1. Frequency of Proteinuria in Trial 99*
Supportive Slides
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Frequency of Proteinuria in Trial 99*
Page 32 - Table 17

2. Mean total protein excretion
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Effect of Back-titration in Patients With an Elevated Urinary Total Protein Excretion Rate
1200
Maximum
90th percentile
1000
800
75th
percentile
Mean total protein excretion
rate, µg/min
600
Median
400
25th
percentile
200
10th
percentile
Minimum
80 mg
40 mg
Rosuvastatin dose
18 patients are included in this figure.
Values below the limit of assay sensitivity are represented as zero.

3. Supportive Slides 32
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Resolution of Proteinuria With Rosuvastatin Dose Reduction First Back-titration Visit (n = 752)
Rosuvastatin dose
Dipstick protein
80 mg
40 mg
None or trace, %
1+, %
≥ 2+, %
80.4
12.0
7.5
93.4
4.8
1.9
Briefing document May 7 renal section, T1 4MSU
21/46 (46%) patients had urine dipstick blood ≥ 1+
20/21 (95%) no longer had combined proteinuria at first back-titration visit.

4. Supportive Slides 40
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Serum Calcium, Phosphorus, and Potassium in Patients With or Without Proteinuria: Rosuvastatin 80 mg Combined All Controlled/Uncontrolled and RTLD Pool
Parameter N
Baseline
On-Treatment
Calcium (mmol/L)
No Proteinuria
Proteinuria
437
145
2.3 (0.1)
Phosphorus (mmol/L)
439
1.1 (0.2)
Potassium (meq/L)
433
4.4 (0.4)
Briefing document May 7 renal section, T1 4MSU
Baseline and on-treatment values for patients with urine dipstick protein
levels that remained “none or trace” or shifted to “++ or greater” during
treatment .

5. Supportive Slides 32
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Frequency of Proteinuria by Visit Combined All Controlled and RTLD Pool
Wk 4
Wk 6
Wk 8
Wk 12
Dose
Urine protein none/ trace/+ at baseline, N
Shift to ++ or greater, %
Urine protein none/ trace/+ at baseline,N
R5 mg 54
1.9
416
0.5 13
259
R10 mg 56
534
1.5 22
260
0.8
R20 mg 60
608
0.7
322
1.2
R40 mg
1659
1.7
389
1.0
1263 1
1205
1.8
R80 mg 55
7.3 95
8.4
PBO 69
315
1.6 28
159
1.3
A10 mg 14
271
297
117
0.9
A20 mg
313
299 2
A40 mg 38
0.0
A80 mg 11 49
S20 mg
294
115
S40 mg
316
S80 mg
305
0.3
285
P20 mg
128
127
P40 mg
Briefing document May 7 renal section, T1 4MSU

6. Supportive Slides 15
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Effect of Back-titration of Rosuvastatin From 80 to 40 mg on Urinary Proteins
Rosuva 80 mg
N=63
Rosuva 40 mg
Change
Protein (nmol/mg Cr)
IgG (157kD)
0.45
0.13
-0.32
Transferrin (90 kD)
0.44
0.11
-0.33
Albumin (69 kD)
0.72
0.29
-0.43
α-1 Microglobulin (31.8 kD)
1.57
0.31
-1.26
Retinol Binding Protein (21.2 kD)
5.19
0.47
-4.72
β-2 Microglobulin (11.8 kD)
0.58
0.27
-0.31
NAG activity (U/mg Cr)
0.03
0.02
-0.01

7. Supportive Slides 32
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Association of Antihypertensive Drug Use With Proteinuria in Hypertensive Patients Receiving Rosuvastatin 40 mg (n = 701) All Controlled/Uncontrolled Pool
ARB
ACEI
CCB
Diuretic
Yes No
N=116
N=585
N=287
N=414
N=194
N=507
N=197
N=504
% ≥ 2+
1.7
2.1
1.9
2.0
1.0
2.4
% ≥ 1+
14.7
12.1
10.5
9.9
12.9
9.1
10.7
Proteinuria - “none or trace” to “2+ or greater”.

8. Supportive Slides 2
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Urinary Protein Electrophoresis Patterns in Patients With Dipstick Positive Proteinuria
Crestor ISSU Table 49
Patients, n
Pattern
Pretreatment ≥ 1+ (N = 13)
On treatment† (N = 53)
Normal 8 15
Tubular 22
Mixed 2 9
Glomerular 3 7
†Baseline none to 1+

9. Most Frequent Adverse Events All Controlled Pool
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Most Frequent Adverse Events All Controlled Pool
Patients, %
Preferred term
Placebo N = 382
Rosuva† N = 5721
Atorva N = 2940
Simva N = 1457
Prava N = 1278
Any AE, %
56.8
50.5
46.0
44.3
43.3
Pharyngitis
7.6
7.5
6.5
6.0
6.1
Pain
4.6
4.0
4.5
Headache
5.0
4.2
3.6
2.9
3.1
Myalgia
1.3
3.5
3.4
2.3
Asthenia
2.6
2.8
2.4
1.6
Back pain
1.8
Abdominal pain
4.7
2.7
2.0
Diarrhea
2.1
Flu syndrome
1.9
Nausea
†Includes data for subjects who received rosuvastatin 80 mg.

10. Most Frequent Adverse Events by Dose Fixed-Dose Controlled Pool
Supportive Slides
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Most Frequent Adverse Events by Dose Fixed-Dose Controlled Pool
Patients, %
Preferred term
Rosuvastatin dose
Placebo N = 365
5 mg N = 838
10 mg N = 1573
20 mg N = 749
40 mg N = 752
80 mg N = 264
Any adverse event
56.2
59.3
50.8
42.7
49.5
59.1
Pharyngitis
7.4
10.9
6.0
6.1
3.6
9.5
Headache
4.9
4.5
4.1
3.5
5.7
Pain
6.6
4.4
2.3
8.0
Myalgia
1.4
3.9
3.3
1.6
7.2
Diarrhea
3.0
3.2
1.5
Abdominal pain
3.1
2.7
1.7
3.4
Nausea
2.6
2.9
Asthenia
2.4
2.5
Constipation
1.2
4.2
Back pain
2.2
2.8
1.9

11. Number of F/U urinalysis visits Median number of F/U visits
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Duration of Treatment and Number of Urinalysis Visits per Dose Combined All Controlled and RTLD Pool
Treatment
Dose N
Mean (SD) days on dose
PYR
Number of F/U urinalysis visits
Median number of F/U visits
Placebo
368
62.6 (21.8) 63
831 2
Rosuvastatin
5 mg
10 mg
20 mg
40 mg
80 mg
639
1189
1437
2496
798
148.6 (131.1)
115.2 (111.9)
67.5 (40.2)
105.8 (78.3)
45.5 (13.5)
260
365
262
719 99
1294
1910
2002
6952
976 1 3
Atorvastatin
696
659
241
105.6 (95.5)
69.2 (42.2)
49.2 (26.3)
46.0 (16.4)
201
125 32 46
1051
805
247
400
Simvastatin
505
352
334
118.3 (95.0)
92.7 (46.5)
51.2 (35.3)
163 89 47
809
508
934
Pravastatin
20 mg 40 mg
187 67
144.6 (112.5)
232.4 (64.3) 74 43
349
117

12. Supportive Slides
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HDL-C: % Change From Baseline Rosuvastatin : Baseline HDL-C < 40 mg/dL or ≥ 40 mg/dL Trial 65 – STELLAR (Wk 6)
< 40 mg/dL
≥ 40 mg/dL N 21 27 27
135
133
130
Data presented as LS mean.

13. Supportive Slides
4/25/2017 6:07 AM
Icterus Case 1 (310/01237)
68 year-old Caucasian male, who after 17 weeks of rosuvastatin 10 mg treatment noted icterus and brown urine
ALT and AST values in this subject increased to 223 U/L (3.4 x ULN) and 91 (2.5 x ULN) with a mildly elevated bilirubin of 2.1 mg/dL (2.1 x ULN)
Patient was hospitalized; rosuvastatin, metformin, captopril, nilvadipine, clopidogrel were all withdrawn
Liver histology showed normal parenchyma. He was discharged.
Follow-up liver function 1 week after the event showed resolution.

14. Supportive Slides
4/25/2017 6:07 AM
Icterus Case 2 (2265/09060)
73 year-old Caucasian male subject, who after 11 weeks of rosuvastatin 10 mg treatment reported icterus.
ALT and AST values in this subject reached 914 (38.1 x ULN) and 699 (38.3 x U/L), respectively, with a bilirubin of 11.8 mg/dL (10.7 x ULN).
Hepatitis titers: HepBs Ag negative, positive IgM Anti-HepBc and HepA IgG antibodies
Follow up liver function tests showed resolution

15. Protein Handling by the Kidney
Supportive Slides
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Protein Handling by the Kidney
Glomerular
proteinuria
Tubular
proteinuria
Normal
Plasma concentration, mg/L
40,000 4
40,000 4
40,000 4 2 2
2000 2 2 2
Filtered load, mg/day if GFR – 150L/day
360
360
360,000
360
360
360
% reabsorbed 95 95 95 95 50 50
Daily excretion, mg 18 18
18,000 18
180
180
Albumin
Low molecular weight proteins

16. N with creatinine increase
Supportive Slides 31
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Creatinine Changes in Patients With Proteinuria at Last Visit, ≥ 96 Wk of Rosuvastatin Treatment Combined All Controlled/Uncontrolled and RTLD Pool
C , C
Rosuva
dose
N with N/Tr at baseline
N (%) with proteinuria
N with creatinine increase
> 30 %
> 0.5 mg/dL
> 1.0 mg/dL
5 mg
239
10 mg
821
4 (0.5)
20 mg
111
1 (0.9)
40 mg 99
2 (2.0)
80 mg
589
37 (6.3) 2
≥ 40 mg†
796
8 (1.0)
†Includes patients who back-titrated from the 80-mg dose.
No patients with creatinine > 1 mg/dL.

17. Post Launch Safety Assessment Ongoing Clinical Trials Program
Supportive Slides
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Post Launch Safety Assessment Ongoing Clinical Trials Program
Atherosclerosis regression
METEOR – 840 patients; placebo-controlled 40 mg
ASTEROID – 400 patients, 40 mg rosuvastatin
Outcomes studies
GISSI-HF – 5250 patients with CHF, placebo-controlled 10 mg rosuvastatin
CORONA – 4800 patients with CHF, placebo-controlled 10 mg rosuvastatin
AURORA patients with CRF on dialysis, placebo-controlled 10 mg rosuvastatin
JUPITER – 15,000 subjects with elevated CRP, placebo-controlled 20 mg rosuvastatin

18. Supportive Slides 37
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Cumulative Risk of Myopathy Patients Receiving ≥ 40 mg of Rosuvastatin Combined All Controlled/Uncontrolled and RTLD Pool

19. Benefit/Risk of High-Dose Statin Therapy
Supportive Slides
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Benefit/Risk of High-Dose Statin Therapy
Rosuva 20 / 40
Atorva 40 / 80
Simva 40 / 80
% LDL-C ↓
55 / 63
50 / 60
41 / 47
ALT > 3 x ULN
0.1 / 0.3
0.6 / 2.3
0.9 / 2.1
CK > 10 x ULN
0.2 / 0.4
0.5 / 0.9
0.1 / 1.2
Proteinuria
0.7 / 1.2
0 / 0.3
0.3 / 0

20. Familial Hypercholesterolemia (FH)
Supportive Slides
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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 years in men, years in women
FH is difficult to treat
Most FH patients cannot be adequately treated to NCEP LDL-C goal

21. Familial Hypercholesterolemia (FH): Cumulative Probability of CAD
Supportive Slides
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Familial Hypercholesterolemia (FH): Cumulative Probability of CAD
1.0
Non-FH Women
0.9
Non-FH Men
0.8
FH Women
0.7
FH Men
0.6
Cumulative probability of
clinical CAD
0.5
0.4
0.3
0.2
0.1
0.0
90+
25-30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
80-85
85-90
Age
MED PED Registry 2001.

22. Supportive Slides
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LDL-C: % Change From Baseline Rosuvastatin vs Atorvastatin: Heterozygous FH Trial 30 (Wk )
20 mg
40 mg
80 mg * * *
*P < .05 vs atorvastatin; data presented as LS means ± SE.

23. Additional LDL-C Reduction Rosuvastatin 40 mg vs 20 mg Study 30
Supportive Slides
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Additional LDL-C Reduction Rosuvastatin 40 mg vs 20 mg Study 30
Baseline LDL-C 290 mg/dL
20 mg: reduction 47% Mean LDL-C = 154 mg/dL
40 mg: reduction 54% Mean LDL-C = 133 mg/dL
Additional LDL-C reduction with 40 mg = 21 mg/dL or 13.6% further decrease over 20 mg

24. Supportive Slides
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LDL-C: % of High-Risk FH Patients Achieving NCEP ATP III LDL-C Goal Trial 30 *
*P < .05

25. Stein, et al. J Am Col Cardiol 2003.
Supportive Slides
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% of High-Risk FH Patients Achieving NCEP ATP III LDL-C Goal in 2 Different Studies
Rosuvastatin 40 mg
Atorvastatin 40 mg + Ezetimibe 10 mg
Atorvastatin 80 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.

26. Mortality log odds ratio % in cholesterol reduction
Supportive Slides 29
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Benefits of Cholesterol Lowering Meta-analysis of 38 Primary and Secondary Intervention Trials
–0.0
–0.2
–0.4
Mortality log odds ratio
–0.6
Total mortality (P = .004)
–0.8
CHD mortality (P = .012)
–1.0 4 8 12 16 20 24 28 32 36 40 44 48 52
% in cholesterol reduction
Gould AL, et al. Circulation. 1998;97:

27. LDL-C 1% decrease reduces CHD risk by 1%
Supportive Slides
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Relationship Between Changes in LDL-C Levels and CHD Risk: NCEP ATP III
LDL-C 1% decrease reduces CHD risk by 1%
Third Report of the NCEP Expert Panel. NIH Publication No

28. HDL-C 1% increase reduces CHD risk by 3%
Supportive Slides
4/25/2017 6:07 AM
Relationship Between Changes in HDL-C Levels and CHD Risk: NCEP ATP III
HDL-C 1% increase reduces CHD risk by 3%
Third Report of the NCEP Expert Panel. NIH Publication No

29. Supportive Slides
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Achievement of NCEP ATP-II LDL-C Goals at Wk 52 (Titrated to Goal as Needed) Rosuvastatin mg compared With Atorvastatin mg Trial 26
Reached on 80 mg
Reached on 40 mg
Reached on 20 mg *
96%
87%
100 90 80
Reached on 10 mg 70 60
Patients, % 50
82% 40
59% 30 20 10
RSV
ATV
*P < .05.

30. Supportive Slides
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Effect of Rosuvastatin on Plasma Concentrations of Ethinyl Estradiol and Norgestrel
Compound
OCS
OCS + rosuvastatin
Treatment effect
90% CI
Ethinyl estradiol Cmax (pg/mL)
159
198
1.25
1.17, 1 .33
Norgestrel Cmax (ng/mL)
3.46
4.27
1.23
1.14, 1.33
Ethinyl estradiol AUC(0-24)(pg·h/mL)
1340
1690
1.26
1.19, 1.34
Norgestrel AUC(0-24)(ng·h/mL)
62.0
82.8
1.34
1.25, 1.43

31. 22
Supportive Slides
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LDL-C: % Change From Baseline Rosuvastatin: Homozygous FH < 18 Yr Trial 54 (Wk )
RSV 20 mg
RSV 40 mg
N = 8 (7 included in analysis). Four patients had defective receptor status; others were unknown.
Range at Wk 12: (–47.5 to –12.5).

32. Supportive Slides
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TG: % Change From Baseline Rosuvastatin vs Placebo: Type IIB and IV Trial 35 (Wk 6)
n = 7 19 10 15 11 12 10 17 10 15
Baseline TG Type IIB = 416 and Type IV = 500. Data presented as LS means.