ORIGINAL ARTICLE
A review of the efficacy of rosuvastatin in patients with type 2
diabetes
J. TUOMILEHTO, L. A. LEITER, D. KALLEND
National Public Health Institute, Helsinki, Finland; St Michael’s Hospital and University of Toronto, Toronto, Canada and Astra Zeneca,
Alderley Park, Cheshire, UK
SUMMARY
It has been estimated that 92% of individuals with type 2
diabetes, without cardiovascular disease (CVD), have a
dyslipidaemic profile. Several guidelines on cardiovascular
risk now recommend that patients with diabetes should
be considered at high risk of CVD and should thus
receive lipid-lowering therapy to reduce low-density lipo-
protein cholesterol (LDL-C) to below 2.5 mmol ⁄ L. Since
their introduction in 1987, statins have revolutionized the
management of CVD. The most recent statin to be intro-
duced, rosuvastatin, has been shown to be the most
effective at lowering LDL-C, as well as consistently rais-
ing HDL-C across the 10–40 mg dose range. This has
been confirmed by many studies, including the Measuring
Effective Reductions in Cholesterol Using Rosuvastatin
Therapy (MERCURY I) study in which rosuvastatin
10 mg was shown to be more effective than commonly
used doses of other statins, both for LDL-C reduction
and achieving treatment target goals. The effectiveness of
rosuvastatin has also been studied in type 2 diabetes
INTRODUCTION
Individuals with diabetes have a two- to four-fold increased
risk of developing cardiovascular disease (CVD) compared
with nondiabetic individuals (1,2), with atherosclerosis and
coronary heart disease (CHD) responsible for most of the
premature morbidity and mortality in this population (3).
Therefore, reduction of cardiovascular risk is vital in people
with type 2 diabetes. Guidelines universally recommend that
diabetes should be considered a CHD-risk equivalent and
that intensive multifactorial intervention is required to treat
all cardiovascular risk factors (4).
Correspondence to:
Professor J. Tuomilehto, National Public Health Institute, Manner-
heimintie 166, Helsinki 00300, Finland
Tel.: +358 94744 8316
Fax: +358 40501 6316
E-mail: jaakko.tuomilehto@ktl.fi
ª 2004 Blackwell Publishing Ltd Int J Clin Pract, October 2004, 58 (Suppl. 143), 30–40
patients in three studies: the URANUS (Use of Rosuvast-
atin vs. Atorvastatin iN type 2 diabetes mellitUS), ANDR-
OMEDA (A raNdomized, Double-blind study to
compare Rosuvastatin [10 & 20 mg] and atOrvastatin [10
& 20 Mg] in patiEnts with type II DiAbetes) and COR-
ALL (COmpare Rosuvastatin [10–40 mg] with Atorvasta-
tin [20–80 mg] on apo B ⁄ apo A-1 ratio in patients with
type 2 diabetes meLLitus and dyslipidaemia) studies.
URANUS and ANDROMEDA showed rosuvastatin to
be more effective than atorvastatin at reducing LDL-C
and achieving treatment target goals. CORALL demon-
strated rosuvastatin 10, 20 and 40 mg to be more effect-
ive at lowering LDL-C than 20, 40 and 80 mg of
atorvastatin, respectively. Ongoing studies will evaluate
whether these properties of rosuvastatin translate into
beneficial effects on atherosclerosis and significant reduc-
tions in cardiovascular events.
Keywords: Diabetic dyslipidaemia; statins; rosuvastatin;
cardiovascular disease
ª 2004 Blackwell Publishing Ltd
Although glycaemic control is clearly important in the
management of diabetes, elevated glucose and insulin con-
centrations do not entirely account for the high incidence
of CVD in patients with type 2 diabetes (5,6). The clinical
focus is now on the implications of insulin resistance and
the associated clustering of modifiable risk factors for
atherosclerosis such as dyslipidaemia (7,8). The Third
National Health and Nutrition Examination Survey (1988–
94) estimated that 92% of individuals with type 2 diabetes
without CVD have a dyslipidaemic profile (9). Several
guidelines on cardiovascular risk now recommend every
patient with type 2 diabetes or type 1 diabetes, especially
those with other risk factors, should be targeted for lipid-
lowering therapy. The primary goal in the guidelines is to
reduce low-density lipoprotein cholesterol (LDL-C) levels in
persons with diabetes to < 2.5 mmol ⁄ L (4,10).
Statin therapy effectively reduces LDL-C, and its use for
treatment of diabetic dyslipidaemia has been investigated in
several recent trials (11). This paper reviews the data on use
of statins for treating dyslipidaemia and focuses on results
EFFICACY OF ROSUVASTATIN IN TYPE 2 DIABETES
from a series of trials dedicated to evaluating the clinical
efficacy and safety of rosuvastatin in patients with type 2
diabetes. It also evaluates the relative benefits of rosuvasta-
tin compared with other statins in terms of LDL-C lower-
ing and improving other elements of lipid profiles (12–14).
Evidence for the added benefits of combining rosuvastatin
with a fibrate are also considered.
CHARACTERISTICS OF DIABETIC
DYSLIPIDAEMIA
Insulin resistance is associated with the clustering of risk
factors known as the metabolic syndrome. The compo-
nents of the metabolic syndrome include dyslipidaemia,
visceral obesity (increased waist circumference), hyperinsu-
linaemia, impaired glucose tolerance (IGT) and hyperten-
sion, all of which are independent risk factors for CVD
and for the development of type 2 diabetes (15–19). The
majority of patients with type 2 diabetes, insulin resist-
ance or metabolic syndrome, exhibit the atherogenic lipo-
protein phenotype (20), characterized by moderately
elevated plasma triglyceride (very low-density lipoprotein
cholesterol [VLDL]), reduced high-density lipoprotein cho-
lesterol (HDL-C), and a predominance of small, dense,
more atherogenic LDL-C (21–23). Indeed, this dyslipidae-
mic state often develops before patients present with type
2 diabetes.
Studies have shown that lipid abnormalities are import-
ant cardiovascular risk factors in patients with type 2 dia-
betes. Raised plasma cholesterol in patients with diabetes
is associated with a disproportionately greater risk of
CVD, with a four times higher cardiovascular mortality in
diabetic patients than in nondiabetic individuals with the
same concentration of serum cholesterol (2). Furthermore,
reducing LDL-C by 1 mmol ⁄ L can equate to a 31%
From the liver
TG TG
C C C C
apoB apoB
VLDL IDL Large
buoyant
LDL
Atherogenic
Figure 1 Profile of atherogenic and anti-atherogenic lipoproteins (Reproduced from Walldius G, Jungner I. Apolipoprotein B and
apolipoprotein A-I: risk indicators of coronary heart disease and targets for lipid-modifying therapy. J Intern Med 2004; 255: 188–205, with
permission from Blackwell Publishing)
ª 2004 Blackwell Publishing Ltd Int J Clin Pract, October 2004, 58 (Suppl. 143), 30–40
31
reduction in cardiovascular risk in patients with type 2 dia-
betes (24).
Even though many individuals with type 2 diabetes have
near normal levels of LDL-C, many aspects of their plasma
lipid profile are regarded as atherogenic. It is now thought
that elevated plasma triglycerides is the primary abnormality
in these patients that leads to both the structural change in
LDL, which makes it more atherogenic, and a reduction in
HDL-C concentrations (8). Both insulin resistance and insu-
lin deficiency reduce the breakdown of VLDL, thereby
increasing plasma concentrations of triglyceride-rich lipopro-
tein particles. A strong association has been found between
fasting triglyceride concentrations and CHD, with a 75%
increase in risk for women and 30% increased risk in men
for every 1 mmol ⁄ L rise in triglycerides (25).
Low HDL-C is the most prevalent lipid abnormality
among US patients with coronary artery disease (CAD) (26).
Reduced levels of apolipoprotein (apo) A-I, a component of
antiatherogenic HDL (Figure 1), are also associated with
increased cardiac events (27). Population studies suggest
that each 0.026 mmol ⁄ L (1 mg ⁄ dL) increase in HDL-C
level imparts a 2% to 5% decrease in coronary risk (28).
A predominance of small, dense, LDL particles is associ-
ated with CHD in young and middle-aged subjects (29–31).
Correspondingly, elevated levels of apo B, a constituent of
atherogenic lipoproteins (LDL, IDL and VLDL) (Fig. 1),
are related to increased cardiac events (27). In trials, meas-
ures of apo B or the apo B ⁄ apo A-I ratio have been found
to be robust markers of cardiovascular risk in patients
(27,32,33), irrespective of the lipid abnormality. Moreover,
apo B, apo A-I and the apo B ⁄ apo A-I ratio retain their
predictive power in patients receiving lipid-modifying ther-
apy. In addition, LDL-C is more likely to be oxidized and
glycated in people with diabetes, both of which further
increase its atherogenicity (34).
Back to the liver
‘Reverse cholesterol
transport’
C
apoB apoB apo A-I
Small
HDL
dense LDL
Anti-atherogenic
32
TREATING DIABETIC DYSLIPIDAEMIA
Based on findings from epidemiological and intervention
studies, lipid targets have been established for patients with
type 2 diabetes. The Third Joint Task Force European
guidelines (2003) recommend that all patients with type 2
diabetes, with or without established CVD should be trea-
ted to target LDL-C levels of 2.5 mmol ⁄ L (4). Although
treatment goals for HDL and triglycerides are not specified,
the guidelines recommend that HDL-C levels of
< 1 mmol ⁄ L in men and < 1.2 mmol ⁄ L in women, and tri-
glyceride levels > 1.7 mmol ⁄ L, should be considered as
markers of increased cardiovascular risk and given appropri-
ate consideration when choosing treatments.
Therapy to improve lipid abnormalities should begin
with lifestyle changes including dietary modification,
weight loss, smoking cessation and increased exercise.
However, although lifestyle changes are the foundation of
treatment, they are often insufficient to achieve and main-
tain the lipid targets recommended in guidelines, especially
in high-risk patients, who may require pharmacological
intervention.
In addition to dietary modification, dietary agents that
inhibit cholesterol absorption, such as plant sterols and
stanols (saturated derivatives of plant sterols) and fibre, can
be used to improve lipid levels. These agents produce mod-
est LDL-C reductions, but can be used in combination with
other cholesterol-lowering agents. As well as their beneficial
cholesterol-lowering effects, soluble fibres (e.g. guar and
pectin) have been shown to lower serum insulin and glu-
cose concentrations, and improve insulin sensitivity (35).
Pharmaceutical cholesterol absorption inhibitors such as
ezetimibe are also available. Ezetimibe can be used as
monotherapy or in combination with other cholesterol-
lowering agents.
Fibrates are useful pharmacological agents for correcting
moderate to severe hypertriglyceridaemia in patients with
type 2 diabetes. It has been postulated that the clinical
benefit of fibrate therapy is a result of increased HDL-C
levels and the correction of hypertriglyceridaemia, which
may have an impact on LDL-C and HDL-C particle hetero-
geneity (36). Currently, however, there is only limited clin-
ical trial evidence that these treatments reduce risk of CHD
(11). The results of the ongoing Fenofibrate Intervention
and Event Lowering in Diabetics (FIELD) Trial (n ¼
9795), which is investigating prospectively the impact of
fenofibrate on primary prevention of CHD events in
patients with type 2 diabetes, are awaited with interest. The
Diabetes Atherosclerosis Intervention Study (DAIS) was
designed to assess the effects of fenofibrate on coronary
atherosclerosis in patients with type 2 diabetes. The results
suggested that fenofibrate reduced progression of CAD in
these patients (37).
ª 2004 Blackwell Publishing Ltd Int J Clin Pract, October 2004, 58 (Suppl. 143), 30–40
EFFICACY OF ROSUVASTATIN IN TYPE 2 DIABETES
LDL-C reduction by statins in patients with type 2
diabetes
Epidemiological and large intervention studies with statins
have amply demonstrated the link between LDL-C levels
and cardiovascular risk. Based on the weight of evidence,
both US and European guidelines have reaffirmed LDL-C
as the primary treatment goal in all high-risk patients, and
statins are often recommended as the first choice for treat-
ment (4,10).
Across all the landmark trials, subgroup analyses have
demonstrated that people with diabetes benefit from statin
therapy in a similar manner to nondiabetic patients, with
broadly equivalent relative cardiovascular risk reductions in
both groups (38–40). In a recent meta-analysis of primary
and secondary prevention trials, statin therapy produced a
22–24% reduction in the risk of future cardiovascular events
in diabetes subgroups (11). The results with respect to pri-
mary events have been confirmed in the Collaborative AtoR-
vastatin Diabetes Study (CARDS) (41–43), involving over
2800 men and women with diabetes (40–75 years). Com-
pared with placebo, atorvastatin 10 mg reduced LDL-C by
40% (a difference of 1.2 mmol ⁄ L; p < 0.0001) and triglycer-
ides by 21% (a difference of 0.4 mmol ⁄ L; p < 0.001) (43).
The improvement in lipid levels seen with atorvastatin was
associated with a significant reduction (37%; p ¼
0.001) in major coronary events and a 48% reduction in
risk for stroke (43). It is hoped that a further prospective
trial, the Atorvastatin Study for Prevention of coronary heart
disease Endpoints in Non insulin dependent diabetes melli-
tus (ASPEN), in 2421 patients with diabetes, with or without
a previous myocardial infarction (MI), will provide additional
insight into the value of statins in type 2 diabetes (44).
The direct correlation between LDL-C and cardiovascular
risk (45) suggests that perhaps an even more intensive
approach to lipid lowering may be warranted (46). Evidence
from three secondary prevention studies have shown that
lowering LDL-C with statin therapy to levels well below cur-
rent target levels of 2.5 mmol ⁄ L further reduces cardiovas-
cular mortality and morbidity (47,48) and inhibits the
progression of atherosclerosis (49). In the PROVE-IT study,
aggressive dosing with statins effectively lowered LDL-C
and reduced cardiovascular events by 16% compared with
less intensive therapy with standard statin doses (47).
Combination therapy with statins
Promising provisional evidence has come from trials of
combination therapy with statins and niacin or fibrates.
These studies suggest that combination therapy may offer
patients more intensive control of LDL-C, as well as HDL-
C and triglycerides, and ultimately even greater risk reduc-
tions, including in patients with diabetes (50–54).
EFFICACY OF ROSUVASTATIN IN TYPE 2 DIABETES
The effect of an atorvastatin-fenofibrate combination or
monotherapy with each drug on lipid profiles has been
assessed in patients with type 2 diabetes and combined hyp-
erlipidaemia, who were free of CAD at the start of the
study (50). The combination therapy reduced total choles-
terol by 37%, LDL-C by 46% and triglycerides by 50%, and
increased HDL-C by 20% from baseline (p < 0.0001 for
all). These changes were significantly better than for
either of the monotherapies. The combination also reduced
the probability of an MI within 10 years from 21.6% at
baseline to 4.2% – an 80% reduction (p < 0.0001). Probab-
ility of a MI with atorvastatin alone was 7.5% and with fen-
ofibrate alone was 10.9% (p < 0.05 vs. the combination for
both) (50).
The HDL Atherosclerosis Treatment Study (HATS)
found that simvastatin plus niacin reduced major clinical
events by 60% in patients with CAD and low HDL-C (51).
A subgroup analysis of this study found that the combina-
tion of simvastatin and niacin was effective in patients with
or without diabetes ⁄ impaired fasting glucose (55). In both
groups simvastatin plus niacin increased HDL-C by 28%,
whereas in the placebo group HDL-C increased by 6%.
Clinical events were lower in the simvastatin plus niacin
group compared with placebo for patients with diabetes
(11% vs. 21%; not significant) and without diabetes (8% vs.
23%; p < 0.01).
The ongoing Action to Control CardiOvascular Risk in
Diabetes (ACCORD) trial examines the ability of combined
fibrate and statin therapy to reduce events in patients with
type 2 diabetes, with or without a history of CVD. All
patients will be randomized to intensive vs. standard treat-
ment for glycaemic control. In addition, some of the
patients will receive standard vs. intensive blood pressure
control, with the others receiving standard vs. intensive
lipid-modifying therapy. The lipid intervention will consist
of simvastatin plus either fenofibrate or placebo. The study
will continue until June 2009.
Beyond lipid lowering – the ‘pleiotropic’ effects of
statins
It has been hypothesized that, in addition to their lipid-
modifying properties, statins have other effects that might
contribute to their cardioprotective benefits (56,57). An area
of ongoing research is the cholesterol-independent or ‘pleio-
tropic’ effects of statins on diabetes and micro- and macro-
vascular complications (58).
Endothelial dysfunction in patients with type 1 diabetes
and type 2 diabetes contributes to micro- and macrovascular
complications (59,60). Although the beneficial effects of sta-
tins on endothelial function were thought to be due to their
lipid-lowering properties, recent studies have indicated that
statins may have other protective effects. For example,
ª 2004 Blackwell Publishing Ltd Int J Clin Pract, October 2004, 58 (Suppl. 143), 30–40
33
statins may restore endothelial nitric oxide production
(61,62) and ameliorate oxidative damage caused by the gen-
eration of endothelial reactive oxygen species (ROS) (63–
65). Markers such as C-reactive protein (CRP) may provide
a measure of the effects of statins in the restoration of
endothelial function. Certainly, recent studies have con-
firmed statins lower CRP levels in diabetic (66) and non-
diabetic patients (67), and that this effect appeared to be
greatest among patients with the highest levels of CRP,
independent of baseline lipid levels (68).
Moreover, it is thought that statins may confer improved
sensitivity to insulin, through an as yet unknown mechanism
(69,70), and therefore may influence progression of IGT to
type 2 diabetes. Some studies have suggested that statins
may reduce the risk of developing diabetes by as much as
30% (71,72), but this has not been confirmed by other large
statin trials such as the Scandanavian Simvastatin Survival
Study (4S) and the Heart Protection Study HPS (73,74).
Through both lipid-lowering and lipid-independent
effects, statins are thought to have a beneficial influence on
rate of progression of microvascular complications (75–80).
Long-term studies would be beneficial in further under-
standing the potential role of statins for slowing the pro-
gression of microvascular and macrovascular complications
in both type 1 diabetes and type 2 diabetes.
As well as the overwhelming evidence for their clinical
benefits, statins have been shown to be cost-effective for
treating patients with diabetes (81–83). Despite this, the
number of patients screened and treated for dyslipidaemia
remains less than optimal (84,85). It is hoped that the ongo-
ing evolution of lipid-lowering treatments and the availabil-
ity of new statins, such as rosuvastatin, will help physicians
meet this treatment gap.
ROSUVASTATIN IN THE MANAGEMENT OF
DYSLIPIDAEMIA
Rosuvastatin 10–40 mg has been extensively evaluated in
adults across a range of dyslipidaemias (53,86–91), including
in patients with the metabolic syndrome or type 2 diabetes.
In all trials, rosuvastatin 10–40 mg has been shown to be
highly efficacious, reducing LDL-C levels by up to 63%, in
patients with LDL-C between 4.1 and 5.7 mmol ⁄ L (86).
Furthermore, rosuvastatin has been shown to increase
HDL-C and improve triglycerides and other components of
the atherogenic lipid profile compared with placebo.
Rosuvastatin 10 mg improved dyslipidaemia in patients
with the metabolic syndrome to a similar degree to those
without the metabolic syndrome in a subanalysis of a study
involving 194 hypercholesterolaemic patients (92). It also
enabled 64% of the patients with the metabolic syndrome
and triglycerides ‡ 5 mmol ⁄ L to meet their ATP III
nonHDL goals (92). This result was confirmed by Shepherd
34
et al. (2003), who showed that among all patients who had
triglycerides ‡ 5 mmol ⁄ L, 71% of these patients met both
their LDL-C and nonHDL goals (93).
Studies have shown that the usual starting dose of rosu-
vastatin (10 mg) is more effective than atorvastatin 10 mg,
simvastatin 10–40 mg and pravastatin 10–40 mg at improv-
ing LDL-C, triglycerides and other components of the
atherogenic lipid profile in patients with hypercholesterolae-
mia (87–89,91). Notably, rosuvastatin 10 mg raised HDL-C
significantly more than atorvastatin 10 mg (87–89,91) and
enabled more patients to achieve their LDL-C goals, redu-
cing the requirement for dose titration (87,93). Furthermore,
switching from atorvastatin 10 mg to rosuvastatin 10 mg
was shown to significantly improved the number of patients
who achieved LDL-C goals (p < 0.05) compared with
patients who remained on atorvastatin in the Measuring
Effective Reductions in Cholesterol Using Rosuvastatin
Therapy (MERCURY I) trial (94). MERCURY I evaluated
rosuvastatin 10 mg in high-risk patients (history of CHD or
atherosclerotic disease, type 2 diabetes, or a high CHD
risk), with raised LDL-C and triglycerides (< 4.5 mmol ⁄ L)
(94).
ROSUVASTATIN IN THE MANAGEMENT OF TYPE
2 DIABETES PATIENTS WITH DYSLIPIDAEMIA
The efficacy of rosuvastatin in modifying the lipid profile in
patients with hypercholesterolaemia is similar in type 2 dia-
betes and in patients without diabetes. This was reflected in
a subgroup analysis of patients with type 2 diabetes from
the MERCURY I trial, which found that 8 weeks of treat-
ment with rosuvastatin 10 mg produced similar improve-
ments in LDL-C (47.2%) compared with the overall
population (47.0%) (94,95).
Three studies have subsequently been conducted to
evaluate rosuvastatin vs. other statins in the management of
dyslipidaemia in patients with type 2 diabetes: URANUS
(Use of Rosuvastatin vs. Atorvastatin iN type 2 diabetes
mellitUS) (12), ANDROMEDA (A raNdomized, Double-
blind study to compare Rosuvastatin [10 & 20 mg] and
Table 1 The effects of rosuvastatin and atorvastatin on the atherogenic lipid profile of patients with type 2 diabetes (From Berne C,
et al. Use of rosuvastatin versus atorvastatin in type 2 diabetes mellitus subjects: results of the URANUS study. 74th European
Atherosclerosis Society Congress. Atherosclerosis 2004; 5 (Suppl 1): 107 Abstract M463.)
Lipid ⁄ lipoprotein Least square mean percentage change from baseline
4 weeks
RSV 10 mg
(n ¼ 232)
LDL-C ) 47.6*
Apo B ⁄ apo A-I ratio ) 43.9*
RSV ¼ rosuvastatin; ATV ¼ atorvastatin; *p £ 0.001 vs. ATV.
ª 2004 Blackwell Publishing Ltd Int J Clin Pract, October 2004, 58 (Suppl. 143), 30–40
EFFICACY OF ROSUVASTATIN IN TYPE 2 DIABETES
atOrvastatin [10 & 20 Mg] in patiEnts with type II DiAbe-
tes) (13), and CORALL (COmpare Rosuvastatin [10–
40 mg] with Atorvastatin [20–80 mg] on apo B ⁄ apo A-1
ratio in patients with type 2 diabetes meLLitus and dyslipid-
aemia) (14).
URANUS study
The URANUS study in Sweden compared rosuvastatin with
atorvastatin for LDL-C reduction and goal achievement.
Rosuvastatin was highly efficacious at modifying components
of the atherogenic lipid profile in patients with a history of
type 2 diabetes (‡ 3 months). Patients had a fasting LDL-
C ‡ 3.3 mmol ⁄ L and triglyceride concentration <
6.0 mmol ⁄ L and were treated with diet modification plus oral
antidiabetic agents, insulin or a combination (12). They were
randomized to a starting dose of either rosuvastatin 10 mg or
atorvastatin 10 mg. Those not reaching the 1998 European
LDL-C goal of < 3.0 mmol ⁄ L received dose titrations to
rosuvastatin 20 mg or 40 mg, or atorvastatin 20 mg, 40 or
80 mg.
At 4 weeks, 81% of patients on rosuvastatin 10 mg com-
pared with 65% of patients on atorvastatin 10 mg achieved
1998 European LDL-C targets (p < 0.001). Compared with
atorvastatin, rosuvastatin improved other lipid variables
including HDL-C and triglycerides, with significant reduc-
tions in apo B ⁄ apo A-I after 4 and 16 weeks of treatment
(p < 0.001) (Table 1).
ANDROMEDA study
The ANDROMEDA study in the UK compared the effects
of the same doses of rosuvastatin and atorvastatin on LDL-
C, other lipids and the inflammatory marker CRP. Adults
with type 2 diabetes and triglycerides £ 6.0 mmol ⁄ L were
eligible (13). Patients initially received 10 mg doses of either
rosuvastatin or atorvastatin for 8 weeks and were then titra-
ted up to 20 mg for a further 8 weeks. Significantly more
patients on rosuvastatin than on atorvastatin achieved the
2003 European LDL-C goal of < 2.5 mmol ⁄ L (Figure 2)
16 weeks
ATV 10 mg RSV 10–40 mg ATV 10–80 mg
(n ¼ 231) (n ¼ 221) (n ¼ 220)
) 38.5 ) 52.3* ) 45.5
) 35.4 ) 46.3* ) 39.6
EFFICACY OF ROSUVASTATIN IN TYPE 2 DIABETES 35

* † at both 8 weeks ()34.0% vs. )21.2%) and 16 weeks

100 94 96 ()39.8% vs. )33.8%) (13).
Patients who achieved goal (%)

90
79
80
70
60
50
40
30
20
10
0 (HbA1c < 10%) and dyslipidaemia (LDL-C ‡ 3.4 mmol ⁄ L
RSV ATV
10 mg 10 mg
8 weeks
Figure 2 Proportion of patients with type 2 diabetes achieving
the 2003 LDL-C goal of 2.5 mmol ⁄ L with starting doses of
rosuvastatin and atorvastatin RSV ¼ rosuvastatin; ATV ¼
atorvastatin; *p < 0.001 RSV 10 mg vs. ATV 10 mg;  p ¼ 0.002
RSV 20 mg vs. ATV 20 mg. (Reproduced with data from
Betteridge JD, Gibson M, on behalf of the ANDROMEDA study
investigators. Effect of rosuvastatin and atorvastatin on LDL-C
and CRP levels in patients with type 2 diabetes: results of the
ANDROMEDA study. 74th European Atherosclerosis Society
Congress. Atherosclerosis 2004; 5 (Suppl 1): 107–8 Abstract M464)
(13). This result reflects the significantly greater reductions
in LDL-C achieved with both the 10 mg (51.3% vs. 39.0%;
p < 0.001) and 20 mg (57.4% vs. 46.0%; p < 0.001) doses
of rosuvastatin compared with atorvastatin (13).
Reductions in median CRP from baseline were also
numerically greater with rosuvastatin than with atorvastatin
87
CORALL study
The CORALL study in the Netherlands was conducted to
compare the effects of rosuvastatin vs. atorvastatin on apo
B ⁄ apo A-I ratios and other lipid parameters. Reflecting the
results from the two previous studies, CORALL found
rosuvastatin to be more effective at reducing LDL-C than
atorvastatin (14). In this trial, adults with type 2 diabetes
RSV ATV
20 mg 20 mg [statin-naı̈ve] or > 3.0 to £ 5.0 mmol ⁄ L [previous statin
16 weeks treatment within 4 weeks] and triglycerides < 4.5 mmol ⁄ L)
were included in the trial. Patients received a starting dose
of rosuvastatin 10 mg or atorvastatin 20 mg for 6 weeks
(14). At subsequent 6-weekly intervals, the dose was
increased to rosuvastatin 20 mg and then 40 mg, or ator-
vastatin 40 mg and then 80 mg for another 6-week period.
Rosuvastatin produced greater reductions in LDL-C than
atorvastatin at the 10 mg vs. 20 mg doses ()45.9% vs.
)41.3%), the 20 mg vs. 40 mg doses ()50.6% vs. )45.6%)
and the 40 mg vs. 80 mg doses ()53.6% to )47.8%)
(p < 0.05 for all) (14).
The CORALL study also provided evidence that rosu-
vastatin ameliorates the atherogenic profile in patients with
type 2 diabetes. Correspondingly, the study found that rosu-
vastatin was highly efficacious in modifying the apolipopro-
tein levels. At weeks 12 and 18, rosuvastatin reduced the
apo B ⁄ apo A-1 ratio significantly more than atorvastatin
(p < 0.05) (Figure 3) (14).

6 weeks 12 weeks 18 weeks

RSV ATV RSV ATV RSV ATV
10 mg 20 mg 20 mg 40 mg 40 mg 80 mg
0
Mean change from baseline in

n=128 n=131 n=128 n=131 n=128 n=131

–10
apo B/apo A-I (%)

–20

–30
–32.4
–34.9 –34.7 –35.8
–40 –39.2 * *
–40.5
* *
–50

Figure 3 Mean percentage change in baseline apoB ⁄ apoA-1 in patients with type 2 diabetes with rosuvastatin 10–40 mg and atorvastatin
20–80 mg. RSV = rosuvastatin; ATV = atorvastatin; apo = apolipoprotein; P < 0.05 vs ATV. (Reproduced with data from Franken AAM,
Wolffenbuttel BHR, Vincent HH, on behalf of the Dutch CORALL Study Group. Cholesterol-lowering effects of rosuvastatin compared
with atorvastatin in patients with type 2 diabetes. 74th European Atherosclerosis Society Congress. Atherosclerosis 2004; 5 (Suppl 1): 118,
Abstract M513.)

ª 2004 Blackwell Publishing Ltd Int J Clin Pract, October 2004, 58 (Suppl. 143), 30–40
36
In these trials, the overall occurrence of adverse events
was similar between atorvastatin and rosuvastatin, with a
low incidence of serious adverse events, which were not
attributed to the study treatments (12–14).
Combination therapy
The efficacy of rosuvastatin as monotherapy and in combi-
nation with fenofibrate has been evaluated in patients with
type 2 diabetes and combined hyperlipidaemia (elevated
total cholesterol ‡ 5.2 mmol ⁄ L and elevated triglycerides
‡ 2.3 and < 9.0 mmol ⁄ L) (53). Fenofibrate and rosuvastatin
monotherapy were equally effective in reducing triglyceride
levels ()30% and )36%, respectively), and increased HDL-
C by +6% and +9.2%, respectively. Monotherapy with
rosuvastatin also improved the LDL-C of patients with type
2 diabetes ()47%). By comparison, fenofibrate produced
smaller changes in LDL-C ()0.7%). Rosuvastatin 10 mg +
fenofibrate 67 mg three times daily reduced triglycerides to
a greater extent than rosuvastatin monotherapy titrated to a
dose of 40 mg ()47% vs. )30%; p £ 0.017), with no signi-
ficant differences between the treatment groups for any
other lipid parameter (53). These results indicate that the
combination of low-dose rosuvastatin with a fibrate can
produce larger reductions in triglycerides than a fibrate
alone.
CONCLUSION
Over 80% of people with type 2 diabetes die of CVD, and
it is now recognized that an atherogenic lipid profile repre-
sents a key risk factor in these patients. In accordance with
the results from epidemiological and intervention studies,
guidelines now agree on the need for intensive LDL-C low-
ering in patients with dyslipidaemia and type 2 diabetes.
Statins represent a break through in the treatment of dysli-
pidaemia and reduction of cardiovascular risk. In addition,
their pleiotropic effects may provide added benefits for
patients with type 2 diabetes. However, despite the risk
reductions that accompany lower LDL-C levels, physicians
may find the new stringent European targets difficult to
achieve in practice, particularly in patients with initially
higher LDL-C levels. Furthermore, it is important that ele-
ments of the diabetic dyslipidaemia other than LDL-C are
targeted.
Rosuvastatin 10–40 mg has been shown to reduce LDL-
C levels in patients with and without diabetes, and to a
degree that will enable a large number of patients with
hypercholesterolaemia to achieve the new European LDL-C
goals. Rosuvastatin is also highly efficacious in modifying
atherogenic lipid profiles, and was found to reduce the apo
B ⁄ apo A-1 ratio in patients with type 2 diabetes signifi-
cantly more than atorvastatin.
ª 2004 Blackwell Publishing Ltd Int J Clin Pract, October 2004, 58 (Suppl. 143), 30–40
EFFICACY OF ROSUVASTATIN IN TYPE 2 DIABETES
In patients with combined hyperlipidaemia, characterized
by both elevated cholesterol levels and triglyceride levels,
both rosuvastatin and fenofibrate monotherapy are equally
effective in lowering triglyceride levels; however, rosu-
vastatin is significantly more effective at reducing LDL-C.
The greater reduction in triglycerides produced by combi-
ning these two therapies suggests that rosuvastatin has
potential either as a monotherapy or in combination with
fenofibrate for the effective management of the dyslipidae-
mias in patients with type 2 diabetes, although rosuvastatin
should be prescribed with caution in combination with
fenofibrate.
Ongoing studies will evaluate whether these properties of
rosuvastatin translate into beneficial effects on atheroscler-
osis and significant reductions in cardiovascular events (96).
They will also provide important information on the role of
rosuvastatin in less well studied groups, including patients
with renal disease (97), and individuals without elevated
LDL-C but at heightened vascular risk as a result of
increased systemic inflammation (98).
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