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original article Diabetes, Obesity and Metabolism 17: 4251, 2015.

2014 John Wiley & Sons Ltd

Twice-daily dapagliflozin co-administered with metformin in type


2 diabetes: a 16-week randomized, placebo-controlled clinical
ORIGINAL
ARTICLE

trial
P.-M. Schumm-Draeger1 , L. Burgess2 , L. Kornyi3 , V. Hruba4 , J. E. Hamer-Maansson5 & T. W. A. de Bruin6
1 Clinic for Endocrinology, Diabetology, Angiology, Academic Teaching Hospital, Munich, Germany
2 TREAD Research, Cardiology Unit, Department of Internal Medicine, Tygerberg Hospital and Stellenbosch University, Parow, South Africa
3 Clinical Pharmacology Unit, Drug Research Center Gygyszervizsgl Kzpont, Balatonfred, Hungary
4 Global Medicines Department, AstraZeneca, Prague, Czech Republic
5 Biostatistics Department, AstraZeneca R&D, Wilmington, DE, USA
6 Global Medicines Department, AstraZeneca, Gaithersburg, MD, USA

Aims: To evaluate the efficacy and safety of twice-daily dosing of dapagliflozin and metformin, exploring the feasibility of a fixed-dose combination.
Methods: In this 16-week, phase III, randomized, double-blind placebo-controlled study, adults who were receiving metformin administered twice
daily (1500 mg/day) and had inadequate glycaemic control were randomized 1 : 1 : 1 : 1 to receive dapagliflozin twice daily (2.5 or 5 mg), placebo or
dapagliflozin 10 mg once daily (which was included as a benchmark). The primary endpoint was change from baseline glycated haemoglobin (HbA1c)
level. Secondary endpoints included changes in fasting plasma glucose (FPG) level and body weight.
Results: Four hundred adults were randomized to dapagliflozin (2.5 mg twice daily, 5 mg twice daily, 10 mg once daily) or placebo co-administered with
metformin twice daily. At 16 weeks, the adjusted mean change in HbA1c from baseline was significantly reduced in the dapagliflozin 2.5 mg twice daily
and 5 mg twice daily groups versus placebo (0.52 vs. 0.30%, p = 0.0106 and 0.65% vs. 0.30%, p < 0.0001). There were also significantly greater
improvements for dapagliflozin twice daily groups versus placebo in FPG body weight and achievement of HbA1c level of <7%. Efficacy outcomes for
dapagliflozin twice daily were numerically similar to those for dapagliflozin once daily. Dapagliflozin twice daily was well tolerated.
Conclusions: Dapagliflozin 2.5 or 5 mg twice daily added to metformin was effective in reducing glycaemic levels in patients with type 2 diabetes
inadequately controlled with metformin alone. This study supports the development of a fixed-dose combination regimen.
Keywords: metformin, phase III study, SGLT2 inhibitor, type 2 diabetes

Date submitted 15 May 2014; date of first decision 20 June 2014; date of final acceptance 30 August 2014

Introduction plasma glucose [9]. This approach reduces hyperglycaemia


independently of insulin secretion or action. Dapagliflozin
Glycaemic control is the primary treatment goal for patients
has been shown to have antihyperglycaemic efficacy, both
with type 2 diabetes mellitus. Metformin, along with lifestyle
alone and in combination with other commonly prescribed
modification, is the recommended first-line therapy [1,2]. With
antidiabetic agents, with optimum efficacy and safety being
progressive deterioration of diabetes control it is frequently
observed at 10 mg/day [5,1014]. Results obtained in studies
necessary to add other antidiabetic agents on to existing therapy
of dapagliflozin co-administered with metformin have shown
[24]. Commonly prescribed add-on antidiabetic agents gener- significant reductions in glycated haemoglobin (HbA1c) and
ally act by increasing insulin secretion or reducing insulin resis- fasting plasma glucose (FPG) [57,15,16]. A fixed-dose com-
tance, but some regimens may cause weight gain, gastrointesti- bination of dapagliflozin and metformin is expected to have
nal side effects, insulin resistance and hypoglycaemia [37]. An complementary effects on glucose metabolism [5,17] and to
add-on agent with a non-insulin-based mechanism of action potentially support weight loss. It may also improve medication
may complement metformin by providing improved glycaemic compliance by simplifying treatment regimens [1822].
control without increased risk of hypoglycaemia. In phase III clinical trials, dapagliflozin has been evaluated
Sodium-glucose co-transporter-2 is the major sodium- as a once-daily treatment, including in combination regimens
glucose co-transporter in the kidney [8]. Dapagliflozin with metformin, dosed either twice daily or once daily as an
inhibits sodium-glucose co-transporter-2, resulting in direct extended-release formulation [23]. Dapagliflozin inhibits renal
excretion of glucose in the urine and removal of excess glucose reabsorption [5] and metformin decreases hepatic glu-
cose output [17]; therefore, based on the complementary action
Correspondence to: P.-M. Schumm-Draeger, Klinikum Bogenhausen, Endocrinology, on glucose metabolism in patients with type 2 diabetes mellitus,
Diabetology and Angiology Clinic, Englschalkinger Strasse 77, 81925 Munich, Germany.
E-mail: petra-maria.schumm-draeger@klinikum-muenchen.de it may be possible to use dapagliflozin in a fixed-dose combi-
nation with metformin immediate release, administered twice
DIABETES, OBESITY AND METABOLISM original article
daily. In the present study, we describe the results of a phase III Response System, which assigned a unique enrolment num-
trial that was designed to determine whether twice-daily dosing ber according to a schedule with balanced blocks prepared by
of dapagliflozin 2.5 or 5 mg had better efficacy than placebo as AstraZeneca; this method was used to allocate patients to treat-
an add-on to metformin in patients with type 2 diabetes with ment groups and maintain double-blind status.
inadequate glycaemic control on metformin alone. The safety Patients were randomized to one of four treatment groups:
and tolerability of twice-daily dosing with dapagliflozin were dapagliflozin 2.5 mg twice daily, dapagliflozin 5 mg twice daily,
also assessed. dapagliflozin 10 mg once daily and placebo twice daily, as
add-on to metformin. The dapagliflozin and metformin tablets
were taken at the same time for the twice-daily dosing regimens.
Materials and Methods The twice-daily dapagliflozin doses were quantitatively equiva-
lent to the once-daily doses of 5 and 10 mg. The dapagliflozin
Trial Design 10 mg once daily treatment group was included as a mea-
A 16-week, international, multicentre, randomized, double- sure of study sensitivity and a benchmark control; outcomes
blind, double-dummy placebo-controlled phase III study was for this dose were statistically tested versus placebo as a sec-
undertaken at 53 sites in Europe and South Africa between ondary objective, but were not formally compared with the
November 2010 and August 2011. This study complied with dapagliflozin twice-daily treatment groups.
the Declaration of Helsinki, International Conference on Har- Treatment-phase study visits took place at weeks 0, 1, 4, 8, 12
monisation/Good Clinical Practice and applicable regulatory and 16. Patients were required to monitor and record their FPG
requirements. The study protocol was approved by the insti- levels at least every other day. Patients who had poor glycaemic
tutional review boards and independent ethics committees control according to study-specific criteria (FPG >15.0 mmol/l
of the participating institutions. All patients provided written during first 4 weeks of treatment period, FPG >13.2 mmol/l
informed consent. The study is registered under clinical trial from weeks 4 to 8, FPG >11.1 mmol/l from weeks 12 to 16) were
registration number NCT01217892 (http://clinicaltrials.gov). discontinued from the study; an increase in metformin dosing
Patients were eligible for inclusion if they were 1877 years was not allowed. Concomitant, non-antidiabetic medications
old, had type 2 diabetes and had been treated with stable (e.g. antihypertensive, diuretic and lipid-lowering drugs) were
doses of metformin 1500 mg/day monotherapy for 10 weeks allowed, but changes in dosing were not allowed during the trial
before enrolment and showed inadequate glycaemic control, unless medically necessary. Upon completion of active study
defined as an HbA1c level 6.7 and 10.5% at screening, or treatment, patients were monitored for 4 weeks to evaluate
HbA1c 6.5 and 10.0% 1 week before randomization. The changes in physical signs, symptoms or laboratory variables that
lower limit was chosen to ensure inclusion of patients with might be related to treatment with dapagliflozin. The last study
a broad range of baseline HbA1c values, including those just visit followed this period.
above the lower target value of 6.5% [24]. Exclusion crite-
ria included: symptoms of poorly controlled diabetes (includ- Objectives and Assessments
ing weight loss, FPG >15.0 mmol/l); renal disorders, includ-
The primary efficacy objective was to compare the change from
ing a calculated creatinine clearance (CrCl) <60 ml/min or
baseline in HbA1c achieved with dapagliflozin 2.5 mg twice
a measured serum creatinine value of 133 mol/l in men
daily and 5 mg twice daily co-administered with metformin
and 124 mol/l in women; urine albumin : creatinine ratio
versus placebo co-administered with metformin after 16 weeks
>1800 mg/g; hepatic disorders, including hepatotoxicity with
of treatment. Key secondary endpoints included the percent
any medication; a recent cardiovascular event or New York
change from baseline in body weight, change from baseline
Heart Association class III or IV congestive heart failure; blood
in FPG at weeks 1 and 16 and proportion of patients with
pressure 160/100 mmHg at randomization; and clinically
HbA1c levels 7% at baseline achieving HbA1c levels <7%
significant haematological or oncological conditions.
after 16 weeks. Other secondary endpoints included change in
seated blood pressure and body weight. Secondary endpoints
Treatments for the benchmark treatment group with dapagliflozin 10 mg
once daily included identical objectives and assessments.
After initial screening and a 1-week enrolment period, there The safety and tolerability of dapagliflozin co-administered
was a 4-week lead-in period. During this period, patients con- with metformin were determined by assessment of adverse
tinued their metformin treatment and received placebo twice events (AEs), including hypoglycaemic events, laboratory val-
daily; metformin study medication was adjusted to 1500, 2000 ues, vital signs (electrocardiogram, blood pressure), calculated
or 2500 mg/day according to a prespecified adjustment table. CrCl, estimated glomerular filtration rate (eGFR) and physical
Diet and lifestyle advice was provided to enhance glycaemic examination findings.
control; this was reinforced at each study visit.
Patients were stratified by HbA1c levels at randomization:
group 1 had HbA1c levels 6.5 and <7.0% (planned maximum Statistical Analysis
was no more than 20% of all participants); group 2 had HbA1c All randomized patients who received at least one dose of
levels 7.0 and 10.0%. This stratification was solely for the double-blind study medication, with a non-missing baseline
purpose of limiting the proportion of patients with low baseline value and at least one post-baseline value for an efficacy vari-
HbA1c. Randomization was conducted via an Interactive Web able, were included in the full analysis set. Missing values at

Volume 17 No. 1 January 2015 doi:10.1111/dom.12387 43


original article DIABETES, OBESITY AND METABOLISM

week 16 were to be replaced by last observation carried for- reduction from baseline for dapagliflozin 10 mg once daily was
ward (LOCF). The study had a power of 90% to detect a 0.5% 0.59% [95% confidence interval (CI) 0.70, 0.47].
difference in mean change from baseline in HbA1c using a There were significant differences in adjusted mean reduc-
two-sample t-test at a 0.025 two-sided significance level (in the tion from baseline in FPG at week 1 and week 16 for both
conservative case where only one treatment group reached sta- dapagliflozin 2.5 and 5 mg twice daily treatment groups ver-
tistical significance). The Hochberg procedure [25] was used sus placebo (p < 0.0001; Table 2, Figure 2B). Among patients
to control the overall type I error rate 0.050 for the com- with HbA1c levels 7% at baseline, significantly more patients
parisons of the two dapagliflozin twice daily groups versus in the dapagliflozin 2.5 and 5 mg twice daily treatment groups
placebo + metformin for the primary efficacy variable. If the achieved an HbA1c level <7% at week 16 than patients in the
test of the primary endpoint was significant for a treatment placebo group (Table 2).
group, statistical significance of secondary outcomes proceeded The adjusted mean percent change in body weight was
for the same treatment group and was evaluated using a hier- also significantly greater in the dapagliflozin 2.5 and 5 mg
archical, fixed-sequence testing procedure (per order of end- twice daily treatment groups than placebo: 2.84, 3.20
points listed above) for the treatment groups, with demon- and 1.04%, respectively (both p < 0.0001 vs. placebo). For
strated statistical significance for the primary outcome; this dapagliflozin 10 mg once daily, the adjusted mean percent
was to protect the global type I error rate for each treatment change in body weight was 2.76% (95% CI 3.36, 2.15).
group. The primary efficacy variable and other continuous effi- The greatest decreases were seen in the first week of treat-
cacy variables were analysed using an analysis of covariance ment. Placebo-subtracted changes in total body weight for the
(ancova) model with treatment group as a fixed effect and dapagliflozin 2.5 and 5 mg twice daily treatment groups were
baseline HbA1c as a covariate. Proportions were analysed using 1.62 and 1.88 kg, respectively (Figure 2C).
the logistic regression methodology described by Zhang et al. Compared with placebo, all dapagliflozin groups showed a
[26] and Tsiatis et al. [27], with adjustment for baseline value. reduction in seated systolic blood pressure, but not in diastolic
Sensitivity analyses included a completers analysis and one that blood pressure (Table S1, Supporting Information).
excluded outliers.
The safety analysis set included all patients who received Safety
one or more doses of double-blind study medication. Safety A summary of AEs reported during the present trial is shown in
variables were to be summarized descriptively. Table 3. The proportions of patients with AEs were low and sim-
ilar across the dapagliflozin 2.5 mg twice daily and 5 mg twice
daily treatment groups (3340.0%); the proportion was slightly
Results higher in the dapagliflozin 10 mg once daily group (46.5%). The
Patients rate of discontinuations attributable to AEs was also low and
similar across all treatment groups. Serious AEs (SAEs) were
A total of 520 patients were enrolled in the study (Figure 1); 400 rare and slightly more frequent in the dapagliflozin 2.5 and 5 mg
were randomly assigned to one of four treatments as add-on twice daily treatment groups (4 and 1%, respectively) than in
to metformin: placebo (n = 101), dapagliflozin 2.5 mg twice the placebo group (0%). No SAEs were treatment-related; SAEs
daily (n = 100), dapagliflozin 5 mg twice daily (n = 100) or were evenly distributed across several system organ classes and
dapagliflozin 10 mg once daily (n = 99). Baseline demographics none led to discontinuation. No deaths or malignancies were
and other characteristics were generally similar across treat- reported during the treatment period.
ment groups (Table 1). The median background dose of met- In total, only three hypoglycaemic events were reported
formin at enrolment and at randomization was 2000 mg/day in dapagliflozin-treated patients. None of these events
across treatment groups. Completion rates were similar across was considered major [i.e. a symptomatic event requiring
treatment groups [between 91% (for dapagliflozin 10 mg once third-party assistance with a capillary or plasma glucose value
daily) and 94% (for dapagliflozin 5 mg twice daily)]. The most (<3.0 mmol/l (<54 mg/dl))], and none led to discontinuation.
frequent reasons for discontinuation were study-specific dis- Other events of special interest generally occurred at low rates
continuation criteria (n = 19), the most commonly reported in all patient groups. Proportions of patients reporting events
being decreased CrCl (n = 12; distributed evenly across the suggestive of urinary tract infection were low and similar
treatment groups), and the other being inadequate glycaemic across treatment groups (5%), with all events considered
control (n = 7; five from the placebo group). mild to moderate. There were no reports of kidney infection.
Events suggestive of genital infections were infrequent (5%)
and reported only in female patients; events were mild or
Efficacy moderate in intensity. Reports of other AEs of special interest
The adjusted mean reduction in HbA1c level was signifi- were absent (e.g. hypotension, dehydration or hypovolaemia,
cantly greater for the dapagliflozin 2.5 and 5 mg twice daily renal impairment, renal failure, fractures or kidney infection)
treatment groups than placebo: 0.52% (p = 0.0106), 0.65% or indicated no increased risk associated with dapagliflozin
(p < 0.0001) and 0.30%, respectively (Table 2, Figure 2A). (AEs of renal impairment, renal failure or urinary stones).
Sensitivity analyses were similar to the main analysis; the Gastrointestinal AEs, which are associated with metformin
adjusted mean reduction in HbA1c level was within 0.03% treatment, were similar across treatment groups and did not
of each main result (data not shown). The adjusted mean increase with the addition of dapagliflozin.

44 Schumm-Draeger et al. Volume 17 No. 1 January 2015


DIABETES, OBESITY AND METABOLISM original article

Figure 1. Patient disposition. Incorrect enrolment included subjects not meeting inclusion criteria or developing an exclusion criterion after being
correctly enrolled. No longer met study criteria refers to protocol-specified discontinuation criteria (e.g. inadequate glycaemic control, decreased creatinine
clearance). BID, twice daily; MET-IR, metformin immediate release.

Laboratory evaluations are shown in Table S1. Dapagli- and to evaluate the safety and tolerability of these treatment
flozin-treated patients showed a large mean increase in urine regimens. Dapagliflozin 2.5 and 5 mg twice-daily doses, which
glucose excretion as measured by spot urine tests, as expected are equivalent to the daily doses of 5 and 10 mg, respectively,
from the mechanism of action (glucuresis); this effect was evi- co-administered with metformin, resulted in statistically
dent at week 1. A mean increase in blood urea nitrogen was significant and clinically meaningful glycaemic reductions
observed from baseline to week 16 in dapagliflozin-treated compared with placebo, measured as reductions in HbA1c
patients (0.180.64 mmol/l). Follow-up monitoring indicated levels and FPG levels after 1 week and 16 weeks, and a greater
that these changes were reversible. No meaningful changes proportion of patients achieving an HbA1c target of <7.0%.
in blood urea nitrogen were observed in the placebo group. Reductions in FPG levels at week 16 in both dapagliflozin
Patients in the dapagliflozin 2.5 and 5 mg twice daily groups twice daily groups approached the recommended therapeutic
showed a slight mean decrease in eGFR from baseline to week targets of 3.97.2 mmol/l [1,2]. Overall, the FPG outcomes for
8 that remained stable until week 16 (change from baseline of dapagliflozin 2.5 and 5 mg twice daily were consistent with the
2.1 and 3.5 ml/min/1.73 m2 at week 16). In the dapagliflozin dapagliflozin 10 mg once daily treatment arm, and were similar
10 mg once daily group, eGFR showed a slight recovery at to those reported previously for dapagliflozin 10 mg once daily
weeks 12 and 16 from the initial decrease. No hepatic impair- in combination with metformin [5,15,16]. Statistically signifi-
ment or increase in liver enzymes was evident in any treatment cant reductions in body weight reported in both dapagliflozin
group. Marked abnormalities of electrolytes were rare. Three twice daily treatment groups were consistent with the weight
patients receiving dapagliflozin 5 mg twice daily and one receiv-
reduction reported with dapagliflozin 10 mg once daily plus
ing placebo showed one or more marked abnormalities of crea-
metformin [5,16].
tine kinase >5 the upper limit of normal. Two patients in the
Marked increases in urine glucose excretion levels were
dapagliflozin 5 mg twice daily group showed marked abnormal-
measured in all dapagliflozin treatment groups, consistent
ities in creatine kinase >10 the upper limit of normal; both
with dapagliflozins mechanism of action and providing
patients reported excessive physical work or exercise.
an explanation for the observed efficacy and weight loss.
Co-administration of dapagliflozin and metformin is expected
Discussion to exert a complementary therapeutic effect on hyperglycaemia
The present study was designed to determine whether in type 2 diabetes because dapagliflozin inhibits renal glucose
twice-daily dosing of dapagliflozin co-administered with reabsorption and metformin decreases hepatic glucose output,
metformin showed better efficacy compared with placebo which explains the glycaemic efficacy observed. Previously,
co-administered with metformin in patients with type 2 dia- dapagliflozin 10 mg once daily co-administered with met-
betes with inadequate glycaemic control on metformin alone, formin in patients with a similar HbA1c range was found to

Volume 17 No. 1 January 2015 doi:10.1111/dom.12387 45


original article DIABETES, OBESITY AND METABOLISM

Table 1. Demographics and baseline characteristics of randomized patients.

Placebo + Dapagliflozin 2.5 mg Dapagliflozin 5 mg Dapagliflozin 10 mg


metformin, twice daily + metformin, twice daily + metformin, once daily + metformin,
n = 101 n = 100 n = 99 n = 99
Mean (s.d.) age, years 58.5 (9.4) 58.3 (9.0) 55.3 (9.3) 58.5 (9.8)
Age category, n (%)
<65 years 77 (76.2) 77 (77.0) 85 (85.9) 70 (70.7)
65 and <75 years 23 (22.8) 21 (21.0) 13 (13.1) 27 (27.3)
75 years 1 (1.0) 2 (2.0) 1 (1.0) 2 (2.0)
Sex, n (%)
Male 47 (46.5) 37 (37.0) 46 (46.5) 49 (49.5)
Female 54 (53.5) 63 (63.0) 53 (53.5) 50 (50.5)
Race, n (%)
White 82 (81.2) 79 (79.0) 84 (84.8) 81 (81.8)
Black 5 (5.0) 10 (10.0) 5 (5.1) 6 (6.1)
Asian 10 (9.9) 8 (8.0) 7 (7.1) 3 (3.0)
Other* 4 (4.0) 3 (3.0) 3 (3.0) 9 (9.1)
Mean (s.d.) body mass index (kg/m2 ) 31.74 (4.69) 33.16 (5.16) 33.09 (4.94) 32.25 (5.01)
Mean (s.d.) seated blood pressure (mmHg)
Systolic 133.4 (11.9) 132.4 (13.3) 130.3 (11.4) 132.2 (12.0)
Diastolic 81.5 (6.7) 80.5 (7.4) 81.3 (6.7) 79.4 (7.7)
Mean (s.d.) duration of type 2 diabetes (years) 5.53 (4.23) 4.80 (3.87) 5.12 (4.20) 5.45 (4.05)
Mean (s.d.) HbA1c, (%) 7.94 (0.85) 7.77 (0.75) 7.78 (0.76) 7.71 (0.71)
HbA1c category (%), n (%)
<7.0 13 (12.9) 10 (10.0) 7 (7.1) 17 (17.2)
7.0 and <8.0 42 (41.6) 58 (58.0) 62 (62.6) 51 (51.5)
8.0 and <9.0 27 (26.7) 25 (25.0) 22 (22.2) 25 (25.3)
9.0 19 (18.8) 7 (7.0) 8 (8.1) 6 (6.1)
Mean (s.d.) FPG (mmol/l) 8.76 (1.99) 8.51 (1.85) 8.62 (1.77) 8.62 (2.01)
eGFR, n (%)
<30 ml/min/1.73 m2 0 0 0 0
30 and <60 ml/min/1.73 m2 4 (4.0) 4 (4.0) 5 (5.1) 5 (5.1)
60 and <90 ml/min/1.73 m2 61 (60.4) 57 (57.0) 55 (55.6) 65 (65.7)
<90 ml/min/1.73 m2 36 (35.6) 39 (39.0) 39 (39.4) 29 (29.3)

eGFR was calculated using the Modification in Diet and Renal Disease formula and is adjusted for body surface area. eGFR, estimated glomerular filtration
rate; HbA1c, glycated haemoglobin; s.d., standard deviation.
*Includes Native Hawaiian or other Pacific Islander, American Indian/Alaska Native or other.
All patients had creatinine clearance 60 ml/min at randomization.

result in improvements in glycaemic control and reductions in brief lead-in period of 4 weeks, which may have limited opti-
body weight, which were maintained over 102 weeks [15]. mum stabilization of the background metformin treatment and
Compared with other dapagliflozin studies [5,10,13], there delayed capture of HbA1c response, and natural study-to-study
was a lower magnitude of placebo-corrected HbA1c reduction variation in outcomes [30,31].
in the present study. The most likely reason for this is that Dapagliflozin 2.5 and 5 mg twice-daily doses were both
because dapagliflozins efficacy is dependent on renal filtration well tolerated, and the incidence of AEs was low. Although
of glucose, the relatively low baseline HbA1c of the patients the relatively short trial duration may limit the extrapolation
in the present study may have affected this result. Baseline of safety assessments to long-term studies, the reported out-
HbA1c has been strongly associated with reduction in HbA1c comes were in keeping with those documented throughout
in studies of oral agents, including dapagliflozin, for the treat- the dapagliflozin clinical development programme, especially
ment of type 2 diabetes [28,29]. Moreover, the HbA1c reduc- long-term studies of >2 years of dapagliflozin co-administered
tion observed in the placebo group, perhaps attributable to the with metformin. Markedly fewer AEs were reported with
reinforcement of diet and lifestyle guidelines, tends to dimin- dapagliflozin 5 mg twice daily than with dapagliflozin 10 mg
ish over time, whereas the benefit from dapagliflozin does not once daily (33.0 and 46.5%, respectively). Discontinuation
[14,15]. Nonetheless, compared with placebo, a significantly rates were low across treatment groups. Despite glycaemic
higher percentage of patients in both dapagliflozin twice daily reductions in a type 2 diabetes mellitus patient population with
groups achieved an HbA1c concentration of <7%, which is the a relatively low HbA1c at baseline, hypoglycaemic events were
recommended target for HbA1c. Other possible contributing rare, and none were major. SAEs were also rare, with no specific
factors to the smaller difference in HbA1c reduction between pattern or trend being evident. In the present study, we closely
dapagliflozin- and placebo-treated patients are the relatively monitored gastrointestinal events, as metformin is associated

46 Schumm-Draeger et al. Volume 17 No. 1 January 2015


DIABETES, OBESITY AND METABOLISM original article
Table 2. Primary and secondary efficacy results at week 16 (last observation carried forward).

Dapagliflozin 2.5 mg Dapagliflozin 5 mg Dapagliflozin 10 mg


Placebo + twice daily + twice daily + once daily +
metformin, metformin, metformin, metformin,
n = 101 n = 100 n = 99 n = 99
HbA1c (%)
n 100 99 97 98
Mean (s.d.) baseline 7.94 (0.852) 7.78 (0.748) 7.79 (0.764) 7.71 (0.713)
Mean (s.d.) week 16 7.59 (0.895) 7.27 (0.777) 7.15 (0.704) 7.16 (0.625)
Mean (s.d.) change from baseline 0.35 (0.679) 0.50 (0.663) 0.65 (0.736) 0.55 (0.546)
Mean (s.e.) adjusted mean change from baseline 0.30 (0.0593) 0.52 (0.0594) 0.65 (0.0600) 0.59 (0.0598)
95% CI for adjusted mean change from baseline 0.42, 0.18 0.63, 0.40 0.77, 0.53 0.70, 0.47
Mean difference versus placebo + MET-IR*(s.e.) 0.22 (0.0840) 0.35 (0.0843) 0.29 (0.0844)
95% CI for mean difference versus placebo + MET-IR 0.38, 0.05 0.52, 0.18 0.45, 0.12
p value versus placebo + MET-IR 0.0106 <0.0001 0.0007
Body weight (kg)
n 101 100 99 99
Mean (s.d.) baseline 88.82 (15.327) 92.49 (18.632) 93.62 (16.641) 90.58 (15.929)
Mean (s.d.) week 16 87.89 (15.474) 89.95 (18.661) 90.82 (17.070) 88.17 (16.195)
Mean (s.e.) % change from baseline 1.12 (0.2508) 2.83 (0.2339) 3.16 (0.3009) 2.79 (0.2422)
Adjusted mean (s.e.) % change from baseline 1.04 (0.3105) 2.84 (0.3099) 3.20 (0.3125) 2.76 (0.3086)
95% CI for adjusted mean % change from baseline 1.65, 0.43 3.45, 2.23 3.82, 2.59 3.36, 2.15
Mean (s.d.) difference versus placebo + MET-IR* 1.82 (0.3630) 2.18 (0.3636) 1.73 (0.3635)
95% CI for mean difference versus placebo + MET-IR 2.53, 1.10 2.89, 1.46 2.44, 1.01
p value versus placebo + MET-IR <0.0001 <0.0001 <0.0001
FPG week 1 (mmol/l)
n 101 99 99 98
Mean (s.d.) baseline 8.76 (1.99) 8.52 (1.85) 8.62 (1.77) 8.62 (2.02)
Mean (s.d.) week 1 8.97 (2.08) 7.96 (1.56) 7.96 (1.47) 7.92 (1.63)
Mean (s.d.) change from baseline 0.21 (1.36) 0.57 (1.21) 0.65 (1.47) 0.70 (1.47)
Adjusted mean (s.e.) change from baseline 0.11 (0.14) 0.76 (0.15) 0.82 (0.15) 0.86 (0.15)
95% CI for adjusted mean change from baseline 0.17, 0.39 1.05, 0.47 1.11, 0.53 1.15, 0.57
Mean difference versus placebo + MET-IR* 0.87 (0.17) 0.93 (0.17) 0.97 (0.17)
95% CI for mean difference versus placebo + MET-IR 1.20, 0.54 1.26, 0.59 1.30, 0.64
p value versus placebo + MET-IR <0.0001 <0.0001 <0.0001
FPG week 16 (mmol/l)
n 101 100 99 98
Mean (s.d.) baseline 8.76 (1.99) 8.51 (1.85) 8.62 (1.77) 8.62 (2.02)
Mean (s.d.) week 16, LOCF 8.20 (1.86) 7.50 (1.52) 7.29 (1.25) 7.58 (1.55)
Mean (s.d.) change from baseline 0.56 (1.71) 1.00 (1.67) 1.33 (1.46) 1.04 (1.32)
Adjusted mean (s.e.) change from baseline 0.58 (0.15) 1.15 (0.15) 1.42 (0.15) 1.13 (0.15)
95% CI for adjusted mean change from baseline 0.87, 0.28 1.45, 0.85 1.73, 1.12 1.43, 0.84
Mean difference versus placebo + MET-IR* 0.58 (0.17) 0.85 (0.17) 0.56 (0.17)
95% CI for mean difference versus placebo + MET-IR 0.92, 0.23 1.19, 0.51 0.90, 0.22
p value versus placebo + MET-IR 0.0010 <0.0001 0.0015
Subjects achieving HbA1c <7% at week 16
n/N 17/87 32/89 37/90 22/81
% 19.5 36.0 41.1 27.2
% adjusted (s.e.) 21.4% (4.170) 33.6% (4.567) 38.2% (4.651) 28.1% (4.619)
95% CI for % adjusted 13.2, 29.6 24.6, 42.5 29.1, 47.3 19.0, 37.1
Mean (s.e.) difference versus placebo + MET-IR (%) 12.2% (6.097) 16.8% (6.153) 6.7% (6.145)
95% CI for mean difference versus placebo + MET-IR 0.2, 24.1 4.8, 28.9 5.3, 18.7
p value versus placebo + MET-IR 0.0455 0.0062 0.2755

CI, confidence interval; FPG, fasting plasma glucose; HbA1c, glycated haemoglobin; LOCF, last observation carried forward; MET-IR, metformin
immediate release; s.d., standard deviation; s.e., standard error.
*Difference in adjusted mean change from baseline versus placebo + MET-IR.
Population with HbA1c >7% at baseline.
Nominal p values; formal statistical comparisons versus placebo were not conducted.

Volume 17 No. 1 January 2015 doi:10.1111/dom.12387 47


original article DIABETES, OBESITY AND METABOLISM

Figure 2. Adjusted mean changes over 16 weeks in: (A) glycated haemoglobin (HbA1c) %; (B) fasting plasma glucose (FPG), mmol/l; and (C) total body
weight (kg). Data are adjusted mean changes from baseline over time (last observation carried forward) for the 16-week double-blind treatment period
(full analysis set). Mean value based on analysis of covariance model with treatment group and stratum as effects and baseline value as covariate. Error
bars represent 95% confidence intervals (CIs) for the adjusted mean change from baseline. Treatment symbols shifted horizontally to prevent error bars
overlapping. BID, twice daily; DAPA, dapagliflozin; HbA1c, glycated haemoglobin; MET, metformin; PBO, placebo; QD, once daily.

48 Schumm-Draeger et al. Volume 17 No. 1 January 2015


DIABETES, OBESITY AND METABOLISM original article
Table 3. Number and percentage of patients with adverse events over the 16-week treatment period (safety analysis set).

Placebo + Dapagliflozin 2.5 mg Dapagliflozin 5 mg Dapagliflozin 10 mg


metformin, twice daily + metformin, twice daily + metformin, once daily + metformin,
n = 101, n = 100, n = 100, n = 99,
n (%) n (%) n (%) n (%)
1 AE 37 (36.6) 40 (40.0) 33 (33.0) 46 (46.5)
1 treatment-related AE 10 (9.9) 5 (5.0) 7 (7.0) 8 (8.1)
1 AE leading to discontinuation 3 (3.0) 5 (5.0) 3 (3.0) 4 (4.0)
1 SAE 0 4 (4.0) 1 (1.0) 2 (2.0)
1 treatment-related SAE 0 0 0 0
1 SAE leading to discontinuation 0 0 0 0
Deaths 0 0 0 0
AEs occurring in 5% of patients in any group
Influenza 3 (3.0) 5 (5.0) 0 2 (2.0)
Hypertension 6 (5.9) 3 (3.0) 0 4 (4.0)
AEs of special interest
Hypoglycaemia 0 1 (1.0) 0 2 (2.0)
Hypotension/dehydration/hypovolaemia 0 0 0 0
Renal impairment/failure 4 (4.0) 5 (5.0) 3 (3.0) 3 (3.0)
Fractures 0 0 0 0
Urinary stones 1 (1.0) 0 0 1 (1.0)
Events suggestive of urinary tract infection 3 (3.0) 2 (2.0) 5 (5.0) 3 (3.0)
Events suggestive of genital infection 1 (1.0) 0 5 (5.0) 3 (3.0)
Kidney infection 0 0 0 0

Includes non-serious AEs with onset on or after the first date of double-blind treatment and on or before the last day of double-blind treatment plus 4 days
or up to follow-up visit if earlier. Includes SAEs with onset on or after the first date of double-blind treatment and on or before the last day of double-blind
treatment plus 30 days or up to follow-up visit if earlier. Events reported based on preferred terms from Medical Dictionary for Regulatory Activities, version
14.0. AE terms of renal impairment/failure were prespecified in the protocol. Hypoglycaemia was defined as a low blood glucose reading [<3.5 mmol/l
(<63 mg/dl)], with or without symptoms; a symptomatic event without a blood glucose reading was considered suggestive of hypoglycaemia. AE, adverse
event; SAE, serious adverse event.

with gastrointestinal AEs; there was no increase reported with <7%, a goal recently emphasized in treatment guidelines [1],
the co-administration of dapagliflozin 2.5 or 5 mg twice daily shows that this combination therapy can be of clinical value.
with metformin. In summary, the data from the present study provide evi-
The decrease in CrCl reported in the dapagliflozin treatment dence that twice-daily co-administration of dapagliflozin and
groups may be a reflection of weight as a factor in the calcu- metformin is effective in reducing HbA1c, FPG and body
lation. A treatment that produces weight loss would result in weight to levels numerically similar to those obtained with
a reduction in calculated CrCl. It has been shown previously dapagliflozin once daily added to metformin. The improvement
that dapagliflozin is associated with a small decrease in eGFR in glycaemic control observed with dapagliflozin twice daily
at week 1 that returns to baseline by week 24 and is then main- co-administered with metformin shows that the combination
tained during further treatment [32]. Similarly, in the present can offer better outcomes to patients without concern for hypo-
study, a small initial decrease in eGFR with dapagliflozin was glycaemic events.
observed for all treatment groups and this did not appear to
affect renal function. Follow-up data beyond week 16 were not
available for eGFR in the present study, although follow-up data Acknowledgements
for calculated CrCl indicated that the observed initial decreases The present study was funded by Bristol-Myers Squibb and
were reversible. Genital infections and urinary tract infections AstraZeneca. Medical writing assistance was provided by Ann
would be expected to increase with dapagliflozin treatment L. Davis, MPH, CMPP, an employee of Bristol-Myers Squibb,
because of the resultant glucosuria; however, the incidences of and Caroline Allinson, BSc, of PPSI (a PAREXEL company).
each were low overall and did not exceed incidences in other Medical writing assistance was funded by Bristol-Myers Squibb
dapagliflozin studies. No events of kidney infection or upper and AstraZeneca.
urinary tract infection were reported, and there were no reports
of renal failure or injury.
The present population of patients with type 2 diabetes melli- Conflict of Interest
tus treated with metformin monotherapy represents an impor- P.-M. S.-D. has received funds for speaking from Sanofi, Novo-
tant target group for the evaluation of combination therapies in Nordisk, Eli Lilly, Novartis, Bristol-Myers Squibb, AstraZeneca,
light of the frequency of suboptimum or inadequate glycaemic MSD and Boehringer Ingelheim. She has also received sup-
control. The greater proportion of patients in the present trial port for advisory boards and clinical trials from Sanofi,
treated with dapagliflozin and metformin who achieved HbA1c NovoNordisk, Bristol-Myers Squibb, AstraZeneca, Boehringer

Volume 17 No. 1 January 2015 doi:10.1111/dom.12387 49


original article DIABETES, OBESITY AND METABOLISM

Ingelheim, Novartis, GlaxoSmithKline and Eli Lilly. L. B. and 12. Rosenstock J, Vico M, Wei L, Salsali A, List JF. Effects of dapagliflozin, an SGLT2
L. K. do not have any conflicts of interest to declare. T. W. inhibitor, on HbA(1c), body weight, and hypoglycemia risk in patients with type
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