Diabetes Care 1

Hiroshi Itoh,1 Issei Komuro,2

Intensive Treat-to-Target Statin Masahiro Takeuchi,3 Takashi Akasaka,4
Hiroyuki Daida,5 Yoshiki Egashira,6
Therapy in High-Risk Japanese Hideo Fujita,7 Jitsuo Higaki,8 Ken-ichi Hirata,9
Shun Ishibashi,10 Takaaki Isshiki,11
Patients With Sadayoshi Ito,12 Atsunori Kashiwagi,13
Satoshi Kato,14 Kazuo Kitagawa,15
Hypercholesterolemia and Masafumi Kitakaze,16 Takanari Kitazono,17
Masahiko Kurabayashi,18
Diabetic Retinopathy: Report of Katsumi Miyauchi,19 Tomoaki Murakami,20
Toyoaki Murohara,21 Koichi Node,22
a Randomized Study Susumu Ogawa,23 Yoshihiko Saito,24
https://doi.org/10.2337/dc17-2224 Yoshihiko Seino,25 Takashi Shigeeda,26
Shunya Shindo,27 Masahiro Sugawara,28
Seigo Sugiyama,29 Yasuo Terauchi,30
Hiroyuki Tsutsui,31 Kenji Ueshima,32
Kazunori Utsunomiya,33
Masakazu Yamagishi,34
Tsutomu Yamazaki,35 Shoei Yo,36
Koutaro Yokote,37 Kiyoshi Yoshida,38
Michihiro Yoshimura,39
Nagahisa Yoshimura,40 Kazuwa Nakao,41 and
Ryozo Nagai,42 for the EMPATHY
Investigators
OBJECTIVE
Diabetes is associated with high risk of cardiovascular (CV) events, particularly in
patients with dyslipidemia and diabetic complications. We investigated the in-
cidence of CV events with intensive or standard lipid-lowering therapy in patients
with hypercholesterolemia, diabetic retinopathy, and no history of coronary artery 1
Department of Endocrinology, Metabolism and
disease (treat-to-target approach). Nephrology, Keio University School of Medicine,
Tokyo, Japan
RESEARCH DESIGN AND METHODS 2
Department of Cardiovascular Medicine, The

CARDIOVASCULAR AND METABOLIC RISK

In this multicenter, prospective, randomized, open-label, blinded end point study, University of Tokyo Graduate School of Medi-
eligible patients were randomly assigned (1:1) to intensive statin therapy targeting cine, Tokyo, Japan
3
Department of Clinical Medicine (Biostatistics
LDL cholesterol (LDL-C) <70 mg/dL (n = 2,518) or standard statin therapy targeting and Pharmaceutical Medicine), School of Phar-
LDL-C 100–120 mg/dL (n = 2,524). macy, Kitasato University, Tokyo, Japan
4
Department of Cardiovascular Medicine, Wa-
RESULTS kayama Medical University, Wakayama, Japan
5
Mean follow-up was 37 6 13 months. LDL-C at 36 months was 76.5 6 21.6 mg/dL in Department of Cardiovascular Medicine, Grad-
uate School of Medicine Juntendo University,
the intensive group and 104.1 6 22.1 mg/dL in the standard group (P < 0.001). The Tokyo, Japan
primary end point events occurred in 129 intensive group patients and 153 standard 6
Sakura Hospital, Fukuoka, Japan
group patients (hazard ratio [HR] 0.84 [95% CI 0.67–1.07]; P = 0.15). The relationship 7
Department of Cardiology, Saitama Medical
between the LDL-C difference in the two groups and the event reduction rate was Center, Jichi Medical University, Saitama, Japan
8
Department of Integrated Medicine and Informat-
consistent with primary prevention studies in patients with diabetes. Exploratory ics, Ehime University Graduate School of Medicine,
findings showed significantly fewer cerebral events in the intensive group (HR 0.52 Toon, Japan
[95% CI 0.31–0.88]; P = 0.01). Safety did not differ significantly between the two
9
Division of Cardiovascular Medicine, Department
of Internal Medicine, Kobe University Graduate
groups.
School of Medicine, Kobe, Japan
10
Division of Endocrinology and Metabolism,
CONCLUSIONS
Department of Internal Medicine, Jichi Medical
We found no significant decrease in CV events or CV-associated deaths with intensive University, Shimotsuke, Japan
11
therapy, possibly because our between-group difference of LDL-C was lower than Division of Cardiology, Cardiovascular Center,
Ageo Central General Hospital, Ageo, Japan
expected (27.7 mg/dL at 36 months of treatment). The potential benefit of achieving 12
Division of Nephrology, Endocrinology and Vas-
LDL-C <70 mg/dL in a treat-to-target strategy in high-risk patients deserves further cular Medicine, Tohoku University Graduate School
investigation. of Medicine, Sendai, Japan
Diabetes Care Publish Ahead of Print, published online April 6, 2018
2 Intensive Statin Therapy in High-Risk Patients
Dyslipidemia and impaired glucose me-
tabolism in diseases such as diabetes are
known risk factors for cardiovascular dis-
ease; patients with both conditions are at
even greater risk of cardiovascular (CV)
events (1–3). Meta-analysis (4) has asso-
ciated lower levels of LDL cholesterol
(LDL-C) with reduced risk of CV events in
patients with type 2 diabetes, and the risk
of CV events increases further in patients
with diabetic retinopathy (5,6). However,
little evidence is currently available on
the efficacy of lipid therapy specifically in
these very high-risk patients.
The association of lower LDL-C and
reduced risk of CV events has spurred
interest in a treat-to-target approach,
adjusting the drug dose to achieve a
specific LDL-C target. However, at the
time of this study, almost all large-scale
lipid-lowering clinical studies with statins
were either placebo controlled or com-
pared treatment results based on statin
type or dose (7). The authors of the 2013
American College of Cardiology (ACC)/
American Heart Association (AHA) guide-
line on lipid management (8) thus con-
cluded that evidence was insufficient to
prove the benefits of treat-to-target and
did not include specific treat-to-target
levels.
To explore the potential benefits of
treat-to-target in very high-risk patients,
13
Kusatsu General Hospital, Kusatsu, Japan
14
Department of Ophthalmology, The University
of Tokyo Graduate School of Medicine, Tokyo,
Japan
15
Department of Neurology, Tokyo Women’s
Medical University School of Medicine, Tokyo,
Japan
16
Division of Cardiology, National Cerebral and
Cardiovascular Center, Suita, Japan
17
Department of Medicine and Clinical Science,
Graduate School of Medical Sciences, Kyushu
University, Fukuoka, Japan
18
Department of Medicine and Biological Science,
Gunma University Graduate School of Medicine,
Maebashi, Japan
19
Department of Cardiology, Graduate School of
Medicine Juntendo University, Tokyo, Japan
20
Department of Ophthalmology, Kyoto Univer-
sity Graduate School of Medicine, Kyoto, Japan
21
Department of Cardiology, Nagoya University
Graduate School of Medicine, Nagoya, Japan
22
Department of Cardiovascular Medicine, Saga
University, Saga, Japan
23
Division of Nephrology, Endocrinology and Vas-
cular Medicine, Tohoku University Hospital, Sendai,
Japan
24
First Department of Internal Medicine, Nara
Medical University, Kashihara, Japan
25
Department of Cardiology, Nippon Medical School
Chiba Hokuso Hospital, Inzai, Japan
we conducted a large-scale clinical study
in patients with hypercholesterolemia and
diabetic retinopathy (type 2 diabetes). Few
prospective clinical studies have evaluated
the efficacy of intensive lipid-lowering ther-
apy specifically in primary prevention pa-
tients with diabetes, particularly for reducing
risk through lipid-lowering intervention in
hypercholesterolemic patients with dia-
betic retinopathy.
The standard versus intEnsive statin
therapy for hypercholesteroleMic Patients
with diAbetic retinopaTHY (EMPATHY)
study examined whether intensive lipid-
lowering therapy is superior to standard
therapy in reducing the incidence of CV
events in patients with hyperlipidemia
and diabetic retinopathy but no history
of coronary artery disease. Patients were
divided into two groups targeting differ-
ent LDL-C levels (,70 or $100 and
,120 mg/dL). Statin therapy, regardless
of statin type, was used to control LDL-C
at the targeted level in each group. Safety
and efficacy were compared between
groups.
The EMPATHY study is the first to assess
the benefits of intensive versus standard
statin therapy for patients with hypercho-
lesterolemia and diabetic retinopathy in a
primary prevention setting. The study also
evaluates the appropriateness of treat-to-
target, because all patients were treated
26
Ideta Eye Clinic, Kumamoto, Japan
27
Department of Cardiovascular Surgery, Tokyo
Medical University Hachioji Medical Center,
Hachioji, Japan
28
Sugawara Medical Clinic, Tokyo, Japan
29
Department of Cardiology, Jinnouchi Hospital,
Kumamoto, Japan
30
Department of Endocrinology and Metabo-
lism, Yokohama City University School of Med-
icine, Yokohama, Japan
31
Department of Cardiovascular Medicine, Faculty
of Medical Sciences, Kyushu University, Fukuoka,
Japan
32
Department of EBM Research, Institute for Ad-
vancement of Clinical and Translational Science,
Kyoto University Hospital, Kyoto, Japan
33
Division of Diabetes, Metabolism and Endo-
crinology, Department of Internal Medicine, The
Jikei University School of Medicine, Tokyo, Japan
34
Department of Cardiovascular and Internal Med-
icine, Kanazawa University Graduate School of
Medicine, Kanazawa, Japan
35
Clinical Research Support Center, The Univer-
sity of Tokyo Hospital, Tokyo, Japan
36
Yo Clinic, Kyoto, Japan
37
Department of Clinical Cell Biology and Med-
icine, Chiba University Graduate School of Med-
icine, Chiba, Japan
38
Sakakibara Heart Institute of Okayama, Okayama,
Japan
Diabetes Care
to achieve specific LDL-C targets by titrat-
ing statin therapy.
RESEARCH DESIGN AND METHODS
Study Design
The study used a multicenter, prospec-
tive, randomized, open-label, blinded end
point (PROBE) design (9) and enrolled pa-
tients at hospitals and family practice clin-
ics across Japan. The study was conducted
under the Declaration of Helsinki and Jap-
anese ethical guidelines for clinical studies.
The protocol was reviewed and approved
by the institutional review board of each
participating center.
Patients
Patients who had elevated LDL-C and di-
abetic retinopathy without a history of
coronary artery disease were eligible for
participation (Supplementary Material).
All patients were enrolled by the inves-
tigators and provided written informed
consent.
Randomization and Masking
A data center provided the computer-
generated allocation sequence, stratified
by sex, age, and baseline hemoglobin A1c
(HbA1c). After patient eligibility was con-
firmed, the investigator contacted the data
center for the allocated treatment. Staff who
generated the allocation sequence were not
involved in patient enrollment.
39
Division of Cardiology, Department of Internal
Medicine, The Jikei University School of Medi-
cine, Tokyo, Japan
40
Kitano Hospital, The Tazuke Kofukai Medical Re-
search Institute, Osaka, Japan
41
Medical Innovation Center, Kyoto University Grad-
uate School of Medicine, Kyoto, Japan
42
Jichi Medical University, Shimotsuke, Japan
Corresponding author: Hiroshi Itoh, hiito@keio
.jp.
Received 24 October 2017 and accepted 12
March 2018.
Clinical trial reg. no. UMIN000003486, www
.umin.ac.jp/ctr/.
This article contains Supplementary Data online
at http://care.diabetesjournals.org/lookup/suppl/
doi:10.2337/dc17-2224/-/DC1.
© 2018 by the American Diabetes Association.
Readers may use this article as long as the work
is properly cited, the use is educational and not
for profit, and the work is not altered. More infor-
mation is available at http://www.diabetesjournals
.org/content/license.
care.diabetesjournals.org
This study was designed to evaluate
the treat-to-target approach, so investiga-
tors could not be blinded to statin types
and doses. We thus selected a PROBE
design rather than a double-blind design.
To eliminate bias, defined end points
were evaluated by a blinded end point
committee.
Procedures
As previously described (9), this PROBE
study constituted a run-in period (4–8
weeks) and a treatment period (2–5.5
years). During run-in, patients received
oral statin monotherapy targeting LDL-C
between 100 and 120 mg/dL. Patients
were then assessed for eligibility and
randomly assigned (1:1) to oral intensive
therapy (targeting LDL-C ,70 mg/dL) or
standard therapy (targeting LDL-C be-
tween 100 and 120 mg/dL). LDL-C levels
were calculated from the Friedewald for-
mula. LDL-C targets were based on guide-
lines in the U.S. and Japan when the
study was designed (10,11). Each inves-
tigator independently selected a statin
for the run-in and treatment periods
for each patient. Statin dose escalation
and switching to another statin were
permitted in both groups. The investi-
gators generally measured LDL-C once
monthly for 6 months after study start to
confirm that the treatment target had
been reached. After that point, LDL-C
was measured every 6 months if values
remained within the treatment target, or
more frequently at the discretion of the
physician (for example, after LDL-C ex-
ceeded the target treatment range, to
confirm that the treatment target had
been reacquired) (9).
Concomitant lipid-lowering therapy was
prohibited with fibrates, ezetimibe, ethyl
icosapentate, anion exchange resins, pro-
bucol, nicotinic acid derivatives, phytoster-
ols, elastase, dextran sulfate sodium sulfur,
pantethine, or polyenephosphatidylcholine.
Details of treatment for diabetes and
hypertension were provided previously,
along with medical histories, baseline
findings, and changes during the treat-
ment period in parameters such as body
weight, blood pressure, blood chemistry,
and electrocardiogram (9). Statin treat-
ment adherence, concomitant use of other
drugs, and adverse events (AEs) were in-
vestigated periodically throughout the
study. The physician determined adher-
ence by questioning each patient during
each visit to the hospital and recording
the patient’s answers. No situations
arose during the study that required
consideration of study discontinuation
or suspension.
Outcomes
The primary and secondary outcomes
of the EMPATHY study were previously
described (9) (Supplementary Material).
The primary outcome was the composite
incidence of CV events, including cardiac,
cerebral, renal, and vascular events, or
CV-associated death. The secondary out-
comes included death from any cause,
individual incidence of study-defined CV
events for the primary end point, inci-
dence of stroke, change in laboratory
variables related to chronic kidney dis-
ease (CKD), and safety. Items assessed for
safety are listed in the Supplementary
Material. Primary and secondary end
points were adjudicated by an event eval-
uation committee whose members were
unaware of the treatment allocation.
In the previous century, coronary artery
disease and stroke were the primary end
points in most large-scale clinical studies of
statins. However, the relationship between
CKD and arteriosclerosis began to be more
widely accepted from about 2000. Today
ischemic heart disease, cerebrovascular
disease, peripheral vascular disease, and
renal impairment are widely understood
to be ischemic conditions, and a meta-
analysis of randomized control and cross-
over studies has shown that statins inhibit
proteinuria and progression of nephropa-
thy (12). We thus selected a range of
primary end points based on arterioscle-
rosis, including renal events.
Statistical Analysis
Statistical methods for the EMPATHY study
were previously described (9). The planned
sample size was 5,000 patients, 2,500 in
each treatment group. This was consid-
ered sufficient to detect a hazard ratio
(HR) of 0.65 for the superiority of inten-
sive therapy with a power of 80% and a
two-sided significance level of 5%. The
incidence of CV events during the
3-year treatment period was estimated
at 2.7% for intensive therapy and 4.1%
for standard therapy, based on earlier
reports in the literature (13–16). We
used these estimates to calculate the sam-
ple size, assuming a withdrawal rate of
15% and a study period of 4.5 years. We
estimated 179 occurrences of the pri-
mary end point by the end of the study.
Itoh and Associates 3
The full analysis set (FAS) was selected
as the main analysis set for efficacy. The
primary and secondary end points were
analyzed in the same way in the FAS and
the per protocol set, and results for the
two sets were examined for consistency.
The FAS comprised all randomly allocated
subjects for whom efficacy data were
available. The per protocol set comprised
all members of the FAS, except for sub-
jects who did not qualify or were not
treated and cases of protocol violation or
noncompliance. All subjects who received
the study treatment at least once and for
whom safety information was available
were included in the safety analysis set.
In all analyses, each subject was included
in the allocation group.
We compared the primary end point
between the treatment groups by log-rank
test, stratified by sex, age, and baseline
HbA1c, and used a stratified Cox propor-
tional hazards model to estimate the HR
and 95% CI.
Interim analysis was performed during
the study at a prespecified time point,
adjusted by the Lan-DeMets a spending
function with O’Brien-Fleming boundaries.
An independent data monitoring commit-
tee assessed the analysis results.
The software used was SAS version 9.2
(SAS Institute).
RESULTS
Study Patients
A total of 5,995 patients were enrolled
between May 2010 and October 2013
(Supplementary Fig. 1) at 772 primary
prevention sites (323 hospitals and
449 clinics) in Japan. Of these patients,
5,144 were randomized to intensive
(2,571) or standard (2,573) statin ther-
apy; 53 in intensive therapy and 49 in
standard therapy were subsequently ex-
cluded from data analysis. Data were an-
alyzed from 5,042 patients (2,518 in the
intensive therapy group and 2,524 in the
standard therapy group). Mean follow-up
was 37 6 13 months.
Baseline Characteristics
Patients randomized to the two treatment
groups had similar baseline characteristics
(Table 1). Atorvastatin, rosuvastatin, and
pitavastatin users accounted for 54.8% of
all patients in the intensive group and
54.4% in the standard group at baseline.
The other patients used pravastatin, flu-
vastatin, or simvastatin. At the end of the
study, the proportion of patients using
4 Intensive Statin Therapy in High-Risk Patients Diabetes Care

Table 1—Demographic characteristics (FAS) would be considered “moderate to low-

Intensive therapy Standard therapy
intensity” statin therapy under ACC/AHA
Characteristics (n = 2,518) (n = 2,524) guidelines.
Male 1,200 (47.7) 1,203 (47.7)
Laboratory Values
Age (years)* 63.0 (10.8) 63.2 (10.4)
The mean level of LDL-C for the patients
Height (cm) 158.9 (9.6) 159.0 (9.5)
in the intensive group was 106.2 6
Weight (kg) 65.2 (13.9) 64.9 (13.7) 26.7 mg/dL (median 105.0 mg/dL) at the
BMI† 25.7 (4.3) 25.6 (4.4) start of treatment. That level decreased
Abdominal circumference (cm) 90.4 (10.6) 90.4 (11.1) to 85.6 6 24.3 mg/dL (83.0 mg/dL) after
Lipid-lowering agents‡ 6 months of treatment and continued
None 1,105 (43.9) 1,040 (41.2) to gradually decline over time, reaching
1 drug 1,406 (55.8) 1,481 (58.7)
$2 drugs 7 (0.3) 3 (0.1)
76.5 6 21.6 mg/dL (73.0 mg/dL) at
36 months of treatment. For patients
Statin‡
No 1,201 (47.7) 1,155 (45.8) treated with standard statin therapy,
Yes 1,317 (52.3) 1,369 (54.2) mean LDL-C was 106.1 6 25.9 mg/dL
Smoking§ 462 (18.3) 480 (19.0) (105.0 mg/dL) at the start of treat-
Family history ment and remained at or near that level
Diabetes 1,334 (53.0) 1,308 (51.8) throughout the treatment period. The
Coronary artery disease 325 (12.9) 318 (12.6) difference between the two groups was
Cerebrovascular disease 494 (19.6) 530 (21.0) 23.6 mg/dL at 1 year and 27.7 mg/dL at
Duration of diabetes (years) 12.8 (8.6) 13.0 (9.0) 3 years. The difference was significant
Diabetic complications from 6 to 60 months after the start of
Neuropathy 777 (30.9) 781 (30.9) treatment (Supplementary Fig. 2).
Nephropathy 1,358 (53.9) 1,290 (51.1) Changes in other lipid parameters are
Hypertension 1,777 (70.6) 1,797 (71.2) shown in Supplementary Table 2. Total
Peripheral artery disease (Fontaine class I) 125 (5.0) 110 (4.4) cholesterol and triglycerides were lower
Other complications and medical history 1,971 (78.3) 2,021 (80.1) in the intensive than the standard group.
Compliance with statin use from provisional HDL-C values differed very little between
enrollment to full enrollment the two groups.
None 13 (0.5) 5 (0.2)
Blood pressure, HbA1c, serum creati-
,50 11 (0.4) 6 (0.2)
50–75 36 (1.4) 28 (1.1)
nine, creatine kinase, and hs-CRP are sum-
$75 2,448 (97.2) 2,477 (98.1) marized in Supplementary Fig. 3. Overall
Funduscopy| findings for each treatment group dif-
Simple retinopathy 1,683 (66.8) 1,669 (66.1) fered little over time, including these para-
Preproliferative retinopathy 423 (16.8) 485 (19.2) meters or hematological results, or liver
Proliferative retinopathy 390 (15.5) 355 (14.1) and renal function test results. After treat-
Other¶ 16 (0.6) 10 (0.4) ment for 1 year and thereafter, mean hs-
HbA1c (%)* 7.8 (1.3) 7.8 (1.3) CRP was significantly lower in the intensive
LDL-C (mg/dL)# 106.2 (26.7) 106.1 (25.9) group than the standard group.
Blood pressure (mmHg)
Systolic 134.6 (16.8) 134.6 (16.3) Efficacy End Points
Diastolic 74.9 (11.5) 74.8 (11.1)
The primary outcome, combined incidence
Estimated glomerular filtration rate
of CV events or deaths associated with CV
(mL/min/1.73 m2) 74.0 (20.6) 74.6 (20.3)
events, was lower in the intensive group
Data are mean (SD) or n (%). *Values were obtained at the time of consent. †The BMI is the weight (LDL-C target ,70 mg/dL, 129 patients)
in kilograms divided by the square of the height in meters. ‡Values were obtained at provisional
enrollment. §Not including past smokers. |Diagnosed by ophthalmologists based on the than the standard group (LDL-C target
modified Davis classification. ¶Includes 17 patients who had a history of laser therapy but no $100 and ,120 mg/dL, 153 patients),
funduscopic findings at enrollment. The remaining nine patients were found to be retinopathy but that difference was not statistically
negative after enrollment. #Values were calculated using the Friedewald equation; LDL-C = total significant (HR 0.84 [95% CI 0.67–1.07];
cholesterol 2 (HDL-C 1 triglyceride/5).
P = 0.15) (Fig. 1). Calculated values for the
primary and secondary outcomes are listed
atorvastatin, rosuvastatin, and pitavasta- intensive group; the mean doses for the in Supplementary Table 3.
tin increased (95.6%) in the intensive standard group remained essentially un- The incidence of deaths from any
group but remained nearly unchanged changed over the course of the study cause did not differ significantly between
(53.4%) in the standard group. For all (Supplementary Table 1). It should be the two groups (HR 1.21 [95% CI 0.77–
statin types, dose at baseline was nearly noted that the statin dose for “intensive” 1.91]) (Fig. 2). The incidence of cerebral
identical between the intensive and stan- therapy in Japan is lower than in the events (cerebral infarction or cerebral
dard groups. By the last visit, statin dose U.S. and Europe; at the last visit in this revascularization) decreased significantly
had increased for all statin types in the study, the dose in the intensive group in the intensive group (HR 0.52 [95% CI
care.diabetesjournals.org Itoh and Associates 5

Figure 1—Cumulative event curve for the primary end point (A) and HR of the primary and secondary end points (each component of primary end points)
in the intensive and standard therapy groups (B). Cardiac events included myocardial infarction, unstable angina requiring unscheduled hospitalization, or
coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting). Cerebral events included cerebral infarction or
cerebral revascularization. Renal events included initiation of chronic dialysis or increase in serum creatinine level by at least twofold (and .1.5 mg/dL).
Vascular events included aortic disease or peripheral arterial disease (aortic dissection, mesenteric artery thrombosis, severe lower limb ischemia
[ulceration], revascularization, or finger/lower limb amputation caused by arteriosclerosis obliterans). P value was calculated using a stratified log-rank
test with sex (male or female), age (,60 or $60 years), and baseline HbA1c (,8.4 or $8.4 [NGSP%]) as stratification factors. HR (95% CI) was estimated
using a stratified Cox proportional hazards model with sex (male or female), age (,60 or $60 years), and baseline HbA1c (,8.4 or $8.4 [NGSP%]) as
stratification factors; P values for secondary end points are nominal. NGSP, national glycohemoglobin standardization program.

0.31–0.88]) (Fig. 1), as did the incidence
of cerebral infarction (HR 0.54 [95%
CI 0.32–0.90]) (Fig. 2). The incidence of
stroke (cerebral infarction, cerebral hem-
orrhage, and subarachnoid hemorrhage),
cerebral hemorrhage, and subarachnoid
hemorrhage did not differ between the
groups (HR 0.64 [95% CI 0.40–1.01], HR
1.34 [95% CI 0.46–3.86], and HR [NA],
respectively). No other significant differ-
ences were noted. The HR for cardiac
events was 0.93 (95% CI 0.65–1.33), for
renal events 1.07 (95% CI 0.72–1.58), and
for vascular events 1.00 (95% CI 0.38–
2.67) (Supplementary Table 3).
Change and percent change from
baseline to 36 months in the parameters
for CKD were evaluated as a secondary
end point. Estimated glomerular filtration
rate decreased by 5.9 mL/min/1.73 m2
(7.8%) in the intensive group and 6.5
mL/min/1.73 m2 (8.3%) in the standard
group. Urine albumin increased by 85.3 mg/g
creatinine (343.2%) and 86.5 mg/g creat-
inine (300.8%), and urine protein in-
creased 10.7 mg/dL (1,503.1%) and
11.0 mg/dL (236.1%) in the intensive
and standard groups, respectively. None
of these parameters differed significantly
between the intensive and standard groups
(Supplementary Table 4).
As part of an exploratory analysis, we
performed subgroup analysis of the pri-
mary end point for both treatment
groups based on various demographic
factors (Supplementary Fig. 4). No sig-
nificant heterogeneity of treatment ef-
fects was seen in any of the factors
examined.
Safety
Overall, a similar percentage of patients
in both groups experienced AEs (inten-
sive 75.3%; standard 75.2%) and serious
AEs (intensive 21.3%; standard 22.0%)
(Table 2). A significantly higher proportion
of patients experienced adverse drug re-
actions (ADRs) in the intensive group
(10.1%) than the standard group (6.7%)
(P , 0.001), but most of those ADRs were
mild. The proportion of serious ADRs was
similar between groups (1.3% vs. 0.9%;
P = 0.22).
CONCLUSIONS
The EMPATHY study assessed the bene-
fits of intensive statin monotherapy for
lipid management in patients with hyper-
cholesterolemia and diabetic retinopathy
in a primary prevention setting. The study
also evaluated the appropriateness of the
treat-to-target approach in this patient
population. Results indicated that lipid-
lowering therapy targeting LDL-C ,70 mg/dL
had no more beneficial effect on the primary
end point than therapy targeting LDL-C of
100–120 mg/dL. In exploratory findings, the
secondary end points of cerebral events and
6 Intensive Statin Therapy in High-Risk Patients Diabetes Care

Figure 2—Cumulative event curve for secondary end points in the intensive and standard therapy groups; death from any cause (A), stroke (B), cerebral
infarction (C), cerebral hemorrhage (D), and subarachnoid hemorrhage (E). P value was calculated using a stratified log-rank test with sex (male or
female), age (,60 or $60 years), and baseline HbA1c (,8.4 or $8.4 [NGSP%]) as stratification factors. HR (95% CI) was estimated using a stratified Cox
proportional hazards model with sex (male or female), age (,60 or $60 years), and baseline HbA1c (,8.4 or $8.4 [NGSP%]) as stratification factors;
P values for secondary end points are nominal. NGSP, national glycohemoglobin standardization program.

cerebral infarction were reduced significantly
in the intensive group. No major safety
concerns were noted.
The Improved Reduction of Out-
comes: Vytorin Efficacy International Trial
(IMPROVE-IT) (17) demonstrated the use-
fulness of intensive lipid therapy for the
secondary prevention of CV events, using
statin and ezetimibe to achieve LDL-C
as low as 50 mg/dL. Our study focused
on primary prevention to expand the
evidence regarding intensive lipid man-
agement using statin monotherapy. How-
ever, our results differed from those
previous studies using statins.
care.diabetesjournals.org Itoh and Associates 7

Table 2—Safety issues: AEs and ADRs

Intensive therapy (n = 2,511) Standard therapy (n = 2,518)
Events (n) Patients (n [%]) Events (n) Patients (n [%]) P value
AEs Total 7,832 1,890 (75.3) 8,189 1,894 (75.2) 0.97
Serious 815 535 (21.3) 901 554 (22.0) 0.55
ADRs Total 368 253 (10.1) 218 168 (6.7) ,0.001
Serious 41 32 (1.3) 28 23 (0.9) 0.22
Main AEs
Hepatobiliary disorders Total 82 71 (2.8) 52 48 (1.9) 0.03
Serious 29 22 (0.9) 14 13 (0.5) 0.13
Renal and urinary disorders Total 200 166 (6.6) 250 215 (8.5) 0.01
Serious 26 21 (0.8) 28 28 (1.1) 0.39
Rhabdomyolysis Total 3 3 (0.1) 4 4 (0.2) 1.00
Serious 1 1 (0.0) 1 1 (0.0) 1.00
Myopathy Total 1 1 (0.0) 0 0 0.50
Serious 1 1 (0.0) 0 0 0.50
Cancer* Total 132 114 (4.5) 107 120 (4.2) 0.63
Serious 94 81 (3.2) 91 80 (3.2) 0.94
P values were calculated using the Fisher exact test. *Including neoplasms benign, malignant, and unspecified, including cysts and polyps.

Why did our study fail to show superior
results for intensive therapy? EMPATHY
included some soft end points that re-
quired subjective assessment, such as re-
vascularization, and renal events that
were attributable to arteriosclerosis. To
evaluate these effects on the study results,
we compared the groups using three-
point major CV events (CV death, nonfatal
myocardial infarction, and nonfatal stroke)
and the primary end point after excluding
renal events. We found no significant
differences (HR 0.82 [95% CI 0.58–1.14]
and HR 0.76 [95% CI 0.57–1.01], respec-
tively) (Supplementary Fig. 5), suggesting
that our study findings were unaffected
by either soft end points or renal events.
Primary end point incidence was 20.41/
1,000 person-years in the standard group
and 17.27/1,000 person-years in the in-
tensive group. The cumulative incidence
at 3 years was 5.8% and 5.4%, respec-
tively, exceeding our earlier estimates of
4.1% and 2.7%. The statistical power of
the study was thus sufficient to detect
significant differences in CV events be-
tween the two groups.
We believe that this study failed to
find a significant reduction in the primary
end point because of the smaller-than-
predicted difference in LDL-C between
the two treatment groups. Our planned
between-group difference in LDL-C was
;40 mg/dL (,70 mg/dL for the intensive
group vs. ;110 mg/dL for the standard
group), and the HR was predicted to be
0.65. However, after 3 years of treatment,
the actual LDL-C difference was 27.7 mg/dL
(76.5 vs. 104.1 mg/dL).
In exploratory findings, we compared
our results to the Cholesterol Treatment
Trialists’ (CTT) meta-analysis (18) and
three primary prevention studies in pa-
tients with diabetes (13–15). We graphed
the relationship between changes in
LDL-C and proportional reduction in event
rate (major CV events including major
coronary events [coronary death or non-
fatal myocardial infarction], stroke of
any type, and coronary revascularization
[angioplasty or bypass grafting]). Inter-
estingly, the slope of the line for the di-
abetes studies seems to be steeper than
the original CTT line (Supplementary Fig.
6). Next, we plotted the findings of the
EMPATHY study. In our study, the predic-
ted between-group difference in LDL-C of
;40 mg/dL should have provided a re-
duction of ;30% in major CV events,
close to this data line and to the originally
predicted primary event reduction rate
(HR 0.65). The observed 20% reduction in
major CV events (HR 0.80 [95% CI 0.59–
1.07]) is quite similar to the reduction that
would be predicted by Supplementary
Fig. 6, given the observed 23.6 mg/dL
reduction in LDL-C (after 1 year). In other
words, the primary results of the EMPA-
THY study, despite not being significant,
are consistent with previous findings. We
hypothesize that if we had achieved the
predicted difference of 40 mg/dL LDL-C
between two treatment groups, the pri-
mary end point would have reached sta-
tistical significance. This suggests that
aggressive LDL-C management may further
reduce risk in patients with conditions such
as hyperlipidemia and diabetic retinopathy.
To further clarify the reasons for the
failure to demonstrate the efficacy of in-
tensive therapy, we performed post hoc
analysis, classifying patient data into four
subcategories (mean LDL-C ,70, 70 to
,100, 100 to ,120, and $120 mg/dL
during the study). Our exploratory find-
ings tended to show event prevention at
lower LDL-C values in both the intensive
and standard groups (Supplementary
Fig. 7). We plan additional exploratory
analysis of between-group comparison,
limited to patients in each group with
LDL-C levels within the targeted range.
We obtained preliminary results show-
ing that the event rate for the primary
end point was significantly lower in the
intensive group than in the standard group.
Our findings from that subanalysis will be
published separately.
In an intervention study where the
control group also receives statin ther-
apy, the duration of follow-up is of
considerable importance. Non-Japanese
studies with a relative difference in LDL-C of
40–50% between two groups required
2 years to show significance in incidence
between groups (19,20). EMPATHY follow-
up time was 3 years, but the between-
group difference in LDL-C was lower than
anticipated; longer follow-up might have
shown greater between-group difference.
Our study data indicated that intensive
therapy favorably affected cerebral events,
particularly cerebral infarction. An in-
ference of significant reduction cannot
be supported given the lack of a statistically
significant difference in the primary end
point. However, we note that in the Stroke
8 Intensive Statin Therapy in High-Risk Patients
Prevention by Aggressive Reduction in
Cholesterol Levels (SPARCL) study (21),
statin therapy effectively reduced cere-
brovascular events when LDL-C was low-
ered to 70 mg/dL, whereas in the Japan
Statin Treatment Against Recurrent
Stroke (J-STARS) study (22), where
LDL-C levels were reduced only to 100
mg/dL, no such efficacy was detected.
Exploratory results from EMPATHY were
similar to those from SPARCL in that LDL-
C reached 70 mg/dL and may confirm that
a decrease in LDL-C contributes to reduc-
ing the event risk for cerebral infarction.
Of further interest, the Japan Diabetes
Complications Study (JDCS) (2) reported
that the incidences of coronary heart
disease and stroke were 9.59/1,000 and
7.45/1,000 person-years, respectively, in
Japanese patients with type 2 diabetes.
In EMPATHY, the incidences of cardiac
events and stroke were 8.13/1,000 and
6.14/1,000 person-years, respectively, in
the standard group. The incidences of
cardiac events and ischemic stroke were
surprisingly similar between the JDCS and
EMPATHY. This is noteworthy because the
EMPATHY study targeted patients who
were already under statin therapy, and
the LDL-C baseline in the standard group
(106 mg/dL) was substantially lower than
in the JDCS patients (120 vs. 135 mg/dL).
These findings suggest that Japanese pa-
tients with diabetic retinopathy may be at
particularly high risk for CV events.
No major AE or severe ADR increases
were associated with statin monotherapy
targeting LDL-C ,70 mg/dL, and rhabdo-
myolysis occurred at a similar rate in both
groups. This suggested low potential risk
for excessive LDL-C reduction by statin
monotherapy. Aggressive LDL-C lowering
might be associated with increased levels
of cerebral hemorrhage, since cerebral
hemorrhage increased with intensive ther-
apy in the SPARCL study (21). However,
subsequent investigation of SPARCL
showed that on-treatment LDL-C did
not predict cerebral hemorrhage (23).
EMPATHY findings showed no intergroup
differences in cerebral hemorrhage, po-
tentially eliminating concerns of in-
creased cerebral hemorrhage risk due to
intensive statin therapy. Although con-
cerns have been raised over worsening of
HbA1c due to statin therapy (24,25), no
such effects were noted in this study.
Key strengths of this study were imple-
mentation of the first-ever assessment
of benefits of intensive statin therapy in
patients with hypercholesterolemia and
diabetic retinopathy in primary preven-
tion; suitability assessment of a treat-to-
target approach for LDL-C management by
titrating statin therapy; and inclusion of
clinics as over half the participating sites so
that patient management was closer to
routine clinical practice, which is advanta-
geous for assessing real-world effects of
lipid-lowering therapy.
Limitations of this study were the use
of PROBE rather than double-blind com-
parison of the two treatment methods;
inclusion of soft end points (although those
end points were assessed by a blinded
independent committee to ensure objec-
tivity); unexpectedly high patient discon-
tinuation from data loss during a major
earthquake, which may have reduced study
power even though discontinuations were
well balanced between the two groups;
and failure to control LDL-C within the
target range in some patients in both
groups, resulting in a smaller-than-planned
intergroup difference in LDL-C that possibly
affected study power. Median LDL-C level
at 6 months in the intensive group was
83.0 mg/dL, indicating failure to reach the
protocol-stipulated target LDL-C level
of ,70 mg/dL. In real-world clinical prac-
tice, many Japanese physicians who are
not lipid management experts worry
about adverse effects such as intracranial
hemorrhage from intensive LDL-C lower-
ing, and may have been somehow af-
fected by these concerns even when
the protocol stipulated the aggressive tar-
get of ,70 mg/dL.
In conclusion, the intensive therapy tar-
geting LDL-C ,70 mg/dL did not reduce
the incidence of composite CV events
more significantly than the standard therapy
targeting LDL-C $100 and ,120 mg/dL.
However, based on previous studies in
patients with diabetes in a primary pre-
vention setting, the event reduction rate
in this study is consistent with expect-
ations regarding the LDL-C difference that
was achieved and might be clinically mean-
ingful. Exploratory results suggest that in-
tensive therapy reduces cerebral events,
especially cerebral infarction, with no in-
crease in AEs in this population.
Acknowledgments. EDIT, Inc. (Tokyo, Japan) pro-
vided medical writing and editing.
Funding and Duality of Interest. This work was
supported by Shionogi & Co., Ltd. H.I. reports
grants and personal fees from Shionogi & Co., Ltd.
Diabetes Care
during the conducting of the study and grants and
personal fees from Takeda Pharmaceutical Co.,
Ltd., Nippon Boehringer Ingelheim Co., Ltd.,
Daiichi Sankyo Co., Ltd., MSD K.K., Mitsubishi
Tanabe Pharma Corp., Shionogi & Co., Ltd., and
Taisho Toyama Pharmaceutical Co., Ltd., grants
from Sumitomo Dainippon Pharma Co., Ltd.,
Astellas Pharma Inc., Kyowa Hakko Kirin Co.,
Ltd., Teijin Pharma Ltd., Mochida Pharmaceutical
Co., Ltd., Ono Pharmaceutical Co., Ltd., Chugai
Pharmaceutical Co., Ltd., Eli Lilly and Company
Japan K.K., and personal fees from Nipro Corp.,
and SBI Pharmaceuticals Co., Ltd. outside the
submitted work. I.K. reports personal fees from
Shionogi & Co., Ltd. during the conducting of the
study and grants and personal fees from Takeda
Pharmaceutical Co., Ltd., Nippon Boehringer
Ingelheim Co., Ltd., Astellas Pharma Inc., Daiichi
Sankyo Co., Ltd., and Otsuka Pharmaceutical Co.,
Ltd., grants from MSD K.K., Shionogi & Co., Ltd.,
GlaxoSmithKline K.K., Sanofi K.K., Genzyme Japan
K.K., Sumitomo Dainippon Pharma Co., Ltd.,
Mitsubishi Tanabe Pharma Corp., and Bristol-
Myers Squibb Company outside the submitted
work. M.T. reports personal fees from Shionogi &
Co., Ltd. during the conducting of the study. T.A.
reports personal fees from Shionogi & Co., Ltd.
during the conducting of the study and grants and
personal fees from St. Jude Medical Japan Co.,
Ltd., Terumo Corp., Daiichi Sankyo Co., Ltd., and
Abbott Vascular Japan Co., Ltd., grants from
Goodman Co., Ltd., Otsuka Pharmaceutical Co.,
Ltd., Pfizer Japan Inc., Bayer Yakuhin, Ltd., and
Boston Scientific Corp., and personal fees from
Nippon Boehringer Ingelheim Co., Ltd. outside
the submitted work. H.D. reports grants and
personal fees from Shionogi & Co., Ltd. during
the conducting of the study, grants and personal
fees from AstraZeneca K.K., Astellas Pharma Inc.,
Abbott Vascular Japan Co., Ltd., Otsuka Pharma-
ceutical Co., Ltd., Kaken Pharmaceutical Co., Ltd.,
Kissei Pharmaceutical Co., Ltd., Kyowa Hakko
Kirin Co., Ltd., Kowa Pharmaceutical Company
Ltd., Sanofi K.K., Daiichi Sankyo Co., Ltd., Sumi-
tomo Dainippon Pharma Co., Ltd., Takeda Phar-
maceutical Co., Ltd., Terumo Corp., Nippon
Boehringer Ingelheim Co., Ltd., Bayer Yakuhin,
Ltd., Pfizer Japan Inc., Philips Respironics GK,
Bristol-Myers Squibb Company, Sanwa Kagaku
Kenkyusho Co., Ltd., Mitsubishi Tanabe Pharma
Corp., MSD K.K., and GlaxoSmithKline K.K., grants
from Eisai Co., Ltd., Teijin Pharma Ltd., Nippon
Shinyaku Co., Ltd., VitalAire Japan K.K., Fujifilm RI
Pharma Co., Ltd., Boston Scientific Corp., Fuji
Chemical Industries Co., Ltd., Fukuda Denshi
Co., Ltd., and Actelion Pharmaceuticals Japan
Ltd., and personal fees from ASKA Pharmaceutical
Co., Ltd., Chugai Pharmaceutical Co., Ltd., Taisho
Toyama Pharmaceutical Co., Ltd., Toa Eiyo Ltd.,
Ono Pharmaceutical Co., Ltd., Medtronic Japan
Co., Ltd., and Mochida Pharmaceutical Co., Ltd.
outside the submitted work. Y.E. reports non-
financial support from Shionogi & Co., Ltd. during
the conducting of the study. H.F. reports other
fees (consultant) from Mehergen Group Hold-
ings, Inc. outside the submitted work. J.H. reports
grants and personal fees from Shionogi & Co., Ltd.
during the conducting of the study and grants and
personal fees from Astellas Pharma Inc., Nippon
Boehringer Ingelheim Co., Ltd., Mochida Pharma-
ceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Takeda
Pharmaceutical Co., Ltd., Sumitomo Dainippon
care.diabetesjournals.org
Pharma Co., Ltd., MSD K.K., Teijin Pharma Ltd.,
Actelion Pharmaceuticals Japan Ltd., Otsuka Phar-
maceutical Co., Ltd., Novartis Pharma K.K., and
Sanwa Kagaku Kenkyusho Co., Ltd. outside the
submitted work. K.H. reports personal fees and
nonfinancial support from Shionogi & Co., Ltd.
during the conducting of the study, grants and
personal fees from Daiichi Sankyo Co., Ltd. and
Mochida Pharmaceutical Co., Ltd., grants from
Actelion Pharmaceuticals Japan Ltd., Eisai Co.,
Ltd., Otsuka Pharmaceutical Co., Ltd., Sumitomo
Dainippon Pharma Co., Ltd., Takeda Pharmaceu-
tical Co. Ltd., Nippon Boehringer Ingelheim Co.,
Ltd., Bayer Yakuhin, Ltd., Sysmex Corp., Med-
tronic Japan Co., Ltd., and St. Jude Medical Japan
Co., Ltd., and personal fees from Kowa Pharma-
ceutical Co., Ltd. outside the submitted work. S.Is.
reports grants and personal fees from Shionogi &
Co., Ltd. during the conducting of the study,
grants and personal fees from Amgen Astellas
BioPharma K.K., Astellas Pharma Inc., Daiichi
Sankyo Co., Ltd., Eli Lilly and Company Japan
K.K., Kowa Pharmaceutical Co., Ltd., Nippon
Boehringer Ingelheim Co., Ltd., Kissei Pharmaceu-
tical Co., Ltd., MSD K.K., Novartis Pharma K.K.,
Mitsubishi Tanabe Pharma Corp., Ono Pharma-
ceutical Co. Ltd., Sanofi K.K., Takeda Pharmaceu-
tical Co., Ltd., Taisho Toyama Pharmaceutical Co.,
Ltd., and Teijin Pharma Ltd., grants from Fujifilm
Pharma Co., Ltd., Sumitomo Dainippon Pharma
Co., Ltd., and Kyowa Hakko Kirin Co., Ltd., and
personal fees from AstraZeneca K.K., Bayer
Yakuhin, Ltd., Novo Nordisk Pharma Ltd., Pfizer
Japan Inc., and Sanwa Kagaku Kenkyusho Co., Ltd.
outside the submitted work. T.I. reports personal
fees and nonfinancial support from Shionogi &
Co., Ltd. during the conducting of the study
and grants and personal fees from Sanofi K.K.,
Sumitomo Dainippon Pharma Co., Ltd., and Daiichi
Sankyo Co., Ltd., grants from Takeda Pharmaceu-
tical Co., Ltd., and Mitsubishi Tanabe Pharma
Corp., and personal fees from Astellas Pharma
Inc., AstraZeneca K.K., and MSD K.K. outside the
submitted work. S.It. reports grants, personal
fees, and nonfinancial support from Shionogi &
Co., Ltd. during the conducting of the study. A.K.
reports personal fees and nonfinancial support
from Shionogi & Co., Ltd. during the conducting
of the study and personal fees from Astellas
Pharma Inc., Sunstar Group Ltd., Eli Lilly and
Company Japan K.K., Sanofi K.K., AstraZeneca
K.K., Takeda Pharmaceutical Co., Ltd., Taisho
Toyama Pharmaceutical Co., Ltd., Nippon Boehringer
Ingelheim Co., Ltd., Kowa Pharmaceutical Co.,
Ltd., and Sanwa Kagaku Kenkyusho Co., Ltd. out-
side the submitted work. S.K. reports grants from
Shionogi & Co., Ltd. during the conducting of the
study. K.K. reports grants and personal fees from
Shionogi & Co., Ltd. during the conducting of the
study. M.Ki. reports grants and personal fees
from Shionogi & Co., Ltd. during the conducting
of the study, grants and personal fees from
Astellas Pharma Inc., Sanofi K.K., Pfizer Japan
Inc., Ono Pharmaceutical Co., Ltd., Novartis
Pharma K.K., Mitsubishi Tanabe Pharma Corp.,
Kyowa Hakko Kirin Co., Ltd., Abbott Japan Co.,
Ltd., and Otsuka Pharmaceutical Co., Ltd., grants
from the Japanese government, Japan Heart
Foundation, Japan Cardiovascular Research Foun-
dation, Calpis Co., Ltd., and Nihon Kohden Corp.,
and personal fees from Daiichi Sankyo Co., Ltd.,
Bayer Yakuhin Ltd., Nippon Boehringer Ingelheim
Co., Ltd., Kowa Pharmaceutical Co., Ltd., Sumitomo
Dainippon Pharma Co., Ltd., Sawai Pharma-
ceutical Co., Ltd., MSD K.K., Shionogi & Co.,
Ltd., AstraZeneca K.K., Asahi Kasei Medical Co.,
Ltd., Novo Nordisk Pharma Ltd., Fujifilm RI
Pharma Co., Ltd., and Japan Medical Data outside
the submitted work. T.K. reports grants and
personal fees from Shionogi & Co., Ltd. during
the conducting of the study, grants and personal
fees from Daiichi Sankyo Co., Ltd. and Bayer
Yakuhin Ltd., and grants from MSD K.K., Novartis
Pharma K.K., Astellas Pharma Inc., and Pfizer
Japan Inc. outside the submitted work. M.Ku.
reports personal fees from Shionogi & Co., Ltd.
during the conducting of the study and grants and
personal fees from Shionogi & Co., Ltd. outside
the submitted work. K.M. reports other (meeting
attendance fee) from Shionogi & Co., Ltd. during
the conducting of the study. T.Mura. reports
personal fees from Shionogi & Co., Ltd. during
the conducting of the study. T.Muro. reports
personal fees from Shionogi & Co., Ltd. during
the conducting of the study, grants and personal
fees from Daiichi Sankyo Co., Ltd., Pfizer Japan
Inc., Kowa Pharmaceutical Co., Ltd., MSD K.K.,
and Mitsubishi Tanabe Pharma Corp., and per-
sonal fees from AstraZeneca K.K. outside the
submitted work. K.N. reports nonfinancial sup-
port from Shionogi & Co., Ltd. during the con-
ducting of the study. S.O. reports personal fees
and nonfinancial support from Shionogi & Co.,
Ltd. during the conducting of the study. Y.Sa.
reports grants, personal fees, and nonfinancial
support from Shionogi & Co., Ltd. during the
conducting of the study and grants, personal
fees, and other (advisory boards) from MSD
K.K., Ono Pharmaceutical Co., Ltd., Mitsubishi
Tanabe Pharma Corp., Pfizer Japan Inc., Novartis
Pharma K.K., grants and personal fees from
Daiichi Sankyo Co., Ltd., Bayer Yakuhin, Ltd.,
Otsuka Pharmaceutical Co., Ltd., Sumitomo Dai-
nippon Pharma Co., Ltd., Astellas Pharma Inc.,
and Takeda Pharmaceutical Co., Ltd., and grants
from Baxter Ltd., Kyowa Hakko Kirin Co., Ltd.,
Teijin Pharma Ltd., Eisai Co., Ltd., Zeria Pharma-
ceutical Co., Ltd., Nihon Medi-Physics Co., Ltd.,
Chugai Pharmaceutical Co., Ltd., Genzyme Japan
K.K., and Medtronic Japan Co., Ltd. outside the
submitted work. Y.Se. reports personal fees from
Shionogi & Co., Ltd. during the conducting of the
study and grants and personal fees from Otsuka
Pharmaceutical Co., Ltd. and Nippon Boehringer
Ingelheim Co., Ltd., and grants from Mitsubishi
Tanabe Pharma Corp., Fujifilm RI Pharma Co.,
Ltd., Roche Diagnostics K.K., MSD K.K., Pfizer
Japan Inc., Bayer Yakuhin, Ltd., and Shionogi &
Co., Ltd. outside the submitted work. T.S. reports
personal fees and nonfinancial support from
Shionogi & Co., Ltd. during the conducting of
the study. S.Sh. reports personal fees and non-
financial support from Shionogi & Co., Ltd. during
the conducting of the study. M.S. reports per-
sonal fees and nonfinancial support from
Shionogi & Co., Ltd. during the conducting of
the study. S.Su. reports personal fees from Shio-
nogi & Co., Ltd. during the conducting of the
study and grants from the Ministry of Education,
Culture, Sports, Science, and Technology in Japan
outside the submitted work. Y.T. reports personal
fees from Shionogi & Co., Ltd. during the con-
ducting of the study and grants and personal fees
from Astellas Pharma Inc., AstraZeneca K.K., Bayer
Itoh and Associates 9
Yakuhin, Ltd., Daiichi Sankyo Co., Ltd., Sumitomo
Dainippon Pharma Co., Ltd., Eli Lilly and Company
Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa
Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co.,
Ltd., MSD K.K., Mitsubishi Tanabe Pharma Corp.,
Nippon Boehringer Ingelheim Co., Ltd., Novo
Nordisk Pharma Ltd., Ono Pharmaceutical Co.,
Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Sanofi
K.K., Shionogi & Co., Ltd., Taisho Toyama Phar-
maceutical Co., Ltd., and Takeda Pharmaceutical
Co., Ltd., and personal fees from Novartis Pharma
K.K. outside the submitted work. H.T. reports
personal fees and nonfinancial support from
Shionogi & Co., Ltd. during the conducting of
the study and grants and personal fees from
Daiichi Sankyo Co., Ltd. and Takeda Pharmaceu-
tical Co., Ltd., grants from Novartis Pharma K.K.
and Astellas Pharma Inc., and personal fees from
MSD K.K., Otsuka Pharmaceutical Co., Ltd., Pfizer
Japan Inc., Mitsubishi Tanabe Pharma Corp.,
Teijin Pharma Ltd., Nippon Boehringer Ingelheim
Co., Ltd., and Bayer Yakuhin, Ltd., and Bristol-
Myers Squibb outside the submitted work. K.Ue.
reports other (contracted work) from Shionogi &
Co., Ltd. during the conducting of the study and
personal fees from Shionogi & Co., Ltd. outside
the submitted work. K.Ut. reports personal fees
and nonfinancial support from Shionogi & Co.,
Ltd. during the conducting of the study and grants
from Sanofi K.K., MSD K.K., Taisho Toyama Phar-
maceutical Co., Ltd., Nippon Boehringer lngel-
heim Co., Ltd., Takeda Pharmaceutical Co., Ltd.,
Eli Lilly and Company Japan K.K., and Novo
Nordisk Pharma Ltd. outside the submitted
work. M.Ya. reports personal fees from Shionogi
& Co., Ltd. during the conducting of the study and
other (donation) from Shionogi & Co., Ltd. out-
side the submitted work. T.Y. reports other (lec-
ture fee) from Shionogi & Co., Ltd. during the
conducting of the study. S.Y. reports other (con-
tracted work) from Shionogi & Co., Ltd. during the
conducting of the study. K.Yok. reports personal
fees from Shionogi & Co., Ltd. during the con-
ducting of the study and grants, personal fees,
and nonfinancial support from MSD K.K., grants
and personal fees from Astellas Pharma Inc.,
Daiichi Sankyo Co., Ltd., Sumitomo Dainippon
Pharma Co., Ltd., Kyowa Hakko Kirin Co., Ltd.,
Mochida Pharmaceutical Co., Ltd., Nippon
Boehringer lngelheim Co., Ltd., Ono Pharmaceu-
tical Co., Ltd., Pfizer Japan Inc., Shionogi & Co.,
Ltd., Taisho Toyama Pharmaceutical Co., Ltd.,
Takeda Pharmaceutical Company Ltd., and Mitsubishi
Tanabe Pharma Corp., grants from Bristol-Myers
Squibb Company, Eli Lilly and Company Japan
K.K., Teijin Pharma Ltd., and Toyama Chemical
Co., Ltd., and personal fees from AstraZeneca
K.K., Eisai Co., Ltd., Kowa Company, Ltd., Kowa
Pharmaceutical Co., Ltd., Sanofi K.K., and Sanwa
Kagaku Kenkyusho Co., Ltd. outside the submit-
ted work. K.Yos. reports personal fees and non-
financial support from Shionogi & Co., Ltd. during
the conducting of the study. M.Yo. reports grants
and personal fees from Shionogi & Co., Ltd.
outside the submitted work. N.Y. reports per-
sonal fees from Shionogi & Co., Ltd. during the
conducting of the study and personal fees
from Shionogi & Co., Ltd. outside the submitted
work. K.N. reports other (contracted) work from
Shionogi & Co., Ltd. during the conducting of the
study and grants from Takeda Pharmaceutical
Co., Ltd. and Fujifilm Pharma Co., Ltd. outside
10 Intensive Statin Therapy in High-Risk Patients
the submitted work. R.N. reports personal fees
from Shionogi & Co., Ltd. during the conducting
of the study and personal fees from Astellas
Pharma Inc., Sumitomo Dainippon Pharma Co.,
Ltd., MSD K.K., Ono Pharmaceutical Co. Ltd.,
Kowa Pharmaceutical Co., Ltd., Mitsubishi Tanabe
Pharma Corp., Nippon Boehringer Ingelheim Co.,
Ltd., Toa Eiyo Ltd., Eisai Co., Ltd., and Nippon
Chemiphar Co., Ltd. outside the submitted work.
No other potential conflicts of interest relevant to
this article were reported.
Author Contributions. H.I., I.K., H.F., T.Muro.,
and T.Y. designed the study, collected and inter-
preted data, and contributed to the writing. M.T.
collected and analyzed data, and contributed to
the writing. T.A., J.H., T.I., A.K., M.Ki., T.K., M.Ku.,
K.No., S.O., Y.Sa., Y.Se., T.S., S.S., and S.Y. inter-
preted data. H.D. and K.Ut. designed the study,
and collected and interpreted data. Y.E. collected
data. K.H., S.It., S.S., K.Yok., and K.Na. designed
the study and interpreted data. S.Is., K.K., Y.T.,
and M.Ya. collected and interpreted data, and
contributed to the writing. S.K. designed the
study, collected data, and contributed to the
writing. K.M. designed the study and collected
data. T.Mura. designed the study. M.S. collected
data and contributed to the writing. H.T. and N.Y.
interpreted data and contributed to the writing.
K.Ue. and R.N. designed the study, interpreted
data, and contributed to the writing. K.Yos. and
M.Yo. collected and interpreted data. All authors
read the drafted manuscript, provided feedback,
and approved the final version of the manuscript.
H.I. is the guarantor of this work and, as such, had
full access to all the data in the study and takes
responsibility for the integrity of the data and the
accuracy of the data analysis.
Prior Presentation. This study was presented at
the European Society of Cardiology Congress
2017 Hot Line session, Barcelona, Spain, 29 Au-
gust 2017.
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