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ABSTRACT
Rosuvastatin, a new statin, has been shown to possess a number of advantageous phar-
macological properties, including enhanced HMG-CoA reductase binding characteristics,
relative hydrophilicity, and selective uptake into/activity in hepatic cells. Cytochrome
P450 (CYP) metabolism of rosuvastatin appears to be minimal and is principally mediated
by the 2C9 enzyme, with little involvement of 3A4; this finding is consistent with the
absence of clinically significant pharmacokinetic drug-drug interactions between rosuva-
statin and other drugs known to inhibit CYP enzymes. Dose-ranging studies in hypercho-
lesterolemic patients demonstrated dose-dependent effects in reducing low-density lipo-
protein cholesterol (LDL-C) (up to 63%), total cholesterol, and apolipoprotein (apo) B
across a 1- to 40-mg dose range and a significant 8.4% additional reduction in LDL-C,
compared with atorvastatin, across the dose ranges of the two agents. Rosuvastatin has
also been shown to be highly effective in reducing LDL-C, increasing high-density lipo-
protein cholesterol (HDL-C), and producing favorable modifications of other elements of
the atherogenic lipid profile in a wide range of dyslipidemic patients. In patients with mild
to moderate hypercholesterolemia, rosuvastatin has been shown to produce large de-
creases in LDL-C at starting doses, thus reducing the need for subsequent dose titration,
and to allow greater percentages of patients to attain lipid goals, compared with available
statins. The substantial LDL-C reductions and improvements in other lipid measures with
rosuvastatin treatment should facilitate achievement of lipid goals and reduce the re-
quirement for combination therapy in patients with severe hypercholesterolemia. In addi-
tion, rosuvastatin’s effects in reducing triglycerides, triglyceride-containing lipoproteins,
non–HDL-C, and LDL-C and increasing HDL-C in patients with mixed dyslipidemia or
elevated triglycerides should be of considerable value in enabling achievement of LDL-C
Address correspondence and reprint requests to: Fergus McTaggart, B.Sc., Ph.D., Principal Scientist, CV & GI
Discovery, AstraZeneca, Mereside Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
Tel: +44 (1625) 515-124. Fax: +44 (1625) 516-667. E-mail: fergus.mctaggart@astrazeneca.com.
303
304 A. G. OLSSON ET AL.
and non–HDL-C goals in the numerous patients with combined dyslipidemias or meta-
bolic syndrome who require lipid-lowering therapy. Rosuvastatin is well tolerated alone,
and in combination with fenofibrate, extended-release niacin, and cholestyramine, and has
a safety profile similar to that of currently marketed statins. A large, long-term clinical
trials program is under way to investigate the effects of rosuvastatin on atherosclerosis and
cardiovascular morbidity and mortality.
INTRODUCTION
Low-density lipoprotein (LDL) is the primary atherogenic lipoprotein. A wealth of ex-
perimental, epidemiological, and clinical data indicate that elevated LDL cholesterol
(LDL-C) or total cholesterol, as a surrogate for LDL-C, is associated with increased risk
of atherosclerosis and coronary heart disease (CHD) and that reduction of LDL-C is asso-
ciated with reduced CHD morbidity and mortality (21). Statin drugs reduce cholesterol
biosynthesis by inhibiting the activity of the HMG-CoA reductase enzyme in converting
HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol synthesis. Statins
are the major pharmacological treatment for a number of dyslipidemias, primarily on the
basis of their ability to effectively reduce LDL-C. A number of large clinical trials have
unequivocally demonstrated the ability of statin therapy to reduce CHD events in indi-
viduals with or without established CHD across a wide range of initial LDL-C levels
(17,33,43,52,53,56).
The observation that the relationship between LDL-C level and CHD risk is continuous
from low to high LDL-C values and the relative failure to achieve guideline-recom-
mended LDL-C levels in clinical practice (20,51,63) have prompted attempts to develop
statins with improved pharmacology profiles, with the objective of greater efficacy in re-
ducing LDL-C. Rosuvastatin (AstraZeneca, Alderley Park, Macclesfield, Cheshire, UK;
licensed from Shionogi & Co., Ltd., Osaka, Japan) is a new statin with pharmacological
and clinical features that distinguish it from other currently available statins. This agent
has been shown to be highly effective in lowering LDL-C and improving other elements
of the atherogenic lipid profile in patients with a variety of dyslipidemias.
CHEMISTRY
Rosuvastatin (rosuvastatin calcium) is a synthetic compound that consists of a single
enantiomer formulated and administered as the calcium salt of the active hydroxy acid; its
chemical name is bis{(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)ami-
no]pyrimidin-5-yl](3R,5S )-3,5-dihydroxyhept-6-enoic acid} calcium salt. The empirical
formula for rosuvastatin calcium is (C22H27FN3O6S)2Ca. Its molecular weight is 1001.14.
The structural formula is shown in Fig. 1. Rosuvastatin calcium is a white amorphous
powder that is sparingly soluble in water and methanol and slightly soluble in ethanol.
OH OH O
Ca2+
N O
O O
S
N N
2
FIG. 1. Chemical structure of rosuvastatin.
heptenoic (heptanoic in some cases) acid chain that mimics the HMG portion of the
HMG-CoA substrate. However, the additional ring structures and substituents of rosuva-
statin differ from those of other statins. Of particular note is the polar methane sulfon-
amide group that confers to the molecule a relatively low lipophilicity.
The additional components of the molecule are also important in enzyme binding, and
subtle differences in the way different statins interact with the enzyme have been revealed
by x-ray crystallography of the statin-enzyme complexes (28). In addition to a number of
interactions with the active site that are common among the statins, rosuvastatin exhibits
a hydrogen bond between a sulfone oxygen atom and the enzyme Ser565, a binding trait
otherwise observed only with atorvastatin (involving its carbonyl oxygen atom), and a
unique polar interaction between the rosuvastatin electronegative sulfone group and the
enzyme Arg568 side chain.
Consistent with these findings, rosuvastatin was found to be a relatively potent in-
hibitor of HMG-CoA reductase, as measured in experiments using a cloned catalytic
fragment of human HMG-CoA reductase. As with other statins, inhibition was compet-
itive for HMG-CoA reductase and noncompetitive with NADPH. The inhibition constant
(Ki) was approximately 0.1 nM. In the presence of a fixed concentration of HMG-CoA
reductase, 50% inhibitory concentration (IC50) values were 5.4 nM for rosuvastatin, com-
pared with 8.2 nM for atorvastatin, 10.0 nM for cerivastatin, 11.2 nM for simvastatin,
27.6 nM for fluvastatin, and 44.1 nM for pravastatin (24,41). Thus, rosuvastatin is a rela-
tively potent inhibitor of HMG-CoA reductase, consistent with some differences in the
way the molecule binds the active site of the enzyme in comparison with other statins.
Assessment of relative lipophilicity of statins showed that the statin octanol-water coef-
ficients were –0.84 log D at pH 7.4 for pravastatin and –0.33 log D for rosuvastatin, com-
pared with values of >1.0 to <2.0 for atorvastatin, fluvastatin, simvastatin (sodium salt),
and cerivastatin, indicating greater lipophilicity on the part of these latter drugs (11,41).
Consistent with its hydrophilic properties, rosuvastatin was found to be highly selective
for effect in hepatocytes, compared with a range of non-hepatic cells. Thus, when incu-
bated with freshly prepared rat hepatocytes, rosuvastatin inhibited cholesterol synthesis in
these cells with an IC50 of 0.2 nM (95% confidence limits, 0.1–0.3 nM), and was found to
be significantly (P < 0.001) more potent than the other statins (IC50 range, 1.2–6.9 nM)
(8). Studies assessing inhibitory effects in hepatic and non-hepatic cells showed that rosu-
vastatin had an approximately 1,000-fold reduced potency in rat fibroblasts, compared
with primary hepatocytes. The log10 ratio for IC50 values in hepatocytes:fibroblasts was
3.3 for rosuvastatin and pravastatin, the other relatively hydrophilic compound, compared
with 2.2 for atorvastatin, 0.54 for simvastatin, –0.04 for fluvastatin, and –0.14 for ceriva-
statin (8,11). Thus, the marked hepatic cell selectivity of both rosuvastatin and pravastatin
is in contrast with that of the more lipophilic compounds.
Studies with 14C-labeled rosuvastatin in rat hepatocytes showed uptake by both non-
specific diffusion and active transport, with a specific uptake Km of 9.2 ìM; comparison
with pravastatin showed that the rate of active uptake clearance (Vmax/Km) for rosuvastatin
was greater and that rosuvastatin competitively inhibited pravastatin uptake with a Ki
value close to the Km for uptake (11,44).
Additional studies indicate high affinity of rosuvastatin for liver-specific organic anion
transport proteins (OATPs), which may mediate efficient uptake into hepatocytes (4).
Measurement of uptake of 3H-labeled rosuvastatin in oocytes expressing OATP-A, which
is expressed in the basolateral membrane of hepatocytes and widely expressed in other
tissues, and in those expressing the predominantly liver-specific OATP-C showed that
uptake was 20-fold greater in oocytes expressing OATP-C than in those expressing
OATP-A or in H2O-injected control oocytes. The apparent Km for interaction between ro-
suvastatin and OATP-C was 7.3 ìM; cis-inhibition studies of 3H-labeled rosuvastatin
uptake indicated that the affinity of rosuvastatin for OATP-C was greater than that for pra-
vastatin (30.3 ìM) and simvastatin (43.1 ìM), but not significantly different from that for
the lipophilic statin atorvastatin (2.5 ìM).
After intravenous administration of 14C-labeled rosuvastatin, 5 mg/kg, to rats, uptake
clearance rates as determined from plasma and tissue radioactivity levels were approxi-
mately 0.9 mL/min/g into the liver, approximately 0.2 mL/min/g into the kidney, and
<0.02 mL/min/g into other tissues (Fig. 2). Pravastatin also exhibited liver uptake selec-
tivity, whereas simvastatin exhibited high uptake into liver and such other tissues as the
adrenals and spleen (11). In summary, effective and selective delivery of rosuvastatin to
the liver is suggested by the combination of the compound’s relative hydrophilicity and its
selectivity for hepatic cells.
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effective dose (ED50) measured 2 to 3 h after administration was 0.8 (95% CI, 0.4–1.5)
mg/kg. Compared with other statins, rosuvastatin had a longer duration of action on rat
hepatic cholesterol synthesis. In the dog, plasma mevalonate levels were significantly re-
duced at 1 to 6 h after single oral administration of the drug at 0.1 mg/kg and higher
doses; the ED50 of rosuvastatin at 4 h after administration was approximately 0.2 mg/kg
(41). Thus, in animal models, rosuvastatin was found to be a potent inhibitor of hepatic
cholesterol synthesis.
LIPID-LOWERING, ANTIATHEROSCLEROTIC,
AND OTHER EFFECTS IN ANIMAL MODELS
Consistent with inhibition of hepatic cholesterol synthesis and lowering of plasma me-
valonate levels, administration of rosuvastatin to dogs once daily in capsules for 14 days
at a dose level of 3 mg/kg reduced plasma cholesterol by 26%, and during administration
for periods of up to 3 months, doses as low as 0.03 mg/kg were significantly effective
(data on file, AstraZeneca). Rosuvastatin also lowered plasma cholesterol and atherogenic
lipoproteins in cynomolgus monkeys and in Watanabe heritable hyperlipidemic (WHHL)
rabbits. In the latter animals, rosuvastatin at doses of 3 to 10 mg/kg administered for 6
months lowered cholesterol levels by 29 and 32%, respectively, and this was accompanied
PHARMACOKINETICS/PHARMACODYNAMICS
Rosuvastatin has been extensively evaluated in clinical trials in adult patients with mild
to moderate hypercholesterolemia and mixed hyperlipidemia (Fredrickson’s type IIa/IIb),
severe hypercholesterolemia (heterozygous familial hypercholesterolemia or homozygous
familial hypercholesterolemia), or hypertriglyceridemia (Fredrickson’s type IIb or IV),
and in combination with other lipid-modifying agents in dyslipidemic patients. A con-
sistent feature of the randomized, controlled trials is that patients underwent a 6-w dietary
lead-in phase with discontinuation of all cholesterol-lowering drugs or supplements; pa-
tients were instructed in the National Cholesterol Education Program (NCEP) step I diet,
and compliance with diet (Eating Pattern Assessment Tool score <28) was a requirement
for entry into the study treatment phase.
Rosuvastatin has been assessed in dose-ranging studies and comparative trials with
other statins in patients with mild to moderate hypercholesterolemia (type IIa/IIb).
Dose-ranging studies
Dose-ranging studies with rosuvastatin have demonstrated marked dose-related reduc-
tions in LDL-C of up to 63% at 40 mg (46). A comparative dose-ranging study with ator-
vastatin, which has been considered the most effective LDL-C–lowering statin (1,29),
showed that rosuvastatin produces a significantly greater reduction in LDL-C across the
dose range.
In a randomized, placebo-controlled, dose-ranging program, 206 patients with LDL-C
>160 and <220 mg/dL (>4.14 and <5.69 mmol/L) and triglycerides <300 mg/dL (<3.39
mmol/L) received double-blind placebo or rosuvastatin 1, 2.5, 5, 10, 20, or 40 mg or
open-label atorvastatin (used as a benchmark, with no statistical comparisons performed)
for 6 w (46). An intent-to-treat analysis of those patients receiving placebo or rosuvastatin,
10, 20, or 40 mg, showed that rosuvastatin produced marked, dose-related reductions in
LDL-C, total cholesterol, and apolipoprotein (apo) B from baseline, compared with place-
bo (Table 1) (data on file, AstraZeneca). Increases in high-density lipoprotein cholesterol
(HDL-C), reductions in triglycerides, and reductions in lipid ratios were also observed for
all three doses.
In a randomized, double-blind trial (31), 374 patients with LDL-C ³160 and <250
mg/dL (³4.14 and <6.46 mmol/L) and triglycerides <400 mg/dL (<4.52 mmol/L) re-
ceived rosuvastatin 5, 10, 20, 40, or 80 mg or atorvastatin 10, 20, 40, or 80 mg for 6 w.
The primary analysis was change in LDL-C across the dose range of the two study drugs
assessed by linear regression analysis. The LDL-C–lowering response with rosuvastatin
was significantly greater (P < 0.001) than that with atorvastatin by 8.4% across the dose
range (Table 2). At doses of 10–80 mg, reductions in LDL-C were 47 to 62% with
variance (ANCOVA).
b All P < 0.001 in favor of rosuvastatin.
c Abbreviations: LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; HDL-C,
Key lipid responses and achievement of LDL-C goals according to the new ATP-III
guidelines (21) and the Joint European Societies guidelines (54) have been analyzed with
pooled 12-w (starting dose) data from these four comparative trials and an additional com-
parative trial of rosuvastatin and atorvastatin in high-risk patients. In this latter trial, de-
TABLE 4. Changes in lipid parameters at 12 w (at initial dose) and at 52 w (with dose titration)
and percentage of patients meeting ATP-II guidelines in comparative study
of rosuvastatin vs. atorvastatin in hypercholesterolemic patients (type IIa/IIb)
Rosuvastatin 5 mg Rosuvastatin 10 mg Atorvastatin 10 mg
(n = 138) (n = 134) (n = 140)
% change from baselinea
LDL-Cb
12 weeks –46c –50c –39
52 weeks –47d –53c –44
TC
12 weeks –32c –35c –28
52 weeks –34 –38c –33
HDL-C
12 weeks +6 +8 +6
52 weeks +2 +3d –1
TG
12 weeks –15 –19 –16
52 weeks –20 –21 –19
Apo B
12 weeks –35d –40d –32
52 weeks –39 –43d –38
Non–HDL-C
12 weeks –41c –46c –37
52 weeks –43d –49c –41
% meeting ATP-II LDL-C goale
All patients
12 weeks 86 89 73
52 weeks 88 98 87
High-risk
12 weeks 62 78 27
52 weeks 65 97 61
a Least-squares mean % change from ANOVA.
b Abbreviations: LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; HDL-C,
high-density lipoprotein cholesterol; TG, triglycerides; Apo, apolipoprotein.
c P < 0.001 vs. atorvastatin.
d P < 0.05 vs. atorvastatin.
e ATP-II LDL-C goals were defined as follows (22): <160 mg/dL (<4.14 mmol/L) in patients with no
coronary heart disease (CHD) and <2 risk factors (low-risk); <130 mg/dL (<3.36 mmol/L) in those
with no CHD and 2 or more risk factors (medium-risk); and £100 mg/dL (£2.59 mmol/L) in those
with CHD or other atherosclerotic disease or diabetes (high-risk). No statistical comparisons were
performed between groups for goal achievement.
Adapted with permission from refs. 47,48.
tails of which have yet to be reported, 383 high-risk patients (with documented atheroscle-
rotic disease or diabetes) meeting lipid entry criteria identical to those of the other four
studies received rosuvastatin 5 mg or 10 mg or atorvastatin for 12 w, followed by a 12-w
dose-titration period (data on file, AstraZeneca). Pooled analysis of the three comparative
trials with atorvastatin (66) showed that both rosuvastatin 5 mg (n = 390) and rosuvastatin
10 mg (n = 389) doses produced significantly greater reductions in LDL-C, compared
with atorvastatin (n = 393) (42 and 47% vs. 36%, both P < 0.001), and that both produced
significantly greater increases in HDL-C (8 and 9% vs. 5.5%, both P < 0.01). Overall,
ATP-III LDL-C goals were achieved by 67% of rosuvastatin 5 mg patients, 76% of rosu-
vastatin 10 mg patients, and 53% of atorvastatin 10 mg patients (both P < 0.01 vs. atorva-
statin) (Table 7). Both rosuvastatin doses were also associated with a significantly greater
achievement of the aggressive LDL-C goal of <100 mg/dL (<2.59 mmol/L) in patients
with CHD or CHD risk equivalents.
In analysis of pooled data from the two trials comparing rosuvastatin with simvastatin
and pravastatin, both rosuvastatin 5 mg (n = 240) and rosuvastatin 10 mg (n = 226) pro-
duced significantly greater reductions in LDL-C, compared with simvastatin 20 mg
(n = 249) (41 and 48% vs. 36%, both P < 0.001) and pravastatin 20 mg (n = 252) (41 and
48% vs. 27%, both P < 0.001) (3,23). Rosuvastatin 10 mg increased HDL-C significantly
more than simvastatin 20 mg (9 vs. 6%, P < 0.05) or pravastatin 20 mg (9 vs. 6%,
P < 0.05). Overall, ATP-III LDL-C goals were achieved in 71% of rosuvastatin 5 mg pa-
tients, 86% of rosuvastatin 10 mg patients, 64% of simvastatin 20 mg patients (P < 0.05
and <0.001), and 49% of pravastatin 20 mg patients (both P < 0.001) (Table 7). Both
rosuvastatin doses also brought significantly more patients to their LDL-C goal of
<100 mg/dL (<2.59 mmol/L).
In comparative trials with atorvastatin, the Joint European Societies (54) guidelines
LDL-C goal of <116 mg/dL (<3 mmol/L) was reached at week 12 by 82% (319/389) of
patients receiving rosuvastatin 10 mg vs. 51% (202/393) of those receiving atorvastatin
TABLE 6. Changes in lipid parameters at 12 w (at initial dose) and at 52 w (with dose titration)
and percentage of patients meeting ATP-II guidelines in comparative study
of rosuvastatin vs. simvastatin and pravastatin in hypercholesterolemic patients (type IIa/IIb)
Rosuvastatin Rosuvastatin Simvastatin Pravastatin
5 mg (n = 123) 10 mg (n = 116) 20 mg (n = 120) 20 mg (n = 118)
% change from baselinea
LDL-Cb
12 weeks –39c,d –47c,d –35 –27
52 weeks –42c –48c,d –38 –32
HDL-C
12 weeks +8 +12c +9 +8
52 weeks +4 +8 +6 +4
TG
12 weeks –18d –22c,d –10 –11
52 weeks –16 –18c –14 –9
Apo B
12 weeks –31c,d –37c,d –27 –20
52 weeks –35c,d –39c,d –31 –25
Non–HDL-C
12 weeks –36c,d –43c,d –31 –25
52 weeks –38c –43c,d –34 –29
% meeting ATP-II LDL-C goale
All patients
12 weeks 80 90 69 53
52 weeks 88 88 73 60
High-risk
12 weeks 48 63 30 9
52 weeks 84 71 30 6
a Least-squares mean % change from ANOVA.
b Abbreviations: LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cho-
lesterol; TG, triglycerides; Apo, apolipoprotein.
c P < 0.05 vs. pravastatin.
d P < 0.05 vs. simvastatin.
e ATP-II LDL-C goals were defined as follows (22): <160 mg/dL (<4.14 mmol/L) in patients with no
coronary heart disease (CHD) and <2 risk factors (low-risk); <130 mg/dL (<3.36 mmol/L) in those
with no CHD and 2 or more risk factors (medium-risk); and £100 mg/dL (£2.59 mmol/L) in those
with CHD or other atherosclerotic disease or diabetes (high-risk). No statistical comparisons were
performed between groups for goal achievement.
Adapted with permission from refs. 6,7.
10 mg (27). In high-risk patients (i.e., those with CHD, diabetes, family history of pre-
mature CHD or peripheral vascular disease, or 10-y CHD risk >20% based on a logistic
regression model), the LDL-C goal was achieved by 81% (255/314) of patients receiving
rosuvastatin 10 mg vs. 49% (160/327) of those receiving atorvastatin 10 mg. In compar-
ative trials with simvastatin and pravastatin, goal was achieved by 80% (181/226) of rosu-
vastatin 10 mg patients vs. 48% (119/248) of simvastatin 20 mg patients and 16%
(40/252) of pravastatin 20 mg patients (50). In high-risk patients, goal was achieved in
78% (125/161) of the rosuvastatin 10 mg group vs. 47% (90/190) of the simvastatin
group and 13% (24/186) of the pravastatin group.
Severe Hypercholesterolemia
TABLE 7. Pooled data analysis: Percentage of patients achieving ATP-III LDL-C goals at initial
doses in comparative trials of rosuvastatin vs. atorvastatin and vs. simvastatin and pravastatina
% meeting ATP-III LDL-C goalb
<100 mg/dL <130 mg/dL <160 mg/dL All risk
Risk group target: (<2.59 mmol/L) (<3.36 mmol/L) (<4.14 mmol/L) group targets
Comparative trials vs. atorvastatin
Rosuvastatin 5 mg (n = 390) 40c 86 95 67d
Rosuvastatin 10 mg (n = 389) 60c 88 96 76d
Atorvastatin 10 mg (n = 393) 19 80 91 53
Comparative trials vs. pravastatin and simvastatin
Rosuvastatin 5 mg (n = 240) 39e,g 80e 91 71e,h
Rosuvastatin 10 mg (n = 226) 63e,i 89e,h 99f,h 86e,i
Simvastatin 20 mg (n = 249) 22.5 74 90 64
Pravastatin 20 mg (n = 252) 5 40 88 49
a Data for rosuvastatin vs. atorvastatin are from ref. 66. Data for rosuvastatin vs. pravastatin adapted
with permission from ref. 3. Data for rosuvastatin vs. simvastatin adapted with permission from
ref. 23.
b ATP-III LDL-C goals were defined as follows (21): <160 mg/dL (<4.14 mmol/L) in patients
without CHD and with <2 risk factors (low-risk); <130 mg/dL (<3.36 mmol/L) in patients without
CHD and with ³2 risk factors and 10-year CHD risk £20% (medium-risk); and <100 mg/dL (<2.59
mmol/L) in patients with CHD or CHD risk equivalent — e.g., 10-year risk >20%, diabetes (high-
risk). Analysis for differences between treatment groups in goal achievement was by logistic re-
gression.
c P < 0.001 vs. atorvastatin.
d P < 0.01 vs. atorvastatin.
e P < 0.001 vs. pravastatin.
f P < 0.05 vs. pravastatin.
g P < 0.01 vs. simvastatin.
h P < 0.05 vs. simvastatin.
i P < 0.001 vs. simvastatin.
tin, and enables more patients to achieve LDL-C goals. Rosuvastatin treatment in patients
with homozygous familial hypercholesterolemia produces clinically significant LDL-C
reductions in the majority of patients.
eride levels, with increases of 9, 15, and 22% being observed according to triglyceride
levels of <150, 150–250, and >250 mg/dL (<1.69, 1.69–2.82, and >2.82 mmol/L), re-
spectively (60).
Hypertriglyceridemia
Combination Studies
Rosuvastatin has been evaluated alone and in combination with fenofibrate in mixed
dyslipidemia patients (type IIb/IV) with type 2 diabetes (18,19), with extended-release
niacin (ERN) in patients with mixed dyslipidemia (type IIb/IV) (9,40), and with chole-
styramine in hypercholesterolemic patients (2). In diabetic patients and patients with
mixed dyslipidemia, rosuvastatin monotherapy improved most lipid measures as much as,
or more than, combinations of lower-dose rosuvastatin with fenofibrate or ERN, sug-
gesting a potential role for monotherapy in some patients in these settings. Advantages of
combination therapy included a significantly greater reduction in triglycerides with the ro-
suvastatin/fenofibrate combination and a significantly greater increase in HDL-C with the
rosuvastatin/ERN combination. No differences in changes in lipid measures were ob-
served between high-dose rosuvastatin alone and in combination with cholestyramine in
hypercholesterolemic patients. Rosuvastatin monotherapy was generally better tolerated
than combined treatment, but the combination did not produce any unexpected or serious
adverse events.
In a 24-w trial (18,19), 216 hyperlipidemic (type IIb or IV dyslipidemia) type 2 diabetic
patients with triglycerides ³200 and <800 mg/dL (³2.26 and <9.03 mmol/L), total cho-
lesterol ³200 mg/dL (³5.17 mmol/L), and HbA1c <10% were randomized to double-blind
rosuvastatin 5 or 10 mg or one of two placebo groups for 6 w. During the subsequent
18-w, open-label, dose-titration phase, fenofibrate titrated from 67 mg once daily to three
times daily was added to both rosuvastatin groups, one placebo group received rosuvasta-
tin 10–40 mg, and one placebo group received fenofibrate 67 mg one to three times daily
if LDL-C remained above 50 mg/dL (1.29 mmol/L). After 6 w, both rosuvastatin groups
had significantly reduced triglycerides, LDL-C, total cholesterol, and apo B and signifi-
cantly increased HDL-C, compared with the combined placebo groups (all P < 0.001).
After 24 w, combined treatment with rosuvastatin 10 mg/fenofibrate 67 mg three times
daily produced a significantly greater reduction in triglycerides, compared with rosuvasta-
tin 10–40 mg alone (47 vs. 30%, P = 0.001) (Table 11). Rosuvastatin 10–40 mg alone re-
duced LDL-C significantly more than both combination treatment with rosuvastatin
5 mg/fenofibrate and fenofibrate monotherapy. Increases in HDL-C were comparable in
all groups. All groups exhibited favorable changes in lipid subfractions. Combination
treatment was well tolerated.
In a 24-w, open-label trial (9,40), 270 patients with total cholesterol ³200 mg/dL
(³5.17 mmol/L), triglycerides ³200 and £800 mg/dL (³2.26 and £9.03 mmol/L; type IIb
or IV dyslipidemia), and HDL-C <45 mg/dL (<1.16 mmol/L) were randomized to one of
four dose-titrated monotherapy or combination therapy arms: rosuvastatin 10–40 mg;
ERN 0.5–2 g; rosuvastatin 10–40 mg + ERN 0.5–1 g; and rosuvastatin 10 mg + ERN
0.5–2 g. Rosuvastatin alone reduced LDL-C by 48%, significantly more than ERN alone
(0%, P < 0.017) and significantly more than combined treatment with rosuvastatin
10 mg/ERN 2 g (36%, P < 0.017) (Table 12); similar differences in reductions were ob-
served in apo B (42 vs. 9 and 34%, both P < 0.017) and non–HDL-C (49 vs. 11% and
38%, both P < 0.017). Combination treatment with rosuvastatin 10 mg/ERN 2 g produced
significantly greater increases than rosuvastatin alone in HDL-C (24 vs. 11%), HDL2 (41
vs. 9%), and apo A-I (11 vs. 5%; all P < 0.017). Rosuvastatin alone was better tolerated
than ERN alone or rosuvastatin/ERN combinations, with most withdrawals due to ad-
verse events being attributable to characteristic niacin side effects. No clinically signif-
icant elevations in liver transaminases or creatine kinase and no increased risk of
myopathy were observed with combined treatment.
TABLE 11. Changes in lipid measures at 24 w in trial of rosuvastatin alone and in combination
with fenofibrate in type 2 diabetic patients with hypercholesterolemia (type IIb/IV)
% change from baselinea
Rosuvastatin Rosuvastatin
Rosuvastatin Fenofibrate 5 mg/fenofibrate 10 mg/fenofibrate
40 mg 67 mg t.i.d.b 67 mg t.i.d. 67 mg t.i.d.
(n = 51) (n = 49) (n = 60) (n = 53)
TG –30 –34 –41 –47c
TC –37 –7 c –31 –36
LDL-C –47 +1c –34c –42
LDL–apo B –30 –3c –31 –33
VLDL-TG –32 –15 –32.5 –41.5
VLDL–apo B –43 –20 –40 –43
Apo C-III –18 –23 –29 –29
HDL-C +6 +9 +11 +12
HDL2 +42 +24 +30 +21
HDL3 +1 +11 +9 +13c
a Least-squares mean % change from ANOVA.
b Abbreviations: t.i.d., three times daily; TG, triglycerides; TC, total cholesterol; LDL-C, low-density
comparisons).
Adapted with permission from refs. 18,19.
comparisons).
Data from refs. 9,42; adapted with permission from ref. 42.
In a 12-w trial (2), 147 patients with LDL-C ³190 and £400 mg/dL (³4.91 and £10.34
mmol/L) and triglycerides <400 mg/dL (<4.52 mmol/L; heterozygous familial or nonfa-
milial hypercholesterolemia) received rosuvastatin 40 mg for 6 w and were subsequently
randomized to rosuvastatin 80 mg alone or rosuvastatin 80 mg + cholestyramine 8 g twice
daily for 6 w. After 12 w, there were no significant differences between the rosuvastatin
group and the rosuvastatin/cholestyramine group in reductions in LDL-C (56 vs. 61%),
total cholesterol (43 vs. 46%), triglycerides (23 vs. 26%), or apo B (47 vs. 48%) or in in-
creases in HDL-C (11 vs. 10%) or apo A-I (8 vs. 10%). No unexpected safety issues arose
with combined treatment.
SAFETY
In clinical evaluation, rosuvastatin treatment has been well tolerated and has shown an
adverse event profile similar to that observed with placebo or comparator statins. Pooled
analysis of rosuvastatin data from phase II/III trials indicates no unexpected adverse ef-
fects based on the drug’s preclinical profile or from consideration of the safety profiles of
other drugs in the statin class (57). In placebo-controlled phase II/III trials, adverse events
irrespective of causality attribution occurred in 55% of 647 patients receiving rosuvastatin
and 53% of 289 receiving placebo and were similar between groups. In all controlled
phase II/III trials, adverse events irrespective of causality attribution occurred in 63.6% of
2579 patients receiving rosuvastatin (all doses pooled) and in 64.9% of 1275 patients re-
ceiving comparator statins (atorvastatin, simvastatin, or pravastatin), with both groups
having similar frequencies of serious adverse events, adverse events leading to study with-
drawal, and treatment-related adverse events (Table 13). The most common adverse
events in the 2579 patients in controlled phase II/III trials were pharyngitis, pain, head-
ache, flu syndrome, and myalgia. Among 3747 patients receiving rosuvastatin in all un-
controlled and controlled phase II/III trials, clinically significant increases in alanine
aminotransferase (levels more than three times the upper limit of normal on two suc-
cessive occasions) occurred in 0.5% during rosuvastatin treatment. The incidence of my-
opathy (creatine kinase increase to >10 times the upper limit of normal + muscle symp-
toms) was 0.2%. All cases of myopathy occurred in patients receiving rosuvastatin 80 mg,
and all occurred in patients who were randomized directly to or force-titrated to this dose
(i.e., dose increase was not based on LDL-C response to treatment).
Following a regularly scheduled review of the benefit:risk ratio for rosuvastatin, Astra-
Zeneca is not seeking approval of the 80-mg dose at the current time. Most patients had
reached the 80-mg dose through forced titration or direct randomization, with very few re-
quiring titration to the maximum dose to achieve LDL-C goals, and the optimal use of this
dose has not yet been shown. The 80-mg dose will be reviewed for possible introduction
at a future date.
There has been little experience with reduction of LDL-C to well below guideline
levels. Since rosuvastatin is highly effective in reducing LDL-C, the safety profile was as-
sessed in patients reaching low LDL-C levels during rosuvastatin treatment. No difference
was observed in the overall safety profile vs. that reported for patients achieving LDL-C
of <80 mg/dL (<2.07 mmol/L) or <50 mg/dL (<1.29 mmol/L) on at least one occasion
during treatment (53). Among 2,579 patients receiving rosuvastatin in controlled phase
II/III trials, LDL-C <80 mg/dL (<2.07 mmol/L) occurred in 971 patients, and levels
<50 mg/dL (<1.29 mmol/L) occurred in 149. Compared with the overall frequency of ad-
verse events irrespective of causality attribution in this population (63.6%), the frequency
was 39.3% in patients with LDL-C <80 mg/dL (<2.07 mmol/L) and 28.2% in those with
levels <50 mg/dL (<1.29 mmol/L). The most common types of adverse events were simi-
lar in the overall population and in the two low LDL-C subgroups (Table 14). Creatine
kinase elevation was reported in 2.1% of patients overall, 1.4% of patients with LDL-C
<80 mg/dL (<2.07 mmol/L), and 0.7% of patients with LDL-C <50 mg/dL
(<1.29 mmol/L).
CONCLUSIONS
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