Exploring the Potential of theSGLT2 Inhibitor Dapaglif lozin inType 1 Diabetes A RandomizedDouble-Blind Placebo-ControlledPilot StudyDiabetes Care 201538412ndash419 | DOI 102337dc13-2955

OBJECTIVE

Insulin adjustments to maintain glycemic control in individuals with type 1 di-abetes often lead to wide glucose fluctuations hypoglycemia and increased bodyweight Dapagliflozin an insulin-independent sodiumndashglucose cotransporter 2(SGLT2) inhibitor increases glucosuria and reduces hyperglycemia in individualswith type 2 diabetes The primary objective of this study was to assess short-termsafety of dapagliflozin in combination with insulin secondary objectives includedpharmacokinetic pharmacodynamic and efficacy parameters

RESEARCH DESIGN AND METHODS

A 2-week dose-ranging randomized double-blind placebo-controlled proof-of-concept study randomly assigned 70 adultswith type 1 diabetes (HbA1c 7ndash10)whowere receiving treatment with stable doses of insulin to one of four dapagliflozindoses (1 25 5 or 10mg) or placebo The insulin dosewas not proactively reduced atrandomization but could be adjusted for safety reasons

RESULTS

Sixty-two patients (886) completed the study Any hypoglycemia was commonacross all treatments (600ndash923) one major event of hypoglycemia occurredwith dapagliflozin 10 mg No diabetic ketoacidosis occurred Pharmacokineticparameters were similar to those observed in patients with type 2 diabetesGlucosuria increased by 88 g24 h (95 CI 55 to 121) with dapagliflozin 10 mg anddecreased by 2215 g24 h (95 CI 2539 to 110) with placebo Changes frombaseline with dapagliflozin 10mg by day 7were as follows2229mmolL (95 CI2371 to 2087 [2413 mgdL 95 CI 2669 to 2157]) for 24-h daily averageblood glucose 2377 mmolL (95 CI 2609 to 2145 [2631 mgdL 95 CI21115 to 2148]) for mean amplitude of glycemic excursion and 2162(95 CI 2294 to 205) for mean percent change in total daily insulin doseCorresponding changes with placebo were as follows 2113 mmolL (95 CI2363 to 137) 2045 mmolL (95 CI 2498 to 408) and 17 (95 CI 2228to 339) respectively However for every efficacy parameter the 95 CIs for alldapagliflozin doses overlapped those for placebo

CONCLUSIONS

This exploratory study of dapagliflozin in adults with type 1 diabetes demon-strated acceptable short-term tolerability and expected pharmacokinetic profilesand increases in urinary glucose excretion Within the dapagliflozin groups dose-related reductions in 24-h glucose glycemic variability and insulin dosewere suggested which provide hope that SGLT2 inhibition may prove in largerrandomized controlled trials to be efficacious in reducing hyperglycemia in type 1diabetes

1Center for Metabolic Research VA San DiegoHealthcare System San Diego CA2University of California San Diego La Jolla CA3Dallas Diabetes and Endocrine Center at Medi-cal City Dallas TX4Bristol-Myers Squibb Braine-lrsquoAlleud Belgium5Bristol-Myers Squibb Princeton NJ

Corresponding author Robert R Henry rrhenryoutlookcom

Received 17 December 2014 and accepted 3 July2014

Clinical trial reg no NCT01498185 clinicaltrialsgov

This article contains Supplementary Data onlineat httpcarediabetesjournalsorglookupsuppldoi102337dc13-2955-DC1

copy 2015 by the American Diabetes AssociationReaders may use this article as long as the workis properly cited the use is educational and notfor profit and the work is not altered

See accompanying articles pp 352355 365 373 376 384 394 403420 429 and 431

Robert R Henry12 Julio Rosenstock3

Steven Edelman12 Sunder Mudaliar12

Alexandros-Georgios Chalamandaris4

Sreeneeranj Kasichayanula5

Allyson Bogle5 Nayyar Iqbal5 James List5

and Steven C Griffen5

412 Diabetes Care Volume 38 March 2015

INHIBITIONOFSO

DIUMndashGLU

COSE

COTR

ANSPORTERS

Insulin therapy for type 1 diabetes pres-ents many challenges to patients andphysiciansOn a day-to-day basismarkeddaily glucose fluctuations and frequenthypoglycemia limit insulin dosing (1) Inthe long-term increasing the insulin doseto achieve andormaintain glycemic con-trol is associated with weight gain (2)whichmay contribute to potential cardio-vascular complications (3)Dapagliflozin a highly selective

orally active inhibitor of sodiumndashglucosecotransporter 2 (SGLT2) reduces hyper-glycemia by inhibiting renal glucosereabsorption independently of insulinIn patients with insulin-treated type 2diabetes dapagliflozin therapy hasbeen shown to improve glycemic controlwith attenuation of insulin-associatedweight gain and without increasing ratesof major hypoglycemia and also withconsistent reductions of systolic bloodpressure (45) This efficacy profile sug-gests that dapagliflozin may offer a po-tential therapeutic advance as an adjunctto insulin therapy in patients with type 1diabetesSince the introduction of insulin in

1922 only one new injectable therapeu-tic class (amylin analog) has been ap-proved for the treatment of type 1diabetes but with a black box warningfor hypoglycemia In addition there areno approved oral therapies for type 1diabetes therefore an unmet need ex-ists for novel therapies in type 1 di-abetes The kidney might become atherapeutic target with the advent ofinsulin-independent selective orally ac-tive glucosuric agents which could po-tentially influence the maladaptivereabsorption of glucose which may per-petuate hyperglycemia that has beenobserved in these patients (6)This pilot study sought to answer the

following research questions First isthe short-term safety and tolerabilityof dapagliflozin acceptable in patientswith type 1 diabetes Second are thepharmacokinetic profile and pharmaco-dynamic activity of dapagliflozin in pa-tients with type 1 diabetes comparableto those previously described in otherpopulations Third do the effects of da-pagliflozin on efficacy parameters after7 days of treatment in patients with type1 diabetes suggest that it may have thepotential to be efficacious in thesepatients

RESEARCH DESIGN AND METHODS

Study DesignThis was a 2-week randomized double-blind parallel-group placebo-controlledexploratory phase 2a pilot study evalu-ating the safety tolerability pharmaco-kinetics and pharmacodynamics ofdapagliflozin in patients with type 1 di-abetes inadequately controlled with in-sulin it was conducted from 3 February2012 to 17 October 2012 The studycomplied with the Declaration of Hel-sinki and the International Conferenceon HarmonisationGood Clinical PracticeGuidelines and was approved by institu-tional review boards and independentethics committees for the partici-pating centers (clinical trial reg noNCT01498185) All participants providedinformed consent

Enrollment CriteriaInclusion criteria included the followingage range 18ndash65 years type 1 diabetestreated with insulin monotherapy eitherby multiple daily injections consisting oflong-acting (basal) plus short-actingprandial (bolus) insulin or continuoussubcutaneous insulin infusion pumpfor $12 months and HbA1c $70 and100 at screening Exclusion criteriaincluded the following a history of type2 diabetes treatment with oral antihy-perglycemic agents within 12 monthsof study commencement or diabeticketoacidosis hospitalization for poorglycemic control and frequent episodesof hypoglycemia within the previous24 weeks (see Supplementary Data fordetailed lists of the inclusion and exclu-sion criteria)

Study Procedures and InterventionsThree days prior to randomization par-ticipants were admitted to an inpatientfacility for collection of baseline dataand confirmation of eligibility Theywere subsequently randomly assignedby a computerized interactive voice re-sponse system to receive daily doses ofdapagliflozin (1 25 5 or 10 mg) ormatching doses of placebo in a 11111ratio in addition to their insulin regimenRandomization was stratified by BMI cat-egory (23 or 23 kgm2) and insulinadministration method (ie multipledaily injection or continuous subcutane-ous insulin infusion) The investigatorsponsor and patients remained blindedto treatment allocation throughout the

double-blind treatment and the follow-up periods

Inpatient double-blind treatmentcontinued for a period of 7 days duringwhich data were collected and analyzedDuring inpatient treatment standard-ized diets and guidance on insulin doseadjustment were given Insulin dose wasnot proactively reduced at study druginitiation However patients and inves-tigators were advised to adjust insulindosing as needed to avoid hypoglycemiaand ensure patient safety Outpatientdouble-blind treatment continued for afurther 7days and on cessationof double-blind treatment follow-up data were col-lected over another 7 days

Primary Objective

Short-term Safety and Tolerability

In order to establish the short-term safetyand tolerability of dapagliflozin in combi-nation with insulin data on safety andtolerability were analyzed after a total of14 days of exposure Key parameters in-cluded general adverse events (AEs)treatment discontinuations hypoglyce-mic events and genital and urinary tractinfections as well other parameters of in-terest such as total daily fluid intake totaldaily urine output body weight bloodpressure and daily urine ketones

Secondary Objectives

Pharmacokinetic and Pharmacodynamic

Parameters

In order to establishwhether the pharma-cokinetic profile and pharmacodynamiceffect on urinary glucose excretion wassimilar to that already well described inother populations the following analyseswere conducted Pharmacokinetic pa-rameters for dapagliflozin and its majorinactive metabolite dapagliflozin 3-O-glucuronide (D3OG) analyzed were asfollows maximum observed plasma con-centration (Cmax) time of maximum ob-served plasma concentration (Tmax) areaunder the concentration-time curve inone dosing interval (AUCt) and ratio ofmetabolite to parent AUC (corrected formolecular weight) The pharmacody-namic parameter analyzed was themean change from baseline in 24-h urineglucose at day 7

Exploratory Efficacy Parameters

To explore the potential of dapagliflozinas an adjunctive treatment for type 1diabetes and to guide future clinicalstudy design considerations the efficacy

carediabetesjournalsorg Henry and Associates 413

parameters analyzed were the meanchanges from baseline at day 7 in thefollowing mean glucose based upon7-point central laboratory glucosemeasurements obtained before and af-ter each meal and at bedtime fastingplasma glucose (FPG) daily average glu-cose (DAG) SD of DAG and mean am-plitude of glucose excursion (MAGE)The latter three parameters were de-rived from 24-h continuous glucosemonitoring (CGM) using a DexcomSEVEN PLUS device The CGM systemwhich remained blinded to the patientand site staff during the recording re-corded data approximately every 5 minand downloaded the data wirelesslyinto a data file Site staff and patientswere fully trained to operate and cali-brate the CGM device according to themanufacturerrsquos instructions Also ana-lyzed were the mean percent changes

from baseline at day 7 in daily basalbolus and total insulin doses

Statistical AnalysisIn this exploratory pilot study meanchanges from baseline and two-sided95 CIs were calculated No statisticalhypothesis testing was performed andno P values were calculated For theanalysis of pharmacokinetic parame-ters geometric means and coefficientsof variation were summarized for CmaxAUCt and the ratio of metabolite toparent AUC Medians and ranges weresummarized for Tmax For the pharmaco-dynamic analysis of 24-h urine glucoseno dapagliflozin versus placebo meandifference calculations were plannedFor the efficacy parameter 7-pointmean glucose dapagliflozin versus pla-cebo mean differences and 95 CIswere prespecified For the remaining ef-ficacy parameters no dapagliflozin

versus placebo mean difference calcula-tions were planned For the analysis ofthe percent changes in insulin dosevalues were log transformed prior toanalysis resulting geometric mean esti-mates and 95 CIs on the log scale werethen back-transformed using the for-mula 100 3 (eEstimate 2 1) to obtainthe mean percent changes from base-line and their associated 95 CIs

RESULTS

PatientsOverall the baseline mean 6 SD HbA1cwas 846 6 081 and the mean agewas 3536 129 years Baseline urinaryglucose FPG and HbA1c trended higherand were more variable in the placebogroup compared with the dapagliflozingroups (Table 1) Of the 70 patients ran-domized 62 (886) completed thestudy (Supplementary Fig 1)

Table 1mdashDemographic and baseline characteristics

Insulin plus placebo(N = 13)

Insulin plus dapagliflozin

1 mg(N = 13)

25 mg(N = 15)

5 mg(N = 14)

10 mg(N = 15)

Age years 345 (122) 337 (91) 357 (139) 348 (140) 375 (152)

Sex n ()Male 8 (615) 5 (385) 11 (733) 8 (571) 8 (533)Female 5 (385) 8 (615) 4 (267) 6 (429) 7 (467)

Race n ()White 11 (846) 11 (846) 14 (933) 14 (1000) 12 (800)BlackAfrican American 1 (77) 1 (77) 1 (67) 0 2 (133)Asian 0 1 (77) 0 0 0Other 1 (77) 0 0 0 1 (67)

Weight kg 780 (114) 770 (167) 774 (134) 673 (76) 784 (199)

BMI kgm2 253 (30) 251 (38) 248 (27) 234 (24) 258 (48)

BMI category n ()23 kgm2 4 (308) 4 (308) 5 (333) 6 (429) 6 (400)23 kgm2 9 (692) 9 (692) 10 (667) 8 (571) 9 (600)

Insulin method n ()Insulin pump 6 (462) 6 (462) 7 (467) 7 (500) 7 (467)Daily injections 7 (538) 7 (538) 8 (533) 7 (500) 8 (533)

Duration of T1D years 162 (97) 201 (96) 217 (123) 172 (106) 181 (140)

HbA1c 875 (092) 821 (068) 845 (086) 850 (078) 839 (082)

HbA1c mmolmol 72 (101) 66 (74) 69 (94) 69 (85) 68 (90)

FPG mmolL 882 (429) 813 (405) 871 (351) 878 (326) 857 (418)

Urinary glucose excretion g24 h 304 (516) 66 (65) 121 (122) 111 (108) 119 (141)

Seated systolic BP mmHg 1133 (112) 1096 (95) 1144 (105) 1136 (109) 1159 (142)

eGFR (MDRD formula) n ()60 mLmin173 m2 0 0 0 1 (71) 0$60 and 90 mLmin173 m2 5 (385) 6 (462) 11 (733) 7 (500) 4 (267)$90 mLmin173 m2 8 (615) 7 (538) 4 (267) 6 (429) 11 (733)

Data are reported as the mean (SD) unless otherwise stated N is the number of randomized patients who took at least one dose of double-blindstudymedication BP blood pressure eGFR estimated glomerular filtration rateMDRDmodification of diet in renal disease Baseline datamissingin one patient

414 Dapagliflozin in Type 1 Diabetes Diabetes Care Volume 38 March 2015

Short-term Safety and TolerabilityAEs are summarized in Table 2 One se-rious AE (gastroparesis) not related totreatment was reported in the dapagli-flozin 5 mg group in a patient with ahistory of gastroparesis which led todiscontinuation of treatment A highpercentage of patients in all treatmentgroups experienced at least one episodeof hypoglycemia with no apparentrelationship to dapagliflozin dose (Table2) one event on day 6 in the dapagliflo-zin 10 mg group was major (defined asrequiring third-party assistance and aplasma glucose value 30 mmolL)which was related to the noncomplianceof the patient to reduce insulin dosing

as instructed by the investigator Thisevent led to discontinuation of treatmenton day 8 because of the investigatorrsquosconcerns regarding the patientrsquos compli-ance with insulin dosing instructions andnutrition during the outpatient periodOne genitourinary infection occurred ineach of the placebo and dapagliflozin 125 and 5 mg groups (Table 2)

There were no apparent effects ofdapagliflozin on fluid intake bodyweight or blood pressure in this rela-tively normal weight and normotensivepopulation (Supplementary Table 1)Total daily urine output tended toshow numeric increases in all groupsbut this increase was larger in the

placebo group compared with the da-pagliflozin groups (Supplementary Ta-ble 1) Positive results of urine ketonetestswere observed in all groups at base-line and appeared to decrease in theplacebo and dapagliflozin 1 and 25 mggroups during study drug administra-tion No instance of diabetic ketoacidosisoccurred

Pharmacokinetic andPharmacodynamic ParametersSteady-state pharmacokinetic resultsshowed that both Cmax and AUCt ap-peared to be dose proportional acrossall dose groups for both dapagliflozinand its metabolite D3OG Dapagliflozin

Table 2mdashOverall summary of patients with an AE and AEs of special interest

Insulin plus placebo(N = 13)

Insulin plus dapagliflozin

1 mg(N = 13)

25 mg(N = 15)

5 mg(N = 14)

10 mg(N = 15)

Overall summary of patients with an AE$1 AE 8 (615) 5 (385) 7 (467) 7 (500) 6 (400)$1 AE related to study treatment 0 2 (154) 2 (133) 2 (143) 0AE leading to study discontinuation 0 0 0 1 (71)dagger 0

$1 SAEDagger 0 0 0 1 (71)dagger 0$1 SAE related to study treatment 0 0 0 0 0SAE leading to study discontinuation 0 0 0 1 (71)dagger 0Deaths 0 0 0 0 0

AEs of special interestHypoglycemic eventssectTotal events n 39 76 31 54 23Total patients with $1 AEs 8 (615) 12 (923) 9 (600) 11 (786) 10 (667)Major episode 0 0 0 0 1 (67)|Minor episode 8 (615) 12 (923) 7 (467) 10 (714) 7 (467)

3 AEs 5 (385) 7 (538) 5 (333) 6 (429) 6 (400)4ndash6 events 2 (154) 2 (154) 2 (133) 2 (143) 1 (67)$7 events 1 (77) 3 (231) 0 2 (143) 0

Other episode 5 (385) 7 (538) 4 (267) 9 (643) 6 (400)3 events 4 (308) 4 (308) 3 (200) 9 (643) 6 (400)4ndash6 events 1 (77) 3 (231) 0 0 0$7 events 0 0 1 (67) 0 0

Discontinuation due to hypoglycemia 0 0 0 0 1 (67)|Events of genital infection or of UTIparaVulvovaginal mycotic infection 0 0 0 1 (71) 0Vaginal infection 0 1 (77) 0 0 0UTI 1 (77) 0 1 (67) 0 0

Data are reported as n () unless otherwise stated N is the number of patients exposed to study medications SAE serious AE UTI urinary tractinfection Counted up to 4 days after last dose date daggerData represent a single patient with gastroparesis on day 10 who discontinued the studyDaggerCounted up to 30 days after last dose date sectHypoglycemic events were collected separately from general AEs If hypoglycemic events qualified asSAEs these events were to be collected and summarized with all other SAEs Otherwise hypoglycemic events were collected and summarizedseparately up to 4 days after the date of the last dose Major hypoglycemia was defined as a symptomatic episode requiring external (third-party)assistance due to severe impairment in consciousness or behavior with capillary or plasma glucose values of30 mmolL (54 mgdL) and promptrecovery after glucose or glucagon administration Minor hypoglycemia was defined as either a symptomatic episode with a capillary or plasmaglucose value of35 mmolL (63 mgdL) regardless of the need for external assistance or an asymptomatic capillary or plasma glucose value of35 mmolL (63 mgdL) that did not qualify as a major episode Other hypoglycemia was defined as a suggestive episode reported but notmeeting the criteria for major or minor episodes ||One patient was listed as having discontinued study participation due to hypoglycemia Thepatient experienced amajor hypoglycemia episode on day 6 while receiving dapagliflozin 10 mg plus insulin which the investigator felt to be relatedto a failure of the patient to reduce insulin as instructed The patient was allowed to continue in the inpatient portion of the study but theinvestigator expressed concerns regarding the compliance of this patient as an outpatient and so the patient had study participation discontinuedon day 8 paraA prespecified list of preferred terms from the Medical Dictionary for Regulatory Activities (MedDRA version 151) was used to identifyevents of genital infection and of UTI in the database

carediabetesjournalsorg Henry and Associates 415

was rapidly absorbed after oral admin-istration withmedian Tmax ranging from050 to 100 h Similarly the medianTmax values for D3OG ranged from 100

to 200 h The ratio of metabolite to par-ent AUC was consistent across all dosegroups ranging from 066 to 076 (Sup-plementary Table 2)

Consistent with its mechanism ofaction a dose-dependent increase in24-h urine glucose was observed withdapagliflozin (Fig 1A) but this was not

Figure 1mdashMeanchanges frombaselineatday7 in24-hurinaryglucoseexcretion (A) averagedaily glucosederived from7-point glucosemonitoring (B) FPG (C)DAG from 24-h CGM (D) SD of glucose values from 24-h CGM (E) and mean amplitude of glycemic excursion from 24-h CGM (F) placebo plus insulindapagliflozin 1mg plus insulin dapagliflozin 25mg plus insulin dapagliflozin 5mg plus insulin and- dapagliflozin 10mg plus insulin Values below thedata points represent themean (95 CI) number of observations and baselinemean (SD) BL baselineD change n is the number of randomized and treatedsubjects with nonmissing baseline and day 7 values To convert glucose values from millimoles per liter to milligrams per deciliter multiply by 18

416 Dapagliflozin in Type 1 Diabetes Diabetes Care Volume 38 March 2015

statistically tested In contrast the 24-hurine glucose decreased in the placebogroup

Exploratory Efficacy ParametersGlycemic efficacy parameters at day 7are summarized in Fig 1BndashF For meanglucose measurements derived from7-point glucose monitoring (Fig 1B andSupplementary Table 3) no differencesbetween the placebo and dapagliflozingroups were observed For all other gly-cemic efficacy parameters (Fig 1CndashF)the 95 CIs of the mean for all dapagli-flozin doses overlapped those of pla-cebo Among the dapagliflozin groupsthe following dose-related trends weresuggested FPG DAG SD of DAG andMAGE showed greater numeric reduc-tions at day 7 with the dapagliflozin 5and 10 mg doses versus the lower dapa-gliflozin doses (Fig 1CndashF) In additionthe dapagliflozin 5 and 10 mg doseswere associated with reductions in themean percent change from baseline atday 7 in total insulin dose of 2193(95 CI 2301 to 268) and 2162(95 CI 2294 to 205) respectivelyhowever it should again be noted thatthe 95 CIs for all dapagliflozin dosesoverlapped those for placebo (Fig 2)

CONCLUSIONS

No unexpected short-term safety con-cerns were identified with dapagliflozintherapy in patients with type 1 diabetesA high percentage of patients experi-enced at least one hypoglycemic eventacross all treatment groups with thenumber of events varying substantiallybetween groups Despite this variationhypoglycemia rates appeared to showno relationship to dapagliflozin doseand it was reassuring that there wasno evidence of a dramatic increase inmajor hypoglycemic events in patientswho received dapagliflozin in combina-tion with insulin of 57 dapagliflozin-treated patients only one patientexperienced a major hypoglycemiaevent It should be noted that insulindoses were not proactively reduced inthis study however on initiation of da-pagliflozin therapy caution andor pro-active insulin dose reduction may berequired given that the insulin dosewas reduced in the dapagliflozin 5 and10 mg groups In addition further largerstudies of longer duration are requiredto fully assess hypoglycemia rates with

Figure 2mdashMean percent change from baseline at day 7 for basal daily insulin dose (A) bolusdaily insulin dose (B) and total daily insulin dose (C ) placebo plus insulin dapagliflozin1 mg plus insulin dapagliflozin 25 mg plus insulin dapagliflozin 5 mg plus insulinand - dapagliflozin 10 mg plus insulin Values below the data points represent the mean(95 CI) number of observations and baseline mean (SD) BL baseline D change IUinternational units n is the number of randomized and treated subjects with nonmissingbaseline and day 7 values Insulin mean percent change from baseline was calculated usingthe geometric mean and was back-transformed from results calculated under logarithmictransformation

carediabetesjournalsorg Henry and Associates 417

dapagliflozin added to insulin in patientswith type 1 diabetes Numeric increasesin urine output were observed in alltreatment groups but there was noevidence of volume depletion with da-pagliflozin therapy and no patient ex-perienced ketoacidosisIn patients with type 1 diabetes da-

pagliflozin exhibited a pharmacoki-netic profile similar to that previouslyobserved in patients with type 2 dia-betes (78) and dose-dependently in-creased urinary glucose excretion aswould be expected from its mecha-nism of actionNo differences between dapagliflo-

zin and placebo were noted for 7-pointmean glucose measurements and dif-ferences from placebo were not esti-mated for other exploratory efficacyparameters While the study was notpowered to test for between-groupdifferences in changes in efficacy para-meters and dapagliflozin 95 CIsoverlapped those of placebo dose-related trends in the magnitude of ef-fect for FPG DAG SD of DAG andMAGE were suggested with dapagliflo-zin therapy (Fig 1CndashF) In addition toreductions in 24-h average glucoselevels and reductions in glycemicvariability lower total insulin dosesparticularly with the 5 and 10 mgdoses of dapagliflozin were suggested(Fig 2C)This study has acknowledged limita-

tions that affect the interpretability ofmany of the changes in efficacy param-eters As the initial safety experience intype 1 diabetes study duration was veryshort and sample sizes in each groupwere small which may have led to ran-domization imbalances contributing tothe higher baseline values in the pla-cebo group versus the dapagliflozingroups for 24-h urine glucose (304 vs66ndash122 g24 h) and HbA1c (87 vs82ndash85) Furthermore given the un-certain safety risks of using an SGLT2inhibitor in the treatment of type 1 di-abetes additional measures to ensurepatient safety were necessary such asvery close monitoring in an inpatientsetting with guidance on insulin doseadjustments These features of thestudy design may have contributed toimprovements in glucose control in allpatients including patients receivingplacebo for whom reductions in gluco-suria occurred

This pilot study provides an initialevaluation of the safety pharmacoki-netic profile and pharmacodynamic ef-fect on urinary glucose excretion ofdapagliflozin in patients with type 1 di-abetes as well as an exploratory evalu-ation of efficacy parameters to guidefuture study design considerations forthe further examination of the potentialrole of dapagliflozin therapy in this pop-ulation There were several suggestivechanges in efficacy parameters of inter-est which provide hope that in largerrandomized controlled trials SGLT2 in-hibition may prove to be efficacious inreducing hyperglycemia in patients withtype 1 diabetes

Acknowledgments The authors thank thestudy participants and investigators In additionto RRH (Center for Metabolic Research VASan Diego Healthcare System and University ofCalifornia San Diego La Jolla CA) and JR (Dal-las Diabetes and Endocrine Center at MedicalCity Dallas TX) the authors thank Martin Kan-kam (Vince And Associates Clinical ResearchOverland Park KS) Eva-Maria Heurich (Com-pass Research LLC Orlando FL) Elaine Watkins(Profil Institute for Clinical Research Inc ChulaVista CA) James Vanderlugt (Jasper Clinic IncKalamazoo MI) Eli Ipp (Los Angeles BiomedicalResearch Institute at Harbor-UCLAMedical Cen-ter Torrance CA) Alex White (ProgressiveMedical Research Port Orange FL) GautamDe-sai (Kansas City University of Medicine and Bio-sciences Kansas City MO) James Borders(Central Kentucky Research Associates IncLexington KY) John Palmer (Regional MedicalClinic-Endocrinology Rapid City SD) and Ra-mon Vargas (Louisiana Research AssociatesInc New Orleans LA) who served as principalinvestigators The authors also thank JulianMartins of inScience Communications SpringerHealthcare for medical writing and editorial as-sistanceDuality of Interest This study was supportedby AstraZeneca and Bristol-Myers Squibb Med-ical writing and editorial assistance was fundedby AstraZeneca and Bristol-Myers Squibb

RRH has served on scientific advisory boardsof and received honoraria or consulting feesfrom the following insulin or SGLT2 manu-facturers Sanofi Novo Nordisk BoehringerIngelheim Bristol-Myers SquibbAstraZenecaJanssen and Merck His institution (VeteransMedical Research Foundation) has managedgrantsresearch support from the following insu-lin or SGLT2 manufacturers Sanofi Novo NordiskEli Lilly Bristol-Myers SquibbAstraZenecaBoehringer Ingelheim Pfizer and JanssenJR has served on scientific advisory boards ofand received honoraria or consulting fees fromthe following insulin or SGLT2 manufacturersSanofi Novo Nordisk Eli Lilly Merck JanssenBoehringer Ingelheim and Lexicon He has alsoreceived grantsresearch support from thefollowing insulin or SGLT2 manufacturers

Sanofi Novo Nordisk Eli Lilly Bristol-MyersSquibb AstraZeneca Merck Pfizer Johnson ampJohnson Janssen Boehringer Ingelheim andLexicon SE has served on scientific advisoryboards of and received honoraria or consultingfees from Abbott Animas AstraZeneca BayerBristol-Myers Squibb Daiichi Sankyo DexcomInsulet LifeScan Lilly Medtronic Merck NovoNordisk Sanofi Aventis and Tandem SM hasserved on scientific advisory boards of andreceived honoraria or consulting fees fromBristol-Myers Squibb and AstraZeneca A-GCSK AB NI JL and SCG are employeesof Bristol-Myers Squibb No other potential con-flicts of interest relevant to this article werereportedAuthor Contributions RRH SE and SMhelped formulate the study concept and designparticipated in the acquisition analysis andinterpretation of the data and contributed towriting and revising of the manuscript JRparticipated in the acquisition analysis andinterpretation of the data and contributed tothewriting and revising of themanuscript A-GCSK AB and SCG helped to formulate thestudy concept and design participated in studysupervision and analysis and interpretation ofthe data and contributed to the writing andrevising of the manuscript NI and JL helpedto formulate the study concept and designparticipated in the analysis and interpretationof the data and contributed to the writing andrevising of the manuscript RRH is the guar-antor of this work and as such had full access toall the data in the study and takes responsibilityfor the integrity of the data and the accuracy ofthe data analysisPrior Presentation Parts of this study werepresented in abstract form at the 73rd ScientificSessions of the American Diabetes AssociationChicago IL June 21ndash25 2013 and at the 49thAnnual Meeting of the European Association forthe Study of Diabetes Barcelona Spain Sep-tember 23ndash27 2013

References1 Weinstock RS Xing D Maahs DM et al T1DExchange Clinic Network Severe hypoglycemiaand diabetic ketoacidosis in adults with type 1diabetes results from the T1D exchange clinicregistry J Clin Endocrinol Metab 2013983411ndash34192 Russell-Jones D Khan R Insulin-associatedweight gain in diabetesdcauses effects andcoping strategies Diabetes Obes Metab 20079799ndash8123 Kilpatrick ES Rigby AS Atkin SL Insulin re-sistance the metabolic syndrome and com-plication risk in type 1 diabetes ldquodoublediabetesrdquo in the Diabetes Control and Com-plications Trial Diabetes Care 200730707ndash7124 Wilding JP Woo V Soler NG et al Dapagli-flozin 006 Study Group Long-term efficacy ofdapagliflozin in patients with type 2 diabetesmellitus receiving high doses of insulin a ran-domized trial Ann Intern Med 2012156405ndash4155 Wilding JP Woo V Rohwedder K Sugg JParikh S for the Dapagliflozin 006 Study Group

418 Dapagliflozin in Type 1 Diabetes Diabetes Care Volume 38 March 2015

Dapagliflozin in patients with type 2 diabetesreceiving high doses of insulin efficacy andsafety over 2 years Diabetes Obes Metab 1 Au-gust 2013 [Epub ahead of print]6 Mogensen CE Maximum tubular reabsorp-tion capacity for glucose and renal hemodynam-cis during rapid hypertonic glucose infusion in

normal and diabetic subjects Scand J Clin LabInvest 197128101ndash1097 Kasichayanula S Chang M Hasegawa Met al Pharmacokinetics and pharmacodynamicsof dapagliflozin a novel selective inhibitor ofsodium-glucose co-transporter type 2 in Japa-nese subjects without and with type 2 diabetes

mellitus Diabetes Obes Metab 201113357ndash3658 Komoroski B Vachharajani N Feng Y Li LKornhauser D Pfister M Dapagliflozin a novelselective SGLT2 inhibitor improved glycemic con-trol over 2 weeks in patients with type 2 diabetesmellitus Clin Pharmacol Ther 200985513ndash519

carediabetesjournalsorg Henry and Associates 419

Dapagliflozin in patients with type 2 diabetesreceiving high doses of insulin efficacy andsafety over 2 years Diabetes Obes Metab 1 Au-gust 2013 [Epub ahead of print]6 Mogensen CE Maximum tubular reabsorp-tion capacity for glucose and renal hemodynam-cis during rapid hypertonic glucose infusion in

normal and diabetic subjects Scand J Clin LabInvest 197128101ndash1097 Kasichayanula S Chang M Hasegawa Met al Pharmacokinetics and pharmacodynamicsof dapagliflozin a novel selective inhibitor ofsodium-glucose co-transporter type 2 in Japa-nese subjects without and with type 2 diabetes

mellitus Diabetes Obes Metab 201113357ndash3658 Komoroski B Vachharajani N Feng Y Li LKornhauser D Pfister M Dapagliflozin a novelselective SGLT2 inhibitor improved glycemic con-trol over 2 weeks in patients with type 2 diabetesmellitus Clin Pharmacol Ther 200985513ndash519

carediabetesjournalsorg Henry and Associates 419