Efficacy and Safety of Canagliflozin in Patients with type 2 diabetes mellitus inadequately...

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

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

Baseline Characteristics


Glycaemic efficacy end-points

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


Greater proportion of patients achieved HbA1c targets with Canagliflozin

PBO, placebo; CANA, canagliflozin


P <0.001 for both CANA doses

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.


Non-Glycemic end-points

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


No notable changes in pulse rate were seen across treatment groups

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

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)


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.


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


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


Efficacy and Safety of Canagliflozin in Patients with type 2 diabetes mellitus inadequately...

Documents

Transcript of Efficacy and Safety of Canagliflozin in Patients with type 2 diabetes mellitus inadequately...