740 Diabetes Care Volume 37, March 2014

Serge A. Jabbour,1 Elise Hardy,2

Dapagliflozin Is Effective as Jennifer Sugg,2 and Shamik Parikh,2 for the

Add-on Therapy to Sitagliptin With Study 10 Group*

or Without Metformin: A 24-Week,

Multicenter, Randomized,
Double-Blind, Placebo-Controlled
Study

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OBJECTIVE
To assess the efficacy and safety of dapagliflozin as add-on therapy in patients with
EMERGING TECHNOLOGIES AND THERAPEUTICS

type 2 diabetes who were inadequately controlled with a dipeptidyl peptidase-4

inhibitor with or without metformin.

RESEARCH DESIGN AND METHODS

In this 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-
group, phase 3 study with a 24-week blinded extension period, 432 patients were
randomized to receive dapagliflozin 10 mg/day or placebo added to sitagliptin (100 mg/
day) 6 metformin (‡1,500 mg/day).

RESULTS
Baseline HbA1c and FPG levels were 7.9% (63.0 mmol/mol) and 162.2 mg/dL
(9.0 mmol/L) for the dapagliflozin group and 8.0% (64.0 mmol/mol) and 163 mg/dL
(9.0 mmol/L) for placebo. At week 24, dapagliflozin significantly reduced mean
HbA1c levels (–0.5% [–4.9 mmol/mol]) versus placebo (0.0% [+0.4 mmol/mol]).
Dapagliflozin reduced body weight versus placebo (–2.1 and –0.3 kg) and reduced
HbA1c levels in patients with baseline values ‡8.0% (–0.8% [8.7 mmol/mol] and
0.0% [0.3 mmol/mol]) and fasting plasma glucose levels (–24.1 mg/dL [–1.3 mmol/L]
and 3.8 mg/dL [0.2 mmol/L]). Similar results were observed when data were stratified 1
Jefferson Medical College of Thomas Jefferson
by background therapy. Glycemic and weight benefits observed at week 24 were University, Philadelphia, PA
maintained through week 48. Changes from baseline in systolic blood pressure at week 2
AstraZeneca, Wilmington, DE
8 were not significantly different between treatment groups. Over 48 weeks, fewer Corresponding author: Serge A. Jabbour,
patients receiving dapagliflozin were discontinued or rescued for failing to achieve [email protected].
glycemic targets compared with placebo. Adverse events were balanced between Received 25 February 2013 and accepted 14
groups, and discontinuation rates were low. At week 48, signs and symptoms sugges- October 2013.
tive of genital infection were more frequent with dapagliflozin (9.8%) than with placebo Clinical trial reg. no. NCT00984867, clinicaltrials
(0.4%). Signs and symptoms suggestive of urinary tract infection were balanced .gov.
between dapagliflozin (6.7%) and placebo (6.2%). This article contains Supplementary Data online
at http://care.diabetesjournals.org/lookup/
CONCLUSIONS suppl/doi:10.2337/dc13-0467/-/DC1.
*A complete list of the Study 10 investigators can
These results suggest that in patients with type 2 diabetes, inadequately con- be found in the Supplementary Data online.
trolled on sitagliptin with or without metformin, add-on treatment with dapa-
© 2014 by the American Diabetes Association.
gliflozin provides additional clinical benefit and is well tolerated. See http://creativecommons.org/licenses/by-
Diabetes Care 2014;37:740–750 | DOI: 10.2337/dc13-0467 nc-nd/3.0/ for details.
care.diabetesjournals.org Jabbour and Associates 741

For patients with type 2 diabetes, An additional secondary benefit of and monitored in accordance with the
multiple agents with complementary SGLT2 inhibition is the elimination of ethical principles of Good Clinical
mechanisms of action are often calories in the form of glucose. Practice as defined by the International
required to adequately manage Consistent long-term weight loss with Conference on Harmonization and
hyperglycemia (1). Most currently 10 mg dapagliflozin of ;1.0–2.6 kg Declaration of Helsinki. An institutional
available oral antidiabetic agents (placebo subtracted) has been observed review board approved the protocol,
(OADs) act by increasing insulin (7,9,11,13). and all subjects gave written, informed
secretion or sensitizing tissues to insulin The current study assesses the efficacy consent.
action and therefore depend upon and safety of dapagliflozin in patients During a 10-week dose-stabilization
pancreatic b-cell function for efficacy. whose HbA1c levels were not adequately period, all patients received sitagliptin
Due to a progressive loss of b-cell controlled with a dipeptidyl peptidase-4 100 mg/day (patients initially taking
function (2), many patients eventually (DPP-4) inhibitor, sitagliptin. vildagliptin switched to sitagliptin).
require multiple agents to achieve Dapagliflozin was evaluated as a dual A 2-week placebo lead-in period
target hemoglobin A1c (HbA1c) levels (1). combination therapy with sitagliptin followed, after which patients with a

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Many currently available agents are and as a triple combination therapy with lead-in HbA1c value $7.0% (53 mmol/
associated with hypoglycemia and/or sitagliptin plus metformin. mol) and #10.0% (86 mmol/mol) were
weight gain, effects that act as barriers randomized equally to dapagliflozin
Although the treatment algorithm from
to the achievement of glycemic and the American Diabetes Association/ 10 mg or placebo for a 24-week double-
weight control. An unmet need European Association for the Study of blind period. Randomized patients were
therefore exists for new agents that are Diabetes notes that adding insulin may stratified by concomitant metformin
weight neutral or lead to weight loss be more effective than adding a third use at baseline: in stratum 1, study
without causing hypoglycemia. oral agent to two oral agents, the treatment was added to sitagliptin
Sodium glucose cotransporter 2 (SGLT2) algorithm includes triple oral therapy monotherapy; in stratum 2, study
is involved in the reabsorption of the as a treatment option when dual treatment was added to sitagliptin
majority of glucose filtered from the therapy fails to control HbA1c levels (14). plus metformin IR ($1,500 mg/day,
glomerular filtrate back into the The American Association of Clinical administered BID with meals).
bloodstream (3,4). Endocrinologists also suggests the use Sitagliptin monotherapy was allowed
of triple therapy as a first approach for only in countries where it was approved.
PCR data show SGLT2 expression to be
the treatment of asymptomatic patients No other OADs were permitted. After
highly specific to the kidney and that the
with HbA1c levels .9% (75 mmol/mol) completion of the double-blind period,
signal for renal expression was 100-fold
(15). In patients with HbA1c levels #9% patients could participate in a 24-week,
higher in the kidney than in the next
(75 mmol/mol), triple therapy is site- and patient-blind extension period.
highest tissue observed (the ileum) (5).
recommended if the patient has an
SGLT2 is expressed predominantly in the Adult patients ($18 years) with type 2
inadequate response to monotherapy
luminal brush border of the renal cortex (6). diabetes were eligible for inclusion. An
or dual therapy. In addition, the
Dapagliflozin is a selective inhibitor of upper age limit was imposed for those
algorithm recommends avoiding weight
SGLT2 and acts to reduce hyperglycemia gain and emphasizes the benefits of receiving metformin where local label
independently of insulin secretion or weight loss in this patient population. restrictions applied. HbA1c values
action. Dapagliflozin reduces systemic between 7.7% (61 mmol/mol) and
Because previous studies have 10.5% (91 mmol/mol) were required for
glycemic load by inhibiting this suggested a reduction in blood pressure
transporter, allowing some filtered individuals not receiving a DPP-4
(BP) with dapagliflozin treatment, this inhibitor at enrollment and between
glucose to pass into the urine for study also included change from
elimination (3). Reduction in HbA1c with 7.2% (55 mmol/mol) and 10.0% (86
baseline in systolic BP (SBP) as a mmol/mol) for those receiving a DPP-4
dapagliflozin was relatively consistent secondary outcome measure in addition
across randomized, controlled, clinical inhibitor. Prior to randomization, HbA1c
to measures of glycemic efficacy and
trials in a variety of settings from values were required to be between
body weight. Background BP
treatment-naive patients (7,8) to first 7.0% (53 mmol/mol) and 10.0% (86
medications were controlled in this
add-on to metformin, sulfonylurea, or mmol/mol) for all patients. Treatment
study to avoid confounding effects on
pioglitazone (9–12), and to patients with OADs other than metformin or
BP measurements.
requiring insulin, with or without DPP-4 inhibitors within the 10 weeks
concomitant OADs (13). The blood RESEARCH DESIGN AND METHODS prior to enrollment was not permitted.
glucose–lowering effect of dapagliflozin Study Design Individuals with type 1 diabetes or
after 6 months of treatment was similar This 24-week, multicenter, randomized, fasting plasma glucose (FPG) .270
to that of metformin-XR monotherapy double-blind, placebo-controlled, mg/dL (15.0 mmol/L) were excluded, as
(12) and, after 1 year of treatment, parallel-group, international phase 3 were pregnant or breast-feeding
was similar to glipizide in patients study (NCT00984867) was conducted in women and patients receiving
poorly controlled on metformin Argentina, Germany, Mexico, Poland, metformin with a calculated creatinine
monotherapy (10). the U.K., and the U.S. It was designed clearance ,60 mL/min or serum
742 Dapagliflozin Add-on to Sitagliptin Diabetes Care Volume 37, March 2014

creatinine values $1.5 mg/dL for men therapeutic glycemic response (HbA1c variables, nominal P values were
or $1.4 mg/dL for women. Patients not ,7.0% [53 mmol/mol]) at week 24, reported for both overall and within-
treated with metformin and with a change in seated SBP from baseline to strata comparisons, although the
baseline calculated creatinine clearance week 24, percent change in fasting lipids significance of the result cannot be
,50 mL/min were excluded. At (total cholesterol, LDL cholesterol, HDL concluded.
enrollment, individuals with SBP $170 cholesterol, and triglycerides) from The proportion of subjects achieving
mmHg and/or diastolic BP $110 mmHg baseline to week 24, and change in therapeutic glycemic response
were excluded, and at randomization, b-cell function (as measured by the (reduction in HbA1c $0.7% [7.7 mmol/
patients were required to have an updated model of the homeostasis mol] at week 24) was analyzed using
SBP ,160 mmHg and/or a diastolic model assessment [HOMA-2]) and previously published methodology
BP ,100 mmHg. insulin resistance (as measured by the (17,18) when there were at least five
HOMA for insulin resistance) (16). responders on average by treatment
Study Treatments group.
Safety End Points
Dapagliflozin 10 mg or placebo was
Safety was evaluated based on reported

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administered orally once daily during RESULTS
adverse events (AEs), laboratory values,
the 24-week double-blind and 24-week
electrocardiogram, pulse, BP, Patients
extension periods. All patients received
hypoglycemic events, calculated The disposition of patients is shown in
open-label oral sitagliptin 100 mg once
creatinine clearance, estimated Supplementary Fig. 1. In summary, 451
daily for the 10-week dose-stabilization
glomerular filtration rate, and physical patients were randomized to receive
period, the 2-week placebo lead-in
examination findings. dapagliflozin (n = 225) or placebo
period, the 24-week double-blind
(n = 226). Of the patients randomized to
treatment period, and the 24-week Statistical Analysis dapagliflozin, 208 (92%) completed the
extension period. Patients in stratum 2 The data were analyzed for the overall 24-week double-blind period, with 202
received open-label oral metformin study population and for each stratum (90%) going on to complete the
immediate release 500-mg tablets separately. Efficacy data were analyzed additional 24-week extension period.
($1,500 mg/day). A rescue therapy, with a full analysis set (FAS) that This compared with 203 (90%) of those
open-label oral glimepiride #6 mg/day included all randomized individuals who receiving placebo at 24 weeks and 185
was given to patients with FPG .270 took at least one dose of double-blind (82%) at 48 weeks. Patient demographic
mg/dL (15.0 mmol/L), weeks 0–4; study medication and had a nonmissing and baseline characteristics are shown
FPG .240 mg/dL (13.3 mmol/L), baseline value and one or more in Table 1 and were balanced between
weeks 4–12; or FPG .200 mg/dL (11.1 postbaseline efficacy values for one or treatments. Mean age was ;55 years,
mmol/L) or HbA1c .8.0% (64 mmol/ more efficacy variables. The safety set 55% were male, mean weight was
mol), weeks 12–24. comprised patients who took one or ;90 kg, mean duration of diabetes
Efficacy End Points
more doses of double-blind study was 5.7 years, and mean baseline
The primary end point was change in medication. HbA1c was ;7.9% (63 mmol/mol).
HbA1c from baseline at week 24. Key The primary efficacy end point (change European sites contributed fewer
secondary end points were change in from baseline HbA1c at week 24) was patients to stratum 1 because of the
total body weight from baseline to week assessed by an ANCOVA model with European label restrictions regarding
24, change in HbA1c in patients with fixed terms for treatment group and the use of sitagliptin as monotherapy,
baseline HbA1c $8% (64 mmol/mol) strata (for the overall population) and resulting in racial/ethnic differences
from baseline to week 24, change in FPG baseline value as a covariate, using last between the two strata. Patients in
from baseline to week 24, change in observation carried forward (LOCF) to stratum 1 (treatment added to
seated SBP in patients with baseline calculate a least squares estimate of the sitagliptin monotherapy) had a higher
seated SBP $130 mmHg from baseline treatment difference. The longitudinal mean baseline HbA1c and were younger,
to week 8, and glycemic response rate repeated measures model included with a shorter duration of diabetes and a
(HbA1c reduction $0.7% [7.7 mmol/ fixed categorical effects of treatment, lower rate of hypertension at baseline,
mol] from baseline) at week 24. The week, treatment-by-week interaction, than those in stratum 2 (treatment
change in 2-h postliquid meal glucose and stratum as well as the continuous added to metformin plus sitagliptin).
(PPG) from baseline (day 0) to week 24 fixed covariates of baseline value and
was also evaluated. Patients fasted for baseline value-by-week interaction. Efficacy
$12 h prior to the visit. The liquid meal Hierarchical closed testing controlled Efficacy of dapagliflozin compared with
was administered immediately after a for type I errors for the primary and key placebo is presented in Table 2
time 0 blood sample was drawn, and secondary end points. Within-stratum (24 weeks, LOCF analyses) and Table 3
blood samples were drawn 2 h after the treatment comparisons were (24 and 48 weeks, longitudinal analyses
start of the liquid meal for PPG, individually tested at a two-sided [LA]).
C-peptide, and insulin determination. significance level of 0.05 for variables Primary End Point
Exploratory end points included found to be significant in the combined A statistically significant reduction from
proportion of subjects achieving a strata analysis. For exploratory baseline in HbA1c was observed in the
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743
Jabbour and Associates

rescue (placebo subtracted, –0.5% [–5.2

placebo at week 24 excluding data after

(placebo subtracted, –0.9% [–9.3 mmol/

significantly versus placebo when added

changes in seated SBP with dapagliflozin

for change in PPG and the proportion of

out to 48 weeks. When data after rescue

baseline HbA1c $8% and change in FPG

mmol/mol]; P , 0.0001, LOCF) (Table 2).

subtracted, –0.6% [–6.4 mmol/mol] LA).

In the entire patient cohort and in each

discontinued for lack of efficacy or were

rescue were included, improvements in

rescued for failing to maintain glycemic

(Table 2), with a mean decrease observed

stratum (Table 2) and were maintained

$130 mmHg, there were no significant

P , 0.0001, LOCF) or to sitagliptin plus
to sitagliptin alone (stratum 1: placebo

population (placebo subtracted, –0.7%

cohort (Table 2) were also significantly

maintained through 48 weeks (Table 3

from baseline to week 24 in the entire

stratum, significance was not assessed

parameters below prespecified rescue

with placebo and were also observed

Statistically significant improvements

reduced with dapagliflozin compared

In patients with baseline seated SBP

subtracted, –0.6% [–6.1 mmol/mol];

subtracted, –0.4% [–4.4 mmol/mol];

in each treatment group in the overall

study population and in each stratum.
receiving placebo. When data after
dapagliflozin group compared with

Dapagliflozin also decreased HbA1c

were observed in the dapagliflozin

change in total body weight in the

were included, reductions in body

overall study population and each

compared with placebo at week 8

group compared with placebo for
Over 48 weeks, 31.8% of patients
mol] LA), and stratum 2 (placebo

Change in HbA1c in patients with

criteria versus 57.6% of patients
[–7.4 mmol/mol] LA), stratum 1
metformin (stratum 2: placebo

and Fig. 1) in the overall study

weight were similar (Table 3).

Improvements in HbA1c were

HbA1c were similar (Table 3).

receiving dapagliflozin were

Key Secondary End Points

within each stratum.

P , 0.0001, LOCF).

Table 1—Demographics and baseline characteristics (FAS)

Entire cohort Sitagliptin monotherapy Sitagliptin plus metformin
Placebo Dapagliflozin Placebo Dapagliflozin Placebo Dapagliflozin
(N = 224) 10 mg (N = 223) (N = 111) 10 mg (N = 110) (N = 113) 10 mg (N = 113)
Mean age, years (SD) 55.0 (10.2) 54.8 (10.4) 53.3 (11.3) 52.6 (10.1) 56.6 (8.8) 56.8 (10.3)
Sex (%)
Male 118 (52.7) 127 (57.0) 51 (45.9) 60 (54.5) 67 (59.3) 67 (59.3)
Race (%)
White 171 (76.3) 161 (72.2) 66 (59.5) 65 (59.1) 105 (92.9) 96 (85.0)
Black 6 (2.7) 11 (4.9) 5 (4.5) 4 (3.6) 1 (0.9) 7 (6.2)
Asian 2 (0.9) 2 (0.9) 0 1 (0.9) 2 (1.8) 1 (0.9)
Other 45 (20.1) 49 (22.0) 40 (36.0) 40 (36.4) 5 (4.4) 9 (8.0)
Mean weight, kg (SD) 89.2 (20.9) 91.0 (21.6) 84.2 (19.7) 88.0 (23.1) 94.2 (20.9) 94.0 (19.8)
Mean seated baseline SBP in patients N = 111 N = 101 N = 45 N = 43 N = 66 N = 58
with SBP $130 mmHg, mmHg (SD) 139.3 (8.5) 140.5 (8.0) 137.9 (6.7) 138.5 (7.6) 140.3 (9.5) 141.9 (8.1)
Mean duration of diabetes, years (SD) 5.64 (5.40) 5.70 (4.87) 4.80 (5.76) 4.68 (4.14) 6.47 (4.91) 6.69 (5.32)
Mean HbA1c (SD), % [mmol/mol] 8.0 (0.8) [64.0 (8.5)] 7.9 (0.8) [63.0 (8.9)] 8.1 (0.8) [65.0 (8.7)] 8.0 (0.8) [64.0 (8.7)] 7.9 (0.8) [63.0 (8.2)] 7.8 (0.8) [62.0 (8.9)]
Mean FPG (SD), mg/dL [mmol/L] 163.0 (34.5) 162.2 (36.8) 161.4 (34.3) 157.3 (32.1) 164.6 (34.7) 167.0 (40.5)
[9.0 (1.9)] [9.0 (2.0)] [9.0 (1.9)] [8.7 (1.8)] [9.1 (1.9)] [9.3 (2.3)]
care.diabetesjournals.org

Absolute 2-h postliquid meal glucose 226.3 (54.0) 227.8 (58.9) 231.2 (55.0) 225.3 (59.0) 221.0 (52.7) 230.2 (59.0)
(SD), mg/dL [mmol/L] [12.6 (3.0)] [12.6 (3.3)] [12.8 (3.1)] [12.5 (3.3)] [12.3 (2.9)] [12.8 (3.3)]
Mean HbA1c (SD) in subgroup with
baseline HbA1c $8.0%, % [mmol/mol] 8.7 (0.5) [71.0 (6.0)] 8.7 (0.5) [71.0 (6.0)] 8.7 (0.6) [72.0 (6.2)] 8.6 (0.5) [71.0 (5.8)] 8.7 (0.5) [71.0 (5.8)] 8.7 (0.6) [71.0 (6.2)]
N is the number of subjects in the FAS. Percentages reported are based on the total number of subjects in each treatment group. The race subgroup of “other” includes subjects with reported race of American
Indian/Alaska Native or other.
 744

Table 2—Adjusted mean change from baseline (LOCF) at week 24 (week 8 and 24 for seated SBP) for efficacy end points (excluding data after rescue; including data after
rescue for SBP)
Entire primary analysis cohort Sitagliptin monotherapy Sitagliptin plus metformin
Placebo Dapagliflozin Placebo Dapagliflozin Placebo Dapagliflozin
(N = 224) 10 mg (N = 223) (N = 111) 10 mg (N = 110) (N = 113) 10 mg (N = 113)
Mean change 0.0 (–0.1 to 0.1) 0.1 (–0.1 to 0.3) 0.0 (–0.2 to 0.1)
Dapagliflozin Add-on to Sitagliptin

HbA1c, % [mmol/mol] 20.5 (–0.6 to –0.4) 20.5 (–0.6 to –0.3) 20.4 (–0.6 to –0.3)
(95% CI) [0.4 (–0.7 to 1.5)] [–4.9 (–6.0 to –3.8)] [1.1 (–0.7 to 2.7)] [–5.1 (–6.9 to –3.4)] [–0.2 (–1.6 to 1.1)] [–4.7 (–6.0 to –3.3)]
Placebo-corrected 20.5 (–0.6 to –0.3) 20.6 (–0.8 to –0.3) 20.4 (–0.6 to –0.2)
change [–5.2 (–6.8 to –3.7)] [–6.1 (–8.6 to –3.7)] [–4.4 (–6.3 to –2.5)]
P , 0.0001† P , 0.0001* P , 0.0001*
Body weight, kg Mean change 20.3 (–0.6 to 0.1) 22.1 (–2.5 to –1.8) 20.1 (–0.5 to 0.4) 21.9 (–2.4 to –1.5) 20.5 (–1.0 to 0.1) 22.4 (–2.9 to –1.8)
(95% CI) Placebo-corrected 21.9 (–2.4 to –1.4) 21.9 (–2.5 to –1.2) 21.9 (–2.6 to –1.1)]
change P , 0.0001† P , 0.0001* P , 0.0001*
HbA1c in patients with n = 99 n = 94 n = 56 n = 55 n = 43 n = 39
baseline HbA1c $8%, Mean change 0.0 (–0.1 to 0.2) 20.8 (–1.0 to –0.7) 0.1 (–0.2 to 0.3) 20.8 (–1.0 to –0.6) 0.0 (–0.2 to 0.2) 20.8 (–1.0 to –0.6)
% [mmol/mol] (95% CI) [0.3 (–1.3 to 2.0)] [–8.7 (–10.5 to –7.1)] [0.7 (–1.7 to 3.1)] [–8.9 (–11.3 to –6.4)] [0.0 (–2.3 to 2.3)] [–8.6 (–11.0 to –6.2)]
Placebo-corrected 20.8 (–1.1 to –0.6) 20.9 (–1.2 to –0.6) 20.8 (–1.1 to –0.5)
change [–9.1 (11.5 to –6.8)] [–9.5 (–12.9 to –6.0)] [–8.7 (–12.0 to –5.4)]
P , 0.0001† P , 0.0001* P , 0.0001*
FPG, mg/dL [mmol/L] Mean change 3.8 (–0.8 to 8.4) 224.1 (–28.7 to –19.5) 4.6 (–2.3 to 11.5) 222.0 (–28.8 to –15.1) 3.0 (–3.2 to 9.3) 226.2 (–32.4 to –19.9)
(95% CI) [0.2 (–0.0 to 0.5)] [–1.3 (–1.6 to –1.1)] [0.3 (–0.1 to 0.6)] [–1.2 (–1.6 to –0.8)] [0.2 (–0.2 to 0.5)] [–1.5 (–1.8 to –1.1)]
Placebo-corrected 227.9 (–34.5 to –21.4) 226.6 (–36.3 to –16.9) 229.2 (–38.0 to –20.4)
change [–1.6 (–1.9 to –1.2)] [–1.5 (–2.0 to –0.9)] [–1.6 (–2.1 to –1.1)]
P , 0.0001† P , 0.0001* P , 0.0001*
Seated SBP in patients with Mean change 25.1 (–7.1 to –3.1) 26.0 (–8.1 to –3.9) 24.2 (–7.1 to –1.4) 26.6 (–9.5 to –3.7) 25.5 (–8.3 to –2.7) 25.3 (–8.3 to –2.3)
baseline seated SBP $130 Placebo-corrected 20.9 (–3.8 to 2.0) 22.4 (–6.4 to 1.7) 0.2 (–3.9 to 4.3)
at week 8, mmHg (95% CI) change P = 0.5583 P = 0.2443 P = 0.9100
2-h postliquid meal glucose, (n = 197) (n = 207) (n = 102) (n = 99) (n = 95) (n = 108)
mg/dL [mmol/L] (95% CI) Mean change 24.8 (–11.3 to 1.8) 247.7 (–54.1 to –41.3) 22.6 (–11.2 to 5.9) 246.3 (–55.0 to –37.6) 27.2 (–17.3 to 2.8) 248.9 (–58.3 to –39.5)
[–0.3 (–0.6 to 0.1)] [–2.7 (–3.0 to –2.3)] [20.1 (–0.6 to 0.3)] [–2.6 (–3.1 to –2.1)] [–0.4 (–1.0 to 0.2)] [–2.7 (–3.2 to –2.2)]
Placebo-corrected 242.9 (–52.1 to –33.8) 243.7 (–55.9 to –31.5) 241.6 (–55.4 to –27.8)
change [–2.4 (–2.9 to –1.9)] [–2.4 (–3.1 to –1.8)] [–2.3 (–3.1 to –1.5)]
Percent of patients with Mean 16.6 (11.7 to 21.4) 35.3 (29.3 to 41.2) 17.2 (10.1 to 24.2) 42.8 (33.9 to 51.6) 16.0 (9.2 to 22.7) 28.0 (20.1 to 35.9)
decrease in HbA1c Placebo-corrected
$0.7% (95% CI) change 18.7 (11.1 to 26.4) 25.6 (14.3 to 36.8) 12.1 (1.7 to 22.5)
N is the number of subjects in the FAS. n is the number of subjects in the FAS with nonmissing baseline and week 24 (LOCF) values. †Significant P value: primary end point tested at a = 0.050; key secondary end
points tested sequentially at a = 0.050. *For variables found to be significant with the combined strata analysis, corresponding within-stratum treatment comparisons were individually tested at a two-sided
significance level of 0.05.
Diabetes Care Volume 37, March 2014

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Table 3—Change from baseline at weeks 24 and 48 for efficacy end points (FAS) (excluding data after rescue unless otherwise specified, longitudinal repeated measures)
Entire primary analysis cohort Sitagliptin monotherapy Sitagliptin plus metformin
Dapagliflozin Placebo Dapagliflozin Dapagliflozin
Weeks Placebo (N = 224) 10 mg (N = 223) (N = 111) 10 mg (N = 110) Placebo (N = 113) 10 mg (N = 113)
HbA1c, % [mmol/mol] (95% CI) 24 Adjusted mean change 0.1 (0.0 to 0.2) 20.4 (–0.5 to –0.3) 0.2 (0.0 to 0.4) 20.4 (–0.6 to –0.2) 0.0 (–0.1 to 0.2) 20.4 (–0.5 to –0.3)
[1.0 (–0.4 to 2.3)] [–4.2 (–5.4 to –2.8)] [2.1 (–0.3 to 4.4)] [–4.0 (–6.1 to –1.9)] [0.1 (–1.5 to 1.6)] [–4.2 (–5.6 to –2.7)]
Placebo-corrected change 20.5 (–0.6 to –0.3) 20.6 (–0.8 to –0.3) 20.4 (–0.6 to –0.2)
care.diabetesjournals.org

[–5.0 (–6.9 to –3.2)] [–6.0 (–9.2 to –2.8)] [–4.3 (–6.3 to –2.1)]

48 Adjusted mean change 0.4 (0.2 to 0.5) 20.3 (–0.4 to –0.2) 0.9 (0.5 to 1.2) 0.0 (–0.3 to 0.3) 0.2 (0.0 to 0.3) 20.4 (–0.6 to –0.3)
[4.2 (2.4 to 5.9)] [–3.3 (–4.7 to –1.9)] [9.3 (5.9 to 12.8)] [0.0 (–2.7 to 2.8)] [1.6 (–0.3 to 3.6)] [–4.8 (–6.3 to –3.3)]
Placebo-corrected change 20.7 (–0.9 to –0.5) 20.9 (–1.3 to –0.5) 20.6 (–0.8 to –0.4)
[–7.4 (–9.6 to –5.2)] [–9.3 (–13.7 to –4.9)] [–6.4 (–8.9 to –3.9)]
HbA1c, % [mmol/mol] (95% CI), 24 Placebo-corrected change 20.4 (–0.5 to –0.2) 20.5 (–0.8 to –0.2) 20.3 (–0.4 to –0.1)
including data after rescue [–4.2 (–5.8 to –2.5)] [–5.4 (–8.2 to –2.6)] [–3.1 (–4.8 to 21.2)]
48 Placebo-corrected change 20.6 (–0.7 to –0.4) 20.5 (–0.8 to –0.2) 20.6 (–0.8 to –0.4)
[–6.1 (–8.0 to –4.3)] [–5.8 (–8.9 to –2.6)] [–6.3 (–8.4 to –4.3)]
Body weight, kg (95% CI) 24 Adjusted mean change 20.2 (–0.6 to 0.2) 22.2 (–2.6 to –1.8) 0.0 (–0.6 to 0.6) 21.9 (–2.4 to –1.4) 20.4 (–1.1 to 0.2) 22.5 (–3.0 to –1.9)
Placebo-corrected change 22.0 (–2.6 to –1.5) 21.9 (–2.6 to –1.1) 22.0 (–2.9 to –1.2)
48 Adjusted mean change 0.2 (–0.4 to 0.8) 22.0 (–2.5 to –1.6) 0.8 (0.0 to 1.7) 21.4 (–2.1 to –0.7) 20.5 (–1.3 to 0.4) 22.5 (–3.2 to –1.8)
Placebo-corrected change 22.2 (–3.0 to –1.5) 22.2 (–3.3 to –1.2) 22.1 (–3.2 to –1.0)
Body weight, kg (95% CI), 24 Placebo-corrected change 22.1 (–2.7 to –1.6) 22.1 (–2.9 to –1.4) 22.1 (–2.9 to –1.3)
including data after rescue 48 Placebo-corrected change 22.5 (–3.1 to –1.8) 22.2 (–3.1 to –1.4) 22.6 (–3.5 to –1.6)
HbA1c, in patients with 24 Adjusted mean change 0.2 (–0.1 to 0.4) 20.8 (–1.0 to –0.6) 0.2 (–0.1 to 0.6) 20.8 (–1.1 to –0.5) 20.4 (ND) 20.9 (ND)
HbA1c $8% adj. mean, [1.9 (–0.9 to 4.6)] [–8.3 (–10.6 to –6.0)] [2.3 (–1.5 to 6.2)] [–8.4 (–11.6 to –5.1)] [–4.6 (ND)] [–9.9 (ND)]
% [mmol/mol] (95% CI) Placebo-corrected change 20.9 (–1.3 to –0.6) 21.0 (–1.4 to –0.5)
[–10.2 (–13.8 to –6.6)] [–10.7 (–15.7 to –5.7)] ND
48 Adjusted mean change 0.3 (–0.2 to 0.7) 20.7 (–1.0 to –0.5) 20.4 (ND) 21.2 (ND) 20.5 (ND) 21.1 (ND)
[2.8 (–2.3 to 7.9)] [–7.9 (–10.7 to –5.0)] [–3.8 (ND)] [–13.0 (ND)] [–5.9 (ND)] [–11.5 (ND)]
Placebo-corrected change 21.0 (–1.5 to –0.5)
[–10.7 (–16.4 to –5.0)] ND ND
FPG, mg/dL [mmol/L] (95% CI) 24 Adjusted mean change 20.5 (–5.1 to 4.0) 224.0 (–28.0 to –20.0) 21.7 (–8.0 to 4.7) 225.7 (–31.1 to –20.3) 20.3 (–7.0 to 6.3) 223.2 (–29.1 to –17.3)
[0.0 (–0.3 to 0.2)] [–1.3 (–1.6 to –1.1)] [–0.1 (–0.4 to 0.3)] [–1.4 (–1.7 to –1.1)] [0.0 (–0.4 to 0.4)] [–1.3 (–1.6 to –1.0)]
Placebo-corrected change 223.4 (–29.5 to –17.4) 224.0 (–32.3 to –15.8)] 222.9 (–31.7 to –14.0)
[–1.3 (–1.6 to –1.0)] [–1.3 (–1.8 to –0.9)] [–1.3 (–1.8 to –0.8)]
48 Adjusted mean change 13.5 (6.8 to 20.2) 219.7 (–24.8 to –14.5) 25.9 (12.8 to 39.0) 214.0 (–23.6 to –4.3) 6.3 (–1.0 to 13.7) 223.7 (–29.6 to –17.7)
[0.8 (0.4 to 1.1)] [–1.1 (–1.4 to –0.8)] [1.4 (0.7 to 2.2)] [–0.8 (–1.3 to –0.2)] [0.4 (–0.1 to 0.8)] [–1.3 (–1.6 to –1.0)]
Placebo-corrected change 233.2 (–41.6 to –24.7) 239.9 (–56.0 to –23.7) 230.0 (–39.4 to –20.6)
[–1.8 (–2.3 to –1.4)] [–2.2 (–3.1 to –1.3)] [–1.7 (–2.2 to –1.1)]
Seated SBP in patients with 24 Adjusted mean change 24.0 (–6.9 to –1.2) 25.7 (–8.2 to –3.2) 24.0 (–7.3 to –0.8) 27.1 (–10.5 to –3.8) 22.4 (–5.7 to 0.9) 26.0 (–9.5 to –2.5)
baseline seated SBP Placebo-corrected change 21.7 (–5.5 to 2.2) 23.1 (–7.7 to 1.5) 23.6 (–8.4 to 1.2)
$130 mmHg (95% CI) 48 Adjusted mean change 25.2 (–8.8 to –1.6) 25.4 (–8.2 to –2.6) 22.9 (–6.0 to 0.2) 27.0 (–10.1 to –3.8) 25.6 (–8.9 to –2.4) 23.5 (–6.8 to –0.3)
Placebo-corrected change 20.2 (–4.8 to 4.4) 24.1 (–8.5 to 0.4) 2.1 (–2.6 to 6.8)
2-h postliquid meal glucose, 24 Adjusted mean change 218.0 (–25.1 to –10.9) 244.2 (–50.1 to –38.4) 211.9 (–21.4 to –2.4) 244.5 (–52.4 to –36.5) 224.1 (–34.6 to –13.6) 244.5 (–53.1 to –35.9)
mg/dL [mmol/L] (95% CI) [–1.0 (–1.4 to –0.6)] [–2.5 (–2.8 to –2.1)] [–0.7 (–1.2 to –0.1)] [–2.5 (–2.9 to –2.0)] [–1.3 (–1.9 to –0.8)] [–2.5 (–3.0 to –2.0)]
(n = 114) (n = 166) (n = 55) (n = 78) (n = 59) (n = 88)
Placebo-corrected change 226.3 (–35.5 to –17.1) 232.6 (–45.0 to –20.2) 220.5 (–34.1 to –6.9)
[–1.5 (–2.0 to –1.0)] [–1.8 (–2.5 to –1.1)] [–1.1 (–1.9 to –0.4)]
48 Adjusted mean change 212.1 (–21.4 to –2.8) 243.0 (–49.9 to –36.0) 24.4 (–21.5 to 12.8) 238.2 (–50.5 to –25.9) 218.6 (–29.1 to –8.1) 247.2 (–55.4 to –39.1)
[–0.7 (–1.2 to –0.2)] [–2.4 (–2.8 to –2.0)] [–0.2 (–1.2 to 0.7)] [–2.1 (–2.8 to –1.4)] [–1.0 (–1.6 to –0.5)] [–2.6 (–3.1 to –2.2)]
(n = 77) (n = 138) (n = 31) (n = 60) (n = 46) (n = 78)
Placebo-corrected change 230.9 (–42.5 to –19.2) 233.8 (–55.0 to –12.6) 228.6 (–42.0 to –15.3)
[–1.7 (–2.4 to –1.1)] [–1.9 (–3.1 to –0.7)] [–1.6 (–2.3 to –0.9)]
Jabbour and Associates

Continued on p. 746
745

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746 Dapagliflozin Add-on to Sitagliptin Diabetes Care Volume 37, March 2014

patients achieving a therapeutic increase with placebo from baseline

response (reduction in HbA1c $0.7%) (76.8 [39.1] index points) to week 24
22.3 (14.7 to 30.0)

25.9 (17.8 to 33.9)

20.5 (11.5 to 29.5)
10.6 (0.9 to 20.3)
10 mg (N = 113)

because of their position in the (81.6 [43.6] index points) that was
Dapagliflozin

sequential testing hierarchy. However, maintained to week 48 (Supplementary

Sitagliptin plus metformin

numerical improvements in the two Table 1). No meaningful difference in

variables were observed at 24 weeks, insulin resistance from baseline (mean
consistent with the significant findings [SD]: placebo, 2.82 [1.31] index points;
of the glycemic variables that occurred dapagliflozin, 2.84 [1.27] index points)
earlier in the hierarchy. These was observed in subjects receiving
Placebo (N = 113)
11.8 (5.9 to 17.6)

5.4 (1.3 to 9.5)

improvements in PPG and therapeutic dapagliflozin to week 24 or 48 (–0.1 and

response were maintained through to 0.1 index points, respectively)
48 weeks (Table 3). The placebo- compared with placebo (–0.1 and 0.3
corrected change in glucose values from index points).
baseline to 2 h was –14.8 mg/dL (0.82
mmol/L) in the overall population, –16.7 Safety and Tolerability

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In the overall safety set, the proportion
37.1 (28.3 to 45.9)
22.6 (11.6 to 33.6)
26.0 (18.0 to 34.0)
21.5 (12.6 to 30.4)

mg/dL (0.93 mmol/L) in stratum 1, and

10 mg (N = 110)

N is the number of subjects in the FAS. ND, not determined. n is the number of subjects in the FAS with nonmissing baseline and week 24 or 48 value.
Dapagliflozin

–12.6 mg/dL (0.70 mmol/L) in stratum 2. of patients reporting at least one AE was
slightly higher in the dapagliflozin group
Sitagliptin monotherapy

Exploratory End Points (24 weeks, 119/225 [52.9%]; 48 weeks,

A higher proportion of subjects 149/225 [66.2%]) versus the placebo
achieved a therapeutic glycemic (24 weeks, 109/226 [48.2%]; 48 weeks,
response, defined as achieving HbA1c 138/226 [61.1%]) group.
levels ,7.0% with dapagliflozin
14.5 (7.9 to 21.0)

4.5 (0.7 to 8.4)

compared with placebo (week 24, 27.8 AEs were mostly mild or moderate.
(N = 111)
Placebo

and 17.9%, respectively; week 48, 22.1 Rates of serious AEs (SAEs) were
and 12.0%, respectively) balanced between the groups (entire
(Supplementary Table 1). A mean cohort 24 weeks: dapagliflozin, 10/225
decrease in seated SBP from baseline to [4.4%]; placebo, 9/226 [4.0%];
week 24 (LOCF) was observed with 48 weeks: dapagliflozin, 15/225 [6.7%];
29.6 (23.7 to 35.5)

25.9 (20.2 to 31.6)

21.0 (14.6 to 27.3)
16.5 (9.2 to 23.9)

placebo, 18/226 [8.0%]).

10 mg (N = 223)

dapagliflozin, with no meaningful mean

Dapagliflozin

change in seated SBP with placebo. Discontinuations due to AEs were few,
Entire primary analysis cohort

Analyses including and excluding data with rates balanced across treatments
after rescue showed similar decreases in (entire cohort 24 weeks: dapagliflozin,
seated SBP in the dapagliflozin group 7/225 [3.1%]; placebo, 5/226 [2.2%];
(–1.8 and –2.1 mmHg, respectively) and 48 weeks: dapagliflozin, 7/225 [3.1%];
no meaningful mean change in seated placebo, 7/226 [3.1%]).
Placebo (N = 224)
13.1 (8.7 to 17.5)

5.0 (2.1 to 7.8)

SBP in the placebo group (0.8 and –0.3, One death occurred in the placebo
respectively; nominal P value ,0.05, group throughout the 24-week short-
including data after rescue). term and 24-week extension periods.
Patients receiving dapagliflozin showed A 65-year-old female Caucasian subject
small increases from baseline to week died of metastatic squamous cell
24 (placebo subtracted [95% CI]) in total carcinoma on study day 117. The subject
cholesterol (3.6% [0.6–6.7]) and HDL received placebo plus sitagliptin 100 mg
Placebo corrected

Placebo corrected

(4.6% [1.8–7.4]). A small increase from in combination with metformin

Adjusted mean

Adjusted mean

baseline to week 24 was observed in LDL 2,000 mg. The SAE was assessed as not
cholesterol with dapagliflozin compared related to the study medication.
with placebo (placebo subtracted 3.6% Few events of hypoglycemia were
[–1.3 to 8.8]), and a small reduction was reported, and none led to treatment
observed in triglyceride levels from
Weeks

discontinuation. Similar numbers of

24

48

baseline to week 24 (placebo subtracted patients reported one or more

–1.9% [–8.2 to 4.8]). Results were hypoglycemic events in both groups
generally similar at 48 weeks
decrease in HbA1c $0.7%

(dapagliflozin 24 weeks 6/225 [2.7%],

Table 3—Continued

(Supplementary Table 1). 48 weeks 12/225 [5.3%]; placebo

Percent of patients with

Using HOMA-2 analysis methodology 24 weeks 4/226 [1.8%], 48 weeks

(16), subjects receiving dapagliflozin 14/226 [6.2%]). Over the 48 weeks,
showed a 24.9% increase in b-cell one event of major hypoglycemia was
(95% CI)

function from baseline (mean [SD]: 72.3 reported in the dapagliflozin group and
[37.3] index points) to week 24 (97.6 one SAE of hypoglycemia in the placebo
[45.8] index points) versus a 5.2% group.
care.diabetesjournals.org Jabbour and Associates 747

Signs, symptoms, and events suggestive

of vulvovaginitis/balanitis or urinary
tract infection (UTI) were captured
based on a list of predefined Medical
Dictionary for Regulatory Activities
(MedDRA) terms. Signs, symptoms, and
events suggestive of genital infection
(safety analysis set) were reported more
frequently in the dapagliflozin group
(24 weeks, 19/225 [8.4%]; 48 weeks,
22/225 [9.8%]) compared with placebo
(24 weeks, 1/226 [0.4%]; 48 weeks,
1/226 [0.4%]). None were assessed as
serious. One subject in the dapagliflozin

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group was discontinued from treatment
due to a vulvovaginal mycotic infection.
Three-quarters of the subjects in the
dapagliflozin group experiencing at least
one event suggestive of genital infection
or at least one AE of genital infection
were female. The majority responded to
one course of treatment; however, one
event required additional treatment
due to an inadequate response to the
initial course.
Whereas the incidence of signs,
symptoms, and events suggestive of UTI
was balanced between dapagliflozin
(24 weeks, 11/225 [4.9%]; 48 weeks,
15/225 [6.7%]) and placebo (24 weeks,
9/226 [4.0%]; 48 weeks, 14/226 [6.2%]),
the number of diagnosed events of
UTI was greater with dapagliflozin
(24 weeks, 8/225 [3.6%]; 48 weeks,
13/225 [5.8%]) compared with placebo
(24 weeks, 3/226 [1.3%]; 48 weeks,
8/226 [3.5%]). This imbalance in events
of UTI was only observed in women. No
AEs in the category of “kidney
infections” were reported throughout
the duration of the study and the
24-week extension period.
Events of hypotension/dehydration/
hypovolemia were balanced across
treatment groups over the 48-week
treatment period (three events in the
dapagliflozin group vs. two in the
placebo group). There were eight events
(3.6%) of renal laboratory parameters,
reported as AEs of renal impairment, in
the dapagliflozin group versus four
events (1.8%) in the placebo group over
the 48-week treatment period; this
Figure 1—Adjusted mean change from baseline in HbA1c over time; 24-week short-term double-
blind treatment period and 24-week extension period, excluding data after rescue for entire imbalance was due to more events of
patient population (A), sitagliptin alone (B), and sitagliptin plus metformin (C). Black circles, “decreased renal creatinine clearance”
placebo plus sitagliptin; black squares, dapagliflozin plus sitagliptin. in the dapagliflozin (four subjects) than
in the placebo group (one subject) and
reflected strict protocol-mandated
748 Dapagliflozin Add-on to Sitagliptin Diabetes Care Volume 37, March 2014

testing requirements that were based targets over time and thereby reduce other dapagliflozin studies of 1 or more
on renal laboratory parameters. AEs of the risk of acute and chronic years’ duration. In stratum 1 (treatment
renal impairment in the dapagliflozin complications. Exercise and dietary added to sitagliptin monotherapy), after
group were due to transient, reversible modifications are the cornerstone of an initial reduction, the HbA1c increased
changes in laboratory parameters that treatment. For most patients, however, over time in the dapagliflozin group
did not require treatment, consistent lifestyle interventions alone are compared with baseline, although to a
with a mild diuretic effect. There was no ineffective in achieving adequate lesser extent than that observed in the
SAE of renal impairment, and AEs glycemic control and pharmacologic placebo group; the placebo-subtracted
leading to discontinuation were intervention is required (19). Due to the change at 48 weeks in the dapagliflozin
balanced across the two treatment progressive decline in b-cell function, group was clinically significant at
groups (two with dapagliflozin and OADs can lose efficacy with prolonged 20.9%.
three with placebo). use and a progression from
The rescue rates observed over
The number of subjects with reported monotherapy to combination (dual or
48 weeks in both arms of this study were
events of neoplasms (benign, malignant, triple) therapies may be necessary (20).
comparable to rates observed with

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or unspecified) over the 24-week study The use of injectable insulin as the third-
other therapeutic agents when such
and 24-week extension was lower in the line treatment in a triple combination
strict rescue criteria, which included
dapagliflozin group (2/225) compared therapy regimen is well established;
mandating rescue of all patients with
with placebo (7/226). One event of however, there is a paucity of
HbA1c .8% at week 12, were
prostate neoplasm and one of thyroid information surrounding the
implemented (24,25). In this particular
neoplasm were reported in the concomitant use of three OADs. Oral
trial, 22% of patients receiving
dapagliflozin group (no definitive thiazolidinediones have been shown to
dapagliflozin achieved target glycemic
cytologic diagnosis was available for be effective as part of a triple
combination with a sulfonylurea and goals of HbA1c ,7% as compared with
either of these patients). Three reports 12% with placebo. Dapagliflozin causes
of basal cell carcinoma and one each of metformin (21,22). In addition,
sitagliptin significantly improved excretion of glucose in proportion to
breast cancer, endometrial cancer,
glycemic control and b-cell function hyperglycemia (and renal filtration), and
fibroma, lipoma, metastatic nevus, and
in patients with type 2 diabetes who as such, lower HbA1c is associated with
metastatic squamous cell carcinoma
had inadequate glycemic control less glucose excretion as HbA1c levels
were reported in the placebo group.
with a sulfonylurea, with or without approach goal. This may also explain the
At week 48, an absolute increase from low rate of hypoglycemia observed with
metformin (23).
baseline in mean hematocrit was this novel therapy.
observed with dapagliflozin (2.2%) The unique mechanism of action of
dapagliflozin, involving the inhibition of Overall, the findings in this study
compared with placebo (–0.5%). Over
SGLT2, is not dependent on the ability of support the value of this novel
48 weeks, there was one case of alanine
the pancreatic b-cells to secrete insulin. mechanism as a treatment for type 2
aminotransferase and/or aspartate
diabetes that is complementary to other
aminotransferase .3 3 the upper limit Thus, dapagliflozin may be an
appropriate choice for a wide range of agents and effective across different
of normal (ULN) in combination with
total bilirubin .1.5 3 ULN in the patients at different stages of type 2 stages of disease.
placebo group and none in the diabetes, including those in the This is the first published study
dapagliflozin group. One case of alanine advanced stages of the disease with evaluating the efficacy and safety of a
aminotransferase .5 3 ULN and one of significantly compromised b-cell triple oral combination therapy that
aspartate aminotransferase .5 3 ULN function who are already receiving one includes dapagliflozin. Reductions in
was observed in each treatment group or more OADs. HbA1c and body weight with
over 48 weeks. There were no clinically The results presented here indicate that dapagliflozin were observed in patients
meaningful mean changes in serum the addition of dapagliflozin to ongoing receiving sitagliptin either alone or in
levels of potassium, sodium, therapy in patients with type 2 diabetes combination with metformin. Slightly
magnesium, calcium, parathyroid inadequately controlled with sitagliptin, greater numerical reductions in HbA1c
hormone, or creatinine. with or without metformin, was well were observed in the sitagliptin
There was a decrease in serum uric acid tolerated over 48 weeks. Glycemic monotherapy stratum than in the
with dapagliflozin (mean [SE], including parameters and body weight were sitagliptin plus metformin stratum; this
data after rescue: 24 weeks, –0.75 [0.06] significantly improved with result was likely due to natural
mg/dL; 48 weeks, –0.76 [0.07] mg/dL) dapagliflozin treatment and were variability given the overlap in 95% CIs
versus placebo (24 weeks, 0.03 [0.06] maintained through the duration of the between comparable treatment groups.
mg/dL; 48 weeks, 0.10 [0.07] mg/dL). study compared with placebo. In The slightly lower baseline HbA1c in the
stratum 2 (treatment added to sitagliptin plus metformin stratum may
CONCLUSIONS metformin and sitagliptin), the HbA1c also have contributed to the observed
Although there is no single approach to change was maintained over time in the findings. In addition, a more advanced
the treatment of type 2 diabetes, the dapagliflozin group compared with stage of disease may have been
overall goal is to maintain glycemic baseline,consistent with findings in encountered in patients receiving both
care.diabetesjournals.org Jabbour and Associates 749

sitagliptin and metformin and this may antihypertensive medication Association for the Study of Diabetes.
also have contributed to the slightly adjustment was allowed prior to Diabetes Care 2009;32:193–203
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Although the efficacy of dapagliflozin with reductions in BP in both the
dapagliflozin and placebo treatment 3. Chao EC, Henry RR. SGLT2 inhibitionda
has not been found to be affected by novel strategy for diabetes treatment. Nat
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glomerular filtration rate, which may be lowering with dapagliflozin. In the
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lower in patients with more advanced mechanisms of Na(+)/glucose
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disease.
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added to sitagliptin with or without meaningful reductions in glycemic List JF. Dapagliflozin monotherapy in type 2
metformin. From a safety perspective, diabetic patients with inadequate glycemic
parameters and body weight that were control by diet and exercise: a randomized,
reports of signs, symptoms, and events sustained through 48 weeks of double-blind, placebo-controlled, phase 3
suggestive of genital infections and treatment. trial. Diabetes Care 2010;33:2217–2224
reports of diagnosed UTIs were elevated 8. List JF, Woo V, Morales E, Tang W, Fiedorek
in patients receiving dapagliflozin and FT. Sodium-glucose cotransport inhibition
were consistent with the known with dapagliflozin in type 2 diabetes.
mechanism of action. A small imbalance Acknowledgments. Medical writing Diabetes Care 2009;32:650–657
assistance was provided by K. Pemberton, PhD,
in events of renal impairment was 9. Bailey CJ, Gross JL, Pieters A, Bastien A, List
of PPSI (a PAREXEL company, Hackensack, NJ).
observed in this study, although such an JF. Effect of dapagliflozin in patients with
Duality of Interest. This study was funded by type 2 diabetes who have inadequate
imbalance was not observed in the AstraZeneca and Bristol-Myers Squibb. S.A.J. glycaemic control with metformin:
general population in the overall belongs to speakers’ bureaus for Eli Lilly and a randomised, double-blind, placebo-
dapagliflozin program. These events Company and Amylin. E.H., S.P., and J.S. are controlled trial. Lancet 2010;375:2223–
were due to transient, reversible, stockholders and/or employees of AstraZeneca. 2233
Medical writing assistance was funded by
nonserious changes in laboratory Bristol-Myers Squibb and AstraZeneca. No other 10. Nauck MA, Del Prato S, Meier JJ, et al.
parameters that did not require potential conflicts of interest relevant to this Dapagliflozin versus glipizide as add-on
therapy in patients with type 2 diabetes
treatment, consistent with a mild article were reported.
who have inadequate glycemic control with
diuretic effect. Small changes in total Author Contributions. S.A.J. and E.H. metformin: a randomized, 52-week,
cholesterol, HDL cholesterol, LDL researched data, contributed to the discussion, double-blind, active-controlled
and wrote, reviewed, and edited the noninferiority trial. Diabetes Care 2011;34:
cholesterol, and triglycerides were
manuscript. J.S. and S.P. researched data, 2015–2022
observed with dapagliflozin compared contributed to the discussion, and reviewed and
with placebo that were unlikely to be edited the manuscript. S.A.J. is the guarantor of 11. Strojek K, Yoon KH, Hruba V, Elze M,
clinically relevant. this work and, as such, had full access to all the Langkilde AMPS, Parikh S. Effect of
data in the study and takes responsibility for dapagliflozin in patients with type 2 diabetes
In previously published trials, BP the integrity of the data and the accuracy of the who have inadequate glycaemic control with
reductions consistent with diuretic data analysis. glimepiride: a randomized,
effects of dapagliflozin have been 24-week, double-blind, placebo-controlled
Prior Presentation. Parts of this study were
trial. Diabetes Obes Metab 2011;13:928–938
observed with monotherapy and in presented at the 72nd Scientific Sessions of the
American Diabetes Association, Philadelphia, 12. Henry R, Murray A, Marmolejo MH,
combination with insulin sensitizers and
PA, 8–12 June 2012. Hennicken D, Ptaszynska A, List JF.
metformin (7–11,13). In patients with Dapagliflozin, metformin-XR, or both
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