This article isprotected bycopyright. Allrights reserved. Accepted Article

article as doi: 10.1 differencesbetween version lead to this may been through the copyediting, typesetting, pagination andproofreading process, which This article hasbeen accepted for publication andundergone full peer review but has not E-mail: [email protected] Tel: +81-3-3972-8111. Fax: +81-3-3972-8245 Itabashi-ku, 30-1 Oyaguchikami-cho, Tokyo 173-8610,Japan. Medicine Metabolic of and Diabetes School Division Diseases,Nihon University of Corresponding author Tokyo, Japan. and safety and safety of IOLITE: 2 1 Hisamitsu Ishihara Title: Running placebo-controlled, double-blind study patients with type 2 diabetes mellitus as ofipragliflozin safety and Efficacy Asahina identifier: Clinicaltrials.gov patients Astellas Pharma Inc., Pharma Astellas Tokyo, Japan. SchoolofMedicine, Nihon University and Metabolic Diseases, Diabetes Division of 2

Aefficacy theshow to placebo-controlled study double-blind, randomized, I pragliflozin asadd- pragliflozin Ipragliflozin add-ontother insulin 111/dom.12745 1 , Susumu Yamaguchi Susumu , : Hisamitsu Ishihara, MD, PhD MD, : Hisamitsu Ishihara, NCT02175784 NCT02175784 O n therapy toinsu n therapy 2 (IOLITE): A (IOLITE): multi-centre, randomized, add-on therapy to insulin in Japanese to insulinin add-on therapy , Ikko Nakao

and the Versionof Record. Please cite this apy in type 2 diabetes patients patients 2diabetes intype apy LI n in 2 , Akira Okitsu T ype 2diab ype 2 E and Seitaro tes mellitus mellitus tes This article isprotected bycopyright. Allrights reserved. Accepted Article Conclusion: patients. 4.0%)occurred5%of (0.0%and in< 2.3%) orgenitaland ipragliflozin: 1.1% infection (placebo tractvs. consistent withurinary Events infection vs.29.1%). patients (14.9% treatment-relatedHypoglycaemia was the in only 5%of adverse event > reported (p= 0.042). change inHbA1c forthe group ×treatment inhibitor of aDPP-4 use/non-use for interactionstatistically significanta Therewas 0.022). (p = adiponectin when usedwitha inhibitor.especially DPP-4 wei body serumC-peptide, and reduced FPG, ipragliflozin groups, respectively (baselin groups,respectively ipragliflozin adjusted mean difference of adjusted Results: examined. metabolic also and endpoints were Safety (FPG) plasma glucose hormones. endpoints fromSecondary included changes inHbA1c in fasting baseline. change endpoint was primary the placebo (n= 87) 175)The or ipragliflozin (n= for 16weeks. to receive randomized were inhibitor (DPP-4) peptidase-4 dipeptidyl with/without a Methods: therapy. ofinsulin stage early in the 2diabetes type with Aims: Abstract To patients ofadd-onipragliflozin efficacyinJapanese the and safety examine The changes in HbA1c were 0.27% and were 0.27% inHbA1c The changes Patients treated with insulin (bolus component < 30% of total daily dose) total dose) daily 30%of < component insulin (bolus treatedwith Patients Ipragliflozin was well toleratedand − 1.07% (95% CI 1.07% (95% e: 8.62% vs. 8.67%), corresponding vs.8.67%), e: 8.62% an to − ght (all p < 0.001), and increased serum serum andincreased ght (all p<0.001), 1.24%, 1.24%, effective in insulin-treated patients, patients, effective insulin-treated in − 0.91%; 0.001). p< Ipragliflozin − 0.79% in the placebo and and placebo inthe 0.79% This article isprotected bycopyright. Allrights reserved. Accepted Article insulin-treated patients. patients. insulin-treated affect inhibitors DPP-4 determinewhether efficacyto in important the ofipragliflozin was reported insulin, because thiscombination with togetheradministered frequently and are used patients, in commonly Japanese (DPP-4) peptidase-4 inhibitorsare weight Dipeptidyl hypoglycaemia gain. and of therisk increasing without tolerated well efficacious and tobe expected is addi its lowriskofhypoglycaemia, action and of and trials nature ipragliflozin becauseobservedthese in of the insulin-independent the[5-7]. Considering beneficial effectsin Japan onglycaemiccontrol ofipragliflozin performed clinical trials of onthebasis drugs withotheroralantidiabetic combination approved recently in Japan for the treatment of type 2diabetes monotherapy or as in long-acting, intermediate-acting, or premixed insulin. ofinsulin therapy,stages in the early patients treatedwith aspatients defined which was required to facilitate cause and hypoglycaemia weight gain. Therefore, novel oral antidiabetic agents are might and life daily totheir is restrictive because it regimen the insulin to intensify However, drug. oralantidiabetic oftenan(other) oraddingreluctant regimen are patients are strategies other treatment Therefore, [4]. targetsofreasons a for variety glycaemic achieve to unable still are patients However, [1-3]. oralantidiabeticdrugs control by some glycaemic inadequate with forpatients option effective an treatment represent insulin andpremixed insulin Basal Introduction Ipragliflozin, a selective sodium–glucose sodium–glucose aselective Ipragliflozin, further improvement in glycaemic control in type 2diabetes control further in type in glycaemic improvement required, such as intensifying the insulin the insulin intensifying required, suchas ng ipragliflozin to ng insulin-treated patients cotransporter(SGLT2) 2 inhibitor, was to be effective [8, 9]. Therefore, it is is it Therefore, 9]. [8, to beeffective This article isprotected bycopyright. Allrights reserved. Accepted Article diabetes with or without a DPP-4 inhibitor. without aDPP-4 with or diabetes over 16weeksinaddition toongoinginsulinth withplacebo compared ipragliflozin administering of and safety theefficacy to examine As partclinicalAs development oftheipragliflozin, aim the of the was study present

erapy in Japanese patients with type 2 in Japanesetype with patients erapy This article isprotected bycopyright. Allrights reserved. Accepted Article an HbA1c of of an HbA1c Patients Patients consent. ClinicalTrials.gov informed written All provided patients NCT02175784). (identifier: at registered was study This and regulations. laws applicable all and Guidelines, of Technical forHuman RequirementsofPharmaceuticals Use forRegistration withGoodClinicalPractice,complied InternationalConference onHarmonisation the whichthe institutional boardat was approved review eachby site.Thestudy study study, inthis participated in Japan sites period. Forty-three 16-weektreatment initial open-label period, extension isongoing which (superiority trial) performed a36-week, March and between 2015,and 2014 period placebo-controlled randomized, consistedofa double-blind, 16-week, This study Study design Materials and Methods 4-week screening massand period, a body index of 20.0–45.0 kg/m inhibitor were eligible if they thehadif been same they drugatafixedprescribed inhibitor dose for wereeligible DPP-4 a using Patients alone. intermediate-actinginsulin long-acting insulin, or ultra-rapid-acting not>30%of insulin component was the total daily dose), or mixed rapid-acting dosesof were prescribed the insulin (providing fixed eligible ifthey tosupport insulinbasal were stageearly of secretion therapy units/day) for units/day) hadprescrib if they been were eligible ≥ 20 years old diagnosed with type 2 diabetes 2 type with diagnosed old years 20

≥ ≥ 6 weeks, alone or in combination with other oral antidiabetic drugs, had had antidiabetic oral withotherdrugs, aloneorincombination 6weeks, 7.5%to ≤ 10.5%, a maximum change in HbA1c of 1% during the maximumin HbA1c of1%duringthe change a 10.5%, ed a stable dose/regimen of insulin (8–40 dose/regimen(8–40 a stable insulin of ed . This report describes the results of the the resultsthe describes of This report . ≥ 12 weeksbefore enrolment 2 . Patients in the the in Patients . ≥ 6 This article isprotected bycopyright. Allrights reserved. Accepted Article patient discontinued the study and was prescribed an appropriate treatment regimen. treatmentregimen. appropriate an prescribed andwas thestudy patient discontinued of the ofdoseadjustments.number Ifthe insulin > 4 dose changed by units,was the study, the maximumthroughout 4 units beadjusteda of could insulin doseby regardless safety. for insulin dose to increase the considered the it necessary investigator The ifFBG(measured SMBG) wa be increased by dose could insulin The symptoms. hypoglycaemic was suspectedofhaving the patient mg/dL and 70 were < days mmol/Lconsecutive concentrations 2 mg/dL) (1on = 18.02 safety reasons. The insulin bereduced at dosecould investigator’s the discretion if FBG treatment the peri during continue unchanged associatedsymptoms withhypoglycaemia diaries). inpatient (valueswererecorded glucos blood self-monitored by (FBG) glucose the2:1 ratio by investigator. ata groups was theprepared by patient registration cent randomization Thelist screening. period before additionalan 4-weekwashout entered treatment period. Patients usingoral antidi throughoutthe unchanged remained ipragliflozin of The dose inhibitor use. DPP-4 mg 50 toreceive randomized were period, then en period,patients screening a4-week After Treatments criteria are listedin the Information. Supporting thestudy.throughout wascontinued itsdose and weeksenrolment before Exclusion Insulin type was unchanged during the treatment period. The dose of insulin was to to ofinsulinwas The dose treatmentperiod.the during wasInsulin unchanged type To measure fasting blood hypoglycaemia risk, patientsinstructedto reduce were

teredsingle-blindplacebo run-in a2-week abetic drugsotherabetic than DPP-4 inhibitors od, unlessdosechangesrequired for od, were s mg/dL> 200 consecutive on 2 or if days e (SMBG) every morning and if they felt ifthey and morning every (SMBG) e re and patients re andpatients were allocated tostudy ipragliflozin or placebo, stratified by by placebo, stratified or ipragliflozin This article isprotected bycopyright. Allrights reserved. Accepted Article and thirst. infarction, cerebral haemorrhagic cerebralinfarction, dehydration, included electrolytes fluidelectrol infection, body volume, and genital tractinfection, those relatedinterest, tohypoglycaemia, including urinary wereevaluated. and severity seriousness, preferred term (MedDRA16.1), andtheir version drug, relationship tothestudy were classifi TEAEs tests. laboratory and use/non-useof DPP-4inhibitors by stratified inpatients and FPG wereexamined HbA1c in Changes bedtime. after breakfast,lunch,1hafter before beforedinner, lunch, hafter dinner, 1 at and before (FBG), and at baseline times: at endbreakfast following the 1 the treatment h of waist leptin, andwas glucagon, adiponectin. circumference, performed SMBG at glycoalbumin,values SMBG glucose (FPG), changesfasting plasma in endpointsincluded Secondary period. treatment 16-week efficacyThe primary change in endpoint was fromHbA1c baseline to end ofthe and Endpoints Assessments continuous use of these agents was prohibited. immunosuppressants, and glucosecould temporarily,glucagon, be administered but Corticosteroids, inhibitors wasenrolment prohibited. usedat DPP-4 thethroughout study. and drugsotherthan antidiabetic insulin useof Concomitant Safety endpoints included vital signs, treatment-emergent vital signs, adverse (TEAEs), included events endpoints Safety The patients’ diet and exercise therapies at enrolment were continued unchanged unchanged continued were The patients’enrolment at therapies exercise and diet

in pre-specified analyses. analyses. inpre-specified ytes. TEAEs related to body fluid volume and and related fluidto body volume TEAEs ytes. We ofspecial TEAEs several examined ed according to system organ class and organ and system to class edaccording recorded by by patient diary,recorded weight, body This article isprotected bycopyright. Allrights reserved. Accepted Article on the body fluid volume and electrolytes) were calculated for each treatment group. treatment for eachgroup. werecalculated and electrolytes) fluid volume on thebody (TEAEs related tracturinary to hypoglycaemia, drug,orofspecialinterestof study TEAEs discontinuation to permanent leading ANCOVA. Similar statisticalmethods were appliedto otherefficacy endpoints. ofuse/non-ussub-group analysis significanc the evaluate to treatment group] group] ×treatment [baseline HbA1c terms analyses. We sub-group for used was method ANCOVAperformed withinteraction of and use/non-use aDPP-4inhibitor and treatmentas effects. groupfixed The same (ANCOVA)of covariance analysis by evaluated a covariate, as value thebaseline with using lastobservationcarriedthe forward imputemethodmissing to data) was analyses. from excluded were dose insulin after changing obtained data efficacy analyses, of treatment asthe defined was end of (SD) or theperiod.treatment drug during study the dose of one atleast received who all patients as defined analysis set, safety usingthe were performed analyses Safety period. treatment the measured during was efficacy variable at leastone andinwhom drug of thestudy leastone dose at received who patients all as defined set, analysis full the outusing carried were Efficacy analyses analysis Statistical Numbers andpercentages patients of withTEAEs, serious adverseevents, TEAEs The primary efficacybaseline from toWeek inHbA1c endpoint (change 16, analysed deviation meanas ± standard descriptively are presented characteristics Baseline n (%) of patients for continuous and cate and forcontinuous (%)ofpatients e ofaDPP-4inhibitor, this from variable excluded was randomized double-blind treatment period. For For double-blindtreatment period. randomized and [use/non-use of and [use/non-use a DPP-4inhibitor of × e of interactions. In the pre-specified interactions. Inthe e of infection, genital infection, and effects infection, and infection,genital gorical variables, respectively. variables, gorical The end This article isprotected bycopyright. Allrights reserved. Accepted Article concentrations. C-peptide of analysis efficacy the adding for except after unblinding, plan analysis No interim analyses were performed. There were no changes to the statistical statistical the to changes no were There were performed. analyses interim No This article isprotected bycopyright. Allrights reserved. Accepted Article stable until week 16. week 16. until stable remained and 12, week until baseline from decreased meanlevel HbA1c thatthe shows − meanintergroup differenceanof adjusted in resulting decreased to7.88%, from 8.67% wher of treatment), 8.90%(end to (baseline) from 8.62% the placebo group: observedin were levels in HbA1c changes Small Efficacy alcohol. consumed formerly ineachof patients were group currentorformer smokers,just currently and half or over (glargineinsulin only long-acting 50% About detemir degludec20.8%). 40.4%, 3.1%, on were group oftheipragliflozin oftheplacebo groupand63.7% and 65.5% placebo group and 6.5% of the ipragliflozin group were mixed the ipragliflozin of treated with6.9%the group and 29.8% insulin, respectively. receiv types Insulinpreparation 8.62 was HbA1c ± 0.86% and 8.67± and 0.77%inthe ipragliflozin placebo groups, the group and34.5%intheplacebo group ipragliflozin were ± 11.1 and58.7 placebo group of patientsin and27.6% ipragliflozin group, the years in the in years ±9.3 groups.Mean was59.2 patient the age characteristics between 169)completedn = study.the Table 1showsnosignificant differences inpatient ipragliflozin (n = 175) (Figure 1). Of these, A wererandomized patients total262 of Patients Results 1.07% (95%interval [CI] confidence − 1.24%, 245 patients (placebo, n =76; ipragliflozin, eas HbA1c levels in the ipragliflozin group group ipragliflozin the in levels HbA1c eas and treated with placebo (n = 87) or (n=87) with placebo treated and group were on intermediate-acting insulin, intermediate-acting insulin, wereon group ed were as follows: 27.6%oftheplacebo were as follows: ed − 0.91%; p < 0.001; Table 0.001; < p 0.91%; 2AFigure 2). ≥ 65 years. At baseline, 65years. This article isprotected bycopyright. Allrights reserved. Accepted Article group (p=0.042). group us interaction for significant statistically a revealed for HbA1c in changes analyses Interaction changes. HbA1c performed for was interaction analysis an difference between-group in HbA1c, the inhibitorson DPP-4 To assess theinfluence of concomitant useof patients a DPP-4without inhibitor. ±8.60% 0.76%and8.62%± forplacebo and ipragliflozin, respectively, in respectively,inhibitor, ipragliflozin, aDPP-4 of use and concomitant with inpatients and for placebo ± and8.70% 0.77% ±0.91% 8.63% levelswere HbA1c The baseline 0.001). 0.001). (p time inSMBGat = with significant all wasassociated points reductions not placebo, Table period. ofthetreatment end the and at at baseline but that ipragliflozin, 2shows at bedtime) and meal each after and points(before time at seven performed was SMBG ( FPG (Figures 3A andB) numerically greatwas (adjustedgroup mean difference: of treatment was greater in the ipragliflozin wasgreaterinthe of treatment ( end to from baseline inglycoalbumin meanin HbA1candFPG,the change the changes which remained week2, by group ipragliflozin − change in FPG infromchange FPG tothe baseline end of treatment was ( mg/dL)mg/dL anddecreased from (+10.4 group 159.9 inthe placebo mg/dL to130.7 − − 31.7 mg/dL; p <0.001;Table31.7 in inthe FPG 2Bshows 2). a decrease Figure 1.20% and1.20% 29.3 mg/dL) 29.3 inthe ipragliflozingroup(Tablemean The 2). adjusted difference forthe The adjusted mean difference (ipragliflozin mean difference (ipragliflozin The adjusted FPG increased from 160.5 mg/dL fromincreased FPG mg/dL160.5 to170.9 at baseline treatment endof the at − 44.5 mg/dL) did not 44.5 in patientswho ( than − 3.84%; 95% CI 95% 3.84%; e/non-use of a DPP-4 inhibitor × treatment × inhibitor of aDPP-4 e/non-use er inpatients whoused inhibitor aDPP-4 constant with until 16.Consistent week − − 3.60%) than in the placebo (+0.20%) (+0.20%) than in3.60%) the placebo placebo) for changes in HbA1c and placebo)changes HbA1c forin − 4.40%, 4.40%, − 40.3 mg/dL(95% CI − − 3.29%; p < 0.001;Tablep < 3.29%; 2). 0.84% and0.84% − 33.4 mg/dL).33.4 − 48.9, This article isprotected bycopyright. Allrights reserved. Accepted Article of treatment in either group (Tableeither group intreatment of 2). Gluc glucagon concentrations were not significantly different (Table ipragliflozin placebogroups and betweenthe the addition, In 2). glucagon concentrations from baseline to the the in per-prreport the glucagonconcentrations affected markedly group, which Accordingly, the values. and this patient we excluded concentrations, glucagon 0.181). Regarding = patients who did not use a DPP-4 inhibitor ( a DPP-4 didnot patients who use DPP-4 inhibitor ( inhibitor DPP-4 end baseline totheof was statis treatment mean adjusted difference (ipragliflozin Table 2).Wethe effects also analysed ofDPP-4inhibitorsonC-peptideThe levels. ipragliflozin ( ipragliflozin treatmentwas different significantly the(0.16ng/mL) placebo between and the μ differencemean (adjusted +0.33 µg/mL)group (0.43 placebo the in than µg/mL) greater (0.76 in but the ipragliflozin treatment slightly significantly end was to the of difference between the placebo ( placebo the between Table different wasnot significantly waist circumference in change contrast,the 2). By than in the placebo ( than inthe The reduction in body weight was signifi was body weight in The reduction Metabolic parameters g/mL; p = 0.022; Tableof = end g/mL; p to the fromC-peptide baseline in change The 2).

− 0.63 cm; p = 0.215;Table= 0.63 cm; p adiponectin fromin mean baselinechange 2).The − 0.08 ng/mL) group (adjusted mean differencemean 0.08 ng/mL) group(adjusted − 0.28 ng/mL; 95% CI 0.28 ng/mL; 95% − − 0.05 kg)groupmean (adjusted difference

0.84 cm) and ipragliflozin0.84 ( and cm) − cantly greater in the ipragliflozin ( ipragliflozin the in greater cantly − placebo) change from placebo) inC-peptide in the agon concentrations remained unchanged in concentrations unchanged remained agon 0.42, − tically significantin who used patients a 0.13 ng/mL; 95% CI 0.13 ng/mL; 95% we found oneoutlier in the ipragliflozin otocol analysis set. The mean changes in mean changes set.analysis The otocol end of treatment were not significantly notsignificantly oftreatmentwere end different between baselineandthe end − 0.13 ng/mL; p < 0.001) but not in but 0.13 ng/mL;in not p< 0.001) − 1.36 1.36 cm) mean groups(adjusted − 0.22 ng/mL 0.22 − − 1.07 kg; 1.07 p<0.001; 0.31, 0.06 ng/mL; p 0.31, 0.06ng/mL; p ; p < 0.001; ; p<0.001; − 1.09 kg) This article isprotected bycopyright. Allrights reserved. Accepted Article drug. the afterandpatient study continued resolvedonset, the drug. Both eventswere 29 days were considand hypokalaemia hepatic function inseverity.mild as classified were events Abnormal These patient. one in hypokalaemia abnormal hepaticfunction and cough inone ipragliflozin group included patient, drug. SeriousTEAEsin study the the considered related tobe but wasnotto arterialmoderate Coronary in stent severity, drug. insertionwas classifiedas the study to infarction cerebral indicating wasnotrelated shown tobeinthethe placebogroup, however, drug;later was study to the patient related that probably be to the investigator by considered was and as severe, classified was infarction Cerebral for those patients. insertion, inone patient each. Both events ledofthestudy discontinuation permanent to coronarycerebral arterial wereserious and placebo infarction group inthe stent TEAEs and two pati group the placebo treatment period. groups,respectively. ipragliflozin and placebo the during deaths werereported No (19/87) drug-related in21.8% TEAEsoccurred TEAEs (Table in (49/87) and (130/175)of 56.3% 3) occurred 74.3% patients, and Safety groups(Tableipragliflozin 2). and different placebo the significantly between werenot end oftreatment the inhibitor (data notThe mean shown). changes fromin leptin concentrations baseline to groupinwith the ipragliflozin and withoutpatients the of use a concomitant DPP-4 During theDuring treatment period, serious TEAEs were reported in twopatients(2.3%)in

ents (1.1%) in the ipragliflozin group(Table(1.1%) intheipragliflozin ents Two 3). ered to be possibly related to the study study related tothe ered tobe possibly in (74/175) ofpatientsthe and 42.3% This article isprotected bycopyright. Allrights reserved. Accepted Article study drug, except for epididymitis. drug, for epididymitis. except study erosion inone patientand genital each. Thes eczema, pruritusepididymitis, genital, and candidiasis patients, inthree vulvovaginal genitalstudy infe to drug. TEAEsrelated Two episodesofcystitis (one patient in eac (one patient). andurethritis patient), (one bacteriuria asymptomatic (onepatient), cystitis itdidnotincrease frequency. hypoglycaemia inHbA1c, reduction treated Although concomitant with ipragliflozin. hypoglycaemia occurred treated in with placeboand 6 patients (10.5%) 30 (28.0%) inhibitor,concomitantof DPP-4 use those with for contrast, In hypoglycaemia. and 22(32.4% treated with (23.3%) placebo concomitant use ofDPP-4inhibitors. Ofthos foods. Noneofthese of sugary theingestion by treatment or any without were resolved TEAEs hypoglycaemia-related the of drug.All the study to related or probably possibly considered were events these of all patients, two in inseverity. mild hypoglycaemia of threeevents for Except (1event). events) andhunger hypoglycaemia (167 in ipragliflozingroupwere of the onset.TEAEs day Hypoglycaemia-related related to drug, the study but the eventswere were 36 events ofhypoglycaemia, allof which were considered possibly or probably (29.7%) group and patients ipragliflozin group,therein the 52 group.In the placebo Drug-related TEAEs linked to urinary tract to urinary linked TEAEs Drug-related We occurrence whether hypoglycaemiawasby influenced analysed of also in (14.9%) theplacebo in 13patients observed were Hypoglycaemia-relatedevents ainsdsotne h td. the study.patients discontinued h group) h group) were unrelated considered to the ction in the ipragliflozin group included included group ipragliflozin the in ction mild in severity and were resolved on the on the mildwere resolvedin severity and e not DPP-4inhibitor,receiving 7patients e events were considered related to the relatedtothe were considered e events ) treated with ipragliflozin experienced experienced ipragliflozin with ) treated infection in the ipragliflozin group were use of DPP-4 inhibitor led to agreater All All of these events were classifiedas This article isprotected bycopyright. Allrights reserved. Accepted Article No change in pulse rate was observed in placebo( changewasobserved the inpulserate No group. either in end oftreatment to the acids from baseline lipoprotein cholesterol, low-de unaltered from baseline in placebo (1.5 ± in placebo from baseline unaltered 8.19). pressureswere and withplacebo (+1.21 ±Systolic blood diastolic compared diastolic changes, respectively) and ipragliflozin groups ( andipragliflozin groups respectively) changes, diastolic groups ( groups Ipragliflozin caused slight decreases in eGFR ( in decreases caused slight Ipragliflozin − 0.1 ± 0.0 min0.1 ±0.0 − 1 ). Therewere nochanges intotal cholesterol, high-density nsity lipoprotein cholesterol, cholesterol, nsity lipoprotein 8.19 and 0.3 ± 9.2 mmHg and± 8.19 0.3 9.2 for systolic and − − 0.5 ± 10.0 min 10.0 ± 0.5 1.19 ± 9.53 mL/min/1.73 m mL/min/1.73 1.19 ±9.53

− 1. triglycerides, or free fatty or freetriglycerides, fatty 4 ± and 14.5 − 1 ) or ipragliflozin − 0.3 ± 9.9). 0.3 ±9.9). 2 ) This article isprotected bycopyright. Allrights reserved. Accepted Article concentrations were similar between the placebo and ipragliflozin groups in patients ipragliflozin groups inpatients andthe were placebo similar concentrations between treaglucagon levelsinpatients [10,11].concentrations in changes However, didnot identify study the present SGLT2 other because added, is serum glucagon increase reportedly inhibitors effectsglucagon-suppressing may ipragliflozin bebeneficial when ofDPP-4inhibitors β ofinsulin re improvement the combined by indicating better efficacy in patients using ipragliflozintheuseinhibitors, DPP-4 treatment andof correlation (p =0.042)between significant a showed statistically analysis An interaction DPP-4 inhibitors. concomitant treatedwith greater into theendoftreatmentbaseline patients were numerically treated a concomitant DPP-4inhibitor,without with or from in reductionsHbA1c the periods. reductionterms in glucose of the placebo in at andatbaseline endoftreatment the co times SMBGperformedday per results [5-7]. of seven The antidiabetic drugs other oral in earlier monotherapywith orinstudies combination administered as of ipragliflozin Notably, thereported with changes from inHbA1c was consistent the change baseline SMBG. and glycoalbumin, FPG, HbA1c, in reductions thesignificant by demonstrated termscontrol; superior glycaemicto placeboin was of improving Ipragliflozin therapy. insulin of stage early the in control glycaemic inadequate and 2 diabetes In thisstudy, efficacy withtype the inpatients of ipragliflozin examined were andsafety Discussion -cell responsiveness in patients using a DPP-4inhibitor. using inpatients -cell responsiveness Alternatively, the Intriguingly, control patients between changesin comparedglycaemic the we when ted with ipragliflozin. Of note, the changes in glucagon inglucagon note,thechanges Of with ipragliflozin. ted a DPP-4inhibitor.might This be explained nfirmed that ipragliflozin was superior to was superior that ipragliflozin nfirmed sistance by ipragliflozin and the improved the improved and ipragliflozin by sistance levels at both fasting and postprandial This article isprotected bycopyright. Allrights reserved. Accepted Article patients with a mean HbA1c of ~8.6% atba of ~8.6% HbA1c mean a with patients of the number in reduction considerable a to see expect would might interms to ongoing therapy ipragliflozin be beneficial of use of a DPP-4inhibitor. Preserving e ipragliflozin-treated patients.This was,how humans. in theeffects possible toestablish on insulin sensitivity of are ipragliflozin needed ofinsulinsensitivity,evaluation direct including inFurtherstudies, humans. resistance with ipragliflozintreatment, suggesting that We [12-14]. reduces insulinresistance found insulin. treatedwith inpatients inhibitor therapy andDPP-4 ipragliflozin combined of clinical benefits the strengthens observation This in hypoglycaemia. an increase accompanied inhibitorwasby not DPP-4 Wevalues. efficacy alsothat the better found tobaseline didnotreturn they oftreatment,although after days 28 later diminished concen study ofempagliflozinglucagon [10], study, present concentr glucagon measured we ofdrugsusedthe combination ineachstudy, or design.In other differences instudy the to due be may or ipragliflozin, of feature a unique be could of effectlack glucagon on this that possible It is concentrations. in glucagon increases with wereassociated which our results dapagliflozin [11],why differ[10]and forempagliflozin reported those from a DPP-4 concomitant use or didnot did who We a in significantconcentrations reduction inC-peptide observed Amodels demonstratedusing that number ofstudies animal SGLT2 inhibition ever,in patientswith observed concomitant ndogenous insulin secretion by adding adding by insulinsecretion ndogenous SGLT2 ameliorates inhibition also insulin trations increased after the initial dose and and dose initial after the trations increased seline because it was previously reported reported becausepreviously seline itwas of ipragliflozin in patients treated with a with treated inpatients of ipragliflozin that serumincreased adiponectinlevels inhibitor (data not shown). inhibitor isunclear It (data notshown). ations after 16weeksof treatment.a In β -cells in our cohortof -cellsin our β -cell protection. We This article isprotected bycopyright. Allrights reserved. Accepted Article ipragliflozin. ipragliflozin. inpatients inrenal changes treatedlong-term function SGLT2with inhibitors,as such Fu 52 weeks [18]. reversedafter partially at 18 eGFR of decline Aninitial weeks. study. duringthe ketoacidosis symptoms of any reported the patients in theof ipragliflozin group andonepatient (1.1%) althoughnone the placebo group, study, “blood ketone bodies increased” was reportedas a TEAE in five patients (2.9%) an SGLT2 inhibitorcombinationwith insulin in [16-18]. with treated were patients in trials which clinical otherin global reported those than less patients, respectively,and no placebo inthe patients,respectively, and seven (4.0%) group,in ipragliflozin inand one (1.1%) the other SGLT2with thatof comparable inhibitors. respectively [17].Thus,hypoglycaemic fre mg ofpatients, mg andin 20% 28% 10 for18weekscausedhypoglycaemia or25 caused hypoglycaemia in 29.2% and 25.0%of and in29.2% caused hypoglycaemia mgmgdapagliflozinfor 12weeksand 20 that in treatmentpatients 10insulin-treated in the none placebo group, of these events were classified asserious.It was reported 7.8% [15]. that the Although the incidence of hypoglycaemia was greater in the ipragliflozin group than in the incidence hypoglycaemiaAlthough ipragliflozin the of group than wasgreater We for16 inwith observedslight in patientstreatedipragliflozin decreases eGFR withSGLT2 about riskofketoacidosis the is concern There Inthis inhibitors [19]. this study,In four (2.3%) in infectionoccurred and genital infection urinary tract β -cell area was reduced by ~45% in Japanese patients with a mean HbA1c of of HbA1c mean a with patients ~45%inJapanese reducedby area was -cell weeks by canagliflozin was reported to be to reported was canagliflozin by weeks group. These rates are comparable with or with are comparable These group. rates ture studies should carefully follow the studies shouldcarefully ture patients, respectively [16].Empagliflozin quency byipragliflozin (29.1%) was quency This article isprotected bycopyright. Allrights reserved. Accepted Article drugs. oralantidiabetic withother combination or monotherapy according studiesin prior to of ipragliflozinas ranges expected within witha treated inhibitor.DPP-4 concomitantly patients of other TEAEs were Incidences Ameliorati FPG,SMBG. decreased and HbA1c, and sulfonylureas. ipragliflo when required is caution Therefore, outbeforetheinitialobservationperiod. washed cause hypoglycaemia, were could injections.basal–bolus Second, other oral anti insulin regimens.weca Thus, In conclusion, ipragliflozin add-on therapy tosignificantly insulinfor16weeks therapy add-on In conclusion,ipragliflozin hadsome limitations.This study First,non nnot generalise the present results to regimens such as resultstoregimenssuch generalise thepresent nnot zin isused in patients treatedwith insulin diabetic drugs, such as that sulfonylureas e of the patients were using intensive intensive were using the patients e of on of glycaemic controlwasgreater in This article isprotected bycopyright. Allrights reserved. Accepted Article manuscript. ofthe andwriting analysis, Y.,S. I. N. and O. contributed A. to st design, I. andS.A.contributedH. tostudy Authors’ contributions of employees Inc.,Japan. Pharma Astellas Y., andMSD.S. HakkoKirin, Pharma,Nordisk Kyowa I. A.are O., N., A. and S. Tanabe Mitsubishi Sanofi, AstraZeneca, Novo Japan,Daiichi-Sankyo, Eli Lilly Pharma, Japan, Ingelheim from PharmaBoehringer Inc.,Ono Astellas Pharmaceutical, and Novartis received IngelheimPharma; Japan, Boehringer grants/research support MitsubishiSanofi, Tanabe MSD, Inc., Pharma Astellas from fees consulting or Pharma, lecture Inc.; Pharma received ofAstellas board advisory scientific hasservedonthe H.I. interestsConflict of Elsevier/ELMCOM™. Dr. provided by and Astellas funded by Ltd.)and Nicholas (EdanzGroup D.Smith sponsored by Astellas Inc.,Japan. Pharma The authorswish to all thank the investigators of eachinvolved in trial. This study was Acknowledgements udy udy design, conduct, study collectiondata and Medical writing and editorial support was editorial supportwas and writing Medical data analysis and writing of the manuscript; the and of writing analysis data This article isprotected bycopyright. Allrights reserved. Accepted Article Investig 2014; Diabetes J mellitus. diabetes 2 type with patients Japanese in ipragliflozin inhibitor control trialdouble-blind glycemic of novel Yoshida KazutaK, A, Kashiwagi S, [5] Suppl 3 2011;Opin MedRes 2Curr glycemicdiabetes. inpoor type of control persistence Tildesley Ross SA, toeffectivetreatment: HD, Barriers insulin Ashkenas the J. [4] Diabetesdiabetes. 2015; Ther Complications 2diabetes.JDiabetes 2015; type Lovre Fonseca V. D, with control in patients insulin timely basal Benefits of [2] ofprint] ahead [Epub future ofbasal insulins. Diabetes Metab ResRev. 2015 Oct 28.doi:10.1002/dmrr.2763. Pettus Cavaiola J,Santos T, Tamborlane WV, Edelman The past, S. present, and [1] References insulin analogs ininitiating, intensifying, Wu T, Betty[3] B, Downie M, etal. patients withtype2 mellitusdiabetes and the long-term renal of impairment: results placebo-controlled study on long-termefficacy and safety of ipragliflozin treatment in A, Takahashi Kashiwagi H,et al. Ishikawa A H, randomized, double-blind, [7] 2015; Metab Obes Diabetes 2diabetes: ILLUMINATE,type arandomized, with Japanese patients metforminof the treatment for with combination in Ipragliflozin A, KazutaK,GotoYoshida Kashiwagi Ueyama E,S, Utsuno A. [6] : 13–20. 5 : 382–391. : 382–391. 17 6 : 304–308. : 304–308. : 273–287. : 273–287. Nagase I. Randomized, placebo-controlled, placebo-controlled, Nagase I.Randomized, or switching insulin regimens in type 2 or in type 2 switching insulin regimens sodium-dependent glucose cotransporter 2 sodium-dependent glucose Practical Guidance on the use of premix of premix the use on Guidance Practical 29 double-blind, placebo-controlled study. placebo-controlled double-blind, : 295–301. : 295–301. 27 27 This article isprotected bycopyright. Allrights reserved. Accepted Article homeostasis pancreatic andpreserves Jurczak MJ, Lee HY, Birkenfeld AL [14] mice. MolMed2012; db/db Curr anovelSGLT2BI-38335, inhibitor, onpancre T, ChenL,Klein with treatment Effects PS. linagliptin Leung ofcombining [13] J Clin 1987; Invest hyperglycemiaof phlorizin normalizes tiss with Correction RA. PapachristouDeFronzo D, GI, Shulman Smith D, Rossetti L, [12] 124 endogenous butenhances insulin sensitivity muscle improves Dapagliflozin MerovciA,Solis-Herrera C,Danieleetal. G, [11] 124 sodium-glucose2 inhibition cotransporter in ty to response al.Metabolic et Frascerra S, E, E, Muscelli Ferrannini [10] (LANTERN) study.(LANTERN) Metab2015; Diabetes Obes safetyevaluationinASP1941 patients with Japanese patients with type 2 diabetes. Endocr J2015; Japanese 2diabetes. patientstype with control via differenteffects hyperglycemic secretion in and glucagon insulin on monotherapymetforminto or sitagliptinimproves insulin Addition of bloodglucose OtsukaY, Yamaguchi A,Kosuda M,NakazakiIshiharaS, Furukawa H. [9] mellitus. EndocrJ2013; 2diabetes type patients with inhibitor ininsulin-treated sitagliptin glycemic DPP-4 improves control Japanese Katsuno T, with the therapy M.Add-on Ikeda H,IdaK,Miyagawa J, Namba [8] : 509–514. : 509–514. : 499–508. 79 : 1510–1515. : 1510–1515. 12 : 995–1004. : 995–1004. beta-cell 2011; Diabetes function. glucose production. J Clin Invest 2014; Invest2014; production. glucose Clin J , etal.SGLT2 improves glucose deletion type 2 diabetes with renal impairment diabetes withrenalimpairment 2 type pe 2 diabetic patients. J Clin Invest 2014; Clin Invest2014; pe 2diabeticpatients. J atic islet andinflammation in function ue sensitivity to insulin in diabetic rats. rats. in to insulin diabetic ue sensitivity 17 : 152–160. 60 62 : 733–742. : 733–742. 3–4. : 133–143. 60 9–9. : 890–898. This article isprotected bycopyright. Allrights reserved. Accepted Article 2015; Endocrinol JClin Metab ketoacidosis. Taylor KI.SGLT2 SI, Rother BlauJE, to may predispose inhibitors [19] therapy inpatients Carediabetes 2015; 2 therapy type Diabetes with with insulin in conjunction used when cotransporter of sodium-glucose2, inhibitor Neal V, B, Perkovic Zeeuw Det al. de Efficacy of an canagliflozin, and safety [18] 936–948. randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab 2015; 2015; ObesMetab trial. Diabetes placebo-controlled double-blind, randomized, a 78-week insulin: basal on controlled inadequately 2diabetes intype basal insulin al.on to Zelleret ofempagliflozin added Impact A, C, J, Jelaska Rosenstock [17] of a novel insulin-independent treatment. Diabetes Care 2009; treatment. Care2009; Diabetes of anovelinsulin-independent applicability sensitizers: insulin ofinsulin plus 2 doses diabetes receiving high type with WildingJP, P, Norwood al.et A T'joenC, inpatients dapagliflozin of study [16] of print. Epub ahead mass beta cell in surgically resected hu Y, J,Saisho Inaishi and alpha on anddiabetes al. Effect et ofobesity SaitoS, [15] man Metab JClinEndocrinol 2016; pancreas. 100 : 2849–2852. : 2849–2852. 38 32 : 403–411. : 1656–1662. : 1656–1662. 17 : This article isprotected bycopyright. Allrights reserved. Accepted Article standard deviation. inhibitor. DPP-4 a without concomitant Valuesminusmeanthe change the as shown are carried forward)ina (with lastobservation Figure 3. x-axis. belowthe is shown point time The ateach number set). ofpatients (full analysis mean deviation standard ± the Figure 2. FAS, set;SAF, fullanalysis set. analysis safety Figure 1. Figure legends Change in HbA1c (A) and FPG (B)fro Change inHbA1c(A)and Time-course as shown (B).Data are HbA1cplasma (A)andfasting glucose of Patient disposition. *Some patients discontinued for more discontinued Patient disposition.for thanreason. patients one *Some ll patients and in patients treated with or with treated and inpatients ll patients m baselineto the end of treatment This article isprotected bycopyright. Allrights reserved. Accepted Article glucose; SBP, pressure; DBP, systolic blood diastolic bloodpressure fasting plasma rate;FPG, filtration glomerular eGFR, estimated mass index; body BMI, Values as the are presented † *Fisher’stest. exact 1. Table <1 3 3.) 9(51 0.953* 0.693* 59 (35.1) 30 (34.5) 107 (63.7) 50 (29.8) 57 11 (65.5) (6.5) 24 (27.6) 6 (6.9) 0.317 0.640 0.921 1.00± 0.63 159.9±45.7 8.67± 0.77 < 15 dose(units/day) insulin Total 160.5±43.4 1.09±0.69 8.62±0.86 Long-acting Intermediate-acting 0.910 Mixed 76.8± 10.1 0.838 Insulin type 131.2±14.0 eGFR 77.0±11.0 0.384 eGFR (mL/min/1.73m 131.6±14.7 0.589* ±8.86 164.08 C-peptide (ng/mL) 0.723 (62.5) 105 163.03±9.74 (mg/dL) FPG 0.415 0.115 58.7± 11.1 (%) HbA1c ± 69.05 11.61 151.1±93.5 51(58.6) before the obse 59.2±9.3 70.32± 12.17 171.4±102.5 washout period a enteredPatients who mellitus (months) diabetes Duration of (mmHg) DBP (mmHg) SBP BMI (kg/m Height (cm) weight (kg) Body Age Age (years) Males Two-sample Two-sample ≥ ≥ ≥ 65 years 24 (27.6) 58 (34.5) 0.322* 0.322* (34.5) 58 24(27.6) 65years 3 1 1.) 8(26 (22.6) 38 16(18.4) (42.3) 71 41(47.1) 30 < 30 15to ≥ 90 mL/min/1.73 m mL/min/1.73 90 Baseline characteristics characteristics Baseline 2 2.2±38 2.1±35 0.089 25.61±3.53 26.42±3.81 ) t test. rvation period Placebo 2 8.1±2.4 39 02 0.162 ± 83.98 20.27 80.11±21.94 ) 2 n 20 (23.0) 59 (35.1) 0.063* 0.063* (35.1) 59 20(23.0) (%)or mean ± deviation. standard 24 (27.6) 43 (25.6) 0.765* 0.765* (25.6) 43 24 (27.6) N =87 Ipragliflozin Ipragliflozin N =168 N P -value † † † † † † † † † † †

This article isprotected bycopyright. Allrights reserved. Accepted Article Table 2. Table oywih k) aeie/ET 02 21 02 19 69.03 ±11.67 /67.94 ±11.58 70.26 ± /70.21 12.16 ±11.94 BaselineEOT / ± 216.14 59.45 (156) /184.39 ±54.60 (120) Bodyweight (kg) 222.65 ±57.88 (84) /211.68 ±63.56 (59) BaselineEOT / Before bedtime ± 228.99 59.11 (160) /204.98 ±49.79 (121) 231.57 ±60.99 (83)/226.01 ±60.44 (59) BaselineEOT / ± 173.99 50.67 (161) /143.51 ±42.89 (121) after 1h dinner 175.02 ±57.69 (84)/173.93 ±51.41 (59) BaselineEOT / Before dinner ± 237.81 52.91 (161) /213.78 ±42.53 (122) 240.31 ±49.16 (84)/239.08 ±45.42 (59) BaselineEOT / after 1h lunch ± 230.91 54.57 (159) /204.46 ±42.78 (123) 242.46 ±56.40 (83)/230.53 ±58.18 (58) BaselineEOT / after 1h breakfast MG(gd) 159.9 ±45.7 /130.7 ±32.3 (167) SMBG (mg/dL) 160.5 ±43.4 /170.9 ±52.0 BaselineEOT / FPG (mg/dL) Before lunch Baseline / EOT 168.61 ± 58.38 (83) / 156.48 ± 43.71 (58) 165.39 ± 165.39 53.75 (161) /135.24 ±42.42 (120) 168.61 ±58.38 (83)/156.48 ±43.71 (58) BaselineEOT / Before lunch /19.88 ±3.41 ± 23.48 3.58 23.43 ±3.92 /23.63 ±4.26 BaselineEOT / Glycoalbumin (%) AMD (95% CI) AMD (95% CI) hne 7.16 ± 60.86 (58) ± 10.85 48.89 (57) Change Change 11.17 ± 47.44(58) Change AMD 11.45 ± 45.46(59) Change AMD (95% 4.45 ± 43.41 (57) Change AMD (95% 7.89 ± 56.08 (57) CI) Change AMD (95% CI) Change AMD (95% 0.20 ±2.08 CI) –40.3 ( AMD ± 150.41 42.44 (161) /124.94 ±26.87 (123) (95% 157.44 ±42.40 (86)/139.82 ±32.99 (58) 10.4 ±39.6 CI) BaselineEOT / Change Change (95% 0.27 ±0.65 Fasting CI) AMDCI) (95% 8.67 ±0.77 /7.88 ±0.81 Change AMD CI) Change 8.62 ±0.86 /8.90 ±1.07 (95% BaselineEOT / AMD HbA1c (%) CI) (95% CI) Efficacyvariables

− lcb N=8) Ipragliflozin (N= 168) Placebo= 87) (N 1.83 ±27.33 (58) − 0.05 ±1.42 − − − − − − − 21.36 ( 33.12 ( 26.82 ( 35.44 ( 28.65 ( 26.37 ( 29.51 ( − − − 1.07 ( 3.84 ( 1.07 ( − − − − − − − − − − − 28.67, 49.05, 41.19, 48.26, 41.62, 39.52, 43.78, 48.9, 48.9, 1.41, 4.40, 1.24, − − − − − − − − − − − 31.7), 31.7), 0.73) 3.29), 0.91), 14.04), 17.19) 12.45) 22.62) 15.69) 13.22) 15.24), , P P P P , , , , , < 0.001 < 0.001 < 0.001 < 0.001 P P P P P P P < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 − − − − − − − − 29.60 ±30.16 (119) 25.28 ±53.04 (115) 29.67 ±47.07 (116) 24.81 ±53.24 (116) 33.37 ±56.07 (116) 26.37 ±50.99 (117) 30.34 ±52.65 (111) 29.3 ±39.4 (167) − − − 1.09 ±1.09 1.27 .0±23 ±3.60 2.33 ±0.79 0.66 This article isprotected bycopyright. Allrights reserved. Accepted Article treatment period; FPG, fasting plasma glucose; SMBG, self-monitored glucose. treatment blood fasting plasmaglucose;SMBG, FPG, period; differencemean (ipragliflozin adjusted AMD, outlier. this after excluding set were concentrations glucagon baseline. Therefore, at test theblood of day the on endoscopy priorto glucagon administered was This patient *One patient had an outlier of1490 pg/mL, whichresulted in the large standard deviation. in parentheses. isgiven the set, number full analysis the in ofpatients differed ofpatients from the number number the Where interval). confidence Valuesmean difference (95% adjusted or deviation mean± standard the as presented are etn(gm) aeie/ET 22 .7/1.6±83 1.9±83 17 10 .3 11.99 ±8.37 (167) /11.05 ± 8.13 12.20 ±8.17 /11.86 ±8.37 BaselineEOT / Leptin (ng/mL) ( Adiponectin 124.4 ±21.9 (167) /120.5 ±22.3 145.5 ±148.5* /122.4 ±26.4 BaselineEOT / Glucagon (pg/mL) -etd n/L Bsln O 10 .9/11 .5(8 1.00 ±0.63 /1.03 ±0.61 (127) ± 1.09 0.69 ± /1.14 (68) 0.65 BaselineEOT / C-peptide (ng/mL) analysis set) set) analysis (per-protocol Glucagon (pg/mL) AMD (95% CI) AMD (95% CI) hne .3±11 0.76 ±1.07 (167) 0.33 (0.05,0.62), 0.43 ±1.10 AMDCI) (95% Change Change ± 0.16 0.37 (68) Change AMD Change AMD 90.79 ±9.59 /90.41 ±9.37 (127) (95% ± 92.80 9.33 /92.00 ±(68) 8.69 (95% BaselineEOT / Waistcircumference CI) CI) μ (cm) Change g/mL) aeie/ET .7±36 .0±39 7.24 ±3.65 (167) / 7.99 ±3.71 7.17 ±3.62 /7.60 ±3.94 BaselineEOT / M 9%C) 1.7 ( AMDCI) (95% Baseline / EOT 129.4 ± 25.7 / 118.6 ± 19.9 (65) 124.6 ± 124.6 / 23.0 117.7 ±22.2 (123) 129.4 ±25.7 /118.6 ±19.9 (65) BaselineEOT / Change − − 0.84 ±3.62 (68) − − 10.8 ±20.1 (65) 23.2 ±150.8 0.34 ±3.88 − also analysed intheper-protocol analysed alsoanalysis placebo); EOT, placebo); end oftherandomized − − − 0.22 ( 0.64 ( 0.63 ( − 1.5 ( − − − − − 0.33, 3.4, 6.8), 1.56, 0.28), 1.63, 0.37), 7.8, 4.8), − 0.11), P P P = 0.510 P P = 0.637 P = 0.022 = 0.171 = 0.215 < 0.001 − − − − 0.91 ±3.51 (167) 1.36 ±3.36 (127) 0.08 ±0.41 (127) − 3.9 ± 20.33.9 (167) ± 6.9 ±19.66.9 (123) This article isprotected bycopyright. Allrights reserved. Accepted Article Table 3. Table Placebo (N = 87) Ipragliflozin (N = 175) (N= Ipragliflozin Placebo=87) (N Gntlifcin 0 40 7 7 (4.0) 0 4 4 (2.3) 0 and electrolytes 1 volume 168 fluid Body 1 (1.1) 52 (29.7) Genital infection 2 36 Urinary tract infection 13 (14.9) 1(0.6) Hypoglycaemia-related events 205 3 ofspecial 1 interest TEAEs 74(42.3) 2(1.1) discontinuation permanent 44 1(1.1) 349 Drug-related TEAEs leading to 19(21.8) 2 130(74.3) Drug-related serious TEAEs 112 2(2.3) Total drug-relatedTEAEs 49(56.3) discontinuation permanent to leading TEAEs Serious TEAEs Total TEAEs n Treatment-emergentadverse events (TEAEs) 11 1 23 4 4(2.3) 1 1 (1.1) 2 2(1.1) 1 1 (1.1) 2 2(1.1) 2 2 (2.3) () Events (%) n () Events (%) This article isprotected bycopyright. Allrights reserved. Accepted Article PT, preferredterm. the as shown are Data eerlifrto 1(.) 0 0 0 2 1 1 2(1.1) 2 1 (1.1) 1(0.6) 1(0.6) 1 3 Dizziness 1 1 1(1.1) 2 3 (1.7) infarction Cerebral 8 1(1.1) 2(2.3) 0 microglobulin increased Urine beta 2 8(4.6) 5 0 Rash 0 164 1 5(2.9) Constipation (1.1) 51(29.1) 1(1.1) Muscle spasms 1 36 candidiasis Vulvovaginal 1(1.1) 0 13(14.9) Thirst 0 1 bodies increased Blood ketone Pollakiuria 0 Hypoglycaemia 2 0 byPTin TEAEs Drug-related 0 3 (1.1) (1.7) 2 3 n (%) of patients or number of events. ofevents. ofpatientsornumber (%) ≥ 1% of patients in either group ineither 1% ofpatients

Other • event Adverse • Lackof efficacy • Discontinued duri Discontinued n This article isprotected bycopyright. Allrights reserved. period Accepted= 4 Article n ng the treatment n n = 11 = 1 = 6 Completed study treatment FAS SAF Placebo n n = 76 = 87 n n = 87 = 87 Provided informed consent Received run-in placebo Randomized n n n = 262 = 327 = 367 Completed study treatment FAS SAF Ipragliflozin n n = 175 = 169 n n = 168 = 175 Other • Withdrew consent criteria eligibility meet not • Did • Other • violation Protocol • request Patient • event Adverse • Withdrew consent • Did not criteria meet eligibility • Discontinued before Discontinued randomization Discontinued duri Discontinued Discontinued before Discontinued run-in period n n = 4 = 2 period n n n = 40* n = 65 = 2 = 1 n ng the treatment n n n = 1 = 6 = 11 = 2 n n =27 = 63 This article isprotected bycopyright. Allrights reserved. Accepted Article B A Ipragliflozin Placebo n Ipragliflozin Placebo n FPG (mg/dL) HbA1c (%) 10.0 100 150 200 250 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 50 6 5 4 3 2 168 123 130 143 155 168 6 5 4 3 2 167 123 130 143 155 168 78 36 187 61 65 73 80 87 78 36 187 61 65 73 80 87 0481216EOT 0481216EOT 168 167 87 87 Placebo Placebo Time (weeks) Time (weeks) Ipragliflozin Ipragliflozin LOCF LOCF (95%CI: (95%CI: − 40.3 mg/dL − 1.07% − − 1.24, 48.9, − − 0.91) 31.7) ChangeAccepted in FPG (mg/dL) ArticleChange in HbA1c (%) ‐ ‐ ‐ ‐ Change in FPG (mg/dL) 2.0 1.5 Change1.0 in0.5 HbA1c (%)0.0 0.5 1.0 − − − − B A − − − − 2.0 1.5 1.0 0.5 0.0 0.5 80 60 40 20 20 0 With DPP-4 inhibitor With DPP-4inhibitor (95%CI: (95%CI: n n 0.28 9.8 = 57 = 57 − 44.5 mg/dL − 1.20% − − 1.40, 55.1, n n Placebo -35.3 -0.94 − = 101 = 101 − 1.00) 33.9) Ipragliflozin Without DPP-4 inhibitor Without DPP-4inhibitor (95%CI: (95%CI: n n 11.7 0.27 = 30 = 30 − 33.4 mg/dL − 0.84% − − 1.12, 47.7, n n -20.2 -0.58 − − = 67 = 66 0.57) 19.0)