Adv Ther (2014) 31:621–638
DOI 10.1007/s12325-014-0126-8
ORIGINAL RESEARCH
Empagliflozin Monotherapy in Japanese Patients
with Type 2 Diabetes Mellitus: a Randomized,
12-Week, Double-Blind, Placebo-Controlled,
Phase II Trial
Takashi Kadowaki • Masakazu Haneda • Nobuya Inagaki • Yasuo Terauchi • Atsushi Taniguchi
Kazuki Koiwai • Henning Rattunde • Hans J. Woerle • Uli C. Broedl
To view enhanced content go to www.advancesintherapy.com
Received: May 6, 2014 / Published online: June 24, 2014
Ó Springer Healthcare 2014
ABSTRACT
Introduction: This study was designed to
determine the efficacy and tolerability of
empagliflozin monotherapy in Japanese
patients with type 2 diabetes mellitus (T2DM).
Methods: Patients with glycosylated hemoglobin
(HbA1c) C7.0–B10% were randomized via an
interactive web response system, and treated
double-blind with empagliflozin 5, 10, 25,
Trial registration: ClinicalTrials.gov #NCT01193218.
On behalf of the EMPA-REG DOSEJAPANTM trial
investigators.
Electronic supplementary material The online
version of this article (doi:10.1007/s12325-014-0126-8)
contains supplementary material, which is available to
authorized users.
T. Kadowaki
Department of Diabetes and Metabolic Diseases,
Graduate School of Medicine, The University of
Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, Japan
M. Haneda
Department of Medicine, Asahikawa Medical
University, Midorigaoka Higashi 2-1-1-1,
Asahikawa, Hokkaido 078-8510, Japan
N. Inagaki
Department of Diabetes, Endocrinology and
Nutrition, Graduate School of Medicine, Kyoto
University, 54 Shogoin-Kawaramachi, Sakyo-ku,
Kyoto 606-8507, Japan
•
50 mg, or placebo once daily for 12 weeks. The
primary endpoint was change from baseline in
HbA1c at week 12. Other endpoints included
percentage of patients with HbA1c \7.0% and
changes from baseline in fasting plasma glucose
(FPG), body weight, and systolic blood pressure
(SBP) at week 12.
Results: A total of 547 patients were
randomized and treated with empagliflozin
5 mg (n = 110), 10 mg (n = 109), 25 mg
(n = 109), 50 mg (n = 110), or placebo
(n = 109) for 12 weeks. Adjusted mean [95%
confidence interval (CI)] differences vs. placebo
in changes from baseline in HbA1c were
-0.72% (-0.87, -0.57) with empagliflozin
5 mg, -0.70% (-0.85, -0.55) with 10 mg,
-0.95% (-1.10, -0.80) with 25 mg, and -0.91
Y. Terauchi
Department of Endocrinology and Metabolism,
Graduate School of Medicine, Yokohama City
University, Yokohama, Kanagawa 236-0004, Japan
A. Taniguchi
K. Koiwai (&)
Clinical Development and Medical Affairs TA-
Diabetes, Nippon Boehringer Ingelheim Co., Ltd.,
Think Park Tower, 2-1-1 Osaki, Shinagawa-ku,
Tokyo 141-6017, Japan
e-mail: kazuki.koiwai@boehringer-ingelheim.com
H. Rattunde
H. J. Woerle
U. C. Broedl
Boehringer Ingelheim Pharma GmbH & Co. KG,
Binger Strasse 173, 55216 Ingelheim, Germany
622
(-1.06, -0.76) with 50 mg (all p\0.001). More
patients with HbA1c C7.0% at baseline reached
HbA1c \7.0% with empagliflozin (19–33%)
than placebo (3%). Compared with placebo,
empagliflozin reduced FPG, body weight
(p\0.001 for all doses for both endpoints) and
SBP (p = 0.001, p = 0.014 and p = 0.003 for
empagliflozin 10, 25, and 50 mg, respectively).
Adverse events were reported by 42% of patients
receiving placebo and 33–38% of patients
receiving empagliflozin. There were few
reports of confirmed hypoglycemic adverse
events or events consistent with urinary tract
infection or genital infection in any treatment
group.
Conclusions: Empagliflozin monotherapy for
12 weeks in Japanese patients with T2DM
reduced HbA1c, FPG, body weight and SBP,
and was well tolerated.
Keywords: Empagliflozin; Glycemic control;
Japanese; Monotherapy; Sodium glucose
cotransporter 2 (SGLT2); Type 2 diabetes
mellitus; Weight
INTRODUCTION
Type 2 diabetes mellitus (T2DM) has been
identified as a healthcare priority by the Japan
Ministry of Health, Labour and Welfare as a
result of the rapidly increasing prevalence and
economic burden of the disease [1]. It was
estimated that there were 7.1 million people
with diabetes in Japan in 2010 (with the
majority of cases being T2DM), which is
predicted to reach 8.9 million in 2030 [2, 3],
due to a growing elderly population and
changes in lifestyle and diet [1, 4].
The management of T2DM in Japan has
mainly involved oral agents such as
sulfonylureas, with increasing use of
Adv Ther (2014) 31:621–638
combination therapy (including biguanides,
meglitinides, a-glucosidase inhibitors and
thiazolidinediones) [5, 6]. However, many of
these treatments are associated with limitations,
including hypoglycemia and weight gain [7].
More recently, DPP-IV inhibitors have become
available. The Japan Diabetes Society
recommends a glycosylated hemoglobin
(HbA1c) target of \6.0% to normalize blood
glucose levels and a target of \7.0% to prevent
complications [8]; however, many patients do
not achieve this level of glycemic control.
The sodium glucose cotransporter 2 (SGLT2),
located in the proximal tubule of the kidney,
facilitates the reabsorption of the majority of
the *180 g of glucose filtered through the
kidneys every day [9]. In patients with T2DM,
SGLT2 inhibition reduces the capacity of the
kidneys to reabsorb glucose, leading to
increased urinary glucose excretion (UGE) and
decreased blood glucose levels [10].
Empagliflozin is a potent and selective
SGLT2 inhibitor [11] that has been shown to
increase UGE in both Japanese and non-
Japanese healthy individuals [12, 13] and
patients with T2DM [14, 15]. In Phase II
studies in non-Japanese patients with T2DM,
empagliflozin 10 and 25 mg used as
monotherapy or as add-on therapy to
metformin improved glycemic control and
reduced body weight and systolic blood
pressure (SBP) [16–18]. Empagliflozin was well
tolerated, with a low incidence of hypoglycemia
[12, 15–18]. More recently, these results have
been supported by data from Phase III studies,
in which reductions in HbA1c were observed
after 24 weeks’ treatment with empagliflozin, in
addition to reductions in weight and blood
pressure, with a low risk of hypoglycemia
[19–23].
This Phase IIb study evaluated the efficacy
and tolerability of once-daily empagliflozin (5,
Adv Ther (2014) 31:621–638
10, 25, and 50 mg) compared with placebo for
12 weeks as monotherapy in Japanese patients
with T2DM and insufficient glycemic control.
METHODS
Study Design
This was a 12-week, randomized, double-blind,
placebo-controlled, parallel-group, dose-finding
study conducted in 32 centers in Japan. The
study was registered with ClinicalTrials.gov
#NCT01193218. All procedures followed were
in accordance with the ethical standards of
the responsible committee on human
experimentation (institutional and national),
and with the Helsinki Declaration of 1975,
as revised in 2000 and 2008, and in
accordance with the International Conference
on Harmonization Harmonized Tripartite
Guideline for Good Clinical Practice, and the
Japanese Good Clinical Practice regulations
(Ministry of Health and Welfare Ordinance
No. 28, March 27, 1997). Informed consent
was obtained from all patients for being
included in the study. The study was approved
by respective Institutional Review Boards and
Competent Authorities according to national
and international regulations.
Patients
This study enrolled male and female patients
with T2DM [aged C20 and B80 years; body mass
2
index (BMI) C18 and B40 kg/m ) on a diet and
exercise regimen who were drug-naive (no anti-
diabetes agents for C10 weeks prior to consent)
and had an HbA1c C7.0% and B10.0% at
screening, or had been receiving 1 oral anti-
diabetes agent other than thiazolidinedione,
glucagon-like peptide analogs or insulin
(unchanged for C10 weeks prior to consent)
623
and had an HbA1c C6.5–B9.0% at screening.
Patients had to have an HbA1c C7.0% and
B10.0% at the start of the 2-week placebo run-in
period.
Key exclusion criteria included uncontrolled
hyperglycemia [plasma glucose [240 mg/dL
([13.3 mmol/L) after an overnight fast during
the washout/placebo run-in period, confirmed
by a second measurement], moderate or severe
renal impairment (estimated glomerular
filtration rate [eGFR] \60 mL/min/1.73 m2;
using the Japanese GFR estimation equation
recommended by the Japanese Society of
Nephrology [24]) or indication of liver disease
(serum alanine aminotransferase, aspartate
aminotransferase, or alkaline phosphatase
[3 9 upper limit of normal) prior to
randomization. Patients were excluded if they
had acute coronary syndrome, a stroke or
transient ischemic attack within 12 weeks of
consent, were receiving anti-obesity drugs
within 12 weeks of consent, had undergone
bariatric surgery within 2 years, were receiving
systemic steroids at the time of consent, had a
change in the dose of thyroid hormones within
6 weeks of consent, or had an uncontrolled
endocrine disorder other than T2DM. Women
of child-bearing potential were required to use
adequate contraception.
Randomization and Interventions
Following screening, patients who had been
receiving unchanged doses of an oral anti-
diabetes agent underwent a 4-week washout
period followed by a 2-week, open-label,
placebo run-in period; drug-naive patients
underwent a 2-week, open-label placebo run-in
period. Eligible patients were randomized
(1:1:1:1:1) to receive once-daily oral
empagliflozin 5, 10, 25, 50 mg, or placebo as
monotherapy for 12 weeks. This was followed
624 Adv Ther (2014) 31:621–638

by a 40-week randomized extension period, in overnight fast, a patient had a confirmed

which patients who received empagliflozin 10 plasma glucose level [240 mg/dL
or 25 mg in the first 12-week treatment period ([13.3 mmol/L) during the first 12-week
continued this treatment, and patients treated treatment period. The choice and dosage of
with placebo, empagliflozin 5 or 50 mg in the rescue therapy (except for pioglitazone) were at
first 12-week treatment period were reallocated the discretion of the investigator, according to
to empagliflozin 10 or 25 mg. Patients received local prescribing information. Short-term
diet and exercise counseling based on local insulin (B2 weeks) was permitted in the event
recommendations. Randomization was of an emergency or hospitalization, at the
performed using a computer-generated discretion of the investigator/treating
random sequence and an interactive web physician.
response system, stratified by previous anti-
diabetes medication (sulfonylurea, non- Endpoints and Assessments
sulfonylurea, none), HbA1c (\8.5% and
C8.5%) and renal function [eGFR \90 mL/ The efficacy and safety results at week 12 are
min/1.73 m2 (impaired) and C90 mL/min/ reported here; results from the 40-week
1.73 m2 (normal)] at screening. In all study extension period will be reported in a separate
arms, four visits were scheduled during the first manuscript. The primary endpoint was change
12-week treatment period. from baseline in HbA1c at week 12. Secondary
Rescue therapy could be initiated at the endpoints were the percentage of patients with
discretion of the investigator if, after an HbA1c C7.0% at baseline who achieved HbA1c

Fig. 1 Patient disposition. AE adverse event, FAS full analysis set [all patients who received C1 dose of study medication
and had a baseline glycosylated hemoglobin (HbA1c) assessment]
Adv Ther (2014) 31:621–638 625

\7.0% at week 12 and change from baseline in
fasting plasma glucose (FPG) at week 12.
Baseline was defined as the last observation
prior to the first intake of randomized study
medication.
Exploratory endpoints included: changes
from baseline in body weight,
circumference, SBP and diastolic blood
pressure (DBP) at week 12; percentage of
patients with [5% reduction in body weight at
week 12; and percentage of patients who had
uncontrolled blood pressure at baseline who
had controlled blood pressure (SBP\130 mmHg
and DBP \80 mmHg) at week 12. The changes
from baseline in HbA1c at week 12 were
analyzed in subgroups of patients with
baseline HbA1c \8.0% and C8.0%.
Safety endpoints included clinical laboratory
tests, vital signs, 12-lead electrocardiogram,
physical examination, use of rescue therapy
and adverse events (AEs, coded according to the
waist Medical Dictionary for Drug Regulatory
Activities; version 15.0). AEs included all
events after intake of the first dose of study
medication up to 7 days after the last dose. AEs
of special interest included: confirmed
hypoglycemic AEs [plasma glucose B70 mg/dL
(B3.9 mmol/L) and/or assistance required];
events consistent with urinary tract infection
(UTI); events consistent with genital infection;

Table 1 Patient demographics and baseline characteristics

Placebo Empagliflozin Empagliflozin Empagliflozin Empagliflozin Total
(n 5 109) 5 mg 10 mg 25 mg 50 mg (n 5 547)
(n 5 110) (n 5 109) (n 5 109) (n 5 110)
Male, n (%) 80 (73.4) 84 (76.4) 77 (70.6) 84 (77.1) 85 (77.3) 410 (75.0)
Age, years 58.7 ± 8.7 57.3 ± 11.2 57.9 ± 9.4 57.2 ± 9.7 56.6 ± 10.3 57.5 ± 9.9
Patients with 37 (33.9) 37 (33.6) 37 (33.9) 38 (34.9) 36 (32.7) 185 (33.8)
previous anti-
diabetes therapy,
n (%)
Body weight, kg 69.0 ± 12.2 72.3 ± 14.7 68.1 ± 14.6 68.3 ± 14.1 68.2 ± 12.3 69.2 ± 13.7
2
BMI, kg/m 25.6 ± 3.4 26.3 ± 4.2 25.3 ± 4.4 25.1 ± 3.8 25.0 ± 3.6 25.5 ± 3.9
Waist 89.7 ± 9.2 91.2 ± 11.4 88.3 ± 11.3 88.4 ± 10.1 87.3 ± 9.6 89.0 ± 10.4
circumference, cm
HbA1c, % 7.94 ± 0.74 7.92 ± 0.70 7.93 ± 0.71 7.93 ± 0.78 8.02 ± 0.65 7.95 ± 0.72
FPG, mg/dL 156.3 ± 28.9 154.0 ± 27.9 156.8 ± 28.5 156.0 ± 29.9 158.0 ± 28.4 156.2 ± 28.6
SBP, mmHg 131.1 ± 14.6 131.1 ± 16.2 127.8 ± 15.3 126.5 ± 14.4 129.6 ± 15.3 129.2 ± 15.2
DBP, mmHg 79.2 ± 9.2 78.8 ± 9.8 78.2 ± 10.4 78.0 ± 9.4 79.4 ± 10.2 78.7 ± 9.8
eGFR, mL/min/ 84.6 ± 14.9 86.5 ± 17.5 85.8 ± 14.6 85.2 ± 15.8 86.5 ± 15.9 85.7 ± 15.7
1.73 m2
Data are mean ± SD or n (%) in the full analysis set (randomized patients who received C1 dose of study drug and had a
baseline HbA1c assessment)
BMI body mass index, DBP diastolic blood pressure, eGFR estimated glomerular filtration rate (using the Japanese GFR
estimation equation [24]), FPG fasting plasma glucose, HbA1c glycosylated hemoglobin, SBP systolic blood pressure
626 Adv Ther (2014) 31:621–638
 Adv Ther (2014) 31:621–638
b Fig. 2 Changes in parameters of glycemic control.
a HbA1c over time (MMRM, OC). b Change from
baseline in HbA1c at week 12 (ANCOVA, LOCF).
c Change from baseline in HbA1c at week 12 in patients
with baseline HbA1c C8.0% (ANCOVA, LOCF).
d Percentage of patients with HbA1c C7.0% at baseline
who achieved HbA1c\7.0% at week 12 (logistic regression
with NCF). e Change from baseline in FPG (MMRM, OC).
f Change from baseline in FPG at week 12 (ANCOVA,
LOCF). Data are adjusted mean ± standard error or % of
patients in the FAS. ANCOVA analysis of covariance, FAS
full analysis set, FPG fasting plasma glucose, HbA1c glycos-
ylated hemoglobin, LOCF last observation carried forward,
MMRM mixed model repeated measures, NCF non-compl-
eters considered failures, OC observed cases
and events consistent with volume depletion.
Events consistent with UTI, genital infection
and volume depletion were identified by using
prospectively defined search categories based on
67, 87 and 8 preferred terms, respectively.
Statistical Analysis
Each dose of empagliflozin was compared with
placebo using a pre-defined hierarchical
sequence, starting with the highest dose. The
next step in the sequence was only undertaken
if the previous step showed superiority over
placebo at a significance level of 5% (2-sided).
A sample size of 100 patients per randomized
treatment group was required to provide a
power of 90% to detect a 0.5% treatment
difference in HbA1c for each empagliflozin
dose compared with placebo with a 2-sided
significance level of 5%, assuming a standard
deviation (SD) of 1.0% and a 10% dropout rate.
The primary analysis was undertaken using
an analysis of covariance (ANCOVA) model,
with treatment, number of previous anti-
diabetes medications and baseline eGFR as
fixed effects and baseline HbA1c as a covariate.
The analysis was undertaken using data from
627
the full analysis set (FAS), i.e., all patients who
received C1 dose of study medication and had a
baseline HbA1c value. Values observed after a
patient started rescue medication were set to
missing. The last observation carried forward
(LOCF) approach was used to impute missing
data. Continuous secondary and exploratory
endpoints were analyzed using the ANCOVA
model described, with the baseline value of the
respective endpoint included as a covariate.
Binary endpoints were analyzed using logistic
regression.
Changes over time in HbA1c, FPG, body
weight and SBP were analyzed using restricted
maximum likelihood-based mixed model
repeated measures (MMRM), performed on the
FAS using observed cases (OC; i.e., without
LOCF). MMRM analyses included treatment,
eGFR, number of previous anti-diabetes
medications, visit, and visit by treatment
interaction as fixed effects, and baseline
HbA1c as a linear covariate. For secondary and
exploratory endpoints, the baseline of the
respective endpoint was included as an
additional covariate. Categorical change in
HbA1c, the proportion of patients with [5%
weight loss and the proportion of patients with
uncontrolled blood pressure at baseline who
had controlled blood pressure at week 12 were
analyzed using logistic regression in the FAS
using non-completers considered failures (NCF)
imputation. The model included continuous
HbA1c, treatment, eGFR, number of previous
anti-diabetes medications, and baseline of the
respective endpoint. Analysis of FPG was
performed using the parameter in mg/dL and
converted to mmol/L using a conversion factor
of 0.0555. Lipid parameters were analyzed using
ANCOVA on the treated set (all patients who
were treated with C 1 dose of study medication)
using LOCF-IR imputation (LOCF without
setting values after rescue therapy to missing).
628 Adv Ther (2014) 31:621–638

Table 2 Summary of changes in glycemic parameters at week 12

Placebo Empagliflozin Empagliflozin Empagliflozin Empagliflozin
5 mg 10 mg 25 mg 50 mg

Primary endpoint
HbA1c at week 12, % 8.19 ± 0.10 7.44 ± 0.07 7.47 ± 0.08 7.22 ± 0.06 7.32 ± 0.08
Change from baseline, % 0.30 ± 0.09 -0.42 ± 0.09 -0.40 ± 0.09 -0.65 ± 0.09 -0.61 ± 0.09
Difference vs. placebo -0.72 ± 0.08 -0.70 ± 0.08 -0.95 ± 0.08 -0.91 ± 0.08
(95% CI) (-0.87, -0.57) (-0.85, -0.55) (–1.10, -0.80) (-1.06, -0.76)
p value \0.001 \0.001 \0.001 \0.001
Secondary endpoints
Patients with HbA1c C7.0% at 3 (2.8) 28 (26.2) 20 (19.0) 34 (32.1) 35 (32.7)
baselinea who reached HbA1c
\7.0% at week 12, n (%)
OR vs. placebo 19.37 10.89 27.62 44.91
p value \0.001 \0.001 \0.001 \0.001
FPG at week 12, mg/dL 160.09 ± 3.15 132.16 ± 1.91 131.00 ± 1.89 122.10 ± 1.82 124.21 ± 2.21
Change from baseline, mg/dL 4.06 ± 2.88 -22.65 ± 2.97 -25.28 ± 2.77 -33.70 ± 2.92 -32.54 ± 2.97
Difference vs. placebo -26.70 ± 2.50 -29.34 ± 2.50 -37.75 ± 2.50 -36.60 ± 2.50
(95% CI) (-31.61, -21.80) (-34.25, -24.42) (-42.66, -32.84) (-41.51, -31.69)
p value \0.001 \0.001 \0.001 \0.001
Subgroup analysis of primary endpoint
Patients with HbA1c \8.0% at baselineb
HbA1c at baseline, % 7.44 ± 0.03 7.45 ± 0.03 7.41 ± 0.04 7.39 ± 0.03 7.45 ± 0.04
HbA1c at week 12, % 7.68 ± 0.08 7.12 ± 0.07 7.10 ± 0.07 6.93 ± 0.05 6.91 ± 0.05
Change from baseline, % 0.32 ± 0.10 -0.26 ± 0.10 -0.21 ± 0.10 -0.37 ± 0.10 -0.46 ± 0.11
Difference vs. placebo -0.58 ± 0.10 -0.53 ± 0.10 -0.69 ± 0.10 -0.79 ± 0.10
(95% CI) (-0.77, -0.39) (-0.73, -0.33) (-0.88, -0.50) (–0.99, -0.58)
p value \0.001 \0.001 \0.001 \0.001
c
Patients with HbA1c C8.0% at baseline
HbA1c at baseline, % 8.72 ± 0.08 8.67 ± 0.08 8.57 ± 0.07 8.70 ± 0.09 8.51 ± 0.06
HbA1c at week 12, % 8.97 ± 0.15 7.97 ± 0.12 7.92 ± 0.12 7.64 ± 0.09 7.68 ± 0.12
Change from baseline, % 0.30 ± 0.11 -0.63 ± 0.11 -0.60 ± 0.11 -1.02 ± 0.11 -0.75 ± 0.10
Difference vs. placebo -0.93 ± 0.12 -0.90 ± 0.12 -1.32 ± 0.12 -1.05 ± 0.11
(95% CI) [-1.17, -0.69) (-1.13, -0.67) (-1.55, -1.08) (-1.27, -0.83)
Adv Ther (2014) 31:621–638 629

Table 2 continued
Placebo Empagliflozin Empagliflozin Empagliflozin Empagliflozin
5 mg 10 mg 25 mg 50 mg

p value \0.001 \0.001 \0.001 \0.001

Data are mean ± standard error (SE) or n (%) except for change from baseline values, which are adjusted mean ± SE ANCOVA in
full analysis set (last observation carried forward), except for patients who reached HbA1c\7% (for which a non-completers considered
failures approach was used)
CI confidence interval, FPG fasting plasma glucose, HbA1c glycosylated hemoglobin, OR odds ratio
a
n = 106 for placebo, n = 107 for empagliflozin 5 mg, n = 105 for empagliflozin 10 mg, n = 106 for empagliflozin 25 mg, n = 107
for empagliflozin 50 mg
b
n = 66 for placebo, n = 68 for empagliflozin 5 mg, n = 60 for empagliflozin 10 mg, n = 64 for empagliflozin 25 mg, n = 51 for
empagliflozin 50 mg
c
n = 43 for placebo, n = 42 for empagliflozin 5 mg, n = 49 for empagliflozin 10 mg, n = 45 for empagliflozin 25 mg, n = 59 for
empagliflozin 50 mg

Safety analyses were performed on the
treated set and were descriptive in nature.
RESULTS
Patient Disposition
A total of 547 patients were randomized and
treated with placebo (n = 109), empagliflozin
5 mg (n = 110), empagliflozin 10 mg (n = 109),
empagliflozin 25 mg (n = 109), or empagliflozin
50 mg (n = 110) for 12 weeks (Fig. 1), and
comprised the FAS. Overall, 528 (96.5%)
patients completed the initial 12-week
treatment period and entered the 40-week
randomized extension. Demographic
baseline characteristics were balanced across
the treatment groups (Table 1). Mean ± SD
baseline HbA1c was 8.0 ± 0.7%; 309 (56.5%)
patients had HbA1c \8.0%, and 362 (66.2%)
patients were drug-naı̈ve.
Efficacy
Adjusted mean HbA1c levels over the 12-week
treatment period are shown in Fig. 2a. At week
12, reductions in HbA1c were significantly
greater with all empagliflozin doses compared
with placebo; adjusted mean [95% confidence
interval (CI)] differences vs. placebo in changes
from baseline were -0.72% (-0.87, -0.57) with
empagliflozin 5 mg, -0.70% (-0.85, -0.55)
with 10 mg, -0.95% (-1.10, -0.80) with
25 mg, and -0.91 (-1.06, -0.76) with 50 mg
(p\0.001 for all doses) (Table 2; Fig. 2b). A
greater reduction in HbA1c occurred in patients
with baseline HbA1c C8.0% compared with
HbA1c \8.0%. In patients with baseline HbA1c
\8.0%, adjusted mean (95% CI) differences vs.
placebo in changes from baseline at week 12
were -0.58% (-0.77, -0.39), -0.53% (-0.73,
and -0.33), -0.69% (-0.88, -0.50), and -0.79%
(-0.99, -0.58) with empagliflozin 5, 10, 25, and
50 mg, respectively (p\0.001 for all doses;
Table 2); in those with baseline HbA1c C8.0%,
adjusted mean (95% CI) differences vs. placebo
in changes from baseline at week 12 were
-0.93% (-1.17, -0.69), -0.90% (-1.13,
-0.67), -1.32% (-1.55, -1.08), and -1.05%
(-1.27, -0.83) with empagliflozin 5, 10, 25, and
50 mg, respectively (p\0.001 for all doses;
Table 2; Fig. 2c). A higher proportion of
630
Fig. 3 Changes in body weight. a Change from baseline in
body weight over time (MMRM, OC). b Change from
baseline in body weight at week 12 (ANCOVA, LOCF).
c Percentage of patients with [5% reduction in body
weight at week 12 (logistic regression with NCF). d Change
from baseline in waist circumference at week 12
patients with HbA1c C7.0% at baseline
achieved HbA1c \7.0% at week 12 with
empagliflozin (19–33%) compared with
placebo [3%; p\0.001 for odds ratio (OR) vs.
placebo with all doses] (Table 2; Fig. 2d).
Adv Ther (2014) 31:621–638
(ANCOVA, LOCF). Data are adjusted mean ± standard
error or % of patients in the FAS. ANCOVA analysis of
covariance, FAS full analysis set, LOCF last observation
carried forward, MMRM mixed model repeated measures,
NCF non-completers considered failures, OC observed cases
Changes from baseline in FPG over time are
shown in Fig. 2e. The adjusted mean (95% CI)
differences vs. placebo in changes from baseline
at week 12 were -26.70 mg/dL (-31.61,
-21.80), -29.34 mg/dL (-34.25, -24.42),
Adv Ther (2014) 31:621–638 631

Table 3 Summary of changes in body weight at week 12

Placebo Empagliflozin Empagliflozin Empagliflozin Empagliflozin
5 mg 10 mg 25 mg 50 mg
Exploratory endpoints
Body weight at week 12, kg 68.3 ± 1.2 69.9 ± 1.4 65.7 ± 1.4 65.7 ± 1.3 65.3 ± 1.1
Change from baseline, kg -0.9 ± 0.2 -2.5 ± 0.2 -2.6 ± 0.2 -2.9 ± 0.2 -3.1 ± 0.2
Difference vs. placebo -1.6 ± 0.2 -1.7 ± 0.2 -2.0 ± 0.2 -2.2 ± 0.2
(95% CI) (-2.0, -1.2) (-2.1, -1.3) (-2.4, -1.6) (-2.6, -1.8)
p value \0.001 \0.001 \0.001 \0.001
Patients with [5% reduction from 3 (2.8) 16 (14.5) 21 (19.3) 34 (31.2) 33 (30.0)
baseline in body weight, n (%)
OR vs. placebo 5.98 8.49 16.04 15.49
(95% CI) (1.69, 21.20) (2.45, 29.44) (4.75, 54.24) (4.57, 52.48)
p value 0.006 \0.001 \0.001 \0.001
Data are mean ± SE or n (%) except for change from baseline values, which are adjusted mean ± SE ANCOVA in the full
analysis set (last observation carried forward) except for patients with [5% reduction in body weight (for which a non-
completers considered failures approach was used)
CI confidence interval, OR odds ratio

-37.75 mg/dL (-42.66, -32.84), and -36.60 mg/
dL (-41.51, -31.69) with empagliflozin 5, 10, 25,
and 50 mg, respectively (p\0.001 for all doses)
(Table 2; Fig. 2f).
Changes from baseline in body weight over
time are shown in Fig. 3a. At week 12,
reductions from baseline in body weight
were significantly greater for all doses of
empagliflozin compared with placebo;
adjusted mean (95% CI) differences vs. placebo
in changes from baseline at week 12 were
-1.6 kg (-2.0, -1.2), -1.7 kg (-2.1, -1.3),
-2.0 kg (-2.4, -1.6), and -2.2 kg (-2.6, -1.8)
with empagliflozin 5, 10, 25, and 50 mg,
respectively (p\0.001 for all doses) (Table 3;
Fig. 3b). More patients achieved a reduction in
body weight[5% at week 12 with empagliflozin
(15–31%) than with placebo (3%) (p = 0.006 for
OR vs. placebo with empagliflozin 5 mg,
p\0.001 for all other doses; Table 3; Fig. 3c).
Adjusted mean (95% CI) differences vs. placebo
in changes from baseline in waist circumference
were -1.1 cm (-1.8, -0.4) with empagliflozin
5 mg (p = 0.002), -1.0 cm (-1.8, -0.3) with
10 mg (p = 0.005), -1.4 cm (-2.1, -0.7) with
25 mg (p\0.001), and -1.3 cm (-2.0, -0.6)
with 50 mg (p\0.001) (Fig. 3d).
Changes from baseline in SBP over time are
shown in Fig. 4a. Adjusted mean (95% CI)
differences vs. placebo in changes from baseline
at week 12 were -1.47 mmHg (-4.01, 1.08) with
empagliflozin 5 mg (p = ns), -4.20 mmHg
(-6.75, -1.64) with empagliflozin 10 mg
(p = 0.001), -3.22 mmHg (-5.78, -0.66) with
empagliflozin 25 mg (p = 0.014), and
-3.83 mmHg (-6.38, -1.28) with empagliflozin
50 mg (p = 0.003) (Table 4; Fig. 4b). Reductions in
SBP were not associated with increases in pulse
rate. Differences vs. placebo in changes from
baseline in DBP were smaller than differences in
SBP (p\0.05 vs. placebo for empagliflozin 10 mg
only; Table 4). In patients with uncontrolled
632
Fig. 4 Changes in blood pressure. a Changes from baseline
in SBP over time (MMRM, OC). b Change from baseline
in SBP at week 12 (ANCOVA, LOCF). c Percentage of
patients who had uncontrolled blood pressure at baseline
and had controlled blood pressure (SBP \130 mmHg and
DBP \80 mmHg) at week 12 (logistic regression with
blood pressure at baseline, significantly more
patients receiving empagliflozin 25 mg had
controlled blood pressure (SBP \130 mmHg and
DBP \80 mmHg) at week 12 compared with
Adv Ther (2014) 31:621–638
NCF). Data are adjusted mean ± standard error or % of
patients in the FAS. ANCOVA analysis of covariance, DBP
diastolic blood pressure, FAS full analysis set, LOCF last
observation carried forward, MMRM mixed model repeated
measures, NCF non-completers considered failures, OC
observed cases, SBP systolic blood pressure
placebo (43% vs. 25%, p = 0.024 for OR vs.
placebo; p = ns for other doses) (Table 4; Fig. 4c).
Rescue therapy was required by two patients
(1.8%) in the placebo group (1 received
Adv Ther (2014) 31:621–638 633

Table 4 Summary of changes in blood pressure at week 12

Placebo Empagliflozin Empagliflozin Empagliflozin Empagliflozin
5 mg 10 mg 25 mg 50 mg
Exploratory endpoints
SBP at week 12, mmHg 128.09 ± 1.37 126.61 ± 1.54 121.61 ± 1.38 121.53 ± 1.40 123.15 ± 1.31
Change from baseline, mmHg -1.38 ± 1.49 -2.85 ± 1.54 -5.57 ± 1.44 -4.60 ± 1.52 -5.21 ± 1.54
Difference vs. placebo -1.47 ± 1.30 -4.20 ± 1.30 -3.22 ± 1.30 -3.83 ± 1.30
(95% CI) (-4.01, 1.08) (-6.75, -1.64) (-5.78, -0.66) (-6.38, -1.28)
p value 0.257 0.001 0.014 0.003
DBP at week 12, mmHg 76.99 ± 0.86 76.54 ± 0.97 74.66 ± 0.89 74.76 ± 0.90 76.07 ± 0.90
Change from baseline, mmHg -2.00 ± 0.90 -2.20 ± 0.93 -3.57 ± 0.87 -3.35 ± 0.92 -3.03 ± 0.93
Difference vs. placebo -0.20 ± 0.78 -1.56 ± 0.78 -1.35 ± 0.78 -1.03 ± 0.78
(95% CI) (-1.73, 1.34) (-3.10, -0.02) (-2.89, 0.19) (-2.57, 0.51)
p value 0.799 0.047 0.085 0.188
Patients with uncontrolled BP at baseline who had 17 (24.6) 21 (31.3) 22 (37.3) 26 (43.3) 25 (37.3)
controlled BP (\130/80 mmHg) at week 12, n (%)a
OR vs. placebo 1.41 1.81 2.39 1.87
(95% CI) (0.66, 3.00) (0.84, 3.91) (1.12, 5.07) (0.89, 3.92)
p value 0.373 0.129 0.024 0.100

Data are mean ± SE or n (%) except for change from baseline values which are adjusted mean ± SE ANCOVA in full analysis set (last observation carried
forward) except for percentage of patients with controlled BP at week 12 (for which a non-completers considered failures approach was used)
BP blood pressure, CI confidence interval, DBP diastolic blood pressure, OR odds ratio, SBP systolic blood pressure
a
n = 69 for placebo, n = 67 for empagliflozin 5 mg, n = 59 for empagliflozin 10 mg, n = 60 for empagliflozin 25 mg, n = 67 for empagliflozin 50 mg

metformin; 1 received a sulfonylurea), and one Events consistent with UTI were reported by
patient (0.9%) in the empagliflozin 50 mg group one (0.9%) patient in each of the placebo,
(who received a meglitinide). empagliflozin 10, 25, and 50 mg groups.
Patients in the empagliflozin groups reported
Safety only mild events consistent with UTI; the
patient receiving placebo reported an event of
Over the 12-week treatment period, the moderate intensity. No events consistent with
percentage of patients with C1 AE was similar UTI led to discontinuation. Events consistent
across all groups (Table 5). Most (99.5%) with genital infection were reported by one
patients with C1 AE reported only events that (0.9%) patient in each of the empagliflozin 5,
were mild or moderate in intensity. Fewer 10, and 50 mg groups (all male patients). All of
patients discontinued due to AEs with these events were mild in intensity and just one
empagliflozin than placebo (Table 5). There patient discontinued as a result of
were no deaths. Only one severe AE was event(s) consistent with genital infection (in
reported during treatment (in a patient the empagliflozin 50 mg group). AEs consistent
receiving placebo). Confirmed hypoglycemic with volume depletion were reported in one
AEs were reported by two patients, one (0.9%) (0.9%) patient in each of the placebo,
receiving empagliflozin 25 mg and one (0.9%) empagliflozin 10 mg, and empagliflozin 25 mg
receiving empagliflozin 50 mg. These events did groups.
not require assistance or lead to drug Changes in laboratory measurements are
discontinuation. shown in Supplementary Table 1. There were
Table 5 Summary of AEs
634

Placebo Empagliflozin 5 mg Empagliflozin 10 mg Empagliflozin 25 mg Empagliflozin 50 mg

(n 5 109) (n 5 110) (n 5 109) (n 5 109) (n 5 110)
One or more AEs 46 (42.2) 36 (32.7) 41 (37.6) 40 (36.7) 42 (38.2)
a
One or more drug-related AEs 8 (7.3) 10 (9.1) 8 (7.3) 12 (11.0) 13 (11.8)
AEs leading to discontinuation 6 (5.5) 1 (0.9) 0 3 (2.8) 4 (3.6)
One or more serious AEs 3 (2.8) 0 0 3 (2.8) 1 (0.9)
Deaths 0 0 0 0 0
AEs with a frequency of [2% in any group (by preferred term)
Nasopharyngitis 10 (9.2) 8 (7.3) 9 (8.3) 11 (10.1) 11 (10.0)
Pharyngitis 1 (0.9) 0 4 (3.7) 3 (2.8) 2 (1.8)
Constipation 3 (2.8) 2 (1.8) 0 4 (3.7) 2 (1.8)
Gastritis 0 1 (0.9) 0 3 (2.8) 1 (0.9)
Back pain 0 4 (3.6) 1 (0.9) 0 0
Pollakiuria 1 (0.9) 4 (3.6) 1 (0.9) 7 (6.4) 6 (5.5)
Thirst 1 (0.9) 2 (1.8) 0 3 (2.8) 3 (2.7)
Special interest categories
Hypoglycemiab 0 0 0 1 (0.9) 1 (0.9)
Events requiring assistance 0 0 0 0 0
Events consistent with urinary tract 1 (0.9) 0 1 (0.9) 1 (0.9) 1 (0.9)
infectionc
Maled 1 (1.3) 0 1 (1.3) 0 0
Femalee 0 0 0 1 (4.0) 1 (4.0)
Events consistent with genital infectionf 0 1 (0.9) 1 (0.9) 0 1 (0.9)
d
Male 0 1 (1.2) 1 (1.3) 0 1 (1.2)
Femalee 0 0 0 0 0
g
Events consistent with volume depletion 1 (0.9) 0 1 (0.9) 1 (0.9) 0

Data are n (%) of patients treated with C1 dose of study drug

AEs adverse events
a
As assessed by the investigator
b
Confirmed events, plasma glucose B70 mg/dL (B3.9 mmol/L) and/or requiring assistance
c
Reports of events consistent with urinary tract infections were based on 67 preferred terms
d
Percentage of number of males in group
e
Percentage of number of females in group
f
Reports of events consistent with genital infection were based on 87 preferred terms
g
Reports of events consistent with volume depletion were based on eight preferred terms
Adv Ther (2014) 31:621–638
Adv Ther (2014) 31:621–638
no relevant changes from baseline in serum
electrolytes or renal function (eGFR). Treatment
with empagliflozin resulted in a reduction in
uric acid and increases in hematocrit,
hemoglobin and red blood cell count.
Compared with placebo, treatment with
empagliflozin resulted in small increases from
baseline in high-density lipoprotein cholesterol
(p B 0.001 for all empagliflozin doses) and
treatment with empagliflozin 50 mg resulted
in a small increase in low-density lipoprotein
cholesterol (p\0.05). Treatment with
empagliflozin also resulted in small decreases
from baseline in triglycerides (p = 0.015 for
empagliflozin 10 mg; p\0.001 for all other
doses). No relevant changes from baseline in
total cholesterol were observed in patients
treated with empagliflozin.
DISCUSSION
In this 12-week trial in Japanese patients with
T2DM, empagliflozin 5–50 mg once daily as
monotherapy led to significant and clinically
meaningful improvements in glycemic control
(HbA1c and FPG) compared with placebo, with
a good tolerability profile. This improvement in
glycemic control is important given that an
increase in HbA1c has been associated with the
incidence and progression of microvascular
complications such as diabetic retinopathy in
Japanese patients with T2DM [25]. A higher
proportion of patients with HbA1c C7.0% at
baseline achieved HbA1c\7.0% at week 12 with
all doses of empagliflozin compared with
placebo. As expected, and as seen in other
trials of SGLT2 inhibitors, greater reductions in
HbA1c were seen in patients with higher
baseline HbA1c compared with lower baseline
levels (C8.0% vs. \8.0%) [26–31]. The effects of
empagliflozin on glycemic control were
consistent with those in a multinational,
635
12-week study of empagliflozin as
monotherapy in drug-naı̈ve patients [16].
Additional non-glycemic benefits were
achieved with empagliflozin including
significant reductions in body weight and
waist circumference, allowing more patients to
achieve a [5% reduction in body weight. In
addition, significant reductions in SBP were
observed. These may prove to be important
benefits as a high waist circumference and
hypertension are associated with an increased
risk of cardiovascular disease in Japanese
patients with T2DM [32, 33].
Empagliflozin was generally well tolerated
over 12 weeks, with a similar number of
patients reporting AEs across groups, and no
evidence of a dose-dependent AE. Confirmed
hypoglycemic AEs were rare with empagliflozin
(2 of 547 patients), consistent with the
mechanism of action of SGLT2 inhibitors,
which is independent of beta-cell function
[10], and similar to findings reported in other
studies with empagliflozin [19–22]. The number
of patients receiving empagliflozin who
reported events consistent with UTI and
genital infection was low, similar to results
seen in trials of other SGLT2 inhibitors in
Japanese patients with T2DM [34, 35].
CONCLUSION
In summary, empagliflozin once daily for
12 weeks as monotherapy in Japanese patients
led to improvements in glycemic control, body
weight and SBP, and was well tolerated. Based
on benefit–risk assessment, empagliflozin 10
and 25 mg are most appropriate for further
investigation in clinical trials, and have been
evaluated in a 24-week, multinational,
monotherapy trial [21] with a long-term (52-
week) extension (NCT01289990), and a 52-week
Japanese study of empagliflozin as add-on to
636
any other class of anti-diabetes
(NCT01368081).
ACKNOWLEDGMENTS
This study was funded by Boehringer
Ingelheim, Ingelheim, Germany and Eli Lilly,
Indianapolis, USA. Page processing charges for
this manuscript were covered by Boehringer
Ingelheim, Ingelheim, Germany. Medical
writing assistance was provided by Clare Ryles
and Elizabeth Ng of Fleishman-Hillard Group
Ltd. and funded by Boehringer Ingelheim,
Ingelheim, Germany. All named authors meet
the ICMJE criteria for authorship for this
manuscript, take responsibility for the
integrity of the work as a whole, and have
given final approval for the version to be
published. These data have been presented in
poster format at the 73rd Scientific Session of
the American Diabetes Association, June 21–25,
2013, Chicago, USA, and at the 57th Annual
Meeting of the Japan Diabetes Society, May
22–24, 2014, Osaka, Japan. These data have
been published in abstract form
supplement of Diabetes (Diabetes 2013; 62
(suppl 1): A297–A298).
Conflict of interest. Takashi Kadowaki has
received honoraria for lectures from MSD, Ono,
Novartis and Sanofi, grants/research support
from Chugai, and scholarship grants from
MSD and Boehringer Ingelheim. Masakazu
Haneda has received honoraria for lectures
from MSD, Novartis, Daiichi-Sankyo, Tanabe-
Mitsubishi, Sanofi, Astellas, Kowa, Taisho and
Boehringer Ingelheim, and research support
from MSD, Daiichi-Sankyo, Tanabe-Mitsubishi,
Eli Lilly, Astellas and Boehringer Ingelheim.
Nobuya Inagaki has participated on advisory
panels for Daiichi-Sankyo, Tanabe-Mitsubishi,
Adv Ther (2014) 31:621–638
agent Taisho and Boehringer Ingelheim, has received
honoraria for lectures from MSD, Ono, Novartis,
Tanabe-Mitsubishi, Eli Lilly, Sanofi, Astra
Zeneca, Astellas, Kowa, Boehringer Ingelheim,
and has received research support from MSD,
Ono, Novartis, Daiichi-Sankyo, Tanabe-
Mitsubishi, Eli Lilly, Sanofi, Astra Zeneca,
Astellas, Bristol-Myers Squibb, Chugai and
Boehringer Ingelheim. Yasuo Terauchi has
received honoraria for lectures from MSD,
Ono, Novartis, Daiichi-Sankyo, Tanabe-
Mitsubishi, Eli Lilly, Sanofi, Astra Zeneca,
Kowa and Boehringer Ingelheim, and
scholarship grants from MSD, Ono, Novartis,
Daiichi-Sankyo, Tanabe-Mitsubishi, Eli-Lilly,
Sanofi, Astra Zeneca, Astellas and Boehringer
Ingelheim. These companies are involved in the
development and/or distribution of SGLT2
inhibitors. Atsushi Taniguchi is an employee
of Boehringer Ingelheim. Kazuki Koiwai is an
employee of Boehringer Ingelheim. Henning
Rattunde is an employee of Boehringer
Ingelheim. Hans J. Woerle is an employee of
Boehringer Ingelheim. Uli C. Broedl is an
employee of Boehringer Ingelheim.
in a
Compliance with ethics guidelines. All
procedures followed were in accordance with
the ethical standards of the responsible
committee on human experimentation
(institutional and national), and with the
Helsinki Declaration of 1975, as revised in
2000 and 2008, and in accordance with the
International Conference on Harmonization
Harmonized Tripartite Guideline for Good
Clinical Practice, and the Japanese Good
Clinical Practice regulations (Ministry of
Health and Welfare Ordinance No. 28, March
27, 1997). Informed consent was obtained from
all patients for being included in the study. The
study was approved by respective Institutional
Review Boards and Competent Authorities
Adv Ther (2014) 31:621–638
according to national and international
regulations.
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