Research Report

Journal of International Medical Research

2014, Vol. 42(2) 457–467
Efficacy of low-dose ! The Author(s) 2014
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DOI: 10.1177/0300060513507648
type 2 diabetes and hypo imr.sagepub.com

high-density lipoprotein
cholesterolaemia
Takuyuki Katabami1, Mariko Murakami1,
Suzuko Kobayashi1, Tomoya Matsui1,
Makoto Ujihara2, Sachiko Takagi2,
Mariko Higa3, Takamasa Ichijo3, Akio Ohta4
and Yasushi Tanaka4

Abstract
Objective: To analyse the efficacy of low-dose rosuvastatin for treating hypo high-density
lipoprotein (HDL) cholesterolaemia in patients with type 2 diabetes and dyslipidaemia.
Methods: Patients with HDL-cholesterol (C) <40 mg/dl and triglycerides (TG) <400 mg/dl who
were receiving treatment with lipid-lowering drugs other than rosuvastatin (or previously
untreated with lipid-lowering drugs) and with low-density lipoprotein [LDL]-C 120 mg/dl were
included. Patients were treated with 2.5 or 5 mg rosuvastatin orally, once daily, to achieve the
target LDL-C level specified in Japanese guidelines. Changes in total cholesterol, HDL-C, TG, LDL-
C, LDL-C/HDL-C and non-HDL-C at 3 and 6 months were prospectively analysed. Safety was
evaluated by examining changes in hepatorenal function, glucose metabolism and creatine kinase.
Results: Out of 49 patients, all lipid parameters other than TG were significantly improved at
3 and 6 months. At 3 months, 83.3% of patients had achieved the target LDL-C level. Among
nonlipid parameters, no changes were observed except for estimated glomerular filtration rate,
which was improved by þ 5.2% and þ 9.6% at 3 and 6 months, respectively.
Conclusions: Low-dose rosuvastatin was effective in improving hypo-HDL cholesterolaemia and
may have renoprotective effects.

1
Division of Metabolism and Endocrinology, Department
of Internal Medicine, St Marianna University School of
Medicine Yokohama City Seibu Hospital, Yokohama, Japan
2
Division of Diabetes and Endocrinology, Department of
Internal Medicine, National Hospital Organization
Yokohama Medical Centre, Yokohama, Japan
3
Division of Diabetes and Endocrinology, Department of
Internal Medicine, Saiseikai Yokohamashi Tobu Hospital,
Yokohama, Japan
4
Division of Metabolism and Endocrinology, Department
of Internal Medicine, St Marianna University School of
Medicine, Kawasaki, Japan
Corresponding author:
Dr Takuyuki Katabami, Division of Metabolism and
Endocrinology, St Marianna University School of Medicine
Yokohama City Seibu Hospital, 1197-1 Yasashi-cho, Asahi-
ku, Yokohama 241-0811, Japan.
Email: t2kataba@marianna-u.ac.jp

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458
Keywords
Type 2 diabetes mellitus, hypo high-density lipoprotein cholesterolaemia, rosuvastatin, low-density
lipoprotein cholesterol, triglycerides, estimated glomerular filtration rate
Date received: 29 August 2013; accepted: 12 September 2013
Introduction
Smoking, dyslipidaemia, hypertension,
obesity, diabetes and lifestyle are known
risk factors for cardiovascular diseases
such as coronary heart disease. Type 2
diabetes – which accounts for the majority
of diabetes cases and is usually accompa-
nied by obesity – is often associated with
dyslipidaemia, including hypo high-density
lipoprotein (HDL) cholesterolaemia, hyper
low-density lipoprotein (LDL) cholestero-
laemia and hypertriglyceridaemia.1,2 Many
patients with type 2 diabetes, therefore, are
at heightened risk of cardiovascular disease
because of concomitant dyslipidaemia,
which is also associated with insulin resist-
ance. Consequently, these patients require
active intervention for correction of dysli-
pidaemia in addition to treatment for
diabetes. Specifically, low HDL-cholesterol
(C) and high LDL-C levels have been
reported to be independent risk factors
for developing cardiovascular disease,3–5
therefore, patients with diabetes and both
of these risk factors require careful and
strict management of LDL-C and HDL-C
levels, in addition to adequate control of
blood glucose.6
Statins have been reported to improve
hyper-LDL cholesterolaemia and hypertri-
glyceridaemia, to increase HDL-C, and to
reduce the risk for cardiovascular disease in
patients with type 2 diabetes and dyslipidae-
mia.7 Meta-analyses using the PubMed and
LIVALOÕ (pitavastatin) effectiveness and
safety (LIVES) Study databases have also
shown that various statins can increase
HDL-C.8,9 A statin-induced increase in
HDL-C is usually accompanied by a
decrease in LDL-C and may be primarily
Journal of International Medical Research 42(2)
explained by a cholesterol ester transfer
protein-mediated mechanism.8 In addition,
there may be different mechanisms involved
in the effects of different statins. For exam-
ple, atorvastatin has been shown to increase
HDL-C in a dose-independent manner,
whereas rosuvastatin was more effective in
increasing HDL-C at lower doses.8,10
Clinical studies that exclusively include
patients with diabetes and hypo-HDL cho-
lesterolaemia may reveal the mechanisms
involved in statin-mediated HDL-C
increase, however, no such studies are cur-
rently reported. There are also currently no
reports on the differences in clinical charac-
teristics between patients who respond to
statin therapy and those who do not, nor are
there studies on the prediction of statin
response.
The present study was conducted to
evaluate the efficacy of rosuvastatin (which
is a potent hydrophilic statin routinely used
in Japan, that decreases LDL-C and also
markedly increases HDL-C10) in patients
with type 2 diabetes and hypo-HDL choles-
terolaemia. Treatment with rosuvastatin
aimed to achieve the target LDL-C levels
specified in the Japan Atherosclerosis
Society guidelines for the diagnosis and
prevention of atherosclerotic cardiovascular
diseases in Japan–2012 version.11 In add-
ition, lipid improvement, safety and factors
that affected changes in HDL-C at 3 and
6 months were evaluated.
Patients and methods
Study population
Patients diagnosed by an investigator (T.K.,
M.M., S.K., T.M., M.U., S.T., M.H., T.I.,
A.O. or Y.T.) as having type 2 diabetes, who
Katabami et al.
also had levels of HDL-C <40 mg/dl and
triglyceride (TG) <400 mg/dl, and were
under regular treatment at the following
institutes in Yokohama, Japan: St Marianna
University School of Medicine Yokohama
City Seibu Hospital; National Hospital
Organization Yokohama Medical Centre;
Saiseikai Yokohamashi Tobu Hospital; St
Marianna University School of Medicine,
between December 2011 and April 2013,
were enrolled into this prospective interven-
tion study. Regardless of LDL-C value,
patients with HDL-C <40 mg/dl and TG
<400 mg/dl who were under treatment with
lipid-lowering drugs other than rosvastatin
were included. Patients with HDL-C
<40 mg/dl and TG <400 mg/dl who were
previously untreated with lipid-lowering
drugs, with LDL-C 120 mg/dl, were also
included. Patients meeting any of the fol-
lowing criteria were excluded from the
study: familial hypercholesterolaemia; his-
tory of hypersensitivity to statins; active
hepatic disease; renal dysfunction; serum
creatine kinase (CK) >1000 IU/l; receiving
cyclosporine therapy; gravidity or potential
gravidity; evidence or family history of
hypothyroidism or hereditary muscular dis-
order (muscular dystrophy, etc.); history of
drug-induced muscle disorder; drug misuse
or alcoholism; patients who, in the opinion
of the investigator, were not appropriate for
the study. Patients who were already receiv-
ing other statin therapies did not undergo
any washout or transition phase before they
started on rosuvastatin.
The study protocol was approved by each
institutional ethical review board (author-
ization approval Nos: 1961, St Marianna
University School of Medicine Yokohama
City Seibu Hospital and St Marianna
University School of Medicine; 20120004,
National Hospital Organization Yokohama
Medical Centre; 2011035, Saiseikai
Yokohama City Tobu Hospital). Written
informed consent was obtained from each
patient.
459
Study design and evaluation
Patients were treated with 2.5 or 5 mg
rosuvastatin orally, once daily, to achieve
the target LDL-C levels of <120 mg/dl for
primary prevention category III or <100 mg/
dl for secondary prevention, in accordance
with the Japan Atherosclerosis Society
guidelines for the diagnosis and prevention
of atherosclerotic cardiovascular diseases in
Japan–2012 version.11 Baseline blood lipid
parameters were measured immediately
prior to the start of rosuvastatin treatment.
Changes in blood lipid parameters (total
cholesterol, HDL-C and TG), proportion of
patients who achieved the treatment goal,
and factors that affected the change in HDL-
C at 3 and 6 months following the start of
treatment with rosuvastatin were analysed.
In principle, changes in nonstudy drugs
(including dose change), or in therapies
that may affect lipid parameters, were not
permitted during the study. Dosage increase
and/or switching of antidiabetics were per-
mitted for patients with glycosylated
haemoglobin (HbA1c) levels >8.0%, if the
attending physician judged it necessary.
The LDL-C level was calculated using the
Friedewald formula;12 the LDL-C/HDL-C
ratio was calculated by dividing the calcu-
lated LDL-C level by HDL-C, and the non-
HDL-C level was calculated by subtracting
HDL-C from total cholesterol.
Safety was evaluated by analysing
changes in HbA1c estimated glomerular fil-
tration rate (eGFR), aspartate aminotrans-
ferase (AST), alanine aminotransferase
(ALT), g-glutamyl transferase (g-GT), CK
and blood urea nitrogen (BUN). HbA1c
levels were expressed in units specified
by the National Glycohemoglobin
Standardization Program (NGSP),13 which
is the international standard (see below).
Measurement
Blood samples (10 ml) were taken from the
antecubital vein at 08:00–09:00 h following
460
an overnight fast. Samples were immediately
centrifuged at 1 500 g for 5 min at room
temperature, and analysed in each hos-
pital by Mitsubishi Kagaku Bio-Clinical
Laboratories, Inc., Tokyo, Japan. TG,
total cholesterol and HDL-C were measured
enzymatically using Determiner L TG II
(Kyowa Medex, Tokyo, Japan), Dia Auto
T-Cho (Dia Reagents, Tokyo, Japan) and
Cholestest HDL (Daiichi Pure Chemicals,
Tokyo, Japan), respectively, by means of an
autoanalyser (Hitachi, Tokyo, Japan)
according to the manufacturers’ instruc-
tions. LDL-C was estimated using the
Friedewald formula (LDL-C ¼ total
cholesterolHDL-CTG  0.2) unless the
patient had a current TG level >400 mg/dl.12
For patients with current TG levels
>400 mg/dl, LDL-C was measured using
the N-geneous assay (Daiichi Pure
Chemicals) according to the manufacturer’s
instructions.
Blood glucose was measured using Sica
Liquid Glu (Kanto Kagaku, Tokyo, Japan)
according to the manufacturer’s instruc-
tions. HbA1c was determined by a latex
cohesion method (Determiner HbA1c,
Kyowa Medex, Tokyo, Japan), calibrated
against a Japanese Clinical Laboratory Use
Certified Reference Material (JCCRM), and
designated as HbA1c (Japanese Diabetes
Society [JDS]). HbA1c (NGSP) was calcu-
lated from HbA1c using the formula:
HbA1c (NGSP) (%) ¼ 1.02  HbA1c (JDS)
(%) þ 0.25 (%).13
Estimated GFR was calculated from
serum creatinine (Cr) concentration using
the revised equation: eGFR (ml/
min/1.73 m2) ¼ 194  Cr1.094  Age0.287
( 0.739, if female).14 AST, ALT, g-GT, CK,
Cr and BUN were determined using enzyme
immunoassays (Iatro-LQ AST, ALT, g-GT,
CK Rate, CRE and UN Rate; Mitsubishi
Kagaku Bio-Clinical Laboratories). Patients
were assessed for chronic kidney disease
using the definitions and staging system
provided in the Japanese Clinical Practice
Journal of International Medical Research 42(2)
Guidebook for Diagnosis and Treatment of
Chronic Kidney Disease – 2012.15
Statistical analyses
Data were presented as mean  SD. Paired
t-test was used to compare numerical data
before and after treatment with rosuvastatin
within the patient group; McNemar’s test
was used to compare the proportion of
patients who achieved the target LDL-C
level before and after treatment with rosu-
vastatin. Pearson’s correlation coefficient
and stepwise multiple regression analysis
were performed to determine factors con-
tributing to the change in HDL-C. Pearson’s
correlation coefficient was also used to ana-
lyse factors contributing to the change in
eGFR. Statistical analyses were performed
using JMPÕ software, version 7.0.2 for
WindowsÕ (SAS Institute, Japan). A
P-value <0.05 was considered statistically
significant.
Results
Patient characteristics
A total of 49 patients were included in the
study; type 2 diabetes-related complications
and cholesterol reducing therapies for the
included patients are shown (Table 1). A
total of 14 patients (28.6%) had been previ-
ously treated with lipid-lowering drugs,
including 11 patients with statins, one
patient with the intestinal cholesterol trans-
porter inhibitor ezetimibe, and one patient
with fibrate (phenofibrate) (Table 1). Forty-
four patients received an initial rosuvastatin
dose of 2.5 mg orally per day and five
patients received an initial dose of 5 mg
orally per day (mean initial dose for all
patients, 2.8  0.8 mg per day; Table 1).
There was a slight, but not statistically
significant, increase in rosuvastatin dose
during the treatment compared with the
starting dose, but the dose remained con-
sistently low throughout the study period
Katabami et al. 461

Table 1. Demographic and baseline clinical char- Table 2. Antidiabetic treatments used during the
acteristics of patients with type 2 diabetes and hypo present study by patients with type 2 diabetes and
high-density lipoprotein cholesterolaemia (n ¼ 49). hypo high-density lipoprotein cholesterolaemia
(n ¼ 49).
Patient
Characteristic group Incidence
Treatment type of use
Age, years
Mean 59.8  15.5 Biguanide 21 (42.9)
Range 22–88 Thiazolidine 2 (4.1)
Sex DPP-4 inhibitor 18 (36.7)
Male 40 (81.6) GLP-1 receptor agonist 2 (4.1)
Female 9 (18.4) Sulfonylurea 13 (26.5)
Complications Glinide 3 (6.1)
Hypertension 7 (14.3) a-glycosidase inhibitor 12 (24.5)
Cerebral infarction 2 (4.1) Insulin 16 (32.7)
Arteriosclerosis obliterans 2 (4.1) Mean number of medications 1.8  1.1
Coronary heart disease 4 (8.2) per patienta
Other cardiovascular disease 1 (2.0)
Previous cholesterol-reducing treatment Data presented as n (%) of patients receiving each
antidiabetic drug, or mean  SD.
Atorvastatin, 10 mg/day 3 a
Some patients received two or more antidiabetic agents
5 mg/day 1 simultaneously.
Pitavastatin, 4 mg/day 2 DPP-4, dipeptidyl-peptidase 4; GLP-1, glucagon-like pep-
1 mg/day 1 tide-1.
Simvastatin, 5 mg/day 3
Pravastatin, 10 mg/day 1
Ezetimibe, 10 mg/day 2 Baseline laboratory values are shown in
Phenofibrate, 200 mg/day 1 Tables 3 and 4. Chronic kidney disease15 at
Cholesterol-reducing therapy stage 2 or more severe was found in 26
in the present study patients (81.3%) and at stage 3 or more
Rosuvastatin initial dose, 44 severe in 15 patients (46.9%). Nineteen
2.5 mg/day patients were withdrawn from the study at
5 mg/day 5 6 months because they were unable to attend
Mean rosuvastatin initial 2.8  0.8 the hospital assessment on the required day
dose, mg/day due to work commitments. In addition, the
Data presented as range, mean  SD, n (%) or n incidence. dosing period for two patients did not reach
6 months, resulting in missing data from the
6-month timepoint.

(3.2  0.8 mg at 3 months; 3.1  1.2 mg at

6 months).
A wide range of antidiabetic treatments
was used by patients at the start of the study
(Table 2). The protocol allowed for dosage
increase and/or switching of antidiabetic
medication in patients with HbA1c values
>8.0% if necessary, however, no such case
was observed. HbA1c values did not change
significantly throughout the period of the
study.
Treatment effect
Statistically significant improvements were
observed in total cholesterol, LDL-C, HDL-
C, LDL-C/HDL-C ratio, and non-HDL-C
at 3 and 6 months (P < 0.01). There was no
statistically significant difference in TG
levels (Table 3). The proportion of patients
who achieved the target LDL-C level at 3
months was 83.3% and at 6 months was
84.0%, showing a significant increase from
462 Journal of International Medical Research 42(2)

Table 3. Effect of rosuvastatin (2.5 mg or 5 mg, orally, per day) on lipoprotein and triglyceride levels in
patients with type 2 diabetes and hypo high-density lipoprotein cholesterolaemia (n ¼ 49).

Analysis timepoint

Change from baseline Change from baseline

Rate of Statistical Rate of Statistical

Parameter Baseline 3 months changea, % significance 6 months changea, % significance

TC, mg/dl 218.1  54.7 172.0  36.5 18.3 P < 0.01 166.8  36.4 18.3 P < 0.01
LDL-C, mg/dl 135.8  45.7 94.8  35.5 26.5 P < 0.01 93.1  32.6 25.0 P < 0.01
(n ¼ 48) (n ¼ 42) (n ¼ 25)
HDL-C, mg/dl 35.4  3.8 39.9  7.5 12.8 P < 0.01 39.3  6.4 11.6 P < 0.01
(n ¼ 49) (n ¼ 44) (n ¼ 26)
LDL-C/HDL-C, 3.9  1.5 2.5  1.1 36.2 P < 0.01 2.4  0.9 32.2 P < 0.01
ratio (n ¼ 48) (n ¼ 40) (n ¼ 24)
TG, mg/dl 200.2  75.6 182.9  122.4 8.9 NS 172.0  121.8 10.6 NS
non-HDL-C, mg/dl 180.0  54.5 132.2  36.2 24.0 P < 0.01 125.2  37.1 24.5 P < 0.01

Data presented as mean  SD or %.

a
Percentages calculated as the average of the change rate for each patient.
NS, no statistically significant difference (P  0.05; paired t-test, baseline versus 3 months; baseline versus 6 months).
TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol;
TG, triglyceride.

Table 4. Effect of rosuvastatin (2.5 mg or 5 mg, orally, per day) on glucose metabolism and renal/hepatic
function in patients with type 2 diabetes and hypo high-density lipoprotein cholesterolaemia (n ¼ 49).

Statistical Statistical
Parameter Baseline 3 months significance 6 months significance

HbA1c, NGSP, % 7.6  2.0 7.1  1.7 NS 7.0  1.3 NS

eGFR, ml/min/1.73 m2 65.5  21.3 68.6  22.6 P < 0.05 69.1  24.1 P < 0.05
AST, IU/l 21.6  8.5 21.9  9.1 NS 22.2  7.9 NS
ALT, IU/l 23.0  15.7 21.2  8.9 NS 23.6  13.4 NS
g-GT, IU/l 30.8  20.8 28.8  17.3 NS 33.5  19.7 NS
CK, IU/l 66.2  28.9 66.1  35.3 NS 63.6  21.1 NS
BUN, mg/dl 16.7  6.5 15.9  5.9 NS 19.4  6.2 NS

Data presented as mean  SD.

NS, no statistically significant difference (P  0.05; paired t-test versus baseline values).
HbA1c, glycosylated haemoglobin; NGSP, National Glycohemoglobin Standardization Program;13 eGFR, estimated
glomerular filtration rate; AST, aspartate aminotransferase; ALT, alanine aminotransferase; g-GT, g-glutamyl transpeptidase;
CK, creatine kinase; BUN, blood urea nitrogen.

the start of treatment at both timepoints
(P < 0.01; Figure 1).
Blood biochemistry analysis showed that
eGFR significantly improved by þ 5.2% at 3
months and þ 9.6% at 6 months, compared
with baseline values (P < 0.05 at both time-
points). No changes were observed in
HbA1c, AST, ALT, g-GT, CK, or BUN.
No serious adverse events or changes in
treatment medication for diabetes were
Katabami et al.
Figure 1. Achievement rate for low-density lipo-
protein cholesterol (LDL-C) target levels set by the
Japan Atherosclerosis Society guidelines for the
diagnosis and prevention of atherosclerotic cardio-
vascular diseases in Japan–2012 version,11 in
patients with type 2 diabetes and hypo high-density
lipoprotein cholesterolaemia (n ¼ 49). Achievement
rate significantly increased from a baseline level of
35.4% to 83.3% after 3 months and 84.0% after 6
months (*P < 0.01 versus baseline; McNemar’s test).
reported throughout the study period
(Table 4).
There was a statistically significant nega-
tive correlation between the change in HDL-
C at 3 months and baseline TG levels
(r2 ¼ 0.194, P < 0.05), but no such correl-
ation at 6 months. Stepwise multiple regres-
sion analysis revealed a statistically
significant negative correlation between the
change in HDL-C at 3 months and TG,
HbA1c, or age at baseline (r2 ¼ 0.45,
P < 0.01). No such correlation was observed
at 6 months.
Discussion
This is the first report describing a prospect-
ive intervention study in which the effects of
a potent statin were studied exclusively in
patients with type 2 diabetes, concomitant
hypo-HDL-cholesterolaemia and hyper-
LDL-cholesterolaemia. In the present
study, the mean initial dose of rosuvastatin
was low (2.8  0.8 mg per day), because
463
treatment aimed to achieve target LDL-C
levels. Despite these low doses, improve-
ments in HDL-C levels were observed at 3
months (þ 12.8%) and 6 months (þ 11.6%).
LDL-C levels are considered to be con-
trolled under 70 mg/dl, however, patients
with lower HDL-C levels have a higher risk
of coronary artery disease than those with
higher HDL-C levels.16 Intensive LDC-C-
lowering therapy with rosuvastatin has been
shown to result in significant regression of
coronary plaque volume in patients with
stable coronary artery disease.17 In that
same study, there was a significant, but
weak, correlation between the percentage
change in total atheroma volume and HDL-
C, as well as in the LDL-C/HDL-C ratio.17
These results indicate that lowering LDL-C
and elevating HDL-C might be beneficial to
prevent cardiovascular disease events.
Data in the present study suggest that
rosuvastatin may increase HDL-C in
patients with diabetes who are more likely
to develop hypo-HDL cholesterolaemia.
Other reports have shown that rosuvastatin
can increase HDL-C and decrease LDL-C in
a dose-dependent manner,18,19 suggesting
that it may be more effective at higher
doses than at the low dose used in the
present study. A high LDL-C/HDL-C ratio
has been reported as a risk factor for
cardiovascular events20 and therefore
requires appropriate control. In the present
study the LDL-C/HDL-C ratio decreased by
36.2% at 3 months and 32.2% at 6 months,
but was not well controlled (mean ratios,
2.48 and 2.37, respectively), suggesting that a
further rosuvastatin dose increase would be
necessary to prevent cardiovascular events.
Potential factors that may affect the
HDL-C-increasing effect of rosuvastatin in
patients with type 2 diabetes were examined.
HDL-C at 3 months was negatively corre-
lated with baseline TG, suggesting that
statins may increase HDL-C less effectively
in patients with higher TG. It has long been
known that patients with type 2 diabetes
464
have hypertriglyceridaemia and hypo-HDL
cholesterolaemia concurrently. In the pre-
sent study, patients with TG <400 mg/dl
were enrolled, with a primary aim of
improving LDL-C levels. The relationship
between TG and HDL-C in lipid metabol-
ism, and the fact that hypo-HDL cholester-
olaemia and hypertriglyceridaemia are
independent risk factors for cardiovascular
events, support the importance of active TG
control.
Multiple regression analysis in the pre-
sent study suggested that the increase in
HDL-C, in response to treatment with
rosuvastatin, was smaller in patients with
higher TG, higher HbA1c and older age at
baseline, compared with other patients.
Insulin resistance in patients with type 2
diabetes is known to reduce the effect of
insulin, which results in a decrease in lipo-
protein lipase activity and an increase in
very-low-density lipoprotein synthesis, des-
pite high blood insulin concentrations.21
These mechanisms may contribute to a
less-marked increase in HDL-C in patients
who have a higher HbA1c or poor glycaemic
control at baseline.
In the present study, TG was shown to
have a statistically significant correlation
with HDL-C at 3 months in both simple
correlation analysis and multiple regression
analysis; however, no such correlation was
shown at 6 months. This may be in part
because fewer patients were followed up at 6
months than at 3 months (26 versus 44
patients, respectively). It may be necessary,
nonetheless, to control HDL-C by selecting
and adjusting dietary therapy, exercise
therapy and pharmacotherapy (including
statins) for individuals with the above-
mentioned risk factors (increased age, high
TG levels and high HbA1c levels).
Nephropathy is one of the most import-
ant complications of diabetes.22 The previ-
ously reported renoprotective effects of
rosuvastatin23,24 were supported in the pre-
sent study by the improvements in eGFR
Journal of International Medical Research 42(2)
observed at both 3 and 6 months, despite
inclusion of fewer patients at the 6 month
follow-up. Since patients with type 2
diabetes often have hypo-HDL cholestero-
laemia and hypertriglyceridaemia concur-
rently, many patients have high LDL-C/
HDL-C ratios despite having not very high
total cholesterol levels. It is noteworthy that
low-dose rosuvastatin not only improved
the lipid parameters, but also improved
eGFR in these patients, who are at height-
ented risk of cardiovascular events. To
further examine this renoprotective effect,
additional analyses were performed in an
attempt to identify a factor or factors that
may have contributed to the improvement of
eGFR in response to treatment with rosu-
vastatin. A significant negative correlation
was demonstrated between the change in
eGFR and the change in LDL-C at 6
months (r2 ¼ 0.36, P < 0.01). Since statins
are known to have lipid metabolism, anti-
inflammatory and antioxidant effects,25 the
significant negative correlation observed in
the present study may be due to the pleio-
tropic effects of rosuvastatin, based on these
mechanisms. In the present study, urine
protein levels were not measured in all
patients, therefore further studies are
required to verify the renoprotective effect
of rosuvastatin in patients with type 2
diabetes and hypo high-density lipoprotein
cholesterolaemia.
While rosuvastatin had no effect on glu-
cose metabolism parameters (such as fasting
blood glucose or HbA1c) in the present
study, large-scale meta-analyses have
reported that the use of statins induced
diabetes, although infrequently, and were
associated with an increased number of new
cases.26,27 It was concluded, however, that
conventional statin therapy should not be
changed, because the benefits for prevention
of cardiovascular events overweigh the glu-
cose metabolism-related risks.26,27 In Japan,
no conclusion has been drawn regarding the
effect of statins on glucose metabolism in the
Katabami et al.
clinical setting,28,29 but HbA1c was not sig-
nificantly affected after long-term (6-month)
treatment with rosuvastatin in the present
study. Given the benefits of statins for
prevention of cardiovascular events, it may
be crucial to continue statin therapy in
patients with type 2 diabetes and dyslipidae-
mia, while monitoring glucose metabolism-
related parameters, including HbA1c.
Although all statins (including rosuvastatin)
may induce various side-effects,30 no adverse
effects were observed following rosuvastatin
therapy, throughout the study period, in the
present analysis.
The results of the present study may be
limited by the fact that there is no alternative
study arm for comparison. In addition, the
period of the study was relatively short at
6 months and the patient numbers were
relatively low, especially at the 6-month
timepoint.
In conclusion, this small-scale 6-month
study showed that low-dose rosuvastatin
markedly decreased LDL-C and improved
low HDL-C levels by 11–12%, in patients
with type 2 diabetes and hypo high-density
lipoprotein cholesterolaemia. Rosuvastatin
treatment appeared to be useful in improv-
ing hypo-HDL cholesterolaemia, in add-
ition to other lipid parameters, in these
patients. Although the effects of statins on
glucose metabolism are yet to be established
in Japan,28,29 low-dose rosuvastatin – a
hydrophilic statin – had no effect on glucose
metabolism in the present study. In add-
ition, low-dose rosuvastatin improved
eGFR, a measure of renal function.
Declaration of conflicting interest
The authors declare that there are no conflicts of
interest.
Funding
This research received no specific grant from any
funding agency in the public, commercial, or not-
for-profit sectors.
465
Acknowledgements
We wish to thank the patients, investigators, and
their staff for participating in this study.
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