Diabetes Care 1

Helena W. Rodbard,1 Anne L. Peters,2 The Effect of Canagliflozin, a April Slee,3 Anjun Cao,4 Shana B. Traina,5 CARE/EDUCATION/NUTRITION/PSYCHOSOCIAL CLIN Sodium Glucose Cotransporter 2 and Maria Alba4 Inhibitor, on Glycemic End Points Assessed by Continuous Glucose Monitoring and Patient-Reported Outcomes Among People With DOI: 10.2337/dc16-1353

OBJECTIVE To assess the effects of canagliflozin, a sodium glucose cotransporter 2 inhibitor, on glycemic parameters and measures of glucose variability assessed by a 9-point self-monitoring blood glucose (SMBG) and continuous glucose monitoring (CGM) profiles, and patient-reported outcomes as an add-on to among partici- pants with type 1 diabetes.

RESEARCH DESIGN AND METHODS In this randomized, double-blind study, 351 participants received canagliflozin 100 or 300 mg or placebo for 18 weeks. Change from baseline in daily mean glucose and SD was measured using a 9-point SMBG profile. In a subset of 89 participants who un- derwent CGM, the change from baseline in mean glucose, measures of glycemic variability (SD, coefficient of variation, and mean amplitude of glycemic excursions), and time spent in glycemic ranges were assessed. Change in treatment satisfaction was evaluated using the Diabetes Treatment Satisfaction Questionnaire (n = 328).

RESULTS At week 18, reductions in daily mean glucose and SD measured using the 9-point 1Endocrine and Metabolic Consultants, Rockville, SMBG profile were seen with canagliflozin 100 and 300 mg versus placebo. Reduc- MD 2 tions in mean glucose (21.2, 20.7, and 0.6 mmol/L) and measures of glycemic Keck School of Medicine of the University of 2 2 Southern California, Los Angeles, CA variability assessed by CGM, such as changes in glucose SD ( 0.3, 0.7, and 3Axio Research, Seattle, WA 0.1 mmol/L), were also seen with canagliflozin 100 and 300 mg versus placebo, 4Janssen Research & Development, LLC, Raritan, respectively. Canagliflozin 100 and 300 mg were associated with increases in time NJ 5 spent within target (glucose >3.9 to £10.0 mmol/L) compared with placebo (11.6%, Janssen Global Services, LLC, Raritan, NJ 10.1%, and 23.5%, respectively) and commensurate reductions in time spent above Corresponding author: Helena W. Rodbard, [email protected]. the target level (glucose >10.0 mmol/L; 212.7%,27.6%, and 5.7%, respectively). fl Received 23 June 2016 and accepted 2 November Participants showed greater improvement in treatment satisfaction with canagli ozin 2016. versus placebo; reductions in insulin dose, SD of glucose, and body weight contributed reg. no. NCT02139943, ClinicalTrials to the relationship between canagliflozin and satisfaction change. .gov. This article contains Supplementary Data online CONCLUSIONS at http://care.diabetesjournals.org/lookup/ Canagliflozin improved indices of glycemic variability and was associated with suppl/doi:10.2337/dc16-1353/-/DC1. improvement in treatment satisfaction versus placebo over 18 weeks among © 2016 by the American Diabetes Association. participants with type 1 diabetes. Although these data from this study demonstrate Readers may use this article as long as the work the potential benefits of canagliflozin in people with type 1 diabetes, canagliflozin is is properly cited, the use is educational and not for profit, and the work is not altered. More infor- not approved for the treatment of type 1 diabetes and should not currently be used mation is available at http://www.diabetesjournals in people with type 1 diabetes. .org/content/license. Diabetes Care Publish Ahead of Print, published online November 29, 2016 2 Effect of CANA on Glycemic Variability and Patient-Reported Outcomes Diabetes Care

Intensive insulin treatment has been Canagliflozin, a sodium glucose co- or continuous subcutaneous insulin in- shown to prevent and delay the develop- transporter 2 (SGLT2) inhibitor approved fusion (CSII). Eligible participants were ment of microvascular and macrovascular for the treatment of (23), 25–65 years of age with BMI values of complications among people with type 1 is under study for type 1 diabetes. Cana- 21–35 kg/m2, fasting C-peptide concen- diabetes (1,2). Even with intensive treat- gliflozin lowers blood glucose through an tration of ,0.2 pmol/L (,0.6 ng/mL), ment, people with type 1 diabetes can insulin-independent mechanism by low- and had type 1 diabetes for $1 years experience acute and profound glucose ering the renal threshold for glucose with an HbA1c of 7.0–9.0% (53–75 fluctuations, which may be related to var- and increasing urinary glucose mmol/mol) at screening. Participants iability in insulin activity and changes in (24–26). Findings from a retrospective were receiving a stable insulin regimen day-to-day activities, such as meal size analysis of people with type 1 diabetes (total daily dose $0.6 international units and type, illness, and level of exercise who were prescribed canagliflozin 100 mg [IU]/kg at screening) with MDI or CSII (3–5). Therefore, one of the major chal- and used CGM showed that canagliflozin for $8 weeks prior to screening. The lenges in the treatment of type 1 diabetes improved measures of glycemic control, key exclusion criteria included a history is to achieve patient-specificglycemic including HbA1c, CGM SD, time in hyper- of type 2 diabetes; a severe hypoglyce- control while avoiding hyperglycemia glycemia, and total daily insulin dose, mic event (i.e., requiring assistance and episodes (6). Glycemic in addition to lowering body weight from another person or resulting in sei- fluctuations can be dangerous, especially (27). In a phase 2 study of canagliflozin zure or loss of consciousness) or DKA because some people may perform un- as an add-on to insulin among partici- within 6 months prior to randomization; healthy behaviors, such as keeping blood pants with type 1 diabetes, canagliflozin myocardial infarction, unstable angina, glucose levels high, to avoid future hypo- 100 and 300 mg provided reductions in revascularization procedure, or cere- glycemic episodes (7–9). HbA1c, body weight, and insulin dose, brovascular accident #12 weeks before Continuous glucose monitoring (CGM) with no increase in documented hypo- screening; history of New York Heart can be an important tool for the aware- glycemia over 18 weeks (28). Canagliflozin Association Class III–IV cardiac dis- ness of glycemic variability among peo- was generally well tolerated with a ease; uncontrolled hypertension; esti- ple with type 1 diabetes (10). Knowledge safety profile consistent with that seen mated glomerular filtration rate (eGFR) of blood glucose fluctuations may help in people with type 2 diabetes, with the ,70 mL/min/1.73 m2; or use of any anti- to improve diabetes management; how- exception of an increased incidence of hyperglycemic agent other than insulin ever, awareness of excessive variability ketone-related adverse events (AEs), in- within 12 weeks before screening. De- can also be frustrating and worrisome cluding (DKA) with tails of the study design have been re- (11). Improvements in glycemic vari- both canagliflozin doses and severe hy- ported (28). ability, as measured by SD of blood glu- poglycemia with canagliflozin 300 mg This study was conducted in accor- cose, have been shown to reduce the (28,29). This manuscript describes the dance with ethical principles that comply risk of hypoglycemia in people with effects of canagliflozin on parameters with the Declaration of Helsinki, and was type 1 diabetes and may also reduce of glycemic control and indices of glu- consistent with Good Clinical Practice and the risk of developing other complica- cose variability from a substudy of par- applicable regulatory requirements. Ap- tions (i.e., peripheral neuropathy and ticipants with type 1 diabetes who used proval was obtained from institutional re- hypoglycemia), although further stud- CGM, as well as data from self-monitoring view boards and independent ethics ies are needed to determine the longer- blood glucose (SMBG) profiles that committees for each participating center. term implications of reduced glycemic were assessed in all participants. To de- Participants provided informed written variability (12–15). Because there is no termine whether canagliflozin impacts consent prior to the study. standardized metric for assessing glu- treatment satisfaction in participants cose variability, the evaluation of multi- with type 1 diabetes, patient-reported Insulin Therapy ple measures can provide an overall outcomes were measured using the Di- To mitigate the potential increased assessment of variability (16,17). Among abetes Treatment Satisfaction Ques- risk of hypoglycemia with canagliflozin, people with type 1 diabetes, improved tionnaire (DTSQ) (30–33). participants with HbA1c #8.0% (#64 glycemic control and lower glycemic mmol/mol) at screening were recom- variability have been associated with RESEARCH DESIGN AND METHODS mended to reduce their basal insulin improved disease-specific quality of life Study Design and Patients dose by 20%; participants with HbA1c and treatment satisfaction related to This randomized, double-blind, treat-to- .8.0% (.64 mmol/mol) at screening better and easier disease management target, placebo-controlled, multicenter, were recommended to reduce their basal (11,18). In turn, greater diabetes treat- phase 2 study consisted of a 2-week pre- insulin dose by 10%. After randomization, ment satisfaction has been associated randomization period followed by an participants were instructed to titrate with better adherence to and compli- 18-week double-blind treatment phase basal and bolus insulin doses to achieve ance with treatment (19,20), better out- and 2 weeks of post-treatment follow- prespecified premealtime and bedtime comes (21), and reduced costs (22). up for all participants. Participants were glucose levels. All changes in insulin Thus, treatments that reduce hypergly- randomized to receive canagliflozin dose were made at the discretion of the cemia and glycemic variability without 100 or 300 mg or placebo once daily investigator upon review of a partici- increasing the risk of hypoglycemia before the first meal of the day. Ran- pant’s recent finger stick glucose values may be beneficial among people with domization was stratifiedbasedonuse and clinical assessment of hypoglycemia type 1 diabetes. of multiple daily insulin (MDI) injections risk (28). care.diabetesjournals.org Rodbard and Associates 3

9-Point SMBG signs measurements, and physical exam- with higher scores representing better sat- All participants (N =351)weretorecord inations. The incidence of documented isfaction. DTSQc scores range from 218 9-point SMBG measurements at base- hypoglycemia, including biochemically to +18, with positive scores reflecting im- line (week prior to randomization) and documented episodes (i.e., concurrent fin- provement in satisfaction relative to at the end of the study (week 17–18). gerstick or plasma glucose of #3.9 mmol/L baseline. Only participants with 2 days of valid [#70 mg/dL]) and severe episodes, was 9-point SMBG reading (i.e., five or also assessed. Statistical Analyses more SMBG values at the following six In the overall population, the change Efficacy and safety analyses were conducted time points: prior to morning meal, from baseline in mean daily glucose and using the modified intent-to-treat 120 min after morning meal, 120 min daily glucose SD based on the 9-point (mITT) analysis set (i.e., all randomized after midday meal, 120 min after the SMBG profile were assessed at week 18. patients who received one or more doses evening meal, 4:00 A.M.,andfastingin In the CGM substudy, the change from of the double-blind study drug). Safety the morning; and one or more SMBG baseline in mean daily glucose parame- analyses included all reported AEs with value among the following three time ters of glucose variability (i.e., SD, coef- onset during the treatment phase (i.e., points: prior to midday meal, prior to ficient of variation, and mean amplitude treatment-emergent AEs). The hypogly- evening meal, and before bedtime) of glycemic excursions [MAGE]), and time cemia event rate was calculated as the were included in the SMBG analysis. spent in the protocol-specified target glu- number of hypoglycemia episodes per pa- During the remainder of the study pe- cose range (.3.9 and #10.0 mmol/L tient-year of exposure. Further details re- riod, participants were required to mea- [.70 and #180 mg/dL]), above target garding statistical analyses have been sure SMBG as per the standard of care. (.10 and .13.9 mmol/L [.180 and reported (28). SMBG measurements were not blinded .250 mg/dL], or below target (#3.9 Change from baseline at week 18 for to participants or investigators. and #2.8 mmol/L [#70 and #50 mg/dL]) dailymeanglucoseanddailySDofglu- were assessed at week 18. Glucose SD cose were summarized for all mITT par- CGM Substudy was calculated using all valid measure- ticipants with sufficient 9-point SMBG CGM assessments were performed in a ments during the two 7-day CGM assess- data at baseline and week 18. Change subgroup (n = 89) at selected study cen- ments. Coefficient of variation was from baseline at week 18 for daily mean ters. Only participants not using CGM at calculated as the ratio of SD to mean glucose; glucose variability end points the time of screening were eligible to par- glucose values. MAGE (i.e., the average (SD, coefficient of variation, MAGE); and ticipate in the optional substudy. Sub- of all glucose excursions .1 SD) was cal- time spent within, below, and above tar- study participants signed a separate culated using the algorithm developed get were summarized for the CGM anal- informed consent form and wore a spon- by Baghurst (34) and Henry et al. (35). ysis set (i.e., all mITT participants with sor-provided CGM device (G4 Platinum; Diabetes treatment satisfaction was sufficient CGM data at baseline and Dexcom) continuously for 7 days during assessed in the total population at base- week 18). Least squares (LS) mean differ- run-in and were required to have $3days line and at week 18 using two versions ences and 95% CIs for MAGE time spent of successful CGM readings (i.e., daily of the DTSQ: the DTSQ status version within, below, and above target levels reading without a continuous interrup- (DTSQs), administered at baseline, and were calculated based on an ANCOVA tion of .120 min in any postmealtime the DTSQ change version (DTSQc), ad- model with treatment and stratification interval or a continuous interruption of ministered after treatment (30–33). factor as fixed effects, and baseline value .180 min during the nocturnal/sleeping The DTSQ is composed of eight items, as a covariate. time interval). After randomization, partic- six of which are used to compute the Changes from baseline in DTSQc ipants repeated the CGM assessment for treatment satisfaction scale score (satis- treatment satisfaction scale score at 7 days from week 17 to 18. Study centers, fied, convenient, flexible, understand- week 18 were compared across treat- participants, and the sponsor were ing, recommend, and continue). These ment groups for all mITT partici- masked to CGM readings. During the components measure participants’ per- pants with DTSQ data at baseline and two separate 1-week CGM procedures, ceptions of satisfaction, convenience, week 18 using an ANCOVA model with participants were required to also obtain and flexibility of their current treatment treatment and stratification factor as 9-point SMBG measurements following as well as participants’ satisfaction with fixed effects and the corresponding the same instructions as the remainder their understanding of diabetes, likeli- baseline score as a covariate. LS mean of the study population. hood to recommend their current treat- differences and 95% CIs for DTSQc treat- End Points and Assessments ment to someone else, and satisfaction ment satisfaction scale scores were esti- The primary efficacy end point was the with continuing their current treatment. mated. Improvement from baseline in proportion of participants at week 18 The remaining two DTSQ items, regard- DTSQc scores and all components was with an HbA1c reduction of $0.4% ing the perception of time spent in hy- defined as any score .0. The proportion ($4.4 mmol/mol) and no increase in perglycemia and hypoglycemia, are of participants with improvement in body weight relative to baseline (28). assessed independently. DTSQs and DTSQc scores and components was com- Change from baseline in insulin dose, DTSQc are available in .100 languages pared using logistic regression models, after the initial down-titration, was as- and were administered in the appropri- adjusted for baseline score and strati- sessed at week 18. Overall safety and ate language based on the location of fication factor. Pearson correlation co- tolerability were assessed based on AE the study center. DTSQs treatment sat- efficients measured the strength of reports, safety laboratory tests, vital isfaction scale scores range from 0 to 36, the relationship between the change in 4 Effect of CANA on Glycemic Variability and Patient-Reported Outcomes Diabetes Care

mediators and DTSQc at week 18. A list of 20.29% [23.2 mmol/mol] and 20.25% and 300 mg provided reductions in of candidate mediators of the effect of [22.7 mmol/mol]) (28). Participants mean glucose at week 18 compared canagliflozin on DTSQc was derived treated with canagliflozin 100 and 300 mg with an increase with placebo (Table 2). based on factors that were observable had larger reductions in the total daily in- Dose-dependent reductions in glucose by and potentially meaningful to par- sulin dose over 18 weeks versus those SD at week 18 were also seen with can- ticipants. Product–method mediation treatedwithplacebo(22.5, 26.0, and 1.6 agliflozin 100 and 300 mg compared analysis, a regression-based technique IU/day, respectively) that were driven by with placebo. Changes in the coefficient that allows the exploration of various reductions in basal insulin (21.0, 22.0, of variation were similar across groups causal pathways, was used to produce and 3.3 IU/day, respectively) (28). since canagliflozin provided reductions upper bounds for the proportion of the The overall incidence of AEs at week 18 inbothmeanglucoseandmeasuresof canagliflozin treatment effect on DTSQc with canagliflozin 100 and 300 mg and glucose variation. Reductions in MAGE scores that was mediated by insulin reduc- placebo was 55.6%, 67.5%, and 54.7%, re- were seen with canagliflozin 100 and tion, improvement in glycemic variability spectively; the incidence of serious AEs 300mgcomparedwithplaceboat (measured by change in daily glucose SD was 7.7%, 6.8%, and 0%, respectively, week 18. via 9-point SMBG), and the percentage and the rates of study discontinuation Representative CGM profiles for par- change in body weight (36,37). were low across groups (28). Increased in- ticipants treated with canagliflozin cidence of ketone-related AEs, including 100 mg and placebo at baseline and RESULTS serious AEs of DKA requiring hospitaliza- week 18 are shown in Supplementary tion, was seen with canagliflozin 100 and Fig. 1. At baseline across treatment Participants 300 mg versus placebo (5.1%, 9.4%, and groups, participants spent ;54–55% In the overall population (N = 351), base- 0%, respectively) (28). The incidence of of the time within target (.3.9 to line demographic and disease character- documented hypoglycemia at week #10.0 mmol/L [.70 to # 180 mg/dL]), istics were generally similar across 18 was 98.3%, 99.1%, and 96.6% with can- ;36–42% of the time above target treatment groups (Table 1) (28). Sixty- agliflozin 100 and 300 mg and placebo, (.10.0 mmol/L [.180 mg/dL]), and seven percent (n = 236) of participants respectively; the incidence of severe hy- ;4–9% of the time below target had sufficientSMBGdataatbaseline poglycemic events was 2.6%, 6.8%, and (#3.9 mmol/L [#70 mg/dL]) (Fig. 2). and week 18 to be included in the SMBG 1.7%, respectively (28). Over 18 weeks, participants treated analysis. with canagliflozin 100 and 300 mg had The CGM substudy included 89 partici- Glycemic End Points Assessed by an increase in time spent within target pants, 75 of whom had successful CGM 9-Point SMBG Profile (Overall compared with a reduction with pla- readings prior to randomization. Baseline Population) cebo, with commensurate reductions in demographic and disease characteristics The changes in daily mean glucose as- time spent above target with canagliflozin in the CGM substudy were generally sim- sessed by 9-point SMBG at week 18 100 and 300 mg compared with an in- ilar to the overall population, though with canagliflozin 100 and 300 mg, crease with placebo. Reductions in the fewer participants reported a history of and placebo were 21.2, 21.1, and percentage of time spent .13.9 mmol/L severe hypoglycemia and fewer partici- 0.2 mmol/L (222.4, 219.4, and 3.0 mg/dL), glucose (.250 mg/dL) were also seen pants were using CSII (Table 1). respectively. The 24-h mean glucose with canagliflozin 100 and 300 mg com- DTSQ data were available for the ma- profiles for canagliflozin 100 and 300 mg pared with placebo (26.0%, 25.2%, jority of participants (93%; n = 328). at week 18 generally showed a down- and 2.5%, respectively). Change in time Baseline demographic and disease char- ward shift of the entire glucose curve spent below target at week 18 was not acteristics among the participants with relative to baseline, with the exception meaningfully different with canagliflozin patient-reported outcomes data were of 120 min after the evening meal, 100 and 300 mg versus placebo. Change generally similar compared with the where baseline and week 18 measure- in time spent #2.8 mmol/L glucose overall population (Table 1). ments with canagliflozin 300 mg were (#50 mg/dL) with canagliflozin 100 and similar (Fig. 1). Changes from base- fi 300 mg and placebo was 0.6%, 21.1%, Ef cacy and Safety (Overall line in daily glucose SD at week 18 with and 21.1%, respectively. Population) canagliflozin 100 and 300 mg and placebo Complete efficacy and safety results for were 20.9, 21.0, and 20.1 mmol/L the overall population have been report- (216.4, 218.1, and 21.9 mg/dL), Diabetes Treatment Satisfaction ed, and key results are briefly summarized Baseline DTSQs treatment satisfaction respectively. below (28). More participants met the scalescoresweresimilarforcanagliflozin primary end point of HbA1c reduction Glycemic End Points Assessed Using 100 and 300 mg and placebo (29.0, 28.4, of $0.4% ($4.4 mmol/mol) and no in- CGM (CGM Substudy) and 28.6, respectively). At week 18, crease in body weight with canagliflozin As in the overall study, HbA1c reductions mean changes in DTSQc treatment sat- 100 and 300 mg versus placebo at week 18 were also seen in the CGM substudy (LS isfaction scale scores were larger with (36.9%, 41.4%, and 14.5%, respectively; mean changes of 20.25%, 20.27%, and canagliflozin 100 and 300 mg compared P , 0.001) (28). HbA1c was reduced at week 0.11% [22.7, 23.0, and 1.2 mmol/mol] with placebo (Fig. 3A), with a greater 18 with canagliflozin 100 and 300 mg with canagliflozin 100 and 300 mg and percentage of participants experiencing compared with placebo (LS mean changes placebo, respectively; differences of any improvement in treatment satisfac- of 20.27%, 20.24%, and 0.01% [23.0,22.6, 20.36% [23.9 mmol/mol] and 20.38% tion with canagliflozin compared with and 0.1 mmol/mol], respectively; differences [24.2 mmol/mol]). Canagliflozin 100 placebo (Fig. 3B). care.diabetesjournals.org Rodbard and Associates 5

Table 1—Baseline demographic and disease characteristics Overall population (28) PBO (n = 117) CANA 100 mg (n = 117) CANA 300 mg (n = 117) Total (N =351) Sex, n (%) Male 63 (53.8) 69 (59.0) 65 (55.6) 197 (56.1) Female 54 (46.2) 48 (41.0) 52 (44.4) 154 (43.9) Age, years* 42.0 6 11.9 42.0 6 11.6 42.8 6 11.0 42.3 6 11.5 Race, n (%)† White 106 (90.6) 111 (94.9) 102 (87.2) 319 (90.9) Black/African American 7 (6.0) 5 (4.3) 5 (4.3) 17 (4.8) Asian 2 (1.7) 0 5 (4.3) 7 (2.0) Other‡ 2 (1.7) 1 (0.9) 5 (4.3) 8 (2.3)

HbA1c* %7.96 0.6 7.9 6 0.5 8.0 6 0.5 7.9 6 0.5 mmol/mol 63 6 6.6 63 6 5.5 64 6 5.5 63 6 5.5 Body weight, kg* 83.0 6 15.4 84.1 6 14.2 82.9 6 15.0 83.4 6 14.8 BMI, kg/m2*28.06 3.6 28.0 6 3.9 28.1 6 3.9 28.1 6 3.8 eGFR, mL/min/1.73 m2* 96.0 6 14.8 97.4 6 14.9 95.8 6 16.5 96.4 6 15.4 Duration of type 1 diabetes, years* 23.3 6 11.0 22.0 6 11.5 21.9 6 10.6 22.4 6 11.0 CSII use, n (%) 72 (61.5) 74 (63.2) 73 (62.4) 219 (62.4) MDI use, n (%) 45 (38.5) 43 (36.8) 44 (37.6) 132 (37.6) Prior severe hypoglycemia, n (%) 18 (15.4) 15 (12.8) 19 (16.2) 52 (14.8) Prior DKA, n (%) 14 (12.0) 13 (11.1) 15 (12.8) 42 (12.0) Patients with valid 9-point SMBG, n (%) 77 (66.4) 81 (69.2) 78 (67.8) 236 (67.2)

CGM substudy PBO (n = 31) CANA 100 mg (n = 28) CANA 300 mg (n =30) Total(N =89)

Sex, n (%) Male 16 (51.6) 18 (64.3) 14 (46.7) 48 (53.9) Female 15 (48.4) 10 (35.7) 16 (53.3) 41 (46.1) Age, years* 43.3 6 13.2 43.2 6 13.2 41.6 6 11.7 42.7 6 12.6 Race, n (%) White 27 (87.1) 27 (96.4) 27 (90.0) 81 (91.0) Black/African American 1 (3.2) 0 2 (6.7) 3 (3.4) Asian 1 (3.2) 0 0 1 (1.1) Other‡ 2 (6.5) 1 (3.6) 1 (3.3) 4 (4.5)

HbA1c* %7.96 0.6 7.8 6 0.5 8.0 6 0.5 7.9 6 0.5 mmol/mol 63 6 6.6 62 6 5.5 64 6 5.5 63 6 5.5 Body weight, kg* 79.7 6 15.7 82.6 6 13.0 83.4 6 17.9 81.9 6 15.7 BMI, kg/m2*27.86 3.9 27.5 6 3.9 28.1 6 4.4 27.8 6 4.0 eGFR, mL/min/1.73 m2* 94.0 6 15.7 95.0 6 14.1 92.3 6 15.3 93.7 6 14.9 Duration of type 1 diabetes, years* 21.6 6 10.1 23.9 6 12.8 19.6 6 10.5 21.6 6 11.1 CSII use, n (%) 17 (54.8) 17 (60.7) 16 (53.3) 50 (56.2) MDI use, n (%) 14 (45.2) 11 (39.3) 14 (46.7) 39 (43.8) Prior severe hypoglycemia, n (%) 2 (6.5) 1 (3.6) 3 (10.0) 6 (6.7) Prior DKA, n (%) 4 (12.9) 3 (10.7) 3 (10.0) 10 (11.2)

Participants in the DTSQ analysis PBO (n = 108) CANA 100 mg (n = 111) CANA 300 mg (n = 109) Total (N =328)

Sex, n (%) Male 58 (53.7) 65 (58.6) 59 (54.1) 182 (55.5) Female 50 (46.3) 46 (41.4) 50 (45.9) 146 (44.5) Age, years* 41.8 6 11.9 42.2 6 11.8 42.6 6 10.9 42.2 6 11.5 Race, n (%)† White 98 (90.7) 106 (95.5) 96 (88.1) 300 (91.5) Black/African American 6 (5.6) 4 (3.6) 5 (4.6) 15 (4.6) Asian 2 (1.9) 0 4 (3.7) 6 (1.8) Other‡ 2 (1.9) 1 (0.9) 4 (3.7) 7 (2.1)

HbA1c* %7.96 0.6 7.8 6 0.5 8.0 6 0.5 7.9 6 0.5 mmol/mol 63 6 6.6 62 6 5.5 64 6 5.5 63 6 5.5 Continued on p. 6 6 Effect of CANA on Glycemic Variability and Patient-Reported Outcomes Diabetes Care

Table 1—Continued Participants in the DTSQ analysis PBO (n = 108) CANA 100 mg (n = 111) CANA 300 mg (n =109) Total(N =328)

Body weight, kg* 83.4 6 14.8 84.1 6 14.1 82.6 6 14.5 83.4 6 14.4 BMI, kg/m2*28.06 3.6 28.0 6 4.0 28.1 6 3.8 28.1 6 3.8 eGFR, mL/min/1.73 m2* 95.9 6 14.8 97.9 6 14.5 95.6 6 16.5 96.5 6 15.3 Duration of type 1 diabetes, years* 23.3 6 10.7 22.0 6 11.5 21.6 6 10.7 22.3 6 11.0 CSII use, n (%) 68 (63.0) 69 (62.2) 70 (64.2) 207 (63.1) MDI use, n (%) 40 (37.0) 42 (37.8) 39 (35.8) 121 (36.9) Prior severe hypoglycemia, n (%) 18 (16.7) 15 (13.5) 18 (16.5) 51 (15.5) Prior DKA, n (%) 13 (12.0) 13 (11.7) 15 (13.8) 41 (12.5) DTSQs§ 28.6 6 5.2 29.0 6 5.5 28.4 6 5.3 28.7 6 5.3 CANA, canagliflozin; PBO, placebo. *Data are mean 6 SD; †Percentages may not total 100.0 due to rounding; ‡Includes multiple, other, and not reported; §Includes participants with all components of the DTSQs treatment satisfaction scale score at baseline or week 18 (N = 324; PBO, n =105; CANA 100 mg, n = 110; CANA 300 mg, n = 109). Overall DTSQ analysis set includes all participants with any individual DTSQ component at both baseline and week 18 (N =328).

Improvement in the six individual perceived time experiencing hyperglyce- suggest that reduction in total insulin DTSQc treatment satisfaction scale score mia were significant with canagliflozin dose, reduction in daily glucose SD as- items was seen for all treatment groups; 100 and 300 mg (OR 3.8 [95% CI 2.2, sessed using the 9-point SMBG profile, five of the six items revealed treatment 6.8] and 5.9 [3.3, 10.8], respectively); and change in body weight accounted differences (Supplementary Fig. 2A). Sat- the proportion with less perceived time for up to 4%, 9%, and 21%, respectively, isfaction with an of understanding of di- experiencing hypoglycemia was signifi- of the relationship between canagliflozin abetes improved within each group, but cant with canagliflozin 300 mg versus treatment and satisfaction change with no observed treatment differences. placebo (OR 2.2 [95% CI 1.2, 3.9]). (Fig. 3C). A greater proportion of participants The estimated correlations between treated with canagliflozin 100 and 300 mg DTSQc and changes in the mediators CONCLUSIONS 2 reported a reduction in perceived time were 0.312 for the percentage change Canagliflozin 100 and 300 mg provided , 2 experiencing hyperglycemia versus pla- in weight (P 0.001), 0.229 for the reductionsinmeanglucoseandim- cebo (Supplementary Fig. 2B). Although change in the SD of blood glucose provements in measures of glycemic fi , 2 these analyses were not prespeci ed for (P 0.001), and 0.159 for the change variability, as measured by SMBG or hypothesis testing, odds ratios (ORs) and in total insulin dose (P = 0.006). Product- CGM, in participants with type 1 diabe- 95% CIs indicate that, relative to placebo, method mediation analyses using pooled tes over 18 weeks. The percentage of the proportion of participants with less canagliflozin 100 and 300 mg groups time spent within the glycemic target range was greater with canagliflozin 100 and 300 mg compared with pla- cebo. The percentage of time spent above the target was lower with both canagliflozin doses compared with pla- cebo. No meaningful changes were seen in the time spent below target across groups. The improvements in glycemic control and measures of gly- cemic variability seen with canagliflozin in the CGM substudy were generally consistent with those reported for other SGLT2 inhibitors as an add-on to insulin in people with type 1 diabetes (35,38–41). Participants in the canagliflozin 100 and 300 mg groups had a significantly greater improvement in treatment sat- isfaction compared with placebo as measured by the DTSQc. The proportion of patients with improvement was greater with each dose of canagliflozin versus placebo; ;95% of all canagliflo- Figure 1—Mean glucose values over time at baseline and week 18 assessed by a 9-point SMBG zin-treated participants experienced at profile. CANA, canagliflozin; PBO, placebo. least some improvement in treatment care.diabetesjournals.org Rodbard and Associates 7

Table 2—Summary of the changes from baseline in measures of glycemic variability at week 18 (CGM Substudy) Parameter PBO (n =24) CANA100mg(n = 25) CANA 300 mg (n =26) Mean glucose, mmol/L (mg/dL) Baseline 9.0 6 1.7 (162.1 6 31.1) 9.8 6 1.5 (175.7 6 27.3) 9.2 6 1.4 (164.9 6 24.4) Change 0.6 6 2.0 (10.2 6 35.2) 21.2 6 1.2 (220.9 6 22.2) 20.7 6 1.2 (212.3 6 21.7) Glucose SD, mmol/L (mg/dL) Baseline 3.8 6 0.7 (68.1 6 12.8) 3.5 6 0.9 (63.5 6 16.3) 3.9 6 0.7 (69.3 6 12.7) Change 0.1 6 0.8 (1.6 6 14.0) 20.3 6 0.9 (25.2 6 16.8) 20.7 6 0.8 (212.2 6 13.9) Coefficient of variation, % Baseline 42.8 6 9.0 36.3 6 8.1 42.3 6 7.3 Change 22.4 6 5.6 1.4 6 9.3 24.8 6 8.3 MAGE, mmol/L (mg/dL) Baseline 9.2 6 1.8 (163.8 6 31.5) 8.4 6 2.0 (149.9 6 36.1) 9.4 6 1.6 (166.6 6 28.8) Change 0.3 6 2.0 (5.1 6 33.8) 20.6 6 2.0 (211.4 6 36.5) 21.8 6 2.1 (232.7 6 37.0) Data are reported as mean 6 SD. CANA canagliflozin; PBO, placebo. satisfaction. Treatment differences were In addition to improving glycemic pa- Patients are less likely to continue with a seen in five of six individual items of the rameters, such has HbA1c, mean daily treatment regimen they perceive to be DTSQc; as expected, an understanding of glucose, and measures of glycemic vari- ineffective, associated with negative diabetes did not show treatment differ- ability, both canagliflozin doses reduced side effects, and/or infringing upon ences in this analysis. Of note, a similar insulin dose and body weight in partici- their lifestyle (44). Several studies have positive impact on treatment satisfac- pants with type 1 diabetes (28). Findings demonstrated a significant link between tion, assessed using the DTSQ, was pre- from the product-method mediation treatment satisfaction and adherence viously reported among participants analyses suggest that insulin reduction, (19), and higher satisfaction has been with type 1 diabetes treated with NPH reduced glycemic variability, and weight associated with better outcomes among insulin plus unmodified human insulin loss contributed to the increased treatment people with diabetes (20,21). These find- who switched to a combination of insulin satisfaction observed with canagliflozin, ings suggest that canagliflozin and, by glargine and , a rapid-acting accounting for ;35% of the relation- extension, other therapies that can offer (42). Participants treated ship between canagliflozin treatment insulin reduction, reduced glycemic var- with canagliflozin also reported a reduc- and satisfaction change. Other, unmea- iability, and weight loss while avoiding tion in the perceived percentage of time sured factors also mediate the relationship hyperglycemia and hypoglycemia can spent in hyperglycemia and hypoglyce- between canagliflozin and treatment sat- lead to increased treatment satisfaction mia. This is consistent with the clinical isfaction. For example, while not evalu- among people with type 1 diabetes. In findings, and also suggests that the mag- ated due to the short duration this study, turn, this may contribute to improved nitude of improvement in glycemic con- weight change patterns over time, in ad- treatment adherence and performance trol with canagliflozin treatment may be dition to overall weight change, can also of self-care behaviors and therefore to large enough to be both noticeable and impact treatment satisfaction and willing- better long-term outcomes (45). meaningful to people with type 1 diabetes. ness to perform healthy behaviors (43). The limitations of this analysis include the small sample size of study partici- pants in the CGM subset and the shorter duration of monitoring in the current study (7 days) compared with recom- mendations in the literature (14 days) (46). Furthermore, CGM was not used for real-time insulin dose adjustments, and mealtimes were not recorded by substudy participants. An additional lim- itation is the lack of a control group that provides glycemic control without im- provement in measures of glycemic var- iability. Therefore, improvements in patient satisfaction due to the reduction in measures of glycemic variability ver- sus the benefits of better glycemic con- trol were not assessed. Additionally, the potential impact of knowledge of CGM data on patient satisfaction was not Figure 2—Change from baseline in the percentage of time spent within, above, and below target evaluated. Data from longer-term stud- at week 18 as measured by CGM. CANA, canagliflozin; PBO, placebo. ies will help to characterize the effects 8 Effect of CANA on Glycemic Variability and Patient-Reported Outcomes Diabetes Care

the potential benefits of canagliflozin in patients with type 1 diabetes, further clinical development must proceed with caution due to the SGLT2 inhibitor– associated complication of DKA in this population and the potential in- creased risk of severe hypoglycemia with canagliflozin 300 mg (29). Potential mit- igation strategies, such as the use of lower doses of canagliflozin, may bal- ance the benefits of canagliflozin treat- ment with the risk of DKA. Additionally, treatment adjustments in the run-in phase prior to baseline DTSQs collec- tion and randomization may have influ- enced baseline DTSQs values; however, treatment comparisons are not systemat- ically impacted. The absolute estimates, however, may not accurately reflect the prestudy treatment experience. In summary, glycemic fluctuations areamajorconcernforpeoplewith type 1 diabetes. In this study, canagliflozin improved glycemic control and measures of glycemic variability, with no increase in documented nonsevere hypoglycemia compared with placebo over 18 weeks in adults with type 1 diabetes that was inadequately controlled with insulin. These improvements, along with the re- duction in insulin dose and weight loss, were associated with noticeable and ro- bust improvements in treatment satisfac- tion, which may lead to better treatment adherence and performance of self-care behaviors in people with type 1 diabetes.

Acknowledgments. The authors thank all in- vestigators, study teams, and patients for par- ticipating in this study. License for use of the Diabetes Treatment Satisfaction Questionnaire (DTSQ), owned by Professor Clare Bradley (Royal Holloway, University of London, Surrey, U.K.), wasprovidedbyHPRLtd.Thequestionnairecanbe found at: www.healthpsychologyresearch.com. Funding. This study was supported by Janssen Research & Development, LLC. Medical writing support was provided by Kimberly Dittmar, PhD, of MedErgy and was funded by Janssen Global Services, LLC. Canagliflozin has been developed Figure 3—A: Mean DTSQc treatment satisfaction scale score (adjusted for baseline score and by Janssen Research & Development, LLC, in stratification factor) (B), proportion of participants with any improvement in DTSQc treatment collaboration with Mitsubishi Tanabe Pharma satisfaction scale score (C), and mediators of the relationship between canagliflozin treatment Corporation. andchangeinoveralltreatmentsatisfactionmeasured by the DTSQc at week 18. CANA, canagliflozin; Duality of Interest. H.W.R. has served as a PBO, placebo. Mediation analysis was performed on the pooled CANA 100 and 300 mg groups. consultantandspeakerforAstraZeneca,Boehringer †P =0.09;‡P = 0.01. Ingelheim, Biodel, Eli Lilly, Janssen, Merck, Novo Nordisk,Sanofi, andRegeneron;andhas received research support from AstraZeneca, Biodel, of canagliflozin on glycemic variability in Canagliflozin is not approved for the Bristol-Myers Squibb, Eli Lilly, Janssen, Merck, Novo Nordisk, Sanofi, and Regeneron. A.L.P. has participants with type 1 diabetes and to treatment of type 1 diabetes and should been an investigator, speaker, and/or consultant explain how canagliflozin-associated not currently be used in type 1 diabetes. for Abbott Diabetes Care, Amgen, AstraZeneca, glycemic benefits impact satisfaction. While the data from this study demonstrate BD, Biodel, Bristol-Meyers Squibb, Boehringer care.diabetesjournals.org Rodbard and Associates 9

Ingelheim, CVS/Caremark, Janssen, Lexicon, Eli 9. Willis WD, Diago-Cabezudo JI, Madec-Hily A, 25. Sha S, Devineni D, Ghosh A, et al. Lilly, Medtronic, Merck, Novo Nordisk, OptumRx, Aslam A. Medical resource use, disturbance of Canagliflozin, a novel inhibitor of sodium glucose Sanofi, Takeda, and Thermalin. A.S. is a full-time daily life and burden of hypoglycemia in insulin- co-transporter 2, dose dependently reduces cal- employee of Axio Research and has received treated patients with diabetes: results from a culated renal threshold for glucose excretion and payment from Janssen for statistical support European online survey. Expert Rev Pharmacoe- increases urinary glucose excretion in healthy of the analyses reported in this manuscript. A.C. con Outcomes Res 2013;13:123–130 subjects. Diabetes Obes Metab 2011;13:669–672 and M.A. are full-time employees of Janssen Re- 10. Tumminia A, Sciacca L, Frittitta L, et al. In- 26. Polidori D, Sha S, Ghosh A, Plum-Morschel¨ search & Development, LLC. S.B.T. is a full-time tegrated insulin pump therapy with continuous L, Heise T, Rothenberg P. Validation of a novel employee of Janssen Global Services, LLC. glucose monitoring for improved adherence: method for determining the renal threshold for Author Contributions. H.W.R. and A.L.P. con- technology update. Patient Prefer Adherence glucose excretion in untreated and canagliflozin- tributed to the conduct of the study; the acqui- 2015;9:1263–1270 treated subjects with type 2 diabetes mellitus. sition, analysis, and interpretation of the data; 11. Pickup JC, Ford Holloway M, Samsi K. Real- J Clin Endocrinol Metab 2013;98:E867–E871 and drafted, reviewed, and approved the man- time continuous glucose monitoring in type 1 27. Argento NB, Nakamura K. Glycemic effects uscript. 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