original article

Diabetes, Obesity and Metabolism 16: 124–136, 2014.

© 2013 John Wiley & Sons Ltd

Dapagliflozin in patients with type 2 diabetes receiving high

doses of insulin: efficacy and safety over 2 years
original
article

J. P. H. Wilding1 , V. Woo2 , K. Rohwedder3 , J. Sugg4 & S. Parikh4 for the Dapagliflozin 006 Study Group†
1 Diabetes and Endocrinology Research Group, Department of Obesity & Endocrinology, Clinical Sciences Centre, University Hospital Aintree, Liverpool, UK
2 Section of Endocrinology and Metabolism, University of Manitoba, Winnipeg, Canada
3 Clinical Development, AstraZeneca, Wedel, Germany
4 Clinical Development, AstraZeneca, Wilmington, DE, USA

Aims: Dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), has been shown to improve glycaemic control, stabilize
insulin dosing and mitigate insulin-associated weight gain over 48 weeks in patients whose type 2 diabetes mellitus (T2DM) was inadequately
controlled despite high doses of insulin. Here the efficacy and safety of dapagliflozin therapy after a total of 104 weeks are evaluated in this
population.
Methods: This was a 24-week, randomized, placebo-controlled, double-blinded, multicentre trial followed by two site- and patient-blinded
extension periods of 24 and 56 weeks (NCT00673231), respectively. A total of 808 patients, whose T2DM was inadequately controlled on
insulin ≥30 IU/day, with or without up to two oral antidiabetic drugs, were randomly assigned to receive placebo or 2.5, 5 or 10 mg/day of
dapagliflozin for 104 weeks. At 48 weeks, patients on dapagliflozin 5 mg were switched to 10 mg. Outcomes over 104 weeks included change
from baseline in HbA1c, insulin dose and body weight; analyses used observed cases and included data after insulin up-titration. Adverse
events (AEs) were evaluated throughout 104 weeks.
Results: Five hundred and thirteen patients (63.6%) completed the study. Mean HbA1c changes from baseline at 104 weeks were −0.4%
in the placebo group and −0.6 to −0.8% in the dapagliflozin groups. In the placebo group, mean insulin dose increased by 18.3 IU/day and
weight increased by 1.8 kg at 104 weeks, whereas in the dapagliflozin groups, insulin dose was stable and weight decreased by 0.9–1.4 kg.
AEs, including hypoglycaemia, were balanced across groups. Proportions of patients with events suggestive of genital infection and of urinary
tract infection (UTI) were higher with dapagliflozin versus placebo (genital infection 7.4–14.3% vs. 3.0%; UTI 8.4–13.8% vs. 5.6%) but most
occurred in the first 24 weeks and most were single episodes that responded to routine management.
Conclusions: Dapagliflozin improved glycaemic control, stabilized insulin dosing and reduced weight without increasing major hypoglycaemic
episodes over 104 weeks in patients whose T2DM was inadequately controlled on insulin. However, rates of genital infection and of UTI were
elevated with dapagliflozin therapy.
Keywords: glycaemic control, insulin, randomized trial, renal glucose handling, SGLT2 inhibitor, type 2 diabetes

Date submitted 16 May 2013; date of first decision 21 June 2013; date of final acceptance 18 July 2013

Introduction include, continuing disease progression, patient non-adherence

Type 2 diabetes mellitus (T2DM) is a complex metabolic
disorder characterized not only by the core pathologies of
insulin resistance and β-cell failure but also by accelerated
lipolysis, incretin deficiency and/or resistance, hyperglucago-
naemia and increased renal glucose reabsorption [1]. The initial
treatment of T2DM with diet and exercise often fails owing
to the progressive nature of the disease, requiring treatment
escalation, initially with oral glucose-lowering therapies, and
later with insulin, to maintain glycaemic control.
Despite these strategies, a substantial proportion of patients
continue to fail to meet glycaemic targets [2–4] for reasons that
Correspondence to: John P. H. Wilding, Diabetes and Endocrinology Research Group,
Department of Obesity & Endocrinology, Clinical Sciences Centre, University Hospital
Aintree, Longmoor Lane, Liverpool, UK.
E-mail: j.p.h.wilding@liverpool.ac.uk
†
A full list of investigators of the Dapagliflozin 006 Study Group is available in Appendix S1.
due to side effects of glucose-lowering agents, and the lack of
therapeutic options that address all the metabolic abnormalities
in T2DM. There is therefore an unmet need for additional
therapies that target new glucose-lowering mechanisms and
provide durable glycaemic control with a favourable benefit-
risk profile.
For those patients receiving insulin therapy, the progressive
nature of T2DM often necessitates an increase in daily insulin
requirement. However, side effects of insulin therapy such as
weight gain, fluid retention and hypoglycaemic events limit the
long-term practicability and acceptability of increasing insulin
doses over time to maintain glycaemic control [5,6].
Interest has focused on the kidney as a potential new
therapeutic target in patients with T2DM because the kidney
filters and reabsorbs approximately 180 g of glucose per day
[7] and in T2DM renal glucose reabsorption is maladaptively
increased [1,8]. The sodium-glucose cotransporter 2 (SGLT2)
is a low-affinity, high-capacity transporter located in the S1
DIABETES, OBESITY AND METABOLISM
segment of the proximal convoluted tubule of the nephron that
mediates the majority of renal glucose reabsorption from the
glomerular filtrate.
Dapagliflozin, a competitive and highly selective inhibitor
of SGLT2 [9,10], reduces renal glucose reabsorption, dose-
dependently increases urinary glucose excretion [11] and
reduces hyperglycaemia in patients with T2DM [12]. Because
dapagliflozin acts independently of insulin secretion or action,
it may provide additional glycaemic control when used with
insulin in patients with advanced β-cell failure [13]. Moreover,
energy loss and osmotic diuresis secondary to increased urinary
glucose excretion and natriuresis may counter insulin-related
weight gain and fluid retention, respectively.
In clinical trials of duration up to 24 weeks in patients with
T2DM, dapagliflozin improved glycaemic control and reduced
body weight when administered as monotherapy [12,14,15]
or when added to metformin [16,17] or glimepiride [18] or
insulin [19]. We recently showed that in patients whose T2DM
was inadequately controlled despite high doses of insulin,
the addition of dapagliflozin improved glycaemic control
whilst reducing body weight and maintaining stable insulin
dosing over 48 weeks. In contrast, patients receiving placebo
required progressive increases in insulin dose to maintain
glycaemic control and gained weight [20]. Here, the durability
of dapagliflozin effect in patients with T2DM over a background
of insulin treatment is evaluated after a total of 104 weeks of
dapagliflozin treatment.
Materials and Methods
Study Design
This double-blinded, placebo-controlled, parallel-group trial
(Clinical trial reg. no. NCT00673231, clinicaltrials.gov.) was
conducted at 126 centres worldwide from 30 April 2008 to
12 January 2011. The protocol was approved by institutional
review boards and/or independent ethics committees, and all
participants gave written, informed consent. The study was
carried out in accordance with the principles of the Declaration
of Helsinki (2004 version) and the requirements of Good
Clinical Practice.
A detailed description of the methods employed for the
initial 24-week double-blinded treatment period and the first
24-week patient- and site-blinded extension period has been
previously published [20]. In brief, a computer-generated,
stratified [with and without oral antidiabetic drug (OADs)],
block-randomization schedule was employed with the goal of
randomly assigning at least 40% of study participants to the
insulin-only stratum; a double-dummy technique was used
because the 10-mg dapagliflozin tablets were slightly larger
than the 2.5- or 5-mg tablets; and, during the further 56-week
patient- and site-blinded extension period, results of which
are reported here, investigators, patients and study monitors
remained blinded to treatment allocation, except for cases of
medical emergencies.
Patients
Patients aged 18–80 whose T2DM was inadequately controlled
(HbA1c 7.5–10.5%) on a stable dose of insulin at ≥30
Volume 16 No. 2 February 2014
original article
units/day for at least 8 weeks with or without up to two OADs
were enrolled. Patients receiving metformin had to be on
≥1500 mg/day or their maximum tolerated dose and patients
receiving other OADs on at least half the daily maximum dose.
Patients were instructed to follow a stable diet and exercise
regimen after enrolment.
Treatments
Patients were initially randomized on a 1 : 1 : 1 : 1 basis to
placebo or dapagliflozin 2.5, 5 or 10 mg once daily, in addition
to open-label therapy with their usual daily insulin dose and
existing OADs. Following completion of 48 weeks of treatment,
patients receiving the dapagliflozin 5-mg dose were switched
to the 10-mg dose for the remainder of the study (referred to
as the dapagliflozin 5/10-mg group in this report).
Throughout the study, insulin dose was held within 10%
of the baseline level unless insulin up-titration was clinically
indicated based upon pre-specified glycaemic criteria. No dose
modifications of blinded study medication or OADs were
allowed, with the exception of decreasing OADs when there
were concerns about hypoglycaemia despite the cessation of
insulin therapy. Up-titration of insulin (defined as an insulin
dose increase of >5 IU/day and an increase of >10% from
baseline) was permitted if at least three fasting self-monitored
blood glucose readings from the 7 days prior to the study visit
or a site-measured fasting blood glucose at the study visit were
>13.3 mmol/l up to week 12; >12.2 mmol/l between weeks 12
and 24; >9.9 mmol/l or if HbA1c was >8% between weeks
25 and 48. Between weeks 52 and 65, insulin up-titration was
permitted if HbA1c was >7.5%, and between weeks 78 and 104
if HbA1c >7.0%, irrespective of fasting blood glucose value.
Insulin could be down-titrated if two or more self-monitored
blood glucose readings were ≤3.8 mmol/l.
Outcome Measures
All primary and key secondary efficacy variables were pre-
specified. The primary efficacy variable was change in HbA1c
from baseline to week 24. Four key secondary efficacy variables
at 24 weeks included: (i) change in total body weight from
baseline; (ii) change in calculated mean daily insulin dose;
(iii) proportion of patients with calculated mean daily insulin
dose reduction ≥10% from baseline and (iv) change in fasting
plasma glucose (FPG) from baseline [20]. At 104 weeks, we
assessed whether the effects on HbA1c, FPG, insulin dose, body
weight and urinary glucose excretion were maintained.
The long-term safety and tolerability of dapagliflozin
treatment over 104 weeks was assessed by collecting data on
adverse events (AEs), laboratory parameters and vital signs.
The use of concomitant medication to control blood pressure
was uncontrolled during the study. A pre-specified list of
Medical Dictionary for Regulatory Activities (MedDRA)
version 12.1 preferred terms was used to identify signs,
symptoms and other reports suggestive of genital infection
and of urinary tract infection (UTI) in the database. This list
included terms for non-specific signs and symptoms suggestive
of genital infection (e.g. genital pruritus, vulvovaginal pruritus,
balanitis) as well as terms for clinical infection (e.g. vaginal
doi:10.1111/dom.12187 125
original article
infection), but did not include terms for sexually transmitted
diseases. Patients reported these events both spontaneously and
in response to questions proactively posed by the investigator
during study visits.
Statistical Analysis
Two analysis sets were defined: (i) the safety analysis set,
consisting of all randomized patients who received ≥1 dose of
study medication, which was used for analysis of safety variables
and (ii) the full analysis set, consisting of all randomized patients
who received ≥1 dose of study medication and who had a non-
missing baseline and ≥1 post-baseline efficacy value for ≥1
efficacy variable, which was used for analysis of efficacy
variables.
®
For continuous efficacy variables, a mixed model (SAS
proc mixed procedure, SAS Institute, Cary, NC, USA) assessed
changes from baseline with fixed effects for treatment group,
stratum (insulin plus OAD use vs. insulin alone), week,
baseline value as a covariate, plus interactions of week with
treatment group and week with baseline value. An unstructured
covariance matrix was applied for repeated measures within
each patient [21]. Analyses over 104 weeks employed observed
cases and included data after insulin up-titration.
Categorical efficacy variables were analysed using the
methodology of Zhang et al. [22], with adjustment for baseline
value and stratum. Patients with missing data were included in
these analyses and considered non-responders.
Point estimates and 95% confidence intervals with nominal
p-values were provided for these analyses as formal statistical
inference was not possible for these long-term data.
The Kaplan–Meier method was used to analyse time to
onset of insulin up-titration for failing to achieve pre-specified
glycaemic targets that were increasingly stringent over time or
patient discontinuation because of poor glycaemic control.
Vital signs, the frequency of general AEs and changes in labo-
ratory parameters were summarized using descriptive statistics.
Results
Patients
Demographic and baseline characteristics were comparable
across all treatment groups (Table 1). The mean duration of
insulin therapy was approximately 6 years, around half the
time as diagnosis of T2DM (13.6 years). Mean daily insulin
dose was 77.1 U, with 17% using only long-acting basal insulin
and 83% using a sliding scale (bolus) regime. Overall, 50%
were receiving other background OADs in addition to insulin
(principally metformin), mean baseline HbA1c was 8.5% and
mean baseline FPG was 9.9 mmol/l. Regarding comorbidities,
40.3, 27.1 and 14.0% had diabetic neuropathy, retinopathy
and nephropathy, respectively, and 85.5, 18.9 and 10.5% had
hypertension, coronary artery disease and peripheral vascular
disease, respectively.
Patient disposition is shown in figure 1. Overall, 63.6% of
patients completed 104 weeks, with 28 patients from the UK
discontinuing the study at 48 weeks owing to lack of timely UK
approval for their continuation into the long-term extension
period.
126 Wilding et al.
DIABETES, OBESITY AND METABOLISM
Change in HbA1c and fasting plasma glucose
Long-term reductions in HbA1c over 104 weeks were evident in
all dapagliflozin groups (Table 2 and figure 2A). The differences
from placebo in HbA1c adjusted mean change from baseline at
104 weeks were −0.4% (95% CI −0.6, −0.2; p = 0.0002) and
−0.4% (95% CI −0.6, −0.2; p = 0.0007) in the dapagliflozin
5/10-mg and 10-mg groups, respectively.
An analysis by stratum (with and without OADs) showed that
the differences between the dapagliflozin 10-mg and placebo
groups in HbA1c adjusted mean changes from baseline at
104 weeks were −0.4% (95% CI −0.7, −0.1; p = 0.0050) in
patients taking insulin plus one or two OADs and −0.3% (95%
CI −0.6, 0.01; p = 0.0563) in those receiving insulin alone.
The differences from placebo in adjusted mean changes in
FPG from baseline at 104 weeks were −0.89 mmol/l (95% CI
−1.48, −0.31; p = 0.0031) and −0.31 mmol/l (95% CI −0.89,
0.28; p = 0.3065) in the dapagliflozin 5/10-mg and 10-mg
groups, respectively.
Change in Insulin Dose
Insulin requirement increased progressively in the placebo
group up to +18.3 IU/day at 104 weeks, whereas insulin
requirement remained stable over 104 weeks in the
dapagliflozin groups (Table 2 and figure 2C). The differences
from placebo in adjusted mean change in daily insulin dose
from baseline at 104 weeks were −16.8 U (95% CI −20.5, −8.0;
p < 0.0001) and −19.2 U (95% CI −25.5, −12.9; p < 0.0001)
in the dapagliflozin 5/10-mg and 10-mg groups, respectively.
The differences in the dapagliflozin 5/10-mg and 10-mg
groups versus placebo in adjusted proportions of patients with
a mean daily insulin dose reduction ≥10% from baseline to
after 104 weeks were 6.3% (95% CI 0.4, 12.1; p = 0.0361) and
10.0% (95% CI 3.6, 16.4; p = 0.0022), respectively.
Over 104 weeks, the probability of insulin up-titration (an
increase in dose of >5 IU/day and an increase of >10% from
baseline) or study discontinuation because of poor glycaemic
control was consistently higher in the placebo group compared
with the dapagliflozin groups (figure 3). The differences from
placebo in adjusted proportions of patients with insulin up-
titration or discontinuation because of poor glycaemic control
at 104 weeks were −23.9% (95% CI −33.0, −14.8) and −24.9%
(95% CI −34.1, −15.6) in the dapagliflozin 5/10-mg and 10-
mg groups, respectively. The majority of these differences
were accounted for by insulin up-titration, with only one
discontinuation in the placebo group because of poor glycaemic
control by 104 weeks.
Change in Body Weight
Total body weight increased progressively in the placebo group,
whereas the reductions in total body weight in the dapagliflozin
groups by 48 weeks were maintained over 104 weeks (Table 2
and figure 2B). The differences from placebo in adjusted mean
change in total body weight from baseline at 104 weeks were
−2.86 kg (95% CI −3.92, −1.80; p < 0.0001) and −3.33 kg
(95% CI −4.38, −2.27; p < 0.0001) in the dapagliflozin 5/10-
mg and 10-mg groups, respectively.
Volume 16 No. 2 February 2014
DIABETES, OBESITY AND METABOLISM original article
Table 1. Demographic and baseline patient characteristics.

Placebo + Dapagliflozin 2.5 mg Dapagliflozin 5/10 mg Dapagliflozin 10 mg

insulin + insulin + insulin + insulin
(N = 193) (N = 202) (N = 211) (N = 194)
Mean age (s.d.), years 58.8 (8.6) 59.8 (7.6) 59.3 (7.9) 59.3 (8.8)
Sex, n (%)
Male 95 (49.2) 100 (49.5) 100 (47.4) 87 (44.8)
Female 98 (50.8) 102 (50.5) 111 (52.6) 107 (55.2)
Race, n (%)
White 186 (96.4) 190 (94.1) 200 (94.8) 184 (94.8)
Black/African American 6 (3.1) 3 (1.5) 5 (2.4) 5 (2.6)
Asian 0 7 (3.5) 3 (1.4) 3 (1.5)
Other 1 (0.5) 2 (1.0) 3 (1.4) 2 (1.0)
Mean weight (s.d.), kg 94.5 (19.8) 93.0 (16.7) 93.3 (17.4) 94.5 (16.8)
Mean BMI (s.d.), kg/m2 33.1 (5.9) 33.0 (5.0) 33.0 (5.3) 33.4 (5.1)
Mean waist circumference (s.d.), cm 110.2 (14.5) 109.7 (13.4) 109.3 (13.4) 109.6 (12.5)
Mean duration of type 2 diabetes (s.d.), years 13.5 (7.3) 13.6 (6.6) 13.1 (7.8) 14.2 (7.3)
Mena duration of insulin treatment (s.d.), years 5.9 (5.9) 6.1 (5.2) 5.8 (5.1) 6.3 (5.7)
Insulin regimen, n (%)
Basal 44 (22.8) 29 (14.4) 31 (14.7) 32 (16.5)
Sliding scale (bolus) 149 (77.2) 173 (85.6) 180 (85.3) 162 (83.5)
Sliding scale (bolus) only 60 (31.1) 81 (40.1) 76 (36.0) 65 (33.5)
Sliding scale (bolus) + basal 89 (46.1) 92 (45.5) 104 (49.3) 97 (50.0)
Mean total daily insulin dose (s.d.), U 73.7 (42.4) 79.6 (46.8) 77.0 (44.3) 78.0 (45.0)
Background OAD, n (%)
None 96 (49.7) 104 (51.5) 104 (49.3) 96 (49.5)
Metformin alone 78 (40.4) 80 (39.6) 78 (37.0) 83 (42.8)
Metformin + sulphonylurea 13 (6.7) 13 (6.4) 12 (5.7) 8 (4.1)
Metformin + thiazolidinedione 1 (0.5) 1 (0.5) 2 (0.9) 0
Metformin + other OAD 1 (0.5) 1 (0.5) 2 (0.9) 1 (0.5)
Other drugs or drug combinations 4 (2.1) 3 (1.5) 13 (6.2) 6 (3.1)
Mean HbA1c (s.d.), % 8.47 (0.77) 8.46 (0.78) 8.62 (0.89) 8.57 (0.82)
Mean fasting plasma glucose (s.d.), mmol/l 9.5 (3.2) 10.0 (3.3) 10.3 (3.3) 9.6 (3.0)
History of diabetes-related diseases, n (%)
Diabetic neuropathy 79 (40.9) 79 (39.1) 86 (40.8) 78 (40.2)
Diabetic retinopathy 48 (24.9) 53 (26.2) 57 (27.0) 59 (30.4)
Diabetic nephropathy 24 (12.4) 31 (15.3) 34 (16.1) 23 (11.9)
Microalbuminuria 30 (15.5) 37 (18.3) 43 (20.4) 33 (17.0)
History of cardiovascular disease, n (%)
Hypertension 168 (87.0) 175 (86.6) 172 (81.5) 169 (87.1)
Coronary artery disease 32 (16.6) 40 (19.8) 36 (17.1) 43 (22.2)
Peripheral vascular disease 20 (10.4) 23 (11.4) 16 (7.6) 25 (12.9)
Concomitant medications, n (%)
Antihypertensive agents 154 (78.2) 170 (84.2) 170 (80.2) 163 (83.2)
Diuretic agents 116 (58.9) 111 (55.0) 104 (49.1) 100 (51.0)
Lipid-lowering agents 122 (61.9) 141 (69.8) 141 (66.5) 134 (68.4)
Acetyl salicylic acid 90 (45.7) 104 (51.5) 104 (49.1) 108 (55.1)

N = number of patients the full analysis set. BMI, body mass index; OAD, oral antidiabetic drug; s.d., standard deviation.

Change in Urinary Glucose Excretion
Dapagliflozin produced rapid and stable increases in urinary
glucose excretion throughout 104 weeks, with the 5/10-mg
group showing a step up in glucose excretion at 52 weeks
coincident with the increase from 5 to 10 mg in this group.
Urinary glucose excretion had returned to baseline levels by
the follow-up visit 3 weeks after treatment discontinuation
(Supporting Information, figure S1).
Safety and Tolerability
Proportions of patients experiencing AEs over 104 weeks were
similar across treatment groups (Table 3). Proportions of
patients with AEs considered treatment-related by a blinded
investigator were higher in the dapagliflozin 5/10 mg (33.0%),
and 10 mg (32.1%) groups compared with the placebo group
(22.8%). Proportions of patients with serious adverse events
(SAEs) were similar across treatment groups. Four SAEs were
considered treatment-related by the investigator (one patient
with renal cancer in the placebo group, one patient with
hypoglycaemia and one with a change of bowel habit both in
the dapagliflozin 5/10-mg group, and one case of constipation
in the dapagliflozin 10-mg group).
Malignant neoplasms were reported in 6 and 15 patients
in the placebo and dapagliflozin groups, respectively. Of the
15 neoplasms reported in the dapagliflozin groups, 4 occurred

Volume 16 No. 2 February 2014 doi:10.1111/dom.12187 127

original article
432 not randomised:
396 incorrect enrolment
1 adverse event
32 withdrew consent
2 lost to follow-up
1 other
Analysis Set
Safety
197
PLA + INS ± OAD
29 not completed:
2 incorrect enrolment
6 adverse event
14 withdrew consent
1 lost to follow-up
3 non-compliance
1 study criteria not met
1 safety
1 other
168 completed
Full Analysis Set
at 24 weeks
193 Analysed
4 missing baseline value and/or
post-baseline efficacy values
11 not completed:
3 adverse event
3 withdrew consent
2 lost to follow-up
3 other
157 completed
Full Analysis Set
at 48 weeks
193 Analysed
4 missing baseline value and/or
post-baseline efficacy values
49 not completed:
4 adverse event
8 withdrew consent
2 non-compliance
6 UK discontinuation
29 other
108 completed
Full Analysis Set
at 104 weeks
193 Analysed
4 missing baseline value and/or
post-baseline efficacy values
Figure 1. Patient disposition. * This patient received no study medication or post-baseline assessments. DAPA, dapagliflozin; INS, insulin; OAD, oral
antidiabetic drug; PLA, placebo.
within 90 days of starting dapagliflozin, 3 were bladder cancers,
and 3 were breast cancers (Table S1).
Three deaths occurred in patients receiving dapagliflozin:
two in the dapagliflozin 5/10-mg group (one from cardiogenic
shock 2 days after an aortic valve replacement and coronary
artery bypass graft 13 days after dapagliflozin had been stopped,
and one from an acute myocardial infarction); and one in the
dapagliflozin 10-mg group (after reporting cardiogenic chest
pain).
128 Wilding et al.
DIABETES, OBESITY AND METABOLISM
1240 patients enrolled
808 randomised 1 no drug intake*
202 212 196
DAPA 2.5 mg + INS ± OAD DAPA 5 mg + INS ± OAD DAPA 10 mg + INS ± OAD
23 not completed: 26 not completed: 18 not completed:
1 incorrect enrolment 3 incorrect enrolment 1 incorrect enrolment
5 adverse event 9 adverse event 6 adverse event
11 withdrew consent 8 withdrew consent 6 withdrew consent
2 lost to follow-up 1 lost to follow-up 2 lost to follow-up
1 non-compliance 4 non-compliance 3 non-compliance
1 safety 1 death
2 other
179 completed 186 completed 178 completed
202 Analysed 211 Analysed 194 Analysed
1 missing baseline value and/or 2 missing baseline value and/or
post-baseline efficacy values post-baseline efficacy values
4 not completed: 12 not completed: 8 not completed:
1 study criteria not met 3 adverse event 3 adverse event
2 withdrew consent 5 withdrew consent 3 withdrew consent
1 other 1 lost to follow-up 2 non-compliance
1 non-compliance
1 death
1 other
175 completed 174 completed 170 completed
202 Analysed 211 Analysed 194 Analysed
1 missing baseline value and/or 2 missing baseline value and/or
post-baseline efficacy values post-baseline efficacy values
41 not completed: 45 not completed: 28 not completed:
5 adverse event 6 adverse event 2 adverse event
7 withdrew consent 13 withdrew consent 1 study criteria not met
2 non-compliance 8 UK discontinuation 6 withdrew consent
7 UK discontinuation 18 other 2 non-compliance
20 other 7 UK discontinuation
10 other
134 completed 129 completed 142 completed
202 Analysed 211 Analysed 194 Analysed
1 missing baseline value and/or 2 missing baseline value and/or
post-baseline efficacy values post-baseline efficacy values
Overall, the proportions of patients with at least
one hypoglycaemic event were balanced across treatment
groups (Table 3). Three patients experienced SAEs due to
hypoglycaemia; two receiving dapagliflozin 5 mg, in whom
the hypoglycaemic event was considered to be severe by the
study investigator and in one patient receiving placebo who
experienced hypoglycaemic coma. No patient discontinued the
study due to hypoglycaemia.
Volume 16 No. 2 February 2014
 Table 2. Efficacy at 104 weeks.

Placebo + insulin Dapagliflozin 2.5 mg + insulin Dapagliflozin 5/10 mg + insulin Dapagliflozin 10 mg + insulin
(N = 193) (N = 202) (N = 211) (N = 194)

HbA1c, %
Baseline (s.d.) 8.46 (0.76) 8.47 (0.78) 8.61 (0.89) 8.58 (0.82)
48 weeks, n 157 172 173 164
Adjusted mean change from baseline (95% CI)* −0.47 (−0.59, −0.36) −0.79 (−0.90, −0.68) −0.96 (−1.07, −0.85) −1.01 (−1.12, −0.89)
Difference vs. placebo (95% CI; p-value) −0.32 (−0.48, −0.16; <0.0001) −0.49 (−0.65, −0.33; <0.0001) −0.53 (−0.70, −0.37; <0.0001)
104 weeks, n 107 132 128 139
Adjusted mean change from baseline (95% CI)* −0.43 (−0.58, −0.28) −0.64 (−0.78, −0.50) −0.82 (−0.96, −0.68) −0.78 (−0.92, −0.65)

Volume 16 No. 2 February 2014

Difference vs. placebo (95% CI; p-value) −0.21 (−0.41, −0.01; 0.0434) −0.39 (−0.59, −0.18; 0.0002) −0.35 (−0.55, −0.15; 0.0007)
Fasting plasma glucose, mmol/l
Baseline (s.d.) 9.48 (3.19) 10.02 (3.34) 10.30 (3.27) 9.63 (3.04)
48 weeks, n 147 165 166 153
Adjusted mean change from baseline (95% CI)* −0.50 (−0.87, −0.13) −1.05 (−1.39, −0.70) −1.18 (−1.52, −0.83) −1.42 (−1.78, −1.06)
DIABETES, OBESITY AND METABOLISM

Difference vs. placebo (95% CI; p-value) −0.54 (−1.05, −0.04; 0.0336) −0.68 (−1.18, −0.17; 0.0084) −0.92 (−1.43, −0.41; 0.0005)
104 weeks, n 101 124 126 133
Adjusted mean change from baseline (95% CI)* −1.00 (−1.43, −0.56) −1.14 (−1.54, −0.74) −1.89 (−2.29, −1.49) −1.30 (−1.69, −0.91)
Difference vs. placebo (95% CI; p-value) −0.14 (−0.73, 0.45; 0.6404) −0.89 (−1.48, −0.31; 0.0031) −0.31 (−0.89, 0.28; 0.3065)
Total body weight, kg
Baseline (s.d.) 94.5 (19.8) 93.0 (16.7) 93.4 (17.4) 94.6 (16.8)
48 weeks, n 157 174 174 166
Adjusted mean change from baseline (95% CI)* 0.82 (0.28, 1.36) −0.96 (−1.47, −0.44) −0.99 (−1.50, −0.48) −1.60 (−2.13, −1.08)
Difference vs. placebo (95% CI; p-value) −1.78 (−2.53, −1.03; <0.0001) −1.82 (−2.56, −1.07; <0.0001) −2.43 (−3.18, −1.68; <0.0001)
104 weeks, n 107 132 128 141
Adjusted mean change from baseline (95% CI)* 1.83 (1.05, 2.61) −0.99 (−1.71, −0.27) −1.03 (−1.75, −0.31) −1.50 (−2.21, −0.78)
Difference vs. placebo (95% CI; p-value) −2.81(−3.87, −1.75; <0.0001) −2.86 (−3.92, −1.80; <0.0001) −3.33 (−4.38, −2.27; <0.0001)
Mean daily insulin dose, U
Baseline (s.d.) 74.0 (42.5) 79.9 (46.9) 77.1 (44.5) 78.0 (45.0)
48 weeks, n 157 173 172 166
Adjusted mean change from baseline (95% CI)* 10.5 ( 7.6, 13.5) −0.9 (−3.7, 1.9) 0.3 (−2.5, 3.1) −0.7 (−3.5, 2.1)
Difference vs. placebo (95% CI; p-value) −11.4 (−15.5, −7.4; <0.0001) −10.2 (−14.3, −6.2; <0.0001) −11.2 (−15.3, −7.2; <0.0001)
104 weeks, n 104 130 128 140
Adjusted mean change from baseline (95% CI)* 18.3 (13.7, 22.9) 4.1 (−0.2, 8.4) 1.6 (−2.7, 5.9) −0.8 (−5.1, 3.5)
Difference vs. placebo (95% CI; p-value) −14.3 (−20.5, −8.0; <0.0001) −16.8 (−23.1, −10.5; <0.0001) −19.2 (−25.5, −12.9; <0.0001)
Proportion of patients with a mean daily insulin dose reduction ≥10% from baseline
48 weeks, x/n 21/193 37/202 37/211 36/194
Adjusted proportion (95% CI)† 10.5% (6.2, 14.9) 18.2 (12.8, 23.5) 17.5% (12.4, 22.7) 18.6% (13.1, 24.0)
Difference vs. placebo (95% CI; p-value) 7.6% (0.8, 14.5; 0.0298) 7.0% (0.3, 13.7; 0.0419) 8.1% (1.1, 15.1; 0.0243)
104 weeks, x/n 14/193 21/202 28/211 33/194
Adjusted proportion (95% CI)† 7.0% (3.4, 10.7) 10.4% (6.2, 14.7) 13.3% (8.7, 17.8) 17.0% (11.8, 22.3)
Difference vs. placebo (95% CI; p-value) 3.4% (−2.2, 9.0; 0.2369) 6.3% (0.4, 12.1; 0.0361) 10.0% (3.6, 16.4; 0.0022)

N = number of patients in the full analysis set. n = number of patients in the full analysis set with non-missing baseline and week 104 values. x = number of patients with the response. s.d., standard deviation.
*Data are adjusted mean changes from baseline and 95% CI estimated from a mixed model with terms for baseline value, treatment, oral antidiabetic drug use, week, week-by-treatment interaction and week-by-baseline value interaction
using the full analysis set and including data after insulin up-titration.
†Data are adjusted proportions derived from logistic regression with adjustment for baseline value and stratum.
original article

doi:10.1111/dom.12187 129
original article DIABETES, OBESITY AND METABOLISM

A PLA + INS DAPA 2.5 mg + INS DAPA 5/10 mg + INS DAPA 10 mg + INS
N = 193 N = 202 N = 211 N = 194
0.0

−0.1

−0.2

−0.3

Change in Mean HbA1c (%) −0.4

−0.5

−0.6

−0.7

−0.8

−0.9

−1.0

−1.1

−1.2
ST period LT period 1 LT period 2
−1.3
0 4 8 12 16 20 24 32 40 48 52 65 78 91 104

Sample size per time point

Study Week
PLA + INS 193 183 173 169 167 164 166 163 159 157 122 116 114 109 107
DAPA 2.5 mg + INS 202 198 190 187 185 181 179 175 176 172 147 142 140 136 132
DAPA 5/10 mg + INS 211 201 195 191 187 187 185 184 180 173 150 143 133 131 128
DAPA 10 mg + INS 193 188 184 183 179 176 173 175 173 164 148 145 144 140 139

B PLA + INS DAPA 2.5 mg + INS DAPA 5/10 mg + INS DAPA 10 mg + INS
N = 193 N = 202 N = 211 N = 194
3.0

2.5

2.0
Change in Mean Total Body Weight (kg)

1.5

1.0

0.5

0.0

−0.5

−1.0

−1.5

−2.0

−2.5
ST period LT period 1 LT period 2
−3.0
0 4 8 12 16 20 24 32 40 48 52 65 78 91 104
Study Week
Sample size per time point, n
PLA + INS 193 185 175 170 170 165 168 164 158 157 122 118 114 110 107
DAPA 2.5 mg + INS 202 198 191 188 188 182 180 176 176 174 147 142 140 136 132
DAPA 5/10 mg + INS 211 201 196 193 190 188 187 184 181 174 150 143 134 132 128
DAPA 10 mg + INS 193 190 186 183 180 178 177 176 174 166 148 146 144 142 141

Figure 2. Adjusted mean changes over 104 weeks in: (A) HbA1c, %; (B) total body weight, kg; and (C) total daily insulin dose, IU. Data are adjusted
mean changes from baseline and error bars are 95% CIs estimated from a mixed model with fixed effects for treatment group, stratum (insulin plus OAD
use vs. insulin alone), week, baseline value as a covariate, plus interactions of week with treatment group and week with baseline value. Analyses used the
full analysis set and included data after insulin up-titration. N is the number of patients in the full analysis set. n is the number of patients in the full
analysis set with non-missing baseline and week (t) values. Treatment group symbols are shifted horizontally to prevent error bar overlapping. DAPA,
dapagliflozin; INS, Insulin; PLA, Placebo.

130 Wilding et al. Volume 16 No. 2 February 2014

DIABETES, OBESITY AND METABOLISM original article
C PLA + INS DAPA 2.5 mg + INS DAPA 5/10 mg + INS DAPA 10 mg + INS
N = 193 N = 202 N = 211 N = 194
24

22

20

18
Change in Mean Daily Insulin Dose (IU)
16

14

12

10

−2

−4

−6
ST period LT period 1 LT period 2
−8
0 4 8 12 16 20 24 32 40 48 52 65 78 91 104
Study Week
Sample size per time point, n
PLA + INS 191 185 176 171 170 165 168 164 158 157 121 118 114 110 104
DAPA 2.5 mg + INS 200 197 189 187 186 181 180 174 176 173 144 142 140 136 130
DAPA 5/10 mg + INS 209 202 194 194 190 188 187 183 181 172 147 142 134 132 128
DAPA 10 mg + INS 194 189 185 183 180 178 177 175 173 166 145 146 144 142 140

Figure 2. Continued

Events suggestive of genital infections and of UTIs were and high density lipoprotein (HDL)-cholesterol (Table S2).
higher in all dapagliflozin groups compared with placebo In the dapagliflozin 10-mg group, small increases in
(Table 3). These events were more common in women, serum creatinine with corresponding decreases in calculated
most were single episodes and most occurred during the first creatinine clearance were observed but without meaningful
24 weeks of treatment (figure S2). Most events suggestive of change in estimated glomerular filtration rate. However,
genital infection or of UTI were classified as mild or moderate these changes in renal parameters and haematocrit were not
in intensity and responded to routine management. Genital accompanied by raised rates of AEs of renal impairment/
infections led to treatment discontinuation in two patients failure or of hypotension/dehydration/hypovolaemia (Table 3)
receiving dapagliflozin during weeks 0–24. Lower UTIs led or of thromboembolism with dapagliflozin. In addition,
to discontinuation in two patients receiving dapagliflozin, fewer patients receiving dapagliflozin showed a worsening
one during weeks 0–24 and one during weeks 24–48; of albuminuria at 104 weeks compared with placebo;
and pyelonephritis led to discontinuation in one patient the proportions of patients transitioning from a normal
receiving dapagliflozin during weeks 0–24. Two further albumin/creatinine ratio (0 to <30 mg/g) or microalbuminuria
patients receiving dapagliflozin developed pyelonephritis, who (30 to <300 mg/g) at baseline to microalbuminuria or
responded to treatment and continued in the study. macroalbuminuria (≥300 mg/g) at 104 weeks were 13.7% in
Patients receiving dapagliflozin reported fewer AEs of the placebo group, and 10.4 and 4.1% in the dapagliflozin 5/10-
peripheral oedema (Table 3). and 10-mg groups, respectively (Table S3). A small percentage
Seated systolic/diastolic blood pressure mean changes increase in HDL-cholesterol was observed in all dapagliflozin
from baseline at 104 weeks were −0.5/−1.3 mmHg in the groups that was not accompanied by any increase in low-density
placebo group and −2.6/−2.9 and −7.5/−4.0 mmHg, in the lipoprotein (LDL)-cholesterol or total cholesterol (Table S2).
dapagliflozin 5/10- and 10-mg groups, respectively. Corre-
sponding changes for heart rate were +1.1, −1.3 and −1.2 bpm.
Clinically meaningful changes in laboratory values of Discussion
interest with absolute changes from baseline greater in After a small initial reduction in HbA1c in the insulin plus
magnitude in all dapagliflozin groups compared with the placebo group, mean HbA1c plateaued over 104 weeks but
placebo group were increases in urinary glucose, haematocrit this was at the expense of progressive increases in mean daily

Volume 16 No. 2 February 2014 doi:10.1111/dom.12187 131

original article DIABETES, OBESITY AND METABOLISM

PLA + INS DAPA 2.5 mg + INS DAPA 5/10 mg + INS DAPA 10 mg + INS
N = 193 N = 202 N = 211 N = 194
0.64
0.60

Probability of Insulin Up-titration or Discontinuation

0.56

0.52

0.48

0.44

0.40

0.36

0.32

0.28
0.24

0.20
0.16

0.12
0.08

0.04

0.00 ST p er iod LT period 1 LT period 2

0 8 16 24 32 40 48 52 65 78 91 104
Weeks
Number of patients at risk, n
PLA + INS 193 148 131 121 109 98 82 63 59 52 50 37
DAPA 2.5 mg + INS 202 185 174 165 152 143 133 114 107 104 95 59
DAPA 5/10 mg + INS 211 186 178 167 162 153 144 123 110 103 99 60
DAPA 10 mg + INS 194 179 168 161 153 149 139 120 116 107 104 70

Figure 3. Probability of insulin up-titration for failing to achieve pre-specified glycaemic targets or of discontinuation because of poor glycaemic control
over time. Symbols represent censored observations. Number of patients at risk is the number of patients at risk at the beginning of the period; N is the
number of patients in the full analysis set; n = number of patients in the full analysis set with non-missing baseline HbA1c values. DAPA, dapagliflozin;
INS, Insulin; PLA, Placebo.

insulin dose and mean total body weight and, moreover, mean without an increase in mean daily insulin requirement for the
HbA1c remained above target levels (absolute value ∼8% at dapagliflozin-treated patients over a 104-week period.
104 weeks). In contrast, mean HbA1c reductions were greater A number of complementary clinical benefits with
in the dapagliflozin plus insulin groups compared with the dapagliflozin of relevance to this population should be noted.
placebo plus insulin group (dapagliflozin vs. placebo difference First, consistent with its insulin independent mechanism of
of −0.39 and −0.35% at 104 weeks for the dapagliflozin 5/10- action and low intrinsic propensity to cause hypoglycaemia
and 10-mg groups, respectively) and occurred in the context of [32], these reductions in HbA1c with dapagliflozin were
sustained weight loss and stable insulin dosing over the entire achieved without any increased risk of major hypoglycaemia.
104-week treatment period. Second, sustained weight loss with reductions in systolic blood
While a target of <7.0% remains appropriate in younger pressure would suggest that dapagliflozin treatment may confer
patients [23,24] based on analyses of the UKPDS trial the potential for cardiovascular risk reduction as suggested
[25–27], for older patients—especially those with a prolonged by a meta-analysis of 14 dapagliflozin clinical trials of up
duration of diabetes, at risk of severe hypoglycaemia, or with to 2 years duration in which the hazard ratio for a composite
comorbidities—a higher target may be warranted based upon endpoint of cardiovascular death, myocardial infarction, stroke
more recent analyses from the ACCORD and VADT trials or hospitalization for unstable angina was 0.819 (95% CI:
[28,29] and other cohort studies [30,31]. For these latter group 0.583, 1.152) [33]. Third, weight loss and reduced AEs of
of patients, a target of around 7.5% has been proposed [24]. peripheral oedema with dapagliflozin compared with placebo
In this study, dapagliflozin stabilized glycaemic control to a may improve patient compliance with treatment [5]. Fourth,
mean level close to 7.5% in a difficult-to-treat population the step up at 52 weeks in urinary glucose in the dapagliflozin
of older patients (mean age 59.3) with T2DM of long 5/10-mg group to a similar level as seen in the 10-mg group
duration (mean age 13.6) and substantial diabetes-related and throughout the study and the fall at follow-up to the level seen
cardiovascular comorbidity (Table 1) who were receiving high in the placebo group, indicates that the pharmacodynamic
doses of insulin and for whom limited treatment options effect is persistent during active therapy and fully reversible
are available. Moreover, this glycaemic control was achieved upon discontinuation of therapy. These data support the use

132 Wilding et al. Volume 16 No. 2 February 2014

DIABETES, OBESITY AND METABOLISM original article
Table 3. Safety and tolerability at 104 weeks.

Placebo + insulin Dapagliflozin 2.5 mg + insulin Dapagliflozin 5/10 mg + insulin Dapagliflozin 10 mg + insulin
(N = 197) (N = 202) (N = 212) (N = 196)
Overall summary of number of patients with an adverse event
One or more AE 154 (78.2%) 162 (80.2%) 166 (78.3%) 157 (60.1%)
One or more drug-related AE 45 (22.8%) 47 (23.3%) 70 (33.0%) 63 (32.1%)
AE leading to discontinuation 13 (6.6%) 10 (5.0%) 20 (9.4%) 11 (5.6%)
One or more SAE 39 (19.8%) 39 (19.3%) 32 (15.1%) 36 (18.4%)
One or more drug-related SAE 1 (0.5%) 0 2 (0.9%) 1 (0.5%)
SAE leading to discontinuation 5 (2.5%) 4 (2.0%) 5 (2.4%) 5 (2.6%)
Deaths 0 0 2 (0.9%) 1 (0.5%)
Number of patients with adverse events with frequency ≥5% in any group*
Nasopharyngitis 27 (13.7%) 35 (17.3%) 39 (18.4%) 33 (16.8%)
Hypertension 23 (11.7%) 22 (10.9%) 21 (9.9%) 19 (9.7%)
Urinary tract infection 7 (3.6%) 12 (5.9%) 20 (9.4%) 17 (8.7%)
Back pain 13 (6.6%) 15 (7.4%) 12 (5.7%) 15 (7.7%)
Arthralgia 15 (7.6%) 8 (4.0%) 11 (5.2%) 13 (6.6%)
Diarrhoea 8 (4.1%) 12 (5.9%) 14 (6.6%) 12 (6.1%)
Hyperhidrosis 6 (3.0%) 4 (2.0%) 6 (2.8%) 11 (5.6%)
Oedema, peripheral 17 (8.6%) 9 (4.5%) 6 (2.8%) 11 (5.6%)
Pain in extremity 6 (3.0%) 11 (5.4%) 15 (7.1%) 11 (5.6%)
Upper respiratory tract infection 12 (6.1%) 9 (4.5%) 13 (6.1%) 11 (5.6%)
Bronchitis 13 (6.6%) 5 (2.5%) 12 (5.7%) 10 (5.1%)
Cough 6 (3.0%) 5 (2.5%) 7 (3.3%) 10 (5.1%)
Headache 18 (9.1%) 12 (5.9%) 14 (6.6%) 10 (5.1%)
Pollakiuria 3 (1.5%) 6 (3.0%) 7 (3.3%) 10 (5.1%)
Vulvovaginal mycotic infection 4 (2.0%) 2 (1.0%) 11 (5.2%) 10 (5.1%)
Influenza 3 (1.5%) 8 (4.0%) 11 (5.2%) 9 (4.6%)
Constipation 3 (1.5%) 13 (6.4%) 8 (3.8%) 8 (4.1%)
Nausea 10 (5.1%) 7 (3.5%) 6 (2.8%) 8 (4.1%)
Number of patients with a special interest adverse event
One or more episodes of hypoglycaemia†
Any episode 122 (61.9%) 140 (69.3%) 130 (61.3%) 119 (60.7%)
Major episodes 2 (1.0%) 4 (2.0%) 3 (1.4%) 3 (1.5%)
Minor episodes 119 (60.4%) 135 (66.8%) 125 (59.0%) 116 (59.2%)
Other episodes 13 (6.6%) 21 (10.4%) 25 (11.8%) 22 (11.2%)
Events suggestive of genital infection‡
Total patients 6/197 (3.0%) 15/202 (7.4%) 27/212 (12.7%) 28/196 (14.3%)
Men 0/98 5/100 (5.0%) 3/100 (3.0%) 12/88 (13.6%)
Single event 0 4 (80.0%) 2 (66.7%) 7 (58.3%)
2–3 events 0 1 (20.0%) 1 (33.3%) 4 (33.3%)
>3 events 0 0 0 1 (8.3)
Women 6/99 (6.1%) 10/102 (9.8%) 24/112 (21.4%) 16/108 (14.8%)
Single event 4 (66.7%) 8 (80.0%) 15 (62.5%) 11 (68.8%)
2–3 events 2 (33.3%) 2 (20.0%) 5 (20.8%) 2 (12.5%)
>3 events 0 0 4 (16.7%) 3 (18.8)
Events suggestive of UTI‡
Total patients 11/197 (5.6%) 17/202 (8.4%) 28/212 (13.2%) 27/196 (13.8%)
Men 4/98 (4.1%) 7/100 (7.0%) 7/100 (7.0%) 6/88 (6.8%)
Single event 3 (75.0%) 4 (57.1%) 4 (57.1%) 5 (83.3%)
2–3 events 1 (25.0%) 2 (28.6%) 3 (42.9%) 1 (16.7)
>3 events 0 1 (14.3) 0 0
Women 7/99 (7.1%) 10/102 (9.8%) 21/112 (18.8%) 21/108 (19.4%)
Single event 6 (85.7%) 6 (70.0%) 12 (57.1%) 14 (66.7%)
2–3 events 0 3 (30.0%) 8 (38.1%) 7 (33.3%)
>3 events 1 (14.3%) 1 (10%) 1 (4.8%) 0
Renal impairment/failure§ 4 (2.0%) 3 (1.5%) 6 (2.8%) 6 (3.1%)
Hypotension/dehydration/hypovolaemia§ 2 (1.0%) 5 (2.5%) 5 (2.4%) 4 (2.0%)

N = number of patients in the safety analysis set and includes data after insulin up-titration. AE, adverse event; SAE, serious adverse event; UTI, urinary tract infection.
*Based on definitive Medical Dictionary of Regulatory Activities (MedDRA, version 12.1) preferred terms.
†Major episode of hypoglycaemia defined as a symptomatic episode requiring external assistance because of severe impairment in consciousness or behaviour with a capillary or
plasma glucose value <3 mmol/l and prompt recovery after glucose or glucagon administration. Minor episode defined as with a symptomatic episode with a capillary or plasma
glucose measurement <3.5 mmol/l, regardless of need for external assistance, or an asymptomatic capillary or plasma glucose measurement <3.5 mmol/l that did not qualify as
a major episode. Other episode of hypoglycaemia defined as suggestive episode reported that did not meet criteria for major or minor episode. No episodes of hypoglycaemia
led to study discontinuation.
‡Events suggestive of genital Infection or UTI were identified in the database using pre-specified lists of preferred terms. These events included signs, symptoms, and other
reports suggestive of genital infection or UTI, as well as definitive terms for genital infection, obtained from spontaneous reporting and active questioning at each study visit.
§These events were also identified in the database using pre-specified lists of preferred terms, but which also included, for example, laboratory values such as serum creatinine.

Volume 16 No. 2 February 2014 doi:10.1111/dom.12187 133

original article
of dapagliflozin as a long-term therapy as it is not affected by
progressive β-cell failure.
Although comparative long-term data are extremely limited,
similar 2-year efficacy patterns have been observed in a
placebo-controlled study of dapagliflozin added to metformin
in patients with inadequate glycaemic control on metformin
alone (i.e. at an earlier stage of disease progression), in which
dapagliflozin 10 mg versus placebo differences at 102 weeks
were −0.80% for HbA1c and −3.1 kg for weight [34]. In
addition, in a head-to-head comparison study of canagliflozin
versus glimepiride in patients with T2DM receiving metformin,
canagliflozin versus glimepiride differences at 104 weeks were
−0.2% for HbA1c and −5.2 kg for weight [35].
As has been noted with the SGLT2-inhibitor class
[15–20,36–39], events suggestive of genital infections and
of UTIs, which included non-specific symptoms as well as
clinically diagnosed infections, were higher in all dapagliflozin
groups compared with placebo and were more commonly
reported in women. However, these episodes mostly occurred
within the first 24 weeks of treatment, were mostly reported
to be of mild or moderate intensity, responded to standard
treatment typically without interruption of dapagliflozin
therapy and rarely led to study discontinuation.
In this study, malignancies were uncommon and overall
rates were balanced across treatment groups. However, there
were three bladder cancers, three breast cancers and one
prostate cancer in the dapagliflozin groups versus none of these
forms of cancer in the placebo group. During the dapagliflozin
clinical trial programme, the overall proportion of patients with
malignant or unspecified tumours was similar between those
treated with dapagliflozin (1.47%) and placebo/comparator
(1.35%). Moreover, dapagliflozin did not induce tumours in
rodents at any of the doses evaluated in 2-year carcinogenicity
studies. When considering the cases of tumours occurring in
the different organ systems, the relative risk associated with
dapagliflozin versus placebo/comparator was above unity for
some tumours (bladder, prostate, breast) and below unity
for others (e.g. blood and lymphatic, ovary, renal tract),
resulting in no overall increased tumour risk associated
with dapagliflozin. The increased or decreased risk was not
statistically significant in any of the organ systems. Considering
the lack of tumour findings in non-clinical studies as well
as the short latency between first drug exposure and tumour
diagnosis, a causal relationship is considered unlikely. As the
numerical imbalance of breast, bladder and prostate tumours
must be considered with caution, it will be further investigated
in post-authorization studies [40].
Although small increases in serum creatinine and
corresponding decreases in calculated creatinine clearance
were observed, there were no clinically meaningful changes in
estimated glomerular filtration rate and fewer patients receiving
dapagliflozin showed a worsening of albuminuria from baseline
to 104 weeks compared with placebo. In addition, there were
no increases in the rate of AEs of renal failure/impairment
or hypotension/dehydration/hypovolaemia despite 53.4% of
patients receiving diuretic medications. Taken together this
would suggest dapagliflozin has no deleterious effect on long-
term renal function.
134 Wilding et al.
DIABETES, OBESITY AND METABOLISM
This study has limitations. First, insulin doses were
not titrated to target; however, this study was designed
to show whether adding dapagliflozin to insulin therapy
can improve glycaemic control, which necessitated that
baseline therapy remain unchanged, unless deteriorating
glycaemic control dictated the clinical need for insulin up- or
down-titration according to predefined study criteria. Second,
approximately 95% of recruited patients were white; however,
pharmacokinetic and pharmacodynamic response has not been
shown to vary according to racial origin [11,41,42]. Third, 28
patients from the UK discontinued the study after 48 weeks for
administrative reasons; however, these discontinued patients
were equally distributed across treatment groups. Finally, the
risk for breast or bladder cancer with dapagliflozin therapy
could not be fully evaluated because of the low number of events
and the lack of statistical power in a study of this sample size and
duration.
In conclusion, in patients whose T2DM was inadequately
controlled despite high-dose insulin therapy, adding
dapagliflozin reduced HbA1c levels and weight over
104 weeks without increasing overall insulin dose or rates of
hypoglycaemia. Conversely, in patients for whom placebo was
added to insulin therapy, a progressive increase in insulin dose
and weight was observed. Overall, dapagliflozin therapy was
well-tolerated, although events suggestive of genital infection
and of UTI were more commonly reported compared with
placebo. These data suggest that dapagliflozin may offer a new
treatment option for patients whose T2DM remains inade-
quately controlled on insulin therapy with or without additional
oral glucose-lowering agents.
Acknowledgements
This study was sponsored by Bristol-Myers Squibb and
AstraZeneca. Medical writing assistance for this manuscript
was provided by Julian Martins, MA MBBS, of inScience
Communications, Springer Healthcare Ltd., and this assistance
was funded by Bristol-Myers Squibb and AstraZeneca.
Conflict of Interest
J. P. H. W. was the study principal investigator; has served
on advisory boards and/or speakers’ bureaus and has received
honoraria or consulting fees from AstraZeneca, Boehringer
Ingelheim, Bristol-Myers Squibb, Johnson & Johnson, Merck,
Novo Nordisk, Takeda, and Astellas and has received grant
support from Merck, Novo Nordisk, and Roche; and is an
investigator for ongoing clinical trials with dapagliflozin. V.
W. was a study trialist; has served on advisory boards and/or
speakers’ bureaus and has received honoraria or consulting
fees from AstraZeneca, Bristol-Myers Squibb, Janssen, Merck,
Novo Nordisk, Sanofi, and Lilly. K. R., J. S. and S. P. are
employees of AstraZeneca.
J. P. H. W., V. W., K. R. and S. P. participated in the study
concept and design. J. P. H. W. and V. W. participated in
acquisition of data. K. R. participated in study supervision. J.
P. H. W., V. W., K. R. and S. P. participated in the analysis
and interpretation of data. J. S. participated in the statistical
Volume 16 No. 2 February 2014
DIABETES, OBESITY AND METABOLISM
verification of data. J. P. H. W., V. W., K. R., J. S. and S. P.
contributed to writing and revising the report.
Supporting Information
Additional Supporting Information may be found in the online
version of this article:
Appendix S1. Dapagliflozin 006 Study Group Study
Investigator List.
Figure S1. Change in urinary glucose excretion throughout
the study and at follow-up.
Figure S2. Percent of patients with events suggestive of (A)
Genital Infection or of (B) Urinary Tract Infection. DAPA,
dapagliflozin; INS, Insulin; PLA, Placebo.
Table S1. Malignant neoplasms.
Table S2. Laboratory values of interest: change from baseline
up to week 104.
Table S3. Proteinuria transitioning.
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