Journal of Atherosclerosis and Thrombosis Vol. 21, No.

563

Original Article

Effects of Pioglitazone on Macrovascular Events in Patients with

Type 2 Diabetes Mellitus at High Risk of Stroke: The PROFIT-J Study
Hidenori Yoshii 1, Tomio Onuma 1, Tsutomu Yamazaki 2, Hirotaka Watada 3, Munehide Matsuhisa 4,
Masayasu Matsumoto 5, Kazuo Kitagawa 6, Masafumi Kitakaze 7, Yoshimitsu Yamasaki 8, Ryuzo Kawamori 9
and the PROFIT-J Study Group

Primary prevention oF hIgh risk Type 2 diabetes in Japan

Department of Medicine, Diabetology and Endocrinology, Juntendo Tokyo Koto Geriatric Medical Center, Juntendo University
School of Medicine, Tokyo, Japan
2
Clinical Research Support Center, University of Tokyo Hospital, Tokyo, Japan
3
Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
4
Diabetes Therapeutics Research Center, The University of Tokushima, Tokushima, Japan
5
Department of Neurology, Hiroshima University Hospital, Hiroshima, Japan
6
Department of Neurology, Stroke Center, Osaka University Graduate School of Medicine, Osaka, Japan
7
Department of Clinical Medicine and Development, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular
Center, Suita, Japan
8
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Osaka, Japan
9
Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan

Aim: The present study evaluated the effects of pioglitazone treatment on the incidence of primary
cardiovascular events in Japanese subjects with type 2 diabetes mellitus at high risk of stroke.
Methods: A prospective, multicenter, randomized, open label, comparative study was conducted
among diabetic patients recruited from 50 medical institutions nationwide. A total of 522 patients
with hypertension and/or dyslipidemia who had one or more silent cerebral infarcts, advanced
carotid atherosclerosis or microalbuminuria at baseline were randomly treated with (n = 254) or without pioglitazone (n = 268) and observed for a medium of 672 days. The hypertension and dyslipidemia were concurrently treated according to the respective treatment guidelines. The primary outcome was the time to the first occurrence of a composite of all-cause death, nonfatal cerebral infarction and nonfatal myocardial infarction.
Results: Treatment with pioglitazone resulted in significant reductions in the levels of HbA1c, diastolic blood pressure and LDL-cholesterol and a significant increase in the levels of HDL-cholesterol.
The pioglitazone non-users exhibited a significant reduction in the LDL-cholesterol levels alone. Primary events were registered during the study period in nine patients in the pioglitazone group and
10 patients in the non-pioglitazone group. The difference in the cumulative incidence of the primary
outcome was not significant between the two groups (1.8% per year).
Conclusions: Pioglitazone therapy produces immediate and effective improvements in glycemic control, diastolic blood pressure and lipid profiles. While this study was too underpowered to determine
the effects of pioglitazone on the incidence of cardiovascular events, the results indicated that two
years of pioglitazone treatment did not produce any statistically significant reductions in the rate of
primary cardiovascular events.
J Atheroscler Thromb, 2014; 21:563-573.
Key words: Pioglitazone, Primary prevention, Mortality-macrovascular events, Diabetes mellitus

Yoshii et al .

564

Introduction
The incidence of diabetes has been increasing
worldwide due to lifestyle and dietary changes. Chronic
hyperglycemia in patients with diabetes causes serious
complications, including micro- and macrovascular
diseases, such as advanced life-threatening ischemic
heart disease and stroke. Importantly, the incidence of
macrovascular diseases is expected to increase in association with the increased prevalence of diabetes.
According to a 4-year follow-up study, risk factors for stroke in patients with type 2 diabetes include
an older age, previous history of cardiovascular disease
or stroke and microvascular complications 1). Carotid
artery atherosclerosis is another risk factor for stroke,
as well as silent cerebral infarction and carotid artery
stenosis 2), in patients with type 2 diabetes, such that
the presence of a common carotid intima-media thickness (IMT) of 1 mm increases the risk of silent cerebral infarction four times compared to its absence 3).
The longevity of patients with diabetes depends
considerably on the development of macroangiopathy.
However, early studies of glucose-lowering therapy
demonstrated that neither primary nor secondary
stroke can be prevented by intensive glucose control in
patients with type 2 diabetes 4). In addition, although
two long-term follow-up studies suggested the importance of blood glucose control with respect to the prevention of macrovascular disease 5, 6), the primary prevention of vascular diseases, including stroke, with the
administration of glucose-lowering agents has thus so
far not been validated in patients with type 2 diabetes 7).
Thiazolidinediones are ligands of the nuclear
transcription factor, peroxisome-proliferator-activated
receptor . Several preclinical studies have indicate that
thiazolidinediones have protective effects against the
development of atherosclerosis 8, 9). However, metaanalyses have reported an increased cardiovascular risk
associated with rosiglitazone use 10, 11). On the other
hand, one meta-analysis of the use of pioglitazone and
cardiovascular safety showed a significant 18% reduction in the risk of a composite of cardiovascular outcomes 12). In addition, pioglitazone therapy has been
found to slow the progression of carotid atherosclerosis compared with glimepiride 13). Furthermore, in a
Address for correspondence: Hirotaka Watada, Department of
Metabolism & Endocrinology, Juntendo University Graduate
School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 1138421, Japan
E-mail: hwatada@juntendo.ac.jp
Received: September 12, 2013
Accepted for publication: December 16, 2013

subanalysis of the PROactive study 14), treatment with

pioglitazone significantly reduced the incidence of secondary stroke by 47% in type 2 diabetics with a history of stroke.
The present study was designed to examine the
effects of pioglitazone therapy on the incidence of primary events of macrovascular disease and mortality
(all-cause death, nonfatal cerebral infarction and nonfatal myocardial infarction) in Japanese patients with
type 2 diabetes at high risk of stroke with a history of
one or more silent cerebral infarcts, advanced carotid
atherosclerosis or albuminuria treated between August
2007 and December 2011.
Materials and Methods
Eligibility and Study Design
The Primary prevention oF hIgh risk Type 2 diabetes in Japan (PROFIT-J) trial was a prospective,
multicenter, randomized, open label, comparative
study of type 2 diabetic patients at high risk of stroke
carried out at 50 medical institutions nationwide.
Patients, both men and women, who had been diagnosed with type 2 diabetes were recruited, excluding
those with a glycated hemoglobin A1c (HbA1c) level
of more than 10.5% (the NGSP value for HbA1c was
calculated using the Japanese Diabetes Society formula, and the HbA1c level was expressed as the
NGSP value in the text) 15). Patients with diabetes mellitus were enrolled if they fulfilled one or more of the
following three criteria: 1) silent cerebral infarction
identified on MRI according to the 2007 guidelines 16);
2) carotid artery atherosclerosis (a mean common
carotid artery IMT of 1 mm), as measured according
to the procedure described previously by Yamasaki et
al.17); and 3) albuminuria (a urinary albumin/creatinine ratio (ACR) of 100 mg/g creatinine in a casual
urine sample).
The subjects ranged from 55 to 85 years old. In
addition to diabetes, they also had hypertension and/
or dyslipidemia, or treated with anti-hypertensive
medications or lipid-lowering agents. The exclusion
criteria included the presence or history of cardiac failure, severe hepatic dysfunction (an ALT 100 or viral
hepatitis), severe renal dysfunction (a serum creatinine
2.5 mg/dL), documented dementia, history of documented cerebral infarction, cerebral hemorrhage,
transient ischemic attack, myocardial infarction,
angina pectoris before study entry, or previous use of
thiazolidinediones within the last 8 weeks of study
entry.
Eligible patients were stratified into 16 bins
according to age at baseline (less than or older than 65

Pioglitazone and Primary Prevention of CVA

years), the HbA1c level (less or higher than 7.7), a

body mass index (BMI) of less or higher than 23.5 kg/
m2 and insulin use (yes or no). The subjects were then
randomly assigned to either the pioglitazone group or
non-pioglitazone group. All patients were treated under
the intent-to-treat principle for three years. The pioglitazone group started with a daily dose of 15 mg pioglitazone, which was then increased up to 45 mg/day
for men and 30 mg/day for women. When the HbA1c
level could not be controlled to 6.9%, other glucose-lowering drugs were added to the treatment regimen. Among the patients who were not treated with
pioglitazone, antidiabetic drugs, excluding pioglitazone,
were used to reduce the HbA1c level to 6.9%. Hypertension and hyperlipidemia were concurrently treated
according to the respective treatment guidelines 18).
The study protocol was approved by the institutional
review board and/or ethics committee of each Hospital/University. All patients provided their written
informed consent. Instructional materials and behavioral counseling for diet therapy were given to each
patient.
This study was registered with the University
Hospital Medical Information Network Clinical Trial
Registry (UMIN000000846).
Study Outcomes and Measured Parameters
The primary outcome of this study was the time
to the first occurrence of any of a composite of allcause death, nonfatal stroke or nonfatal myocardial
infarction. The secondary outcome was the incidence
of cerebral infarction, transient ischemic attack (TIA),
cerebral hemorrhage, myocardial infarction, angina
pectoris, percutaneous coronary intervention/coronary
bypass surgery (PCI/CABG) and acute coronary syndrome, excluding myocardial infarction.
Urinary ACR was conducted as scheduled. Systolic blood pressure (SBP) and diastolic blood pressure
(DBP) were measured in the supine position. The
HbA1c, low-density lipoprotein cholesterol (LDLcholesterol), high-density lipoprotein cholesterol
(HDL-cholesterol) and triglyceride (TG) level were
directly measured at 0, 6, 12, 24 and 36 months during the observation period. Adverse effects, such as
hypoglycemia, peripheral edema, heart failure and
hepatic dysfunction, related to the use of pioglitazone
and other diabetic drugs were examined at each visit.
Statistical Analysis
The Hisayama Study reported that macrovascular events occur at a frequency of 11.6 events per 1,000
patients with diabetes per year 19). The recruited subjects had at least two more risk factors for future car-

565

diovascular events, one of which represented the presence of atherosclerosis or related tissue damage, which
are considered to be higher risk factors than other general risk factors. A previous study demonstrated that
patients with diabetes and two more risk factors
exhibit an almost three-fold increased risk of cardiovascular events compared to patients with diabetes
only 20). Therefore, the incidence of the primary outcome in this study was estimated to be 10% over a
follow-up period of three years among the subjects not
treated with pioglitazone and to diminish by 40%
among the patients treated with pioglitazone. Assuming
a power of 85% and statistical significance of 0.05,
the calculated sample size of one arm was 720. Therefore, the estimated sample size was 1,000 for each arm
of the study.
The mean values are expressed as the meanSD.
Differences in categorical variables between the two
groups were evaluated using Fishers exact test, while
differences in continuous variables between the two
groups were assessed using the unpaired t -test. In the
survival analysis, the last date of survival was defined
by the date of occurrence of the first event or the date
of patient withdrawal.
Chronological changes in the variables were evaluated after excluding patients with missing entry data.
A two-way repeated measured analysis of variance was
performed in each group. If the differences in the
chronological changes or the values observed between
the two groups were significant, the mean values were
evaluated using Dunnetts multiple comparison test.
The cumulative incidence of each event was calculated using the Kaplan-Meier method. Kaplan-Meier
curves were evaluated according to the log-rank test.
The hazard ratio was calculated according to the Cox
proportional hazard model. A p value of 0.05 was
considered to be significant in all analyses. All statistical analyses were performed using the R 2.15.1 software program (R Foundation For Statistical Computing, Wien, Austria).
Results
A pre-designed interim analysis performed on
October 2011 showed that the estimated incidence of
primary outcome was 3.6% during an average intervention period of 562 days, with a forecasted threeyear incidence of 5.4%. The latter rate was almost half
that predicted in the study protocol. The incidence of
primary outcome was less than half of 12% for three
years, which was reported in a follow-up study of Japanese type 2 diabetic patients with advanced atherosclerosis of the carotid artery, urinary microalbumin-

566

Yoshii et al .

Table 1. Baseline characteristics of the participating patients

Males (%)
Age (year)
Height (cm)
Weight (kg)
Body Mass Index (kg/m2)
Waist circumference (cm)
Duration of diabetes mellitus (years)
HbA1c (%)
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
Urinary albumin-creatinine ratio (mg/g Cr)
LDL-cholesterol (mg/dL)
HDL-cholesterol (mg/dL)
Triglyceride (mg/dL)
Glucose-lowering agents used at study entry
Sulfonylurea (%)
-Glucosidase inhibitors (%)
Biguanide (%)
Glinide (%)
Insulin (%)
Dipeptidyl peptidase-4 inhibitors (%)
Other drugs for cardiovascular diseases
Antihypertensive agents (%)
Lipid-lowering agents (%)

Pioglitazone group
(n = 234)

Non-pioglitazone group
(n = 247)

148/234 (63.2)
69.06.9
159.68.7
61.911.4
24.23.3
87.18.2
11.18.8
7.430.84
136.016.8
77.311.1
222.7619.1
115.430.7
54.814.7
140.877.0

163/247 (66.0)
68.97.3
160.38.4
62.410.0
24.33.3
87.68.8
11.59.0
7.430.97
136.115.1
76.010.6
223.5521.4
113.227.0
54.014.5
140.876.0

0.5673
0.8473
0.3979
0.6067
0.8034
0.5468
0.6268
0.9764
0.9730
0.2158
0.9883
0.4197
0.5218
0.9970

105/231 (45.4)
91/231 (39.4)
75/231 (32.5)
29/231 (12.6)
16/231 (6.9)
0/231 (0.0)

116/247 (47.0)
79/247 (32.0)
73/247 (29.6)
43/247 (17.4)
16/247 (6.5)
1/247 (0.4)

0.7832
0.1041
0.5527
0.1596
0.8569
1.0000

131/234 (56.0)
96/234 (41.0)

162/247 (65.6)
114/247 (46.2)

0.0321
0.2707

uria ( 30 mg/g creatinine) or two or more risk factors, such as hypertension, dyslipidemia and obesity 21).
Furthermore, the low incidence observed in this study
was similar (1.7% for one year) to that of Japanese
type 2 diabetic subjects free of a history of previous
cardiovascular events (JPAD study) 22). Moreover, the
Kaplan-Meier curve showed no significant differences
in the primary or secondary endpoints between the
two groups (p = 0.9914). From an ethical point of
view, the data and safety monitoring committee recommended the discontinuation of this study.
Ultimately, a total of 522 diabetic patients (254
patients in the pioglitazone group and 268 patients in
the non-pioglitazone group) were recruited from 50
medical institutions nationwide, comprising 165 patients
with silent cerebral infarction, 204 patients with
advanced carotid atherosclerosis and 173 patients with
microalbuminuria. After excluding eight participants
(six treated with pioglitazone and two treated without
pioglitazone) who withdrew their consent after entry
and 33 participants with a lack of follow-up data, the
remaining 234 patients treated with pioglitazone and
247 patients treated without pioglitazone were fol-

lowed. The mean duration of follow-up until the

interim analysis was 557 days in the pioglitazone
group (n = 234) and 598 days in the non-pioglitazone
group.
The baseline characteristics of the study subjects
are shown in Table 1. The mean age and proportion
of men were similar between the pioglitazone and
non-pioglitazone groups. The HbA1c, LDL-cholesterol, HDL-cholesterol and triglyceride levels were
also similar between the two groups. Furthermore, the
mean systolic/diastolic blood pressure, urinary albumin ACR and creatinine level were similar between
the two groups. There were no differences in the use
of sulfonylureas, -glycosidase inhibitors, biguanides,
glinides, insulin or dipeptidyl peptidase-4 inhibitors at
study entry between the two groups (Table 1). A significantly smaller proportion of patients in the pioglitazone group used antihypertensive medications than
those in the non-pioglitazone group (p = 0.0321); however, no such differences were noted with respect to
the use of lipid-lowing drugs.
The composite endpoint of all-cause death, nonfatal cerebral infarction and nonfatal myocardial

Pioglitazone and Primary Prevention of CVA

567

Cumulative rrate of event (%)

(A) Primary outcome

Pioglitazone
Non-pioglitazone

HR=1.053 (p=0.9114)

200

234
247

190
231

400

600

800

1000

78
80

52
42

Follow-up period (days)

163
208

147
190

(B) Primary + Secondary outcomes

Cumulative rate of event (%)

10

Number at risk
Pioglitazone
Non-ioglitazone

HR=0.995 (p=0.9898)

0
Number at risk
Pioglitazone
234
Non-ioglitazone 247

200

190
230

400

600

800

1000

163
207

147
180

77
80

51
42

Follow-up period (days)

Fig. 1. Kaplan-Meier curves for the primary (A) and secondary outcomes (B) of treatment with
and without pioglitazone.
The hazard ratio and p value were calculated according to the Cox proportional hazard model without
adjustment and the log-rank test, respectively. The primary outcome included a composite endpoint of
all-cause death, nonfatal cerebral infarction and nonfatal myocardial infarction. The secondary outcome included TIA, angina pectoris, PCI/CABG and acute coronary syndrome.

infarction occurred in a total of nine patients (one,

three and five events, respectively) in the pioglitazone
group and 10 patients (two, four and four events,
respectively) in the non-pioglitazone group during the
intervention period (Fig. 1A). The Kaplan-Meier anal-

ysis indicated no differences in the cumulative incidence of the primary outcome between the two groups
(HR: 1.053, 95% CI: 0.427-2.593, p = 0.9114, according to the log-rank test).
With regard to the secondary outcome, three

Yoshii et al .

568

Pioglitazone

HbA11c

8.4
8.0

non-Pioglitazone
non
Pioglitazone

7.4
7.0

**

**

**

**

**

**

**

**

6.0
6.4

**p<0.001 vs. baseline;

5.4
5.0

P<0.001, p<0.0001

12

15

18

21

24

155
199

150
197

145
188

Follow-up period (months)

Number at risk
Pioglitazone
Non-pioglitazone

between groups

233
247

206
241

200
242

187
227

189
227

157
203

Fig. 2. Changes in glycated hemoglobin in the pioglitazone and non-pioglitazone groups.

The difference in HbA1c between each time point and baseline was evaluated using paired Dunnetts t -test, while the differences
between the two groups were examined using Welchs t -test. The vertical bars represent the standard deviation.

events of angina pectoris (1.2%) were recorded in the

pioglitazone group, compared with two events of
angina pectoris and one event of TIA (1.2%) in the
non-pioglitazone group. PCI/CABG and acute coronary syndrome, excluding myocardial infarction, were
not recorded in either group. Similar to that observed
for the primary outcome, the Kaplan-Meier analysis
showed no differences between the two groups in the
cumulative incidence of the primary plus secondary
outcome (HR: 0.995, 95% CI: 0.445-2.222, p =
0.9898, Fig. 1B).
Treatment with pioglitazone resulted in a significant reduction in the mean HbA1c level from 7.43%
at baseline to 7.02% at three months (p 0.0001) and
6.90% at six months (p 0.0001) (Fig. 2). This parameter remained stable at approximately 6.9% during the
two-year observation period. On the other hand, no
significant serial changes were observed in the nonpioglitazone group (baseline: 7.43%). The percentage
of patients with an HbA1c level of 6.9% was significantly (p = 0.0015) higher in the pioglitazone group
(from 24.0% to 49.8%) than in the non-pioglitazone
group (from 28.3% to 36.0%). The proportion of
patients in the non-pioglitazone group requiring other
glucose-lowering drugs tended to be higher than that
of patients in the pioglitazone group.

In the pioglitazone group, the mean HDL-cholesterol level was significantly higher at six months
(59.515.9 mg/dL) relative to the baseline value
(54.814.7 mg/dL, p = 0.012) and remained elevated
during the 24-month treatment period. In comparison, this parameter did not change significantly in the
non-pioglitazone group (Fig. 3A). In both groups, the
LDL-cholesterol levels were significantly lower at 24
months than at baseline (pioglitazone: 107.026.1 vs
115.430.8 mg/dL, non-pioglitazone: 105.426.4
vs 113.227.0 mg/dL, respectively, Fig. 3B). In both
groups, no significant changes were noted in the
serum triglyceride levels (Fig. 3C). The patients in the
pioglitazone group showed a significant reduction in
diastolic blood pressure throughout the intervention
period, although no such changes were observed in
systolic blood pressure. In the non-pioglitazone group,
no significant changes were observed in either systolic
or diastolic blood pressure. Furthermore, there were
no significant changes in body weight, BMI or
abdominal circumference in either group.
The mean urinary ACR decreased from 223
620 at baseline to 201.7412 at 24 months (n = 116)
in the pioglitazone group. In contrast, this parameter
increased from 223521 at baseline to 343913 at
24 months (n = 148) in the non-pioglitazone group.

Pioglitazone and Primary Prevention of CVA

HDL-Cholesteerol

80

569

(A)

70

(p=0.032)**

(p=0.012)**

60
50
40
p=0.0002*

30

p=0.0164*

p=0.0036*

LDL-Cholesteerol (mg/dL)

20

(B)
140
120

(p=0.024)**
(p
0.024)
(p=0.013)**

100
80

Pioglitazone

non-Pioglitazone

60

(C)

*p: between two groups, **p vs baseline

Triglycerid
de (mg/dL)

250

p=0.075*

200
150

(p=0.013)**

100
50
0

12

24

Time (months)
Fig. 3. Changes in blood lipid profiles in the pioglitazone and non-pioglitazone
groups.
The differences in the blood lipid profile between each time point and baseline were evaluated using paired Dunnetts t -test, while the differences between the two groups were tested
using Welchs t -test. The vertical bars represent the standard deviation.

However, these changes were not significant, and there

were no significant differences between the two
groups.
A total of 39 adverse events were registered in 33
patients (rate: 14.1%) in the pioglitazone group, compared with 13 events in 10 patients (5.3%) in the

non-pioglitazone group (p = 0.0001). These events

included peripheral edema (n = 12) and cancer (n = 3)
in the pioglitazone group and cancer (n = 5) and cataracts (n = 3) in the non-pioglitazone group. One patient
in the non-pioglitazone group died from rectal cancer
during the observation period.

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570

Discussion
In a recent multicenter study, we reported the
effectiveness of pioglitazone in reducing the intimamedia thickness of the common carotid artery in Japanese subjects with type 2 diabetes for up to three
years 17). Based on these results, we designed the present study to examine the effects of pioglitazone on
macrovascular diseases (all-cause death, nonfatal cerebral infarction and nonfatal myocardial infarction) in
Japanese patients with type 2 diabetes at high risk of
stroke. However, this study was clearly too underpowered to definitively prove the effectiveness of pioglitazone in reducing macrovascular disease due to the
small sample size. On the other hand, during the
24-month intervention period, treatment with pioglitazone significantly reduced the levels of glycated
hemoglobin, diastolic blood pressure and LDL cholesterol and significantly increased the level of HDL cholesterol. In contrast, the LDL cholesterol level was the
only parameter to show a significant improvement in
the non-pioglitazone group. Some of the positive
effects of pioglitazone identified in the present study
were also previously reported by our group, including
the effects on glycated hemoglobin and HDL cholesterol 17). Other researchers have also reported that pioglitazone therapy results in a significant reduction of
systolic blood pressure in type 2 diabetic patients 23).
Comparing pioglitazone with rosiglitazone, a previous study reported that treatment with pioglitazone
increases the LDL cholesterol level, although the
increase is lower than that achieved with rosiglitazone.
In addition, pioglitazone therapy has been reported to
decrease triglycerides, while rosiglitazone increases triglycerides 24). Furthermore, the HDL cholesterol level
has been reported to increase more significantly following treatment with pioglitazone than with rosiglitazone 25, 26). In the present study, we found a similar
trend with respect to the effects on lipid profiles following pioglitazone treatment.
The present multicenter intervention study demonstrated a discrepancy between risk reduction and
the final outcome, i.e., improvements in several risk
factors in patients treated with pioglitazone, with no
differences in the incidence of cardiovascular events.
What is the reason for this discrepancy ? One explanation is that significant risk reduction for two years
might be insufficient to manifest a significant difference in the primary and secondary outcomes. At baseline, the mean HbA1c level was 7.4%, with a mean
systolic blood pressure of 136 mmHg and a mean
LDL cholesterol of 114 mg/dL. These values were
lower than those reported in the PROactive Study. In

the present study, treatment with pioglitazone resulted

in a reduction of HbA1c to 6.9% at 24 months,
which was smaller than that reported in a previous
study (0.9%) 27). Therefore, these improvements may
not culminate in a significant reduction in the incidence of cardiovascular events.
Another possibility is that a larger proportion of
patients in the non-pioglitazone group required additional glucose-lowering drugs, which may have
resulted in a reduction in the frequency of cardiovascular events comparable to that observed in the pioglitazone group. With regard to the glucose-lowering
drugs used in the present cohort, the proportion of
patients in the non-pioglitazone group treated with
biguanides increased significantly from 40.1% at the
start of the study to 50.8% at 24 months (p 0.05).
In contrast, this proportion decreased from 31.6% to
28.1% in the pioglitazone group. Several studies have
shown that metformin, a representative biguanide,
reduces the rate of cardiovascular events in patients
with type 2 diabetes 28). In addition, a meta-analysis
demonstrated that treatment with acarbose, an -glucosidase inhibitor, reduces cardiovascular events in
type 2 diabetics 29). In the present study, the proportion of patients treated with -glucosidase inhibitors
increased from 39% at baseline to 44% at 24 months
in the non-pioglitazone group, although the change
was not statistically significant.
The third possibility is that the present study
included patients at high risk of stroke, but without a
previous history of stroke. In fact, we enrolled diabetic
patients who met one or more of the three entry criteria: silent cerebral infarction, advanced carotid atherosclerosis (an IMT of 1.0 mm) or albuminuria (an
ACR of 100 mg/g creatinine). Evidence suggests
that these conditions are associated with an increased
frequency of cardiovascular events. Indeed, in the subanalysis of the PROactive study, treatment with pioglitazone was found to be significantly reduce the incidence of secondary stroke by 47% in the type 2 diabetes patients with a previous history of stroke 1). However, that subanalysis also showed that pioglitazone
therapy reduced the incidence of the primary outcome
by only 6% (p = 0.350) and did not decrease the incidence of primary stroke (HR = 1.06). Taken together,
the results of the subanalysis of the PROactive study
and our present findings suggest that the risk of primary stroke in the present study is comparable to that
observed in patients without a previous history of
stroke rather than those with a previous history of
stroke in the PROactive study.
In conclusion, the present study indicated that
treatment with pioglitazone produces immediate and

Pioglitazone and Primary Prevention of CVA

effective improvements in glycemic control, blood

pressure and lipid profiles in type 2 diabetic patients
at high risk of stroke, compared with non-pioglitazone
medications. The observed incidence of all-cause
death, nonfatal cerebral and myocardial infarction
decreased to a low level (1.8% per year), which is
comparable with that observed in Japanese type 2 diabetics without a history of cardiovascular disease.
However, our results indicate that the favorable effects
of two years of treatment with pioglitazone did not
translate into a reduction in the incidence of primary
cardiovascular events relative to that observed with
treatment with other agents.
Acknowledgments
This study was supported by the Japan Cardiovascular Research Foundation.
Conflicts of Interest
TY has received lecture fees from Astrazeneca,
Shionogi, Dainippon Sumitomo Pharm and Takeda
Pharmaceutical Co. and research funds from Astrazeneca and Dainippon Sumitomo Pharm. HW has
received lecture fees from Boehringer Ingelheim, SanofiAventis, Ono Pharmaceutical Co., Novo Nordisk
Pharma, Novartis Pharmaceuticals, Eli Lilly, Sanwakagaku Kenkyusho, Daiichi Sankyo Inc., Takeda Pharmaceutical Co., MSD, Dainippon Sumitomo Pharm.
and Kowa Co. and research funds from Boehringer
Ingelheim, Pfizer, Mochida Pharmaceutical Co. SanofiAventis, Novo Nordisk Pharma, Novartis Pharmaceuticals, Sanwakagaku Kenkyusho, Terumo Corp. Eli
Lilly, Mitsubishi Tanabe Pharma, Daiichi Sankyo Inc.,
Takeda Pharmaceutical Co., MSD, Shionogi, Pharma,
Dainippon Sumitomo Pharma, Kissei Pharma and
Astrazeneca. MM has received lecture fees from SanofiAventis, Novo Nordisk Pharma, Novartis Pharmaceuticals and Mitsubishi Tanabe Pharma and research
funding from Terumo Corp. Nikkiso Corp. KK has
received lecture fees from Sanofi-Aventis. RK has
received lecture fees from Takeda Pharmaceutical Co.,
Sanofi-Aventis, Dainippon Sumitomo Pharm., Novartis Pharmaceuticals, Eli Lilly, Boehringer Ingelheim,
Daiichi Sankyo Inc., MSD, Astrazeneca and Shionogi.
Appendix
Organizing Committee: Ryuzo Kawamori (Chair),
Yoshimitu Yamasaki, Hirotaka Watada, Munehide Matsuhisa
Event Ascertainment Committee: Masayasu Mat-

571

sumoto, Shunsuke Otsuki, Kazuo Kitagawa, Masafumi Kitakaze

Data and safety monitoring committee: Masayasu
Matsumoto, Masafumi Kitakaze
Medical expert for the epidemiological analysis:
Tutomu Yamazaki
Participants in the Profit-J study group:
Bellland General Hospital: Toshihito Yagi, Ebina
General Hospital: Shun Itoh, Ehime Prefecture Central Hospital: Osamu Ebisui, Yasuhiro Inoue, Keizo
Ohno and Hitoo Tokunaga, Ehime Prefecture Imabari
Hospital: Yasuhiko Hara, Handa Medical Clinic:
Nobuo Handa, Hiroshima Red Cross Hospital &
Atomic-bomb Survivors Hospital: Hideki Nojima,
Hiroshima University Hospital: Kiminori Yamane,
Ikebuchi Clinic: Motoyoshi Ikebuchi, Iwashina Clinic:
Hirozumi Iwashina, Juntendo Tokyo Koto Geriatric
Medical Center: Takashi Nomiyama, Tomio Onuma,
Keiko Yamashiro and Hidenori Yoshii, Juntendo
University Nerima Hospital: Masahiko Kawasumi,
Toshiko Narahashi, Masumi Tanimoto and Tomoaki
Yoshihara, Juntendo University Hospital: Shinji Hagiwara, Akio Kanazawa, Kazunori Shimada and Hirotaka Watada, Juntendo University Shizuoka Hospital:
Jong Bock Choi, Juntendo University Urayasu Hospital: Saeko Kimura, Hajime Koyano and Masashi Taki,
Kanda Internal Clinic: Tsutomu Kanda, Kansai Rosai
Hospital: Tsunehiko Yamamoto, KKR Takamatsu
Hospital: Satoshi Murao, Koga General Hospital:
Tadanobu Kuribayashi, Matsushima clinic: Hiroyuki
Matsushima, Mihara Medical Association Hospital:
Ken Okusaki, Miyake Internal/Gastro Clinic: Yasuyuki Miyake, Naka Memorial Clinic: Takeshi Osonoi,
Naoki Owada and Miyoko Saito, Nakajima Internal
Clinic: Yuzuru Nakajima, Nishiyodo Hospital: Yoshie
Yuuki, Osaka University hospital: Hideaki Kanetou
and Takaaki Matsuoka, Osaka General Medical Center: Kentarou Ikeda, Otoshi Medical Clinic: Kentaro
Ohtoshi, Shiraiwa Medical Clinic: Toshihiko Shiraiwa,
Yano Internal Clinic: Makoto Yano, Yotsuba Circulation Clinic: Mitsunori Abe, Yura Hospital: Hiroyuki
Fujieda, Daisuke Ogawa, Jun Wada
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