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CYP2C9 genetic polymorphism is a potential predictive marker for the efficacy of
rosuvastatin therapy
Jiayao Lin1 MD, Yu Zhang1,＊MD, Houguang Zhou1 MD,PhD, Xinqing Wang1 MD, Wenwen
Wang1 MD
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Department of Geriatrics, Huashan Hospital, Fudan University. Shanghai 200040, China.
Short title: CYP2C9 polymorphism and the efficacy of rosuvastatin
*
Corresponding author:
Yu Zhang, MD,
Department of Geriatrics, Huashan Hospital, Fudan University, 12 Middle Wulumuqi Rd,
Shanghai 200040, China.
Phone: 8621-52889999,
Fax: 8621-6248919,
Email: [email protected]
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Abstract:
Aims This study aimed to evaluate the associations of CYP2C9 genetic polymorphism with
the efficacy and safety of rosuvastatin in Chinese patients with hyperlipidemia.
Methods: A total of 218 patients with hyperlipidemia were selected and treated with 10 mg
rosuvastatin per day for 12 weeks. Blood samples were collected prior to the treatment, and
after 4, 8 and 12 weeks of treatment. Genotyping for CYP2C9 polymorphisms was performed
using allele-specific real-time PCR.
Results: 197 out of 218 patients featured a wild-type CYP2C9*1/*1 genotype, and 21 patients
featured a CYP2C9*3 mutation genotype. No patients with CYP2C9*2 alleles were identified.
16 patients discontinued the medication due to adverse effects. After the 12 weeks of
treatment, we observed significant reductions in total cholesterol (TC), triglycerides and
low-density lipoprotein (LDL) levels compared to baseline (P < 0.05). Patients with the
mutant genotype showed a higher TC-lowering and LDL-lowing effect compared to those
with wild-type genotypes (TC: 45.05% vs. 38.96%, P=0.041; LDL: 44.97% vs. 39.28%,
P=0.029). The frequency of adverse reactions in the studied patients did not differ by
CYP2C9 genotypes (P > 0.05).
Conclusions: This study suggests that the CYP2C9 polymorphism may be involved in the
lipid-lowering efficacy of rosuvastatin in patients with hyperlipidemia.
Key words: CYP2C9, polymorphism, rosuvastatin, hyperlipidemia, efficacy, tolerability
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Introduction
Statins are the most common drugs for the treatment of hyperlipidemia. Statins reduce the
plasma level of total cholesterol （ TC ） , and can prevent atherosclerosis and other
cardiovascular diseases by inhibiting the intracellular production of cholesterol and
upregulating the expression of low-density lipoprotein (LDL) receptors in liver[1]. Compared
to other statins (e.g. atorvastatin, simvastatin, and pravastatin), rosuvastatin delivers the
greatest reduction in LDL cholesterol, and more than 80% of patients can reach their LDL
cholesterol goal on the typical 10 mg dose of rosuvastatin[2].
However, there is well-known inter-individual variability in cholesterol-lowering during
therapy with statins. In a large clinic trial, patients treated with simvastatin, 80 mg daily after
6 months of treatment, had a mean reduction rate of 46% in LDL.The top 5% of responders
had a reduction ranged from 63-76%, whereas the bottom 5% responders with a reduction
rate ranged from 23% to 20%[3]. Similarly, poor or diminishing responses have been
observed in a minority of hyperlipidemia patients treated with lovastatin and rosuvastatin [4].
At present, inter-individual variability in response to rosuvastatin treatment in subjects with
hypercholesterolemia has not been clearly established.
Most statins, except pravastatin, primarily undergo phase I metabolism by the superfamily
cytochrome p450 (CYP) in the liver[5]. The metabolism of rosuvastatin is principally
mediated by the CYP2C9 enzyme, with some involvement of CYP3A4 and CYP2C8[6].
More than 30 single nucleotide polymorphisms (SNP) have been identified in the regulatory
and coding regions of the CYP2C9 gene, and three alleles, CYP2C9 *1, *2 and *3, are present
in most ethnic populations[7]. Using in vitro experiments, the allelic variants, CYP2C9*2 and
CYP2C9*3, code for enzymes with approximately 10–40% and 5–15% of the activity of the
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wild-type form CYP2C9*1, respectively[8]. This polymorphism divides the populations into
two phenotypes: extensive metabolizers (EM) and poor metabolizers (PM), leading to
individual and racial differences in drug metabolism [9].
In this study, we hypothesized that CYP2C9 gene polymorphism may also play an important
role in metabolism of rosuvastatin, thus affecting drug efficacy and safety indirectly.
CYP2C9 EM may not reach therapeutic concentrations at customary doses due to a faster
drug metabolism, leading to therapeutic failure with rosuvastatin. In contrast, PM may show
increased concentrations of metabolized drugs at conventional doses, increasing the risk of
ADRs such as liver and kidney toxicity. In the present study, we recruited 72 Han Chinese
patients with hyperlipidemia to assess the relationships between CYP2C9 polymorphism and
the efficacy and toxicity of rosuvastatin.
Materials and Methods
Study Subjects
We recruited 218 subjects with primary hyperlipidemia and mixed dyslipidemia from the
outpatient clinic of the Huashan Hospital, Fudan University from January 2012 to December
2013. There are two primary eligibility criteria, as follows: (1) TC ≥ 5.18 mmol/L, and (or)
LDL ≥ 3.37 mmol/L treated with a lipid-lowering diet; (2) Without previously using statin
and fibrate drugs together. This study was reviewed and approved by the Fudan University
Institutional Review Board.
Treatment with rosuvastatin and biochemistry testing
All subjects were on a lipid-lowering diet for at least eight weeks prior to entry into the study.
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After an overnight fast, 2 mL blood samples were collected from each patient prior to
rosuvastatin treatment for CYP2C9 genotyping and baseline biochemical examination. Then
all patients were treated with a single lipid-lowering therapy of rosuvastatin (Crestor,
AstraZeneca UK limited) at 10 mg per night for 12 weeks. Blood samples were collected and
all biochemistry tests were conducted at 4 weeks, 8 weeks and 12 weeks treatment. The
biochemistry tests for lipid profiles included TC, triglycerides (TG), high-density lipoprotein
(HDL), LDL, alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine
phosphokinase (CPK) and serum creatinine (Scr), and were performed using the HITACHI
7600-020 automatic biochemistry analyzer in the Chemical Pathology laboratory of Huashan
Hospital, Fudan University. Efficacy evaluations were as follows: (1) The changes of plasma
TC and LDL after treatment; and (2) The proportion of patients who achieved treatment
targets (e.g. LDL < 2.59 mmol/L, according to the National Cholesterol Education Program
(NCEP) Adult Treatment Panel (ATP) III guidelines) [10].
CYP2C9 genotyping
Genomic DNA was isolated from whole peripheral blood samples by Tiangen RelaxGene
Blood Kit (Tiangen Inc, Beijing, China). Genotyping for polymorphisms of CYP2C9 was
performed by a PCR based restriction fragment length polymorphism (RFLP) approach using
an AB7500 Real-time PCR (Applied Biosystems, Foster City, CA) as previously described
[11].
Statistical analysis
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Statistical analysis was conducted using the package SPSS 17.0 (SPSS Inc, Chicago, IL, USA)
for Windows, and a two tailed p-value less than 0.05 was considered statistically significant.
Each polymorphism was tested for deviation from Hardy-Weinberg equilibrium by
comparing the observed and expected genotype frequencies using the ᵡ2 test with one degree
of freedom. Quantitative data were presented as mean ± standard deviation (SD).
Non-numeric data were presented as frequency. The effects of the rosuvastatin on the
concentration of lipid profiles were assessed by one-way analysis of variance (ANOVA) with
post hoc Bonferroni correction for multiple comparisons. In order to evaluate genetic
polymorphisms and lipid lowering response to rosuvastatin, independent samples t-test was
performed. Associations between serum lipid profile, adverse drug reactions, gender, baseline
characteristics of the patients and CYP2C9 polymorphisms were evaluated using Fisher’s
exact test of probabilities.
Results
Characteristics of study participants
A total of 218 patients who met the selection criteria were included in this study. The median
age was 58.2 years (range, 36-82 years). The patients consisted of 142 men (65.1%) and 76
women (34.9%). There were 114 (52.3%) patients with hypertension, 61 (28.0%) patients
with coronary heart disease, 83 (38.1%) patients with type 2 diabetes, 47 (21.6%) patients
with hyperuricemia and gout, and 94 (43.1%) patients with fatty liver. 122 of 218 patients
(46.0%) had a history of smoking.
Frequency distributions of CYP2C9 genotypes
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All 218 patients could be genotyped unambiguously for the most common CYP2C9 alleles of
CYP2C9*1, CYP2C9*2, and CYP2C9*3. Of the 218 patients, 197 (127 male and 70 female)
had a wild-type CYP2C9*1/*1 genotype, whereas 21 (9.6%) had at least one mutated
CYP2C9*3 allele. There were 18 (8.3%) subjects (13 male and 5 female) with the
heterozygous CYP2C9*1/*3 genotype. and 3 (1.3%) subjects (2 male and 1 female) with the
homozygous CYP2C9*3/*3 genotype. However, The CYP2C9*2 mutated allele was not
observed in the studied subjects. All the genotype distributions were in Hardy-Weinberg
equilibrium (P > 0.05). No statistical differences in the distribution of genotypes and
phenotype were ascertained by gender (P > 0.05) (Table 1).
Association between CYP2C9 genotypes and characteristics of patients
We classified 218 patients into two groups based on CYP2C9 mutant allele (*3). Among
them, 197 patients featured the wild-type genotype (CYP2C9*1/*1), and 21 patients carried at
least one mutant genotype (CYP2C9*3/*3 or *1/ *3). There was no significant difference in
baseline lipid profiles (ALT, Scr, CPK, LDL and TC) among wild-type and mutant genotypes.
No significant differences were observed in sex, BMI, Comorbidity diseases such as
hypertension，hypertension, fatty liver, hyperuricemia, smoking status，and baseline hepatic
and renal function between wild-type groups and mutant genotypes groups.
Intolerability and Efficacy of rosuvastatin therapy for patients with hypercholesterolemia
Of 218 patients, 202 patients were treated with rosuvastatin (10 mg per day) for 12 weeks.
other sixteen patients (10 male, 6 female) did not complete the study due to elevated
transaminases, elevated CPK or irresistible gastrointestinal disorders. Nine of them left the
study at 4 weeks, six patients quit between 5-8 weeks, and one patient quit between 9-12
weeks (Table 2). The median duration of their treatment was 34 days (range, 4-84 days). The
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frequency of adverse reactions is 7.34%.
The common ADRs included gastrointestinal reactions (three patients had abdominal
distension and one patient had constipation). There are seven patients with abnormal liver
function with no clinical symptoms during follow-up. There were five patients with elevated
CPK, but lacking muscular soreness symptoms. After discontinuation and symptomatic
treatment, the gastrointestinal reactions and elevated transaminases and CPK values returned
to normal within one week in six patients and within two weeks in the other ten patients. No
serious adverse events such as myopathy/muscle dissolution or drug-induced liver injury
were observed in this clinical trial.
Before treatment, the TC,TG, LDL and HDL level of 202 patients complete 12 weeks of
treatment were 6.79±0.95 mmol/L, 3.32±1.31 mmol/L, 3.98±0.69 mmol/L and 1.17±0.25
mmol/L respectively. After the 4-weeks treatment, the levels of TC, TG, and LDL were
significantly decreased, and HDL was significantly increased compared with their baseline
levels (p < 0.05) (Table 3). The serum TC and LDL concentrations decreased by 27.37% and
22.93%, respectively, compared with the baseline levels. The target lipid levels, defined
according to the NCEP ATP III guidelines, were achieved in 30.69% (62 cases) of patients in
this study. After the 8-week treatment, serum TC and LDL concentrations decreased by
35.32% and 33.17%, respectively, compared to baseline levels (p < 0.01), and the target
levels were achieved in 56.93% (115 case) of patients. Following the 12-week treatment,
serum TC and LDL concentrations reduced by 39.16% and 41.49%, respectively, compared
to baseline levels (p < 0.01), and the target levels were achieved in 75.74% (153 cases) of
patients (Table 3).
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The relationship between CYP2C9 genotype and lipid-lowering efficacy and Intolerability of
the rosuvastatin
After the 12-week treatment, the reduction of the serum TC levels was 2.70 ± 0.31 mmol/L
(38.96%) and 3.14 ± 0.25 mmol/L (45.05%) in patients with the CYP2C9 wild-type and
mutant genotype, respectively, and the difference on the reduction of TC between the two
groups reached statistical significance (P = 0.041). The reduction of the serum LDL levels
after the 12-week treatment was 1.52 ± 0.38 mmol/L (39.28%) and 1.79 ± 0.32 mmol/L
(44.97%) in patients with the CYP2C9 wild-type and mutant genotype, respectively. The
reduction of LDL between the two groups are also significantly different (P = 0.029).
Furthermore, we compared the proportion of patients who achieved ATP III guidelines
targets (LDL < 2.59 mmol/L). No significant difference on the compliance rate of LDL was
observed between wild-type genotype and mutant genotype patients [74.59% (138/185) vs.
88.23% (15/17), P = 0.337] (Table 4).
Regarding the intolerability evaluations, sixteen of 218 (7.34%) patients terminated their
involvement in the study due to ADRs. Among these 16 patients, 12 patients are CYP2C9
wild-type and 4 patients with CYP2C9*3. The adverse reaction rate of mutant genotype
patients was higher than that of wild genotype patients (19.05% vs. 6.09%). However，No
significant difference on the frequency of adverse reactions was observed among wild
genotype and mutant genotype patients (P = 0.085; Table 4).
Discussion
In this study, rosuvastatin was tolerated by 202 patients at the dosage of 10 mg/d. Only 16
patients discontinued the medication due to adverse effects (7.34%). No patient had
hepatotoxicity and myolysis. We showed that rosuvastatin had a time-dependent effect on
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lipid-lowering response, after 4-week, 8-week and 12-week treatment with rosuvastatin (10
mg/day). There was a significant reduction in TC、TG、LDL levels and increase in HDL-C
levels compared to the baseline after treatment. We also showed that subjects with the
CYP2C9 mutant genotype showed a higher TC-lowering and LDL-lowing effect compared to
those with the wild-type genotype.
There is inter-individual variability in the lipid-lowering efficacy of the rosuvastatin. Some
patients with rosuvastatin at a low dose of 5 mg/d can be in compliance with lipid-lowering
and even occurred adverse reactions, while some subjects with rosuvastatin at a high dose of
20-40mg/d cannot be in compliance with lipid-lowering and thus leading withdrawal and
dressing of the drug ultimately. In this study, we also observed the variation in the
lipid-lowering response. Of the 202 patients completed the treatment, 153 patients (75.74%)
achieved the 2002 ATP III guidelines LDL-C goal, and 24.26% of patients did not achieve
the LDL-C target goal of 100mg/dl, which is needed to increase and adjust dosage.
Individual differences in drug metabolism are primarily due to CYP450 genetic variations [9].
At least thirty CYP2C9 polymorphisms have been reported. CYP2C9*1 was the most
common allele (wild type) followed by the CYP2C9*3 allele (15%), the others alleles are
absent in East Asian populations[12-14]. In our study, CYP2C9 mutation alleles were only
found in 21 of 218 Chinese hyperlipidemia patients, including 18 subjects with the
heterozygotes mutation (CYP2C9*1/*3) and 3 subjects with the homozygote mutation
genotype (CYP2C9*3/*3). No subjects with CYP2C9*2 alleles were identified. The
frequency of mutant alleles and genotypes of this polymorphism was similar to the results
reported previously in a Japanese population [15] and in a Chinese healthy population [16].
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In vitro, the CYP2C9*2 and CYP2C9*3 variants, code for enzymes with approximately
10–40% and 5–15% of the activity of the wild-type CYP2C9*1, respectively [8].The
decreased CYP2C9 activity may cause slow metabolism, and thus, a higher plasma
concentration of rosuvastatin, which increases the risk of ADRs at conventional doses. The
impact of the CYP2C9 polymorphisms on drug metabolism was first investigated and has
been extensively studied in warfarin therapy[17-20].
Currently, a limited number of studies have been conducted to investigate the relation
between CYP2C9 gene polymorphisms and lipid-lowering response to stains. Kirchheiner et
al. [21, 22] reported that the pharmacokinetics of fluvastatin (e.g. AUC) differed significantly
in CYP2C9 genotype in 24 patients after taking 40 mg of fluvastatin daily for 14 days (P <
0.00001). Subjects carrying the CYP2C9*3/*3 genotype had a three-fold increase of the AUC
of fluvastatin compared to subjects with the wild-type CYP2C9*1/*1 genotype. In our study,
after treatment with 10 mg rosuvastatin for 12 weeks, we found that subjects with the mutant
CYP2C9*1/*1 genotype showed a higher TC-lowering and LDL-lowing effect compared to
patients with the wild-type t genotype. The percentage reduction in TC and LDL showed a
statistically significant difference between patients with wild-type and mutant CYP2C9
genotypes. Patients with wild-type CYP2C9 also showed a slightly lower compliance rate of
LDL target achievement compared to patients with mutant CYP2C9, however, this finding
did not reach statistical significance. These results suggested that the pharmacokinetics of
rosuvastatin may be influenced, to some extent, by CYP2C9 polymorphisms. These results
also support our hypothesis that patients with CYP2C9 mutations may show increased
concentrations of metabolized drugs, increasing the risk of adverse drug reactions. In contrast,
patients with CYP2C9 wild type may not reach therapeutic concentrations at conventional
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doses, leading to therapeutic failure with rosuvastatin
As the limitations of the current study, we acknowledged that the major drawback was the
relatively small sample size. Further studies that utilize larger sample sizes are needed to
assess the possible link between CYP2C9 genetic variants and the activity of CYP2C9 in
vitro. Nevertheless, we observed significant reductions in TC, TG and LDL levels and
increase in HDL-C levels after the treatment of 10 mg/d rosuvastatin for 12 weeks. Patients
with the mutant CYP2C9 genotypes showed a higher TC-lowering and LDL-lowing effect
compared to those with wild-type genotypes. Our study suggested that the CYP2C9
polymorphism may be involved in the lipid-lowering efficacy of rosuvastatin in patients with
hyperlipidemia.
Acknowledgments
This work was supported by the research funding from Huashan Hospital, Fudan University
and the research funding from Shanghai Medical Association geriatrics specialist branch.
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Table 1 Frequency of alleles and genotypes for CYP2C9 by gender in 218 patients
Total patients
By gender
Genotypes/phenotypes
(%)
Male
Female
P value
Allele frequency
CYP2C9*1
412 (94.5%)
CYP2C9*3
24 (5.5%)
CYP2C9*2
0
CYP2C9*1/ *1
197(90.3%)
127
70
CYP2C9*1/ *3
18 (8.3%)
13
5
CYP2C9*3/ *3
3 (1.3%)
2
1
EM (*1/ *1)
197 (90.3%)
127
70
PM(*1/ *3 and*3/ *3)
21 (9.6%)
15
6
Genotypes
0.341
Phenotype
0.525
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Table 2 Study outcomes of patients with hyperlipidemia after treatment of 10 mg/d
rosuvastatin for 12 weeks
Elevated
transaminases
(n)
Elevated
CPK
(n)
GI Disorders
(n)
Discontinue
treatment
patients
(n)
Remaining
patient
(n)
Baseline
0
0
0
0
218
1-4 weeks
3
2
4
9
209
5-8 weeks
4
2
0
6
203
9-12 weeks
0
1
0
1
202
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Table 3 Comparison of lipid profiles in hypercholesterolemia patients before and after
treatment with rosuvastatin (mmol/L, X ± s)
Lipid
Baseline
profile
*
After 4-week
After 8-week
After 12-week
treatment
treatment
treatment
TC
6.79±0.95
4.92±0.81*
4.34±0.63**
4.12±0.48**
TG
3.32±1.31
3.02±0.91*
2.64±0.80*
2.33±0.62*
LDL
3.98±0.69
3.07±0.43*
2.65±0.40**
2.31±0.37**
HDL
1.17±0.25
1.19±0.23*
1.21±0.25*
1.32±0.31**
P < 0.05, ** P < 0.01, compared to the baseline.
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Table 4 Association of the CYP2C9 polymorphism with the lipid-lowering efficacy and
intolerability of the rosuvastatin
Patients with
Patients with
wild-type
mutant
CYP2C9
CYP2C9
Baseline
6.93 ± 0.35
6.97 ± 0.21
12-week treatment
4.23 ± 0.37
3.83 ± 0.32
Changes
2.70 ± 0.31
3.14 ± 0.25
Baseline
3.87 ± 0.46
3.98 ± 0.37
12-week treatment
2.35 ± 0.43
2.19 ± 0.39
Changes
1.52 ± 0.38
1.79 ± 0.32
0.029 a
74.59%
88.23%
0.337 b
6.09 (12/197)
19.05 (4/21）
0.085b
Lipid levels
P value
TC (mmol/L)
Efficacy
0.041 a
LDL (mmol/L)
Compliance
rate
of
LDL（%）
Frequency of adverse
Intolerability
reactions (%)
a
Changes from the baseline were assessed by independent samples t-test.
were analyzed by Fisher’s exact test of probabilities.
b Frequencies