1. Int J Clin Pract, December 2013, 67, 12, 1267-1282
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, December 2013, 67, 12,

2. Patients & Study Design
Pretreatment Period
Double-blind Treatment Period
Core Period
Extension Period
PBO
On protocol-specified doses* of MET/SU
A1C ≥7% and ≤10.5%
2-week single- blind
placebo run-in
A1C ≥7% and ≤10.5% R
CANA 100 mg
On MET/SU below protocol-specified doses*
A1C ≥7.5%
Titrate MET/SU
(up to 4 wks)
2.Stable MET/SU
dose (8 wks)
CANA 300 mg
Continue stable doses of MET/SU
Screening Visit
AHA Adjustment Period Start
Week -2
Day 1
Baseline
Week 26
Week 52
*Protocol-specified = MET, 2,000 mg/day [or 1,500 mg/day if intolerant of higher dose];
SU, at least half-maximal labeled dose.
Int J Clin Pract, December 2013, 67, 12, 1267–1282

3. Baseline Characteristics
Int J Clin Pract, December 2013, 67, 12, 1267–1282

4. Glycaemic efficacy end-points

5. Significant and sustained reduction in HbA1c at 52 weeks with Canagliflozin
LS mean
change
–0.96%
–0.74%
0.01%
–0.75%
P <0.001
–0.97% 6 12 18 26
Time point (wk)
Baseline (%)
8.1
-1.0
At week 26, HbA1c was significantly reduced from baseline with CANA 100 and 300mg compared with PBO (P <0.001 for both CANA doses) 34 42 52
PBO, placebo; CANA, canagliflozin; LS, least squares; SE, standard error.
mITT, LOCF
Int J Clin Pract, December 2013, 67, 12, 1267–1282 5

6. Greater proportion of patients achieved HbA1c targets with Canagliflozin
P <0.001 for both CANA doses
At Week 26, a greater proportion of subjects treated with CANA 100 or 300 mg compared with PBO achieved HbA1c <7.0% (43.2%, 56.6%, and 18.0%, respectively; P <0.001 for both CANA doses)
PBO, placebo; CANA, canagliflozin
Int J Clin Pract, December 2013, 67, 12, 1267–1282 6

7. Reduction in FPG* & PPG with Canagliflozin as add-on to MET + SU
FPG* (Week 52)
2-hour PPG (Week 26)
Baseline
(mmol/L)
Baseline
(mmol/L)
Significant improvements from baseline in FPG were observed at week 26 with canagliflozin 100 and 300 mg compared with placebo; differences in LS mean changes vs. placebo were –1.2 and –1.9 mmol/l, respectively (p < for both canagliflozin doses).
PBO, placebo; CANA, Canagliflozin; LS, least squares; SE, standard error
FPG: Fasting Blood Glucose. PPG: Postprandial Glucose.
*P <0.001 vs PBO.
mITT, LOCF
Int J Clin Pract, December 2013, 67, 12, 1267–1282

8. Non-Glycemic end-points

9. No notable changes in pulse rate were seen across treatment groups
Reduction in SBP & body weight with Canagliflozin as add-on to MET + SU
SBP (Week 52)
BW (Week 52)
Baseline
(mmHg)
Baseline
(kg)
(0.9, –1.2, and –0.4 beats per minute for canagliflozin 100 and 300 mg and placebo, respectively).
No notable changes in pulse rate were seen across treatment groups
PBO, placebo; CANA, canagliflozin; LS, least squares; SE, standard error.
SBP: Systolic Blood Pressure. BW: Body weight
mITT, LOCF
Int J Clin Pract, December 2013, 67, 12, 1267–1282

10. Increase in HDLc was observed with Canagliflozin at week 52
Triglycerides
LDL-C
HDL-C
LDL-C/HDL-C
Non–HDL-C
Baseline (mmol/L)†
Significant increases in high-density lipoprotein cholesterol (HDL-C) were observed with CANA 100 and 300 mg compared with PBO (P <0.001 and P <0.01, respectively). Compared with PBO, CANA 100 and 300 mg showed trends toward improvement in triglycerides at Week 26, but these did not reach statistical significance. Modest, dose-related increases in low-density lipoprotein cholesterol (LDL-C) were observed with CANA 100 and 300 mg relative to PBO.
LOCF (last observation carried forward); LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; LS, least squares; SE, standard error; PBO, placebo; CANA, canagliflozin; NS, not significant.
Statistical comparison for CANA 100 and 300 mg vs PBO not performed (not pre-specified) for LDL-C, LDL-C/HDL-C, and non–HDL-C.
‡Unit of mol/mol for LDL-C/HDL-C.
mITT, LOCF
Int J Clin Pract, December 2013, 67, 12, 1267–1282 10

11. Effect of Canagliflozin on indices of -cell function
At week 26, improvements in -cell function were observed with Canagliflozin as compared with placebo
Canagliflozin was associated with increases in HOMA2-%B among patients who participated in the frequently-sampled mixed-meal tolerance test (FS-MMTT)
Int J Clin Pract, December 2013, 67, 12, 1267–1282

12. Overall Safety and Selected AEs at week 52
Types of AEs
Subjects, n (%)
PBO (n = 156)
CANA 100 mg (n = 157)
CANA 300 mg (n = 156)
Any AE
111 (71.2)
106 (67.5)
114 (73.1)
AEs leading to discontinuation
7 (4.5)
11 (7.0)
12 (7.7)
AEs related to study drug*
24 (15.5)
41 (26.1)
57 (36.5)
Serious AEs
13 (8.3)
8 (5.1)
Deaths
Genital mycotic infection
Male†,‡
1 (1.3)
6 (7.9)
5 (5.7)
Female§,|
4 (5.0)
15 (18.5)
13 (18.8)
UTI
Osmotic diuresis-related Aes #
3 (1.9)
9 (5.7)
11 (7.1)
Volume-related Aes ^
1 (0.6)
6 (3.8)
Hypoglycaemia $
28 (17.9)
53 (33.8)
Severe episodes
AE, adverse event; PBO, placebo; CANA, canagliflozin; UTI, urinary tract infection.
*Possibly, probably, or very likely related to study drug, as assessed by investigators.
†PBO, n = 76; CANA 100 mg, n = 76; CANA 300 mg, n = 87.
‡Including balanitis, balanitis candida, and balanoposthitis (inflammation of the glans penis and foreskin).
§PBO, n = 80; CANA 100 mg, n = 81; CANA 300 mg, n = 69.
|Including vaginal infection, vulvovaginal candidiasis, vulvovaginal mycotic infection, and vulvovaginitis. #Include Increased urine frequency. Increased urine volume.
^ Includepostural hypotemsion, syncope, dizziness. $ Include biochemically documented episodes (<3.9 mmol/L) with/out symptoms.
Int J Clin Pract, December 2013, 67, 12, 1267–1282

13. Overall Safety Summary
Canagliflozin was generally well tolerated over 52 weeks
Genital mycotic infections were generally mild or moderate in severity, treated by antifungal therapies, and led to few study discontinuations
AEs related to osmotic diuresis (e.g. pollakiuria, polyuria) were low
AEs related to volume depletion (e.g. postural dizziness, hypotension) were generally low and similar across treatment groups
There was no increase in the rates of severe hypoglycemic events with canagliflozin
Int J Clin Pract, December 2013, 67, 12, 1267–1282

14. Conclusion
Canagliflozin in patients with T2DM inadequately controlled with metformin plus sulphonylurea
Improved glycaemic control
Reduced body weight
Was generally well tolerated compared with placebo over 52 weeks
Int J Clin Pract, December 2013, 67, 12, 1267–1282