Clinical research

European Heart Journal (2005) 26, 26642672

doi:10.1093/eurheartj/ehi482

A COmparative study with rosuvastatin in subjects

{
with METabolic Syndrome: results of the COMETS study
Anton F.H. Stalenhoef1*, Christie M. Ballantyne2, Cinzia Sarti3, Jan Murin4, Serena Tonstad5,
Helen Rose6, and Wim Wilpshaar6
1

Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; 2 Department of
Medicine, Baylor College of Medicine, Houston, TX, USA; 3 Department of Epidemiology and Health Promotion, National
Public Health Institute, Helsinki, Finland; 4 1st Internal Department, University Hospital, Bratislava, Slovakia; 5 Department
l University Hospital, Oslo, Norway; and 6 Clinical Science, AstraZeneca, Maccleseld, UK
of Preventive Medicine, Ulleva
Received 23 May 2005; revised 5 August 2005; accepted 11 August 2005; online publish-ahead-of-print 5 September 2005

Metabolic syndrome;
Statins;
Low-density lipoprotein
cholesterol

Aims The efcacy and safety of rosuvastatin, atorvastatin, and placebo were compared in patients with
the metabolic syndrome.
Methods and results Patients with the metabolic syndrome with low-density lipoprotein cholesterol
(LDL-C)
3.36 mmol/L (130 mg/dL) and multiple risk factors conferring a 10-year coronary heart
disease risk score of .10% were randomized (2:2:1) to receive rosuvastatin 10 mg, atorvastatin
10 mg, or placebo for 6 weeks. Subsequently, the rosuvastatin 10 mg and placebo groups received rosuvastatin 20 mg and the atorvastatin 10 mg group received atorvastatin 20 mg for 6 weeks. LDL-C was
reduced signicantly more in patients receiving rosuvastatin 10 mg when compared with those receiving
atorvastatin 10 mg at 6 weeks [intention-to-treat (ITT) population by randomized treatment: 41.7 vs.
35.7%, P , 0.001; ITT population by as-allocated treatment: 42.7 vs. 36.6%, P , 0.001]. Signicant
LDL-C reductions were also observed in patients receiving rosuvastatin when compared with those
receiving atorvastatin at 12 weeks (48.9 vs. 42.5%, P , 0.001). More patients achieved LDL-C goals
with rosuvastatin when compared with atorvastatin. Rosuvastatin increased high-density lipoprotein
cholesterol signicantly more than atorvastatin. Treatments were well tolerated.
Conclusion At equivalent doses, rosuvastatin had a signicantly greater effect than atorvastatin in lowering LDL-C and improving the lipid prole and was well tolerated in patients with the metabolic
syndrome.

Introduction
The metabolic syndrome is a complex constellation of
disorders that increase the risk of coronary heart disease
(CHD).13 The major components of the metabolic
syndrome are abdominal obesity, dyslipidaemia, impaired
glucose regulation, and hypertension.4 Estimates of the
prevalence of the metabolic syndrome vary with the criteria
used to dene the condition, but are likely to increase in line
with worldwide epidemiological trends in obesity and diabetes, together with greater longevity. Changes in lifestyle
are fundamental to reducing many of the risk factors associated with the metabolic syndrome,5 but some patients may
also require pharmacological intervention for the management of dyslipidaemia, hypertension, and hyperglycaemia.
The atherogenic dyslipidaemia associated with the
metabolic syndrome is characterized by low levels of highdensity lipoprotein cholesterol (HDL-C) and high levels of

* Corresponding author. Tel: 31 243 618819; fax: 31 243 541 734.

E-mail address: a.stalenhoef@aig.umcn.nl
The COMETS study was carried out at 68 centres in Belgium, Finland,
The Netherlands, Norway, Slovakia, the UK, and the USA.
{

triglyceride (TG); in diabetic patients, a preponderance of

small low-density lipoprotein (LDL) particles is often
seen.6 Many patients may also have raised LDL-C, although
this is not part of the diagnostic criteria, and the risk of
CHD in patients with the metabolic syndrome is increased
irrespective of LDL-C levels.1,4
Statins lower blood cholesterol levels and reduce the risk
of cardiovascular events in many patient types and are
therefore recommended as rst-line agents for lowering
LDL-C.4,7 Statins also improve other aspects of the lipid
prole, for example, by increasing HDL-C and lowering TG
to some extent. Furthermore, statins have pleiotropic
effects, such as reducing oxidative stress and modulating
inammatory responses,8 and these effects may improve
other risk factors associated with the metabolic syndrome.
To date, evidence suggesting that statins can improve lipid
levels in patients with the metabolic syndrome has been
limited to post hoc subgroup analyses.912 Results of the
COmparative study with rosuvastatin in subjects with
METabolic Syndrome (COMETS, 4522IL/0069), the rst large,
international, prospective, randomized trial of statin therapy
in this patient group, are reported here.

& The European Society of Cardiology 2005. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org

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KEYWORDS

COMETS study

Methods
Study design
COMETS was a double-blind, double-dummy, randomized, multinational, three-arm, parallel-group study comparing the efcacy of
rosuvastatin with that of atorvastatin or placebo in patients with
the metabolic syndrome. Patients were recruited from 68 primary
care and specialist centres in Belgium, Finland, The Netherlands,
Norway, Slovakia, the UK, and the USA. Following a 4-week dietary
lead-in period, during which they were asked to follow the National
Cholesterol Education Program Adult Treatment Panel III (NCEP ATP
III) therapeutic lifestyle-change diet, eligible patients were randomized (2:2:1) to receive rosuvastatin 10 mg, atorvastatin 10 mg, or
placebo once daily for 6 weeks (Figure 1 ). The rosuvastatin 10 mg
and placebo groups then received rosuvastatin 20 mg and the
atorvastatin 10 mg group received atorvastatin 20 mg for a further
6 weeks to assess whether additional benet was observed by
increasing the dose.

Eligible patients were men and women aged
18 with the metabolic
syndrome as dened by the presence of at least three of the
following: abdominal obesity (waist circumference .102 cm for
men and .88 cm for women); TG
1.70 mmol/L (150 mg/dL);
HDL-C ,1.04 mmol/L (40 mg/dL) for men and ,1.30 mmol/L
(50 mg/dL) for women; blood pressure
130/85 mmHg or receiving
antihypertensive treatment; and fasting blood glucose
6.11 mmol/L
(110 mg/dL).4 Patients with diabetes [fasting glucose .6.94 mmol/L
(125 mg/dL)] were excluded. Patients were also required to
have LDL-C
3.36 mmol/L (130 mg/dL) and additional multiple
risk factors conferring a 10-year CHD risk score of .10% . Other
major exclusion criteria included the following: use of lipidlowering agents within the past 6 months; TG
5.65 mmol/L
(500 mg/dL); LDL-C
6.48 mmol/L (250 mg/dL); documented
history of CHD or other atherosclerotic disease; a history of known
familial hypercholesterolaemia; a history of serious or hypersensitivity reactions to other statins; uncontrolled hypothyroidism;
uncontrolled hypertension; acute liver disease or hepatic dysfunction [hepatic transaminases or bilirubin
1.5 the upper limit of
normal (ULN)]; unexplained serum creatine kinase (CK) .3 ULN;
and use of prohibited concomitant medications.
The study was conducted in accordance with the principles of the
Declaration of Helsinki and good clinical practice, with local Ethics
Committee approval being obtained at each centre. All patients
were fully informed and written consent was obtained.

Assessments
Blood samples were collected at 24 weeks (beginning of the dietary
lead-in period), 22 weeks, 0 weeks (randomization), 6 weeks, and
12 weeks. Laboratory samples for lipids, clinical chemistry, and

Figure 1

COMETS study design. ATV, atorvastatin; RSV, rosuvastatin.

haematology were centrally analysed (Medical Research Laboratories, Highland Heights, KY, USA).
The primary efcacy variable was percentage change from baseline in LDL-C levels after 6 weeks of treatment (rosuvastatin
10 mg vs. atorvastatin 10 mg). Secondary objectives included comparisons of rosuvastatin 10 mg with atorvastatin 10 mg or placebo
at 6 weeks and the combined rosuvastatin 10/20 mg and placebo/
rosuvastatin 20 mg groups with the atorvastatin 10/20 mg group at
12 weeks in terms of percentage change from baseline in LDL-C;
LDL-C goal achievement [1998 and 2003 (post hoc analysis)
European, NCEP ATP III, and LDL-C ,2.59 mmol/L (100 mg/dL), a
pre-specied level agreed at the time of study design]; NCEP ATP
III non-HDL-C goal achievement for patients with TG
2.26 mmol/L
(200 mg/dL); percentage changes from baseline in total cholesterol
(TC), HDL-C, non-HDL-C, TG, lipoprotein ratios, apolipoproteins
(Apos), high-sensitivity C-reactive protein (hsCRP), fasting plasma
glucose, and insulin resistance using homeostasis model assessment
(HOMA). Additional post hoc analyses were performed to compare
hsCRP levels in all patients at baseline and 12 weeks and to
compare changes in hsCRP levels between treatment groups at 6
and 12 weeks in patients with elevated baseline hsCRP (
2 mg/L
or .3 mg/L). Safety was assessed from the incidence of adverse
events (AEs) and abnormal laboratory data.

Statistical analysis
A total of 133 patients per active treatment group were required for
90% power to detect a clinically signicant 6% difference at the 5%
two-sided level for the primary variable of percentage change from
baseline in LDL-C for rosuvastatin vs. atorvastatin at 6 weeks, with
an assumed standard deviation of 15%. Assuming a screen failure
rate of 60%, approximately 940 patients were required to be
screened. Assuming a dropout of 10% during the randomized treatment period, 150 patients per active treatment arm and 75 patients
for the placebo group were required to be randomized.
Efcacy data were evaluated on the basis of the intention-totreat (ITT) and per-protocol (PP) populations. The ITT population
consisted of patients with at least one dose of study medication,
a baseline reading, and at least one post-baseline assessment for
one or more lipid variables in the randomized treatment period. A
misunderstanding by some investigators led to the misrandomization
of 42 patients. These patients were allocated a blinded bottle of
treatment medication instead of receiving the next available randomization number. This was a genuine error, and as it occurred
blind to treatment, it is not felt to have introduced bias into the
study. The ITT population was therefore analysed in two ways: the
ITT population by randomized treatment was analysed according
to the treatment group to which the patients should have been
assigned by the randomized schedule and the ITT population by
as-allocated treatment was analysed according to the treatment
group to which the patients were actually assigned.
The primary result for the primary efcacy variable was ITT population by randomized treatment using the last observation carried
forward (LOCF). All efcacy variables were also analysed using LOCF
on the ITT population by as-allocated treatment. This approach was
chosen as it uses the ITT approach but is deemed more clinically relevant, because it is likely to be more reective of treatment effects.
Results for the primary efcacy variable are presented for the ITT
population by randomized and as-allocated treatments. Thereafter,
results are presented for all efcacy variables for the ITT population
by as-allocated treatment. The PP population excluded misrandomized patients and those with other major violations (inclusion/
exclusion criteria not met at screening or randomization) or deviations
(non-compliance with treatment, additional cholesterol-lowering
drugs, study blind-broken prematurely); patients with violations or
deviations were identied before the study was unblinded.
Efcacy endpoints were analysed using analysis of variance
(ANOVA). HOMA and hsCRP data were analysed using a nonparametric KruskalWallis test. The percentage of patients

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Patients

2665

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A.F.H. Stalenhoef et al.

achieving LDL-C goals was compared by logistic regression analysis.

Percentage change from baseline in C-reactive protein for each
treatment group was analysed using a Wilcoxon Signed Rank test.
hsCRP results are not normally distributed and are highly skewed;

the median values were therefore chosen as the most appropriate

statistic to summarize these data. On the basis of the actual treatment received, safety data were evaluated for all patients who
received at least one dose of study medication.

Table 1 Patient characteristics (randomized population by as-allocated treatment)

Age, years, mean (SD)

Range
Gender, men, n (%)
Race, Caucasian, n (%)
Body mass index (kg/m2), mean (SD)
Metabolic syndrome criteria, n (%)
Abdominal obesitya
TG
1.70 mmol/L (150 mg/dL)
Low HDL-Cb
Blood pressure
130/85 mmHg
Fasting glucose 6.116.94 mmol/L
(110125 mg/dL)
NCEP ATP III risk category,c n (%)
High
Medium
Low
a

RSV 10/20 mg (n 165)

ATV 10/20 mg (n 157)

Placebo/RSV 20 mg (n 79)

58.1 (9.4)
3180
100 (60.6)
163 (98.8)
30.5 (3.6)

57.3 (9.4)
3582
106 (67.5)
154 (98.1)
31.1 (3.5)

57.8 (9.0)
4076
51 (64.6)
75 (94.9)
30.5 (3.9)

150 (90.9)
138 (83.6)
84 (50.9)
160 (97.0)
35 (21.2)

147 (93.6)
131 (83.4)
70 (44.6)
154 (98.1)
43 (27.4)

73 (92.4)
73 (92.4)
29 (36.7)
76 (96.2)
18 (22.8)

44 (26.7)
119 (72.1)
2 (1.2)

45 (28.7)
110 (70.1)
2 (1.3)

22 (27.8)
56 (70.9)
1 (1.3)

Waist circumference .102 cm for men and .88 cm for women.

HDL-C , 1.04 mmol/L (40 mg/dL) for men and ,1.30 mmol/L (50 mg/dL) for women.
NCEP ATP III risk categories: high, CHD or CHD-risk equivalent or 10-year CHD risk .20%; medium, 2 risk factors and 10-year CHD risk 20%; low, 01 risk
factor.4
b
c

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Figure 2 Patient ow and statistical analysis sets. The two ITT groups did not contain an identical set of patients. Five patients who inadvertently received trial
medications different from that required by the allocated patient number were also included in the safety analysis.

COMETS study

2667

Results

(reductions of 42.7 and 36.6% for rosuvastatin 10 mg and

atorvastatin 10 mg, respectively, P , 0.001) (Figure 3 and
Table 3 ). In addition, rosuvastatin 10 mg reduced LDL-C signicantly more than placebo (42.7 vs. 0.3%, P , 0.001; ITT
population by as-allocated treatment) (Figure 3 and
Table 3 ). At 12 weeks, signicant reductions in LDL-C were
observed in the rosuvastatin combined group when
compared with the atorvastatin group (48.9 vs. 42.5%,
P , 0.001; ITT population by as-allocated treatment)
(Figure 3 and Table 3 ). All further results are presented
for the ITT population by as-allocated treatment; however,
similar results were obtained in analyses of the ITT population by randomized treatment and the PP population.
Substantially, more patients achieved LDL-C goals in the
rosuvastatin group than in the atorvastatin group
(Table 4 ), indicating a clinically relevant effect. For
example, the 1998 European LDL-C goal13 was achieved by

Patient characteristics

Efcacy
Rosuvastatin was more effective than atorvastatin on the
primary endpoint (percentage change from baseline): rosuvastatin 10 mg reduced LDL-C levels from baseline signicantly more than atorvastatin 10 mg (41.7 vs. 35.7%,
P , 0.001 for the ITT population by randomized treatment)
after 6 weeks of treatment. Analysis of the ITT population by
as-allocated treatment produced very similar results

Figure 3 Percentage change from baseline in LDL-C levels (ITT population

by as-allocated treatment). LSM, least-squares mean.  P , 0.001 vs. RSV at
the same time point.

Table 2 Baseline levels (ITT population by as-allocated treatment)

RSV 10/20 mg
(n 164)
Lipoprotein/lipid levels (mmol/L), mean (SD)
TC
LDL-C
HDL-C
Non-HDL-C
TG
Lipoprotein ratio, mean (SD)
TC/HDL-C
LDL-C/HDL-C
Non-HDL-C/HDL-C
Apo levels, mean (SD)
ApoB (mg/dL)
ApoA-1 (mg/dL)
ApoB/ApoA-1
HsCRP level (mg/L), median (10th and 90th
percentiles)
Fasting plasma glucose (mmol/L), mean (SD)
Insulin resistance, median (10th and
90th percentiles)
Non-HDL-C, non-high-density lipoprotein cholesterol.

6.48
4.40
1.13
5.35
2.34

ATV 10/20 mg
(n 155)

Placebo/RSV 20 mg
(n 78)

(0.81)
(0.70)
(0.25)
(0.76)
(0.79)

6.47 (0.79)
4.35 (0.65)
1.16 (0.25)
5.30 (0.76)
2.25 (0.78)

6.60 (0.78)
4.42 (0.67)
1.20 (0.25)
5.40 (0.78)
2.42 (0.84)

5.93 (1.16)
4.02 (0.87)
4.93 (1.16)

5.78 (1.28)
3.88 (0.90)
4.78 (1.28)

5.72 (1.21)
3.83 (0.91)
4.72 (1.21)

161.6 (25.4)
148.4 (27.1)
1.12 (0.23)
2.3 (0.9, 8.1)

160.6 (25.6)
151.3 (24.3)
1.09 (0.23)
2.8 (0.7, 8.2)

164.4 (25.7)
154.0 (22.6)
1.09 (0.24)
2.5 (0.7, 8.2)

5.61 (0.57)
2.5 (1.4, 5.3)

5.60 (0.66)
2.5 (1.3, 5.2)

5.62 (0.70)
2.5 (1.1, 5.2)

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From 1338 patients entering the dietary lead-in period, 401

were randomized into the study and received study medication, and 397 and 318 patients fullled the criteria for
the ITT and PP populations, respectively (Figure 2 ).
Discontinuation rates were low [rosuvastatin 10/20 mg,
eight patients (4.8%); atorvastatin 10/20 mg, eight patients
(5.1%); placebo/rosuvastatin 20 mg, four patients (5.1%)].
The treatment groups were very similar at baseline in
terms of demographic and clinical variables (Table 1 ).
Over 80% of patients had abdominal obesity, elevated TG
[
1.70 mmol/L (150 mg/dL)], or hypertension (Table 1 ).
The majority of patients were categorized as medium risk,
according to NCEP ATP III guidelines. A total of 10 patients
in the rosuvastatin 10/20 mg group, seven patients in the
atorvastatin 10/20 mg group, and six patients in the
placebo/rosuvastatin 20 mg group fullled the criteria for
the more stringent 2003 European goal of LDL-C
,2.5 mmol/L (100 mg/dL). Baseline levels of lipoproteins,
lipids, Apos, inammatory markers, fasting plasma
glucose, and insulin resistance were similar among treatment groups (Table 2 ).
Study medication compliance was high and similar among
treatment groups (rosuvastatin 10/20 mg, 96.3%; atorvastatin 10/20 mg, 95.9%; placebo/rosuvastatin 20 mg, 94.6%).

2668

A.F.H. Stalenhoef et al.

79% of patients receiving rosuvastatin compared with 71%

receiving atorvastatin (P , 0.05) and 3% receiving placebo
at 6 weeks (P , 0.001) and 90% of rosuvastatin-treated
patients compared with 83% of atorvastatin-treated patients
at 12 weeks (P , 0.05). Achievement of 2003 European
LDL-C goals was similar to that of 1998 European goals as
LDL-C ,3.0 mmol/L (115 mg/dL) was the relevant goal for
most patients. Rosuvastatin enabled the majority of patients
with elevated TG to achieve non-HDL-C goals (Table 4 ).

Percentage improvements in TC, HDL-C, and non-HDL-C

from baseline were signicantly greater in the rosuvastatin
group when compared with the atorvastatin group at 6 and
12 weeks (Table 3 ). By 12 weeks, HDL-C increased by
10.4% with rosuvastatin when compared with 5.8% with atorvastatin (P , 0.01). Reductions in TG were similar in the
rosuvastatin and atorvastatin groups. Signicant improvements in TC/HDL-C, LDL-C/HDL-C, non-HDL-C/HDL-C, ApoB,
ApoA-1, and ApoB/ApoA-1 were also observed in the

Table 3 Percentage change from baseline in lipoprotein, lipid, and lipoprotein ratio levels (ITT population by as-allocated treatment)
LSM change from baseline (%) (SE)
6 weeks

12 weeks

TC
LDL-C
HDL-C
Non-HDL-C
TG
TC/HDL-C
LDL-C/HDL-C
Non-HDL-C/HDL-C
ApoB
ApoA-1
ApoB/ApoA-1

231.9
242.7
9.5
240.6
219.1
237.2
247.1
245.0
235.1
6.1
238.2

(0.8)
(1.1)
(1.0)
(1.0)
(2.2)
(0.9)
(1.1)
(1.1)
(1.0)
(0.9)
(1.1)

ATV 10 mg
(n 155)

Placebo
(n 78)

RSV combined
(n 242)

228.1 (0.8)
236.6 (1.1)
5.1 (1.0)
235.3 (1.0)
220.9 (2.2)
231.0 (1.0)
239.1 (1.2)
237.8 (1.2)
231.2 (1.1)
1.2 (0.9)
231.5 (1.1)

20.7 (1.1)
20.3 (1.5)
1.1 (1.4)
20.9 (1.4)
22.8 (3.1)
21.1 (1.3)
20.8 (1.6)
21.2 (1.6)
20.1 (1.4)
1.2 (1.3)
20.5 (1.5)

236.8
248.9
10.4
246.6
222.9
241.7
252.7
250.5
240.8
6.5
243.8

ATV 10/20 mg
(n 155)

(0.7)
(0.9)
(1.0)
(0.9)
(1.8)
(0.9)
(1.0)
(1.1)
(0.9)
(0.9)
(1.0)

232.5
242.5
5.8
240.8
225.2
235.5
244.9
243.2
235.9
2.7
237.0

(0.9)
(1.2)
(1.2)
(1.1)
(2.2)
(1.2)
(1.3)
(1.4)
(1.2)
(1.1)
(1.2)

SE, standard error of the mean.


P , 0.001 vs. RSV at same time point.

P , 0.01 vs. RSV at same time point.

Table 4 Proportion of patients achieving lipid goals (ITT population by as-allocated treatment)
Patients achieving goals, n/total (%)
6 weeks

1998 European LDL-C goala

2003 European LDL-C goalsb
NCEP ATP III LDL-C goalsc
LDL-C ,2.59 mmol/L (100 mg/dL)
NCEP ATP III non-HDL-C goal in
patients with baseline
TG
2.26 mmol/L (200 mg/dL)d
NCEP ATP III non-HDL-C goal in
patients with TG remaining at

2.26 mmol/L (200 mg/dL) at
6 and 12 weeksd
a

12 weeks

RSV 10 mg

ATV 10 mg

Placebo

RSV combined

ATV 10/20 mg

(n 164)
128/162 (79)
128/162 (79)
134/162 (83)
99/162 (61)

(n 155)
107/151 (71)
105/151 (70)
109/151 (72)
70/151 (46)

(n 78)
2/78 (3)
2/78 (3)
8/78 (10)
1/78 (1)

(n 242)
209/232 (90)
204/232 (88)
211/232 (91)
185/232 (80)

(n 155)
120/145 (83)
118/145 (81)
114/145 (79)
85/145 (59)

(n 78)
59/76 (78)

(n 69)
45/67 (67)

(n 42)
0/42

(n 120)
100/115 (87)

(n 69)
52/65 (80)

(n 32)
20/31 (65)

(n 31)
14/31 (45)

(n 30)
0/30

(n 37)
28/37 (76)

(n 19)
10/19 (53)

LDL-C ,3.0 mmol/L (,115 mg/dL).13

LDL-C ,2.5 or 3.0 mmol/L (,100 or 115 mg/dL) depending on risk category.7
c
LDL-C ,2.59, 3.36, or 4.14 mmol/L (,100, 130, or 160 mg/dL) depending on risk category.4
d
Non-HDL-C ,3.36, 4.14, or 4.91 mmol/L (,130, 160, or 190 mg/dL) depending on risk4; no formal statistical analyses were performed.

P , 0.05 vs. RSV at same time point.

P , 0.001 vs. RSV at same time point.
 
P , 0.01 vs. RSV at same time point.
b

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RSV 10 mg
(n 164)

COMETS study

2669

rosuvastatin group when compared with the atorvastatin

group at 6 and 12 weeks (Table 3 ).
During the study, median hsCRP decreased in both treatment groups, although data were variable. At 12 weeks,
hsCRP levels were signicantly reduced when compared
with baseline in both groups, with no signicant difference
between treatments (Table 5 ). Rosuvastatin and atorvastatin substantially reduced hsCRP levels in patients with
hsCRP
2 mg/L (n 236) or .3 mg/L (n 170) at baseline,
with no signicant difference between treatments at 6 and
12 weeks (Table 5 ).
Changes in fasting plasma glucose were small, with no signicant difference between treatment groups (Table 6 ).
There was also no signicant difference in insulin resistance
between the groups (Table 6 ). The mean glycated haemoglobin (HbA1C) level was 5.7% at baseline; mean HbA1C
levels were similar at 6 and 12 weeks and across both treatment groups.

Safety
Both rosuvastatin 10/20 mg and atorvastatin 10/20 mg were
well tolerated, with a similar incidence of treatmentemergent AEs (Table 7 ). After 6 weeks of treatment, the
most commonly reported AEs were headache, back pain,
and myalgia, whereas after 12 weeks they were myalgia,

Discussion
COMETS is the rst prospectively designed study to evaluate
the comparative efcacy of statin treatment in patients with
the metabolic syndrome. Treatment for 6 weeks with

Table 5 Change from baseline in hsCRP in all patients and in those with hsCRP
2 mg/L (n 236) or .3 mg/L (n 170) at baseline (ITT
population by as-allocated treatment)
Median change in hsCRP from baseline (%) (10th and 90th percentiles)
6 weeks

12 weeks

RSV 10 mg
(n 164)

ATV 10 mg
(n 155)

Placebo
(n 78)

RSV combined
(n 242)

ATV 10/20 mg
(n 155)

All patients

218.2
(264.9, 89.2)

216.1
(270.1, 116.7)

26.2
(255.2, 119.7)

228.6
(267.6, 75.0)

227.7
(268.4, 78.7)

Patients with
hsCRP
2 mg/L
at baseline

220.0
(274.2, 62.5)

224.7
(277.2, 96.9)

210.0
(267.0, 68.9)

235.0
(274.5, 35.8)

231.1
(271.4, 37.4)

Patients with
hsCRP .3 mg/L
at baseline

223.7
(280.6, 37.6)

232.2
(280.4, 78.0)

29.9
(268.3, 49.3)

240.7
(278.3, 27.0)

230.1
(273.4, 37.6)

Note: All patients 12-week data; comparisons among treatment groups were not signicant at the same time point.

P , 0.001 vs. baseline.

Table 6 Change from baseline in fasting plasma glucose and insulin resistance (ITT population by as-allocated treatment)
Change from baseline (%)
6 weeks

Fasting plasma glucose, LSM (SE)

Insulin resistance, median (10th
and 90th percentiles)

12 weeks

RSV 10 mg
(n 164)

ATV 10 mg
(n 155)

Placebo
(n 78)

RSV combined
(n 242)

ATV 10/20 mg
(n 155)

0.1 (0.7)
2.7 (239, 66)

1.7 (0.7)
7.2 (236, 81)

0.6 (1.0)
0.8 (238, 63)

1.8 (0.8)
12.1 (237, 97)

3.1 (1.0)
12.1 (232, 75)

Comparisons between treatment groups were not signicant at the same time point.

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arthralgia, and back pain. The majority of AEs were of a

mild-to-moderate intensity. Three patients experienced
non-fatal serious adverse events (SAEs) of dizziness, chondropathy (both atorvastatin 10/20 mg group), and myalgia
(rosuvastatin 10/20 mg group), all of which were resolved.
There were two deaths during the study owing to cardiovascular events (atorvastatin 10/20 mg group), but these were
considered to be unrelated to the treatment by the study
investigator. There were no reported cases of rhabdomyolysis or acute renal failure.
Clinically important elevations in alanine aminotransferase (.3 ULN) occurred in one patient (rosuvastatin
10/20 mg). One patient in the atorvastatin 10/20 mg group
experienced CK .10 ULN without muscle symptoms.
Myalgia was associated with CK .10 ULN in one patient
in the rosuvastatin 10/20 mg group, which was indicative
of myopathy. No changes in serum creatinine levels were
observed during the study. There were no clinically relevant
changes in haematology, clinical chemistry, and renal function observed in either treatment arm.

2670

A.F.H. Stalenhoef et al.

Table 7 Treatment-emergent AEs, SAEs, discontinuations due to AEs, and most commonly reported treatment-emergent AEs (events that
occurred in three or more patients in any treatment group)
Number of patients with AEs, n (%)
Period 1
ATV 10 mg (n 154)

Placebo (n 79)

41 (25.2)
0
0
2 (1.2)

39 (25.3)
3 (1.9)
1 (0.6)
3 (1.9)

14 (17.7)
0
0
3 (3.8)

8 (4.9)
3 (1.8)
3 (1.8)
3 (1.8)
2 (1.2)
1 (0.6)
1 (0.6)

4 (2.6)
3 (1.9)
2 (1.3)
1 (0.6)
4 (2.6)
3 (1.9)
3 (1.9)

1 (1.3)
1 (1.3)
2 (2.5)
2 (2.5)
0
0
0

Period 2a

Any AE
SAE
SAE leading to death
Discontinuation due to AE
Most commonly reported AE
Myalgia
Arthralgia
Back pain

RSV 10/20 mg (n 158)b

ATV 10/20 mg (n 150)b

Placebo/RSV 20 mg (n 75)b

35 (22.2)
1 (0.6)
0
2 (1.3)

31 (20.7)
1 (0.7)
1 (0.7)
1 (0.7)

18 (24.0)
0
0
0

4 (2.5)
3 (1.9)
0

1 (0.7)
2 (1.3)
1 (0.7)

3 (4.0)
0
3 (4.0)

a
Two non-serious AEs also occurred in two patients who did not receive the correct study medication at the appropriate time in error; one AE occurred in a
patient receiving ATV 20 mg in Period 1 and the other AE occurred in a patient receiving RSV 20 mg in Period 2.
b
n-values include only those patients who received a dose of Period 2 study medication.

rosuvastatin 10 mg was signicantly more benecial than

atorvastatin 10 mg and placebo for lowering LDL-C. The percentage reduction from baseline in LDL-C was also signicantly greater in the rosuvastatin group compared with
the atorvastatin group after 12 weeks of treatment.
Consistent with the greater reductions in LDL-C, more
patients in the rosuvastatin group achieved LDL-C goals
when compared with the atorvastatin and placebo groups.
Improvements in TC, HDL-C, and non-HDL-C were also signicantly greater with rosuvastatin than with atorvastatin
or placebo, whereas decreases in TG were similar in both
active treatment groups. Low HDL-C and raised TG are
included in diagnostic criteria for the metabolic syndrome,
and in selecting appropriate therapy to treat the complex
pattern of lipid abnormalities associated with the metabolic
syndrome, it is important to use agents that provide optimal
improvements in these variables.
Results of COMETS are consistent with subgroup analyses
from other studies of rosuvastatin that included patients
with the metabolic syndrome. In a pooled analysis of
efcacy trials, rosuvastatin 10 mg improved the lipid
prole to a similar extent in hypercholesterolaemic patients
with and without the metabolic syndrome.10 In an analysis of
goal achievement in patients with the metabolic syndrome
included in the Measuring Effective Reductions in
Cholesterol Using Rosuvastatin therapY (MERCURY) I study,
treatment with rosuvastatin 10 mg had signicant benets

in modifying lipid levels and in achieving goals when

compared with atorvastatin 10 mg, simvastatin 20 mg, and
pravastatin 40 mg.11 COMETS is also consistent with data
showing that in patients with hypercholesterolaemia, rosuvastatin was signicantly more effective than atorvastatin
at lowering LDL-C and raising HDL-C.1416 Statin-induced
LDL-C reductions have been shown to decrease cardiovascular events by 2437%,17 and several large-scale, randomized
trials evaluating clinical outcomes of rosuvastatin therapy
are ongoing.18 Further studies are now required to evaluate
whether improvements in the lipid prole seen in the
present study lead to increased patient survival and
reduced morbidity in patients with the metabolic syndrome.
A central role of inammation at all stages of atherosclerosis is well established,19 and baseline hsCRP levels are a
robust and independent predictor of future cardiovascular
events.20,21 Furthermore, hsCRP measurement may add clinically important prognostic information concerning future
vascular risk in patients with the metabolic syndrome.22
Statins reduce hsCRP levels, with a greater benet shown
for individuals with elevated hsCRP.22 Although COMETS did
not demonstrate any signicant difference between treatments, 2829% reductions in hsCRP were observed after 12
weeks in all patients, with 3040% reductions observed in
patients with elevated hsCRP at baseline. Data regarding
the effects of rosuvastatin on outcomes in patients with elevated C-reactive protein (
2 mg/L) levels will be provided by

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Any AE
SAE
SAE leading to death
Discontinuation due to AE
Most commonly reported AE
Headache
Back pain
Myalgia
Constipation
Fatigue
Dizziness
Muscular weakness

RSV 10 mg (n 163)

COMETS study

Acknowledgements
We gratefully acknowledge the investigators, their coinvestigators and study co-ordinators, and the patients who participated in this trial. This study was supported by AstraZeneca.
Editorial assistance was provided by Emma Marshman during the
preparation of this report.
Conict of interest: A.F.H.S. and co-authors would like to disclose
their associations with several pharmaceutical companies. A.F.H.S.
has received departmental research funds and consultancy fees
from AstraZeneca, Pzer, and Merck. Dr C.M.B. has received
research support from AstraZeneca, diaDexus, Gene Logic, GlaxoSmithKline, Integrated Therapeutics, Kos, Merck, Novartis, Pzer,
Reliant, Sankyo Pharma, and Schering-Plough; is a consultant for
AstraZeneca, Bayer, Merck, Novartis, Pzer, Reliant, and ScheringPlough; and is a member of the speakers bureau for AstraZeneca,
Bristol Myers-Squibb, Kos, Merck, Novartis, Pzer, Reliant, SanoSynthelabo, and Schering-Plough. Dr C.S. and Dr J.M. have no nancial associations that could pose a conict of interest in connection
with this manuscript. Professor S.T. has received honoraria for
lectures given for AstraZeneca, Pzer, Merck, Schering-Plough,
Novartis, Roche, Abbott, and Sano-Aventis.

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the ongoing Justication for the Use of Statins in Primary

Prevention: an Intervention Trial Evaluating Rosuvastatin
(JUPITER) trial.23
Insulin resistance is characteristic of the metabolic syndrome;4 however, only a small number of studies have investigated the effects of statin therapy on insulin resistance.24,25
In COMETS, a small percentage of patients were glucose
intolerant, and therefore, it was unlikely that changes in
insulin resistance would be observed. Further work is
needed to assess the effects of statins on insulin resistance,
specically in patients with glucose intolerance.
Throughout this study, both treatments were well tolerated and the AE prole was consistent with that reported
previously for rosuvastatin and atorvastatin.2628 Few SAEs
were observed, reecting previous data indicating that
SAEs resulting from statin treatment are rare.29 As the
largest study to date focusing on statin therapy solely in
patients with the metabolic syndrome, COMETS supports
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reported previously by two post hoc subgroup analyses.12,30
Further long-term studies in large numbers of patients will
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treatment in this population.
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was signicantly more effective than atorvastatin for
reducing LDL-C levels, enabling patients to achieve lipid
goals and improving other aspects of the atherogenic lipid
prole in patients with the metabolic syndrome. These
data provide a basis for improving the management of dyslipidaemia and cardiovascular risk in the increasing number of
patients requiring treatment for the metabolic syndrome.

2671

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