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diabetes research and clinical practice 106 (2014) 50–56

Contents available at ScienceDirect

Diabetes Research
and Clinical Practice
jou rnal hom ep ag e: w ww.e l s e v i er . c om/ loca te / d i ab r es

Pharmacokinetic and pharmacodynamic study of

ipragliflozin in Japanese patients with type 2
diabetes mellitus: A randomized, double-blind,
placebo-controlled study§

Takeshi Kadokura a,*, Noriko Akiyama a, Atsunori Kashiwagi b,

Atsushi Utsuno a, Kenichi Kazuta a, Satoshi Yoshida a,
Itsuro Nagase a, Ronald Smulders c, Shigeru Kageyama d
Astellas Pharma Inc. Japan, Tokyo, Japan
Shiga University of Medical Science, Shiga, Japan
Astellas Pharma Global Development Europe, Leiden, The Netherlands
The Jikei University School of Medicine, Tokyo, Japan

article info abstract

Article history: Aims: Ipragliflozin is a novel and highly selective sodium–glucose transporter 2 (SGLT2)
Received 6 September 2013 inhibitor that reduces plasma glucose levels by enhancing urinary glucose excretion in patients
Received in revised form with type 2 diabetes mellitus (T2DM). We examined the pharmacokinetic and pharmacody-
15 May 2014 namic characteristics of two oral doses of ipragliflozin in Japanese patients with T2DM.
Accepted 20 July 2014 Methods: In this randomized, placebo-controlled, double-blind study, patients were treated
Available online 26 July 2014 with placebo, 50 mg or 100 mg ipragliflozin once daily for 14 days. Plasma and urine
pharmacodynamic parameters were measured on Days 1 and 14, and pharmacokinetic
Keywords: parameters on Day 14. Pharmacodynamic characteristics included area under the curve
Ipragliflozin (AUC) for plasma glucose and insulin for 0–3 h (AUC0–3h) and 0–24 h (AUC0–24h). Pharmaco-
Fasting glucose kinetic characteristics included AUC0–24h, maximum ipragliflozin concentration (Cmax), and
Postprandial glucose time to maximum plasma ipragliflozin concentration (tmax).
SGLT2 Results: Thirty patients were enrolled; 28 were included in pharmacokinetic/pharmacodynam-
Type 2 diabetes ic analyses and 30 in safety analyses. Administration of 50 and 100 mg ipragliflozin significantly
reduced fasting plasma glucose, as well as the AUC0–3h and AUC0–24h for plasma glucose relative
to placebo. Both doses of ipragliflozin also reduced AUC0–24h for insulin, body weight, and
glycoalbumin, while urinary glucose excretion increased remarkably. Cmax and AUC0–24h were
1.7- and 1.9-fold higher, respectively, in the 100-mg group than in the 50-mg group.
Conclusions: Ipragliflozin increased urinary glucose excretion and improved fasting and
postprandial glucose, confirming its pharmacokinetic/pharmacodynamic properties in
Japanese patients with T2DM.
# 2014 Elsevier Ireland Ltd. All rights reserved.

Results of this study were presented as a poster at the 71st Scientific Sessions of the American Diabetes Association, San Diego, CA,
USA (June 24–28, 2011) and at the 55th Annual Meeting of the Japan Diabetes Society, Yokohama, Japan (May 17–19, 2012).
* Corresponding author. Tel.: +81 3 3244 2579; fax: +81 3 3243 5732.
E-mail address: (T. Kadokura).
0168-8227/# 2014 Elsevier Ireland Ltd. All rights reserved.
diabetes research and clinical practice 106 (2014) 50–56 51

study. After providing informed consent, patients entered a 1-

1. Introduction to 2-week screening period, with an additional 13-day
washout for those previously using oral hypoglycemic agents.
Sodium–glucose transporter 2 (SGLT2) is a member of the SGLT All patients received placebo during the run-in period. Upon
family of solute transporters. It is highly expressed in proximal confirmation of eligibility, the patients were randomized in a
tubules in the kidney, where it plays a key role in glucose double-blind manner to receive 50 mg ipragliflozin, 100 mg
reabsorption [1]. Inhibition of SGLT2 was demonstrated to ipragliflozin, or placebo, which were to be administered once
suppress renal glucose reabsorption and therefore enhance daily before breakfast for 2 weeks. Patients were hospitalized
urinary glucose excretion (UGE) in vivo [2]. Consequently, from Days 2 to 1 and from Days 13 to 15 at either Keiyukai
inhibition of SGLT2 was proposed as an insulin-independent Moriya Keiyu Hospital (Moriya, Ibaraki, Japan) or Kunwakai
approach for treating type 2 diabetes mellitus (T2DM) [3]. Aiwa Clinic (Koshigaya, Saitama, Japan) for pharmacodynam-
Several SGLT2 inhibitors, including ipragliflozin, have since ic/pharmacokinetic assessments, urine collection, and clinical
been developed, representing a new class of oral hypoglyce- investigations, with a follow-up visit at 1–3 weeks.
mic agents. Eligible patients were randomly and equally assigned to the
Ipragliflozin is a potent and selective inhibitor of SGLT2 three groups (1:1:1 ratio; block size = 3) in accordance with an
in vitro, and increases UGE in a dose-dependent manner assignment list, which was prepared by an assignment
in vivo [4]. Studies in healthy volunteers have confirmed that manager who was independent of the sponsor. The assign-
ipragliflozin also dose-dependently increases UGE in humans ment schedule was sealed by the assignment manager until
[5,6]. Subsequent studies have shown that ipragliflozin, by the code was broken. Patients in the 100-mg group took two
enhancing UGE, decreases fasting plasma glucose (FPG) and tablets containing 50 mg ipragliflozin. Patients in the 50-mg
glycosylated hemoglobin (HbA1c) in patients with T2DM [7,8]. group took one 50-mg tablet and one placebo tablet. Patients in
In a phase II study conducted in Japanese patients, the placebo group took two placebo tablets. The appearances
treatment with 50 or 100 mg ipragliflozin for 12 weeks led to of the placebo/active tablets and their packaging were
significant reductions in HbA1c, FPG, and body weight [5]. To indistinguishable. To maintain blinding, the investigators,
date, however, the pharmacodynamic and pharmacokinetic study collaborators, and subjects were to refrain from
properties of ipragliflozin in Japanese patients with measuring urinary glucose levels, unless deemed necessary
T2DM have not been reported. Therefore, we conducted a for safety reasons. During the study, patients were prohibited
14-day, placebo-controlled, pharmacokinetic/pharmacody- from using oral hypoglycemic drugs from 13 days before the
namic study to determine the effects of two doses of start of screening, insulin from 12 weeks before the start of
ipragliflozin on daily plasma glucose profiles and urinary screening, or diuretics from the start of screening until the end
glucose excretion, specifically in Japanese patients with T2DM. of the treatment period. Continuous use of corticosteroids/
immunosuppressants/glucose/glucagon, changes to diet ther-
apy, and initiation of hospitalization therapies for controlling
2. Methods plasma glucose were also prohibited from the start of
screening to the end of the treatment period. However,
2.1. Patients temporary or topical administration of corticosteroids, immu-
nosuppressants, glucose, or glucagon was permitted.
Eligible patients were aged 20–74 years, had been diagnosed The study protocol, patient informed consent forms, and
with T2DM for 12 weeks, were drug-naive or on mono- case report forms were approved by institutional review
therapy, had a body mass index (BMI) of 20–45 kg/m2, HbA1c boards at each participating site. The study was conducted in
(NGSP units) of 7.4–10.5%, FPG levels of 126 to <240 mg/dL, accordance with Good Clinical Practice, the International
and fasting serum C-peptide level of >0.6 ng/mL. Patients Conference on Harmonization guidelines, and local laws and
previously using oral hypoglycemic drugs entered a manda- regulations. Compliance with Good Clinical Practice was
tory washout period of 13 days before starting the present evaluated by auditors who were independent to the study
study. Patients were excluded from the study if they had management. This study was registered at
advanced diabetes complications (neuropathy, retinopathy, (identifier: NCT01023945).
nephropathy, and macroangiopathy), had used insulin within
12 weeks of starting the study, had chronic diseases requiring 2.3. Pharmacodynamic and pharmacokinetic assessments
continuous administration of corticosteroids or immunosup-
pressants, were using diuretics, or had evidence of renal Pharmacodynamic and pharmacokinetic assessments were
disease, among other criteria. All patients provided written conducted during hospitalization. During hospitalization,
informed consent before enrollment. patients were provided standardized meals at 08:30, 12:30,
and 18:30. The same meals were provided to each patient
2.2. Study design and treatments during hospitalization and the subjects were asked to eat a
constant amount. Blood samples were collected at 0 (before
This was a multicenter, placebo-controlled, double-blind breakfast), 0.5, 1, 1.5, 2, 3, 4 (before lunch), 5, 6, 7, 10 (before
study that examined the pharmacodynamics, pharmacoki- dinner), 11,12,13, and 24 h (before study drug administration)
netics, and safety profiles of two oral doses of ipragliflozin (50 on Days 1 and 14 to determine plasma glucose and serum
and 100 mg) administered for 14 days in Japanese patients insulin levels. Blood samples for FPG, fasting serum insulin
with T2DM. Supplementary Fig. 1 shows the design of the (FSI), and glycoalbumin assessment were collected on Day 1
52 diabetes research and clinical practice 106 (2014) 50–56

(before study drug administration) and Day 15. Urinary pharmacokinetic, and safety analysis sets. The pharmacody-
samples were collected over 0–4 h (before lunch, 08:30– namic analysis set (PDAS) consisted of all patients who
12:30), 4–10 h (before dinner, 12:30–18:30), and 10–24 h (before received at least one dose of the study drug and had adequate
study drug administration, 18:30–08:30) periods on Days 1 data for the plasma glucose profile or UGE at the end of the
and 14 to measure urine volume, and urinary glucose and study. The pharmacokinetic analysis set (PKAS) consisted of
creatinine concentrations. all subjects who received at least one dose of the study drug
Pharmacodynamic parameters included plasma glucose and whose plasma ipragliflozin concentration was measured
(daily profile, including area under the concentration–time one or more times. The safety analysis set (SAF) consisted of all
curve from 0 to 3 h [AUC0–3h] and 0 to 24 h [AUC0–24h], FPG, and patients who received at least one dose of the study drug.
PPG at 1 and 2 h after breakfast) and serum insulin (daily Baseline characteristics are presented as the number of
profile, FSI, AUC0–24h, and AUC0–3h). The pharmacokinetic patients or mean  standard deviation (SD). The mean  SD
parameters were the maximum concentration (Cmax), AUC0–24h values were calculated for pharmacokinetic and pharmaco-
of ipragliflozin, time to Cmax (tmax), apparent terminal elimina- dynamic parameters at each time-point. The changes from
tion half-life (t1/2), oral clearance (CL/F), renal clearance (CLR), baseline (i.e., Day 1 to Day 14 or Day 1 to Day 15) in
amount excreted in urine (Ae), and fraction of drug excreted in pharmacodynamic parameters (FPG, plasma glucose AUC0–3h,
urine (Ae%). Urinary pharmacodynamic parameters were 24-h plasma glucose AUC0–24h, and FSI) were compared by analysis
UGE and 24-h urine volume. of covariance with the baseline value as a covariate and
Other clinically relevant outcomes assessed in the study treatment group as a fixed effect. For UGE and urine volume,
were body weight and glycoalbumin. We measured glycoal- the cumulative values were calculated at each time-point,
bumin rather than HbA1c as the former reflects glucose together with their changes from baseline. Clinical laboratory
control over a much shorter period (2 weeks) compared with parameters at each time-point were analyzed descriptively.
1–2 months for HbA1c. Clinical laboratory tests, as well as For the serum concentrations of total ketone bodies and free
measurement of plasma and urinary ipragliflozin concentra- fatty acids, the changes from baseline (Day 1) to Day 15 are
tions, were performed at Mitsubishi Chemical Medience Corp. presented, and the differences from placebo were estimated
(Tokyo, Japan). HbA1c was measured using an enzymatic using 95% confidence interval (CI). TEAEs are presented as the
assay, insulin by a microparticle enzyme immunoassay, and number of patients.
glycoalbumin by an enzymatic assay.
To measure plasma ipragliflozin concentrations, blood
samples were collected in heparin-coated tubes and centri- 3. Results
fuged for 10 min at 2000  g. The plasma samples were then
frozen at 20 8C and sent to Mitsubishi Chemical Medience 3.1. Patient disposition and characteristics
Corp. Plasma ipragliflozin concentrations were measured
using a validated liquid chromatography–tandem mass Between November 2009 and March 2010, 30 patients were
spectrometry (LC–MS/MS) procedure with a lower limit of enrolled in this study. Two patients discontinued during the
quantification (LLOQ) of 1 ng/mL for 0.2 mL of plasma. To treatment period because of TEAEs (one each treated with 50
measure urinary ipragliflozin, collected urine was stored at and 100 mg ipragliflozin), so no pharmacokinetic or pharma-
4 8C until the end of the collection period, then mixed and codynamic data at the end of treatment could be obtained for
stored at 20 8C before being sent to Mitsubishi Chemical these patients. Therefore, 28 patients were included in the
Medience Corp. Urinary ipragliflozin concentrations were PDAS and PKAS. All 30 patients were included in the SAF.
measured using a validated LC–MS/MS procedure with a LLOQ Table 1 summarizes the characteristics of patients in each
of 2 ng/mL for 0.2 mL of plasma. group, using the PDAS. Baseline HbA1c levels were similar
between the placebo and 100 mg ipragliflozin groups, but were
2.4. Safety higher in the 50-mg group, whereas FPG and 24-h UGE values
were similar in all three groups.
Safety parameters, including adverse events (AEs), laboratory
tests (hematology, biochemistry, and urinalysis; performed at 3.2. Pharmacodynamics
Mitsubishi Chemical Medience Corp.), vital signs (supine blood
pressure and supine pulse rate), and 12-lead electrocardiogra- In both ipragliflozin groups, the plasma glucose levels
phy were monitored throughout the study. Treatment- measured throughout the day were lower on Day 14 than at
emergent adverse events (TEAEs) were classified according baseline (i.e., Day 1), whereas plasma glucose profiles were
to system organ class and preferred term (MedDRA version similar on Days 1 and 14 in the placebo group (Fig. 1A–C). FPG
10.1). decreased significantly from Day 1 to Day 15 in both
ipragliflozin groups compared with the placebo group.
2.5. Statistical analysis Additionally, PPG levels measured at 1 and 2 h after breakfast
were lower on Day 14 than on Day 1 in both ipragliflozin
We planned to enroll eight subjects per group, considering the groups, but not in the placebo group. The mean  SD changes
number of subjects that was deemed sufficient for pharmaco- in 2-h PPG were 60.1  45.5 mg/dL and 62.9  34.3 mg/dL in
dynamic assessment of ipragliflozin, and considering the the 50 and 100 mg ipragliflozin groups, versus 1.9  39.8 mg/
feasibility of the study. For this study, we defined three sets of dL in the placebo group (Fig. 2A). Plasma glucose AUC0–3h
patients for statistical analyses: the pharmacodynamic, (postprandial) and AUC0–24h (all day) decreased significantly
diabetes research and clinical practice 106 (2014) 50–56 53

Table 1 – Patient characteristics (PDAS).

Placebo (n = 10) 50 mg ipragliflozin (n = 9) 100 mg ipragliflozin (n = 9)
Male 5 (50.0) 6 (66.7) 8 (88.9)
Female 5 (50.0) 3 (33.3) 1 (11.1)
Age (years) 60.0  7.72 59.3  9.64 57.0  13.19
BMI (kg/m2) 26.23  2.83 25.07  3.11 26.84  3.46
Body weight (kg) 66.72  7.72 68.44  13.58 75.07  13.89
HbA1c, %* (mmol/mol) 8.4  0.9 (67.7  10.01) 8.9  0.8 (73.3  8.59) 8.2  1.0 (65.2  11.42)
FPG (mg/dL) 177.5  33.8 172.9  25.5 165.3  35.1
FSI (mU/mL) 7.23  4.07 5.48  2.23 7.27  3.83
1-h PPG (mg/dL) 306.8  48.4 294.0  44.0 286.1  44.6
2-h PPG (mg/dL) 310.3  63.5 292.3  46.8 274.0  57.2
24-h UGE (g) 27.0  35.2 29.1  33.2 23.5  29.4
Prior diabetes medication (yes) 7 (70.0) 4 (44.4) 3 (33.3)
Glycoalbumin, % of total albumin 23.81  4.84 24.86  4.47 22.59  6.00
HbA1c values were measured according to Japanese Diabetes Society (JDS) standards and are presented in National Glycohemoglobin
Standardization Program (NGSP) units [11] and as International Federation of Clinical Chemistry (IFCC) units (mmol/mol) [12,13].
PDAS, pharmacodynamic analysis set; FPG, fasting plasma glucose; PPG, postprandial glucose; FSI, fasting serum insulin.

from Day 1 to Day 14 in both ipragliflozin groups compared similar in both groups. By contrast, 24-h UGE did not change
with the placebo group (Table 2). Mean serum insulin levels on significantly in the placebo group (increase of 5.3  19.3 g)
Day 14 were generally lower than those on Day 1 in both from Day 1 to Day 14 (Fig. 2B). The mean 24-h urine volume
ipragliflozin groups, but not in the placebo group (Fig. 1D–F). remained unchanged from Day 1 to Day 14 in the placebo
FSI decreased significantly in both ipragliflozin groups but not group (there was a non-significant decrease of 61 mL), but
in the placebo group. increased slightly in the 50 and 100 mg ipragliflozin groups by
224.4 mL and 203.3 mL, respectively.
3.3. Urinary pharmacodynamics
3.4. Pharmacokinetics
Mean 24-h UGE increased significantly from Day 1 to Day 14
by 80.6  22.2 g and 89.7  12.3 g in the 50 and 100 mg Ipragliflozin was rapidly absorbed in both dose groups, reaching
ipragliflozin groups, respectively, although the changes were peak concentrations within 1 h after dosing. Thereafter, plasma

Fig. 1 – ((A)–(C)) Plasma glucose profiles on Days S1 and 14 in the placebo (A), 50 mg ipragliflozin (B), and 100 mg ipragliflozin
(C) groups. ((D)–(F)) Serum insulin profiles on Days S1 and 14 in the placebo (D), 50 mg ipragliflozin (E), and 100 mg
ipragliflozin (F) groups. Values are shown as the mean W SD.
54 diabetes research and clinical practice 106 (2014) 50–56

Fig. 2 – (A) Changes in 2-h postprandial plasma glucose from Day S1 to Day 14. (B) Changes in mean cumulative urinary
glucose excretion (UGE) over 24 h from Day S1 to Day 14. Values are shown as the mean W SD.

ipragliflozin concentrations declined in a biphasic manner. 3.5. Other outcomes

Supplementary Table 1 summarizes the pharmacokinetic
parameters, including Cmax, AUC0–24h, tmax, t1/2, CL/F, and CLR Glycoalbumin, assessed in the PDAS, increased slightly in the
in the PKAS. The mean plasma Cmax and AUC0–24h were placebo group (0.46  1.44%) but decreased in the 50 mg
approximately 1.7- and 1.9-fold higher, respectively, in the (2.63  1.73%) and 100 mg (1.74  1.25%) ipragliflozin
100-mg group than in the 50-mg group. tmax, t1/2, and CL/F groups from Day 1 to Day 15. The mean changes in body
were similar in both groups. In terms of urinary pharmacoki- weight, assessed in the PDAS, were 1.51  0.523 kg and
netics, Ae was about 2-fold higher in the 100-mg group than in 1.19  0.443 kg in the 50 and 100 mg ipragliflozin groups
the 50-mg group. Ae% was very low in both groups. The mean versus 0.20  0.572 kg in the placebo group.
Cmax in patients with T2DM was approximately 10–30% higher
than the previously reported value in healthy subjects. By 3.6. Safety
contrast, the mean AUC0–24h was comparable in both
populations [5]. Nevertheless, the differences in Cmax be- Safety was assessed in all 30 patients enrolled in the study.
tween the two studies are small and are unlikely to be Five patients in the 50 mg ipragliflozin group experienced
clinically relevant. seven TEAEs and three in the 100 mg ipragliflozin group

Table 2 – Changes in pharmacodynamic parameters from baseline to Day 14 (PDAS).

Placebo (n = 10) 50 mg ipragliflozin (n = 9) 100 mg ipragliflozin (n = 9)
Plasma glucose AUC0–3h, (h mg/dL) 2.3  99.5 172.6  106.6 174.6  92.0
Difference in adjusted mean change (95% CI)* – 184.8 (274.7, 94.9) 200.6 (293.3, 107.9)
Plasma glucose AUC0–24h (h mg/dL) 63.8  732.5 1103.7  693.9 919.9  636.0
Difference in adjusted mean change (95% CI)* – 1214.1 (1844.4, 583.9) 1094.5 (1735.4, 453.7)
FPG (mg/dL) 0.3  20.5 31.6  24.3 35.8  29.1
Difference in adjusted mean change (95% CI)* – 33.7 (54.3, 13.1) 40.9 (61.8, 20.0)
1-h PPG (mg/dL)y 3.5  23.8 53.1  34.2 58.7  32.4
2-h PPG (mg/dL)y 1.9  39.8 60.1  45.5 62.9  34.3
FSI (mU/mL) 0.54  2.08z 1.31  1.21 2.38  1.88
Difference in adjusted mean change (95% CI)* – 2.26 (3.86, 0.65) 2.93 (4.50, 1.36)
Serum insulin AUC0–3h (h mU/mL)y 8.8  18.7 9.7  7.2 9.4  11.1
Serum insulin AUC0–24h (h mU/mL)y 4.4  70.3 93.8  57.2 53.1  77.3
Body weight (kg)y 0.20  0.57 1.51  0.52 1.19  0.44
Glycoalbumin (%)y 0.46  1.44 2.63  1.73 1.74  1.25
Values are means  SD or means (95% CI). PDAS, pharmacodynamic analysis set; FPG, fasting plasma glucose; PPG, postprandial glucose; FSI,
fasting serum insulin.
ANCOVA with baseline value as a covariate. Significance was defined as an upper limit of the 95% CI of <0 mg/dL, <0 mU/mL or <0 h mg/dL.
Analyzed descriptively.
n = 9.
diabetes research and clinical practice 106 (2014) 50–56 55

Table 3 – Summary statistics and changes from baseline in total serum ketone and free fatty acid levels (SAF).
Time-point Day 1 End of Follow-up Change from Difference vs.
treatment baselinez placebo (95% CI)
Total serum ketones* (mmol/L)
Placebo (n = 10) 110.9  140.7 125.3  170.4 80.8  68.4 (26.8–253.0) 14.3  36.8
(24.8–499.0) (30.0–600.0) (30.0, 101.0)
50 mg (n = 10) 78.2  52.9 268.8  174.6y 51.2  26.5y (22.0–99.9)y 187.6  170.5y 173.2 (56.9–289.5)
(27.1–213.0) (59.9–553.0)y (22.8, 448.0)y
100 mg (n = 10) 98.8  75.1 347.6  255.3y 44.7  16.5 (25.1–75.3) 248.8  239.9 234.5 (73.2–395.7)
(32.6–261.0) (138.0–974.0)y (71.0, 788.0)
Free fatty acids (mEq/L)
Placebo (n = 10) 0.48  0.16 0.49  0.19 0.51  0.21 (0.18–0.82) 0.006  0.130
(0.30–0.75) (0.24–0.85) (0.220, 0.240)
50 mg (n = 10) 0.52  0.16 0.57  0.10 0.39  0.13 (0.22–0.67) 0.042  0.217 0.036 (0.132, 0.204)
(0.24–0.79) (0.34–0.71) (0.450, 0.300)
100 mg (n = 10) 0.46  0.15 0.57  0.16 0.33  0.08 (0.18–0.47) 0.106  0.146 0.100 (0.030, 0.230)
(0.27–0.72) (0.38–0.81) (0.080, 0.330)
Values are means  SD (range). SAF, safety analysis set.
Includes acetoacetic acid and 3-hydroxybutyric acid.
n = 9.
Change from Day 1 to Day 14.

experienced three TEAEs (Supplementary Table 2). There were approached the maximum of around 90 g in Japanese T2DM
five drug-related TEAEs in four patients in the 50-mg group, patients. These results suggest that increased drug exposure
and two drug-related TEAEs in two patients in the 100-mg hardly affected the pharmacodynamic properties of 50 or
group. All TEAEs were classified mild in severity (i.e., did not 100 mg ipragliflozin, compared with lower doses. This also
affect daily activities), with the exception of a nonfatal indicates that the increase in UGE is determined by the plasma
myocardial infarction in one patient in the ipragliflozin glucose level and renal function (i.e., glomerular filtration rate)
50 mg group, which was assessed as moderate (i.e., it affected within the therapeutic dose range [9].
normal daily activities). The myocardial infarction was A phase II study showed that treatment with 50 or 100 mg
observed in the follow-up period (Day 21), after 14 days of ipragliflozin for 12 weeks produced significant reductions in
repeated dosing with ipragliflozin was completed. The patient HbA1c, FPG, and body weight in Japanese T2DM patients [7].
was discharged on Day 27, and recovery was confirmed on Day However, the daily pharmacodynamic profiles after adminis-
51. Two patients discontinued treatment because of mild tering ipragliflozin have not been reported in Japanese T2DM
TEAEs (toxic skin eruption and rash). No hypoglycemic events, patients until now. The present study showed that 50 and
urinary tract infection, genital infection, or pollakiuria were 100 mg ipragliflozin improved FPG, FSI, PPG, AUC0–3h (post-
reported. Elevations of serum ketone bodies were reported as prandial), and AUC0–24h (all day) in Japanese T2DM patients.
TEAEs in one patient in each of the ipragliflozin groups. The Urine volume increased slightly from baseline in both
total serum ketone levels, which included acetoacetic acid and ipragliflozin groups, although the changes were small because
3-hydroxybutyric acid levels, increased in both ipragliflozin of the urine volume measured at baseline (2000–2800 mL).
groups, but not in the placebo group, from Day 1 to Day 14 Mean water intake measured at each time remained almost
(Table 3). The total serum ketone levels tended to be lower at unchanged in all three groups. As expected, the reductions in
the follow-up visit than on Day 1 in all three groups. The FPG and PPG were coupled with significant increases in UGE in
mean  SD changes in free fatty acid levels were both ipragliflozin groups, whereas no changes in glucose
0.042  0.217 mEq/L and 0.106  0.146 mEq/L in the 50 and profiles or UGE occurred in the placebo group. The reductions
100 mg ipragliflozin groups, respectively, versus in plasma glucose levels led to reductions in glucose load,
0.006  0.130 mEq/L in the placebo group. which consequently reduced the demand for insulin to
support metabolic activity. Additionally, the reductions in
plasma glucose levels probably led to a reduction in
4. Discussion glucotoxicity, as shown by the reductions in glycoalbumin.
In this study, TEAEs were reported in seven and three
Ipragliflozin is a potent and selective inhibitor of SGLT2 patients in the 50 and 100 mg ipragliflozin groups, respective-
in vitro, and increases UGE in a dose-dependent manner ly, but none were reported in the placebo group. These
in vivo [4]. Clinical studies have demonstrated that ipragli- included cardiac disorders, laboratory disorders, and skin and
flozin increases UGE in healthy subjects without changing subcutaneous tissue disorders.
plasma glucose levels [5,6]. In healthy Japanese subjects, up to Elevated ketone bodies were reported as a TEAE in two
70 g of glucose was excreted over 24 h after a single 300 mg patients. As the blood glucose levels were well controlled in
dose, while up to 50 g of glucose was excreted over 24 h after both patients, the elevated serum ketone bodies were
multiple doses of 50 or 100 mg [5]. The present study showed considered to be related to compensatory fatty acid metabo-
that 24-h UGE after multiple doses of 50 or 100 mg ipragliflozin lism. The increase in total serum ketone levels was probably
56 diabetes research and clinical practice 106 (2014) 50–56

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in vivo. Naunyn Schmiedebergs Arch Pharmacol
particular, the study was only 14 days long, which means the
improvements in glycemic control cannot be generalized to [5] Kadokura T, Saito M, Utsuno A, Kazuta K, Yoshida S,
the longer-term outcomes. However, our objective was not to Kawasaki S, et al. Ipragliflozin (ASP1941), a selective
examine the long-term outcomes, but rather to investigate the sodium-dependent glucose cotransporter 2 inhibitor, safely
pharmacodynamic and pharmacokinetic properties of ipragli- stimulates urinary glucose excretion without inducing
flozin in Japanese patients with T2DM. hypoglycemia in healthy Japanese subjects. Diabetol Int
In conclusion, the present results have confirmed the
[6] Veltkamp SA, Kadokura T, Krauwinkel WJ, Smulders RA.
pharmacodynamic and pharmacokinetic properties of ipragli-
Effect of ipragliflozin (ASP1941), a novel selective sodium-
flozin in Japanese patients with T2DM, as increases in UGE dependent glucose co-transporter 2 inhibitor, on urinary
lead to improvements in FPG and PPG. glucose excretion in healthy subjects. Clin Drug Investig
[7] Kashiwagi A, Kazuta K, Yoshida S, Nagase I. Randomized,
Disclosure placebo-controlled, double-blind glycemic control trial of
novel SGLT2 inhibitor ipragliflozin in Japanese patients with
type 2 diabetes mellitus. J Diabetes Investig 2014;5:382–91.
TK, NA, AU, KK, SY, and IN are employees of Astellas Pharma
[8] Schwartz SL, Akinlade B, Klasen S, Kowalski D, Zhang W,
Inc. RS is an employee of Astellas Pharma Global Develop- Wilpshaar W. Safety, pharmacokinetic, and
ment. AK and SK have acted as consultants for Astellas pharmacodynamic profiles of ipragliflozin (ASP1941), a
Pharma Inc. novel and selective inhibitor of sodium-dependent glucose
co-transporter 2, in patients with type 2 diabetes mellitus.
Diabetes Technol Ther 2011;13:1219–27.
Conflicts of Interest [9] Ferrannini E, Veltkamp SA, Smulders RA, et al. Renal
glucose handling: impact of chronic kidney disease and
sodium-glucose cotransporter 2 inhibition in patients with
There is no conflict of interest. type 2 diabetes. Diabetes Care 2013;36:1260–5.
[10] Bolinder J, Ljunggren O, Kullberg J, Johansson L, Wilding J,
Langkilde AM, et al. Effects of dapagliflozin on body weight,
Acknowledgements total fat mass, and regional adipose tissue distribution in
patients with type 2 diabetes mellitus with inadequate
glycemic control on metformin. J Clin Endocrinol Metab
Ipragliflozin is under development by Astellas Pharma Inc. and
Kotobuki Pharmaceutical Co., Ltd. This study was sponsored [11] Kashiwagi A, Kasuga M, Araki E, Oka Y, Hanafusa T, Ito H,
by Astellas. Medical writing and editorial support was funded et al. International clinical harmonization of glycated
by Astellas and provided by Dr. Nicholas D. Smith and hemoglobin in Japan: from Japan Diabetes Society to
ELMCOMTM. National Glycohemoglobin Standardization Program
values. Diabetol Int 2012;3:8–10.
[12] Hoelzel W, Weykamp C, Jeppsson JO, Miedema K, Barr JR,
Goodall I, et al. IFCC reference system for measurement of
hemoglobin A1c in human blood and the national
Appendix A. Supplementary data standardization schemes in the United States, Japan, and
Sweden: a method-comparison study. Clin Chem
Supplementary data associated with this article can be 2004;50:166–74.
found, in the online version, at [13] Weykamp C, John WG, Mosca A, Hoshino T, Little R, Jeppsson
j.diabres.2014.07.020. JO, et al. The IFCC reference measurement system for HbA1c:
a 6-year progress report. Clin Chem 2008;54:240–8.