EURO PEAN

SO CIETY O F
CARDIOLOGY

Original scientific paper

Doses of rosuvastatin, atorvastatin and

simvastatin that induce equal reductions
in LDL-C and non-HDL-C: Results from
the VOYAGER meta-analysis

European Journal of Preventive

Cardiology
2016, Vol. 23(7) 744747
! The European Society of
Cardiology 2015
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DOI: 10.1177/2047487315598710
ejpc.sagepub.com

Bjorn W Karlson1,2, Michael K Palmer3, Stephen J Nicholls4,

Pia Lundman5 and Philip J Barter6

Abstract
Background: Achieving the greatest reduction in atherogenic lipoproteins requires the optimum dose and potency of
statin. Using data from the VOYAGER meta-analysis, we determined doses of rosuvastatin, atorvastatin and simvastatin
that induce equal reductions in low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol
(non-HDL-C).
Methods: Least squares mean percentage change in LDL-C and non-HDL-C was calculated using 38,052 patient
exposures to rosuvastatin 540 mg, atorvastatin 1080 mg and simvastatin 1080 mg. Equipotent doses were estimated
by linear interpolation between actual adjacent doses.
Results: Rosuvastatin 5 mg reduced LDL-C by 39% and non-HDL-C by 35%. Equivalent reductions in LDL-C required
atorvastatin 15 mg or simvastatin 39 mg. Equivalent reductions in non-HDL-C required atorvastatin 14 mg or simvastatin
42 mg. Rosuvastatin 10 mg reduced LDL-C by 44% and non-HDL-C by 40%. Equivalent reductions in LDL-C required
atorvastatin 29 mg or simvastatin 72 mg. Equivalent reductions in non-HDL-C required atorvastatin 27 mg or simvastatin
77 mg. Rosuvastatin 20 mg reduced LDL-C by 50% and non-HDL-C by 45%. Equivalent reductions in LDL-C and nonHDL-C required atorvastatin 70 mg and atorvastatin 62 mg, respectively, and were not achieved with the maximum
80 mg dose of simvastatin. Rosuvastatin 40 mg reduced LDL-C by 55% and non-HDL-C by 50%. Comparable reductions
were not achieved with the maximum 80 mg doses of atorvastatin or simvastatin.
Conclusions: Regarding reductions in LDL-C and non-HDL-C, each rosuvastatin dose is equivalent to doses 33.5
times higher for atorvastatin and 78 times higher for simvastatin.

Keywords
Rosuvastatin, atorvastatin, simvastatin, low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol
Received 27 March 2015; accepted 13 July 2015

AstraZeneca, Molndal, Sweden

Department of Molecular and Clinical Medicine, Sahlgrenska Academy,
University of Gothenburg, Sweden
3
School of Healthcare Science, Manchester Metropolitan University, UK
4
South Australian Health and Medical Research Institute, University of
Adelaide, Australia
5
Danderyd Hospital, Karolinska Institute, Sweden
6
University of New South Wales, Australia
2

Introduction
There is a well-documented linear relationship between
reductions in low-density lipoprotein cholesterol
(LDL-C) mediated by statin therapy and reductions
in the risk of major cardiovascular events.13 There
is increasing recognition that reductions in nonhigh-density lipoprotein cholesterol (non-HDL-C)
may be even better than LDL-C as a predictor of benet.46 Increasingly, guidelines recommend non-HDL-C
as an additional therapeutic target to reduce cardiovascular risk.5,7,8

Corresponding author:
Bjorn W Karlson, AstraZeneca R&D Molndal, Pepparedsleden 1,
Molndal, SE-431 83, and Department of Molecular and Clinical Medicine,
Institute of Medicine, Sahlgrenska Academy, University of Gothenburg,
SE-413 45, Gothenburg, Sweden.
Email: Bjorn.W.Karlson@astrazeneca.com

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Karlson et al.

745

Each doubling of statin dose has been shown to

result in an approximately 56% greater reduction in
LDL-C,9 and as statin doses increase, a greater percentage of high-risk patients achieve recommended LDL-C
goals,10 as dened by the 2011 European Society of
Cardiology/European Atherosclerosis Society guidelines.5 However, it is well established that equal doses
of dierent statins are not equipotent in their ability to
reduce atherogenic lipids. Studies have demonstrated
that a greater percentage of patients achieve lipid
goals with each dose of rosuvastatin 1040 mg than
with equal or higher doses of atorvastatin or simvastatin.10,11 Additionally, in a study conducted in patients
with hypercholesterolaemia, switching statin therapy
from atorvastatin or simvastatin to equal or lower
doses of rosuvastatin was shown to result in signicantly greater reductions in LDL-C:HDL-C and nonHDL-C:HDL-C ratios.12 This makes obvious the
importance of choosing the optimal dose and potency
of statin therapy to achieve the greatest reduction in
atherogenic lipoprotein levels, and therefore the greatest reduction in cardiovascular risk, while limiting the
risk of dose-dependent adverse eects associated with
statin therapy.
The aim of the present analysis was to use data
from the VOYAGER (an indiVidual patient data
meta-analysis Of statin therapY in At risk Groups:
Eects of Rosuvastatin, atorvastatin and simvastatin)
database to determine the doses of rosuvastatin, atorvastatin and simvastatin that induce an equal eect on
LDL-C and non-HDL-C.

Methods
Study design
Data were obtained from VOYAGER, an individual
patient data meta-analysis composed of 32,258 patients
from 37 randomised clinical studies that compared the
eects on plasma lipid levels of rosuvastatin, atorvastatin and simvastatin. The overall patient population
included in the meta-analysis and the methods used
have been reported previously.9 In this analysis, a
total of 38,052 patient exposures to daily treatment
with rosuvastatin 5, 10, 20 and 40 mg, atorvastatin 10,
20, 40 and 80 mg, and simvastatin 10, 20, 40 and 80 mg
were used. As 11 studies included in the analysis
involved forced titration to higher statin doses, a
number of patients were exposed to more than one
statin dose.

Statistical analyses
In the overall VOYAGER individual patient data
meta-analysis, the percentage change for each lipid

variable was calculated from baseline to the end of

each xed-dose study period. Changes in lipid levels
were compared using a single mixed-eects model
that used xed eects for statin doses and a random
eect for trial. Results are expressed as least squares
(LS) mean  standard error of mean (SEM). For the
present analysis, the LS mean percentage change from
baseline in LDL-C and non-HDL-C was calculated,
and equipotent doses were estimated by linear interpolation between actual adjacent doses.

Results
Baseline demographic data have been published previously.9 In brief, patients had a mean (standard deviation (SD)) age of 60.0 (11.1) years; 56.7% were men
and 79.9% were white. The overall mean (SD) baseline
LDL-C level was 170.9 (38.7) mg/dl (4.4 (1.0) mmol/l),
and the mean (SD) baseline non-HDL-C level was
205.2 (41.8) mg/dl (5.3 (1.1) mmol/l).

Low-density lipoprotein cholesterol

Each doubling of statin dose resulted in an additional
56% reduction in LDL-C for each statin.
Rosuvastatin at a daily dose of 5 mg reduced LDL-C
from baseline by a LS mean (SEM) of 38.8% (0.9%).
Similar reductions in LDL-C required an estimated
15 mg of atorvastatin and 39 mg of simvastatin
(Figure 1). Rosuvastatin at a daily dose of 10 mg
reduced LDL-C from baseline by a LS mean (SEM)
of 44.1% (0.6%). Similar reductions required an estimated 29 mg of atorvastatin and 72 mg of simvastatin
(Figure 1). Rosuvastatin at a daily dose of 20 mg
reduced LDL-C from baseline by a LS mean (SEM)
of 49.5% (0.5%). A comparable reduction required
an estimated 70 mg of atorvastatin (Figure 1) and
was not achieved with the maximum 80 mg dose of
simvastatin, which reduced LDL-C by a LS mean
(SEM) of 45.0% (1.0%). Rosuvastatin at a daily dose
of 40 mg reduced LDL-C by a LS mean (SEM) of
54.7% (0.4%), which was greater than that achieved
with the maximum licensed doses of either atorvastatin
(80 mg), which reduced LDL-C by a LS mean (SEM) of
50.2% (0.4%), or simvastatin (80 mg) (Figure 1).

Non-high-density lipoprotein cholesterol

Each doubling of statin dose resulted in an additional
46% reduction in non-HDL-C for each statin.
Rosuvastatin at a daily dose of 5 mg reduced nonHDL-C from baseline by a LS mean (SEM) of 35.4%
(0.8%). Similar reductions required an estimated 14 mg
of atorvastatin and 42 mg of simvastatin (Figure 2).
Rosuvastatin at a daily dose of 10 mg reduced

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746

European Journal of Preventive Cardiology 23(7)

LS mean % change in LDL-C

Rosuvastatin
Atorvastatin
Simvastatin

10
20
30
40
50
60
5

10

20

40

80

2981
1324
542

2070
478

Statin dose (mg)

Discussion

Patients numbers
Rosuvastatin
Atorvastatin
Simvastatin

668

11650
7804
165

3551
3896
2923

LS mean % change in non-HDL-C

Figure 1. Least squares mean percentage reduction in LDL-C

with licensed doses of rosuvastatin, atorvastatin and simvastatin
and assessment of the doses of atorvastatin and simvastatin
providing equal effects to rosuvastatin 5, 10 and 20 mg.
LS: least squares; LDL-C: low-density lipoprotein cholesterol.

Rosuvastatin
Atorvastatin
Simvastatin

10
20
30
40
50
60
5

10

20

40

80

2983
1324
548

2072
479

Statin dose (mg)

Patients numbers
Rosuvastatin
Atorvastatin
Simvastatin

670

11674
7837
165

3554
3908
2917

A comparable reduction required an estimated 62 mg

of atorvastatin and was not achieved with the
maximum licensed dose of simvastatin (Figure 2),
which reduced non-HDL-C by a LS mean (SEM)
of 40.5% (0.9%). Rosuvastatin at a daily dose of
40 mg reduced non-HDL-C by a LS mean (SEM)
of 49.9% (0.3%), which was greater than that achieved
with the maximum licensed doses of atorvastatin
(80 mg), which reduced non-HDL-C by a LS mean
(SEM) of 46.6% (0.4%), or simvastatin (80 mg)
(Figure 2).

Figure 2. Least squares mean percentage reduction in nonHDL-C with licensed doses of rosuvastatin, atorvastatin and
simvastatin and assessment of the doses of atorvastatin and
simvastatin providing equal effects to rosuvastatin 5, 10 and
20 mg.
LS: least squares; non-HDL-C: non-high-density lipoprotein
cholesterol.

non-HDL-C from baseline by a LS mean (SEM) of

40.2% (0.5%). Similar reductions required an estimated
27 mg of atorvastatin and 77 mg of simvastatin (Figure 2).
Rosuvastatin at a daily dose of 20 mg reduced
non-HDL-C by a LS mean (SEM) of 45.1% (0.4%).

The VOYAGER database, comprising 32,258 patients

randomly assigned to treatment with xed doses of
rosuvastatin, atorvastatin and simvastatin, provides a
unique opportunity to determine the doses of the three
agents that are required to achieve equivalent reductions in LDL-C and non-HDL-C.
The current analysis shows that for any given milligram dose, rosuvastatin achieved reductions in LDL-C
approximately 33.5 times greater than those achieved
with atorvastatin and 7 times greater than those
achieved with simvastatin. It is of interest to note that
the recent American College of Cardiology/American
Heart Association 2013 lipid guideline identies both
rosuvastatin 20 mg and atorvastatin 40 mg as highintensity statin therapies with an anticipated ability to
lower LDL-C by 50%.13 The current analysis suggests
that while a 20 mg dose of rosuvastatin reduces LDL-C
by a LS mean of 49.5%, achievement of a comparable
reduction in LDL-C with atorvastatin requires a daily
dose of approximately 70 mg.
We also investigated the doses of rosuvastatin, atorvastatin and simvastatin required to achieve equivalent
reductions in the level of non-HDL-C. Overall, the
results mirrored those observed for the reductions in
LDL-C: each dose of rosuvastatin was the equivalent
of an approximately 3 times higher milligram dose of
atorvastatin and of an approximately 8 times higher
milligram dose of simvastatin.
These results clearly show that statins are not
equipotent in their ability to lower LDL-C and nonHDL-C and this should be taken in to account when
considering treatment options. The US Food and Drug
Administration recommends that statins should be prescribed at the lowest dose that achieves the goals of
therapy so as to avoid certain dose-dependent adverse
events.14
The value of including non-HDL-C in this analysis is
related to the fact that the non-HDL lipoproteins
include the sum of all atherogenic lipoproteins in
plasma. The concentration of non-HDL-C has been
found in several analyses to be a robust and

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Karlson et al.

747

independent predictor of coronary heart disease4,15

with a predictive power greater than that of LDL-C.
Non-HDL-C levels are thought to provide a more
accurate reection of atherogenicity, especially in certain patient groups, such as those with diabetic dyslipidaemia or metabolic syndrome in whom there is
frequently an elevated concentration of triglyceriderich lipoproteins and their atherogenic remnants.8
Indeed, a number of guidelines now recommend
non-HDL-C as a primary or alternative treatment
target.5,7,8,16
In conclusion, these results highlight the fact that
the reductions in levels of LDL-C and non-HDL-C
achieved by treatment with statins are dependent on
both the choice and dose of statin administered. This
information should help guide clinicians in their decisions about the best agent to be used to lower the levels
of atherogenic lipoproteins in individual patients to
reduce the risk of a cardiovascular event.

5.

6.

7.

8.

9.

Declaration of conflicting interests

The author(s) declared the following potential conicts of
interest with respect to the research, authorship, and/or publication of this article: BW Karlson is an employee of
AstraZeneca; M Palmer has received fees for statistical analysis from AstraZeneca; SJ Nicholls has received research support from AstraZeneca; P Lundman has received speaker fees
from AstraZeneca; and PJ Barter has received research support and speaker fees from AstraZeneca.

10.

11.

12.

Funding
The author(s) disclosed receipt of the following nancial support for the research, authorship, and/or publication of this
article: This study was supported by AstraZeneca. Editorial
support was provided by Alex Mellors, Prime Medica,
Knutsford, Cheshire, UK, funded by AstraZeneca.

13.

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