rosuvastatin

RosuvastatinA Review of its Use in the Prevention of Cardiovascular Disease in

Apparently Healthy Women or Men with Normal LDL-C Levels and

Elevated hsCRP Levels

Natalie J. Carter

Adis, a Wolters Kluwer Business, Auckland, New Zealand

Various sections of the manuscript reviewed by:M.J. Banach, Department of Cardiology, Medical University of Lodz, Lodz, Poland; L. Masana, Lipid Research Unit, Sant Joan UniversityHospital, Reus, Spain; B. Pitt, Division of Cardiology, University of Michigan Hospital, Ann Arbor, Michigan, USA; B. Tomlinson,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong; N.D. Wong, UCI Heart DiseasePrevention Program, University of California at Irvine, Irvine, California, USA.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘rosuvastatin’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietarydatabase). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was alsorequested from the company developing the drug.

Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘rosuvastatin’ and (‘c-reactive’ or ‘c-reactive-protein’ or ‘CRP’ or ‘prevention’). Searches were lastupdated 8 September 2010.

Selection: Studies in apparently healthy women or men with normal LDL-C levels and elevated hsCRP levels who received rosuvastatin. Inclusion of studies was based mainlyon the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamicand pharmacokinetic data are also included.

Index terms: rosuvastatin, cardiovascular disease prevention, hsCRP, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384

2. Pharmacodynamic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385

2.1 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385

2.2 Lipid and Anti-Inflammatory Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385

2.3 Other Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 386

2.4 Special Populations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 386

2.5 Pharmacodynamic Drug-Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387

3. Pharmacokinetic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387

3.1 Absorption and Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387

3.2 Metabolism and Elimination. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387

3.3 Special Patient Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387

3.4 Pharmacokinetic Drug-Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388

4. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388

4.1 Primary Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389

4.1.1 Cardiovascular Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389

4.1.2 Thromboembolic Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390

4.2 Secondary Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391

4.2.1 Stratification According to On-Treatment Laboratory Measures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391

4.2.2 Stratification According to Baseline Factors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391

5. Tolerability. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393

6. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395

ADIS DRUG EVALUATIONAm J Cardiovasc Drugs 2010; 10 (6): 383-400

1175-3277/10/0006-0383/$49.95/0

ª 2010 Adis Data Information BV. All rights reserved.

7. Place in the Prevention of Cardiovascular Disease in Apparently Healthy Women or Men with Normal LDL-C Levels

and Elevated hsCRP Levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395

Abstract Rosuvastatin (Crestor�) is an HMG-CoA reductase inhibitor (statin) that has both lipid-lowering and anti-

inflammatory effects. The drug has various indications in the US, including the primary prevention of

cardiovascular disease (CVD) in patients with no clinical evidence of coronary heart disease who are at

increased risk of CVD based on their age, a high-sensitivity C-reactive protein (hsCRP) level of ‡2mg/L,and at least one other CVD risk factor.

The efficacy of rosuvastatin in apparently healthy women (aged ‡60 years) or men (aged ‡50 years) with

normal low-density lipoprotein cholesterol (LDL-C) levels and elevated hsCRP levels was demonstrated in the

large, randomized, double-blind, multinational, JUPITER trial. Relative to placebo, rosuvastatin 20mg once

daily for a median follow-up of 1.9 years significantly reduced the occurrence of first major cardiovascular

events in this trial (primary endpoint). A between-group difference in favor of rosuvastatin was also demon-

strated for various other endpoints, including overall deaths and the nonatherothrombotic endpoint of venous

thromboembolism. Rosuvastatin remained more effective than placebo when primary endpoint results were

stratified according to various baseline factors, including in patient subgroups thought to be at low risk ofCVD.

In addition, rosuvastatin was associated with reductions in LDL-C and hsCRP levels, and these reductions

appeared tooccur independently of eachother. The greatest clinical benefitwas observed in rosuvastatin recipients

achieving anLDL-C level of<1.8mmol/L (<70mg/dL) andanhsCRP level of<2mg/Lor, evenmore so,<1mg/L.Rosuvastatin was well tolerated in the JUPITER trial, withmost adverse events beingmild tomoderate in

severity. Myalgia, arthralgia, constipation, and nausea were the most commonly occurring treatment-

related adverse events, and the incidence of monitored adverse events and laboratory measurements was

generally similar in the rosuvastatin and placebo groups.

It is not yet knownwhether themechanism of benefit of rosuvastatin is via lipid effects, anti-inflammatory

effects, or a mixture of both, and the use of rosuvastatin solely on the basis of elevated hsCRP levels is

controversial. Nonetheless, the drug remains an important pharmacologic option in the prevention of CVD,

and has demonstrated efficacy in preventing major cardiovascular events in apparently healthy women

(aged ‡60 years) or men (aged ‡50 years) with normal LDL-C levels and elevated hsCRP levels.

1. Introduction

Cardiovascular disease (CVD) is the leading cause of death in

the US, with more people dying each year from CVD than from

cancer, chronic lower respiratory tract diseases, and accidents

combined.[1] The termCVD encompasses a wide range of cardio-

vascular-related diseases, including hypertension, coronary heart

disease (CHD) [i.e. myocardial infarction (MI) or angina pecto-

ris], heart failure, stroke, and congenital cardiovascular defects.[1]

The risk of developing CVD increases with age, and the disease is

more common in men than in women in younger age groups,

although this difference disappears with advancing age.[1] By

40 years of age, the lifetime risk of developing CVD is >1 in 2 for

women, and 2 in 3 for men.[1] Overall, an estimated 81 million

adults in the US have one or more types of CVD at any given

time, with >38 million of these adults being aged ‡60 years.[1]

The risk of developing CVD is commonly assessed using the

Framingham risk model (or a variation of this model), with

patients being stratified into low- (10-year risk <10%), inter-

mediate- (10-year risk 10–20%), or high- (10-year risk >20%)

risk groups according to age, sex, systolic blood pressure, serum

total cholesterol level, high-density lipoprotein cholesterol

(HDL-C) level, and whether or not they smoke; diastolic blood

pressure, low-density lipoprotein cholesterol (LDL-C) level, a

family history of premature CHD, and/or a history of diabetesmellitus is also taken into account in some instances.[2-4] How-

ever, a proportion of patients considered to be at low risk of

CVD based on these traditional risk factors will go on to develop

CVD (section 7).[5,6] Therefore, identification of other factors that

may enable physicians to identify more patients at risk of CVD is

of interest,[3,6] particularly those that enable reclassification of

intermediate-risk patients as either low- or high-risk.[3]

HMG-CoA-reductase inhibitors (statins) are lipid-lowering

agents that are recommended in current US guidelines as first-

line treatment options for the pharmacologic lowering of

LDL-C levels.[2,4] In clinical trials, some of these drugs also had

beneficial effects on inflammatory biomarkers (e.g. C-reactive

protein [CRP] levels) in patients with dyslipidemia, including

those at high-risk of developing CVD and those with estab-

lished CVD (section 2.2).[7] Moreover, these anti-inflammatory

384 Carter

ª 2010 Adis Data Information BV. All rights reserved. Am J Cardiovasc Drugs 2010; 10 (6)

effects were associated with clinical benefits that were in-

dependent of those associated with changes in the lipid profile

in patients with stable CVD or acute coronary syndrome (sec-

tion 2.2).[8-13] Based on findings from these and other trials, it

was postulated that high-sensitivity CRP levels (i.e. CRP levels

measured with a high-sensitivity assay [hsCRP]) may be of use

as an additional marker of CVD risk.[14,15]

Rosuvastatin (Crestor�) is one of the statins for which anti-

inflammatory effects have been demonstrated in dyslipidemic

patients (section 2.2) [reviewed by Keating and Robinson[7]]. To

further explore the relationship between rosuvastatin-associated

reductions in hsCRP and CVD prevention, the efficacy of the

drug was investigated in apparently healthy women or men with

normal LDL-C levels and elevated hsCRP levels in the pivotal

JUPITER (Justification for the Use of statins in Prevention: an

Intervention Trial Evaluating Rosuvastatin) trial.[15] Subsequent

to the favorable results observed in this trial (section 4),[15] the

approved indications of rosuvastatin in the US were expanded to

include the primary prevention ofCVD in patientswith no clinical

evidence ofCHD,whoare at increased risk ofCVDbased on their

age, an hsCRP level of ‡2mg/L, and the presence of at least one

other CVD risk factor (section 6).[16] The drug is also indicated for

the management of various dyslipidemias and to slow the pro-

gression of atherosclerosis (section 6).[16]

The use of rosuvastatin in the management of dyslipide-

mia[17,18] or to slow the prevention of atherosclerosis[7] has been

reviewed previously. This article specifically focuses, from aUS

perspective, on the use of rosuvastatin in the prevention of

CVD in apparently healthy women ormenwith normal LDL-C

levels and elevated hsCRP levels, as well as reviewing aspects of

its pharmacologic properties and tolerability that are relevant

to this population of patients.Where data are unavailable in the

main patient population, key information from studies in other

patient populations are provided.

2. Pharmacodynamic Profile

2.1 Mechanism of Action

As for all statins, rosuvastatin is an inhibitor of HMG-CoA

reductase, an enzyme involved in the pathway leading to the

generation of cholesterol.[7] Rosuvastatin is relatively hydro-

philic and is highly selective for hepatic cells.[7] The uptake of

rosuvastatin into the liver is mediated by organic anion-trans-

porting polypeptide (OATP)-1B1 (formerly OATP-C), a liver-

specific transport protein.[19] Rosuvastatin is a high-affinity

substrate for OATP-1B1, and has a higher affinity for this

transport protein than other statins.[7]

2.2 Lipid and Anti-Inflammatory Effects

The pharmacologic effects of rosuvastatin in patients with

hypercholesterolemia and/or other dyslipidemias (including

high-risk patients and special patient populations) with or with-

out CVD have been well described previously.[7,17,18] In brief,

rosuvastatin decreased LDL-C levels by up to 57%, and to re-

commended goals in up to 84% (National Cholesterol Educa-

tion Program [NCEP] Adult Treatment Panel [ATP] III goals)

or 89% (Joint European Societies’ 1998 goals) of patients in

clinical trials (reviewed by Keating and Robinson[7]). In gen-

eral, total cholesterol, triglyceride, and apolipoprotein (apo) B

levels were decreased, and HDL-C and apoA1 levels were in-

creased by the drug.[7]

In addition to its beneficial effects on the lipid profile, rosu-

vastatin also demonstrated anti-inflammatory properties in this

population of patients by decreasing CRP, fibrinogen, and pro-

inflammatory cytokine levels.[7] Similar improvements in in-

flammatory parameters have been observed in patients with stable

CVD or acute coronary syndrome, and these improvements were

associated with clinical benefits that were independent of those

associated with changes in the lipid profile (section 1).[8-13]

In general, rosuvastatin 5–40mg/day for 6–24 weeks was as

effective or more effective (p < 0.05) than other statins (ator-

vastatin 10–80mg/day, pravastatin 10–40mg/day, and/or sim-

vastatin 10–80mg/day) in decreasing LDL-C, total cholesterol,

apoB, or CRP levels in patients with hypercholesterolemia

(and/or other dyslipidemias) with or without CVD, with some

between-group differences in favor of rosuvastatin also being

demonstrated for changes inHDL-C, apoA1, and, less frequently,

triglyceride levels (reviewed by Keating and Robinson[7]).

Rosuvastatin also demonstrated beneficial lipid-lowering and

anti-inflammatory effects in patients with normal LDL-C levels

(<3.4mmol/L [<130mg/dL]) and elevated hsCRP (‡2.0mg/L)levels in the pivotal JUPITER trial.[15] Relative to baseline mea-

surements, median hsCRP levels were decreased by 48–57%,

median LDL-C levels by 49–51%, and median triglyceride levels

by 10–16% after treatment with rosuvastatin 20mg once daily for

12, 24, 36, or 48 months (figure 1). Rosuvastatin also increased

median HDL-C levels by 2–6% over the same treatment period

(figure 1).[15] Aside from median HDL-C levels at 48 months,

which were similar in both the rosuvastatin and placebo groups,

all other between-group differences in hsCRP, LDL-C, trigly-

ceride, andHDL-C levels were significantly (p£ 0.003) in favor of

rosuvastatin at all timepoints (figure 1).[15]

Furthermore, rosuvastatin-related reductions in LDL-C

and hsCRP levels were associated with clinical benefit in the

JUPITER trial, particularly when both parameters were reduced

Rosuvastatin: A Review 385


to below predetermined goals (i.e. <1.8mmol/L [<70mg/dL])for LDL-C levels and <1 or <2mg/L for hsCRP levels) [sec-

tion 4.2.1].[15]

2.3 Other Effects

As reviewed previously,[7] rosuvastatin has demonstrated many

other pharmacodynamic effects in in vitro, animal, and clinical

studies. For example, in patients with hypercholesterolemia or

CVD, rosuvastatin decreased plasma asymmetric dimethylargi-

nine levels, improved flow-mediated dilation, increased parox-

onase-1 activity, decreased levels of oxidative stress markers, and

attenuated the postprandial rise in platelet count.[7] In murine

models of carotid artery injury, platelet aggregation and the en-

dothelial injury-related thrombotic response were attenuated,

vascular lesion development and fibrin deposition were decreased,

re-endothelialization was promoted, and smooth muscle cell and

collagen content were increased after treatment with rosuvasta-

tin.[7] Furthermore, expression of CD40 and metalloproteinase

(MMP)was inhibited by rosuvastatin in apoE knockoutmice, and

this effect was increased when rosuvastatin was coadministered

with candesartan.[7] In addition, rosuvastatin reduced the in vitro

secretion of MMP-7 in human monocyte-derived macrophages

and inhibited the expression of protease-activated receptor-1

thrombin receptor on platelets isolated from rosuvastatin-treated

patients with metabolic syndrome.[7]

2.4 Special Populations

LDL-C levels were decreased in a gene-dose dependent man-

ner in Chinese patients with hypercholesterolemia[20,21] and in

post-MI patients[22] (>96%EuropeanCaucasian[23]) who received

rosuvastatin for at least 4 weeks in clinical studies. Of all the

polymorphisms genotyped in one of the Chinese studies, genetic

variability in the gene encoding for ATP-binding cassette G2

protein (an efflux transporter) was most highly associated with

this gene-dose response.[21] In the Chinese studies, patients who

were homozygous for the c.421A variant allele (c.421AA geno-

type; n= 39[20] and 55[21]) had a significantly (p£ 0.0006) greaterpercent change in LDL-C levels from baseline to endpoint than

those who were homozygous for the wild-type allele (c.421CC

genotype; n= 158[20] and 191[21]) [-57%[20,21] vs -49%[21] and

-50%[20]]. Chinese patientswhowere heterozygous for the c.421A

variant allele (c.421AC genotype; n= 108[20] and 136[21]) had an

intermediate response to rosuvastatin therapy (percent change in

LDL-C levels of -54%[20,21]). Similar findings were seen in the

EuropeanCaucasian study,with a significant (p= 0.01) differencebeing observed in 3-month LDL-levels between patients with the

0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0a

c

b

d

hsC

RP

(m

g/L)

ROSPL

** ****

**

0

0.5

1.0

1.5

2.0

Baseline 12 mo 24 mo 36 mo 48 mo

HD

L-C

(m

mol

/L) ** ** *

0

0.5

1.0

1.5

2.0

2.5

3.0

LDL-

C (

mm

ol/L

)

** ** ** **

0

0.5

1.0

1.5

2.0

Baseline 12 mo 24 mo 36 mo 48 mo

TG

(m

mol

/L)

** ****

**

Fig. 1. Pharmacologic effects of rosuvastatin (ROS) in patients (pts) with normal low-density lipoprotein-cholesterol (LDL-C) levels and elevated high-

sensitivity C-reactive protein (hsCRP) levels. Median (a) hsCRP, (b) LDL-C, (c) high-density lipoprotein-cholesterol (HDL-C), and (d) triglyceride (TG) levels at

baseline and after 12, 24, 36, or 48 months of treatment with ROS 20mg or placebo (PL) once daily in the JUPITER trial. * p = 0.003, ** p < 0.001 vs PL.

386 Carter


c.421CC genotype (n= 231) and those with either the c.421AA or

c.421ACgenotype (n= 79) [2.0 vs 1.8mmol/L (76 vs 68mg/dL)].[22]

Pharmacokinetic data discussed in section 3.3 are reflective of these

results.

2.5 Pharmacodynamic Drug-Drug Interactions

Coadministration of rosuvastatin with other lipid-lowering

drugs (e.g. fibric acid derivatives [e.g. fenofibrate, gemfibrozil] or

niacin), cyclosporine (ciclosporin), atazanavir/ritonavir, or lopi-navir/ritonavir may increase the risk of developing myopathy.[16]

Because of this, although concomitant use of rosuvastatin and

fenofibrate did not alter the pharmacokinetics of either drug to a

clinically relevant extent (section 3.4), the manufacturer’s pre-

scribing information recommends reducing the dose of rosuvas-

tatin when the two drugs are combined.[16] For similar reasons, a

reduction in rosuvastatin dose should be considered if the drug is

administered in conjunction with niacin.[16]

Rosuvastatin increased the anticoagulant effect of warfarin

in healthy volunteers and in patients who received the drugs

concomitantly (section 3.4).[24] In patients already receiving

warfarin, the international normalized ratio should be de-

termined prior to initiating treatment with rosuvastatin, and

should continue to be monitored frequently during the initial

concomitant treatment period.[16]

3. Pharmacokinetic Profile

The pharmacokinetics of rosuvastatin have not been specifically

studied in healthy women or men with normal LDL-C levels and

elevated hsCRP. This section provides an overview of the pharm-

acokinetics of rosuvastatin in healthy volunteers or other pop-

ulations of patients, which have been reviewed elsewhere.[7,17,18]

3.1 Absorption and Distribution

In healthy volunteers, rosuvastatin demonstrated linear, dose-

dependent increases in the geometricmeanmaximumplasma con-

centration (3.8–10.3ng/mL) [Cmax] and the mean area under the

plasma concentration-time curve (AUC) from time zero to the last

measurable concentration (31.6–98.2 ng�h/mL) [AUClast] over a

dose range of 10–40mg.[25] The AUC from time zero to 24 hours

also increased with rosuvastatin dose (30.7–84.4 ng�h/mL); how-

ever, the median time to Cmax (5.0 hours) was not dose depend-

ent.[25] The estimated absolute oral bioavailability of rosuvastatin

after a single oral 40mg dose was »20%.[26]

Steady-state concentrations were achieved by the eighth day

of treatment with rosuvastatin 10mg once daily.[27] The

pharmacokinetics of rosuvastatin were not affected by the time

of day at which the drug was administered,[27] and adminis-

tration with (as opposed to without) food did not alter the

pharmacokinetics to a clinically relevant extent.[16]

Rosuvastatin is 88% bound to plasma proteins, mainly al-

bumin.[16] The estimated volume of distribution at steady state is

134L, indicating that the drug is widely distributed to the tis-

sues.[26] As demonstrated by a >70% rate of nonrenal clearance

and a high hepatic extraction ratio (section 3.2), it appears that

rosuvastatin is distributed extensively into the human liver.[26]

3.2 Metabolism and Elimination

The primary elimination route of rosuvastatin is via the

liver.[28] Because of its low bioavailability and high hepatic

extraction ratio of 0.63, the drug is thought to undergo first-

pass metabolism.[26] Rosuvastatin may also undergo entero-

hepatic recirculation, as demonstrated by secondary peaks in

individual plasma concentration-time profiles.[25,26,28]

Rosuvastatin is not extensively metabolized,[29] and the cy-

tochrome P450 (CYP) system plays only a minor role in its

metabolism.[29,30] CYP2C9 is the main CYP isozyme involved

in the small proportion of rosuvastatin metabolism that occurs

via the CYP system; CYP3A4 does not contribute to this

process.[29,30] The HMG-CoA reductase inhibitory activity of

N-desmethyl rosuvastatin (the major metabolite of rosuvasta-

tin) is about one-sixth to one-half that of the parent drug.[16]

In healthy volunteers, excretionof a single radiolabelleddose of

rosuvastatinwas complete after 240 hours.[28]Approximately 90%of the dose was excreted in the feces (70% of the radioactive dose

within 24–72 hours), and the remainder in the urine.[28] Un-

changed drug accounted for the majority (»77%) of the total ad-

ministered dose recovered in the feces, and the two rosuvastatin

metabolites identified accounted for 6% and 2%.[28]

The geometric mean plasma clearance of rosuvastatin 8mg

after a single intravenous dose was 48.9L/h.[26] Approximately

28%of total body clearance occurs via the renal route,with at least

90% of this being accounted for by net tubular secretion;[26] the

remainder of total body clearance occurs via the hepatic route.[16]

Rosuvastatin plasma concentrations decreased in a biphasic

manner after oral administration, first during the distribution

phase (up to »18 hours), and then during a longer terminal

elimination phase.[25,28] After a single oral dose of rosuvastatin

40mg, the mean terminal elimination half-life was »20 hours.[26]

3.3 Special Patient Populations

Age and sex did not alter the pharmacokinetics of rosuvas-

tatin to a clinically relevant extent.[31] However, rosuvastatin



geometric meanAUClast andCmax values were »2-fold higher inAsian versus Caucasian patients.[32] On the basis of this finding,

a reduced dose of rosuvastatin is recommended in Asian

patients (section 6).[16]

Exposure to rosuvastatin was affected by hepatic dysfunc-

tion, with Cmax and AUC values increasing by 60% and 5% in

patients with mild (Child-Pugh class A) hepatic impairment

andby 100% and21% in thosewithmoderate (Child-Pugh classB)

hepatic impairment relative to healthy volunteers.[16] Plasma

concentrations of rosuvastatin were also increased in patients

with alcohol-related, chronic liver disease.[16] Because of this,

rosuvastatin is contraindicated in patients with active liver

disease (or unexplained persistent transaminase elevations),

and should be used with caution in those with a history of

chronic liver disease or excess alcohol use (section 5).[16]

Renal impairment of mild or moderate (creatinine clearance

[CLCR] ‡30 but £80mL/min/1.73m2) severity did not alter the

pharmacokinetics of rosuvastatin.[16] However, exposure to ro-

suvastatin was increased by »3-fold in patients with severe renal

impairment (CLCR <30mL/min/1.73m2) who were not receiving

dialysis compared with healthy volunteers.[16] Because of this, the

US prescribing information recommends commencing rosuvas-

tatin at the lowest dose of 5mg in patients with severe renal im-

pairment who are not receiving hemodialysis, and that the dose is

not increased to above 10mg (section 6).[16] No dose reductions

are required in those with mild or moderate renal impairment.[16]

The pharmacokinetics of rosuvastatin were affected by

genetic variability in the ABCG2 gene in Chinese[33] and Fin-

nish[34] healthy volunteers. In the Finnish study, 1% of the over-

all study population (n = 660) had the c.421AA genotype, 17%had the c.421AC genotype, and 82% had the c.421CC genotype.

In individuals with the c.421AA genotype who underwent

pharmacokinetic testing (n = 4), the AUC from time zero to

infinity was 100% greater than in those with the c.421AC gen-

otype (n = 12) and 144% greater than in those with the c.421CC

genotype (n = 16). In addition, the Cmax was significantly higher

in healthy volunteers with the c.421AA genotype than in those

with the c.421AC (108%) or c.421CC genotypes (131%). The

effects of such findings on the pharmacodynamics of rosuvas-

tatin are discussed in section 2.4.[34]

3.4 Pharmacokinetic Drug-Drug Interactions

As expected with a drug that is not metabolized by CYP3A4

(section 3.2), the pharmacokinetics of rosuvastatin were not

altered by coadministration with the CYP3A4 inhibitors

erythromycin,[35] ketoconazole,[36] or itraconazole.[37] In addi-

tion, coadministration with the CYP2C9 and CYP2C19 in-

hibitor fluconazole[38] or with the CYP2C9 substrate warfarin

did not affect the pharmacokinetics of rosuvastatin.[24]

The pharmacokinetics of rosuvastatin were not altered to a

clinically significant extent by the lipid-lowering agents feno-

fibrate,[39] ezetimibe,[40] or omega-3 fatty acids (ethyl-eicosa-

pentaenoic acid plus ethyl-docosahexaenoic acid).[41] However,

coadministration with gemfibrozil increased rosuvastatin ex-

posure by »2-fold.[42] Because of the pharmacodynamic effects

this may cause (section 2.5), the US prescribing information

recommends that the combination of rosuvastatin and gemfi-

brozil be avoided and, if the combination is indicated, that the

dosage of rosuvastatin should not exceed 10mg once daily.[16]

Rosuvastatin AUC was increased by up to 3-fold and Cmax

by up to 7-fold when the drug was coadministered with the

atazanavir/ritonavir[43] or lopinavir/ritonavir.[44] If one of thesecombinations is indicated, the dosage of rosuvastatin should

be limited to 10mg once daily.[16] Rosuvastatin exposure was

increased by »2-fold[45] and <1.5-fold[44] when the drug was

administered with tipranavir/ritonavir[45] or fosamprenavir/ritonavir.[44] Because of this, it is advised that such combina-

tions are used with caution.[16]

It is also recommended that the dose of rosuvastatin is lim-

ited to 5mg when the drug is coadministered with cyclo-

sporine,[16] because of the associated increase (AUC24 by 7-fold

and Cmax by 11-fold) in rosuvastatin exposure observed when

the two drugs are combined.[46]

Simultaneous administration of rosuvastatin with alumi-

nium andmagnesium hydroxide antacid decreased rosuvastatin

exposure by »50%; however, when the drugs were administered

2 hours apart, rosuvastatin exposure was decreased by only

»20%.[47]

Rosuvastatin did not alter the pharmacokinetics of digoxin,[48]

cyclosporine,[46] ezetimibe,[40] or fenofibrate[39] to a clinically rel-

evant extent, or that of ethinylestradiol or norgestimate in wo-

men receiving a combined oral contraceptive.[49] Despite the

pharmacodynamic effect observed when rosuvastatin and

warfarin are combined (section 2.5), the plasma concentrations

of R- and S-warfarin were not altered to a clinically significant

extent when the two drugs were coadministered.[24] However, it

is possible that some other pharmacokinetic interaction, such

as a reduced clearance of unbound R- or S-warfarin may ac-

count for the pharmacodynamic effect.[24]

4. Therapeutic Efficacy

The efficacy of rosuvastatin in the prevention of CVD in

apparently healthy women or men with normal LDL-C levels

and elevated hsCRP levels was explored in the large (n= 17802),

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randomized, double-blind, placebo-controlled, multinational

JUPITER trial.[50] Results discussed in this section are from

primary analyses conducted in the overall patient population

(section 4.1)[15,51-53] and of secondary analyses in which primary

endpoint results were stratified according to various baseline

(section 4.2.2)[54-59] or on-treatment (section 4.2.1) factors.[59,60]

Some data are available as an abstract.[56] Additional infor-

mation available in the manufacturer’s US prescribing infor-

mation are discussed where appropriate.[16]

Women aged ‡60 years and men aged ‡50 years were eligiblefor the JUPITER trial if they had no past medical history of

CVD (i.e. MI, stroke, arterial revascularization, or other cor-

onary risk equivalent[14]) and if they had an hsCRP level of

‡2.0mg/L, an LDL-C level of <3.4mmol/L (<130mg/dL), anda triglyceride level of <5.65mmol/L (<500mg/dL).[50]

Key exclusion criteria included previous or current use of

any lipid-lowering therapy; current use of postmenopausal hor-

mone replacement therapy or immunosuppressants; an ALT

level >2 · the upper limit of normal (ULN), a creatine kinase

level >3 · the ULN, a thyroid-stimulating hormone level >1.5 ·the ULN, and/or a creatinine level >2.0mg/dL (150 mmol/L);a history of any nonbasal or nonsquamous cell carcinoma in

the past 5 years; a history of diabetes, uncontrolled hyperten-

sion, or a chronic inflammatory condition (e.g. severe arthritis,

systemic lupus erythematosus, or inflammatory bowel disease);

and a recent history of drug or alcohol abuse or any other

medical illness that might affect the results of the study.[50]

After a 4-week run-in phase, eligible patients were ran-

domized 1 : 1 to receive oral rosuvastatin 20mg (n = 8901) orplacebo (n = 8901) once daily for up to 5 years.[15] However,

because rosuvastatin demonstrated a clear benefit over placebo

in an interim efficacy analysis, the study was terminated after a

median follow-up duration of 1.9 years (maximum follow-up of

5 years).[15] Results in this section pertain to the results of the

interim efficacy analysis, unless otherwise specified.

The primary efficacy endpoint of the JUPITER trial was

the occurrence of first major cardiovascular events, which in-

cluded the combined incidence of nonfatal MI, nonfatal

stroke, hospitalization for unstable angina, arterial revascula-

rization procedures, and deaths due to cardiovascular causes.[15]

The incidences of each individual component of the pri-

mary efficacy endpoint were secondary endpoints,[14,15] as

were the incidences of total mortality,[14,15] noncardiovascular

deaths,[14] venous thromboembolism,[14] diabetes,[14] and bone

fractures.[14] The frequency of newly diagnosed diabetes oc-

curring in the JUPITER trial is discussed in section 5; data

pertaining to the incidence of bone fractures are not yet avail-

able. Primary endpoint results were also stratified according

to the hsCRP (<2 or ‡2mg/L and <1 or ‡1mg/L) and LDL-C

level (<1.8 or ‡1.8mmol/L [<70 or ‡70mg/dL]) achieved at

the 1-year follow-up in a prespecified analysis (section 4.2.1),[60]

and according to various baseline factors in a number of

post hoc analyses[54-59] (section 4.2.2). The hsCRP and LDL-C

cut-off levels for the secondary analysis were chosen on the

basis of results from an hypothesis-generating analysis[61]

from an earlier study (the AFCAPS/TexCAPS [Air Force/Texas Coronary Atherosclerosis Prevention Study][62]).[6,60]

All efficacy analyses were conducted in the intent-to-treat

population.[15]

A total of 89 890 patients were screened for enrollment into

the JUPITER trial, of which 72 000 were ineligible for inclusion

(i.e. »5 patients needed to be screened to identify one eligible

patient).[15] The most common reasons for exclusion were

LDL-C levels ‡3.4mmol/L (‡130mg/dL) [37 611 patients] or

hsCRP levels <2.0mg/L (25 993 patients).[15]

4.1 Primary Analysis

Thebaseline characteristics of patients in the JUPITER trial did

not appear to differ between treatment arms.[15] Themedian age of

patients was 66.0 years, 38.2% of patients were women, and 25.2%were black orHispanic.[15] There was a high percentage of patients

with risk factors for CHD, with 58% having hypertension,[16] 41%having metabolic syndrome,[15] 23% having low HDL-C levels,[16]

16% being cigarette smokers,[15,16] and 12% having a family his-

tory of premature CHD;[15,16] approximately 17% of patients were

receiving regular aspirin.[15] Based on the Framingham risk crite-

ria, the estimated 10-year risk of developingCHDwas 11.6% in the

studypatient population.[16]Median levels ofLDL-C,HDL-C, and

triglycerides at baseline were 2.8mmol/L (108mg/dL), 1.3mmol/L(49mg/dL), and 1.3mmol/L (118mg/dL), respectively, in both the

rosuvastatin and placebo groups.[15] In the rosuvastatin group,

themedian baseline hsCRP level was 4.2mg/L and, in the place-

bo group, it was 4.3mg/L.[15]

4.1.1 Cardiovascular Events

Rosuvastatin significantly (p< 0.00001) reduced the occur-

rence of first major cardiovascular events in apparently healthy

women andmen with normal LDL-C levels and elevated hsCRP

levels by almost one-half.[15] The rate per 100 person-years of

first major cardiovascular events, as defined in figure 2, was 0.77

in the rosuvastatin group and 1.36 in the placebo group (primary

endpoint; see figure 2 for actual event numbers).[15] The benefits

of rosuvastatin over placebo for the prevention of first major

cardiovascular events translated into a relative risk reduction of

44%[51] (hazard ratio [HR] 0.56; 95% confidence interval [CI]



0.46, 0.69[15]), and a number of patients who needed to be treated

(NNT) to prevent one first major cardiovascular event of 215,[51]

95,[15,51] 31,[15,51] and 25[15,51] after 1,[51] 2,[15,51] 4,[15,51] and 5[15,51]

years of rosuvastatin treatment, respectively; the 4-year absolute

risk rates were projected over an average 5-year treatment period

to obtain the 5-year NNT value.[15,51]

When each component of the primary endpoint was ana-

lyzed separately, a significant difference was seen between the

rosuvastatin and placebo groups in the incidence of nonfatal

MI (rate per 100 person-years 0.12 vs 0.33; p < 0.00001; HR

0.35; 95% CI 0.22, 0.58),[15,16] nonfatal stroke (rate per 100

person-years 0.16 vs 0.31; p= 0.003; HR 0.52; 95% CI 0.33,

0.80),[15,16] and arterial revascularization procedures (rate per

100 person-years 0.38 vs 0.71; p < 0.0001;HR 0.54; 95%CI 0.41,

0.72).[15,16] However, there was no significant between-group

difference for the endpoints of hospitalization for unstable

angina (rate per 100 person-years 0.09 vs 0.14 in the placebo

group)[15] or cardiovascular deaths (rate per 100 person-years

0.19 vs 0.24).[16] See figure 2 for actual event numbers.

Although the between-group difference in the incidence of

cardiovascular deaths was not significant,[16] a between-group

difference in favor of rosuvastatin was demonstrated for the

incidence of deaths from any cause (198 vs 247 events; rate per

100 person-years 1.00 vs 1.25; p = 0.02; HR 0.80, 95% CI 0.67,

0.97).[15] The incidence of noncardiovascular deaths was not

reported.

As well as reducing the incidence of nonfatal MI and of

nonfatal stroke, rosuvastatin was also associated with a sig-

nificant (p £ 0.002) reduction in the overall incidence of fatal or

nonfatal MI (31 vs 68 events; rate per 100 person-years 0.17 vs

0.37; HR 0.46; 95% CI 0.30, 0.70)[15] and the overall incidence

of fatal or nonfatal strokes (33 vs 64 events; rate per 100 person-

years 0.18 vs 0.34; HR 0.52; 95% CI 0.34, 0.79)[15,53] relative to

placebo. The between-group difference in the incidence of

stroke was primarily accounted for by the difference in the

incidence of ischemic stroke between the two groups (23 vs 47

events; rate per 100 person-years 0.12 vs 0.25; p = 0.004; HR

0.49; 95% CI 0.30, 0.81), with no significant between-group

differences being demonstrated for the incidence of hemor-

rhagic stroke or transient ischemic attacks.[53]

Rosuvastatin remained significantly more effective than

placebo when primary endpoint results were stratified accord-

ing to various baseline factors, including age, sex, race, and

geographic region.[15] Moreover, a between-group difference in

favor of rosuvastatin was demonstrated in all patient sub-

groups, regardless of whether they were at a low or high base-

line risk of cardiovascular events.[15] For example, rosuvastatin

was more effective than placebo in patients who did or did not

smoke, in those with a body mass index (BMI) of <25.0,25.0–29.9, or ‡30.0 kg/m2, in those with or without a history of

hypertension or metabolic syndrome, and in those with or

without a family history of CHD.[15] Furthermore, a between-

group difference in favor of rosuvastatin was observed in

patients with a Framingham risk score of £10% and in those

with a score of >10%, and was also noted in patients who had at

least one NCEP ATP III risk factor at baseline as well as in

those who had none.[15] Moreover, relative to placebo, rosu-

vastatin significantly reduced the incidence of first major

cardiovascular events occurring in patients who had no risk

factors for CVD other than increased age and an elevated

hsCRP level.[15] Results of analyses[54-59] in which primary

endpoint results were stratified according to some of these (or

other) key baseline factors are discussed further in section 4.2.2.

4.1.2 Thromboembolic Events

Rosuvastatin also appeared to be effective in reducing the

incidence of venous thromboembolism (i.e. pulmonary embo-

lism or deep-vein thrombosis), with 34 events occurring in the

rosuvastatin group versus 60 events in the placebo group (rate

per 100 person-years 0.18 vs 0.32; p = 0.007; HR 0.57; 95%CI 0.37, 0.86).[52] A significant difference was also seen between

rosuvastatin and placebo recipients for the combined incidence

0

50

100

150

200

250

300

Tota

l CV ev

ents

Arteria

l

reva

scula

rizat

ion

CV-re

lated

dea

ths

Nonfat

al str

oke

Nonfat

al M

I

Hospit

aliza

tion

for u

nsta

ble a

ngina

No.

of e

vent

s

ROSPL

***

***

**

*

Fig. 2. Efficacy of rosuvastatin (ROS) in preventing major cardiovascular

(CV) events in apparently healthy women or men with normal low-density

lipoprotein cholesterol levels, and elevated high-sensitivity C-reactive protein

levels. Results of an interim analysis at a median follow-up of 1.9 years of the

large, double-blind, multinational JUPITER trial in which patients (pts) were

randomized to receive ROS 20mg (n = 8901) or placebo (PL; n= 8901) oncedaily.[15,16] A major CV event was defined as a nonfatal myocardial infarction

(MI), nonfatal stroke, hospitalization for unstable angina, an arterial re-

vascularization procedure, or death due to a CV cause. Analyses were in the

intent-to-treat population. * p= 0.003, ** p <0.0001, *** p <0.00001 vs PL.

390 Carter


of the primary composite endpoint and venous thromboemb-

olism (173 vs 305 events; rate per 100 person-years 0.93 vs 1.66;

p < 0.001; HR 0.56; 95% CI 0.47, 0.68).[52]

4.2 Secondary Analyses

4.2.1 Stratification According to On-Treatment

Laboratory Measures

Rosuvastatin was associated with significant reductions in

hsCRP and LDL-C levels (section 2.2).[60] However, it ap-

peared that rosuvastatin recipients who achieved an LDL-C

level of <1.8mmol/L (<70mg/dL) [n= 5606] at the 1-year follow-up may have had lower LDL-C levels at baseline than those

who did not achieve this goal (n = 2110) [2.7 vs 2.9mmol/L(104 vs 112mg/dL); statistical analyses not available].[60] Sim-

ilarly, it appeared that patients who achieved an hsCRP level of

<2mg/L (n = 3411) at the 1-year follow-up may have had lower

hsCRP levels at baseline than those who did not achieve this

goal (n = 4305) [3.2 vs 5.4mg/L; statistical analyses not avail-able].[60] A number of other potential confounding factors were

also observed between the various groups and, thus, results

were adjusted to account for these differences (table I).[60]

Stratification of primary endpoint results according to the

hsCRP and LDL-C levels achieved after 1 year of rosuvastatin

therapy demonstrated that rosuvastatin-related reductions in

these laboratory measures were associated with a favorable

clinical response, which was not entirely explained by reductions

in LDL-C levels alone.[60] For example, recipients of rosuvasta-

tin who achieved an hsCRP level <2mg/L (with or without a

reduction in LDL-C levels <1.8mmol/L [<70mg/dL]) had a 62%reduction in the risk of a first major cardiovascular event oc-

curring relative to recipients of placebo (p= 0.007; age-adjustedHR [HRage] 0.38; 95% CI 0.26, 0.56) and those who achieved an

LDL-C level <1.8mmol/L (<70mg/dL) [with or without a re-

duction in hsCRP levels <2mg/L] had a 55% reduction in the risk

(p= 0.001; HRage 0.45; 95% CI 0.34, 0.60) [table I].[60]

Moreover, although hsCRP and LDL-C level reductions were

only weakly correlated in individual patients (Spearman correla-

tion coefficient [r]= 0.10), rosuvastatin recipients with an LDL-C

level <1.8mmol/L (<70mg/dL) and an hsCRP level of <2mg/L,or, even more so, <1mg/L had the lowest risk of a first major

cardiovascular event occurring relative to the other subgroups

(table I).[60] In terms of relative risk reduction, rosuvastatin re-

cipients achieving an hsCRP level <2mg/L and an LDL-C level

<1.8mmol/L (<70mg/dL) had a 65% reduction in the risk of a first

major cardiovascular event occurring relative to placebo recipi-

ents (p= 0.033; fully-adjusted HR [HRfully adjusted] 0.35; 95%CI 0.23, 0.54), and those achieving an hsCRP level <1mg/L and

an LDL-C level <1.8mmol/L (<70mg/dL) had a 79% reduction

in the risk (p= 0.037; HRfully adjusted 0.21; 95% CI 0.09, 0.51).[60]

There was no relationship between on-treatment HDL-C or

apoA1 levels and the incidence of first major cardiovascular

events.[59]

4.2.2 Stratification According to Baseline Factors

hsCRP, LDL-C, HDL-C, and Apolipoprotein A1 Levels

In general, the risk of a first major cardiovascular event

occurring in the JUPITER trial increased with increasing

baseline hsCRP level.[58] In men, for every increase of one in the

log-transformed hsCRP level, the risk of a primary endpoint

event occurring increased by 1.3-fold (p = 0.002). Although re-

sults of this same analysis for the primary endpoint in women

were not significant, similar findings to those observed in men

were demonstrated for other efficacy endpoints. Because the

rosuvastatin-associated relative risk reduction was similar

across the hsCRP tertiles in men receiving rosuvastatin, the

greatest reduction in the risk of a major cardiovascular event

occurring inmenwas observed in those with hsCRP levels in the

highest tertile at baseline (i.e. >5.4mg/L). Although the rela-

tionship between baseline hsCRP levels and primary endpoint

events was less clear in women for the tertile analysis, a sig-

nificant relationship was seen for other endpoints.[58]

Baseline HDL-C or apoA1 levels were not predictive of re-

sidual cardiovascular risk in rosuvastatin recipients.[59] In

contrast to the placebo arm, in which the number of primary

endpoint events occurring decreased with increasingHDL-C or

apoA1 quartile, there was no relationship between baseline le-

vels ofHDL-Cor apoA1 and the number of first cardiovascular

events occurring in the rosuvastatin arm.[59]

Fasting Glucose Levels

Although there was a higher incidence of physician-reported

diabetes in rosuvastatin recipients than in placebo recipients

(section 5), the efficacy of rosuvastatin did not appear to be

affected by fasting glucose levels, with the number of primary

endpoint events being significantly lower in the rosuvastatin

versus placebo groups in patients with impaired fasting glucose

levels at baseline (n = 5504) [p = 0.037; HR 0.69; 95% CI 0.49,

0.98] as well as in those with normal fasting glucose levels at

baseline (n = 12 170) [p < 0.001; HR 0.51; 95% CI 0.40, 0.67];[56]

quantitative data are not available for this analysis.

Renal Dysfunction

Regardless of treatment group, patients withmoderate chronic

kidney disease (defined as an estimated glomerular filtration rate

[eGFR] of <60mL/min/1.73m2) [n= 3267] were at a significantly



(p= 0.0002) higher risk of first major cardiovascular events

than those with normal kidney function (defined as an eGFR

‡60mL/min/1.73m2) [n= 14528], as demonstrated by a signif-

icantly higher number of primary endpoint events reported in

patients with moderate chronic kidney disease versus those with

normal renal function (incidence rate per 100 person-years 1.51 vs

0.95; HR 1.54; 95% CI 1.23, 1.92).[57] All other baseline charac-

teristics differed significantly (p£ 0.03) between patients with

moderate chronic kidney function and those with normal kidney

function, but there were no differences in the baseline character-

istics of patients with moderate chronic kidney function who re-

ceived rosuvastatin and those who received placebo.[57]

The efficacy of rosuvastatin was not altered by the presence of

renal dysfunction.[57] For example, rosuvastatin was associated

with a significantly lower number of primary endpoint events than

placebo in both the subgroup of patients with moderate chronic

kidney disease (rate per 100 person-years 1.08 vs 1.95; p= 0.002;HR0.55; 95%CI 0.38, 0.82) and in the subgroupwith normal renal

function (incidence rate per 100person-years 0.69 vs 1.21; p< 0.001;HR 0.57; 95%CI 0.45, 0.72). This translated into a 5-year NNT of

14 in the subgroupofpatientswithmoderate chronic kidneydisease

and 35 in the subgroup with normal kidney function.[57]

Sex of Patient

Aside from the proportion of women and men receiving

aspirin (16.4% vs 16.8%) and the baseline triglyceride levels

(both 1.3mmol/L [118mg/dL]), all other baseline character-

istics differed significantly (p £ 0.02) between women (n = 6801)and men (n = 11 001).[55] For example, women were older than

men (median age of 68 vs 63 years), smoked less (7.6% vs

Table I. Efficacy of rosuvastatin (ROS) in preventing the occurrence of first major cardiovascular (CV) events in apparently healthy women ormen with normal

low-density lipoprotein cholesterol (LDL-C) levelsa and elevated high-sensitivity C-reactive protein (hsCRP) levelsb in the JUPITER trial.[60] Incidence of the first

occurrence of nonfatalmyocardial infarction, nonfatal stroke, hospitalization for unstable angina, arterial revascularization procedures, andmortality due to aCV

event over a median follow-up period of 1.9 years (maximum of 5 years) [primary endpoint] when stratified according to the hsCRP and LDL-C levels obtained

after 1 year of treatment with ROS 20mg or placebo (PL) once daily. Analyses are in the intent-to-treat population

Pt group No. of pts in

subgroup

No. of events Incidence rate

(per 100 person-y)

HRage adjusted

(95% CI)cHRfully adjusted

(95% CI)c

PL 7832 189 1.11 1.00 1.00

ROS

hsCRP <2mg/L 3411 31 0.42 0.38 (0.26, 0.56)* 0.36 (0.24, 0.54)e

hsCRP ‡2mg/L 4305 72 0.77 0.69 (0.53, 0.91)* 0.68 (0.51, 0.89)e

LDL-C <1.8mmol/Ld 5606 64 0.51 0.45 (0.34, 0.60)** 0.45 (0.33, 0.59)e

LDL-C ‡1.8mmol/Ld 2110 39 0.91 0.89 (0.63, 1.25) 0.85 (0.60, 1.21)

hsCRP <2mg/L and LDL-C <1.8mmol/Ld 2685 23 0.38 0.35 (0.23, 0.54)e 0.35 (0.23, 0.54)--

hsCRP <2mg/L and LDL-C ‡1.8mmol/Ld 726 8 0.54 0.54 (0.27, 1.10) 0.42 (0.18, 0.94)e

hsCRP ‡2mg/L and LDL-C <1.8mmol/Ld 2921 41 0.62 0.55 (0.39, 0.77)e 0.53 (0.38, 0.74)e

hsCRP ‡2mg/L and LDL-C ‡1.8mmol/Ld 1384 31 1.11 1.06 (0.72, 1.55) 1.06 (0.72, 1.55)

hsCRP <1mg/L and LDL-C <1.8mmol/LLd 944 5 0.24 0.21 (0.09, 0.52)e 0.21 (0.09, 0.51)-

hsCRP ‡1mg/L and LDL-C <1.8mmol/Ld 4662 59 0.56 0.50 (0.38, 0.67)e 0.49 (0.37, 0.66)e

hsCRP <1mg/L and LDL-C ‡1.8mmol/Ld 236 3 0.64 0.65 (0.21, 2.03) 0.46 (0.11, 1.85)

hsCRP ‡1mg/L and LDL-C ‡1.8mmol/Ld 1874 36 0.95 0.91 (0.64, 1.30) 0.89 (0.62, 1.28)

hsCRP ‡1mg/L and/or LDL-C ‡1.8mmol/Ld 6772 98 0.67 0.61 (0.48, 0.77)e 0.59 (0.46, 0.75)-

hsCRP ‡2mg/L and/or LDL-C ‡1.8mmol/Ld 5031 80 0.74 0.67 (0.52, 0.87)e 0.64 (0.49, 0.84)--

a The median LDL-C level at baseline was 2.8mmol/L (108mg/dL).

b The median hsCRP level at baseline was 4.2mg/L in the ROS group and 4.3mg/L in the PL group.

c Hazard ratios (HR)were fully adjusted for age (HRage adjusted) or for age, sex, blood pressure, bodymass index, smoking status, parental history of premature

coronary heart disease, and baseline LDL-C, hsCRP, and HDL-C levels (HRfully adjusted).

d An LDL-C level of <1.8mmol/L is equivalent to a level of <70mg/dL.

e p-Value not reported.[60]

HDL-C=high-density lipoprotein cholesterol; pt =patient. * p =0.007, ** p= 0.001 vs PL in the age-adjusted analysis; - p = 0.037, -- p = 0.033 vs PL in the

fully-adjusted analysis.

392 Carter


21.0%), were more likely to havemetabolic syndrome (46.7% vs

38.7%), and had higher hsCRP (median of 4.6 vs 4.1mg/L) andLDL-C (2.82 vs 2.80mmol/L [109 vs 108mg/dL]) levels.[55]

Rosuvastatin effectively reduced the number of first major

cardiovascular events occurring in both women and men.[55]

Although the primary endpoint incidence rates in rosuvastatin

or placebo recipients appeared to be lower in women (0.56 vs

1.04 per 100 person-years; p = 0.002) than in men (0.88 vs 1.54

per 100 person-years; p < 0.0001), the relative risk reduction

was similar in both women (HR 0.54; 95% CI 0.37, 0.80) and

men (HR 0.58; 95% CI 0.45, 0.73). The benefit of rosuvastatin

over placebo in preventing one first major cardiovascular event

translated into a 5-year NNT of 36 in women and 22 in men.[55]

Age of Patient

Relative to younger patients (aged 50–69 years; n = 12 107),elderly patients (aged 70–97 years; n = 5695) appeared more

likely to have hypertension (53–54% vs 66%) or a Framingham

risk score of >10 (41% vs 69%), but less likely to be obese (i.e.

BMI of ‡30 kg/m2) [40% vs 32–33%] or to be smokers (19% vs

8–9%) [statistical analyses not available].[54] Most other base-

line characteristics were similar between the two groups, al-

though it appeared that more elderly than younger patients

were women (51–52% vs 32%).[54] Within these subgroups,

there did not appear to be any between-group differences in the

baseline characteristics of patients who received rosuvastatin

and those who received placebo.[54]

Patient age did not appear to affect the efficacy of rosuvastatin

in reducing the occurrence of first major cardiovascular events,

with the number of primary endpoint events being signifi-

cantly (p < 0.001) lower in both elderly (75 vs 119 events; rate

per 100 person-years 1.22 vs 1.99; HR 0.61; 95% CI 0.46, 0.82)

and younger (67 vs 132 events; rate per 100 person-years 0.54 vs

1.06; HR 0.51; 95% CI 0.38, 0.69) rosuvastatin recipients than

in placebo recipients.[54] The absolute treatment effect was 0.77

per 100 person-years in those aged ‡70 years (95%CI 0.32, 1.22)

and 0.52 per 100 person-years in those aged <70 years (95% CI

0.29, 0.74), and this translated into a 4-year NNT of 24 and

36,[54] and a 5-year NNT of 19 and 29.[51]

5. Tolerability

The tolerability profile of rosuvastatin has beenwell described

previously.[7,17,18] This section focuses on the tolerability profile

of rosuvastatin in apparently healthy women and men with

normal LDL-C levels and elevated hsCRP levels, as observed in

the JUPITER trial.[15] Patients in this trial received rosuvastatin

20mg (n= 8901) or placebo (n= 8901) once daily.[15] Results are

from an interim analysis conducted at a median duration of 1.9

years (maximum duration of 5 years)[15] [see section 4 for further

study design details and efficacy results].

Rosuvastatin was generally well tolerated in apparently

healthy women or men with normal LDL-C levels and elevated

hsCRP levels, with serious adverse events occurring at a similar

frequency in the rosuvastatin versus placebo arms (15.2% vs

15.5%).[15] Study discontinuations due to adverse events oc-

curred in 6.6% of rosuvastatin recipients and 6.2% of placebo

recipients, with myalgia being the most common cause.[16]

The most frequently reported treatment-related adverse events

associatedwith rosuvastatinweremyalgia, arthralgia, constipation,

and nausea (figure 3; statistical analyses not available for these

results).[16] Thenature of these treatment-related adverse eventswas

similar to those in a pooled safety analysis of clinical trial data

(n= 5394; rosuvastatin 5–40mg/day) presented in the manufactu-

rer’s US prescribing information[16] and a pooled safety analysis[63]

of an integrated clinical trial database of 33 trials (n= 16876; ro-suvastatin 5–40mg/day) discussed in a previous review.[7]

Moreover, the incidences of rosuvastatin-related myalgia,

nausea, and constipation reported in the JUPITER trial (figure 3)

were similar to the incidences (myalgia [6.3%], constipation

[4.7%], and nausea [6.3%]) reported in patients receiving rosu-

vastatin 20mg (n = 64) in the placebo-controlled trials (n = 744;rosuvastatin dose 5–40mg) included in the pooled safety ana-

lysis reported in the manufacturer’s prescribing information.[16]

Arthralgia was not among the most commonly reported rosu-

vastatin-related adverse events in this pooled analysis.[16]

In general, the incidence of monitored adverse events (figure 4)

and the levels of laboratorymeasurements at study endpoint were

0

1

2

3

4

5

6

7

8

9

10

Myalgia Arthralgia Constipation Nausea

Pat

ient

s (%

)

ROSPL

Fig. 3. Tolerability of rosuvastatin (ROS) in apparently healthy women or

men with normal low-density lipoprotein cholesterol levels and elevated high-

sensitivity C-reactive protein levels. Incidence of treatment-related adverse

events occurring in patients receiving ROS 20mg (n= 8901) or placebo

(PL; n = 8901) once daily in the pivotal JUPITER trial.[16] Results are from an

interim analysis at a median follow-up duration of 1.9 years.



similar in the rosuvastatin and placebo groups.[15] However, the

median glomerular filtration rate at 12 months (66.8 vs

66.6mL/min/1.73m3; p= 0.02) and the median glycosylated he-

moglobin level at 24 months (5.9% vs 5.8%; p= 0.001) were sig-nificantly higher in the rosuvastatin versus placebo groups.[15]

Increases in glycated hemoglobin and fasting serum glucose levels

have been reported previously with statins, including rosuvasta-

tin.[16] Although there was no significant between-group differ-

ence in the median fasting glucose level at 24 months (98mg/dL[5.4mmol/L] in both groups) or the proportion of patients with

glycosuria at 12months (36% vs 32%) in the JUPITERtrial, newly

diagnosed (by a physician) diabetes was reported in a significantly

higher proportion of patients in the rosuvastatin arm than in the

placebo arm (3.0% vs 2.4% of patients; p= 0.01).[15]

Statins, including rosuvastatin, have been associated with

rare cases of myopathy and rhabdomyolysis with acute renal

failure secondary tomyoglobinuria.[16] The risk of such adverse

events occurring is highest at a rosuvastatin dose of 40mg, but

they may also occur at lower doses.[16] The risk of developing

myopathy with rosuvastatin may also be increased by coad-

ministration with various other drugs (e.g. fibric acid de-

rivatives or niacin), and a reduction in the dose of rosuvastatin

is recommended for some combinations (section 2.5). In addi-

tion, caution should be exercised when using rosuvastatin in

patients with an increased risk of developing skeletal muscle-

related adverse events, such as patients aged ‡65 years, or thosewith uncontrolled hypothyroidism or renal impairment.[16]

Rosuvastatin should be discontinued if the patient develops

markedly elevated creatinine kinase levels or myopathy (either

confirmed or suspected), and the drug withheld if the patient

develops any acute, serious condition that may be suggestive of

myopathy or that may predispose them to developing renal

failure secondary to rhabdomyolysis (e.g. dehydration, hypo-

tension, major surgery, sepsis, trauma, uncontrolled seizures,

or a severe electrolyte, endocrine, or metabolic disorder).[16] In

the JUPITER trial, ten episodes of myopathy occurred in 8901

patients in the rosuvastatin group (0.1%) and nine episodes

occurred in 8901 patients in the placebo group (0.1%).[15] One

episode of rhabdomyolysis was reported in a rosuvastatin re-

cipient after the trial had been closed; this event was nonfatal

and occurred in an elderly patient (aged 90 years) with febrile

influenza, pneumonia, and trauma-induced myopathy,[15] and

a history of moderate chronic kidney disease.[57]

Elevations in transaminase levels have also been reported with

statins, with 1.1% of rosuvastatin recipients and 0.5% of placebo

recipients having a serum transaminase level of >3· theULN in a

pooled analysis of placebo-controlled trials reported in the

manufacturer’s prescribing information.[16] Most transaminase

elevations are transient and resolve or improve with continued

treatment or a brief drug-free period.[16] However, rare cases of

jaundice have been reported.[16] Because of this, serum trans-

aminase levels should be measured before initiation of rosuvas-

tatin, 12 weeks after initiation of rosuvastatin or a dose

adjustment, and periodically thereafter.[16] If ALT or AST levels

remain >3· the ULN, the dose of rosuvastatin should be de-

creased or the drug discontinued.[16] Rosuvastatin should be used

with caution in patients with a history of chronic liver disease or

excess alcohol use, and is contraindicated in thosewith active liver

disease (section 3.3).[16] In the JUPITER trial, elevation of ALT

levels to >3· the ULN on consecutive visits occurred in 0.3% of

patients (23 events in 8901 patients) in the rosuvastatin arm and

0.2% (17 events in 8901 patients) in the placebo arm.[15]

Although atorvastatin (another statin) was associated with a

significantly higher incidence of hemorrhagic strokes than

placebo in a previous clinical study,[64] the incidence of hem-

orrhagic strokes in the JUPITER trial was low and similar in

both the rosuvastatin and placebo treatment arms (6 [0.07%] vs

9 [0.10%] events in 8901 patients).[15]

Rosuvastatin demonstrated a similar tolerability profile

in patients withmoderate chronic kidney disease versus thosewith

normal renal function.[57] However, the number of patients with

newly diagnosed diabetes was significantly higher in recipients of

rosuvastatin than placebo in the group of patients with normal

0

5

10

15

20

25

GI diso

rder

Mus

cular

sym

ptom

s#

Renal

disor

der

New D

x can

cer

New D

x DM

Bleedin

g

Hepat

ic dis

orde

r

Death

from

canc

er

Pat

ient

s (%

)

ROSPL

*

Fig. 4. Tolerability of rosuvastatin (ROS) in apparently healthy women or

men with normal low-density lipoprotein cholesterol levels and elevated high-

sensitivity C-reactive protein levels. Incidence of monitored adverse events

occurring in patients receiving ROS 20mg (n= 8901) or placebo (PL;

n = 8901) once daily in the pivotal JUPITER trial.[15] Results are from an in-

terim analysis at a median follow-up duration of 1.9 years. DM= diabetesmellitus; Dx = diagnosis; GI =gastrointestinal; # =muscular symptoms in-

cluded muscular weakness, stiffness, or pain. * p =0.01 vs ROS.

394 Carter


renal dysfunction (216 vs 164 events; p= 0.01) but not in those

with moderate chronic kidney disease (54 vs 52 events), as was the

incidence of newly diagnosed renal disorders (388 vs 339 events

[p= 0.05] and 146 vs 141 events).[57] The one case of rhabdomyoly-

sis that occurred during the trial was in a rosuvastatin recipient

with moderate chronic kidney disease.[57]

In general, sex did not appear to affect the tolerability profile

of rosuvastatin.[55] However, the incidence of newly diagnosed

diabetes was significantly higher in women receiving rosuvas-

tatin than in those receiving placebo (108 vs 71 events; p= 0.008),whereas there was no significant between-group difference in the

incidence of newly diagnosed diabetes in men (162 vs 145 events)

[p-value for heterogeneity of diabetes by sex= 0.16].[55] Of in-

terest, although previous reports suggested the possibility of

women having an increased risk of cancer-related deaths with

statin treatment over placebo (reviewed by Mora et al.[55]), no

such finding was observed in the JUPITER trial, with death

related to cancer being reported in 0.2% of women in both the

rosuvastatin and placebo groups, and in 0.2% and 0.3% of men

receiving rosuvastatin or placebo (p= 0.03).[55]

In the JUPITER trial, elderly patients (aged 70–97 years) ap-

peared to have a higher incidence of monitored adverse events and

serious adverse events than younger patients (aged 50–69 years),

regardless of treatment arm (no statistical comparisonavailable).[54]

However, no statistically significant differences were demonstra-

ted between rosuvastatin and placebo recipients with regard to the

incidence of themajority ofmonitored adverse events in either the

elderly or younger patient groups.[54] The only between-group

difference identified was in the incidence of bleeding events, which

occurred at a significantly lower rate in rosuvastatin than placebo

recipients in the younger age group (rate per 100-person years 1.03

vs 1.32; HR 0.78; 95% CI 0.62, 0.98).[54]

6. Dosage and Administration

In the US, rosuvastatin is approved as an adjunctive therapy

to a healthy diet (i.e. a diet low in saturated fat and cholesterol)

in adult patients with primary hyperlipidemia,mixed dyslipidemia,

hypertriglyceridemia, or primary dysbetalipoproteinemia (hyper-

lipoproteinemia type III), and in combination with other lipid-

lowering drugs (or alone if no other treatments are available) in

adults with homozygous familial hypercholesterolemia.[16] It is

also approved for use in pediatric patients (aged 10–17 years)

with heterozygous familial hypercholesterolemia, and to slow

the progression of atherosclerosis in adults.[16] More recently,

rosuvastatin has also been approved for use in the primary

prevention of CVD (i.e. MI, stroke, or arterial revasculariza-

tion procedures) in patients with no clinical evidence of CHD

who are at increased risk of developing CVD based on their age

(‡60 years for women and ‡50 years formen), an hsCRP level of

‡2mg/L, and the presence of ‡1 other risk factor (e.g. hyper-

tension, low HDL-C level, smoking, or a family history of

premature CHD).[16]

In general, the recommended dosage of rosuvastatin for the

approved indications is 5–40mg once daily, with the usual

starting dosage being 10–20mg once daily.[16] In the JUPITER

trial, the benefit of rosuvastatin over placebo in reducing the

incidence of major cardiovascular events in apparently healthy

women or men with normal LDL-C levels and elevated hsCRP

levels was demonstrated at a rosuvastatin dosage of 20mg once

daily (section 4). According to the manufacturer’s US pre-

scribing information, rosuvastatin should be started at a lower

dose and then titrated according to response and individual

targets.[16]Where relevant, only patients who have not achieved

the target LDL-C level with rosuvastatin 20mg should receive

rosuvastatin 40mg.[16] Rosuvastatin can be administered at any

time of the day, without regard for food.[16]

In the US, rosuvastatin dose reductions (or restrictions) are re-

commended in patients receiving concomitant fenofibrate or niacin

(section 2.5), and in those receiving concomitant gemfibrozil (if the

combination is unavoidable), cyclosporine, atazanavir/ritonavir, orlopinavir/ritonavir (section 3.4).[16] Dose reductions are also re-

commended in Asian patients or patients with severe renal im-

pairment who are not receiving hemodialysis (section 3.3).[16] Local

prescribing information should be consulted for further informa-

tion regarding contraindications, warnings, precautions, dose ad-

justments, and use in special populations.

7. Place in the Prevention of Cardiovascular

Disease in Apparently Healthy Women or Men with

Normal LDL-C Levels and Elevated hsCRP Levels

CVD is the leading cause of death in the US, and is associated

with a large economic burden.[1] In theUS in 2010, the total direct

and indirect costs incurred by this disease will reach an estimated

$US503.2 billion.[1] Furthermore, it has been estimated that CVD

(including CHD and diabetes) will cost US society up to $US9.5

trillion over the next 30 years (2008 estimate).[65]

Prevention of CVD involves the detection and treatment of

modifiable CVD risk factors.[2] Risk interventions currently

recommended by US guidelines include control of blood pres-

sure and blood lipids (via lifestyle modifications and/or phar-macologic therapy); management of medical conditions, such

as diabetes and chronic atrial fibrillation; administration of

aspirin to patients at a higher risk of CHD than others, par-

ticularly those with a 10-year Framingham risk of ‡10%; and a



variety of lifestyle modifications, including complete cessation

of smoking, adoption of a healthy eating pattern, bodyweight

management, and regular physical exercise.[2] According to

NCEP, a 20–30% reduction in LDL-C levels may be achieved

by losing 10 pounds (if overweight) and changing to a more

suitable diet (i.e. one high in soluble fiber and plant sterols/stanols, but low in saturated fat and cholesterol).[66] Assuming a

100% efficacy, if all patients adopted recommended healthy

lifestyle practices and received all the risk interventions for

which they were eligible, an estimated two-thirds of MIs and

one-third of strokes would be prevented in the US each year.[65]

However, the cost of utilizing such strategies would increase the

direct medical cost associated with CVD by »$US7.6 trillion

over a 30-year period (2008 costs).[65]

One way in which the economic burden associated with CVD

may be reduced is by improvement of the Framingham risk

model, with the aim of reclassifying a proportion of intermediate-

risk patients into the low- or high-risk categories.[3] If additional

CVD risk factors were identified and added into themodel, then it

is possible that preventative treatment may be reserved for those

who are likely to benefit from it, thereby allowing the benefits of

screening to bemaximized and any associated harms (e.g. adverse

effects associated with drugs, false-positive results, unnecessary

invasive diagnostic procedures) to be minimized.[3]

HsCRP is a sensitive (but nonspecific) inflammatory bio-

marker that is independently associated with incident CHD eve-

nts,[67] and may be of use in assessing CVD risk.[67,68] Elevated

CRP levels are associated with CVD risk factors, such as obesity,

smoking, and inactivity, and various longitudinal studies have

demonstrated a reduction in CRP levels of up to 41% after in-

troduction of long-term (at least 6 months) exercise training

(reviewed by Plaisance and Grandjean[69]). The inflammatory

hypothesis of atherothrombosis has gathered much evidence over

the past two decades, and it now appears that inflammation plays

a fundamental role in the mediation of atherothrombosis at all

stages of the disease.[70,71] Of the various inflammatory markers

that were considered by the Centers for Disease Control and

Prevention (CDC) and theAmericanHeartAssociation (AHA) as

potentially useful predictors of CVD risk, hsCRPwas the favored

option because of its stability, and the availability, precision, ac-

curacy, and standardization of the assay.[71]

Rosuvastatin is an HMG-CoA reductase inhibitor (statin)

that was shown to lower hsCRP levels (and improve lipid levels)

in numerous clinical trials conducted in patients with dyslipi-

demia, including those at high-risk of developing CVD and

those with established CVD (sections 1 and 2.2). Where investi-

gated, these hsCRP level reductions were associated with clinical

benefit (sections 1 and 2.2). The pivotal JUPITER trial was de-

signed to further explore the relationship between rosuvastatin-

associated reductions in hsCRP levels and the prevention of

CVD.[15] Patients eligible for this trial were apparently healthy

individuals with normal LDL-C (<3.4mmol/L [<130mg/dL])and triglyceride (<5.65mmol/L [<500mg/dL]) levels, and ele-

vated hsCRP levels (‡2.0mg/L) [section 4].

All patients in the JUPITER trial had baseline LDL-C levels

that fell below the recommended NCEP ATP III goal of <3.4mmol/L (<130mg/dL) and, thus, would not normally have been

eligible for treatment with a statin.[4] Nonetheless, rosuvastatin

significantly reduced the incidence of first major cardiovascular

events occurring in the trial by almost one-half relative to pla-

cebo (primary endpoint; section 4.1.1 and figure 2). The inci-

dences of MI (nonfatal or nonfatal plus fatal), stroke (nonfatal

or nonfatal plus fatal; primarily ischemic stroke), arterial revas-

cularization, and death from any cause were also significantly

decreasedwith rosuvastatin versus placebo (section 4.1.1), aswas

the incidence of the nonatherothrombotic endpoint of venous

thromboembolism (section 4.1.2). No statistical between-group

difference was demonstrated in the incidences of cardiovascular

death or hospitalization for unstable angina (section 4.1.1). The

beneficial effects of rosuvastatin were observed in all patient

subgroups (sections 4.1.1 and 4.2), including those thought

to be at low-risk of developing CVD, such as patients with

elevated hsCRP levels but no other risk factors for CVD except

for age (section 4.1.1).

Furthermore, the 5-year NNT for the JUPITER primary

endpoint (25) was similar to (or numerically smaller than) those

observed in previous primary prevention trials of statins that

predominantly enrolled men with dyslipidemia (40–70) and in

secondary prevention trials in high-risk patients (15–33) [reviewed

by Ridker et al.[51] and by Libby and Crea[72]]. In addition, the

JUPITER 5-year NNT for the primary endpoint was numerically

smaller than those previously published for other well established

preventative therapies, including antihypertensive drugs (80–160)

and aspirin (>300).[51,72] Therefore, it is possible that a number of

patient subgroups who would not normally be eligible for pre-

ventative therapy with statins may benefit from receiving such

drugs, and that these benefits may be similar to those of other

preventative therapies already considered to be effective.[51]

However, caution should be exercised when comparing NNT

values across different trials and for different drugs.[51]

Although some of the observed between-group difference in

the incidence of the primary endpoint in the JUPITER trial may

have been attributable to further lowering of LDL-C levels to

<1.8mmol/L (<70mg/dL), a between-group difference in favor of

rosuvastatin was also observed in the patient groups that did not

achieve an LDL-C level of <1.8mmol/L (<70mg/dL) but did

396 Carter


achieve an hsCRP level of <1 or <2mg/L (section 4.2.1). Further-

more, the greatest reductions in the risk of first major cardio-

vascular events were seen in the groups of patients achieving both

an LDL-C level of <1.8mmol/L (<70mg/dL) and an hsCRP level

of <2mg/L or, even more so, <1mg/L. Of interest, a retrospective

analysis of results from the placebo cohort in the JUPITER trial

demonstrated that tracking of hsCRP levels was strong through-

out the trial, indicating that hsCRP levels would most likely have

remained elevated in the absence of rosuvastatin treatment.[73]

Therefore, the beneficial effect of rosuvastatin in preventing CVD

appears to be attributable to both its lipid-lowering and anti-

inflammatory effects.[60]

When JUPITER inclusion criteria (i.e. hsCRP and LDL-C

levels) were retrospectively applied to individuals participating in

the 1999–2004 National Health and Nutrition Examination Sur-

vey (a nationwide survey thought to be representative of the

general US population), it was demonstrated that »6.5 million

women (aged ‡60 years) and men (aged ‡50 years) would have

been eligible for inclusion in the trial.[68] Furthermore, although

not all would have been eligible for the JUPITER trial, an esti-

mated »10.0 million elderly patients (i.e. aged ‡60 years for

women and ‡50 years for men) and »54.4 million patients aged

‡20 years would be newly eligible for statin therapy based on an

hsCRP level of ‡2mg/L,[68] assuming that these individuals would

not otherwise have met criteria for statin therapy because of

‘‘optimal lipid levels’’ (i.e. lipid levels below recommended NCEP

ATP III goals for drug therapy).[68] Moreover, it has been pre-

dicted through modelling that the addition of hsCRP levels to

traditional CVD risk factors would result in the reclassification of

11% of intermediate-risk men into the high-risk category and, if

appropriate preventative strategies were instigated, that this

would prevent 47.8CHDevents per 1000men aged 40–79 years.[3]

The use of hsCRP levels in the CVD risk stratification process

showsmuch promise.[61] However, there ismuch debate about the

appropriateness of adding this nontraditional risk factor to those

that are already well established.[72,74] Current US guidelines do

not recommend measuring hsCRP levels for the purpose of CVD

risk stratification in asymptomatic patients with no history of

CVD[3] or in the general population.[71] However, the CDC/AHA

guidelines do support the use of hsCRP levels as an additional

marker of CVD risk in specific populations of patients, partic-

ularly those who are determined to be at an intermediate risk

of CVD disease when traditional risk factors are taken into

account.[71] According to these guidelines, this latter recom-

mendation would allow clinicians to reclassify intermediate-risk

patients into high- or low-risk groups, thereby further clarifying

whether the patient would or would not benefit from further

investigations and/or instigation of preventative therapies.[71]

Physicians may also find it useful to measure hsCRP levels in

patients with metabolic syndrome.[75] Moreover, JUPITER study

investigators indicate that hsCRP levels should be measured in

conjunction with lipid levels in all postmenopausal women and in

all male patients aged ‡50 years.[6]

The instigation of rosuvastatin (or another statin) on the

basis of elevated hsCRP levels is another area of controversy.[51]

The CDC/AHA guidelines do not make risk intervention

recommendations based on hsCRP levels, although these

guidelines have not been updated since the JUPITER trial re-

sults became available.[71] However, according to the lead in-

vestigator for the JUPITER trial, high-dose statins, such as

rosuvastatin, should be considered in postmenopausal women

andmen aged ‡50 years who are found on twooccasions to havean hsCRP level >2mg/L or any other traditional risk factor (e.g.

an LDL-C level >4.1mmol/L [>160mg/dL] or a total choles-

terol :HDL-C ratio of >6) for which a statin would be pre-

scribed.[6] In patients of this demographic with an hsCRP level

<2mg/L, an LDL-C level <4.1mmol/L (<160mg/dL), no family

history of premature atherosclerosis, and no personal history of

CVD or diabetes, initiation of statin therapy was not thought to

be cost effective and, hence, was not recommended.[6]

However, concern exists around the design of the JUPITER

trial, particularly with regard to the mechanism of benefit of

rosuvastatin and whether CVD risk can be reduced solely

through the inhibition of the inflammatory process.[72,76] To

address these concerns and further assess the inflammatory

hypothesis of atherothrombosis, a randomized, double-blind,

placebo-controlled trial (CIRT [Cardiovascular Inflammation

Reduction Trial]) is currently investigating the use of very low

dose methotrexate versus placebo in the secondary prevention

of major cardiovascular events in patients with known CVD

and persistently elevated CRP levels despite usual cardiovascu-

lar treatments.[76] Methotrexate has previously been shown to

reduce several inflammatory biomarkers without affecting other

components of the atherothrombotic process.[76] Therefore, if the

CIRT trial was to demonstrate a clear benefit of methotrexate

over placebo, then the inflammatory hypothesis of athero-

thrombosis would gain further weight and a new approach to the

prevention of CVD may potentially be identified.[76]

Another point of concern related to the designof the JUPITER

trial was the exclusion of patients with normal hsCRP levels,[77-79]

meaning that it was not possible to establish whether the benefi-

cial effects of rosuvastatin were confined to patients with ele-

vated hsCRP levels or whether patients with normal hsCRP

levels would also benefit from receiving the drug.[77] Such patients

were not included the trial because previous studies had failed

to demonstrate any benefit of statin treatment in this patient



population.[15] Although it would be helpful to evaluate the effi-

cacy of rosuvastatin in patients with elevated hsCRP versus those

with normal hsCRP in order to further clarify the use of hsCRP

levels in CVD risk assessment,[78] it is unlikely that such a study

will be conducted as it is unlikely to be feasible in terms of stat-

istical power and sample size.[15]

However, recent results from a retrospective analysis[80] of

the randomized, placebo-controlled, METEOR (Measuring

Effects on intima media Thickness: an Evaluation Of Rosu-

vastatin) trial[81] demonstrated that rosuvastatin 40mg once

daily significantly reduced hsCRP levels in patients with nor-

mal baseline hsCRP levels (plus elevated LDL-C levels and

modest carotid intima-media thickness) whowere thought to be

at low-risk of CVD, and that these reductions were independent

of the rosuvastatin-associated LDL-C effects.[80] Therefore, it

can be concluded that rosuvastatin is also effective in patients

with normal hsCRP levels, and that rosuvastatin-associated

reductions in hsCRP levels occur through an independent

pathway and are unlikely to be a secondary result of LDL-C

level reductions, as has previously been suggested.[80]

Rosuvastatin was generally well tolerated in the JUPITER

trial, with themajority of adverse events beingmild tomoderate in

severity and similar to those observed in other populations of

patients receiving rosuvastatin in clinical trials (section 5). Myal-

gia, arthralgia, constipation, and nauseawere themost commonly

reported treatment-related adverse events (figure 3). In general,

the incidences of monitored adverse events (figure 4) and labor-

atory measurements at study endpoint were similar in the rosu-

vastatin and placebo groups. However, newly diagnosed diabetes

(physician assessed) was reported in a significantly higher pro-

portion of rosuvastatin than placebo recipients throughout the

study (section 5). In addition, the median glomerular filtration

rate at 12months and themedian glycosylatedhemoglobin level at

24 months were significantly higher in the rosuvastatin than pla-

cebo groups. None of these endpoints were adjudicated by the

endpoint committee.[15] Furthermore, no significant between-

group difference was demonstrated in the systematic protocol

specified measurements of fasting blood glucose and glycos-

uria.[15] However, increases in glycosylated hemoglobin and fast-

ing serumglucose levels have previously been reportedwith statins

(including rosuvastatin) in other patient populations.[16]

In a recent meta-analysis of 13 randomized, placebo-

controlled or standard-of-care statin trials (n = 91 140) that

included data from the JUPITER trial, an additional 174 cases

of incident diabetes were reported in statin versus placebo/standard-of-care recipients and this translated into a 9% in-

crease in the risk of diabetes in these patients during the 3- to

4-year treatment period.[82] In absolute terms, this amounted to

one new case of diabetes per 255 patients receiving statin

therapy for 4 years, or 12.23 cases per 1000 patient-years; the

corresponding rate with standard-of-care treatment was 11.25

cases per 1000 patient-years.[82] Elderly patients appeared to be

at particularly high risk of statin-associated dysglycemia, ac-

cording to a meta-regression analyses of these pooled data.[82]

Although this increased risk should be taken into account when

considering the use of statins in patients at low risk for CVD or

in those groups for which statin treatment has not been proven,

patients in whom statins are indicated should continue to re-

ceive these drugs because of the clear benefits they have in

preventing macrovascular disease.[82] However, it is recom-

mended that elderly statin recipients are monitored for dys-

glycemia throughout the treatment period.[82]

In conclusion, rosuvastatin is an HMG-CoA reductase in-

hibitor that has both lipid-lowering and anti-inflammatory ef-

fects. In the JUPITER trial, the drug was effective in preventing

first major cardiovascular events in apparently healthy women

(aged ‡60 years) or men (aged ‡50 years) with normal LDL-C

levels and elevated hsCRP levels. It is not yet clear whether the

mechanism of benefit of rosuvastatin is related to its lipid-

lowering properties, anti-inflammatory properties, or amixture

of both. Furthermore, administration of rosuvastatin based

solely on elevated hsCRP levels remains controversial. How-

ever, regardless of these issues, rosuvastatin remains an im-

portant pharmacologic option in the prevention of CVD, and

may potentially be of benefit in certain subgroups of patients in

whom statins would not normally be indicated.

Disclosure

The preparation of this review was not supported by any external

funding. During the peer review process, the manufacturer of the agent

under review was offered an opportunity to comment on this article.

Changes resulting from comments received were made on the basis of

scientific and editorial merit.

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Correspondence: Natalie J. Carter, Adis, a Wolters Kluwer Business, 41

Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore 0754,

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