualify for statin therapy, rosuvastatin significantly
reduced all-cause mortality by 20 percent.

30. JUPITER
Conclusions – Efficacy II
Benefits of rosuvastatin were consistent in all sub-groups
evaluated regardless of age, sex, ethnicity, or other baseline
clinical characteristic, including those with elevated hsCRP
and no other major risk factor.
Rates of hospitalization and revascularization were reduced
by 47 percent within a two-year period suggesting that the
screening and treatment strategy tested in JUPITER is
likely to be cost-effective, benefiting both patients and payers.
The Number Needed to Treat in JUPITER was 25 for the primary
endpoint, a value if anything smaller than that associated
with treating hyperlipidemia in primary prevention.

31. JUPITER
Conclusions - Safety
With regard to safety , the JUPITER results
show no increase in serious adverse events among those
allocated to rosuvastatin 20 mg as compared to placebo
in a setting where half of the treated patients achieved
levels of LDL< 55 mg/dL (and 25 percent had LDL < 44
mg/dL).
show no increase in myopathy, cancer, hepatic
disorders, renal disorders, or hemorrhagic stroke with
treatment duration of up to 5 years
show no increase in systematically monitored glucose or
glucosuria during follow-up, but small increases in
HbA1c and physician reported diabetes similar to that
seen in other major statin trials

32. Is the benefit observed in the JUPITER trial associated with achieving
Achieved LDLC, Achieved hsCRP, or Both?
Is the benefit observed in the JUPITER
trial associated with achieving
a low level of LDLC,
a low level of hsCRP
or both?
Do we need to achieve the “dual targets”
of low LDLC and low hsCRP in order to
maximize the benefit of statin therapy?

33. JUPITER Predicted Benefit Based on LDL Reduction vs Observed Benefit
Ridker et al NEJM 2008
Proportional reduction in vascular event rate (95% CI)
CTT
JUPITER PREDICTED
TNT
PROVE-IT
A-to-Z
IDEAL
Mean LDL cholesterol difference between treatment groups (mmol/l)

34. JUPITER Predicted Benefit Based on LDL Reduction vs Observed Benefit
Ridker et al NEJM 2008
JUPITER OBSERVED
Proportional reduction in vascular event rate (95% CI)
CTT
JUPITER PREDICTED
TNT
PROVE-IT
A-to-Z
IDEAL
Mean LDL cholesterol difference between treatment groups (mmol/l)

35. Following Initiation of Statin Therapy
Clinical Importance of Achieving LDL-C < 70 mg/dL and hsCRP < 2 mg/L
Following Initiation of Statin Therapy
LDL>70, hsCRP>2
LDL<70, hsCRP>2
LDL>70, hsCRP<2
LDL<70, hsCRP<2 2 4 6 8 10
Recurrent Myocardial Infarction or Death
(percent)
180
360
540
720
900
Follow-up (days)
Follow-up (days)
PROVE IT – TIMI 22
NEJM 2005;352:20-28.
A to Z
Circulation 2006;114:281-8

36. 1. LDL-C is a strong, independent predictor of future CV events
PROVE IT, A to Z, AFCAPS/TexCAPS, REVERSAL Dose Correct Use of Statin Therapy Require Evaluation for both LDLC and hsCRP?
1. LDL-C is a strong, independent predictor of future CV events
2. Statins Lower LDL-C
3. The level of LDL-C achieved after starting statin therapy predicts recurrent event rates (ie “lower is better”)
1. hsCRP is a strong, independent predictor of future CV events
2. Statins Lower hsCRP
3. The level of hsCRP achieved after starting statin therapy predicts recurrent event rates (ie “lower is better”)
Dual Goals for Statin Therapy :
LDL-C < 70 mg/dL and hsCRP < 2 mg/L

37. Among men over 45 and post-menopausal women:
JUPITER
Implications for Primary Prevention
Ridker et al NEJM 2008
A simple evidence based approach to statin therapy
for primary prevention.
Among men over 45 and post-menopausal women:
If diabetic or family history, treat
If LDLC > 160 mg/dL, treat
If hsCRP > 3 mg/L, treat

38. Public Health Implications
JUPITER
Public Health Implications
Ridker et al NEJM 2008
Application of the simple screening and treatment strategy
tested in the JUPITER trial over a five-year period could
conservatively prevent more than 250,000 heart attacks,
strokes, revascularization procedures, and cardiovascular
deaths in the United States alone.
We thank the 17,802 patients and the >1,000 investigators
worldwide for their personal time, effort, and commitment
to the JUPITER trial.

39. “An Examination of the JUPITER Trial”
Christie Ballantyne, MD
Chief, Section of Atherosclerosis and Vascular Medicine
Director, Center for Cardiovascular Disease Prevention
Co-Director, Lipid Metabolism and Atherosclerosis Clinic
Methodist DeBakey Heart Center
Baylor College of Medicine
Houston, TX

40. Disclosure
Disclosure of Unlabeled Use and Investigational Product Discussions:
Dr. Ballantyne has indicated that his presentation will not include the discussion of unlabeled uses of commercial products or products that have not yet been approved by the FDA for use in the United States for any purpose.
Disclosure of Affiliations and Significant Relationships:
Dr. Ballantyne has received honoraria related to speakers’ bureau activities from AstraZenece, Merck, Pfizer, Reliant, and Schering-Plough. He has also received grant support related to research activities from Abbott, ActivBiotics, Gene Logic, GlaxoSmithKline, Integrated Theraputics, Merck, Pfizer, Schering-Plough, Sanofi-Synthelabo, and Takeda. Dr. Ballantyne has also received honoraria related to consulting activities from Abbott, AstraZeneca, Atherogenics, Merck, Merck Schering-Plough, Novartis, Pfizer, Reliant, Schering-Plough, Sanfi-Synthelabo, Takeda, and GlaxoSmithKline.