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Daniel Weiss MD CDE FACP Endocrinology/Metabolism Your Diabetes Endocrine Nutrition Group, LLC Mentor Clinical Assistant Professor of Medicine, CWRU. Update on Lipids and what’s new with CV risk in Type 2 Diabetes. A new study to assess cardiovascular outcomes in Type 2 Diabetes: ACCORD

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Update on lipids and what s new with cv risk in type 2 diabetes l.jpg

Daniel Weiss MD CDE FACP

Endocrinology/Metabolism

Your Diabetes Endocrine Nutrition Group, LLC

Mentor

Clinical Assistant Professor of Medicine, CWRU

Update on Lipids andwhat’s new with CV risk in Type 2 Diabetes


Outline l.jpg

A new study to assess cardiovascular outcomes in Type 2 Diabetes: ACCORD

The Heart Protection Study

A new look at statin treatment

How effective is our current therapy

Crestor

the most studied statin prior to FDA approval

Outline


Factors that may promote macrovascular disease in diabetes l.jpg

Increased thrombogenicity

Abnormal platelet function and abnormal coagulation

Dyslipidemia

Hypertension

Impaired endothelial and vascular smooth muscle function

Increased reactive oxygen species

H2O2, O2-, OH-

Tobacco use

Hyperglycemia

Beckman et al JAMA ( May) 2002; 287: 2570- 81.

Factors that may promote macrovascular disease in diabetes


Slide4 l.jpg

ACCORD trial: Glycemia Hypothesis

In middle-aged or older people with type 2 diabetes at high risk for a CVD event:

Does a therapeutic strategy that targets HbA1c < 6.0% reduce the rate of CV events more than a strategy that targets HbA1c 7.0% to 7.9% (with expectation of a median of 7.5%)?


Slide5 l.jpg

ACCORD: Action to Control Cardiovascular Risk in Type 2 Diabetes

  • ACCORD: HbA1c < 6% vs. 7.0 to 7.9%

    • Systolic blood pressure of < 140 vs <120

    • Simvastatin with or without fenofibrate

    • Patients age 40 or older if have event; others 55 or older

  • Study Medications provided free

  • Planned minimum 5 years

  • Multicenter (US and Canada) with multiple sites in the greater Cleveland area


Potential patients can call 800 320 2833 l.jpg

Potential patients can call

800-320-2833

ACCORD trial


Factors that may promote macrovascular disease in diabetes7 l.jpg

Increased thrombogenicity

Abnormal platelet function and abnormal coagulation

Dyslipidemia

Hypertension

Impaired endothelial and vascular smooth muscle function

Increased reactive oxygen species

H2O2, O2-, OH-

Tobacco use

Hyperglycemia

Beckman et al JAMA ( May) 2002; 287: 2570- 81.

Factors that may promote macrovascular disease in diabetes


Do patients with cad easily reach ldl goals with statin therapy alone l.jpg

318 men patients with CAD and LDL-C > 130 randomized to open label, treat-to-target study over 54 weeks

Titrated every 12 weeks until LDL goal of

105 mg/dl reached.

Mean LDL-C of 173 at baseline

Conducted in 1997 when maximum fluvastatin and simvastatin doses were 40 mg

Brown AS et al J Am Coll Cardiol 1998; 32: 665

Do Patients with CAD Easily Reach LDL Goals with Statin Therapy Alone?


Chd patients often do not achieve ncep goal with monotherapy l.jpg

CHD Patients Often Do Not Achieve NCEP Goal with Monotherapy

Brown et al. (1998) J Am Coll Cardiol32:665-672


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Clinical Pharmacology of Rosuvastatin


Molecular structure of rosuvastatin l.jpg

Molecular Structure of Rosuvastatin

Statin Pharmacophore

Methane-Sulfonamide Group

O

(3R, 5S)

H

O

O

O

H

F

CH3

CH3

N

N

H3C

N

CH3

S

O

O

Adapted with permission from McTaggart F, et al. Am J Cardiol. 2001;87(suppl):28B-32B. [illus. Page 29B]


Pharmacokinetics of rosuvastatin l.jpg

Pharmacokinetics of Rosuvastatin

  • Absorption/Distribution

  • Hepatoselective and relatively hydrophilic

  • The absolute bioavailability of rosuvastatin is approximately 20%

  • Rapidly absorbed (peak plasma concentration reached in 3-5 hours)

  • Cmax and AUC increase in proportion to dose

  • Significant LDL-C reduction is seen with or without food, regardless of the time of day

  • Highly protein bound (88% - mostly albumin; reversible, independent of plasma levels)

CRESTOR® (rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003.


Pharmacokinetics of rosuvastatin19 l.jpg

Pharmacokinetics of Rosuvastatin

  • Metabolism

  • >90% of HMG-CoA reductase inhibitory activity occurs via the parent compound, rosuvastatin1

    • The major metabolite, N-desmethyl rosuvastatin is formed primarily by cytochrome P450 (CYP450) isoenzyme 2C92

    • N-desmethyl rosuvastatin has ~1/6 to ½ the HMG-CoA reductase inhibitory activity of rosuvastatin1

  • Rosuvastatin is not extensively metabolized1

    • Rosuvastatin had no significant inhibitory effect on CYP450 isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, or 3A4 in human hepatic tissue in vitro studies2

1.CRESTOR® (rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003.

2. McCormick AD, et al. J Clin Pharmacol. 2000;40:1055. Abstract 46.


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Pharmacokinetics of Rosuvastatin

  • Excretion

  • Following oral administration, rosuvastatin and its metabolites are primarily excreted in the feces (90%)

  • Elimination half-life is approximately 19 hours

  • After IV dose, total body clearance 28% via renal and 72% via hepatic routes

CRESTOR® (rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003.


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Pharmacokinetic Profile of Selected Statins

  • Pravastatin

Rosuvastatin

Atorvastatin

Simvastatin

CYP450 3A4

Metabolism

No

Yes

Yes

No

Clinically

Significant Metabolites

No

Yes

Yes

No

Dual renal /

hepatic

Primarily

hepatic

Duel renal / hepatic

Duel renal / hepatic

Plasma Clearance

Relatively

Hydrophilic

Yes

No

No

Yes

Hepatoselective

Yes

Yes

Yes

Yes

Bioavailability

20%

14%

<5%

17%

Elimination

Half-life* (hours)

19

14

1.9

77

*Elimination T1/2 of drug and metabolites, if any.

CRESTOR®(rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003. Atorvastatin Calcium Prescribing Information 2002,Pfizer Inc, NY, NY; Simvastatin Prescribing Information, Merck & Co., Inc., Whitehouse Station, NJ; Pravastatin Prescribing Information 2003, Bristol-Meyers Squibb Company, Princeton, NJ


Rosuvastatin drug interaction studies l.jpg

Rosuvastatin Drug Interaction Studies

DigoxinNo change in digoxin level

FenofibrateNo significant change in rosuvastatin or fenofibrate levels

GemfibrozilClinically significant increase in rosuvastatin level;90 and 120% increase AUC and Cmax

Antacid (aluminum/magnesium hydroxide combination)54% decrease in rosuvastatin level when coadministered; no clinically significant change when given 2 hours after rosuvastatin

Oral contraceptivesEthinyl estradiol level increased 26%; norgestrel level increased 34%

KetoconazoleNo change in rosuvastatin level

ErythromycinSmall decrease in rosuvastatin level; not clinically significant

Itraconazole39% increase in rosuvastatin AUC; not clinically significant

Fluconazole14% increase in rosuvastatin AUC; not clinically significant

CyclosporineNo significant change in cyclosporine concentration; clinically significant 11- and 7-fold increase in rosuvastatin Cmax and AUC

WarfarinNo change in warfarin; clinically significant increase in INR

CRESTOR® (rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003.


Clinical pharmacology of rosuvastatin special populations l.jpg

Clinical Pharmacology of RosuvastatinSpecial Populations

  • Race

    • A population pharmacokinetic analysis revealed no clinically relevant differences in pharmacokinetics among Caucasian, Hispanic, and Black or Afro-Caribbean groups

    • Pharmacokinetic studies show an approximate 2-fold elevation in median exposure (AUC) in Japanese subjects residing in Japan and in Chinese subjects residing in Singapore when compared with Caucasians residing in North America and Europe

      • No studies directly examining Asian ethnic populations residing in the U.S. are available, so the contribution of environmental and genetic factors to the observed increases in rosuvastatin drug levels have not been determined

CRESTOR® (rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003.


Clinical pharmacology of rosuvastatin special populations24 l.jpg

Clinical Pharmacology of RosuvastatinSpecial Populations

  • Gender

    • There were no differences in plasma concentrations of rosuvastatin between men and women

  • Geriatric

    • There were no differences in plasma concentrations of rosuvastatin between the nonelderly and elderly populations (age 65 years)

  • Pediatric

    • In a pharmacokinetic study, 18 patients (9 boys and 9 girls) 10 to 17 years of age with homozygous FH received single and multiple oral doses of rosuvastatin. Both Cmax and AUC of rosuvastatin were similar to values observed in adult subjects administered the same doses

CRESTOR® (rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003.


Clinical pharmacology of rosuvastatin special populations25 l.jpg

Clinical Pharmacology of RosuvastatinSpecial Populations

  • Renal Insufficiency

    • Mild to moderate renal impairment (creatinine clearance ≥30 mL/min/1.73m2) had no influence on plasma concentrations of rosuvastatin when oral doses of 20 mg rosuvastatin were administered for 14 days. However, plasma concentrations of rosuvastatin increased to a clinically significant extent (about 3-fold) in patients with severe renal impairment (CLcr <30 mL/min/1.73m2) compared with healthy subjects (CLcr >80 mL/min/1.73m2)

  • Hemodialysis

    • Steady-state plasma concentrations of rosuvastatin in patients on chronic hemodialysis were approximately 50% greater compared with healthy volunteer subjects with normal renal function

CRESTOR® (rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003.


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Clinical Pharmacology of RosuvastatinSpecial Populations

  • Hepatic Insufficiency

    • In patients with chronic alcohol liver disease, plasma concentrations of rosuvastatin were modestly increased. In patients with Child-Pugh A disease, Cmax and AUC were increased by 60% and 5%, respectively, as compared with patients with normal liver function. In patients with Child Pugh B disease, Cmax and AUC were increased 100% and 21%, respectively, compared with patients with normal liver function

CRESTOR® (rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003.


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Rosuvastatin Clinical Trial Program


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Clinical Trial Program for Rosuvastatin: Overview2-7

  • Worldwide comprehensive program of 10,2751 patients, more than any other statin at their time of FDA approval

    • Types of trials:

      • Efficacy across the dose range

      • Comparator

      • Combination therapy

  • Outcomes program under way

1. CRESTOR®(rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003 2. New Drug Application for Lipitor (four-month safety update) 3. New Drug Application for Baycol (conclusion with regards to safety) 4. New Drug Application for Lescol (exposure) 5. New Drug Application for Mevacor (safety report and analysis) 6. New Drug Application for Zocor (simvastatin safety update II) 7. New Drug Application for Pravachol (medical officer’s review and evaluation of NDA report


Rosuvastatin dose ranging program l.jpg

Rosuvastatin Dose-Ranging Program

A multicenter, double-blind, placebo-controlled dose-ranging study to assess the lipid-regulating effects of rosuvastatin in patients with primary hypercholesterolemia


Rosuvastatin dose ranging program30 l.jpg

Rosuvastatin Dose-Ranging Program

RSV 1, 2.5, 5,10, 20, or 40 mg vs placebo (n=111)

Study Design

Randomized, double-blind, 6-week, phase II trial

  • Men (18–70 y) and women (50–70 y, postmenopausal)

    • Fasting: LDL-C >160 and <240 mg/dL; TG <300 mg/dL

    • Baseline mean LDL-C: 191 mg/dL

6-week dietary lead-in, then patients were randomized to

6 weeks of active treatment

  • Primary outcome: percentage change from baseline in LDL-C at 6 weeks

End Points

RSV, rosuvastatin; The dose range for rosuvastatin is 5 to 40 mg once daily

Data on file, (Study 8, DA-CRS-05) AstraZeneca Pharmaceuticals LP, Wilmington, DE.


Rosuvastatin dose ranging program dose response relationship l.jpg

Rosuvastatin Dose-Ranging ProgramDose-Response Relationship

0

–10

–20

–30

–40

–50

–60

–70

Percent Change in LDL-C at 6 Weeks

n=13

n=17

n=17

n=17

n=18

–7

Mean Percent Change From

Baseline in LDL-C

–45*

–52*

–55*

–63*

5 mg

Placebo

10 mg

20 mg

40 mg

Observed data in ITT population. *P<.001 vs placebo

Data on file, (Study 8, DA-CRS-05) AstraZeneca Pharmaceuticals LP, Wilmington, DE.


Rosuvastatin dose ranging program dose response relationship32 l.jpg

Rosuvastatin Dose-Ranging Program Dose-Response Relationship

2

4

6

8

–52

–63

Therapeutic Response Seen Within 1 Week

Week

0

10

0

–7

–10

–20

Mean Percent Change From

Baseline in LDL-C

Placebo

Rosuvastatin 10 mg

Rosuvastatin 40 mg

–30

–40

–50

–60

–70

Observed data in ITT population.

Data on file, (Study 8, DA-CRS-05) AstraZeneca Pharmaceuticals LP, Wilmington, DE.


Rosuvastatin dose ranging program33 l.jpg

Rosuvastatin Dose-Ranging Program

  • Conclusions

  • Rosuvastatin produced marked dose-related decreases in LDL-C, with reductions of 45% to 63% across the dose range of 5 to 40 mg

  • Rapid onset of action with a therapeutic response seen within 1 week

1. Data on file, (Study 8, DA-CRS-05) AstraZeneca Pharmaceuticals LP, Wilmington, DE.

2. CRESTOR®(rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003


Rosuvastatin nda phase iii trials overview l.jpg

Rosuvastatin NDA Phase III Trials Overview


Rosuvastatin nda phase iii trials overview35 l.jpg

Rosuvastatin NDA Phase III Trials:Overview

  • Types of trials:

    • Efficacy and safety across the dose range

    • Comparator:

      • Atorvastatin, simvastatin, pravastatin

    • Combination therapy:

      • Niacin, fenofibrate, cholestyramine, HRT

HRT, hormone replacement therapy.


Rosuvastatin nda phase iii trials inclusion criteria l.jpg

Rosuvastatin NDA Phase III Trials:Inclusion Criteria

  • Inclusion Criteria:

    • No upper age limit defined

    • Creatinine cutoff of 2.5 mg/dL at entry in most trials*

    • Women of childbearing potential were included provided they were not pregnant and were using appropriate contraception

    • Adequately controlled hypertension; for diabetics, diabetes under adequate glycemic control (hemoglobin A1c <9%)

  • Patient Populations Included

    • Established atherosclerosis

    • Postmenopausal women

    • Homozygous FH† and Heterozygous FH

    • Hypertriglyceridemia

    • Diabetics

*Except for those that evaluated combination therapy with extended-release niacin or fenofibrate

†Familial hypercholesterolemia


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Tendon xanthomas


Stellar l.jpg

STELLAR

  • 6 week randomized, 15-arm trial directly comparing efficacy of rosuvastatin vs select statins in more than 2240 patients with Type IIa/IIb dyslipidemia

Rosuvastatin

10-40 mg

Atorvastatin

10-80 mg

Simvastatin

10-80 mg

Pravastatin

10-40 mg

Jones PH, Davidson MH, Stein EA, et al. Am. J. Cardiology 2003; 93:152-160.


Stellar dose range comparison of rosuvastatin vs other statins l.jpg

STELLAR  Dose-Range Comparison of Rosuvastatin vs. Other Statins

Rosuvastatin

(n=480)

Atorvastatin

(n=641)

Simvastatin

(n=655)

10

mg

10

mg

20

mg

20

mg

40

mg

40

mg

80

mg

80

mg

10

mg

20

mg

40

mg

10

mg

20

mg

40

mg

Study Design

After a 6-week dietary lead-in, 2240 patients were randomized to the following arms to receive 6 weeks active treatment:

Pravastatin

(n=492)

Jones PH, Davidson MH, Stein EA, et al. Am. J. Cardiology 2003; 93:152-160.


Demographics and baseline lipids l.jpg

Demographics and Baseline Lipids

Gender

Male

Mean

Female

58

231

249

187-194

50-51

179-183

58

321

320

189-190

50-51

174-181

58

322

333

187-190

50-51

172-182

57

248

244

187-190

49-50

179-187

Age (years)

Mean baseline lipids (mg/dL)

LDL-C

HDL-C

TG

Rosuvastatin

Atorvastatin

Simvastatin

Pravastatin

Jones PH, Davidson MH, Stein EA, et al. Am. J. Cardiology 2003; 93:152-160.


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STELLAR

Atorvastatin (mg)

10

20

40

10

20

40

Simvastatin (mg)

Pravastatin (mg)

10

20

40

Comparisons of interest:

  • Rosuvastatin 10 mg vs:

  • Rosuvastatin 20 mg vs:

Atorvastatin (mg)

20

40

80

Simvastatin (mg)

20

40

80

Pravastatin (mg)

20

40

-

  • Rosuvastatin 40 mg vs:

Atorvastatin (mg)

40

80

-

Simvastatin (mg)

40

80

-

Pravastatin (mg)

40

-

-

Jones PH, Davidson MH, Stein EA, et al. Am. J. Cardiology 2003; 93:152-160.


Efficacy results l.jpg

STELLAR

Efficacy Results


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Percentage Change From Baseline in LDL-C at Week 6 by Dose (ITT)1,2

0

–10

Pravastatin

–20

Simvastatin

–30

–40

–50

–60

Dose

10 mg

20 mg

40 mg

80 mg

Rosuvastatin

Atorvastatin

Mean Percent Change From Baseline in LDL-C (SE)

*

**

  • *P<.002 vs atorvastatin 10 mg; simvastatin 10 mg, 20 mg, 40 mg; pravastatin 10 mg, 20 mg, 40 mg

  • **P<.002 vs atorvastatin 20 mg, 40 mg; simvastatin 20 mg, 40 mg, 80 mg; pravastatin 20 mg, 40 mg

  • † P<.002 vs atorvastatin 40 mg; simvastatin 40 mg, 80 mg; pravastatin 40 mg

  • Jones PH, Davidson MH, Stein EA, et al. Am. J. Cardiology 2003; 93: 152-160.

  • Data on file, DA-CRS-02 AstraZeneca Pharmaceuticals LP, Wilmington, DE.


Percentage change in ldl c pairwise comparisons with rosuvastatin 10 mg l.jpg

Percentage Change in LDL-C: Pairwise Comparisons with Rosuvastatin 10 mg

20

40

0

–10

–20

–30

–40

–50

–60

Rosuvastatin

(mg)

Atorvastatin

(mg)

Simvastatin

(mg)

Pravastatin

(mg)

20

40

20

40

10

10

10

10

Mean Percent Change From Baseline in LDL-C (SE)

-20.1

-24.4

-28.3

-29.7

-35.0

-36.8

-38.8

-42.6

-45.8

*

-47.8

*P<.002 vs atorvastatin 10 mg; simvastatin 10 mg, 20 mg, 40 mg; pravastatin 10 mg, 20 mg, 40 mg

1. Jones PH, Davidson MH, Stein EA, et al. Am. J. Cardiology 2003; 93:152-160.

2. Data on file, DA-CRS-02 AstraZeneca Pharmaceuticals LP, Wilmington, DE.


Percentage change in ldl c pairwise comparison of rosuvastatin 20 mg and 40 mg l.jpg

Percentage Change in LDL-C: Pairwise Comparison of Rosuvastatin 20 mg and 40 mg

20

40

20

40

80

20

40

0

20

40

80

–10

–20

–30

–40

–50

–60

–52.4

*

–55.0

**

Rosuvastatin

(mg)

Atorvastatin

(mg)

Simvastatin

(mg)

Pravastatin

(mg)

Mean Percent Change From Baseline in LDL-C (SE)

-24.4

-29.7

-35.0

-38.8

-42.6

–45.8

-47.8

–51.1

*P<.002 vs atorvastatin 20 mg, 40 mg; simvastatin 20 mg, 40 mg, 80 mg; pravastatin 20 mg, 40 mg

** P<.002 vs atorvastatin 40 mg; simvastatin 40 mg, 80 mg; pravastatin 40 mg

1. Jones PH, Davidson MH, Stein EA, et al. Am. J. Cardiology 2003; 93: 152-160.

2. Data on file, DA-CRS-02 AstraZeneca Pharmaceuticals LP, Wilmington, DE.


Percentage change from baseline in hdl c at week 6 by dose itt l.jpg

Percentage Change From Baseline in HDL-C at Week 6 by Dose (ITT)

9.6

**

9.5

*

7.7

12

6.8

10

6.0

5.7

5.6

5.3

5.2

4.8

4.4

4.4

8

3.2

6

2.1

4

2

0

Mean Percent Change From Baseline in HDL-C

10

20

40

10

20

40

80

10

20

40

80

10

20

40

Atorvastatin

(mg)

Simvastatin

(mg)

Pravastatin

(mg)

Rosuvastatin

(mg)

*P<.002 vs pravastatin 10 mg

**P<.002 vs atorvastatin 20 mg, 40 mg, 80 mg; simvastatin 40 mg; pravastatin 20 mg, 40 mg

† P<.002 vs atorvastatin 40 mg, 80 mg; simvastatin 40 mg; pravastatin 40 mg

Jones PH, Davidson MH, Stein EA, et al. Am. J. Cardiology 2003; 93:152-160.


Percentage change from baseline in triglycerides at week 6 by dose itt l.jpg

Percentage Change From Baseline in Triglycerides at Week 6 by Dose (ITT)

10

20

40

10

20

40

80

10

20

40

0

10

20

40

80

-5

-10

-11.9

-14.8

-15

-17.6

-18.2

-19.8

*

-20

-20

-22.6

-23.7

**

-25

-26.1

-26.8

-28.2

-30

Rosuvastatin

(mg)

Atorvastatin

(mg)

Simvastatin

(mg)

Pravastatin

(mg)

-7.7

-8.2

Mean Percent Change From Baseline in TG Levels

-13.2

*P<.002 vs pravastatin 10 mg, 20 mg

**P<.002 vs simvastatin 40 mg; pravastatin 20 mg, 40 mg

† P<.002 vs simvastatin 40 mg; pravastatin 40 mg

Jones PH, Davidson MH, Stein EA, et al. Am. J. Cardiology 2003; 93:152-160.


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STELLAR Overall Conclusions

  • STELLAR was a very large statistically powerful statin comparative trial

  • Rosuvastatin demonstrated statistically significant improvements in the atherogenic lipid profile compared to atorvastatin, simvastatin, and pravastatin

Jones PH, Davidson MH, Stein EA, et al. Am. J. Cardiology 2003; 93:155-160.


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Safety and Prescribing Information for Rosuvastatin


Safety of rosuvastatin l.jpg

Safety of Rosuvastatin

  • Adverse Reactions Summary

  • Rosuvastatin is generally well tolerated; adverse reactions have usually been mild and transient

  • The most frequent adverse events thought to be related to rosuvastatin were myalgia (3.3%), constipation (1.4%), asthenia (1.3%), abdominal pain (1.3%) and nausea (1.3%)1,2

  • Discontinuations due to adverse events in placebo controlled clinical studies of up to 12 weeks duration occurred in 3% of patients taking rosuvastatin and 5% of patients taking placebo

1. CRESTOR®(rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003.

2. Data on file, (DA-CRS-01) AstraZeneca Pharmaceuticals LP, Wilmington, DE.


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Adverse Events in 2% of Rosuvastatin Patients Regardless of Causality

Data From Placebo-Controlled Trials

Percent of Patients

Adverse Event

Rosuvastatin

(N=744)

Placebo

(N=382)

Pharyngitis 9.07.6

Headache5.5 5.0

Diarrhea 3.4 2.9

Dyspepsia 3.4 3.1

Nausea3.43.1

Myalgia2.81.3

Asthenia 2.7 2.6

Back pain2.62.4

Flu syndrome2.31.8

Urinary tract infection2.31.6

Rhinitis2.22.1

Sinusitis2.01.8

CRESTOR®(rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003.


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Rosuvastatin Discontinuation in Placebo-Controlled Clinical Trials

Clinical Trials of Up to 12 Weeks Duration at All Doses

10

8

6

Percent of Patients

5

4

3

2

0

Rosuvastatin

Placebo

CRESTOR®(rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003.


Safety of rosuvastatin53 l.jpg

Safety of Rosuvastatin

0.4%

Rosuvastatin 5 mg

0%

Rosuvastatin 10 mg

0%

Rosuvastatin 20 mg

0.1%

Rosuvastatin 40 mg

Liver Enzymes

Incidence of Persistent Transaminase Abnormalities* in Clinical Trials

*Defined as >3 x ULN on 2 or more consecutive occasions in serum transaminase in fixed dose trials.

CRESTOR®(rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003.


Safety of rosuvastatin54 l.jpg

Safety of Rosuvastatin

  • Alterations in Liver Enzymes

  • Serum transaminase elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy

  • Liver function tests are recommended before and at 12 weeks following both the initiation of therapy and any elevation in dose, and periodically (eg, semiannually) thereafter

  • Rosuvastatin should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease (see CLINICAL PHARMACOLOGY, Special Populations, Hepatic Insufficiency). Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of rosuvastatin

CRESTOR®(rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003.


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Safety of Rosuvastatin

  • Myopathy/Rhabdomyolysis

  • Incidence of treatment-related myopathy*in clinical trials was 0.1% in patients treated with up to rosuvastatin 40 mg

  • Factors that may predispose patients to myopathy with HMG-CoA reductase inhibitors include:

    • Advanced age (65 years)

    • Hypothyroidism

    • Renal insufficiency

  • The incidence of myopathy increased at doses above recommended dosage range (i.e. 80-mg dose) with rosuvastatin

  • *Defined as muscle symptoms and CK level > 10 x ULN.

CRESTOR®(rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003.


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Safety of Rosuvastatin

  • Myopathy/Rhabdomyolysis (cont.)

  • Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with rosuvastatin and with other drugs in this class

    • Rare cases were seen with higher than recommended doses (80 mg) of rosuvastatin in clinical trials

  • The risk of myopathy during treatment with rosuvastatin may be increased with concurrent administration of other lipid-lowering therapies, or cyclosporine, or in circumstances which increase rosuvastatin blood levels

  • Patients should be advised to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by fever or malaise

CRESTOR®(rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003.


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Safety of Rosuvastatin

  • Combination Lipid-Lowering Therapy

  • The benefit of further alterations in lipid levels by the combined use of rosuvastatin with fibrates or niacin should be carefully weighed against the potential risks of this combination

  • Combination therapy with rosuvastatin and gemfibrozil should generally be avoided

CRESTOR®(rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003.


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Prescribing Information

  • Laboratory Tests

  • In the clinical trial program dipstick positive proteinuria and microscopic hematuria were observed in patients treated with rosuvastatin

    • predominantlyabove the recommended dose range (i.e. 80-mg)

  • However, this finding was more frequent in patients taking rosuvastatin 40 mg compared to lower doses or comparator statins, though it was generally transient and was not associated with worsening renal function

  • Although the clinical significance of this finding is unknown, a dose reduction should be considered for patients on rosuvastatin 40 mg therapy with unexplained persistent proteinuria during routine urinalysis testing

CRESTOR®(rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003.


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Frequency of Proteinuria* Pooled data from controlled clinical trials**

Treatment

Dose

N

Patients, % (95% CI)

Placebo

-

330

0.6 (0.1, 2.2)

Rosuvastatin

5 mg

10 mg

20 mg

40 mg

587

1008

872

1850

0.2 (0.0, 0.9)

0.6 (0.2, 1.3)

0.7 (0.3, 1.5)

1.2 (0.7, 1.8)

Atorvastatin

10 mg

20 mg

40 mg

80 mg

628

438

63

342

0.5 (0.1, 1.4)

0.5 (0.1, 1.6)

0 (0.0, 5.7)

0.3 (0.0, 1.6)

Simvastatin

20 mg

40 mg

80 mg

452

314

325

1.1 (0.4, 2.6)

0.3 (0.0, 1.8)

0 (0.0, 1.1)

Pravastatin

20 mg

40 mg

162

64

0.6 (0.0, 3.4)

0 (0.0, 5.6)

*Proteinuria - “none or trace” at baseline to “2+ or greater” at final study visit

**Combined All Controlled and RTLD Pool

Data on file, (DA-CRS-07) AstraZeneca Pharmaceuticals LP, Wilmington, DE.


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Prescribing Information

  • CRESTOR®(rosuvastatin calcium) is indicated:

    • As an adjunct to diet to reduce elevated total-C, LDL-C, ApoB, non–HDL-C, and TG levels and to increase HDL-C in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson Type IIa and IIb)

    • As an adjunct to diet for the treatment of patients with elevated serum TG levels (Fredrickson Type IV)

    • To reduce LDL-C, total-C, and Apo B in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are unavailable

CRESTOR®(rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003.


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Prescribing Information

  • CRESTOR® (rosuvastatin calcium) is contraindicated in patients with a known hypersensitivity to any component of this product

  • CRESTOR is contraindicated in patients with active liver disease or with unexplained persistent elevations of serum transaminases.

  • HMG-CoA reductase inhibitors are contraindicated during pregnancy and in nursing mothers. CRESTOR should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards

CRESTOR®(rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003.


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Prescribing Information

  • Coadministration of rosuvastatin to patients on stable warfarin therapy resulted in clinically significant rises in INR (>4, baseline 2 to 3). In patients taking coumarin anticoagulants and rosuvastatin concomitantly, INR should be determined before starting or changing therapy with rosuvastatin and frequently enough during early therapy to ensure that no significant alteration of INR occurs

  • Safety and effectiveness in pediatric patients have not been established

CRESTOR®(rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003.


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Dosage and Administration

The patient should be placed on a standard cholesterol-lowering diet before receiving CRESTOR® (rosuvastatin calcium) and should continue on this diet during treatment. CRESTOR can be administered anytime of day, with or without food.

Primary Hypercholesterolemia and Mixed Dyslipidemia

  • The dose range for CRESTOR is 5 to 40 mg once daily. Therapy with CRESTOR should be individualized according to goal of therapy and response

  • The usual recommended starting dose of CRESTOR is 10 mg once daily. Initiation of therapy with 5 mg once daily may be considered for patients requiring less aggressive LDL-C reductions or who have predisposing factors to myopathy. For patients with marked hypercholesterolemia (LDL-C >190 mg/dL) and aggressive lipid targets, a 20 mg starting dose may be considered

  • 40 mg dose should be reserved for those patients who have not achieved goal LDL-C at 20 mg

CRESTOR®(rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003.


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Dosage and Administration

  • Severe Renal Insufficiency

  • No dosage modification is necessary for patients with mild to moderate renal insufficiency

  • For patients with severe renal impairment (ClCr <30 mL/min/1.73 m2) not on hemodialysis, dosing should be started at 5 mg once daily and not exceed 10 mg once daily

  • Concomitant lipid-lowering therapy

  • If combined with gemfibrozil, the dose of CRESTOR should be limited to 10 mg once daily (see WARNINGS)

CRESTOR®(rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003.


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Dosage and Administration

  • Homozygous Familial Hypercholesterolemia

  • Recommended starting dose of CRESTOR is 20 mg once daily

    • The maximum recommended daily dose is 40 mg

    • CRESTOR should be used in these patients as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are unavailable

  • Concurrent Cyclosporine

  • In patients taking cyclosporine, therapy should be limited to CRESTOR 5 mg once daily

CRESTOR®(rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003.


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Dosage and Administration

  • In patients taking cyclosporine, therapy should be limited to CRESTOR® (rosuvasatin calcium) 5 mg once daily

  • If CRESTOR is used in combination with gemfibrozil, the dose of CRESTOR should be limited to 10 mg once daily*

  • For patients with severe renal insufficiency the dosing of CRESTOR should be started with 5 mg once daily and not exceed 10 mg once daily

*Note that the combination of rosuvastatin and gemfibrozil should generally be avoided

CRESTOR® (rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003.


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CRESTOR®(rosuvastatin calcium)Summary

  • Across the dose range of 5-40 mg, CRESTOR demonstrated LDL-C reductions of 45-63% CRESTOR1

  • Crestor reduced LDL-C across the dose range in multiple comparator trials that included atorvastatin2

  • CRESTOR 5 mg to 40 mg increased HDL-C between 8% and 14% (vs 3% with placebo)1

  • CRESTOR was generally well tolerated in an extensive preapproval clinical program involving >10,000 patients. The most frequent adverse events thought to be related to CRESTOR were myalgia (3.3%), constipation (1.4%), asthenia (1.3%), abdominal pain (1.3%), and nausea (1.3%)3

1. CRESTOR®(rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003.

2. Data on file, DA-CRS-02 AstraZeneca Pharmaceuticals LP, Wilmington, DE.

3. Data on file, DA-CRS-01 AstraZeneca Pharmaceuticals LP, Wilmington, DE.


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CRESTOR®(rosuvastatin calcium)

Thank you for your attention!

Daniel Weiss MD CDE FACP PNS

Endocrinology

Mentor


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