original article

Diabetes, Obesity and Metabolism 16: 215–222, 2014.

© 2013 John Wiley & Sons Ltd

Pharmacokinetics, pharmacodynamics and safety of

empagliflozin, a sodium glucose cotransporter 2 (SGLT2)

original
inhibitor, in subjects with renal impairment

article
S. Macha1 , M. Mattheus2 , A. Halabi3 , S. Pinnetti4 , H. J. Woerle2 & U. C. Broedl2
1 Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA
2 Boehringer Ingelheim GmbH & Co. KG, Ingelheim, Germany
3 CRS Clinical Research Services, Kiel, Germany
4 Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany

Aims: Empagliflozin is a selective sodium glucose cotransporter 2 (SGLT2) inhibitor that inhibits renal glucose reabsorption and is being
investigated for the treatment of type 2 diabetes mellitus (T2DM).
Methods: In this open-label study, the effect of renal impairment on the pharmacokinetics, pharmacodynamics and safety of a 50 mg dose
of empagliflozin was investigated in 40 subjects, grouped according to estimated glomerular filtration rate (eGFR).
Results: Maximum empagliflozin plasma concentrations were similar in subjects with normal renal function and renal impairment. Area under
the empagliflozin concentration-time curve (AUC0 –∞ ) values increased by approximately 18, 20, 66 and 48% in subjects with mild, moderate,
severe renal impairment and renal failure/end stage renal disease (ESRD), respectively, in comparison to healthy subjects. This was attributed
to decreased renal clearance (CLR ). Urinary glucose excretion (UGE) decreased with increasing renal impairment and correlated with decreased
eGFR and CLR . Empagliflozin was well tolerated, with no increase in adverse events associated with renal impairment.
Conclusions: Renal insufficiency resulted in decreased CLR of empagliflozin, moderately increased systemic exposure and decreased UGE.
A single 50 mg dose of empagliflozin was well tolerated in subjects with normal renal function and any degree of renal impairment. The
pharmacokinetic results of this study indicate that no dose adjustment of empagliflozin is required in patients with renal impairment.
Keywords: diabetes, empagliflozin, pharmacodynamics, pharmacokinetics, renal impairment, SGLT2 inhibitor

Date submitted 8 April 2013; date of first decision 13 May 2013; date of final acceptance 11 July 2013

Introduction 30–59); stage 4 is a severe decrease in GFR (GFR 15–29) and

Diabetes is a major public health problem, with a prevalence
that is expected to reach 552 million people worldwide by
2030 [1]. Type 2 diabetes mellitus (T2DM) accounts for 90%
of all diabetes cases [2]. Most medications for the treatment
of T2DM act through insulin-dependent mechanisms; the
progressive loss of beta-cell function that is characteristic of
T2DM means that most patients with T2DM ultimately require
multiple therapies to maintain glycaemic control [3–6].
Nephropathy is a well-established complication of poor
glycaemic control in patients with diabetes. An estimated
10–36% of patients with T2DM have some degree of renal
impairment [7] and chronic kidney disease (CKD) is present
in approximately 40% of patients with diabetes [8]. CKD has
been classified into five stages, where stage 1 is kidney damage
with normal glomerular filtration rate (GFR; ml/min/1.73 m2 )
of ≥90; stage 2 is kidney damage with a mild decrease in GFR
(GFR 60–89); stage 3 is a moderate decrease in GFR (GFR
Correspondence to: Sreeraj Macha, Clinical Pharmacokinetics and Pharmacodynamics,
Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877,
USA.
E-mail: sreeraj.macha@boehringer-ingelheim.com
stage 5 is kidney failure (GFR <15 or dialysis) [9].
The use of a number of anti-diabetes agents is restricted
in patients with renal impairment [5]. Metformin is
contraindicated in patients with renal dysfunction due to the
risk of accumulation and lactic acidosis. Caution is advised
with the use of insulin secretagogues in renally impaired
patients. The dipeptidyl peptidase-4 (DPP-4) inhibitors
saxagliptin, sitagliptin and vildagliptin (but not linagliptin) are
predominantly excreted renally, so dose reduction is necessary
in patients with advanced CKD [5].
Empagliflozin is a potent and selective sodium glucose
cotransporter 2 (SGLT2) inhibitor (IC50 : 3.1 nM; pIC50 ± s.e.:
8.5 ± 0.02 nM) with a >2500-fold selectivity for SGLT2
over SGLT1 [10]. By blocking SGLT2, empagliflozin blocks
reabsorption of glucose from the glomerular filtrate in the
proximal tubule of the kidney, leading to urinary glucose
excretion (UGE) [11,12], which results in a reduction in fasting
plasma glucose and glycosylated haemoglobin (HbA1c) in
patients with T2DM [13,14].
Single oral doses of empagliflozin (0.5–800 mg) exhibit
linear pharmacokinetics in healthy subjects [11]. After multiple
oral doses (up to 100 mg once daily for 4 weeks) in patients
with T2DM, empagliflozin is rapidly absorbed (reaching peak
original article
levels after 1.5 h) with a mean terminal elimination half-life
(t 1/2 ) of between 13 and 17 h [12]. Glucuronidation is the major
metabolic pathway for empagliflozin, and no major metabolites
of empagliflozin were detected in human plasma (data not
published). Approximately 11–19% of the administered dose
is excreted unchanged in urine [11]. As renal function
may affect the pharmacokinetics and pharmacodynamics
of empagliflozin, this study was undertaken to determine
the effect of renal impairment on the pharmacokinetics,
pharmacodynamics and safety of a single 50 mg oral dose
of empagliflozin.
Materials and Methods
The study protocol was approved by the independent ethics
committee Ethikkommission Schleswig-Holstein, Bad Sege-
berg, Germany and the German Competent Authority—the
Federal Institute for Drugs and Medical Devices (Bundesinstitut
für Arzneimittel und Medizinprodukte, BfArM), Bonn, Ger-
many. The study was conducted in compliance with the Decla-
ration of Helsinki (1996) and the International Conference on
Harmonization Good Clinical Practice (ICH-GCP) guidelines.
The study was registered with the EU Clinical Trials Register
(Eudra CT number: 2008-006086-86) and conducted at two
German centres: CRS Clinical Research Services Kiel GmbH,
Kiel and Profil Institut für Stoffwechselforschung GmbH,
Neuss. All participants provided written informed consent.
Subjects
Male and female subjects aged 18–75 years weighing at least
45 kg (females only) and with a body mass index (BMI) of
18–34 kg/m2 were eligible for inclusion in this study. Partici-
pants with normal renal function (eGFR >90 ml/min/1.73 m2 ;
control) were required to have T2DM. Patients with mild
renal impairment (eGFR 60–89 ml/min/1.73 m2 ), moderate
renal impairment (eGFR 30–59 ml/min/1.73 m2 ), severe renal
impairment (eGFR <30 ml/min/1.73 m2 ) or renal failure/end
stage renal disease (ESRD) (requiring dialysis) did not need
to have T2DM. eGFR was calculated using the Modification
of Diet in Renal Disease (MDRD) formula: 186 × serum
creatinine−1.154 × age−0.203 × [0.742 if female].
Subjects were excluded from the study if they had recently
participated in a study (multiple-dose: within 2 months; single-
dose: within 1 month), were abusing alcohol (males >60 g/day;
females >40 g/day) or drugs, had donated >100 ml blood in the
previous 4 weeks, were taking concomitant medications known
to inhibit or induce p-glycoprotein or cytochrome P450 3A, or
had any medical or laboratory results deviating from normal
and of clinical relevance.
Subjects with renal impairment were excluded if they had
significant diseases other than renal impairment or T2DM,
including moderate and severe concurrent hepatic impair-
ment, haemoglobin <8 g/dl indicating severe renal anaemia
(erythropoietin could be used to maintain haemoglobin lev-
els), and intake of drugs with a long half-life (>24 h) within the
previous month (or within 10 half-lives of that drug, if longer),
except for those being taken for the treatment of renal disease.
216 Macha et al.
DIABETES, OBESITY AND METABOLISM
The investigators, in cooperation with nephrology centres,
aimed to recruit eight subjects for every group. Subjects with
normal renal function were matched to those in the renal
impairment groups by age (±5 years) and weight (±15%),
where possible.
Study Design
This two-centre, open-label, parallel-group study was under-
taken to assess the effect of renal function on the pharma-
cokinetics, pharmacodynamics and safety of a single 50 mg
dose of empagliflozin. Subjects were screened for eligibility up
to 21 days prior to study drug administration. Following an
overnight fast, subjects were admitted to the research unit and
received a 50 mg dose of empagliflozin with 240 ml of water
(day 1). Water was allowed ad libitum except for 1 h before
and 1 h after study drug administration. Following medical
surveillance for 24 h, subjects were discharged (day 2) and were
monitored as outpatients until they attended an end-of-study
examination (within 14 days after the last trial procedure).
Pharmacokinetic Endpoints
One objective of the study was to determine the effect of renal
impairment on the relative bioavailability of empagliflozin,
based on the primary endpoints of AUC0−∞ (area under the
concentration-time curve of empagliflozin in plasma from time
0 extrapolated to infinity) and Cmax (maximum concentration
of empagliflozin in plasma). Secondary pharmacokinetic
endpoints included: t max (time to peak empagliflozin plasma
levels), t 1/2 , fe0–96 (fraction of the dose excreted in urine
following drug administration), CLR,0–96 (renal clearance) and
plasma protein binding of empagliflozin.
Pharmacodynamic Endpoint
The pharmacodynamic endpoint of the study was the
cumulative amount of UGE over a 24 h period following drug
administration (UGE0–24 ), relative to baseline, with a baseline
measurement obtained over 24 h preceding administration of
study drug.
Safety Endpoints
The safety evaluation was based on monitoring vital signs,
12-lead electrocardiograms (ECGs), physical examinations,
clinical laboratory tests, adverse events (AEs) and a global
assessment of tolerability made by the investigator (with
options of ‘good’, ‘satisfactory’, ‘not satisfactory’ or ‘bad’). AEs
were assessed throughout the study, and were coded using the
Medical Dictionary for Drug Regulatory Activities (MedDRA)
version 12.1 (http://www.meddramsso.com). Vital signs (blood
pressure and pulse rate), ECG and physical examination
were assessed at the screening visit and at the end-of-study
examination. Vital signs were also measured prior to dosing.
Clinical laboratory tests (haematology, clinical chemistry, urine
analysis) were conducted at the screening visit, prior to dosing,
and at the end-of-study examination. Urinary creatinine and
glucose were determined in −24 to 0 h and 0 to 24 h fractions.
Volume 16 No. 3 March 2014
DIABETES, OBESITY AND METABOLISM original article
Table 1. Demographics and baseline characteristics based on the treated set.

Renal impairment Total

Normal renal function Mild Moderate Severe Renal failure/ESRD
n 8 9 7 8 8 40
Female, n (%) 7 (87.5) 6 (66.7) 3 (42.9) 1 (12.5) 4 (50.0) 21 (52.5)
Age, years
Median (range) 56 (38–67) 61 (42–69) 64 (48–74) 56 (34–74) 40 (36–70) 56 (34–74)
Weight, kg
Median (range) 81.70 (67.5–98.3) 70.20 (60.5–90.3) 78.60 (73.6–101.8) 75.10 (65.2–103.0) 77.25 (63.0–98.0) 78.30 (60.5–103.0)
BMI, kg/m2
Median (range) 28.85 (26.0–33.1) 26.80 (21.7–30.1) 28.10 (24.6–34.0) 23.85 (19.6–32.5) 26.85 (22.1–33.8) 27.65 (19.6–34.0)

ESRD, end stage renal disease; BMI, body mass index.

A
Empagliflozin plasma concentration (nmol/l)

1500 Normal
Mild
10000 Moderate
Empagliflozin plasma
concentration (nmol/l)

Severe
1000
1000 ESRD
100

10

500 1
0 24 48 72 96
Time (h)

0
0 24 48 72 96
Time (h)

B C

Figure 1. Exposure to a single oral 50 mg dose of empagliflozin in subjects with normal and impaired renal function. (A) Mean plasma concentration-time
profiles (insert: semi-log plot) (n = 40). (B) AUC0 –∞ and (C) Cmax ; midline of boxes are medians, and boundaries are 25th and 75th percentiles; whiskers
are the standard span for the quartiles (1.5 × interquartile range).

Volume 16 No. 3 March 2014 doi:10.1111/dom.12182 217

original article
Sample Collection and Analysis
Approximately 124 ml of blood was taken from every subject
over the course of the study for clinical laboratory tests (44 ml),
pharmacokinetic assessments (50 ml) and determination of
protein binding (30 ml). Blood samples for clinical laboratory
testing were collected after subjects had fasted for at least 10 h.
For quantification of empagliflozin plasma concentrations,
2.7 ml of blood was taken from a forearm vein in a K3 -EDTA
(tripotassium ethylenediaminetetraacetic acid)-anticoagulant
blood drawing tube at pre-dose and 0.33, 0.67, 1, 1.5, 2, 2.5,
3, 4, 6, 8, 10, 12, 14, 24, 36, 48, 72 and 96 h post-dose. Within
30 min of collection, the samples were centrifuged for 10 min
at 2000–4000 g and 4–8 ◦ C. The EDTA plasma obtained was
stored at −18 ◦ C until it was shipped on dry ice for analysis.
Urine was collected over 24 h prior to drug administration
and at the following intervals following drug administration:
0–4, 4–8, 8–12, 12–24, 24–36, 36–48, 48–72 and 72–96 h.
Urine containers were weighed empty and at the end of every
sampling period and the difference was recorded as the urine
volume (weight was set equal to volume, i.e. 1 kg = 1 l). Urine
containers were refrigerated until 25 h after drug administration
and aliquots were stored at −18 ◦ C until shipped on dry ice for
analysis.
Empagliflozin concentrations in plasma and urine were
determined by validated high performance liquid chromatog-
raphy, tandem mass spectrometry (HPLC-MS/MS) assays.
Empagliflozin and the internal standard [13 C6 ]-empagliflozin
were extracted from urine or plasma by supported liquid
extraction. After evaporation under nitrogen, the residue
was reconstituted and analysed using liquid chromatography
with MS/MS detection. The lower limit of quantification for
empagliflozin in human plasma was 1.11 nmol/l, with linear-
ity to 1110 nmol/l using a sample volume of 0.15 ml, and in
human urine was 4.44 nmol/l, with linearity to 4440 nmol/l
using a sample volume of 0.05 ml. For both plasma and urine,
results were calculated using peak area ratios and calibration
curves were created using weighted (1/x2 ) quadratic regression.
For determination of protein binding of empagliflozin, 10 ml
blood was collected at pre-dose, 1.5 and 3 h post-dose. Blood
was centrifuged for 10 min at 4000 g and 4 ◦ C, and the plasma
was stored at −20 ◦ C until it was shipped on dry ice for analysis.
The binding of empagliflozin and the internal standard [13 C6 ]-
empagliflozin to human plasma protein was determined by
equilibrium dialysis at 37 ◦ C. As a quality control measure,
protein-binding analyses were performed using the pre-dose
plasma samples.
Pharmacokinetic parameters were calculated using
WinNonlinTM software (v5.01, Pharsight Corporation,
Mountain View, CA, USA). Cmax and t max values were
directly determined from the plasma concentration time
profiles of each subject. The apparent terminal rate constant
(λz ) was estimated from a regression of ln(C) versus time
over the terminal log-linear drug disposition portion of
the concentration-time profiles. The t 1/2 was calculated
as the quotient of ln(2) and λz . Area under the plasma
concentration-time curve to the last time point (AUC0–tz ) was
calculated using the linear trapezoidal method for ascending
concentrations and the log trapezoidal method for descending
218 Macha et al.
DIABETES, OBESITY AND METABOLISM
concentrations. The AUC0−∞ value was estimated as the
sum of AUC to the last measured concentration, with the
extrapolated area given by the quotient of the last measured
concentration and λz . The amount of drug (Ae ) excreted
unchanged in urine in each collection interval was determined
by the product of the urine concentration and the urine
volume. The fraction of the dose (f e ) that was excreted
unchanged in urine was determined by the quotient of the
sum of drug excreted over all dosing intervals and the dose
administered. CLR was determined as the quotient of Ae
over AUC. Cumulative UGE was calculated using the glucose
concentration measured in every urine sample collected
from −24 to 0 h and 0 to 96 h after dosing. UGE (mg) was
calculated as follows: glucose concentration (mg/dl) × urine
volume (dl).
Statistical Analysis
All subjects who provided at least one observation for at least
one primary endpoint without any protocol violations relevant
to pharmacokinetic evaluation were included in the analysis
of relative bioavailability (pharmacokinetic analysis set). All
subjects with a baseline UGE value (0–24 h pre-dose) and a
UGE value from 0 to 24 h post-dose without any protocol
violations relevant to UGE analysis were included in the UGE
analysis set. All safety analyses were performed on all subjects
who received study drug (treated set).
One objective of the study was to investigate the relative
bioavailability of empagliflozin in subjects with normal renal
function (R) compared with subjects with various degrees
of renal impairment (T1–4), by presenting point estimators
[adjusted geometric mean (gMean) T/R ratios] of AUC0–∞
and Cmax and their two-sided 90% confidence intervals
(CIs). AUC0–∞ and Cmax were analysed using an analysis
of variance (anova) model on the logarithmic scale including
a fixed effect corresponding to the renal function (normal,
mild impairment, moderate impairment, severe impairment
or renal failure/ESRD). The change in UGE 0–24 h from
baseline after drug administration was analysed by an analysis
of covariance (ancova) model including baseline UGE values
as a continuous covariate, and a fixed effect corresponding
to the renal function. Descriptive statistics were calculated for
all pharmacokinetic and pharmacodynamic parameters. Safety
analyses were descriptive in nature.
Results
Subjects
Forty subjects (21 female and 19 male) participated in this
open-label, parallel-group study: eight with T2DM and
normal renal function (eGFR >90 ml/min/1.73 m2 ; con-
trol); nine with T2DM and mild renal impairment (eGFR
60–89 ml/min/1.73 m2 ); seven with T2DM and moderate renal
impairment (eGFR 30–59 ml/min/1.73 m2 ); eight with severe
renal impairment (eGFR <30 ml/min/1.73 m2 ), four of whom
also had T2DM; and eight subjects with renal failure/ESRD
requiring dialysis, none of whom had T2DM. Subjects in the
group with normal renal function were matched to those in the
Volume 16 No. 3 March 2014
DIABETES, OBESITY AND METABOLISM original article
Table 2. Pharmacokinetic and pharmacodynamic parameters for empagliflozin after administration of a single oral 50 mg dose.

Renal impairment
Normal
renal function Mild Moderate Severe Renal failure/ESRD
Pharmacokinetics n=8 n=9 n=7 n=8 n=8
AUC0–∞ , nmol × h/l 10 600 (16.4) 12 700 (20.8) 13 000 (25.1) 17 700 (17.8) 16 600 (38.7)
Cmax, nmol/l 1240 (23.5) 1500 (29.4) 1290 (37.9) 1520 (31.6) 1290 (27.5)
t max , h* 1.0 (1.0–3.0) 2.5 (2.0–4.0) 2.0 (1.5–3.0) 2.0 (0.7–4.0) 2.5 (1.5–3.0)
t 1/2 , h 19.9 (58.8) 24.6 (84.5) 23.8 (87.9) 27.9 (76.8) 22.0 (74.3)
f e0–96 , % 16.1 (26.7) 11.7 (36.4) 7.7 (70.1) 3.6 (36.1) 0.3 (56.4)
CLR,0–96 , ml/min 28.5 (20.5) 18.6 (46.9) 11.8 (69.6) 4.0 (30.6) 0.5 (59.1)
Pharmacodynamics n=8 n=7 n=5 n=6 n=5
UGE0–24 , baseline, g 4.49 (2.88) 4.16 (3.08) 0.97 (0.49) 0.97 (0.43) 2.16 (2.00)
UGE0–24 , g 102.13 (7.92) 65.75 (7.31) 56.64 (17.13) 19.22 (4.04) 2.93 (1.28)
Change from baseline, g 97.64 (7.20) 61.59 (6.89) 55.67 (16.89) 18.25 (3.93) 0.78 (0.90)

Pharmacokinetic values are mean (coefficient of variation [%]) unless otherwise stated; pharmacodynamic values are mean (standard error). ESRD, end
stage renal disease; AUC0-∞ , area under the concentration-time curve of empagliflozin in plasma from time 0 extrapolated to infinity; Cmax , maximum
concentration of empagliflozin in plasma; t max , time to peak empagliflozin plasma levels; t 1/2 , terminal elimination half-life; fe0-96 , fraction of the dose
excreted in urine following drug administration; CLR, 0-96 , renal clearance; UGE, urinary glucose excretion.
*Data are median (range).

Figure 2. (A) CLR from 0 to 96 h; (B) AUC0−∞ and (C) cumulative amount of glucose excreted in urine in 24 h versus eGFR after administration of a
single oral 50 mg dose in subjects with normal and impaired renal function (n = 40).

renal impairment groups by age (±5 years) and weight (±15%).
Demographic and baseline characteristics are shown in
Table 1.
All 40 entered subjects received a single 50 mg oral dose of
empagliflozin (Boehringer Ingelheim Pharma GmbH & Co.
KG, Biberach, Germany) and completed the study. All subjects
were included in the pharmacokinetic analysis set and treated
set. In total, 31 subjects were included in the UGE analysis set;
6 did not have baseline values and/or values for 24 h following
dosing (2 subjects each with mild, moderate and severe renal
impairment) and 3 subjects with renal failure/ESRD had no
urine output.

Volume 16 No. 3 March 2014 doi:10.1111/dom.12182 219

original article DIABETES, OBESITY AND METABOLISM

Table 3. Relative bioavailability of empagliflozin (50 mg qd) in subjects with impaired renal function compared with subjects with normal renal function
(n = 40).

90% CI for adjusted GMR

Renal impairment group Parameter Adjusted GMR (renal impaired/normal group) Lower limit (%) Upper limit (%)
Mild AUC0–∞ 118.2 96.2 145.4
Cmax 118.8 93.6 150.8
Moderate AUC0–∞ 119.9 96.3 149.5
Cmax 102.3 79.3 131.9
Severe AUC0–∞ 166.3 134.4 205.7
Cmax 120.7 94.4 154.3
Renal failure/ESRD AUC0–∞ 148.3 119.9 183.4
Cmax 103.8 81.2 132.6

ESRD, end stage renal disease; CI, confidence interval; GMR, geometric mean ratio.

Figure 3. Mean cumulative amounts of glucose excreted in urine after administration of a single oral 50 mg dose in subjects with normal and impaired
renal function (n = 31).

Pharmacokinetics severe renal impairment and renal failure/ESRD, respectively,

Empagliflozin was rapidly absorbed after oral administration
in all subjects (figure 1A). The rate of absorption was slightly
slower in subjects with renal impairment compared with
those with normal renal function, with a median t max of
2.0–2.5 h and 1.0 h, respectively (Table 2). After reaching
peak levels, empagliflozin plasma concentrations declined in
a biphasic manner with a rapid distribution phase followed
by a slower elimination phase (figure 1A). The mean t 1/2
of empagliflozin increased slightly with increasing renal
impairment: mean t 1/2 was approximately 20 h in subjects
with normal renal function and approximately 28 h in those
with severe renal impairment (Table 2). CLR of empagliflozin
following study drug administration decreased with increasing
renal impairment (Table 2, figure 2A), leading to an increase in
the overall exposure (AUC0–∞ ) of empagliflozin (figure 2B).
There were also decreases in the mean fe0–96 with increasing
renal impairment (Table 2).
Relative Bioavailability. The AUC0–∞ increased by approx-
imately 18, 20, 66 and 48% in subjects with mild, moderate,
as compared with subjects with normal renal function (Tables
2, 3, figure 1B). The Cmax was similar in subjects with moderate
renal impairment, renal failure/ESRD and those with normal
renal function and was slightly (∼20%) higher in subjects with
mild or severe renal impairment as compared to subjects with
normal renal function (Table 3, figure 1C).
Protein Binding. The proportion of empagliflozin bound to
plasma proteins ranged from 81.0 to 85.1% at 1.5 h post-
dose, with no relevant differences over time. Renal impairment
resulted in a slight (∼4%) decrease in the degree of plasma
protein binding, from 85.1% with normal renal function to
81.1% with renal failure/ESRD at 1.5 h post-dose, leading to
an approximate 27% increase in the unbound fraction (f u )
of empagliflozin in those with renal failure/ESRD; the f u was
14.9% in subjects with renal failure/ESRD and 18.9% in those
with normal renal function. A similar reduction in protein
binding was observed in the in vitro protein-binding analysis of
pre-dose plasma samples, from 83.6% in subjects with normal
renal function to 81.1% in subjects with renal failure/ESRD.

220 Macha et al. Volume 16 No. 3 March 2014

DIABETES, OBESITY AND METABOLISM
Pharmacodynamics
The cumulative amount of glucose recovered in urine decreased
with increasing renal impairment (Table 2, figures 2C, 3).
The total amount of glucose excreted in urine (change from
baseline) over 24 h was 97.6 g in subjects with normal renal
function, decreasing to approximately 0.8 g in subjects with
renal failure/ESRD (Table 2). Consistent results were observed
in a statistical model with adjustment for renal function and
UGE at baseline. The decrease in glucose excretion followed
the same pattern as the decreases in the empagliflozin renal
clearance with increasing renal impairment (figures 2A, C).
Safety and Tolerability
A total of 6 treatment-emergent AEs were reported by 4 of the
40 subjects. All were mild in intensity. AEs were considered
drug-related by the investigator in two subjects: erythema and
pruritus in a subject with moderate renal impairment, and
pruritus in a subject with renal failure/ESRD. All AEs resolved
without treatment by the end of the study. No effects on safety
laboratory values, vital signs or ECG parameters were observed.
The investigators rated the global tolerability of empagliflozin
as ‘good’ for all participants.
Discussion
This study was undertaken to determine the effect of
different degrees of renal impairment on the pharmacokinetics,
pharmacodynamics and safety of a single dose of empagliflozin.
Exposure to empagliflozin increased moderately with
increasing renal impairment. The upper limits of 90% CIs
for both AUC0–∞ and Cmax were outside the standard
bioequivalence boundaries (80–125%) in all renal impairment
groups. The effect was greater on the extent of exposure
compared with peak levels (AUC0–∞ and Cmax , respectively),
suggesting that the effect was due to decreased clearance
of empagliflozin. Indeed, the moderate increase in systemic
exposure to empagliflozin could be explained by the decrease
in CLR of empagliflozin leading to a slight increase in t 1/2 .
AUC0–∞ was higher by approximately 18, 20, 66 and 48%
in subjects with mild, moderate, severe renal impairment and
renal failure/ESRD, respectively, than in those with normal
renal function. Peak plasma levels of empagliflozin in subjects
with moderate renal impairment or renal failure/ESRD were
similar to those in subjects with normal renal function, and were
approximately 20% higher in those with mild and severe renal
impairment compared to subjects with normal renal function.
The pharmacokinetic properties of empagliflozin were largely
unaltered by renal impairment, suggesting that no dose
adjustments are required in patients with renal impairment.
Protein binding of empagliflozin was slightly lower in
subjects with renal impairment than in those with normal
renal function (81.1% in subjects with renal failure/ESRD vs.
85.1% in subjects with normal renal function at 1.5 h post-
dose), and the f u of empagliflozin was approximately 27%
higher at 1.5 h post-dose in subjects with renal failure/ESRD
compared with those with normal renal function. This slight
increase in the free fraction of drug could have contributed
Volume 16 No. 3 March 2014
original article
partially to the changes in apparent volume of distribution.
However, any effect of decreased protein binding on exposure
in subjects with renal impairment could have been offset by
a rapid decrease in CLR , with an overall effect of increased
exposure in subjects with renal impairment.
The pharmacodynamic results of this study indicate that
treatment with empagliflozin leads to increases in UGE in
patients with mild and moderate renal impairment, as well
as in those with normal renal function. This suggests that
clinically meaningful reductions in plasma glucose levels might
be obtained with empagliflozin even in patients with moderate
renal impairment (CKD stage 3), although reductions in HbA1c
cannot be predicted solely based on UGE. A potential limitation
of this study is that, although all subjects with normal renal
function or mild or moderate renal impairment had T2DM,
only four of the eight subjects with severe renal impairment and
none of the participants with renal failure/ESRD had T2DM.
Thus, the ability of empagliflozin to increase UGE in patients
with T2DM and severe renal impairment or renal failure/ESRD
may have been underestimated.
The increasing exposure to empagliflozin with increasing
renal impairment had no effect on the incidence of AEs. AEs
were reported by one patient with normal renal function
and moderate impairment and two patients with renal
failure/ESRD. The only AEs reported during the study were
headache, nausea, erythema, pruritus and diarrhoea. No AEs
were serious or severe, and all patients recovered by the
end of the trial without therapy. Single dose administration
of empagliflozin in patients with various degrees of renal
impairment had no clinically relevant effects on laboratory
values, vital signs or ECG parameters. The safety and efficacy
of empagliflozin in patients with T2DM and renal impairment
will be determined by the results of a dedicated 52-week Phase
III trial (NCT01164501).
In conclusion, the increase in exposure to empagliflozin with
increasing renal impairment was moderate, with no significant
increase in maximum plasma concentrations. On the basis of
pharmacokinetics, no dose adjustment is required in patients
with renal insufficiency. Empagliflozin increased UGE in
subjects with normal renal function and mild or moderate renal
impairment and showed little to no effect on UGE in subjects
with severe renal impairment or renal failure/ESRD. A single
50 mg dose of empagliflozin was well tolerated in all subjects.
Acknowledgements
This study was funded by Boehringer Ingelheim. The authors
acknowledge Andreas Port for his contributions related to
the planning and conduct of the studies, and his support in
preparing the clinical trial reports and manuscript. The authors
would also like to thank Lois Rowland for coordinating the
bioanalytical analyses, Dale Sharp for coordinating the protein-
binding analysis, Tim Heise, Principal Investigator at the second
site (Profil, Neuss), Haidar Maatouk, who was the responsible
research physician at CRS and Leszek Nosek, who was the
responsible clinical research physician at the second site (Profil,
Neuss). Medical writing assistance, supported financially by
Boehringer Ingelheim, was provided by Isobel Lever and Wendy
doi:10.1111/dom.12182 221
original article
Morris of Fleishman-Hillard Group Ltd during the preparation
of this manuscript. The authors were fully responsible for all
content and editorial decisions, were involved at all stages of
manuscript development and have approved the final version.
Conflict of Interest
S. M., M. M., S. P., H. J. W. and U. C. B. are employees of
Boehringer Ingelheim. A. H. has no conflict of interests to
disclose.
The authors meet criteria for authorship as recommended
by the International Committee of Medical Journal Editors
(ICMJE). S. M., M. M. and S. P. made substantial contributions
to the conception and design of the study and were involved
in the analysis and interpretation of data. A. H. was involved
in the acquisition and interpretation of data. U. C. B. was
involved in the interpretation of the data. All authors were
involved with drafting the article or revising it critically for
important intellectual content and all authors have approved
the final version.
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Volume 16 No. 3 March 2014