Canagliflozin in Conjunction With Sulfonylurea Maintains Glycemic Control and Weight Loss Over 52 Weeks: A Randomized, Controlled Trial in Patients With Type 2 Diabetes Mellitus

Clinical Therapeutics/Volume ], Number ], ]]]]

Canagliflozin in Conjunction With Sulfonylurea Maintains Glycemic Control and Weight Loss Over 52 Weeks: A Randomized, Controlled Trial in Patients With Type 2 Diabetes Mellitus Jean-Franc¸ois Yale, MD, CSPQ, FRCPC1; John Xie, PhD2; Stephen E. Sherman, PhD3; and Claude Garceau, MD, FRCP4 1

Department of Medicine, McGill University, Montreal, Quebec, Canada; 2Janssen Research & Development, Raritan, New Jersey; 3Janssen Inc., Toronto, Ontario, Canada; and 4Institut Universitaire de Cardiologie et de Pneumologie de Que´bec, Quebec City, Quebec, Canada

ABSTRACT Purpose: Our aim was to investigate the long-term efficacy and safety of canagliflozin, a sodium−glucose co-transporter 2 inhibitor, added to background sulfonylurea (SU) monotherapy for patients with type 2 diabetes mellitus. Methods: The CANagliflozin cardioVascularAssessment Study (CANVAS) was a double-blind, placebo-controlled cardiovascular outcomes study that randomly assigned participants to receive placebo or canagliflozin 100 or 300 mg once daily in addition to routine therapy. CANVAS included a prespecified SU substudy of patients taking background doses of SU monotherapy; data from the primary efficacy evaluation at 18 weeks have been published previously. We performed a retrospective analysis of the SU substudy at 52 weeks to measure long-term efficacy and safety of canagliflozin used with an SU. The primary objective of the long-term extension was to assess the change from baseline to 52 weeks in glycosylated hemoglobin (HbA1c). Findings: A total of 215 patients were included in the 52-week extension study. Patients receiving both 100-mg and 300-mg doses of canagliflozin achieved a sustained reduction in HbA1c relative to patients receiving placebo (−0.61% [95% CI, −0.941% to −0.282%] and −0.66% [95% CI, −0.993% to −0.332%], respectively), regardless of baseline HbA1c, duration of diabetes, SU dose, estimated glomerular filtration rate, or body mass index. A sustained reduction in fasting plasma glucose was also found in both 100-mg and 300-mg groups, relative to the placebo group (−2.04 mmol/L [95% CI, −2.778 to

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−1.299 mmol/L] and −1.88 mmol/L [95% CI, −2.623 to −1.146 mmol/L], respectively). Weight was reduced significantly at 52 weeks in both 100-mg and 300-mg groups, relative to placebo (−1.9% [95% CI, −3.2% to −0.7%] and −2.0% [95% CI, −3.2% to –0.7%], respectively). Reduction in systolic blood pressure was also reported for both dose groups relative to the placebo group, but there was no clear difference in HDL-C, LDL-C, or triglyceride levels. Canagliflozin was generally well tolerated. While documented hypoglycemia occurred in 14% of patients on placebo, the frequency of hypoglycemia with the addition of canagliflozin was similar. There was an increased frequency of genital mycotic infections in both men (5.1%) and women (10.4%) in both canagliflozin groups combined, relative to the placebo group (0%), and their frequency increased in the higherdose group. There was a slightly higher rate of renal impairment in those treated with canagliflozin versus placebo (2.1% vs 0%). Implications: After 52 weeks, patients receiving canagliflozin added to background SU had sustained reductions in HbA1c and fasting plasma glucose, without increasing hypoglycemia and body weight; safety findings were generally consistent with the known safety profile of the drug. ClinicalTrials.gov identifier: NCT01032629. (Clin Ther. ]]]];]:]]]–]]]) & 2017 Elsevier HS Journals, Inc. All rights reserved.

Accepted for publication October 2, 2017. http://dx.doi.org/10.1016/j.clinthera.2017.10.003 0149-2918/$ - see front matter & 2017 Elsevier HS Journals, Inc. All rights reserved.

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Clinical Therapeutics Key words: canagliflozin, cardiovascular disease, SGLT2 inhibitor, sulfonylureas, type 2 diabetes, weight loss.

INTRODUCTION Worldwide, there are more than 284 million cases of diabetes, 90% of which are classified as type 2 (T2DM).1 T2DM is associated with obesity, physical inactivity, increased blood pressure, abnormal blood lipid levels, and increased risk of thrombosis.2 As such, patients with T2DM experience high mortality and morbidity, with twice the risk of developing cardiovascular disease.3 Moreover, the prevalence of T2DM and the complexity of its management are growing exponentially, placing an enormous burden on health care resources worldwide.4 For patients with T2DM, an important goal of treatment is to maintain glycemic control; however, most are unable to do so through lifestyle changes alone, and will eventually require multiple therapies.5 Although metformin is widely recommended as firstline therapy, sulfonylureas (SUs) may be selected when metformin is contraindicated or because of physician or patient preference.5 While SUs are effective for controlling hyperglycemia, glycemic control is often transient, and their use is associated with hypoglycemia and weight gain.5 Patients therefore often require additional therapies and would benefit from agents that can sustain glycemic control without increasing hypoglycemia and weight gain.6,7 Sodium−glucose co-transporter 2 inhibitors are a class of antidiabetic agents that act by preventing glucose reabsorption in the proximal tubule, leading to an increase in urinary glucose excretion, which reduces plasma glucose concentration.8,9 Of agents in this class, canagliflozin, dapagliflozin, and empagliflozin have been approved in Canada,10–12 the United States,13 and Europe,14 as, among other indications, add-on therapy when adequate glucose control cannot be achieved with SUs alone. Canagliflozin has been shown to improve glycemic control and reduce body weight and systolic blood pressure in patients with T2DM when used as monotherapy or added to metformin, metformin plus SU, metformin plus pioglitazone, or metformin plus sitagliptin.8,15–18 The use of canagliflozin given as add-on therapy for patients on background SUs has been examined as

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part of a substudy of the recently completed CANVAS study. CANVAS was a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial, with a total of 4330 patients randomly assigned to receive placebo, canagliflozin 100 mg, or canagliflozin 300 mg.19 Results from the prespecified SU substudy at 18 weeks found significant improvements in glycosylated hemoglobin (HbA1c) versus placebo (−0.74% [95% CI, −1.15% to −0.33%]; P o 0.001 and −0.83% [95% CI, −1.24% to −0.42%]; P o 0.001) and fasting plasma glucose (FPG) (−2.1 mmol/L [95% CI, −3.0 to −1.2 mmol/L] and −2.7 mmol/L [95% CI, −3.6 to −1.7 mmol/L) with canagliflozin 100 and 300 mg, respectively. In addition, body weight was reduced with canagliflozin 300 mg (−1.8% [95% CI, −3.2% to −0.4%]; P ¼ 0.014), but unchanged with canagliflozin 100 mg (−0.4% [95% CI, −1.8% to 1.0%]; P ¼ 0.557). Safety findings included an increase in hypoglycemic episodes (at the 300-mg dose), as well as male and female genital mycotic infections, pollakiuria, and thirst. Here, we present results from the 52-week follow-up of patients from the SU substudy to examine the ability of canagliflozin to maintain glycemic control and to provide further safety and tolerability data.

METHODS Design The CANVAS study and SU substudy are randomized, double-blinded trials and have been described previously by Neal et al19 and Fulcher et al20, respectively. At 52 weeks follow-up, we performed a retrospective analysis of the SU substudy to examine the longer-term efficacy and safety of canagliflozin. The subset of patients included in the extension of the SU substudy were participants who were taking approved therapeutic doses of SU monotherapy at baseline. This is in contrast to the previous 18-week study, which included only those patients with ≥½ maximal doses of SU. Specifically, the present study included patients receiving glipizide ≥2.5 mg, glipizide extended release ≥5 mg, glyburide or glibenclamide ≥1.25 mg, glimepiride ≥1 mg, gliclazide ≥40 mg, or gliclazide modified release ≥30 mg (Figure 1).

Background Drug Treatments Participants were required to have stable background SU monotherapy for 8 weeks before screening

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J.-F. Yale et al.

.Diet and exercise .counseling Counseling on

AHA regimen stable period

hypoglycemia recognition and management

Patients with T2DM, HbA1c 7-10.5%, not on antihyperglycemic agent (AHA) or on any AHA(s) in a stable (≥8 weeks) regimen, either

Canagliflozin 300 mg

Single-blind placebo run-in and diet/exercise stable period

1) ≥30 yrs of age, with history of documented CV disease (≥70%) or 2) ≥50 yrs of age with 2 or more CV risk factors (<30%)

Week -3 Screening

Adjust AHA regimen to achieve glycemic targets

Week -2 Run-in Start

R

Canagliflozin 100 mg

Stable SU doses Fasting fingerstick glucose at site ≥6.1 mmol/L

Placebo

Day 1 Baseline

Week 18

Week 26

Week 39

Week 52 Final Study Visit Follow-up Analysis

Figure 1. Study design. and to continue on the same SU dose for the first 18 weeks, if possible, to allow for the evaluation of shortterm effects of canagliflozin on biomarkers while on stable background therapy. Criteria for the initiation of glycemic rescue therapy in the 18-week study have been published previously.19 In summary, from day 1 to week 18, criteria were based on an FPG value exceeding predefined specific glucose cut points. After week 18, it was left to the discretion of the investigator to adjust the treatment regimen in order to achieve target glycemic control per standard diabetes care guidances. Glycemic rescue therapy involved stepwise addition of non-insulin antihyperglycemic agents, followed by insulin therapies, as instituted by investigators using local guidelines for glycemic targets. Unlike in the 18-week published analysis, patients who received a dose adjustment of their current SU treatment were not considered rescued and were included in the 52-week analysis.

Outcomes The primary efficacy outcome for the substudy extension was change in HbA1c from baseline to week 52. Secondary efficacy outcomes evaluated at week 52 were body weight, FPG, proportion of participants reaching HbA1c o7.0%, systolic blood pressure, triglycerides, and HDL-C. Adverse events (AEs), including those preidentified as of special interest (ie, genital mycotic infections, urinary tract infections, and AEs related to osmotic diuresis and reduced

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intravascular volume) were recorded. Hypoglycemia episodes were also reported and defined broadly in this study, including cases where a patient experienced either a biochemically confirmed hypoglycemic episode (fingerstick plasma glucose ≤3.9 mmol/L; whether symptomatic or asymptomatic) or a severe hypoglycemic episode, defined as the subgroup of cases where a patient required the assistance of others, lost consciousness, or experienced a seizure. After the 18week treatment period, follow-up measurements were conducted at weeks 26 (HbA1c, FPG, and safety), 39 (HbA1c, serum chemistry, and safety), and 52 (HbA1c, FPG, fasting lipids, ECG, hematology, urinalysis, serum chemistry, and safety).

Statistical Analysis Efficacy and safety analyses were performed using the modified intent-to-treat population, consisting of all randomized patients to receive 1 or more doses of the study drug. The last observation carried forward approach was used to impute missing efficacy data. For patients who received rescue therapy, the last post-baseline value before the initiation of rescue therapy was used for analysis. Rescue therapy was defined as investigator-documented rescue therapy during the first 18 weeks of the study or any additional antihyperglycemic agents other than SU after the first 18 weeks, but before week 52. An ANCOVA model, including treatment as a fixed effect and corresponding baseline value as a covariate, was used for primary and continuous

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Clinical Therapeutics

215 Patients eligible for SU monotherapy substudy

69 received Placebo

. . . .

74 received CANA 100 mg

12 discontinued1

. . . . . .

2 death 2 lost to follow-up 4 personal reasons

3 withdrawal of consent 1 other

.

. 57 completed study day 3651

72 received CANA 300 mg

15 discontinued 4 adverse event

11 discontinued 4 adverse event . 2 personal reasons . 4 withdrawal of consent . 1 other

.

1 death 1 lost to follow-up 1 noncompliance with study drug 5 personal reasons 1 withdrawal of consent 2 other

59 completed study day 365

61 completed study day 365

24 received glycemic rescue

13 received glycemic rescue

12 received glycemic rescue

1 received SU dose increase2

1 received SU dose decrease; 2 received SU dose increase

2 received SU dose decrease;

69 included in mITT analysis (LOCF)

74 included in mITT analysis (LOCF)

1

1 2

72 included in mITT analysis (LOCF)

Note that the number of patients who completed day 365 of the study and the number of patients who discontinued could include patients who received glycemic rescue treatment by addition of an AHA. Dose adjustment of the SU was not considered glycemic rescue

Figure 2. Study flow diagram.

secondary end points. Least squares means and 2-sided 95% CIs were calculated for the comparison of each canagliflozin dose versus placebo. A logistic regression model with treatment as a factor and baseline HbA1c as a covariate was used for the analysis of the proportion of patients reaching HbA1c o7.0%. A prespecified, hierarchical testing sequence was used to evaluate the prespecified 18-week hypotheses and estimate P values. For end points that were not prespecified for hypothesis testing, point estimates and 95% CIs are provided in lieu of P values.

Compliance with Ethics The study was conducted in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964, as revised in 2013, and is consistent with Good Clinical Practice Guideline. Regulatory approval for the conduct of the trial was obtained in each country, and ethics approval was received for every site before initiation. Informed consent was obtained from all patients included in the CANVAS trial.

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RESULTS A total of 215 patients from the CANVAS study were eligible for the SU substudy (Figure 2). Patients were randomly assigned 1:1:1 to receive placebo (n ¼ 69), canagliflozin 100 mg (n ¼ 74), or canagliflozin 300 mg (n ¼ 72). A total of 38 patients discontinued treatment, with 12, 15, and 11 discontinuations in the placebo, canagliflozin 100-mg, and canagliflozin 300mg groups, respectively. Overall, 177 patients completed the 52-week follow-up, with 24, 13, and 12 patients requiring glycemic rescue therapy at some point during the study. A total of 6 patients had changes to their background SU dose during the study; 3 patients in the canagliflozin groups combined had a decrease and 3 patients (1 in the placebo and 2 in the canagliflozin groups combined) had an increase in SU dose.

Baseline Characteristics Key baseline characteristics were balanced across groups, as summarized in Table I. The mean (SD) values for the total population at study entry were: age 64.8 (8.05) years, HbA1c 8.3% (1.02%), and weight 81.8 (18.19) kg. Participants had a mean

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Table I. Baseline demographic and disease characteristics. Canagliflozin Dose Characteristic

Placebo (n ¼ 69)

100 mg (n ¼ 74)

Sex, n (%) Male 41 (59.4) 37 (50.00) Female 28 (40.6) 37 (50.0) Age, y, mean (SD) 64.3 (7.76) 64.3 (8.49) Aged 65 y or older, n (%) 36 (52.2) 35 (47.3) Race, n (%) White 51 (73.9) 49 (66.2) Black or African American 1 (1.4) 0 Asian 15 (21.7) 24 (32.4) Other 2 (2.9) 1 (1.4) Weight, kg, mean (SD) 84.2 (18.97) 80.7 (16.63) 36 (52.2) 40 (54.1) BMI o30 kg/m2, n (%) BMI, mean (SD) 25.9 (2.8) 25.9 (2.8) 33 (47.8) 34 (45.9) BMI ≥30 kg/m2, n (%) BMI, mean (SD) 35.2 (4.5) 34.3 (2.5) Duration of diabetes, y, mean (SD) 11.4 (7.15) 9.7 (6.55) Duration of oral antidiabetic treatment, y, mean (SD) 8.1 (5.32) 7.7 (6.16) 8.4 (1.14) 8.3 (0.97) HbA1c, %, mean (SD) FPG, mmol/L, mean (SD) 10.0 (2.79) 9.8 (2.92) eGFR category, n (%) 20 (29.0) 28 (37.8) 30 to o60 mL/min/1.73 m2 39 (56.5) 38 (51.4) 60 to o90 mL/min/1.73 m2 ≥90 mL/min/1.73 m2 9 (13.0) 7 (9.5) Serum creatinine, μmol/L, mean (SD) 90.7 (26.0) 91.1 (22.4)

300 mg (n ¼ 72)

Total (n ¼ 146)

42 30 65.8 41

(58.3) (41.7) (7.88) (56.9)

79 67 65.1 76

(54.1) (45.9) (8.20) (52.1)

52 3 16 1 80.5 48 25.5 24 35.6 8.8 7.8 8.1 9.3

(72.2) (4.2) (22.2) (1.4) (18.97) (66.7) (2.8) (33.3) (4.4) (6.24) (6.14) (0.95) (2.11)

101 3 40 2 80.6 88 25.7 58 34.9 9.2 7.7 8.2 9.6

(69.2) (2.1) (27.4) (1.4) (17.76) (60.3) (2.8) (39.7) (3.4) (6.39) (6.13) (0.96) (2.56)

28 35 9 93.7

(38.9) (48.6) (12.5) (26.9)

56 73 16 92.4

(38.4) (50.0) (11.0) (24.7)

BMI ¼ body mass index; eGFR ¼ estimated glomerular filtration rate; FPG ¼ fasting plasma glucose; HbA1c ¼ glycosylated hemogloblin.

duration of diabetes of 9.9 years, with a mean of 7.8 years of antidiabetic therapy. The most common background SU therapies were glimepiride (37%), glyburide/glibenclamide (27%), and gliclazide modified release (20%). There were a total of 16 (7.4%) patients who received prior treatment with metformin: 5 (7.2%) in the placebo group, 6 (8.1%) in the canagliflozin 100-mg group, and 5 (6.9%) in the canagliflozin 300-mg group. Median SU doses at baseline are presented in the Supplemental Appendix in the online version at http://dx.doi.org/10.1016/j. clinthera.2017.10.003. For each SU, the range of doses used in the study was distributed across the recommended therapeutic range.

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Efficacy At 52 weeks follow-up, patients receiving both 100mg and 300-mg doses of canagliflozin achieved a sustained reduction in HbA1c relative to patients receiving placebo (−0.61% [95% CI, −0.94% to −0.28%] and −0.66% [95% CI, −0.99% to −0.33%], respectively) (Table II, Figure 3A). In addition, patients in both groups receiving canagliflozin had a significant reduction in HbA1c from baseline to week 52, regardless of baseline HbA1c, duration of diabetes, SU dose, or body mass index; reductions in HbA1c from baseline were numerically greater than those observed in the placebo group (Supplemental Appendix in the online version at http://dx.doi.org/10.1016/j.clinthera.2017.10.003.).

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Clinical Therapeutics

Table II. Summary of efficacy outcomes for canagliflozin. Canagliflozin 100 mg vs Placebo Variable

Canagliflozin 300 mg vs Placebo

LS Mean

95% CI

LS Mean

95% CI

−0.61 15.9 −1.9 −2.0 −2.9 4.39 3.70 10.93 6.66 −4.34

−0.94 to −0.28 1.3 to 30.4 −3.2 to −0.7 −2.8 to −1.3 −6.8 to 1.1 −2.4 to 11.2 −1.9 to 9.3 0.0 to 21.8 −3.6 to 16.9 −17.1 to 8.5

−0.66 21.1 −2.0 −1.9 −2.3 4.38 4.10 8.14 3.47 −4.50

−0.99 to −0.33 6.2 to 36.1 −3.2 to −0.7 −2.6 to −1.1 −6.3 to 1.6 −2.3 to 11.1 −1.5 to 9.7 −2.6 to 18.9 −6.7 to 13.6 −17.0 to 8.1

Change in HbA1c, % Proportion with HbA1c o7.0%, % % Change in weight Change in FPG, mmol/L Change in systolic BP, mm Hg % Change in fasting serum cholesterol (mmol/L) % Change in fasting serum HDL-C (mmol/L) % Change in fasting serum LDL-C (mmol/L) % Change in fasting LDL-C/HDL-C (mol/mol) % Change in fasting triglycerides (mmol/L)

BP ¼ blood pressure; FPG ¼ fasting plasma glucose; HbA1c ¼ glycosylated hemoglobin; LS Mean ¼ least squares mean.

A sustained reduction in FPG was also found in both the 100-mg and 300-mg canagliflozin groups, relative to the placebo group (−2.0 mmol/L [95% CI, −2.8 to −1.3 mmol/L]; −1.9 mmol/L [95% CI, −2.6 to −1.1 mmol/L, respectively) (Table II, Figure 3B). In addition, weight was significantly reduced at 52 weeks in patients receiving both the 100-mg and 300-mg doses of canagliflozin, relative to patients receiving placebo (−1.9% [95% CI, −3.2% to −0.7%] and −2.0% [95% CI, −3.2% to −0.7%], respectively) (Table II, Figure 3C). Reduction in systolic blood pressure was also found in patients receiving the 100mg and 300-mg doses of canagliflozin relative to patients receiving placebo (−2.9 mm Hg [95% CI, −6.8 to 1.1 mm Hg] and −2.3 mm Hg [95% CI, −6.3 to 1.6 mm Hg], respectively) (Table II). There was no clear difference in HDL-C, LDL-C, or triglyceride levels among the groups (Table II). A total of 24 (34.8%) patients were rescued in the placebo group compared with 13 patients (17.6%; hazard ratio [HR] ¼ 0.44 [95% CI, 0.22–0.86]) receiving the 100-mg dose and 12 patients (16.7%; HR ¼ 0.37 [95% CI, 0.18–0.75]) receiving the 300mg dose of canagliflozin.

Safety Canagliflozin was generally well tolerated. Table III presents AEs occurring more frequently in patients

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receiving canagliflozin than placebo. AEs of special interest are presented in Table IV. A total of 8 patients discontinued treatment due to AEs; reasons reported included hypoglycemia (n ¼ 1), increased blood creatinine (n ¼ 1), renal impairment (n ¼ 1), cardiac failure (n ¼ 2), vulvovaginitis (n ¼ 1), erythematous rash (n ¼ 1), and metastatic colon cancer (n ¼ 1). Discontinuations due to hypoglycemia, increased blood creatinine, renal impairment, vulvovaginitis, and rash might have been related to treatment. Serious adverse events (SAEs) were experienced by 25 patients, who reported a total of 39 SAEs in the 52-week study period: 11 patients in the placebo group reported 20 SAEs; 6 patients in the canagliflozin 100-mg group reported 8 SAEs; and 8 patients in the canagliflozin 300-mg group reported 11 SAEs. Six SAEs were considered possibly related to study drug, including 4 events experienced by 2 patients in the placebo group and a single event in each of the canagliflozin 100-mg and 300-mg groups. There was a total of 4 deaths; 2 in the placebo group (1 chronic cardiac failure, 1 sudden death) and 2 in the canagliflozin 100-mg group (2 cardiac failures), with no deaths deemed related to treatment by the investigators. There was an increased frequency of genital mycotic infections in both men (5.1%) and women (10.4%) in both canagliflozin groups combined,

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HbA1c (%):LS Mean Change+/-SE

A

0.3 0.2 0.1 0.0 -0.1 -0.2 -0.3 -0.4 -0.5 -0.6 -0.7 -0.8 -0.9 -1.0 Week 12 LOCF

Baseline

Week 18 LOCF

Week 26 LOCF

Week 39 LOCF

Week 52 LOCF

Time (Weeks) Placebo

FPG (mmol/L): LS Mean Change+/-SE

B

Cana 100 mg

Cana 300 mg

1.5 1.0 0.5 0.0 -0.5 -1.0 -1.5 -2.0 -2.5

Baseline

Week 6 LOCF

Week 12 LOCF

Week 18 LOCF

Week 26 LOCF

Week 39 LOCF

Week 52 LOCF

Time (Weeks) Placebo

C

Cana 100 mg

Cana 300 mg

1.0

Weight (%):LS Mean Change+/-SE

0.5 0.0 -0.5 -1.0 -1.5 -2.0 -2.5 -3.0

Baseline

Week 6 LOCF

Week 12 LOCF

Week 18 LOCF

Week 26 LOCF

Week 52 LOCF

Time (Weeks) Placebo

Cana 100 mg

Cana 300 mg

Figure 3. (A) LS mean change from baseline in glycosylated hemoglobin (HbA1c) (B) LS mean change from baseline in fasting plasma glucose (FPG). (C) LS mean change from baseline in weight. Cana ¼ canagliflozin; LOCF ¼ last observation carried forward; LS ¼ least squares.

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Clinical Therapeutics Table III. Treatment-emergent adverse events (regardless of causality) in ≥2% of patients with canagliflozin and more frequently than in the placebo group.* Canagliflozin Dose Body System or Organ Class Gastrointestinal disorders Gastritis General disorders and administration site conditions Asthenia Chest pain Pyrexia Infections and infestations Cystitis Herpes zoster Pharyngitis Staphylococcal infection Tooth infection Upper respiratory tract infection Viral infection Musculoskeletal and connective tissue disorders Muscular weakness Nervous system disorders Dizziness Headache Neuralgia Skin and subcutaneous tissue disorders Rash Vascular disorders Peripheral arterial occlusive disease ⁎

100 mg (n ¼ 74)

300 mg (n ¼ 72)

Total (n ¼ 146)

0

3 (4.1)

0

3 (2.1)

0 1 (1.4) 0

1 (1.4) 2 (2.7) 1 (1.4)

2 (2.8) 4 (5.6) 2 (2.8)

3 (2.1) 6 (4.1) 3 (2.1)

0 1 (1.4) 1 (1.4) 0 0 3 (4.3) 0

0 0 3 (4.1) 0 0 4 (5.4) 0

2 (2.8) 2 (2.8) 0 2 (2.8) 2 (2.8) 1 (1.4) 2 (2.8)

2 2 3 2 2 5 2

0

0

2 (2.8)

2 (1.4)

0 1 (1.4) 1 (1.4)

2 (2.7) 2 (2.7) 2 (2.7)

0 2 (2.8) 1 (1.4)

2 (1.4) 4 (2.7) 3 (2.1)

0

0

2 (2.8)

2 (1.4)

0

1 (1.4)

2 (2.8)

3 (2.1)

(1.4) (1.4) (2.1) (1.4) (1.4) (3.4) (1.4)

Values are n (%). Percentages calculated with the number of patients in each group as denominator. Events captured as adverse events of special interest are not repeated in this table.

relative to placebo (0%), and their frequency increased in the higher-dose group. There was also a slightly higher rate of renal impairment in those treated with canagliflozin versus placebo (2.1% vs 0%). Of these patients, 3 had worsening of renal function, 4 had increasing blood creatinine, and 3 had increasing blood urea nitrogen. In addition, there were more fractures reported with the canagliflozin groups combined versus placebo (5 vs 1 patients, respectively). A total of 3 patients in the canagliflozin groups

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Placebo (n ¼ 69)

combined (vs 1 patient given placebo) reported vascular occlusive disease, including 2 with peripheral artery disease and 1 with left-leg arterial insufficiency. However, there was no increase in frequency of osmotic diuresis or hypoglycemia with the use of canagliflozin, and no treatment-related deaths. There were also no patients with amputations, diabetic ketoacidosis, skin ulcers, hepatic injury, or peripheral ischemia ulcers reported during the study.

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J.-F. Yale et al. Table IV. Overall summary and adverse events of special interest.* Canagliflozin Dose Body System or Organ Class Overall summary of patients with an AE Any AE AEs leading to discontinuation AEs related to study drug† Serious adverse events Serious adverse events leading to discontinuation Deaths AEs of special interest Venous thromboembolic events Genital infections Male Female Osmotic diuresis Nocturia Pollakiuria Polydipsia Polyuria Thirst Urine output increased Urinary tract infections Hyperkalemia Hyperuricemia Volume-related events Hypotension Hypovolemia Hypoglycemia Severe hypoglycemia Fracture Severe hypersensitivity or cutaneous reactions Renal related Blood creatinine increased Blood urea increased Renal impairment

Placebo (n ¼ 69)

100 mg (n ¼ 74)

300 mg (n ¼ 72)

Total (n ¼ 146)

48 1 14 11 1 2

42 (56.8) 4 (5.4) 11 (14.9) 6 (8.1) 1 (1.4) 2 (2.7)

48 (66.7) 4 (5.6) 18 (25.0) 8 (11.1) 1 (1.4) 0

90 (61.6) 8 (5.5) 29 (19.9) 14 (9.6) 2 (1.4) 2 (1.4)

0

0

1 (1.4)

1 (0.7)

0 0

1 (2.7) 3 (8.1)

3 (7.1) 4 (13.3)

4 (5.1) 7 (10.4)

0 1 (1.4) 1 (1.4) 1 (1.4) 0 0 2 (2.9) 1 (1.4) 1 (1.4)

1 (1.4) 1 (1.4) 0 0 1 (1.4) 1 (1.4) 3 (4.1) 0 0

0 3 (4.2) 0 0 2 (2.8) 1 (1.4) 5 (6.9) 0 1 (1.4)

1 (0.7) 4 (2.7) 0 0 3 (2.1) 2 (1.4) 8 (5.5) 0 1 (0.7)

1 (1.4) 0 8 (10.8) 1 (1.4) 2 (2.7) 1 (1.4)

1 (1.4) 0 11 (15.3) 0 3 (4.2) 0

2 (1.4) 0 19 (13.0) 1 (0.7) 5 (3.4) 1 (0.7)

3 (4.1) 2 (2.7) 0

1 (1.4) 1 (1.4) 3 (4.2)

4 (2.7) 3 (2.1) 3 (2.1)

1 10 1 1

(69.6) (1.4) (20.3) (15.9) (1.4) (2.9)

0 (1.4) (14.5) 0 (1.4) (1.4)

1 (1.4) 1 (1.4) 0

AE ¼ adverse event. ⁎ Values are n (%). Percentages calculated with the number of patients in each group as denominator. † Related to study drug includes relationship determined by investigators: possibly related, probably related, and very likely related.

November ]]]]

9

Clinical Therapeutics

DISCUSSION With the extended follow-up of the SU substudy, sustained efficacy was found for the primary outcome, HbA1c, in the groups receiving canagliflozin. At 18 weeks, HbA1c was reduced significantly, by −0.74% and −0.83% in the groups receiving the 100-mg and 300-mg doses of canagliflozin, respectively, relative to those receiving placebo. This reduction in HbA1c was sustained at 52 weeks with both 100-mg and 300-mg doses of canagliflozin, with reductions in HbA1c of −0.61% (95% CI, −0.94% to −0.28%) and −0.66% (95% CI, −0.99% to −0.33%) relative to placebo, respectively. These changes in HbA1c are consistent with previous studies using canagliflozin; for example, a study by Wilding et al21 reported reductions in HbA1c of −0.74% and −0.96% at 52 weeks in patients receiving 100-mg and 300-mg doses of canagliflozin added to metformin and SU, respectively. Changes in HbA1c were also similar to those found with other sodium−glucose co-transporter 2 inhibitors, such as in the study by Strojek et al, which reported reductions of −0.37% (95% CI, −0.60% to −0.14%) to −0.70% (95% CI, −0.92% to −0.47%) relative to placebo with dapagliflozin, 5 mg and 10 mg, respectively, when added to SU.22 Reduced HbA1c with canagliflozin versus placebo was achieved in the extension study, regardless of baseline HbA1c, duration of diabetes, SU dose, or body mass index. At 18 weeks, FPG was reduced in the patients receiving 100-mg and 300-mg doses of canagliflozin (−2.1 mmol/L and −2.7 mmol/L, respectively) relative to those receiving placebo. These reductions were also sustained at 52 weeks with both 100 mg and 300 mg doses of canagliflozin relative to placebo (−2.0 and −1.9, respectively). These reductions in HbA1c and weight are similar to those found with dapagliflozin when added to SU after 48 weeks of follow-up.22 Of interest, in the 18-week analysis, patients receiving the 300-mg dose (−1.8%; P ¼ 0.014), but not the 100-mg dose (−0.4%; P ¼ 0.557), of canagliflozin achieved a significant reduction in weight.20 However, weight was significantly reduced at 52 weeks in patients receiving 100-mg and 300-mg canagliflozin, relative to those receiving placebo (−1.9% [95% CI, −3.2% to −0.7%] and −2.0% [95% CI, −3.2% to −0.7%], respectively). The study by Wilding et al21 found that weight was reduced in patients receiving both 100-mg and 300-mg doses of canagliflozin, when

10

combined with both metformin and SU at both week 26 and week 52. It is therefore possible that at week 18, the lower dose of canagliflozin combined with SU was not sufficient to reduce weight, but that with sustained treatment, significant weight loss was achieved. While SUs are effective for controlling hyperglycemia, their use is associated with weight gain.5 Therefore, the fact that patients receiving canagliflozin achieved an overall reduction in weight suggests canagliflozin is able to mitigate the SU effect. There were no new safety signals found in the 52week extension of the SU substudy, with both doses of canagliflozin being well tolerated. A greater number of genital mycotic infections were reported with canagliflozin, as per the 18-week results,20 and the combination with metformin and SU study by Wilding et al.21 There were also slightly more patients with renal dysfunction (2.1% vs 0%) and vascular disorders (2.1% vs 0%) in the canagliflozin group relative to placebo in the extension study. However, this finding was not supported within the overall CANVAS study population, where there appeared to be a protective effect of canagliflozin on estimated glomerular filtration rate, renal replacement therapy, or renal death (HR ¼ 0.6; 95% CI, 0.47– 0.77) and no increase in venous thromboembolic events (1.7% and 1.7%, respectively).23 Given the small numbers of patients with renal dysfunction and vascular disorders in the SU 52-week extension, these findings might have occurred by chance. Moreover, unlike the overall results of the CANVAS study, which found an increased risk of amputations (primarily at the level of the toe or metatarsal) in the canagliflozin groups (HR ¼ 1.97; 95% CI, 1.41–2.75), there were no amputations reported in this CANVAS substudy.23 There were also no patients with diabetic ketoacidosis, skin ulcers, hepatic injury, or peripheral ischemia in any of the treatment groups. However, there were slightly more fractures in the canagliflozin group combined versus placebo group (5 vs 1 patients, respectively). Discontinuations due to hypoglycemia, blood creatinine increased, renal impairment, vulvovaginitis, and rash might have been related to treatment. However, although there were 4 deaths during the study, none were treatment related. This finding is supported by results of the larger CANVAS population, where there was a significant reduction in major adverse cardiac events in patients receiving canagliflozin.23

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J.-F. Yale et al. When comparing the results of the 18-week and 52-week analyses, it is important to note that the 18-week analysis did not include patients with SU dose adjustments. However, adjustments occurred in 6 patients only, with 3 patients in the canagliflozin groups combined having a decrease and 3 patients (1 in the placebo and 2 in the canagliflozin groups combined) having an increase in SU dose. Given the small number of patients with changes in SU dose, it is unlikely that this would affect results. In addition, by including patients with SU dose adjustments in the analysis, the study population more closely resembles that which would be seen in clinical practice. Importantly, there was no difference in efficacy outcomes when separate analyses excluding patients with a change in SU dose or including patients with any glycemic rescue therapy were performed. In addition to limitations of the SU substudy published previously,20 a number of additional limitations should be considered for the extension study. Firstly, the extension analysis was retrospective in nature. However, baseline characteristics appeared equally distributed between groups, with no clear differences likely to affect results. Secondly, the sample size included in the analysis was smaller than that included in other sodium−glucose co-transporter 2 inhibitor studies, such as the 48-week extension study of dapagliflozin added to background SU.22 However, the power of our study was adequate to detect differences between groups in the primary outcome, HbA1c, and additional significant differences were found for FPG and weight. Finally, it is important to note that some patients were exposed to metformin previously. As metformin is the recommended first-line therapy for T2DM,5 it is important to ensure that the use of SU was not due to a failed trial of metformin. Given that only 16 of 215 (7.4%) patients had previous exposure to metformin, prior use was unlikely to influence results significantly. Although metformin is widely recommended as firstline therapy, SUs may be selected when metformin is contraindicated or because of physician or patient preference.5 It is therefore likely that most patients included in our study were given SUs not because of failed metformin therapy but because of physician or patient preference. Taken together with previous data reporting meaningful reductions in HbA1c in patients receiving canagliflozin added to metformin and SU,21 the results of our study indicate that the combination

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of canagliflozin and SU is effective for reducing HbA1c, regardless of the use of metformin.

CONCLUSIONS In this long-term extension of the SU substudy, the long-term efficacy and safety of canagliflozin added to SU was assessed in patients with T2DM. At 18 weeks, patients receiving both 100-mg and 300-mg doses of canagliflozin had reduced HbA1c and FPG; weight was reduced in the 300-mg dose group only. At 52 weeks, patients receiving both doses of canagliflozin achieved a sustained reduction in HbA1c, FPG, and weight, with additional reductions in blood pressure. Canagliflozin was well tolerated, with a safety profile reasonably consistent with that reported in previous studies. Although metformin is the standard treatment in this setting, many patients are given SU due to contraindications, or due to patient or physician preference. Our study suggests that canagliflozin added to SU can achieve long-term efficacy and safety in this setting.

ACKNOWLEDGMENTS All authors contributed equally to the study concept. SES developed the analysis plan and JX led the statistical analysis. JFY and CG provided the clinical interpretation of the results. All authors contributed to the preparation and revision of the manuscript. The authors thank Anna Christofides of IMPACT Medicom Inc, who contributed to the development of the paper by providing medical writing assistance.

CONFLICT OF INTEREST This study was funded by Janssen Research & Development, LLC. Stephen Sherman is an employee of Janssen Inc. John Xie is an employee of Janssen Research & Development. Jean-François Yale and Claude Garceau received honoraria for advisory boards or lectures from Janssen, Astra Zeneca, Boehringer-Ingelheim, Eli Lilly, Novo Nordisk, Sanofi, Merck, and Takeda.

SUPPLEMENTARY MATERIAL Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10. 1016/j.clinthera.2017.10.003.

11

Clinical Therapeutics

REFERENCES 1. Farag YM, Gaballa MR. Diabesity: an overview of a rising epidemic. Nephrol Dialysis Transplant. 2011;26:28–35. https://academic. oup.com/ndt/article-lookup/doi/ 10.1093/ndt/gfq576. Accessed October 2017. 2. National Institute for Health and Care Excellence (NICE). Type 2 diabetes in adults: management. https://www.nice.org.uk/guidance/ ng28. Accessed October 2017. 3. Sarwar N, Gao P, Seshasai SR, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375: 2215–2222. https://www.ncbi. nlm.nih.gov/pubmed/20609967. Accessed October 2017. 4. Liebl A, Khunti K, Orozco-Beltran D, Yale JF. Health economic evaluation of type 2 diabetes mellitus: a clinical practice focused review. Clin Med Insights Endocrinol Diabetes. 2015;8:13–19. https://www.ncbi. nlm.nih.gov/pmc/articles/PMC43 74638/. Accessed October 2017. 5. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2012;55:1577–1596. 6. American Diabetes Association. Standards of medical care in diabetes–2015: summary of revisions. Diabetes Care. 2015;38(Suppl):S4. http://care.diabetesjournals.org/ content/38/Supplement_1. Accessed October 2017. 7. Neumiller JJ, White JR Jr., Campbell RK. Sodium-glucose co-transport inhibitors: progress and therapeutic potential in type 2 diabetes mellitus. Drugs. 2010;70:377–385.

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8. Rosenstock J, Aggarwal N, Polidori D, et al. Dose-ranging effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as addon to metformin in subjects with type 2 diabetes. Diabetes Care. 2012;35:1232–1238. 9. Polidori D, Sha S, Ghosh A, et al. Validation of a novel method for determining the renal threshold for glucose excretion in untreated and canagliflozin-treated subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2013;98:E867– E871. 10. AstraZeneca Canada Inc. PRFORXIGA® [product monograph]. Mississauga, ON: AstraZeneca Canada Inc; 2016. 11. Janssen Inc. PrINVOKAMET® [product monograph]. Raritan, NJ: Janssen, Inc; 2017. 12. Boehringer Ingelheim (Canada) Ltd. PrJARDIANCE ™ [product monograph]. Burlington, ON: Boehringer Ingelheim (Canada) Ltd; January 9, 2017. 13. US Food and Drug Administration. FDA Drug Safety Communication: FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. https://www.fda.gov/ Drugs/DrugSafety/ucm475463. htm. Accessed June 1, 2017. 14. European Medicines Agency. EMA confirms recommendations to minimise ketoacidosis risk with SGLT2 inhibitors for diabetes. http://www.ema.europa.eu/docs/ en_GB/document_library/Press_re lease/2016/02/WC500202388. pdf. Accessed October 2017. 15. Stenlof K, Cefalu WT, Kim KA, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab. 2013;15:372–382.

16. Cefalu WT, Leiter LA, Yoon KH, et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet. 2013;382:941–950. 17. Devineni D, Morrow L, Hompesch M, et al. Canagliflozin improves glycaemic control over 28 days in subjects with type 2 diabetes not optimally controlled on insulin. Diabetes Obes Metab. 2012;14:539– 545. 18. Qiu R, Balis D, Capuano G, et al. Canagliflozin: Efficacy and Safety in Combination with Metformin Alone or with Other Antihyperglycemic Agents in Type 2 Diabetes. Diabetes Ther. 2016;7:659–678. https://www.ncbi.nlm.nih.gov/ pmc/articles/PMC5118239/. Accessed October 2017. 19. Neal B, Perkovic V, Matthews DR, et al. Rationale, design and baseline characteristics of the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R): A randomized, placebo-controlled trial. Diabetes Obes Metab. 2017;19: 387–393. 20. Fulcher G, Matthews DR, Perkovic V, et al. Efficacy and Safety of Canagliflozin Used in Conjunction with Sulfonylurea in Patients with Type 2 Diabetes Mellitus: A Randomized, Controlled Trial. Diabetes Ther. 2015;6:289–302. https://www.ncbi.nlm.nih.gov/ pmc/articles/PMC4575303/. Accessed October 2017. 21. Wilding JP, Charpentier G, Hollander P, et al. Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial. Int J Clin Pract. 2013;67:1267–1282.

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J.-F. Yale et al. 22. Strojek K, Yoon KH, Hruba V, et al. Dapagliflozin added to glimepiride in patients with type 2 diabetes mellitus sustains glycemic control and weight loss over 48 weeks: a randomized, doubleblind, parallel-group, placebocontrolled trial. Diabetes Ther. 2014;5:267–283. https://www. ncbi.nlm.nih.gov/pmc/articles/ PMC4065289/. Accessed October 2017. 23. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017;377:644–657. http://www. nejm.org/doi/full/10.1056/NEJ Moa1611925#t=article. Accessed October 2017.

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13

Clinical Therapeutics

SUPPLEMENTARY MATERIAL See Figure 1A and Table A1

Subgroup Treatment Age < 65 Years Placebo

n

Baseline value

Difference (a) vs Placebo (95% CI)

LS mean Change in HbA1c (%)

30

8.61%

Cana 100 mg

38

8.33%

–0.74 (–1.21,–0.27)

Cana 300 mg

30

8.07%

–0.64 (–1.14,–0.14)

Placebo

32

8.24%

Cana 100 mg

32

8.20%

–0.44 (–0.92, 0.03)

Cana 300 mg

41

8.18%

–0.68 (–1.13,–0.23)

33

8.47%

36 47

8.26%

–0.59 (–1.10,–0.07)

8.09%

–0.56 (–1.05,–0.07)

Age ≥ 65 Years

Baseline BMI < 30 kg/m2 Placebo Cana 100 mg Cana 300 mg Baseline BMI ≥ 30 kg/m2 Placebo

29

8.36%

Cana 100 mg

34

8.28%

–0.64 (–1.04,–0.24)

Cana 300 mg

24

8.22%

–0.86 (–1.29,–0.42)

Placebo

18

8.28%

Cana 100 mg

27

8.39%

–0.89 (–1.55,–0.24)

27

8.14%

–1.14 (–1.80,–0.49)

Baseline eGFR < 60 mL/min/1.73 m2

Cana 300 mg Baseline eGFR ≥ 60 mL/min/1.73 m2 Placebo Cana 100 mg

44

8.47%

42

8.22%

–0.55 (–0.93,–0.18)

44

8.13%

–0.48 (–0.85,–0.11)

Placebo Cana 100 mg

23

8.49%

39

8.18%

–0.73 (–1.19,–0.28)

Cana 300 mg

44

8.14%

–0.65 (–1.09,–0.20)

39

8.37%

31

8.38%

–0.42 (–0.92, 0.08)

27

8.11%

–0.63 (–1.15, 0.10)

Placebo Cana 100 mg

42

7.75%

52

7.80%

–0.49 (–0.84, 0.14)

Cana 300 mg

56

7.74%

–0.60 (–0.95,–0.26)

Cana 300 mg Duration of Diabetes < 10 years

Duration of Diabetes ≥ 10 years Placebo Cana 100 mg Cana 300 mg Baseline HbA1c < 9.0%

Baseline HbA1c ≥ 9.0% Placebo

20

9.82%

Cana 100 mg

18

9.62%

–0.95 (–1.75,–0.14)

Cana 300 mg

15

9.60%

–0.80 (–1.65, 0.04)

Baseline SU Dose < 1/2 Maximal Placebo

22

8.29%

Cana 100 mg

30

8.24%

–0.37 (–0.85, 0.11)

Cana 300 mg

32

7.95%

–0.42 (–0.90, 0.06)

Baseline SU Dose ≥ 1/2 Maximal Placebo

40

8.49%

Cana 100 mg

40

8.29%

–0.72 (–1.17, –0.27)

Cana 300 mg

39

8.28%

–0.79 (–1.24,–0.34)

–2.0

–1.5

–1.0

–0.5

0.0

0.5

1.0

(a) Pairwise comparison: Cls are based on the ANCOVA model with treatment and baseline HbA1c.

Figure 1A. Sub-analysis of Baseline Demographic Factors Related to HbA1c. (BMI = body mass index)

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J.-F. Yale et al.

Table A1. Sulfonylurea Daily Doses at Baseline. Sulfonylurea (dose range)⁎

PBO (N ¼ 69)

CANA 100 CANA 300 CANA Total Overall Total mg (N ¼ 74) mg (N ¼ 72) (N ¼ 146) (N ¼ 215)

N 3 5 Median 10.0 10.0 Range (5.0;20.0) (2.5;20.0) Glipizide ER N 1 2 (5 – 20 mg/day) Median 10.0 7.5 Range (10.0;10.0) (5.0;10.0) Glyburide/ Glibenclamide N 20 24 (1.25 – 20 mg/day) Median 10.0 10.0 Range (1.3;20.0) (5.0;20.0) Glimepiride N 23 25 (1 – 8 mg/day) Median 4.0 4.0 Range (0.5;8.0) (1.0;8.0) Gliclazide N 8 6 (40 – 320 mg/day) Median 60.0 80.0 Range (30.0;320.0) (60.0;160.0) Gliclazide MR N 14 12 (30 – 120 mg/day) Median 60.0 60.0 Range (30.0;240.0) (30.0;240.0) Glipizide (2.5 – 40 mg/day)

⁎

5 10.0 (5.0;20.0) 3 10.0 (5.0;10.0) 14 9.4 (5.0;15.0) 32 4.0 (0.5;10.0) 2 165.0 (90.0;240.0) 16 60.0 (30.0;120.0)

10 10.0 (2.5;20.0) 5 10.0 (5.0;10.0) 38 10.0 (5.0;20.0) 57 4.0 (0.5;10.0) 8 85.0 (60.0;240.0) 28 60.0 (30.0;240.0)

13 10.0 (2.5;20.0) 6 10.0 (5.0;10.0) 58 10.0 (1.3;20.0) 80 4.0 (0.5;10.0) 16 80.0 (30.0;320.0) 42 60.0 (30.0;240.0)

Labelled dose range based on minimum and maximum doses approved in Canada, US or EU. A total of 6 patients were taking SU doses outside of this range at baseline; 3 patients in the placebo arm received doses below those recommended, 1 received a higher dose, and 2 patients in the 100 and 300 mg canagliflozin arms received SU doses higher than recommended.

Details of Patients with Serious Adverse Events Six SAEs were considered possibly related to study drug, including 4 events experienced by 2 patients in the placebo group and a single event in each of the canagliflozin 100 mg and 300 mg groups. All four patients with possibly related serious adverse events (SAEs) recovered; the cases are summarized here. One SAE involved a 70-year-old male receiving placebo, who experienced hyperglycemia beginning on day 48 of the study. The event resolved after 4 days and an interruption in treatment. Another patient in the placebo group experienced the SAEs of rectal hemorrhage, constipation, and anemia beginning on day 355 of study drug, and was treated with antibiotics, iron and folate. This 48-year-old male had been receiving concomitant aspirin and

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clopidogrel for more than a year prior to the onset of these events, which were discontinued at the time of the SAE. None of these SAEs resulted in a change to study drug treatment. A 62-year-old male patient in the canagliflozin 100 mg group experienced the possibly related SAE of device-related infection, involving a post-ureteroscopy stent on day 289 of treatment. The event resolved after 14 days of cefuroxime and removal of the stent, with no change to study drug treatment. A 72-year-old male in the 300 mg canagliflozin group, experienced the possibly related SAE of pulmonary embolism 16 days after starting the study. Canagliflozin was discontinued and the patient recovered after treatment with phenprocoumon.

13.e2