Efficacy and Safety of Canagliflozin in Patients with type 2 diabetes mellitus inadequately...
-
Upload
clifton-goodwin -
Category
Documents
-
view
213 -
download
0
Transcript of Efficacy and Safety of Canagliflozin in Patients with type 2 diabetes mellitus inadequately...
![Page 1: Efficacy and Safety of Canagliflozin in Patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial.](https://reader035.fdocuments.us/reader035/viewer/2022062806/5697bfe21a28abf838cb4269/html5/thumbnails/1.jpg)
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, 1267-1282
![Page 2: Efficacy and Safety of Canagliflozin in Patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial.](https://reader035.fdocuments.us/reader035/viewer/2022062806/5697bfe21a28abf838cb4269/html5/thumbnails/2.jpg)
Patients & Study Design
*Protocol-specified = MET, 2,000 mg/day [or 1,500 mg/day if intolerant of higher dose]; SU, at least half-maximal labeled dose.
Pretreatment PeriodDouble-blind Treatment Period
Screening Visit
Week -2 Day 1Baseline
AHA Adjustment Period Start
• On protocol-specified doses* of MET/SU
• A1C ≥7% and ≤10.5%
Week 52
Continue stable doses of MET/SUContinue stable doses of MET/SU
CANA 300 mg
CANA 100 mg
PBO
•On MET/SU below protocol-specified doses*•A1C ≥7.5%
1.Titrate MET/SU(up to 4 wks)
2.Stable MET/SU dose (8 wks)
A1C≥7% and ≤10.5%
2-week single-blind
placebo run-in
R
Core Period Extension Period
Week 26
Int J Clin Pract, December 2013, 67, 12, 1267–1282
![Page 3: Efficacy and Safety of Canagliflozin in Patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial.](https://reader035.fdocuments.us/reader035/viewer/2022062806/5697bfe21a28abf838cb4269/html5/thumbnails/3.jpg)
Baseline Characteristics
Int J Clin Pract, December 2013, 67, 12, 1267–1282
![Page 4: Efficacy and Safety of Canagliflozin in Patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial.](https://reader035.fdocuments.us/reader035/viewer/2022062806/5697bfe21a28abf838cb4269/html5/thumbnails/4.jpg)
Glycaemic efficacy end-points
![Page 5: Efficacy and Safety of Canagliflozin in Patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial.](https://reader035.fdocuments.us/reader035/viewer/2022062806/5697bfe21a28abf838cb4269/html5/thumbnails/5.jpg)
Significant and sustained reduction in HbA1c at 52 weeks with Canagliflozin
PBO, placebo; CANA, canagliflozin; LS, least squares; SE, standard error.
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
0.2
LS m
ean c
han
ge
(±S
E)
from
bas
elin
e (%
)PBO CANA 100 mg CANA 300 mg
LS meanchange
–0.96%
–0.74%
0.01%
–0.75%P <0.001
–0.97%P <0.001
0 6 12 18 26
Time point (wk)
Baseline (%) 8.18.18.1
-1.0
34 42 52
mITT, LOCF
Int J Clin Pract, December 2013, 67, 12, 1267–1282
![Page 6: Efficacy and Safety of Canagliflozin in Patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial.](https://reader035.fdocuments.us/reader035/viewer/2022062806/5697bfe21a28abf838cb4269/html5/thumbnails/6.jpg)
Greater proportion of patients achieved HbA1c targets with Canagliflozin
PBO, placebo; CANA, canagliflozin
Int J Clin Pract, December 2013, 67, 12, 1267–1282
P <0.001 for both CANA doses
![Page 7: Efficacy and Safety of Canagliflozin in Patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial.](https://reader035.fdocuments.us/reader035/viewer/2022062806/5697bfe21a28abf838cb4269/html5/thumbnails/7.jpg)
Reduction in FPG* & PPG with Canagliflozin as add-on to MET + SU
FPG* (Week 52)
Baseline (mmol/L) 9.4 9.6 9.3
mITT, LOCF
PBO, placebo; CANA, Canagliflozin; LS, least squares; SE, standard errorFPG: Fasting Blood Glucose. PPG: Postprandial Glucose.
-1.1
-2.6
-3.1
-4
-3
-2
-1
0
LS m
ean
chan
ge (
±SE)
fr
om b
asel
ine (
mm
ol/L
)
PBO CANA 100 mg CANA 300 mg
2-hour PPG (Week 26)
Baseline (mmol/L) 15.5 16.5 16.0
*P <0.001 vs PBO.
Int J Clin Pract, December 2013, 67, 12, 1267–1282
![Page 8: Efficacy and Safety of Canagliflozin in Patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial.](https://reader035.fdocuments.us/reader035/viewer/2022062806/5697bfe21a28abf838cb4269/html5/thumbnails/8.jpg)
Non-Glycemic end-points
![Page 9: Efficacy and Safety of Canagliflozin in Patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial.](https://reader035.fdocuments.us/reader035/viewer/2022062806/5697bfe21a28abf838cb4269/html5/thumbnails/9.jpg)
Reduction in SBP & body weight with Canagliflozin as add-on to MET + SU
BW (Week 52)
Baseline (kg) 90.8 93.5 93.5
mITT, LOCF
PBO, placebo; CANA, canagliflozin; LS, least squares; SE, standard error.SBP: Systolic Blood Pressure. BW: Body weight
SBP (Week 52)
Baseline (mmHg) 130.1 130.4 130.8
Int J Clin Pract, December 2013, 67, 12, 1267–1282
No notable changes in pulse rate were seen across treatment groups
![Page 10: Efficacy and Safety of Canagliflozin in Patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial.](https://reader035.fdocuments.us/reader035/viewer/2022062806/5697bfe21a28abf838cb4269/html5/thumbnails/10.jpg)
Increase in HDLc was observed with Canagliflozin at week 52
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.
LDL-C HDL-CTriglycerides LDL-C/HDL-C Non–HDL-C
Baseline (mmol/L)† 2.2 2.1 2.3 2.8 2.7 2.6 1.2 1.2 1.1 2.4 2.4 2.4 3.8 3.6 3.7
mITT, LOCFInt J Clin Pract, December 2013, 67, 12, 1267–1282
![Page 11: Efficacy and Safety of Canagliflozin in Patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial.](https://reader035.fdocuments.us/reader035/viewer/2022062806/5697bfe21a28abf838cb4269/html5/thumbnails/11.jpg)
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
![Page 12: Efficacy and Safety of Canagliflozin in Patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial.](https://reader035.fdocuments.us/reader035/viewer/2022062806/5697bfe21a28abf838cb4269/html5/thumbnails/12.jpg)
Overall Safety and Selected AEs at week 52
Types of AEsSubjects, 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) 7 (4.5) 8 (5.1)Deaths 0 0 0Genital mycotic infectionMale†,‡ 1 (1.3) 6 (7.9) 5 (5.7)Female§,| 4 (5.0) 15 (18.5) 13 (18.8)
UTI 12 (7.7) 13 (8.3) 13 (8.3)Osmotic diuresis-related Aes # 3 (1.9) 9 (5.7) 11 (7.1)Volume-related Aes ^ 3 (1.9) 1 (0.6) 6 (3.8)Hypoglycaemia $ 28 (17.9) 53 (33.8) 57 (36.5)Severe episodes 1 (0.6) 1 (0.6) 1 (0.6)
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
![Page 13: Efficacy and Safety of Canagliflozin in Patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial.](https://reader035.fdocuments.us/reader035/viewer/2022062806/5697bfe21a28abf838cb4269/html5/thumbnails/13.jpg)
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
![Page 14: Efficacy and Safety of Canagliflozin in Patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial.](https://reader035.fdocuments.us/reader035/viewer/2022062806/5697bfe21a28abf838cb4269/html5/thumbnails/14.jpg)
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