Dia Care-2015-Neal-403-11

Efficacy and Safety ofCanaglif lozin an Inhibitor ofSodiumndashGlucose Cotransporter 2When Used in Conjunction WithInsulin Therapy in Patients WithType 2 DiabetesDiabetes Care 201538403ndash411 | DOI 102337dc14-1237

OBJECTIVE

There are limited data about the effects of sodiumndashglucose cotransporter 2 inhib-itors when used with insulin We report the efficacy and safety of canagliflozin inpatients with type 2 diabetes using insulin

RESEARCH DESIGN AND METHODS

The CANagliflozin CardioVascular Assessment Study is a double-blind placebo-controlled study that randomized participants to placebo canagliflozin 100 mg orcanagliflozin 300 mg once daily added to a range of therapies The primary endpoint of this substudy was the change in HbA1c from baseline at 18 weeks amongpatients using insulin 52-week effects were also examined

RESULTS

Individuals receiving insulin at baseline were randomized to receive placebo (n5690) canagliflozin 100 mg (n 5 692) or canagliflozin 300 mg (n 5 690) Theseindividuals were 66male and had a median age of 63 years mean HbA1c of 83(67 mmolmol) BMI of 331 kgm2 estimated glomerular filtration rate of 75mLmin173m2 fasting plasma glucose of 92 mmolL and amedian daily insulindose of 60 IU Most individuals were using basalbolus insulin Reductions inHbA1c with canagliflozin 100 and 300 mg versus placebo were 2062 (95 CI20692054268 mmolmol [95 CI275259] P lt 0001) and2073 (95CI20812065280 mmolmol [95 CI289271] P lt 0001) at 18 weeks and2058 (95 CI20682048263 mmolmol [95 CI274252]) and2073(95 CI 2083 2063 280 mmolmol [95 CI 291 269]) at 52 weeks Therewere significant falls in fasting plasma glucose body weight and blood pressureat both time points and there was a greater incidence of hypoglycemia genitalmycotic infections and hypovolemia with both canagliflozin doses

CONCLUSIONS

Canagliflozin added to insulin therapy improved glycemic control and decreasedbody weight There was a greater frequency of several anticipated side effectsalthough few led to discontinuation of treatment

1The George Institute for Global Health The Uni-versity of Sydney and the Royal Prince AlfredHospital Sydney Australia2Department of Clinical Pharmacy and Pharma-cology University of Groningen UniversityMedical Centre Groningen Groningen theNetherlands3Department of Medicine Stanford UniversitySchool of Medicine Stanford CA4The Royal North Shore Hospital and Universityof Sydney Sydney Australia5Janssen Research amp Development LLCRaritan NJ6University of Oxford Oxford UK

Corresponding author Bruce Neal bnealgeorgeinstituteorgau

Received 15 May 2014 and accepted 29 October2014

Clinical trial reg no NCT01032629 clinicaltrialsgov

This article contains Supplementary Data onlineat httpcarediabetesjournalsorglookupsuppldoi102337dc14-1237-DC1

A complete list of the CANVAS Trial Collabora-tive Group and collaborating sites can be foundin the Supplementary Data online

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 412420 429 and 431

Bruce Neal1 Vlado Perkovic1

Dick de Zeeuw2 Kenneth W Mahaffey3

Greg Fulcher4 Kirk Ways5 Mehul Desai5

Wayne Shaw5 George Capuano5

Maria Alba5 Joel Jiang5

Frank Vercruysse5 Gary Meininger5 and

David Matthews6 on behalf of the

CANVAS Trial Collaborative Group

Diabetes Care Volume 38 March 2015 403

INHIBITIO

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Type 2 diabetes causes a large burden ofdisease around the world (1) The con-trol of blood glucose levels is central tothe management of symptoms and theprevention of complications (2) Thereare a broad range of treatments thatcan be used to lower blood glucose lev-els butmany patients still fail to achievetargets (3) Accordingly new therapiesthat can lower blood glucose levels withgood safety and tolerability have signif-icant potential in the future manage-ment of the conditionInhibition of the sodiumndashglucose co-

transporter 2 (SGLT2) is a novel strategyfor glucose control (4ndash9) SGLT2 is ahigh-capacity and low-affinity glucosetransporter that is expressed in the lu-minal membranes of the proximal renaltubules and is responsible for themajor-ity of glucose reabsorption from the tu-bular lumen An inherited deficiency ofSGLT2 can produce renal glucosuriawith some affected individuals excretingas much as 100 g of urinary glucose perday (5) Canagliflozin is an orally activeinhibitor of SGLT2 that reduces proximaltubular glucose reabsorption and in-creases urinary glucose excretion (10ndash13) Treatment produces a significantloss of glucose with beneficial effectson glycemic control body weight andblood pressure (1214ndash22) Small in-creases in LDL and HDL cholesterol havebeen observed with the ratio remainingunchanged (23)Canagliflozin has a low risk of hypo-

glycemia in the absence of concomitanttherapy although rates may be in-creased when used in conjunction withinsulin or insulin secretagogues (2324)The risks of genitourinary infectionsand lower urinary tract infections areelevated with canagliflozin (232526)but the risks of upper urinary tract in-fections are not and the rates of treat-ment discontinuation attributed to sideeffects are low (1214ndash22) This reportdefines the effects of canagliflozin onindicators of glycemia safety and toler-ability when used in conjunction withinsulin therapy in a prespecified sub-study of the CANagliflozin CardioVascu-lar Assessment Study (CANVAS)


Overall Design of the CANVAS TrialCANVAS is a randomized double-blindplacebo-controlled parallel-group mul-ticenter trial The study is ongoing and

has randomized 4330 individuals on a111 basis to placebo canagliflozin100 mg or canagliflozin 300 mg withthe primary objectives being to deter-mine the efficacy and safety of cana-gliflozin compared with placebo

Objectives and Specific Hypothesesfor the Insulin SubstudyThe purpose of the insulin substudy ofthe CANVAS trial was to define the 18-week effects of canagliflozin (when usedin addition to insulin therapy at a doseof $20 IUday) on a range of efficacysafety and tolerability outcomes in pa-tients with type 2 diabetes with inade-quate glycemic control The objectivesof the substudy were to assess sepa-rately the effects of each dose of cana-gliflozin compared with placebo onHbA1c safety and tolerability at the18-week follow-up The primary hy-pothesis was that each dose of cana-gliflozin would produce a greaterreduction in HbA1c compared withplacebo

Secondary objectives of the substudywere to determine the effects at the 18-week follow-up of each dose of canagli-flozin compared with placebo on bodyweight fasting plasma glucose propor-tion of participants reaching HbA1c

70 (53 mmolmol) systolic and di-astolic blood pressure and fastingplasma lipids (ie triglycerides HDLcholesterol LDL cholesterol total cho-lesterol and the ratio of LDL cholesterolto HDL cholesterol) For the 52-week as-sessment the defined objectives wereto determine the effects of each doseof canagliflozin compared with placeboon fasting plasma glucose body weightsystolic and diastolic blood pressureand fasting plasma lipids The prespeci-fied hypotheses for the secondary ob-jectives were related to the 18-weekeffects on fasting plasma glucose theproportion of participants reachingHbA1c 70 (53 mmolmol) and bodyweight

RecruitmentRecruitment for the CANVAS study wasperformed at 386 centers in 24 countriescommencing in December 2009 andcompleting in March 2011 (clinical trialreg no NCT01032629 clinicaltrialsgov) The 12-month follow-up of the fi-nal participants included in this substudywas completed in March 2012 Regula-tory approval for the conduct of the trial

was obtained in each country and ethicsapproval was received at every site priorto initiation of the trial

Participant Inclusion and ExclusionCriteriaParticipants in the CANVAS trial are menand women with type 2 diabetes whohave inadequate glycemic control(HbA1c $70 [53 mmolmol] and105 [91 mmolmol]) despite currentmanagement with glucose-loweringstrategies and are at an elevated riskof cardiovascular disease The subsetincluded in the insulin substudy com-prised participants that were using$20 IUday insulin at baseline All par-ticipants were required to provide in-formed consent be willing and able toadhere to the study protocol require-ments and successfully complete thetrial screening and run-in period To en-sure the recruitment of a broad pop-ulation group there were minimalrestrictions on the use of backgroundtherapies Patients using insulin pumpswere not excluded from the study Allparticipants had an established or anelevated risk of cardiovascular diseaseand were either$30 years of age with ahistory of symptomatic atheroscleroticvascular disease (coronary cerebrovas-cular or peripheral) or$50 years of agewith two or more of the following riskfactors$10 years duration of diabetessystolic blood pressure 140 mmHgwhile receiving one or more or antihy-pertensive agents current smoking mi-croalbuminuria or macroalbuminuriaor HDL cholesterol1 mmolL Individ-uals with an estimated glomerular filtra-tion rate (eGFR) 30 mLmin173 m2

at baseline were not eligible for inclu-sion in the study Other exclusion crite-ria were typical of those usually invokedfor a trial of this stage in this patientgroup (27)

Screening and Run-in PeriodAll potential participants completed ascreening visit to establish initial eligibil-ity and progressed to a 2-week single-blind placebo run-in period if thescreening criteria were met The pri-mary purpose of the run-in period wasto exclude prior to randomizationthose individuals who were unlikely toadhere to the long-term treatment andfollow-up regimen required by the trial

404 CANVAS Insulin Substudy Diabetes Care Volume 38 March 2015

RandomizationRandomization was performed centrallythrough an interactive voice response sys-tem or an interactive web response sys-tem Participants were randomly assignedon thebasis of a computer-generated ran-domization schedule prepared by thestudy sponsor Randomization was in a111 ratio to one of three treatmentgroups canagliflozin 100 mg canagliflo-zin 300 mg or matching placebo usingrandomly permuted blocks with stratifi-cation by use of background glucose-lowering therapy at screening (ie insulinalone insulin plus metformin or insulinplus any other glucose-lowering agent)

Postrandomization Study Treatmentand ControlStudy treatment was provided in identi-cal blister cards of canagliflozin 100 mgcanagliflozin 300 mg or placebo Partic-ipants took their study treatment oncedaily before the first meal of the daywith all participants and all study staffremaining blinded to individual treat-ment allocation

Background Drug TreatmentsParticipants were required to be receiv-ing stable background glucose-loweringtherapy including insulin for 8 weeksbefore screening and to persist withthis treatment regimen unchangedif possible for the first 18 weeks afterrandomization The rationale for thisstrategy was the desire to evaluate theshort-term (18-week) effects of canagli-flozin on biomarkers while receivingconstant background therapy A stabledose of insulin was defined as no changein the type(s) of insulin used and nochange of 15 in the total daily doseof insulin used (averaged over 1 week toaccount for day-to-day variability) Cri-teria for the institution of glycemic res-cue therapy in the first 18 weeks afterrandomization were provided for pa-tients with significant derangements ofblood glucose levels during the initial18-week period (Supplementary Table3) After week 18 glycemic manage-ment was at the discretion of the re-sponsible investigator in line withapplicable local guidelines Likewisethe use of all other therapies was man-aged according to best practice andinstituted according to local guidelinesand policies throughout the studyperiod

Follow-up SchedulePostrandomization follow-up was sched-uled at 2 4 6 9 12 18 26 39 and 52weeks after randomization The follow-upperformed at 2 4 and 9 weeks after ran-domization was by telephone unless aface-to-face consultation was deemednecessary Every follow-up contact in-cluded inquiry about adverse events(including safety outcomes) and con-comitant therapies and a review of thepatient diary entries and self-monitoredblood glucose results All face-to-facevisits also included prescription of studymedication and recording of physicalmeasurements Individuals who prema-turely discontinued study treatmentwere encouraged to return for regularassessments to ensure full ascertain-ment of study outcomes and to supportan intention-to-treat analysis for alloutcomes

OutcomesThe primary efficacy outcome for thissubstudy was the change in HbA1c Thesecondary efficacy outcomes were fastingplasma glucose proportionof participantsreaching HbA1c 70 (53 mmolmol)body weight systolic and diastolicblood pressure and fasting plasma lip-ids (ie triglycerides HDL cholesterolLDL cholesterol total cholesterol andthe ratio of LDL cholesterol to HDLcholesterol)

Safety was defined based upon theoccurrence of adverse events coded us-ing the Medical Dictionary for Regula-tory Activities (MedDRA) with datareported for all adverse events seriousadverse events deaths and adverseevents prespecified as being of specificinterest (ie genital mycotic infectionsin women and men upper and lowerurinary tract infections fractures andphotosensitivity) Hypoglycemia episodesdefined as biochemically documented epi-sodes (concurrent fingerstick or plasmaglucose 39 mmolL irrespective ofsymptoms) and severe hypoglycemiaepisodes (ie requiring the assistanceof another individual or resulting in sei-zure or loss of consciousness) were alsoreported The proportion of participantspermanently discontinuing randomizedtreatment was recorded

Statistical AnalysesEfficacy and safety analyses were perfor-med using the modified intent-to-treatpopulation consisting of all eligible

randomized patients who received $1dose of the study drug The last observa-tion carried forward (LOCF) approach wasused to impute missing efficacy data Ef-ficacy end points of a continuous naturewere assessed using an ANCOVA modelwith treatment and stratification factor(ie background glucose-lowering ther-apy at screening) as fixed effects and thecorresponding baseline value as a cova-riate Least squares mean differencesbetween treatment groups and the asso-ciated two-sided 95CIswere estimatedbased on this model The categorical sec-ondary efficacy end point (ie the pro-portion of patients reaching HbA1c

70 [53 mmolmol]) was analyzedusing a logistic regression model includ-ing terms for treatment and stratifica-tion factor and adjusting for baselineHbA1c as a covariate A prespecified hi-erarchical testing sequence which con-trols the type I error rate by ordering thehypotheses to undergo statistical test-ing was used to evaluate the prespeci-fied 18-week hypotheses (28) For allother outcomes where no hypothesiswas prespecified the data are pre-sented as point estimates and 95 CIswith no P value The primary efficacyanalyses at 18 weeks were calculatedcensoring the data after the initiationof rescue therapy All other analyseswere computed regardless of theuse of nonrandomized backgroundtherapies

The constancy of effects in participantsubgroups defined by sex age race eth-nicity BMI baseline HbA1c and baselineeGFRwas explored for the 52-week timepoint Analyses were undertaken for theprimary outcome only with the effectsin subgroups compared using tests ofthe treatment by subgroup interactionto assess homogeneity A series of sen-sitivity analyses was calculated to checkthe robustness of the study findingsFirst the 18-week efficacy analyseswere repeated including participants re-gardless of whether they required res-cue therapy Second the efficacyanalyses were repeated for all CANVAStrial participants who recorded any useof insulin at baseline (ie $1 IUdayn = 2168 see data in SupplementaryData) and third for the smaller groupof participants using a baseline insulindose of $30 IUday (n = 1718 datanot shown but conclusions not differ-ent) Finally subsequent to locking the

carediabetesjournalsorg Neal and Associates 405

substudy database there were two indi-viduals identified who had implausiblelow LDL cholesterol values at baseline(possibly because of laboratory errors)who were excluded from the lipid ana-lyses but were included in all otheranalyses

RESULTS

During a recruitment period of 15months there were 7691 individualswho were screened and 4330 whowere randomized (Supplementary Fig1) There were 2074 CANVAS trial par-ticipants who met the inclusion criteriafor this substudy (insulin use at a doseof $20 IUday) with 2 participants ex-cluded from the final analysis sincethey received no dose of the random-ized treatment Furthermore therewere 94 individuals receiving treatmentwith insulin at baseline at a dose of 1ndash19IUday and therewere 1718 individualsin the subset of participants receivinginsulin at baseline at a dose$30 IUdayAmong the 2072 individuals included inthe primary analysis there were 690 as-signed to placebo 692 assigned to cana-gliflozin 100 mg and 690 assigned tocanagliflozin 300 mg (SupplementaryFig 1) Four percent of each active treat-ment group and 8 of the placebogroup required rescue therapy duringthe first 18 weeks At the end of 52weeks the change in the total dailydose of insulin from baseline was 44IUday (11) 220 IUday (21) and243 IUday (24) among individualsreceiving placebo canagliflozin 100mg and canagliflozin 300 mg respec-tively A total of 88 of participantscompleted the scheduled 52-weekfollow-up visits At 18 weeks therewere an estimated 94 assigned to pla-cebo 95 assigned to canagliflozin 100mg and 94 assigned to canagliflozin300 mg who were still receiving random-ized treatment the corresponding per-centages at 52 weeks were 85 89and 89 respectively

Baseline Characteristics ofParticipantsAt entry into the study the median ageof participants was 63 years the meanHbA1c was 83 (67 mmolmol) themean BMI was 331 kgm2 the meaneGFR was 75 mLmin173 m2 and themean fasting plasma glucose was 92mmolL (Table 1) The median daily

insulin dose was 60 IU with most usingbasalbolus insulin regimens The meanduration of diabetes was 16 years Aboutone-quarter of participants were receiv-ing background sulfonylurea therapytwo-thirds were receiving metformintherapy and three-quarters each werereceiving statin and antithrombotic ther-apy All characteristics were balancedacross randomized groups at baseline

Effects of Canaglif lozin on EfficacyOutcomesBoth doses of canagliflozin significantlyreduced the primary outcome of HbA1crelative to placebo at week 18 (both P0001) with comparable reductions alsoseen at week 52 (Table 2 Fig 1) Therewere also reductions in the secondaryoutcomes of body weight and fastingplasma glucose (all P 0001 Table 2)and increases in the proportion of pa-tients achieving HbA1c 70 (53mmolmol) (both P 0001 Fig 1)with both canagliflozin doses versus pla-cebo at week 18 Similar effects wereseen for all outcomes at week 52 Cana-gliflozin 100 and 300 mg also provideddose-dependent reductions in systolicblood pressure compared with placeboat both time points (Table 2) The higherdose of canagliflozin raised HDL choles-terol levels compared with placebo atboth 18 and 52 weeks but the lowerdose raised levels only at 52weeks Cana-gliflozin 100 and 300mg caused an eleva-tion in LDL cholesterol at 18 and 52weeks but there was no detectablechange in the ratio of LDL cholesterolto HDL cholesterol at either time pointfor either dose There was a reduction intriglycerides only with the 300-mg doseat 52 weeks Where effects were appar-ent they were mostly numericallygreater for the higher dose Analysesthat did not censor individuals requiringrescue therapy in the first 18 weeksshowed almost identical results (Supple-mentary Table 1) Likewise sensitivityanalyses that included patients using in-sulin at any dose (Supplementary Table2) or only at doses $30 IU (data notshown) did not change the conclusionsSubgroup analyses identified greater ef-fects on HbA1c only for younger individ-uals compared with older individuals (P =002) and for more obese individuals com-pared with less obese individuals (P =005) but there was no evidence of aninteraction between treatment effect

and the other baseline characteristicsstudied (all P values 017 Supplemen-tary Fig 2) Active treatment was ob-served to reduce albuminuria at bothdoses at 12- and 52-week time pointscompared with placebo with mean re-ductions in the albumin-to-creatinineratio of 296 (95 CI 2130 261)for the 100-mg dose and 295 (95CI 2129 260) for the 300-mg doseat 52 weeks

Effects of Canagliflozin on Safety andTolerability OutcomesAt 52 weeks of follow-up adverseevents were reported for 77 78and 81 of participants treated withplacebo canagliflozin 100 mg and cana-gliflozin 300 mg respectively (Table 3)The corresponding percentages for seri-ous adverse events were 17 14 and15 respectively Adverse events lead-ing to discontinuation of treatmentwere significantly more frequent withcanagliflozin treatment compared withplacebo as were genital mycotic infec-tions in men and women and volume-related adverse events Genital mycoticinfections were more common withboth doses of canagliflozin for womenand men but there was no evidence ofan increased rate of upper or lower uri-nary tract infections Adverse events at-tributable to volume depletion weremostly postural hypotension and dizzi-ness The rates of documented hypogly-cemia were not significantly greaterwith canagliflozin than placebo andthe proportion of cases defined as se-vere hypoglycemia was low and wasnot significantly different across treat-ment groups (Table 3) There was a de-cline in the mean eGFR at 52 weeks of212 mLmin173 m2 (95 CI 223201) with the 100-mg dose and 221mLmin173 m2 (95 CI 232 209)with the 300-mg dose These effectswere attenuated compared with the18-week findings of a decline in meaneGFR of 226 mLmin173 m2 (95 CI236 216) with the 100-mg dose and232mLmin173m2 (95 CI242222)with the 300-mg dose

CONCLUSIONS

There were clear beneficial effects onHbA1c of adding canagliflozin to back-ground insulin therapy These benefitswere apparent at 18 weeks and weresustained through 52 weeks for both


doses of canagliflozin compared withplacebo The reductions in HbA1c wereaccompanied by favorable effects onbody weight and blood pressure whichwere also observed for both doses andover 52 weeks These benefits wereaccompanied by the adverse effects

anticipated for the drug class (24) Ef-fects on lipid metabolism were incon-sistent but the broad pattern wassimilar to that reported previously (23)The net impact of the changes in lipidparameters produced by canagliflozin isuncertain with the elevation in LDL

cholesterol accompanied by a rise inHDL cholesterol that leaves the ratio ofLDL cholesterol to HDL cholesterol un-changed The hazard ratio for cardiovas-cular events reported during theregulatory review process prior to mar-keting was not suggestive of harm and

Table 1mdashBaseline characteristics of randomized participants using insulin (Dagger20 IUday) at baseline

Placebo(n = 690)

Canagliflozin 100 mg(n = 692)


Age (years) median (range) 630 (38ndash82) 620 (32ndash83) 630 (37ndash85)

Female () 34 33 35

Race ()White 75 76 76Asian 18 15 15Black 3 2 3Otherdagger 5 7 6

Current smoker n () 114 (17) 96 (14) 99 (14)

Duration of diabetes (years) mean (SD) 160 (78) 164 (73) 163 (74)

Insulin dose (IUday) median 58 60 60

Insulin therapy n ()DaggerBasal plus bolus 427 (62) 443 (64) 428 (62)Basal alone 178 (26) 189 (27) 182 (26)Bolus alone 76 (11) 49 (7) 66 (10)

Other drug therapy n ()Sulfonylurea 170 (25) 165 (24) 156 (23)Metformin 438 (64) 435 (63) 430 (62)Statin 521 (76) 538 (78) 513 (74)Antithrombotic 504 (73) 501 (72) 506 (73)

Microvascular disease n ()Retinopathy 193 (28) 189 (27) 213 (31)Nephropathy 146 (21) 141 (20) 133 (19)Neuropathy 277 (40) 260 (38) 293 (43)

Atherosclerotic vascular disease n ()sectCoronary 350 (51) 343 (50) 378 (55)Cerebrovascular 110 (16) 107 (16) 118 (17)Peripheral 109 (16) 115 (17) 135 (20)Any 436 (63) 434 (63) 470 (68)

BMI (kgm2) mean (SD) 331 (65) 330 (65) 333 (62)

Body weight (kg) mean (SD) 948 (223) 944 (216) 948 (213)

SBP (mmHg) mean (SD) 1378 (162) 1369 (167) 1371 (167)

DBP (mmHg) mean (SD) 772 (103) 762 (99) 763 (98)

HbA1c mean (SD) 83 (09) 83 (09) 83 (09)mmolmol 670 (98) 670 (98) 670 (98)

FPG (mmolL) mean (SD) 92 (27) 92 (27) 92 (28)

Total cholesterol (mmolL) mean (SD) 43 (12) 43 (12) 43 (10)

Triglycerides (mmolL) mean (SD) 20 (19) 20 (13) 19 (13)

HDL cholesterol (mmolL) mean (SD) 12 (03) 12 (03) 12 (03)

LDL cholesterol (mmolL) mean (SD) 22 (09) 22 (09) 23 (09)

LDL-to-HDL cholesterol ratio mean (SD) 20 (09) 19 (08) 20 (09)

eGFR (mLmin173 m2) mean (SD) 749 (192) 762 (191) 737 (187)

eGFR 60 mLmin173 m2 n () 140 (20) 130 (19) 149 (22)

ACR (mgg) mean (SD) 1395 (4596) 1058 (4182) 1133 (3448)

Microalbuminuria n () 159 (23) 188 (27) 156 (23)

Macroalbuminuria n () 69 (10) 46 (7) 54 (8)

ACR albumin-to-creatinine ratio DBP diastolic blood pressure FPG fasting plasma glucose SBP systolic blood pressure Percentages may nottotal 100 due to rounding daggerIncluding American Indian or Alaskan Native Native Hawaiian or other Pacific Islander multiple other and unknownDaggerData on dosing regimen are missing for 1ndash2 of individuals sectSome participants had more than one type of atherosclerotic disease at baseline


ruled out large adverse effects of thecompound (23)The observed additive effects of cana-

gliflozin on top of insulin are anticipated

on the basis of the different mechanismof action of the compound Becausecanagliflozin acts independently of insu-lin it should be an effective treatment

choice at most stages of the disease andalso when used in conjunction withmost other glucose-lowering therapiesFurthermore the combination of cana-gliflozin with insulin may offer advant-ages compared with the combination ofinsulin with other oral agents becausethe use of canagliflozin may mitigateagainst the risks of hypoglycemia andweight gain that can be exacerbatedby some other drug classes (29) Thesubset of patients among whom glucose-lowering efficacy might be reduced isthose with renal impairment (23) andthis might explain the lesser effect ofcanagliflozin among older individualsin this study Alternatively this mayalso be a chance finding because asfor the observed interaction with obe-sity the P value was not extreme andage and obesity have not been identi-fied as effect modifiers in larger datasets (23)

The 300-mg dose of canagliflozin wasassociated with numerically greater ef-fects on most efficacy outcomes al-though the incremental changes weremoderate when compared against thedifferences between the 100-mg doseof canagliflozin and placebo The addi-tional efficacy effects conferred by thehigher dose were achieved at the

Table 2mdashEffects of each dose of canagliflozin compared with placebo on primary secondary and other efficacy outcomes at18 and 52 weeks in patients using insulin (Dagger20 IUday)

18 weeks 52 weeksdagger

Canagliflozin 100 mgvs placebo

(n = 661 vs 636)Dagger







Change in HbA1csect 2062 (2069 2054)| 2073 (2081 2065)| 2058 (2068 2048) 2073 (2083 2063)mmolmol 268 (275 259) 280 (289 271) 263 (274 252) 280 (291 269)

Change in body weight ()sect 219 (222 216)| 224 (227 221)| 228 (233 224) 235 (239 230)

Change in FPG (mmolL)sect 212 (214 209)| 216 (218 213)| 211 (214 209) 215 (217 212)

Change in SBP (mmHg) 223 (237 210) 241 (255 228) 231 (246 217) 262 (277 248)

Change in DBP (mmHg) 210 (218 202) 217 (225 209) 212 (220 203) 224 (232 215)

Proportion with HbA1c 70 ()sect 115 (76 154)| 174 (133 215)| 133 (93 174) 187 (145 230)

Change in HDL cholesterol () 11 (208 30) 45 (26 64) 23 (05 41) 50 (33 68)

Change in triglycerides () 210 (255 34) 227 (271 18) 216 (265 33) 256 (2105 207)

Change in LDL cholesterol ()para 55 (209 119) 49 (215 113) 35 (220 89) 68 (13 122)

Change in total cholesterol () 11 (207 30) 28 (09 47) 16 (205 37) 31 (10 52)

Change in LDL-to-HDL cholesterol ratio ()sect 40 (225 104) 04 (260 68) 11 (246 68) 07 (250 64)

Change in non-HDL cholesterol () 10 (216 36) 22 (204 48) 18 (213 49) 27 (205 57)

Data are presented as difference (95 CI) DBP diastolic blood pressure FPG fasting plasma glucose SBP systolic blood pressure For patients notrequiring rescue therapy daggerFor all participants regardless of need for rescue therapy DaggerExact n for the primary outcome or patients with missing datathe last observation was carried forward sectIndicates end points that were prespecified for hypothesis testing at week 18 |P 0001 vs placebo forall prespecified hypotheses paraOutlying data from two subjects were excluded at week 52 Differences (95 CI) vs placebo for canagliflozin 100 mgand 300mg with outliers included the following LDL cholesterol 167 (03 330) and 74 (291 238) respectively LDL-to-HDL cholesterol ratio112 (222 247) and 08 (2127 143) respectively

Figure 1mdashEffects of each dose of canagliflozin compared with placebo on measures of glycemia inpatients using insulin ($20 IUday) A LS mean change in HbA1c from baseline to week 52 Forpatients with missing data the last observation was carried forward B Proportion of patients reach-ing HbA1c 70 (53 mmolmol) at 18 and 52 weeks LS least squares P 0001 vs placebo


expense of an increased risk of drug-related adverse events driven primarilyby a dose-related increase in side effectsattributable to volume depletion Thebalance of risks and benefits associatedwith each dose will need to be deter-mined on an individual basis by the pre-scribing physicianThe adverse effects of canagliflozin

observed in this subset of patients usingbackground insulin are those antici-pated for the drug class (24) Genitalmycotic infections were common butwere generally mild or moderate in in-tensity were managed with topical ororal antifungal drugs and led to few dis-continuations of randomized treatmentRates of urinary tract infections werenot clearly higher although pooled anal-yses of larger data sets show that this isan adverse effect of this drug class whenused in patients with diabetes (24)Symptoms attributable to volume de-pletion were dose related but did notcause serious adverse outcomes Therehave been reports (24) of adverse ef-fects of blood pressurendashlowering agentson fall-related fractures attributed tovolume depletion and this also may bean effect of the SGLT2 drug class Thefew fracture events recorded in this sub-study were however balanced across

groups The observed decline in eGFRoccurred relatively early (ie withinthe first 3ndash6 weeks after initiating ther-apy with canagliflozin) was attenuatedover time and was not associated withan excess of renal adverse events Thetime course of the decline in eGFR par-allels that of reduced numbers of intra-vascular volume adverse events whichalso start early after initiating therapywith canagliflozin (30) The reduction inthe albumin-to-creatinine ratio couldbe attributed to the effects of canagli-flozin on blood pressure or blood glu-cose and there is also some evidenceto support a mechanism based upontubuloglomerular feedback (31) Themechanism for weight loss was not ex-plored in this trial but other studies(15) have reported that about two-thirds of the effect is due to a reductionin fat

A key strength of this study is its largesize and its robust randomized and con-trolled design The conduct of analysesat both 18 and 52 weeks provides esti-mates of both short- and medium-termeffects although the long-term impactof canagliflozin in this group remains tobe established The completeness offollow-up for the main efficacy andsafety outcomes was good and the

findings were robust to a series of sen-sitivity analyses It is possible that someindividuals may have been unblindedbecause of the effects of active treat-ment on diuresis or glucosuria but thisis unlikely to have substantively im-pacted the main trial conclusions whichare based mostly on fairly objective out-come measures The absence of clearevidence about the effects of canagliflo-zin on definitive clinical outcomes in ei-ther this population using insulin or inbroader patient groups with diabetesremains a significant shortcoming ofthe existing evidence base althoughthis should be rectified as a series oflarge ongoing trials are completed overthe coming years The enrollment of ahigh-risk patient group in the CANVAStrial was performed both to ensurethat the study had power to addressits efficacy and safety objectives and toincrease the diversity of participants inthe broader canagliflozin developmentprogram While aspects of the resultsobtained here cannot be generalizeddirectly to other patient populationsit is likely that the proportionate ef-fects observed here are more broadlyapplicable Older patients may have in-dividualized HbA1c targets above the70 level defined as a secondary out-come for this study It is of note thatsimilarly large and significant benefitsof canagliflozin compared with placebowere also observed when effects ontarget levels of 75 and 80 wereexamined

In conclusion canagliflozin appears tooffer significant benefits when used inconjunction with insulin therapy How-ever additional data are required forthe subset of patients using insulinand for patients with diabetes morebroadly to objectively define the ef-fects of canagliflozin on major clinicaloutcomes

Acknowledgments The authors thank KimberlyDittmar of MedErgy for technical editorialassistance The authors also acknowledge thefollowing committees and sponsor of the CANa-gliflozin CardioVascular Assessment Study Steer-ing CommitteedD Matthews (Co-chair)B Neal (Co-chair) G Fulcher K MahaffeyV Perkovic G Meininger and D de ZeeuwIndependent Data Monitoring CommitteedP Home (Chair) J Anderson I Campbell J LachinD Scharfstein S Solomon and R Uzzo EndpointAdjudication CommitteedG Fulcher J AmerenaC Chow G Figtree J French G Hillis B Jenkins

Table 3mdashEffects of each dose of canagliflozin compared with placebo on safetyoutcomes at 52 weeks

Placebo(n = 690)

Canagliflozin100 mg(n = 692)


All adverse events 533 (77) 540 (78) 558 (81)Serious adverse events 115 (17) 94 (14) 104 (15)Deaths 10 (1) 6 (1) 7 (1)Event leading to discontinuation 34 (5) 29 (4) 48 (7)Events related to study drug 144 (21) 233 (34) 267 (39)

InfectionsGenital mycotic infections in

women 7 (3) 41 (18) 32 (13)Genital mycotic infections in mendagger 7 (2) 35 (8) 55 (12)Upper urinary tract infections 4 (1) 4 (1) 0Lower urinary tract infections 36 (5) 36 (5) 42 (6)

Documented hypoglycemia 333 (48) 409 (59) 396 (57)Severe hypoglycemia 27 (4) 31 (5) 38 (6)

Osmotic diuresisndashrelated adverse events 17 (2) 59 (9) 69 (10)

Volume-related adverse events 14 (2) 25 (4) 42 (6)

Renal-related adverse events 6 (1) 5 (1) 7 (1)

Photosensitivity events 1 (01) 1 (01) 3 (04)

Fractures 11 (2) 18 (3) 8 (1)

Data are presented as n () Women placebo n = 232 canagliflozin 100 mg n = 227canagliflozin 300 mg n = 244 daggerMen placebo n = 458 canagliflozin 100 mg n = 465canagliflozin 300 mg n = 446


R Lindley B McGrath A Street and J WatsonSponsordJanssen Research amp DevelopmentLLCFunding BN is supported by an AustralianResearch Council Future Fellowship and a Na-tional Health and Medical Research CouncilSenior Research Fellowship VP is supportedby a Senior Research Fellowship from theAustralian National Health and Medical Re-search CouncilDuality of Interest The CANVAS trial is fundedby Janssen Research amp Development LLC Tech-nical editorial assistance was funded by JanssenGlobal Services LLC BN holds a research grantfor this study from Janssen and for other large-scale cardiovascular outcome trials from RocheServier and MerckSchering-Plough BN hasreceived honoraria or travel support for contri-butions to the continuing medical educationprograms of Abbott Novartis Pfizer Rocheand Servier VP has served on advisory boardsandor spoken at scientific meetings spon-sored by Janssen Baxter AbbVie AstellasBoehringer Ingelheim AstraZeneca Merckand GlaxoSmithKline and has a policy of hono-raria going to his employer DdZ has served as aconsultant to AstraZeneca Amgen AbbotMerck Bristol-Myers Squibb Novartis VitaeTakeda HemoCue Johnson amp Johnson ReataAstellas AbbVie and ChemoCentryx KWMhas provided continuing medical education onbehalf of andor has served as a consultant tothe American College of Cardiology AstraZenecaBayer Boehringer Ingelheim Bristol-MyersSquibb Eli Lilly Forest GlaxoSmithKline Johnsonamp JohnsonMedtronicMerck Spring PublishingThe Medicines Company and WebMD GF hasserved on advisory boards for Johnson amp Johnsonand as a consultant to Janssen KW GC FVand GM are full-time employees of JanssenResearch amp Development LLC and are share-holders of Johnson amp Johnson MD WS MAand JJ are full-time employees of JanssenResearch amp Development LLC DM has servedon advisory boards or as a consultant for NovoNordisk GlaxoSmithKline Novartis Eli LillySanofi Aventis Janssen and Servier and hasgiven lectures for Novo Nordisk Servier SanofiAventis Eli Lilly Novartis Janssen and AcheLaboratories DM receives current researchsupport from Janssen and the National Insti-tute for Health Research No other potentialconflicts of interest relevant to this articlewere reportedAuthor Contributions BN contributed tothe design and conduct of the study and theinterpretation of the data wrote the first draftof the manuscript and reviewed and approvedthe manuscript VP DdZ KWM GF andDM contributed to the design and conduct ofthe study and the interpretation of data andreviewed and approved the manuscript KWcontributed to the design of the study and theanalysis and interpretation of data and re-viewed and approved the manuscript MDand FV contributed to the conduct of the studyand the acquisition and interpretationof data andreviewed and approved the manuscript WScontributed to the design and conduct of thestudy and the acquisition of data and re-viewed and approved the manuscript GCand JJ contributed to the analysis and in-

terpretation of the data and reviewed andapproved the manuscript MA contributed tothe interpretation of the data and reviewedand approved the manuscript GM contrib-uted to the design and conduct of the studyand the acquisition analysis and interpreta-tion of the data and reviewed and approvedthe manuscript BN and MD are the guar-antors of this work and as such had fullaccess to all the data in the study and takeresponsibility for the integrity of the data andthe accuracy of the data analysisPrior Presentation Parts of this study werepreviously presented in abstract form at the48th Annual Meeting of the European Associa-tion for the Study of Diabetes Berlin Germany1ndash5 October 2012 and at the World DiabetesCongress of the International Diabetes Fed-eration Melbourne Victoria Australia 2ndash6December 2013

References1 Unwin N Gan D Mbanya J et al DiabetesAtlas Brussels Belgium International DiabetesFederation 20092 Turnbull FM Abraira C Anderson RJ et alControl Group Intensive glucose control andmacrovascular outcomes in type 2 diabetes Di-abetologia 2009522288ndash22983 American Diabetes Association Executivesummary standards of medical care in dia-betesd2010 Diabetes Care 201033(Suppl 1)S4ndashS104 List JF Woo V Morales E Tang W FiedorekFT Sodium-glucose cotransport inhibition withdapagliflozin in type 2 diabetes Diabetes Care200932650ndash6575 Wright EM Renal Na(+)-glucose cotransport-ers Am J Physiol Renal Physiol 2001280F10ndashF186 Bailey CJ Renal glucose reabsorption inhib-itors to treat diabetes Trends Pharmacol Sci20113263ndash717 Mogensen CE Maximum tubular reabsorp-tion capacity for glucose and renal hemodynam-cis during rapid hypertonic glucose infusion innormal and diabetic subjects Scand J Clin LabInvest 197128101ndash1098 Mather A Pollock C Glucose handling by thekidney Kidney Int Suppl 2011S1ndashS69 Rahmoune H Thompson PW Ward JMSmith CD Hong G Brown J Glucose transport-ers in human renal proximal tubular cellsisolated from the urine of patients with non-insulin-dependent diabetes Diabetes 2005543427ndash343410 Devineni D Morrow L Hompesch M et alCanagliflozin improves glycaemic control over28 days in subjects with type 2 diabetes notoptimally controlled on insulin Diabetes ObesMetab 201214539ndash54511 Polidori D Sha S Ghosh A Plum-MorschelL Heise T Rothenberg P Validation of a novelmethod for determining the renal threshold forglucose excretion in untreated and canagliflozin-treated subjects with type 2 diabetes mellitusJ Clin Endocrinol Metab 201398E867ndashE87112 Rosenstock J Aggarwal N Polidori D et alCanagliflozin DIA 2001 Study Group Dose-rangingeffects of canagliflozin a sodium-glucose cotrans-porter 2 inhibitor as add-on to metformin in

subjects with type 2 diabetes Diabetes Care2012351232ndash123813 Sha S Devineni D Ghosh A et alCanagliflozin a novel inhibitor of sodium glu-cose co-transporter 2 dose dependently re-duces calculated renal threshold for glucoseexcretion and increases urinary glucose excre-tion in healthy subjects Diabetes Obes Metab201113669ndash67214 Bode B Stenlof K Sullivan D Fung A UsiskinK Efficacy and safety of canagliflozin treatmentin older subjects with type 2 diabetes mellitusa randomized trial Hosp Pract (1995) 20134172ndash8415 Cefalu WT Leiter LA Yoon K-H et al Efficacyand safety of canagliflozin versus glimepiride inpatients with type 2 diabetes inadequately con-trolled with metformin (CANTATA-SU) 52 weekresults from a randomised double-blind phase3 non-inferiority trial Lancet 2013382941ndash95016 Lavalle-Gonzalez FJ Januszewicz ADavidson J et al Efficacy and safety of canagli-flozin compared with placebo and sitagliptin inpatients with type 2 diabetes on backgroundmetformin monotherapy a randomised trialDiabetologia 2013562582ndash259217 Schernthaner G Gross JL Rosenstock Jet al Canagliflozin compared with sitagliptinfor patients with type 2 diabetes who do nothave adequate glycemic control withmetforminplus sulfonylurea a 52-week randomized trialDiabetes Care 2013362508ndash251518 Stenlof K Cefalu WT Kim KA et al Long-term efficacy and safety of canagliflozinmonotherapy in patients with type 2 diabetesinadequately controlled with diet and exercisefindings from the 52-week CANTATA-M studyCurr Med Res Opin 201430163ndash17519 Stenlof K Cefalu WT Kim K-A et al Efficacyand safety of canagliflozin monotherapy in sub-jects with type 2 diabetes mellitus inadequatelycontrolled with diet and exercise DiabetesObes Metab 201315372ndash38220 Wilding JP Charpentier G Hollander P et alEfficacy and safety of canagliflozin in patientswith type 2 diabetes mellitus inadequately con-trolled with metformin and sulphonylureaa randomised trial Int J Clin Pract 2013671267ndash128221 Yale JF Bakris G Cariou B et al Efficacy andsafety of canagliflozin in subjects with type 2diabetes and chronic kidney disease DiabetesObes Metab 201315463ndash47322 Inagaki N Kondo K Yoshinari T MaruyamaN Susuta Y Kuki H Efficacy and safety ofcanagliflozin in Japanese patients with type 2diabetes a randomized double-blind placebo-controlled 12-week study Diabetes ObesMetab 2013151136ndash114523 Janssen Research amp Development LLC En-docrinologic and Metabolic Drugs AdvisoryCommittee Canagliflozin as an adjunctivetreatment to diet and exercise alone or coad-ministered with other antihyperglycemicagents to improve glycemic control in adultswith type 2 diabetes mellitus JNJ-28431754(Canagliflozin) NDA 204042 [Internet] 2013Available from httpwwwfdagovdownloadsadvisorycommitteescommitteesmeetingmaterialsdrugsendocrinologicandmetabolicdrugsadvisorycommitteeucm334551pdfAccessed 15 January 2014


24 Vasilakou D Karagiannis T Athanasiadou E

et al Sodium-glucose cotransporter 2 inhibitors

for type 2 diabetes a systematic review and

meta-analysis Ann Intern Med 2013159262ndash

27425 Nicolle LE Capuano G Fung A Usiskin K Uri-

nary tract infection in randomized phase III studies

of canagliflozin a sodium glucose co-transporter 2

inhibitor Postgrad Med 20141267ndash1726 Nyirjesy P Sobel JD Fung A et al Genital

mycotic infections with canagliflozin a sodium

glucose co-transporter 2 inhibitor in patients

with type 2 diabetes mellitus a pooled analysis

of clinical studies Curr Med Res Opin 2014301109ndash111927 Neal B Perkovic V de Zeeuw D et al Ratio-nale design and baseline characteristics of theCanagliflozin Cardiovascular Assessment Study(CANVAS)da randomized placebo-controlledtrial Am Heart J 2013166217ndash223 e1128 Koch G Gansky S Statistical considerationsfor multiplicity in confirmatory protocols DrugInf J 199630523ndash53429 Inzucchi SE Bergenstal RM Buse JB et alAmerican Diabetes Association (ADA) EuropeanAssociation for the Study of Diabetes (EASD)Management of hyperglycemia in type 2

diabetes a patient-centered approach positionstatement of the American Diabetes Association(ADA) and the European Association for theStudy of Diabetes (EASD) Diabetes Care 2012351364ndash137930 Usiskin K Kline I Fung A Mayer CMeininger G Safety and tolerability of canagli-flozin in patients with type 2 diabetes mellituspooled analysis of phase 3 study results Post-grad Med 201412616ndash3431 Abdul-Ghani MA Norton L Defronzo RARole of sodium-glucose cotransporter 2 (SGLT2) inhibitors in the treatment of type 2 diabetesEndocr Rev 201132515ndash531


Type 2 diabetes causes a large burden ofdisease around the world (1) The con-trol of blood glucose levels is central tothe management of symptoms and theprevention of complications (2) Thereare a broad range of treatments thatcan be used to lower blood glucose lev-els butmany patients still fail to achievetargets (3) Accordingly new therapiesthat can lower blood glucose levels withgood safety and tolerability have signif-icant potential in the future manage-ment of the conditionInhibition of the sodiumndashglucose co-

transporter 2 (SGLT2) is a novel strategyfor glucose control (4ndash9) SGLT2 is ahigh-capacity and low-affinity glucosetransporter that is expressed in the lu-minal membranes of the proximal renaltubules and is responsible for themajor-ity of glucose reabsorption from the tu-bular lumen An inherited deficiency ofSGLT2 can produce renal glucosuriawith some affected individuals excretingas much as 100 g of urinary glucose perday (5) Canagliflozin is an orally activeinhibitor of SGLT2 that reduces proximaltubular glucose reabsorption and in-creases urinary glucose excretion (10ndash13) Treatment produces a significantloss of glucose with beneficial effectson glycemic control body weight andblood pressure (1214ndash22) Small in-creases in LDL and HDL cholesterol havebeen observed with the ratio remainingunchanged (23)Canagliflozin has a low risk of hypo-

glycemia in the absence of concomitanttherapy although rates may be in-creased when used in conjunction withinsulin or insulin secretagogues (2324)The risks of genitourinary infectionsand lower urinary tract infections areelevated with canagliflozin (232526)but the risks of upper urinary tract in-fections are not and the rates of treat-ment discontinuation attributed to sideeffects are low (1214ndash22) This reportdefines the effects of canagliflozin onindicators of glycemia safety and toler-ability when used in conjunction withinsulin therapy in a prespecified sub-study of the CANagliflozin CardioVascu-lar Assessment Study (CANVAS)


Overall Design of the CANVAS TrialCANVAS is a randomized double-blindplacebo-controlled parallel-group mul-ticenter trial The study is ongoing and

has randomized 4330 individuals on a111 basis to placebo canagliflozin100 mg or canagliflozin 300 mg withthe primary objectives being to deter-mine the efficacy and safety of cana-gliflozin compared with placebo

Objectives and Specific Hypothesesfor the Insulin SubstudyThe purpose of the insulin substudy ofthe CANVAS trial was to define the 18-week effects of canagliflozin (when usedin addition to insulin therapy at a doseof $20 IUday) on a range of efficacysafety and tolerability outcomes in pa-tients with type 2 diabetes with inade-quate glycemic control The objectivesof the substudy were to assess sepa-rately the effects of each dose of cana-gliflozin compared with placebo onHbA1c safety and tolerability at the18-week follow-up The primary hy-pothesis was that each dose of cana-gliflozin would produce a greaterreduction in HbA1c compared withplacebo

Secondary objectives of the substudywere to determine the effects at the 18-week follow-up of each dose of canagli-flozin compared with placebo on bodyweight fasting plasma glucose propor-tion of participants reaching HbA1c

70 (53 mmolmol) systolic and di-astolic blood pressure and fastingplasma lipids (ie triglycerides HDLcholesterol LDL cholesterol total cho-lesterol and the ratio of LDL cholesterolto HDL cholesterol) For the 52-week as-sessment the defined objectives wereto determine the effects of each doseof canagliflozin compared with placeboon fasting plasma glucose body weightsystolic and diastolic blood pressureand fasting plasma lipids The prespeci-fied hypotheses for the secondary ob-jectives were related to the 18-weekeffects on fasting plasma glucose theproportion of participants reachingHbA1c 70 (53 mmolmol) and bodyweight

RecruitmentRecruitment for the CANVAS study wasperformed at 386 centers in 24 countriescommencing in December 2009 andcompleting in March 2011 (clinical trialreg no NCT01032629 clinicaltrialsgov) The 12-month follow-up of the fi-nal participants included in this substudywas completed in March 2012 Regula-tory approval for the conduct of the trial

was obtained in each country and ethicsapproval was received at every site priorto initiation of the trial

Participant Inclusion and ExclusionCriteriaParticipants in the CANVAS trial are menand women with type 2 diabetes whohave inadequate glycemic control(HbA1c $70 [53 mmolmol] and105 [91 mmolmol]) despite currentmanagement with glucose-loweringstrategies and are at an elevated riskof cardiovascular disease The subsetincluded in the insulin substudy com-prised participants that were using$20 IUday insulin at baseline All par-ticipants were required to provide in-formed consent be willing and able toadhere to the study protocol require-ments and successfully complete thetrial screening and run-in period To en-sure the recruitment of a broad pop-ulation group there were minimalrestrictions on the use of backgroundtherapies Patients using insulin pumpswere not excluded from the study Allparticipants had an established or anelevated risk of cardiovascular diseaseand were either$30 years of age with ahistory of symptomatic atheroscleroticvascular disease (coronary cerebrovas-cular or peripheral) or$50 years of agewith two or more of the following riskfactors$10 years duration of diabetessystolic blood pressure 140 mmHgwhile receiving one or more or antihy-pertensive agents current smoking mi-croalbuminuria or macroalbuminuriaor HDL cholesterol1 mmolL Individ-uals with an estimated glomerular filtra-tion rate (eGFR) 30 mLmin173 m2

at baseline were not eligible for inclu-sion in the study Other exclusion crite-ria were typical of those usually invokedfor a trial of this stage in this patientgroup (27)

Screening and Run-in PeriodAll potential participants completed ascreening visit to establish initial eligibil-ity and progressed to a 2-week single-blind placebo run-in period if thescreening criteria were met The pri-mary purpose of the run-in period wasto exclude prior to randomizationthose individuals who were unlikely toadhere to the long-term treatment andfollow-up regimen required by the trial














RESULTS







CONCLUSIONS







Placebo(n = 690)




Female () 34 33 35


Current smoker n () 114 (17) 96 (14) 99 (14)







BMI (kgm2) mean (SD) 331 (65) 330 (65) 333 (62)


SBP (mmHg) mean (SD) 1378 (162) 1369 (167) 1371 (167)

DBP (mmHg) mean (SD) 772 (103) 762 (99) 763 (98)


FPG (mmolL) mean (SD) 92 (27) 92 (27) 92 (28)







eGFR 60 mLmin173 m2 n () 140 (20) 130 (19) 149 (22)

ACR (mgg) mean (SD) 1395 (4596) 1058 (4182) 1133 (3448)











































Placebo(n = 690)











Fractures 11 (2) 18 (3) 8 (1)


































RESULTS







CONCLUSIONS







Placebo(n = 690)




Female () 34 33 35


Current smoker n () 114 (17) 96 (14) 99 (14)







BMI (kgm2) mean (SD) 331 (65) 330 (65) 333 (62)


SBP (mmHg) mean (SD) 1378 (162) 1369 (167) 1371 (167)

DBP (mmHg) mean (SD) 772 (103) 762 (99) 763 (98)


FPG (mmolL) mean (SD) 92 (27) 92 (27) 92 (28)







eGFR 60 mLmin173 m2 n () 140 (20) 130 (19) 149 (22)

ACR (mgg) mean (SD) 1395 (4596) 1058 (4182) 1133 (3448)











































Placebo(n = 690)











Fractures 11 (2) 18 (3) 8 (1)























RESULTS







CONCLUSIONS







Placebo(n = 690)




Female () 34 33 35


Current smoker n () 114 (17) 96 (14) 99 (14)







BMI (kgm2) mean (SD) 331 (65) 330 (65) 333 (62)


SBP (mmHg) mean (SD) 1378 (162) 1369 (167) 1371 (167)

DBP (mmHg) mean (SD) 772 (103) 762 (99) 763 (98)


FPG (mmolL) mean (SD) 92 (27) 92 (27) 92 (28)







eGFR 60 mLmin173 m2 n () 140 (20) 130 (19) 149 (22)

ACR (mgg) mean (SD) 1395 (4596) 1058 (4182) 1133 (3448)











































Placebo(n = 690)











Fractures 11 (2) 18 (3) 8 (1)


























Placebo(n = 690)




Female () 34 33 35


Current smoker n () 114 (17) 96 (14) 99 (14)







BMI (kgm2) mean (SD) 331 (65) 330 (65) 333 (62)


SBP (mmHg) mean (SD) 1378 (162) 1369 (167) 1371 (167)

DBP (mmHg) mean (SD) 772 (103) 762 (99) 763 (98)


FPG (mmolL) mean (SD) 92 (27) 92 (27) 92 (28)







eGFR 60 mLmin173 m2 n () 140 (20) 130 (19) 149 (22)

ACR (mgg) mean (SD) 1395 (4596) 1058 (4182) 1133 (3448)











































Placebo(n = 690)











Fractures 11 (2) 18 (3) 8 (1)




























































Placebo(n = 690)











Fractures 11 (2) 18 (3) 8 (1)






























Placebo(n = 690)











Fractures 11 (2) 18 (3) 8 (1)























































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