Pharmacology & Pharmacy, 2010, 1, 53-59
doi:10.4236/pp.2010.12008 Published Online October 2010 (http://www.SciRP.org/journal/pp)
53
Antioxidant Effect of Atorvastatin in Type 2
Diabetic Patients
Najah R. Hadi1, Mohammad A. Abdelhussein2, Omran M. O. Alhamami1,
Ammar R. Muhammad Rudha1, Ekhlas Sabah
1Department of Pharmacology, Faculty of Medicine, Kufa University, Najaf, Iraq; 2Department of Medicine, Faculty of Medicine,
Kufa University, Najaf, Iraq.
Received August 26th, 2010; revised September 12th, 2010; accepted September 20th, 2010.
ABSTRACT
Evidence has long been existed regarding the relationship between oxidative stress and diabetes. The present study was
conducted to assess the effect of atorvastatin on selected oxidative stress parameters and its effect on lipid profile pa-
rameters in dyslipidaemic type 2 diabetic patients. Fifty nine dyslipidaemic type 2 diabetic patients were included in
this study. A full history was taken and general examination was performed. The patients were taking an oral hypogly-
caemic drug (glibenclamide) during the study. The patients were followed up for 60 days and divided randomly into 2
groups. Group I (n = 31) received no drug and served as dyslipidaemic diabetic control. Group II (n = 28) received
atorvastatin tablets 20 mg once daily at night. Blood samples were drawn from the patients at the beginning and after
60 days of follow up between 8:30 and 10:30 am after at least 12-14 hours fasting. Fasting blood glucose, lipid profile,
selective oxidative stress parameters, glutathione S reductase (GSH), malondialdehyde (MDA) levels, glutathione S
transferase (GST) and catalase (CAT) activities were measured. Renal and hepatic functions were also assessed. The
results showed that atorvastatin treatment produced significant increase in serum levels of GSH and High Density
Lipoprotein (HDL), while serum levels of MDA, Total Cholesterol (TC), Triglyceride (TG), Low Density Lipoprotein
Cholesterol (LDL-C) and Very Low Density Lipoprotein (VLDL) were significantly decreased. However, no significant
effect was observed regarding CAT and GST activity. There were insignificant correlations between atorvastatin in-
duced changes in the oxidation markers and the observed changes of the lipid profile. In conclusion, the antioxidant
effect of atorvastatin could be unrelated to its hypolipidemic action as there was insignificant correlation between
changes in lipid profile and oxidative stress in this study.
Keywords: Atorvastatin, Type 2 Diabetes, Oxidative Stress, Dyslipidaemia
1. Introduction
Oxidative stress is defined as tissue injury resulting from
a disturbance in the equilibrium between the production
of reactive oxygen species (ROS) (also known as free
radicals) and antioxidant defense mechanisms [1]. Under
physiologic conditions, the antioxidant defenses are able
to protect against the deleterious effects of ROS, but un-
der conditions where either an increase in oxidant gen-
eration, a decrease in antioxidant protection or a failure
to repair oxidative damage, accumulation of free radicals
ensures, leading to cellular and tissue damage [2]. Excess
generation of ROS in oxidative stress have pathological
consequences including damage to polyunsaturated fatty
acids in membrane lipids, proteins, DNA and ultimately
cell death [3]. ROS have been implicated in many dis-
ease state including neurodegenerative disease like
Alzheimer’s and Parkinson’s disease, atherosclerosis,
inflammatory conditions, certain cancers, diabetes melli-
tus (DM), cataract in the eye, pulmonary, renal, heart
diseases and the process of aging [4,5]. Diabetes mellitus
is a group of metabolic disorders with one common
manifestation: hyperglycaemia associated with defects in
insulin secretion, action or both. Traditionally it has been
classified into two forms Type 1 DM and Type 2 DM [6].
Type 2 DM which is known to be multifactorial, result-
ing from combination of various factors such as impaired
fatty acid metabolism, central fat deposition leading to
insulin resistance in various tissues (liver, muscles, adi-
pose) [7], beta-cell secretary defect and obesity [4]. Evi-

Antioxidant Effect of Atorvastatin in Type 2 Diabetic Patients
54
dence has long existed regarding the relationship be-
tween oxidative stress and DM [8]. Eisei N. et al. postu-
lated that oxidative stress is involved in the onset and
progression of diabetes, initiation and exacerbation of
micro- and macrovascular complications in diabetes and
recently oxidative stress status markers have been asso-
ciated directly with the severity and prognosis of diabetes
[9]. There are multiple sources of oxidative stress in DM,
including non enzymatic (glucose autoxidation, non en-
zymatic glycation of proteins), enzymatic (NADPH oxi-
dase, nitric oxide synthase) and mitochondrial pathway
[10].
Dyslpidaemia is used to describe a group of conditions
in which there are abnormal levels of lipid and lipopro-
tein in the blood [11]. In type 2 diabetes, dyslipidaemia is
characterized by elevated circulating levels of TG, de-
creased circulating levels of HDL and usually accompa-
nied by an elevation of small dense LDL-cholesterol par-
ticles [12]. There is an evidence indicating that hyper-
lipidaemia is associated with enhanced oxidative stress
[13]. Atorvastatin belongs to 3-hydroxy-3-methylglutaryl-
coenzyme A (HMG-CoA) reductase inhibitors, (or statins)
which are potent inhibitors of cholesterol biosynthesis
that are used extensively to treat patients with hypercho-
lesterolaemia [14,15]. Atorvastatin is a synthetic lipid
lowering agent [16]. It is a competitive inhibitor of
HMG-CoA reductase which catalyzes the conversion of
HMG-CoA to mevalonate, an early rate limiting step in
cholesterol biosynthesis resulting in depletion the intra-
cellular supply of cholesterol [17]. Inhibition of choles-
terol biosynthesis is accompanied by an increase in he-
patic LDL receptor on the cell surface which promotes
uptake and clearance of circulating LDL. Thus the end
result is a reduction in plasma cholesterol by both low-
ered cholesterol synthesis and by increased catabolism of
LDL [15]. Atorvastatin also reduces VLDL-C, TG and
produces variable increase in HDL-C [18]. Atorvastatin
is safe and generally well tolerated [19]. Mild gastroin-
testinal side effects like dyspepsia, flatulence, abdominal
pain, diarrhea and constipation may occur. Other side
effects include headache, rash, pruritus and malaise. The
most detrimental adverse effect of atorvastatin is hepato-
toxicity and myopathy [20].
Munford [21] and Shishehbor et al. [22] stated that the
overall clinical benefits observed with atorvastatin ther-
apy appear to be greater than what might be expected
from changes in lipid levels alone, suggesting effects
beyond cholesterol lowering called pleiotropic effects.
Vishal et al. indicated that some of the cholesterol-inde-
pendent effects of atorvastatin involve improving endo-
thelial function, enhancing the stability of atherosclerotic
plaques, decreasing oxidative stress, decreasing inflam-
mation, improve insulin resistance, inhibiting the throm-
bogenic response in the vascular wall and impede tumor
cells. Further more statin have other extrahepatic benefi-
cial effects on the immune system, central nervous sys-
tem and bone [23]. Atorvastatin possesses antioxidant
properties by reducing lipid peroxidation and ROS pro-
duction [23]. It reduces the susceptibility of lipoproteins
to oxidation both in vitro and in vivo, i.e., they decrease
the LDL oxidation [23].
The Aim of This Study was to clarify the effect of
atorvastatin on selected oxidative stress parameters na-
mely (reduced glutathione (GSH), lipid peroxidation
product malondialdehyde (MDA) levels, glutathione –S-
transferase (GST) and catalase (CAT) activities) and
lipid profile in dyslipidaemic type 2 diabetic patients.
2. Materials and Methods
2.1. Materials
Atorvastatin (Atorfit 20, Ajanta Pharma Limited, India,),
EDTA & GSH (Biochemicals Co. Ltd.), DTNB (Sigma
Co. Ltd.), Trichloroacetic acid (TCA) & Thiobuteric acid
(TBA) (Merk Co. Ltd.) were obtained as a gift samples.
CDNB, K2HPO4, KH2PO4, Na2HPO4, H2O2 (Analar
company) were purchased commercially and used as
received.
2.2. Patients
Fifty nine patients (age: 57.16 ± 1.34 years; 32 men & 27
women) with type 2 DM and dyslipidaemia were in-
cluded in this study after obtaining their written consent
and formal approval of the human experimentation
committee at the Faculty of Medicine, Kufa University.
The mean fasting blood glucose was (7.91 ± 0.7 mmol/l),
with a mean duration of diabetes of (8.4 ± 1.08 years).
The mean LDL-C level was (5.48 ± 0.72 mmol/l). The
patients were chosen randomly from Al- Hakeem center
for researches and treatment of DM at Al-Sadr Teaching
Hospital in Najaf City in the period between 5th Nov.
2006 to 24th June 2007. These patients underwent full
history and complete physical examination. Patients with
the following criteria were excluded from the study: 1)
Patients who use any vitamin preparations, or statins in
the last three months [24]; 2) Patients with renal insuffi-
ciency, defined as a serum creatinine level equal to or
more than 1.8 mg/dl [24]; 3) Patients with liver disease
[22]; 4) Hypertensive patients, as this condition affects
oxidative stress [13] and antihypertensive drugs may
affect lipid profile and oxidative stress in hypertensive
patients [25,26]; 5) Patients with chronic inflammatory
diseases [24]; 6) Alcoholics & smokers were also ex-
cluded [27]. The patients were using glibenclamide
(Glibesyn, Medochemie LTD-Cyprus; Glibils, Hikma-
Jordon) (an oral hypoglycaemic agent) during the study

Antioxidant Effect of Atorvastatin in Type 2 Diabetic Patients
55
as a treatment for their diabetes. According to the design
of the study, type 2 diabetic patients were followed up
for 60 days and divided randomly into two groups:
Group I (n = 31) received no drug and served as dyslipi-
daemic diabetic control. Group II (n = 28): received
atorvastatin tablets 20 mg once daily at night (Atorfit 20).
Only forty six patients continued to the end of the study
while thirteen patients were withdrawn (eight patients
from Group I and five patients from Group II) because of
non compliance. The patients were put on diet control
and followed up every two weeks during the time of the
study in order to make sure that they were using the
medication properly and to regularly checking fasting
blood glucose. Values of fasting blood glucose before,
during and after the study were controlled within the
previously mentioned range. Blood samples were drawn
from the patients at the beginning and after 60 days of
follow up between 8:30 & 10:30 am after at least 12-14
hours fasting. Fasting blood glucose, lipid profile, se-
lected oxidative stress parameters (GSH, MDA levels,
GST, CAT activities) were measured. Renal and hepatic
functions were also assessed.
2.3. Sample Preparation
From each patient, 3 ml of blood was obtained without
using heparin after an overnight fasting. The blood was
placed in serum tube and left to stand for 30 minutes.
The serum was prepared by centrifugation at 3000 rpm
for 10 minute, 1.5 ml of serum was obtained for deter-
mination of experimental parameters which included
GSH, MDA (the byproduct of lipid peroxidation), GST
enzyme, CAT enzyme and lipid profile.
2.4. Serum Reduced Glutathione (GSH) Assay
Serum GSH was estimated according to a modified
method of Ellman [28]. Briefly, Stock standard solution
was prepared fresh daily by dissolving 0.0307 gm of
GSH in a final volume of 100 ml of (0.2M) EDTA solu-
tion. Dilutions were made in EDTA solution to 50, 100,
150, 200, 250, 300, 400, 500 µM. The absorbance of this
series of known concentrations was determined spectro-
photometricaly using Shimadzu UV-1650P (UV-visible)
at 412 nm to construct the calibration curve, “Figure 1”.
2.5. Serum Lipid Peroxidation Product (MDA)
Assay
The level of serum MDA was determined by a modified
procedure described by Guidet and Shah [29]. Add 1 ml
of TCA 17.5% and 1 ml of 0.6% thiobarbituric acid
(TBA) to 0.15 ml of serum sample. The solution was
mixed well by vortex, incubated in boiling water bath for
15 minutes, then allowed to cool. 1 ml of 70% TCA was
Figure 1. Standard curve for determination of reduced glu-
tathione level.
added, and the mixture was allowed to stand at room
temperature for 20 minutes, centrifuged at 2000 rpm for
15 minutes, and the supernatant was taken out for scan-
ning spectrophotometrically at 532 nm using Shimadzu
UV-1650P (UV-visible) Spectrophotometer.
Absorbance 532
LЄ
at nm
TheconcentrationofMDA 
(1)
L: Light path (1 cm)
: Extinction coeffoent 1.56105M 1Є.Cm 1
Total volume
: Volume of the sample Ddilution factor 
2.6. Serum GST Enzyme Activity Assay
The absorption technique [30] includes mixing of 2.7 ml
of Phosphate buffer (pH = 6.25) with 100 µL of serum
and 100 µL of CDNB (1-chloro, 2, 4-dinitro benzene)
and then after 3 minutes with 100 µL of GSH solution.
After mixing the solutions, the absorbance was read
every minute for 10 minutes at wave length 340 nm.
Calculation:
AVt 1000
10
Vs b
U
Activity ofGSTL



  
 (2)
ΔA = absorbance difference between the first and tenth
minute
Vt = The total volume
Vs = Sample volume
Є = 9.6 mM-1cm-1
b = 1 cm.
A31000
10
9.60.1 1 Activity ofGST

 (3)
2.7. Serum Catalase Activity Assay
The absorption technique [31] include mixing of 2 ml of

Antioxidant Effect of Atorvastatin in Type 2 Diabetic Patients
56
diluted serum with 1ml of H2O2 The solution was mixed
well and the first absorbance (A1) was read after 15 sec-
onds (t1) then the second absorbance (A2) after 30
seconds (t2) at a wave length 240 nm. 1 ml of Phosphate
buffer solution was used instead of H2O2 for the blank
solution.
Calculation:
3A1
K2. 60
t2
Vt
x
xlog x
Vs A
 (4)
K = rate constant of the reaction
Δt = (t2 – t1) 15 seconds
A1 = absorbance after 15 seconds
A2 = absorbanse after 30 seconds
Vt = total volume (3ml)
Vs = volume of the sample
2.8. Serum Lipid Profile Assay
Total cholesterol, Triglyceride and HDL were measured
according to procedures supplied by Spinreact company
kits, using Shimadzu UV-1650P (UV-visible)) Spectro-
photometer. Serum LDL measure according to the fol-
lowing equation [32]
LDL= total cholesterol - HDL – VLDL (5)
VLDL= TG/2.2. (6)
2.9. Statistical Methods
The data expressed as mean ± SEM unless otherwise
stated. Statistical analyses were done by using paired
t-test. Pearson,s correlations were also performed with
significant difference set at P < 0.05.
3. Results
3.1. Effect of Atorvastatin on Oxidative
Parameters
Atorvastatin treatment increased serum GSH and reduced
MDA level significantly (P 0.05) while no significant
change in serum GST and CAT activity was observed (P
0.05). There was no significant change (P 0.05) in oxida-
tive stress parameters in diabetic control group apart
from significant increase in MDA level “Table 1”.
3.2. Effect of Atorvastatin on Lipid Profile
A significant decrease in serum TC, TG, LDL and VLDL
and significant increase in HDL levels after atorvastatin
treatment (P 0.05) while no significant change in lipid
profile in diabetic control group was observed “Table 2”.
3.3. Correlations between Observed Changes in
Oxidation Markers and Observed Changes
in Lipid Parameters in Atorvastatin Group
There were no significant correlations between atorvas-
tatin induced changes in the oxidation markers and the
observed changes in the lipid profile (P 0.05) “Table 3”.
4. Discussion
4.1. Effect of Oxidative Stress Parameters
The significant increase in GSH and significant decrease
in MDA levels (P 0.05) following atorvastatin treatment
is supported by the findings of Save et al. [33] and Koter
et al. [34], respectively. The most likely explanation for
the increment of GSH and reduction of MDA by ator-
vastatin was attributed to the antioxidant mediated effect
of atorvastatin which results from inhibition of mevalo-
nate pathway. This effect results in a reduction in the
synthesis of important intermediates including isopre-
noids ((farnesyl pyrophosphate & geranylgeranyl pyro-
phosphate). The latter serve as lipid attachments for in-
tracellular signaling molecules in particular inhibition of
small GTPase binding proteins (Rho, Rac, Ras and G
proteins) whose proper membrane localization and func-
tion are dependent on isoprenylation. These proteins
modulate a variety of cellular processes including sig-
naling, differentiation and proliferation [35,36]. Atorvas-
tatin attenuates endothelial reactive oxygen species (ROS)
Table 1. Effect of atorvastatin (20 mg/day) on oxidative stress parameters after 60 days of treatment and changes in
dyslipidaemic diabetic control (n = 23 in each group).
Diabetic control Atorvastatin
Parameters
Before treatment After treatment Before treatment After treatment
GSH(mmol/l) 0.24 ± 0.0079 0.22 ± 0.0036* 0.23±0.0034 0.40±0.0009**
MDA(mol/l) 1.25 × 10–4 1.59×10–4 1.24×10–4 0.24×10–4
± 0.0146 ±0.0210** ±0.0178 ± 0.004**
GST(U/l) 13.68 ± 0.18 13.87 ± 0.2194* 13.95 ± 0.234 14.07 ± 0.212*
CAT(K/ml) 0.49 ± 0.0123 0.5001 ± 0.016* 0.48 ± 0.0133 0.483 ± 0.012*
*p > 0.05; **p < 0.01; Values expressed as mean ± SEM.

Antioxidant Effect of Atorvastatin in Type 2 Diabetic Patients
57
Table 2. Effect of atorvastatin (20 mg/day) on lipid profile after 60 days of treatment and changes in dyslipidaemic
diabetic control ( n = 23 in each group).
Diabetic control Atorvastatin
Parameters Before treatment After treatment Before treatment After treatment
TC(mmol/l) 6.99 ± 0.1173 6.74 ± 0.0332* 7.49 ± 0.0230 4.38 ± 0.0189**
TG(mmol/l) 2.78 ± 0.0645 2.68 ± 0.0159* 2.84 ± 0.0145 1.78 ± 0.0069**
HDL(mmol/l) 0.81 ± 0.0300 0.76 ± 0.0114* 0.76 ± 0.0159 1.06 ± 0.0109**
LDL(mmol/l) 4.90 ± 0.1300 4.75 ± 0.0339* 5.43±0.0243 2.51 ± 0.0168**
VLDL(mmol/l) 1.26 ± 0.0129 1.21 ± 0.0031* 1.29±0.0029 0.81 ± 0.0013**
*p > 0.05; **p < 0.01; Values expressed as mean ± SEM.
Table 3. Pearson,s correlation for changes in the oxidative
markers and lipid parameters in the atorvastatin group.
parameter GSH MDA GST CAT
TC −0.232 0.042 0.427 −0.119
TG −0.172 −0.105 0.039 −0.135
HDL-C −0.223 −0.068 0.220 −0.139
LDL-C −0.083 0.088 0.329 −0.032
VLDL-C −0.157 0.001 −0.031 −0.055
P > 0.05 non significant.
formation, through attenuating endothelial superoxide
anion production, by inhibition of NAD(P)H oxidase
activity via Rho dependent mechanism. Some of anti-
oxidant effects of atorvastatin may be due to its metabo-
lites such as hydroxyl metabolites which have direct an-
tioxidant effect. Atorvastatin improves and preserves the
level of vitamin C, E and endogenous antioxidant such as
reduced glutathione [16]. The protective effects of ator-
vastatin on ROS including cholesterol dependent and non
cholesterol dependent antioxidative properties [16].
Serum GST enzyme activity did not significantly
change in atorvastatin treatment and this finding was
consistent with Passi et al. [37] who concluded that ator-
vastatin had no effect on GST activity.
It was also noted that atorvastatin showed insignifi-
cant change in the CAT activity which is in agreement
with Passi et al. [37]. However, our results conflict with
the findings of Wassmann et al. who concluded that ator-
vastatin caused a significant increase in the CAT activity
[38]. This confliction may be due to the fact that the
sample size may be relatively small permitting chance
observations to exert substantial effects.
4.2. Effect on Lipid Profile
A significant decrease in serum level of TC, TG, LDL
and VLDL and significant increase in serum level of
HDL by atorvastatin treatment are in agreement with the
findings obtained by Diabetes Atorvastatin Lipid Inter-
vention study group [39] and Save et al. [33]. The me-
chanism involved is most likely attributed to the ability
of atorvastatin to impair cholesterol synthesis via inhib-
iting the enzyme HMG-CoA reductase, which is the rate
limiting step in cholesterol biosynthesis. This leads to
both, decrease circulating lipoproteins and increase their
uptake by up regulating hepatic LDL-C receptors. The
overall lipid lowering effect include increase uptake and
degradation of LDL-C, inhibition of LDL-C oxidation,
reduction in cholesterol accumulation and esterification
and decreases lipoprotein secretion and cholesterol syn-
thesis [22,40] .
4.3. Correlations between the Observed Changes
in the Oxidation Markers and the
Improvement of Lipid Profile in
Atorvastatin
According to this study there were insignificant correla-
tions between the observed changes in the pleiotropic
effect of atorvastatin, regarding antioxidant properties
and the improvement in the lipid profile. The same find-
ings was reported by Sakabe et al. [41]. This pleiotropic
effect of atorvastatin is due, predominantly, to inhibition
of isopreniods but not cholesterol synthesis [42].
From the results of this study, we can conclude that,
atorvastatin increased GSH, reduced MDA levels and
had no effect on CAT and GST activities. Atorvastatin
reduced TC, TG, LDL-C, VLDL-C and increased HDL-C
levels. Also there were no correlations between the ob-
served changes in the oxidation markers and the im-
provement of the lipid profile in the atorvastatin.
5. Conclusions
The antioxidant effect of atorvastatin could be unrelated
to its hypolipidemic action as there was insignificant

Antioxidant Effect of Atorvastatin in Type 2 Diabetic Patients
58
correlation between changes in lipid profile and oxidative
stress in this study.
6. Acknowledgements
Special thanks to everybody that help us in accomplish-
ing this work.
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