Research Article

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A clinically significant interaction between warfarin

and simvastatin is unique to carriers of the
CYP2C9*3 allele
Background: Simvastatin interacts with warfarin, but the strength of the interaction varies between
individual patients, indicating a genetic predisposition. Patients & methods: The influence of the CYP2C9*2
and CYP2C9*3 polymorphisms on the interaction between simvastatin and warfarin was analyzed in data
from 1132 patients. Results: Simvastatin use reduced warfarin dose requirements by 29% in carriers of
the CYP2C9*3 allele, compared with 5% in noncarriers. A regression model showed a significant influence
of CYP2C9*3 on the drug–drug interaction, predicting a warfarin dose reduction of 25% in CYP2C9*3
heterozygotes and 43% in CYP2C9*3 homozygotes. Conclusion: Our data indicate that the CYP2C9*3
polymorphism predisposes for a pharmacologic interaction between warfarin and simvastatin.
Original submitted 5 January 2012; Revision submitted 15 February 2012

KEYWORDS: CYP n drug interactions n genetic polymorphism n simvastatin n warfarin
Warfarin is the world-leading oral anti­coagulant
used for the treatment and prevention of throm-
boembolic disease. It has a narrow therapeutic
interval with an exponential increase in the
frequency of hemorrhagic complications as the
anticoagulant effect reaches supratherapeutic
levels. Hence, it is not surprising that the use of
drugs interacting pharmacologically with war-
farin has been identified as an independent risk
factor for severe bleeding [1] .
The S-enantiomer of racemic warfarin is
a much more potent anticoagulant than the
R-enantiomer [2,3] . S-warfarin is almost exclu-
sively metabolized and inactivated by the
hepatic CYP2C9 enzyme, and polymorphisms
in the CYP2C9 gene have a major impact on
individual dose requirements [4] . R-warfarin,
metabolized by CYP1A2, CYP2C19 and
CYP3A4, only makes a limited contribution to
the overall warfarin effect and CYP2C9 enzyme
inhibition is likely to be the most common
mechanism involved in warfarin drug–drug
interactions [2] .
Simvastatin is commonly used to treat hyper-
lipidemia and for prevention of cardiovascular
events [5] . The combined use of simvastatin
and warfarin is not uncommon. Data from
the Prescribed Drug Register in Sweden, with
a population of around 9 million people, indi-
cate that almost 40,000 patients used warfarin
together with simvastatin during a 4-month-
period in 2010 [Holm J, Eliasson E, Eiermann B,
Sjöborg B, Mannheimer B, Unpublished Data] . It has
been found that concomitant use of simvastatin
Marine L Andersson*,
Erik Eliasson
and warfarin slightly increases the risk for & Jonatan D Lindh
Karolinska Institutet, Department of
gastro­i ntestinal bleeding [6] . Several studies Laboratory Medicine, Division of
have addressed the issue of an apparent inter- Clinical Pharmacology, Karolinska
action between simvastatin and warfarin [7–10] . University Hospital Huddinge,
SE 141 86, Stockholm, Sweden
In summary, the anticoagulant effect of warfa- *Author for correspondence:
rin, as measured by international normalized Tel.: +46 8 585 810 64
Fax: +46 8 585 810 70
ratio (INR), was 8–27% higher in simvastatin- marine.andersson@karolinska.se
treated patients and the warfarin maintenance
dose was unchanged and down to 18% lower in
patients cotreated with simvastatin.
An underlying mechanism for this drug–drug
interaction has not yet been resolved. Indeed,
there is controversy in the literature whether
simvastatin and/or its active acid form may
inhibit CYP2C9 or CYP3A4-dependent war-
farin metabolism [11–14] . In addition, there are
indications that the interaction is more pro-
nounced in some patients [15,101] and may not
even be detectable in others [8] . Considering that
the CYP2C9 polymorphism involves the expres-
sion of CYP2C9 enzyme variants that differ in
catalytic activity, we wished to explore whether
susceptibility to simvastatin-induced increase in
INR during warfarin treatment was related to
CYP2C9 genotype.
Patients & methods
„„ Study population
Study data was obtained from the WARG
study, a prospective cohort study of risk fac-
tors for adverse outcomes in warfarin-treated
patients [16] . Between 2001 and 2005, 1523
Swedish first-time users of warfarin were
included in the WARG cohort, and clinical part of

10.2217/PGS.12.40 © 2012 Future Medicine Ltd Pharmacogenomics (2012) 13(7), 757–762 ISSN 1462-2416 757
Research Article Andersson, Eliasson & Lindh
parameters were recorded from the onset of
therapy. Warfarin doses and concomitant use
of other drugs were recorded separately for each
treatment day, but patients’ compliance was not
studied. In addition, patients were genotyped
for polymorphisms of potential importance for
the warfarin effect, including CYP2C9*2 and
CYP2C9*3.
To be included in the current study, patients
had to meet the following criteria:
ƒƒReceived warfarin for at least 28 days;
ƒƒ
Not using drugs known to alter INR through
pharmacokinetic or pharmacodynamic inter-
actions with warfarin [101] , apart from
simvastatin;
ƒƒ
Successfully genotyped for CYP2C9;
ƒƒPatients cotreated with simvastatin and war-
farin should have received the drugs
concomitantly for at least 28 days.
The study was approved by the Regional
Ethics Committee at Karolinska Institutet,
Stockholm (Registration Number: 00-449).
Written informed consent was obtained in
accordance with the Declaration of Helsinki.
„„ Statistical analyses
In the main analysis, warfarin doses were com-
pared between patients cotreated with warfarin
and simvastatin and patients receiving warfarin
without simvastatin (controls). In simvastatin-
exposed patients, the median weekly war-
farin dose was calculated using data from a
90-day period starting on day 15 of cotreat-
ment. Ninety days was set as the cut-off since
the compliance to statin therapy is known to
decrease relatively rapidly over time, and pre-
vious research has shown that approximately
one-third of the patients stop taking simvastatin
regularly within 6 months from the first pre-
scription [17] . In patients where the simvastatin
treatment lasted for less than 104 days, warfarin
doses were censored from the day of statin with-
drawal and onwards. Owing to the inclusion
criteria of at least 28  days on statin therapy,
all patients contributed with data from at least
14 days of concomitant treatment.
For each patient in the control group the
median weekly warfarin dose was calculated
from day 15 of treatment up to a maximum
of 90 days. The first 14 days of treatment were
excluded since many patients never reach steady
state during this time and since warfarin is usu-
ally given in higher loading doses during the first
days of treatment.
758 Pharmacogenomics (2012) 13(7)
To comply with the assumption of nor-
mal distribution, all warfarin doses were
log-transformed prior to the statistical analyses.
The effect of the CYP2C9 genotype on the
association between simvastatin exposure and
warfarin dose was investigated in a multi­
variable regression model, adjusting for age,
gender and for the main effects of simvastatin
use and CYP2C9 genotype. Independent fac-
tors entered into this model were age, gender
(coded as 0 or 1), simvastatin use (0 or 1), num-
ber of CYP2C9*2 alleles (0, 1 or 2), number
of CYP2C9*3 alleles and two interaction terms,
simvastatin × number of CYP2C9*2 alleles and
simvastatin × CYP2C9*3 alleles. In this model,
a significant interaction term indicates that the
percentage reduction in warfarin dose associ-
ated with simvastatin use is dependent on the
CYP2C9 allele included in the interaction term.
In a secondary analysis, log-transformed
warfarin doses were compared between users
and nonusers of simvastatin by Student’s t-test,
without adjustment for differences in age, gender
and CYP2C9 genotype distributions. Similarly,
subgroup analyses were performed to compare
the effect within different genotype groups.
All statistical analyses were performed
using R version 2.10.1 [102] , and p-values
<0.05 (two-sided) were considered statistically
significant.
Results
In total, 1132 of the 1523 patients in the
WARG study met the inclusion criteria. Among
these, 143 patients were included in the simv-
astatin group and 989 in the control group.
Characteristics of the included patients are pre-
sented in Table 1. There were no significant differ-
ences in CYP2C9 allele frequencies between the
two groups and the genotypes were in Hardy–
Weinberg equilibrium. Notably, the groups
differed significantly regarding age and gender
distribution.
Overall, simvastatin treatment was associated
with 8.0% lower warfarin dose requirements
(95% CI: -14.1 to -0.1; p = 0.045). The results
from the multivariate regression are presented
in Table 2 . As expected, age, gender, number of
CYP2C9*2 alleles and number of CYP2C9*3
alleles were all found to be significantly asso-
ciated with warfarin dose requirements. In
addition, there was a significant (p  <  0.001)
interaction between use of simvastatin and the
number of CYP2C9*3 alleles, indicating that
the CYP2C9 genotype had a direct influence
on the magnitude of the warfarin–simvastatin
future science group
 CYP2C9*3 allele & a clinically significant warfarin–simvastatin interaction Research Article
drug–drug interaction. According to the mul- Table 1. Characteristics of the study population.
tivariable model, simvastatin exposure would
Parameter Simvastatin Controls
have no effect on the warfarin dose in noncar-
riers of the CYP2C9*3 allele, while reducing the Patients 143 989
warfarin dose by 25% in heterozygous carriers Median age (IQR) 70.08 (63.61–74.11) 64.87 (55.94–74.25)
of the CYP2C9*3 allele, and by 43% in patients Sex female/male (%) 39/104 (27/73) 356/633 (36/64)
homozygous for CYP2C9*3. By contrast, there
*1/*1 (%) 100 (69.9) 644 (65.1)
was no influence of the CYP2C9*2 allelic vari-
ant on the interaction between simvastatin and *1/*2 (%) 21 (14.7) 190 (19.2)
warfarin dose (p = 0.62). *1/*3 (%) 14 (9.8) 124 (12.5)
In the unadjusted subgroup analyses (Figure 1) , *2/*2 (%) 5 (3.5) 12 (1.2)
simvastatin had no significant effect on the war-
farin dose requirements in patients lacking the *2/*3 (%) 1 (0.7) 15 (1.5)
CYP2C9*3 allele (-4.8%, 95% CI: -11.67–2.60). *3/*3 (%) 2 (1.4) 4 (0.4)
Patients with the CYP2C9*1/*3 genotype had IQR: Interquartile range.
significantly lower warfarin doses (-21.4%, 95%
CI: -36.29 to -2.91) if treated with simvastatin, substrates is affected to different extents by the
compared to patients with the same genotype CYP2C9*3 polymorphism. For example, there
but not taking simvastatin. Among patients with is no apparent change in the clearance of diclof-
the CYP2C9*3/*3 genotype the warfarin dose enac [20] , whereas the clearance of (S)-warfarin
was 37.6% (95% CI: -66.7–16.4) lower in those is reduced by 48% in patients genotyped as
receiving simvastatin, although the difference CYP2C9*1/*3 [21] . In  vitro data have shown
was not statistically significant (p = 0.104). that specific inhibitors of CYP2C9 may differ
in K i values between the CYP2C9*1- and the
Discussion CYP2C9*3-encoded enzymes [22] . There is also
In this study, we investigated the potential influ- human in vivo data suggesting that the CYP2C9
ence of CYP2C9 genotype on the interaction inhibitor fluconazole could lack inhibitory effect
between warfarin and simvastatin, and found in patients expressing the CYP2C9*3 variant [23] .
that the magnitude of the interaction was sig- Simvastatin is a lactone prodrug that rap-
nificantly larger among subjects carrying the idly hydrolyses in vivo to its active form, sim-
CYP2C9*3 allele. vastatin acid [24] . According to in vitro experi-
The specific SNP that defines the CYP2C9*3 ments, it appears that simvastatin acid does not
allele variant leads to an amino acid replacement inhibit the CYP2C9.1 enzyme, or other com-
(isoleucine to leucine) in position 359 of the cor- mon drug-metabolizing CYPs [12] . However,
responding enzyme [18] . This position is located it is still unclear whether simvastatin acid (or
in the active site in what appears to be part of simvastatin lactone) has a different affinity
the substrate-binding region [19] . Warfarin has a and inhibitory effect on CYP2C9.3. We sug-
much lower affinity for the CYP2C9*3-encoded gest that the genotype-­dependent interaction
enzyme variant, compared to both the CYP2C9*1 between warfarin and simvastatin seen in our
and CYP2C9*2. In  vivo studies have revealed study actually may indicate that simvastatin
that the pharmacokinetics of different CYP2C9 lactone or simvastatin acid specifically inhibits

Table 2. Results of multiple regression.

Predictor b Effect on warfarin dose p-value
Age -0.012 (-0.013 to -0.010) -1.2% (-1.33 to -1.03) <0.0001
Male sex 0.103 (0.059–0.146) 10.8% (6.08–15.72) <0.0001
Simvastatin 0.018 (-0.056–0.092) 1.8% (-9.64–5.41) ns
CYP2C9*2 alleles (n) -0.203 (-0.252 to -0.153) -18.3% (-22.28 to -14.19) <0.0001
CYP2C9*3 alleles (n) -0.384 (-0.445 to -0.323) -31.9% (-35.91 to -27.62) <0.0001
Interaction simvastatin × *2 -0.032 (-0.161 to -0.096) -3.2% (-14.85–10.13) ns
Interaction simvastatin × *3 -0.281 (-0.447 to -0.115) -24.5% (-36.08 to -10.86) 0.0009
Values are presented as mean (95% CI).
b values refer to log-transformed doses and the effect on doses to nontransformed doses.
ns: Nonsignificant. 

future science group www.futuremedicine.com 759

Research Article Andersson, Eliasson & Lindh
120 80
100
60
Warfarin dose (mg/week)
80
60 40
40
20
20
0 0
No statin Statin
CYP2C9*3, n = 0
Figure 1. Observed mean warfarin dose requirements in simvastatin-treated patients
versus nonexposed patients with 0, 1 or 2 CYP2C9*3 alleles.
the CYP2C9*3-encoded variant of the enzyme.
The drug–drug interaction may therefore be
restricted to carriers of the CYP2C9*3 allele,
and homozygous carriers in particular.
One previously proposed mechanism behind
the interaction is inhibition of the metabolism
of (R)-warfarin caused by competitive inhibition
of CYP3A4 by simvastatin [6] . This would cause
an increase in INR and decreased warfarin dose
requirements. However, CYP2C9*3 carriers have
very low levels of (R)-warfarin in plasma [25] . This
is explained by lower doses of warfarin and also
the higher proportion of (S)-warfarin as a result
of slower CYP2C9-dependent metabolism of
this enantiomer. Therefore, contribution of the
(R)-enantiomer to the anticoagulant effect is
likely to be negligible. Hence, it seems unlikely
that even a substantial rise in the (R)-warfarin
levels would cause changes in warfarin dose
requirements as large as those observed in the
current study.
As previously demonstrated, the CYP2C9*2
allele had a significant impact on warfarin dose
requirements, but in contrast to CYP2C9*3 it
had no modulating effect on the drug–drug
interaction between simvastatin and warfarin
(Table 2) [4] . Since the two polymorphisms are
located in different regions of the CYP2C9 gene
and have dissimilar effects on the enzyme kinet-
ics [26] it is comprehensible that the gene–drug
interaction may be restricted to the CYP2C9*3
variant allele.
760 Pharmacogenomics (2012) 13(7)
20
15
10
5
0
No statin Statin No statin Statin
CYP2C9*3, n = 1 CYP2C9*3, n = 2
In addition to CYP2C9, other polymorphic
genes have been associated with altered warfa-
rin dose requirements. For example, it is well-
established that the -1639G>A substitution of the
VKORC1 gene has a large impact on the sensi-
tivity to warfarin, presumably owing to reduced
levels of the drug’s target, vitamin  K epoxide
reductase [27] . Likewise, the V433M variant of
CYP4F2, involved in the metabolism of vitamin
K, has been associated with reduced warfarin
dose requirements and there is limited evidence
that polymorphisms of the APOE, EPHX, GGCX
and CALU genes may modulate the sensitivity to
warfarin [28,29] . Since these genes are not involved
in the disposition of warfarin, the polymorphisms
are not expected to interfere with pharmacoki-
netic drug–drug interactions involving warfarin.
However, the mechanism of the simvastatin–
warfarin interaction has not yet been established
and an influence of polymorphic genes other than
CYP2C9 cannot be excluded.
The design of this study has specific strengths
that consolidate the validity of our findings.
Most importantly, the large number of well-
characterized patients included in the study
enabled the detection of a gene–drug interaction,
which may have passed unnoticed in a smaller
setting owing to the relatively low frequency of
variant CYP2C9 alleles. In addition, all study
data were collected from the onset of warfarin
therapy by investigators unaware of the patient
CYP2C9 genotypes, reducing the risk of bias.
future science group
 CYP2C9*3 allele & a clinically significant warfarin–simvastatin interaction
Although the modulating effect of the
CYP2C9*3 allele on the drug–drug interaction
between simvastatin and warfarin was highly
statistically significant and mechanistically
plausible, the finding should be interpreted
with caution until reproduced in independent
patient cohorts. Also, the proposed mechanism
of allele-specific enzyme inhibition is a hypo­
thesis that remains to be proven, for example, by
determination of simvastatin K i for the different
CYP2C9 enzyme variants in vitro.
Conclusion
Our study shows that the influence of simvastatin
use on warfarin dose requirements differs signifi-
cantly between patients with different CYP2C9
genotypes, and we propose that this may be due
to allele-specific enzyme inhibition by simvas-
tatin and/or simvastatin acid. Potentially, our
findings offer an explanation for the inconsistent
reports of the warfarin–simvastatin interaction
found in the published literature and they are
an impetus for further research on the genetic
aspects of drug–drug interactions.
Research Article
enzymes are involved in the metabolism of the
new drug candidate. Similar attention will also
be directed towards obvious co-medication can-
didates; whether or not there is any foreseeable
risk that these drugs may interfere with regards
to metabolism and elimination. The present
work highlights the future need to consider
pharmacogenetic factors that may influence on
the individual susceptibility to critical drug–drug
interactions. For new drugs, it is believed that
this will become an important step in both pre-
authorization identification and postmarketing
surveillance of vulnerable patient subpopulations.
Financial & competing interests disclosure
This study was supported by grants from Karolinska Institutet
and the Stockholm County Council. JD Lindh has previously
received a consultant fee from Nycomed AB. The authors have
no other relevant affiliations or financial involvement with
any organization or entity with a financial interest in or
financial conflict with the subject matter or materials discussed
in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of
this manuscript.

Future perspective Ethical conduct of research

It is well established that polypharmacy is com-
mon in elderly patients, and that the frequency of
clinically significant drug–drug interactions will
increase in an aging patient population. In the
process of drug development, it is important to
understand at an early stage whether polymorphic
The authors state that they have obtained appropriate insti­
tutional review board approval or have followed the princi­
ples outlined in the Declaration of Helsinki for all human
or animal experimental investigations. In addition, for
investi­gations involving human subjects, informed consent
has been obtained from the participants involved.

Executive summary
Background
ƒƒ Simvastatin interacts with warfarin, but the strength of the interaction varies between individual patients, indicating a genetic
predisposition.
Patients & methods
ƒƒ The influence of CYP2C9 genotype on the magnitude of the interaction between simvastatin and warfarin was investigated in a
multivariable regression model using data from 1132 genotyped patients.
Results
ƒƒ Simvastatin reduced warfarin dose requirements significantly more in carriers of CYP2C9*3 compared to noncarriers.
ƒƒ After adjustment for age and sex, simvastatin reduced warfarin dose requirements by 25% in heterozygous carriers of CYP2C9*3 and
by 43% in homozygous carriers.
ƒƒ The CYP2C9*2 polymorphism had no influence on the interaction between simvastatin and warfarin.
Conclusion
ƒƒ Our data indicate that the CYP2C9*3 polymorphism predisposes for a pharmacologic interaction between warfarin and simvastatin.

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