Dia Care 2010 Ferrannini 2217 24

Dapagliflozin Monotherapy in Type 2Diabetic Patients With InadequateGlycemic Control by Diet and ExerciseA randomized, double-blind, placebo-controlled, phase 3 trial

ELE FERRANNINI, MD1

SILVIA JIMENEZ RAMOS, MD2

AFSHIN SALSALI, MD3

WEIHUA TANG, PHD4

JAMES F. LIST, MD, PHD3

OBJECTIVE — Dapagliflozin, a highly selective inhibitor of the renal sodium-glucose co-transporter-2, increases urinary excretion of glucose and lowers plasma glucose levels in aninsulin-independent manner. We evaluated the efficacy and safety of dapagliflozin in treatment-naive patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS — This was a 24-week parallel-group, dou-ble-blind, placebo-controlled phase 3 trial. Patients with A1C 7.0 –10% (n � 485) wererandomly assigned to one of seven arms to receive once-daily placebo or 2.5, 5, or 10 mgdapagliflozin once daily in the morning (main cohort) or evening (exploratory cohort).Patients with A1C 10.1–12% (high-A1C exploratory cohort; n � 73) were randomly as-signed 1:1 to receive blinded treatment with a morning dose of 5 or 10 mg/day dapagliflozin.The primary end point was change from baseline in A1C in the main cohort, statisticallytested using an ANCOVA.

RESULTS — In the main cohort, mean A1C changes from baseline at week 24 were �0.23%with placebo and �0.58, �0.77 (P � 0.0005 vs. placebo), and �0.89% (P � 0.0001 vs.placebo) with 2.5, 5, and 10 mg dapagliflozin, respectively. Signs, symptoms, and other reportssuggestive of urinary tract infections and genital infection were more frequently noted in thedapagliflozin arms. There were no major episodes of hypoglycemia. Data from exploratorycohorts were consistent with these results.

CONCLUSIONS — Dapagliflozin lowered hyperglycemia in treatment-naive patients withnewly diagnosed type 2 diabetes. The near absence of hypoglycemia and an insulin-independentmechanism of action make dapagliflozin a unique addition to existing treatment options for type2 diabetes.

Diabetes Care 33:2217–2224, 2010

The need for optimal management ofglycemia in patients with type 2 di-abetes has long been recognized,

owing to the well-established associationbetween sustained hyperglycemia and se-rious microvascular complications in-cluding retinopathy, neuropathy, andnephropathy (1). However, because met-abolic risk factors frequently occur as a

cluster, it is difficult to control glycemia inpatients with type 2 diabetes without neg-atively affecting one or more of the asso-ciated risk factors of hypertension,obesity, and hyperlipidemia. This fact isexemplified by the treatment-limitingside effects of many available antidiabetesagents, particularly in patients with alonger duration of disease (2–5). Sulfo-

nylureas, thiazolidinediones, and insulinare all associated with weight gain in pa-tients with diabetes (6,7). Negative effectson associated metabolic risk factors arenot limited to antidiabetes agents; as anexample, treatment of hypertension withthiazides is associated with increased uricacid levels and a worsening of hypergly-cemia (8–10). In addition to the deleteri-ous effect on metabolic comorbidities andfor some agents an increased risk of hy-poglycemia, treatment with most antidia-betes agents is further confounded by aloss of efficacy over time, in part due tothe progressive worsening of diabetescharacterized by insulin resistance andimpaired glucose-stimulated insulinsecretion (11).

An on-going effort to identify newtreatment strategies for diabetes has led tothe development of dapagliflozin, the firstin a class of compounds referred to as so-dium-glucose cotransporter 2 (SGLT2)inhibitors. SGLT2 is located almost exclu-sively in the kidney proximal tubuleswhere it reabsorbs most of the �180 g ofglucose that is filtered through the glo-meruli each day. Dapagliflozin is a highlyselective and reversible inhibitor ofSGLT2. A prolonged pharmacokinetichalf-life due to the C-aryl glucoside-derived chemical structure, as well as anearly 3,000-fold selectivity for SGLT2versus SGLT1, make it possible for dapa-gliflozin to be administered in an unmod-ified oral form without affecting SGLT1-mediated glucose transport in othertissues (12–14). Dapagliflozin can inhibitup to one-half of the filtered glucose frombeing reabsorbed by the kidney, resultingin a dose-dependent increase in urinaryglucose excretion and, ultimately, im-provement in glycemic parameters (15–18). Also relevant here are observationsthat the renal reabsorptive capacity forglucose may be increased in patients withdiabetes (19,20). On the basis of thesefindings, we conducted a phase 3 trial ofdapagliflozin, administered as mono-therapy for 24 weeks to treatment-naive

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

From the 1Department of Internal Medicine, University of Pisa School of Medicine, Pisa, Italy; the 2HospitalJardines De Guadalupe, Guadalajara, Mexico; 3Bristol-Myers Squibb, Princeton, New Jersey; and 4Bristol-Myers Squibb, Hopewell, New Jersey.

Corresponding author: Ele Ferrannini, [email protected] 30 March 2010 and accepted 14 June 2010. Published ahead of print at http://care.

diabetesjournals.org on 21 June 2010. DOI: 10.2337/dc10-0612. Clinical trial reg. no. NCT00528372,clinicaltrials.gov.

© 2010 by the American Diabetes Association. Readers may use this article as long as the work is properlycited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be herebymarked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

E m e r g i n g T r e a t m e n t s a n d T e c h n o l o g i e sO R I G I N A L A R T I C L E

care.diabetesjournals.org DIABETES CARE, VOLUME 33, NUMBER 10, OCTOBER 2010 2217

patients with type 2 diabetes. Here we re-port results from the study.

RESEARCH DESIGN ANDMETHODS — Men and women withtype 2 diabetes, aged 18–77 years, wereenrolled between September 2007 andJuly 2008 at 85 sites in the U.S., Canada,Mexico, and Russia. Eligible patients weretreatment-naive subjects whose hypergly-cemia was inadequately controlled withdiet and exercise alone. Entry criteria in-cluded BMI �45 kg/m2 and fasting C-peptide �1.0 ng/ml. Patients wereexcluded if they had a history of type 1diabetes, serum creatinine �133 �mol/l(men) or �124 �mol/l (women), urinealbumin-to-creatinine ratio �200 mg/mmol, aspartate transaminase and/or ala-nine transaminase �3 times the upperlimits of normal, creatine kinase �3 timesthe upper limit of normal, symptoms ofseverely uncontrolled diabetes (includingmarked polyuria and polydipsia with�10% weight loss during the last 3months before enrollment); significant re-

nal, hepatic, hematological, oncological,endocrine, psychiatric, or rheumatic dis-eases, a cardiovascular event (includingNew York Heart Association class III/IVcongestive heart failure) within 6 monthsof enrollment, and severe uncontrolledblood pressure (systolic blood pressure�180 mmHg and/or diastolic blood pres-sure �110 mmHg).

This was a 24-week randomized, par-allel-group, double-blind, placebo-controlled phase 3 trial with a 2-weekdiet/exercise placebo lead-in (1 week forpatients with enrollment A1C 10.1–12.0%). The respective institutional re-view board or independent ethicscommittee approved the study protocol,and all patients gave informed consent.Patients with A1C 7.0–10% were ran-domly assigned equally to one of sevenarms to receive once-daily placebo or 2.5,5, or 10 mg dapagliflozin, administeredonce daily either in the morning (maincohort) or evening (exploratory cohort)for 24 weeks. Patients with A1C 10.1–12% (high-A1C exploratory cohort) were

assigned randomly in a 1:1 ratio to receiveblinded treatment with a morning dose of5 or 10 mg/day dapagliflozin (a placebogroup was not included because of thehigh A1C levels). Patients with fastingplasma glucose (FPG) �270 mg/dl atweek 4, �240 mg/dl at week 8, or �200mg/dl at weeks 12–24 were eligible foropen-label rescue medication (500 mg met-formin, titrated as needed up to 2,000 mg).Patients with A1C �8.0% for 12 weeks de-spite a maximum tolerated metformin dosewere discontinued. Throughout the study,patients received diet/exercise counselingper American Diabetes Associationrecommendations.

End points and assessmentsThe primary efficacy end point waschange from baseline in A1C at week 24in the main patient cohort. Secondary ef-ficacy measures included change frombaseline at week 24 in FPG and bodyweight. Efficacy measures assessed in theexploratory evening dose and high-A1Ccohorts included change from baseline at

Figure 1—Patient disposition.

Dapagliflozin in type 2 diabetes

2218 DIABETES CARE, VOLUME 33, NUMBER 10, OCTOBER 2010 care.diabetesjournals.org

week 24 in A1C, FPG, and body weight.For patients requiring rescue medication,data obtained after rescue were excludedfrom efficacy analyses. Fractional renalglucose excretion was calculated as theratio of urine to plasma glucose multi-plied by the ratio of plasma to urinecreatinine.

Safety assessments included vitalsigns, laboratory measurements, and ad-verse events (coded using preferred termsof the Medical Dictionary for RegulatoryActivites [MedDRA version 11.1]). In ad-dition, at each visit, patients were activelymonitored for clinical signs and symp-toms suggestive of urinary tract infections(UTIs) and genital infections. UTIs andgenital infections are reported here as anadverse event of special interest and in-clude any of the prospectively defined 20preferred terms relating to possible upperUTI events, 44 preferred terms relating topossible non–upper UTI events, and 49preferred terms relating to possible geni-tal infections (including bacterial and my-cotic infections). Patients were instructedto self-monitor their blood glucose dailyand to report any unusually high or lowblood glucose event or any symptomssuggestive of hypoglycemia.

Statistical analysisAnalyses of change from baseline inA1C, FPG, and body weight were per-formed using an ANCOVA with treat-ment group as effect and baseline valueas covariate. Point estimates and 95%CI were calculated for the mean changefrom baseline within each treatmentgroup as well as for the difference inmean change from baseline betweentreatment groups. Per the study design,no P values were generated for endpoints in exploratory cohorts.

RESULTS — A total of 485 patientswere randomly assigned to the mainmorning dose and exploratory eveningdose cohorts (Fig. 1). In addition, 74patients were randomly assigned to theexploratory, high-A1C cohort, of which73 patients took at least one dose ofstudy medication. Demographic andbaseline characteristics are shown inTable 1.

In the main cohort, mean A1C reduc-tions were dose ordered and apparent byweek 4 and maintained thereafter (Fig.2A). Mean A1C reductions from baselineat week 24 in the main cohort rangedfrom �0.58 to �0.89% with dapagliflo-zin compared with �0.23% with pla-

Table

1—D

emographics

andbaseline

characteristics

Placebo

Primary

cohortE

xploratorycohorts

Dapagliflozin

morning

doseD

apagliflozinevening

doseD

apagliflozinm

orningdose

(A1C

�10.1)

2.5m

g5

mg

10m

g2.5

mg

5m

g10

mg

5m

g10

mg

n75

6564

7067

6876

3439

Age

(years)52.7

�10.3

53.0�

11.752.6

�10.9

50.6�

9.9754.3

�11.5

54.5�

11.050.7

�9.7

48.3�

9.347.9

�12.1

Men

31(41.3)

36(55.4)

31(48.4)

34(48.6)

29(43.3)

29(42.6)

39(51.3)

24(70.6)

23(59.0)

Wom

en44

(58.7)29

(44.6)33

(51.6)36

(51.4)38

(56.7)39

(57.4)37

(48.7)10

(29.4)16

(41.0)A

1C(%

)7.84

�0.87

7.92�

0.907.86

�0.94

8.01�

0.967.99

�0.99

7.82�

0.917.99

�1.05

10.82�

0.9310.73

�0.85

FPG(m

g/dl)159.9

�42.1

164.1�

48.0162.2

�45.0

166.6�

41.5160.6

�45.9

157.0�

50.9168.1

�57.9

231.6�

65.1241.2

�65.7

Weight

(kg)88.8

�19.0

90.8�

22.887.6

�17.1

94.2�

18.788.3

�20.5

89.2�

20.592.1

�22.0

88.7�

19.287.5

�22.7

BMI

(kg/m2)*

32.3�

5.532.6

�5.5

31.9�

4.833.6

�5.4

32.2�

5.332.8

�5.3

33.3�

5.632.6

�4.6

31.1�

5.9D

iabetesduration

(years)0.50

(0.10,3.40)0.50

(0.1,2.90)0.25

(0.10,1.40)0.45

(0.10,3.40)0.20

(0.10,1.20)0.50

(0.15,2.20)0.40

(0.10,2.45)0.65

(0.20,2.50)1.40

(0.20,3.50)

Data

arem

eans�

SD,n

(%),or

median

(quartile1,quartile

3).*Mean

baselinevalue

forpatients

who

haveat

leastone

postbaselineBM

Im

easurement.

Ferrannini and Associates


cebo. The reductions were statisticallysignificant with 5 and 10 mg dapagliflozin(P � 0.0005 and P � 0.0001, respec-tively, vs. placebo). At the end of study, ahigher proportion of patients in dapagli-flozin arms reached the American Diabe-tes Association/European Association forthe Study of Diabetes target A1C of �7%(41, 44, and 51% with 2.5, 5, and 10 mgdapagliflozin, respectively, vs. 32% withplacebo).

Reductions in FPG were apparent asearly as week 1. Throughout the study,FPG reductions were more marked in 5and 10 mg dapagliflozin arms and werestatistically significant at week 24 (Fig.2B, Table 2). Mean body weight decreaseswere greater with all dapagliflozin dosesthan with placebo, although they didnot reach statistical significance (Fig.3C, Table 2).

In the exploratory evening dose co-hort, changes from baseline in A1C, FPG,and body weight at week 24 were similarto those seen in the main patient cohort(Table 2). In the exploratory high-A1Ccohort (10.1–12% at enrollment), treat-ment with dapagliflozin for 24 weeks ledto numerically greater reductions in meanA1C and FPG from baseline than thoseobserved in other cohorts (Table 2). Sub-group analyses of the main patient cohortby baseline A1C were consistent with theability of dapagliflozin to cause greaterA1C reductions in patients with highbaseline A1C. In patients with baselineA1C �9%, changes in mean A1C frombaseline at week 24 were �1.23 � 0.98,�1.98 � 0.90, and �1.90 � 0.79% with2.5, 5, and 10 mg dapagliflozin groups,respectively, compared with 0.16 �2.50% with placebo.

Treatment with dapagliflozin did notresult in any clinically meaningfulchanges from baseline in serum electro-lytes including serum sodium (Table 2).There were no clinically relevant changesin any renal function parameter includingserum creatinine, blood urea nitrogen, orcystatin C. In addition, there were no clin-ically relevant changes in mean serum al-bumin with dapagliflozin treatment.Small, numerical decreases from baselinein high-sensitivity C-reactive protein(placebo-subtracted adjusted meanchange from baseline value [SE] rangedfrom �1.53 [1.06] to �2.67 [1.10] mg/l)and serum uric acid were observed inmost dapagliflozin arms. Small, dose-ordered mean increases in hematocrit (upto 2.4%) were observed with dapagliflo-zin. A decrease in mean seated blood

Figure 2—Changes in glycemic parameters over time. A: Mean change from baseline in A1C afteradjustment for baseline value. B: Mean change from baseline in FPG after adjustment for baselinevalue. C: Mean change from baseline in body weight after adjustment for baseline value. Error barsrepresent 95% CIs.



Table

2—C

hangesfrom

baselineat

week

24in

efficacy

parameters,vitalsigns,and

laboratoryvalues

Placebo

Primary

cohortE

xploratorycohorts

Dapagliflozin

morning

doseD

apagliflozinevening

doseD

apagliflozinm

orningdose

(A1C

�10.1)

2.5m

g5

mg

10m

g2.5

mg

5m

g10

mg

5m

g10

mg

n75

6564

7067

6876

3439

A1C

(%)*†

�0.23

�0.10

�0.58

�0.11

�0.77

�0.11¶

�0.89

�0.11#

�0.83

�0.11

�0.79

�0.11

�0.79

�0.10

�2.88

�1.41‡

�2.66

�1.26‡

FPG(m

g/dl)*†�

4.1�

3.9�

15.2�

4.2�

24.1�

4.3¶�

28.8�

4.0#�

25.6�

4.1�

27.3�

4.2�

29.6�

4.0�

77.1�

53.4‡�

84.3�

61.0‡W

eight(kg)*†

�2.2

�0.4

�3.3

�0.5

�2.8

�0.5

�3.2

�0.5

�3.8

�0.5

�3.6

�0.5

�3.1

�0.4

�2.1

�3.4‡

�1.9

�3.5‡

Urinary

glucose:creatinine

(g/g)§�0.96

�2.87

12.12�

2.9817.68

�3.28

33.80�

3.0824.24

�3.07

38.00�

3.0945.80

�2.86

NA

NA

VitalsignsSeated

systolicblood

pressure(m

mH

g)§�

0.9�

1.8�

4.6�

1.8�

2.3�

1.9�

3.6�

1.9�

4.0�

2.3�

5.2�

1.7�

2.3�

1.4�

5.7�

2.1�

2.5�

2.1Seated

diastolicblood

pressure(m

mH

g)§�

0.7�

1.0�

2.8�

1.1�

1.7�

1.1�

2.0�

1.1�

3.2�

1.2�

2.0�

1.1�

1.0�

1.0�

3.3�

1.6�

2.9�

1.5Laboratory

valuesSerum

creatinine(�

mol/l)§

�0.4

�0.9

�0.6

�1.3

�2.0

�1.4

�1.1

�1.0

�0.5

�0.9

1.8�

0.9�

1.9�

1.70.0

�1.2

0.6�

1.4Serum

albumin

(g/l)§�

0.1�

0.30.6

�0.4

0.3�

0.40.9

�0.3

0.0�

0.31.0

�0.4

1.3�

0.30.4

�0.5

0.7�

0.4C

ystatinC

(mg/l)§

�0.014

�0.012

�0.009

�0.014

0.005�

0.014�

0.003�

0.0160.014

�0.012

0.024�

0.009�

0.015�

0.0260.070

�0.025

�0.045

�0.063

Hem

atocrit(%

)§�

0.38�

0.251.60

�0.33

1.74�

0.402.38

�0.44

1.23�

0.261.92

�0.30

2.41�

0.300.77

�0.57

1.88�

0.42Serum

uricacid

(�m

ol/l)†§�

11.9�

5.6�

39.3�

6.0�

50.6�

6.1�

51.7�

5.8�

59.5�

5.9�

43.4�

6.0�

49.4�

5.6N

AN

ABlood

ureanitrogen

(mm

ol/l)§0.2

�0.2

0.6�

0.20.6

�0.2

0.4�

0.20.6

�0.2

0.7�

0.20.4

�0.2

0.6�

0.20.9

�0.3

Serumelectrolytes§

Sodium(m

mol/l)

�0.1

�0.3

�0.1

�0.3

�0.9

�0.4

�0.4

�0.4

�0.1

�0.3

�0.2

�0.3

0.1�

0.31.7

�0.6

0.5�

0.5Potassium

(mm

ol/l)�

0.03�

0.06�

0.05�

0.050

�0.05

�0.01

�0.06

�0.03

�0.06

�0.09

�0.05

�0.08

�0.06

�0.05

�0.08

�0.02

�0.06

Calcium

(mm

ol/l)0.01

�0.01

0.03�

0.020.00

�0.02

0.03�

0.010.01

�0.01

0.04�

0.020.04

�0.02

NA

NA

Magnesium

(mm

ol/l)�

0.25�

0.180

�0.20

0.50�

0.260

�0.26

0�

0.250.15

�0.22

�0.20

�0.27

NA

NA

Inorganicphosphorus

(mm

ol/l)�

0.01�

0.020.01

�0.02

0.04�

0.030.05

�0.02

0.04�

0.020.08

�0.02

0.06�

0.020.04

�0.03

0.07�

0.02

Data

arem

eans�

SEM

unlessotherw

iseindicated.N

A,notassessed.*A

ssessedin

patientsw

ithoutmissing

baselineand

week

24values

with

lastobservationcarried

forward.†M

eanvalue

afteradjustmentforbaseline

value.‡Data

arem

eans�

SD.§A

ssessedin

patientsw

ithoutm

issingbaseline

andw

eek24

values.�Ratio

fromm

orningfasting

spoturine

test.¶P�

0.001;#P�

0.0001(�

�0.019

two-sided

applying

Dunnett

adjustment;secondary

endpoints

were

testedusing

asequentialprocedure).



pressure with no notable increase in or-thostatic hypotension was observed in thedapagliflozin arms (Table 2). Rates of hy-potension/dehydration/hypovolemiawere similar among placebo and dapagli-flozin arms. Treatment with dapagliflozindid not alter the lipid profile of patients,although small numerical increases inHDL cholesterol were noted in all dapa-gliflozin arms (placebo-subtracted ad-justed mean change from baseline value[SE] ranged from 0.02 [0.07] to 0.17[0.08] mmol/l).

Glucose-to-creatinine ratios werehigher with dapagliflozin than with pla-cebo (Table 2). Higher values with theevening dose presumably reflect the phar-macokinetic half-life of dapagliflozin. Inpooled data from the morning andevening cohorts, changes from baseline infractional renal glucose excretion at week24 were significantly related (r � �0.13,P � 0.008) with the correspondingchanges in body weight, such that acrossall study arms greater renal glucose losseswere associated with larger decrements inbody weight. A similar trend was foundfor changes in glucose excretion andchanges in A1C (P � 0.11).

Adverse events are summarized in

Table 3. There was one death due to amotor vehicle accident in the 10 mgdapagliflozin group. There were no ma-jor episodes of hypoglycemia in thisstudy, and none of the patients discon-tinued the study medication due to hy-poglycemia. An increased incidence insigns and symptoms and other reportssuggestive of UTIs and genital infec-tions was noted with dapagliflozin treat-ment. Safety data in the exploratoryevening dose cohort were similar tothose in the morning dose cohort. Asmall number of patients (n � 6) expe-rienced nocturia with the evening dose(one, two, and three patients in the 2.5,5 or 10 mg dapagliflozin evening dosearms, respectively, and none with themorning dose). There were no other no-table differences in the number or typeof adverse events reported with theevening dose.

CONCLUSIONS — Administrationof dapagliflozin as monotherapy to treat-ment-naive patients with type 2 diabetesresulted in clinically meaningful de-creases in A1C and FPG, along with favor-able effects on weight, blood pressure,and other metabolic parameters. Al-

though the decrease in body weight in ourstudy did not reach statistical significancecompared with placebo, dapagliflozintreatment did lead to increased renal glu-cose excretion. This glucose excretionpersisted for the full 24-week study pe-riod and was consistent with the urinaryloss of �200 –300 calories/day as re-ported previously (17). A factor that mayhave lessened the effect of dapagliflozinon weight was the large placebo effect inthis study, which was probably due to agreater impact of diet/exercise counselingon motivated patients with newly diag-nosed diabetes in a clinical trial setting. Itshould also be noted that the progressivedecrease in weight over time had notreached a plateau by the end of study;thus, long-term studies are needed tomore precisely gauge the effect of dapagli-flozin on weight in the monotherapy set-ting. Furthermore, in exploratory analysisof pooled data greater increments in frac-tional renal glucose excretion were asso-ciated with greater decrements in bodyweight, suggesting a link between themechanism of action of dapagliflozin andclinical outcome.

Data from the high-A1C cohort are ofparticular relevance given the mechanism

Table 3—Adverse events

Placebo

Primary cohort Exploratory cohorts

Dapagliflozin morning dose Dapagliflozin evening dose

Dapagliflozinmorning dose(A1C �10.1)#

2.5 mg 5 mg 10 mg 2.5 mg 5 mg 10 mg 5 mg 10 mg

n 75 65 64 70 67 68 76 34 39AEsAt least one AE 45 (60.0) 41 (63.1) 37 (57.8) 48 (68.6) 45 (67.2) 44 (64.7) 45 (59.2) 27 (79.4) 28 (71.8)At least one serious AE 3 (4.0) 0 1 (1.6) 1 (1.4) 1 (1.5) 1 (1.5) 1 (1.3) 0 0Discontinuation for AE 1 (1.3) 2 (3.1) 3 (4.7) 5 (7.1) 0 4 (5.9) 3 (3.9) 0 0Discontinuation for serious AE 0 0 1 (1.6) 0 0 1 (1.5) 1 (1.3) 0 0Most common AEs (�10% in any group)

by MedDRA preferred term*Nasopharyngitis 4 (5.3) 7 (10.8) 3 (4.7) 2 (2.9) 7 (10.4) 5 (7.4) 4 (5.3) 4 (11.8) 4 (10.3)Diarrhea 1 (1.3) 4 (6.2) 1 (1.6) 1 (1.4) 3 (4.5) 7 (10.3) 3 (3.9) 2 (5.9) 1 (2.6)Headache 5 (6.7) 5 (7.7) 3 (4.7) 4 (5.7) 3 (4.5) 9 (13.2) 9 (11.8) 5 (14.7) 6 (15.4)

Events by special interest categoryHypoglycemia† 2 (2.7) 1 (1.5) 0 2 (2.9) 1 (1.5) 0 1 (1.3) 1 (2.9) 0Events suggestive of UTIs‡ 3 (4.0) 3 (4.6) 8 (12.5) 4 (5.7) 5 (7.5) 8 (11.8) 5 (6.6) 3 (8.8) 6 (15.4)Events suggestive of genital infections§ 1 (1.3) 5 (7.7) 5 (7.8) 9 (12.9) 6 (9.0) 3 (4.4) 2 (2.6) 2 (5.9) 7 (17.9)Hypotensive events 1 (1.3) 0 0 1 (1.4) 3 (4.5) 0 0 1 (2.9) 1 (2.6)

Data are n (%) and include data after rescue. *Additional adverse events (AEs) with �5% incidence in any of the primary cohort and exploratory evening dose armswere arthralgia, pharyngitis, upper respiratory infection, UTI, back pain, dizziness, constipation, influenza, myalgia, peripheral edema, pain in extremity, andinsomnia. †None of the hypoglycemic events led to discontinuation from the study, and none was a major episode, defined as a symptomatic episode requiringthird-party assistance due to severe impairment in consciousness or behavior, with a capillary or plasma glucose value �54 mg/dl, and prompt recovery after glucoseor glucagon administration. ‡These events included signs, symptoms, and other reports suggestive of UTIs. §These events included signs, symptoms, and otherreports suggestive of genital infections. #Not placebo controlled.



of action of dapagliflozin as an SGLT2 in-hibitor. Patients with high A1C at enroll-ment are likely already to present withglycosuria as their filtered glucose loadmay exceed the absorption capacity of thekidney. However, dapagliflozin was ableto elicit a considerable improvement inglycemia in the exploratory high-A1C co-hort. Results from subgroup analysis ofpatients with baseline A1C �9% werealso consistent with the observation thatdapagliflozin continues to be efficaciousin patients who present with higher A1Clevels.

There were no major episodes of hy-poglycemia in this study. After prospec-tively defined monitoring (see RESEARCH

DESIGN AND METHODS), signs and symptomssuggestive of UTIs and genital infectionswere more frequently reported in thedapagliflozin arms. The reported signs/symptoms/events of UTIs and genital in-fections resolved with standard care andrarely led to discontinuation.

The decrease in mean systolic and di-astolic blood pressure noted in this studyis in keeping with the diuretic effect ofdapagliflozin. Also consistent with this ef-fect is the increase in hematocrit levelsnoted in the dapagliflozin arms. In addi-tion to blood pressure, favorable, albeitsmall, effects were also noted in severalother clinical parameters including HDLcholesterol, uric acid, and high-sensitivityC-reactive protein. Although effects onweight, blood pressure, and other meta-bolic risk factors were small, they mayhave a cumulative benefit in the longterm.

Most notably, lowering of plasma glu-cose with dapagliflozin is accompaniedby a urinary loss of calories, suggesting ashift toward negative net energy balance.This effect of dapagliflozin is unlike thatof other antidiabetic agents, which oftencause weight gain as they lower plasmaglucose concentrations. Given its effect onnet energy balance and its insulin-independent mechanism, dapagliflozin islikely to have beneficial effects in a widespectrum of patients with diabetes(17,18).

Acknowledgments— This study was fundedby Bristol-Myers Squibb and AstraZeneca.

E.F. has attended advisory board meetingsand has consulted for Bristol-Myers Squibband AstraZeneca. S.J.R. was a trialist for thisstudy. No other potential conflicts of interestrelevant to this article were reported.

E.F. analyzed and interpreted data, contrib-uted to writing of the manuscript, and re-

viewed/edited the manuscript. S.J.R. obtaineddata and reviewed the manuscript. A.S. de-signed the study, acquired data, analyzed andinterpreted data, contributed to writing of themanuscript, and reviewed/edited the manu-script. W.T. analyzed and interpreted data,performed statistical analysis and verifieddata, contributed to writing of the manuscript,and reviewed/edited the manuscript. J.F.L. de-signed the study, analyzed and interpreteddata, contributed to writing of the manuscript,and reviewed/edited the manuscript.

Parts of this study were presented in ab-stract form at the 20th World Diabetes Con-gress, Montreal, Quebec, Canada, 18 –22October 2009.

We thank the investigators and contributorsfrom each of the study sites. We also thankSudha Vemuri, Ph.D., an employee of Bristol-Myers Squibb, for her writing and editorialsupport.

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