Canagliflozin for the treatment of type 2 diabetes: a comparison between Japanese and non-Japanese patients

Figures & data

Box 1. Drug summary.

Drug name	Canagliflozin
Phase	Launched
Indication	Type 2 diabetes mellitus
Pharmacology description	Selective sodium-glucose co-transporter 2 inhibitor
Route of administration	Oral
Chemical structure
Pivotal trials	Phase II dose finding study (TA-7284-04) [51], phase III study (TA-7284-05 and 06) [52,53]

Table 1. Clinical trials of canagliflozin (CAN) conducted in Japan and discussed in the current review.

Study	Study name	Phase	Number of patients	Design	MT/concomitant therapy	Study regimen (mg)	Treatment period	Clinicaltrial.gov
Iijima et al. 2015 [40]	TA-7284–02	I	61	db	MT	CAN 25, 100, 200, 400 PBO	1 day and 16 days	NCT00707954
Inagaki et al. 2014 [43]	TA-7284–07	I	24	ol, co	MT	CAN 100, 200	1 day	NCT01512849
Inagaki et al. 2013 [51]	TA-7284–04	II	383	db	MT	CAN 50, 100, 200, 300 PBO	12 weeks	NCT01022112
Inagaki et al. 2014 [52]	TA-7284–05	III	272	db	MT	CAN 100, 200 PBO	24 weeks	NCT01413204
Inagaki et al. 2015 [53]	TA-7284–06	III	1299	ol	MT/add on^a	CAN 100, 200	52 weeks	NCT01387737
Inagaki et al. 2016 [54]	TA-7284–11	IV	146	db	INS	CAN 100 PBO	16 weeks	NCT02220920
Harashima et al. 2017 [56]	TA-7284–12	IV	71	ol	LIR	CAN 100	52 weeks	NCT02227849
Inagaki et al. 2017 [55]	TA-7284–13	IV	143	ol	INS	CAN 100	36 weeks/52 weeks	NCT02622113
Kinoshita et al. 2014 [50]	TA-7284–10	–	44^b	ol, co	TNL	CAN 200 TNL 40	1 day and 9 days	–
Kadowaki et al 2017 [64]	MT-2412-J03	III	138	db	TNL	CAN 100 PBO	24 weeks	NCT02354235
Kadowaki et al 2017 [65]	MT-2412-J01	III	153	ol	TNL	CAN 100	52 weeks	NCT02220907

co, crossover; db, double-blind; INS, insulin; LIR, liraglutide; MT, monotherapy; ol, open label; PBO, placebo; TNL, teneligliptin.

^aThe add-on drugs were sulfonylurea, glinide, α-glucosidase inhibitor, biguanide, thiazolidinedione, or dipeptidyl peptidase-4 inhibitor.

^bHealthy volunteers.

Figure 1. (a) Plasma concentration–time profiles after canagliflozin treatment of Japanese patients on days 1 and 16. Data are presented as mean ± standard deviation. Reproduced from [40] with permission of Springer Nature. (b) Relationship between dose and renal threshold for glucose excretion (RT_G0–24 h) in Japanese and non-Japanese patients with type 2 diabetes mellitus after multiple-dose treatment with canagliflozin [data taken from 40,45,46].

TA-7284-02: Japanese; DIA1023, NAP1002: non-Japanese.

Table 2. Pharmacokinetic profile of canagliflozin 100 mg in patients (Japanese and non-Japanese) with T2DM [40,41,43–45].

	Day	n	Cmax (ng/mL)	AUC (ng•h/mL)	tmax (h)	t1/2 (h)	Urinary excretion rate (%)	AR
Japanese patients
T2DM	1	12	1126 (228)	5468 (899)^a	1.0 [1.0–1.5]	10.2 (1.9)	0.384 (0.084)
T2DM	16	12	1136 (330)	6635 (1367)^a	1.0 [1.0–1.5]	11.8 (3.2)	0.641 (0.204)	1.21 (0.12)
T2DM and:
Normal renal function and mild renal impairment^c	1	12	1214 (338)	6929 (1734)^b	1.0 [1.0–3.0]	12.6 (3.1)	0.541 (0.168)
Moderate renal impairment^d	1	12	1197 (311)	8766 (2551)^b	1.0 [1.0–3.0]	15.5 (4.4)	0.538 (0.229)
Non-Japanese patients
T2DM	1	8	1096 (444)	6357 (1431)^a	1.5 [1.0–5.0]	–	0.55 (0.10)
	7	8	1227 (481)	8225 (1947)^a	1.5 [1.0–5.0]	13.7 (2.1)	0.75 (0.23)	1.29 (0.11)
T2DM	1	10	773 (213)	5957 (1580)^a	4.0 [1.5–6.0]	14.7 (4.1)	–

Values shown are mean (SD) or median [range].

AR, accumulation ratio; AUC, area under the concentration–time curve; C_max, peak plasma concentration; n, number of patients; SD, standard deviation; T2DM, type 2 diabetes mellitus; t_1/2, elimination half-life; t_max, time to peak plasma concentration.

^aAUC_0–24h.

^bAUC_0–∞.

^ceGFR ≥ 80 mL/min/1.73 m².

^deGFR ≥ 30 and <50 mL/min/1.73 m².

Figure 2. Effect of canagliflozin monotherapy and combination therapy on (a) mean change in HbA1c from baseline and (b) mean percent change in body weight from baseline in placebo-controlled studies (TA-7284–04, −05, and −11) and open-label studies (TA-7284–06, −12, and −13) in Japanese patients with type 2 diabetes.

Data shown are mean ± standard deviation (TA-7284–04, −05, and −11); or mean ± 95% confidence interval (TA-7284–06, −12, and −13). Bars at the end of treatment represent last observation carried forward. HbA1c, hemoglobin A1c; CAN, canagliflozin; PBO, placebo; SU, sulfonylurea; α-GI, α-glucosidase inhibitor; TZD, thiazolidinedione; DPP-4, dipeptidyl peptidase-4 inhibitor.

Figure 3. Effect of canagliflozin monotherapy and combination therapy on (a) mean change in systolic blood pressure from baseline, and (b) diastolic blood pressure from baseline, in placebo-controlled studies (TA-7284–04, −05, and −11) and open-label studies (TA-7284–06, −12, and −13) in Japanese patients with type 2 diabetes.

Data shown are mean ± standard deviation (TA-7284–04, −05, and −11); or mean ± 95% confidence interval (TA-7284–06, −12, and −13). Bars at the end of treatment represent last observation carried forward. SBP, systolic blood pressure; DBP, diastolic blood pressure; CAN, canagliflozin; PBO, placebo; SU, sulfonylurea; α-GI, α-glucosidase inhibitor; TZD, thiazolidinedione; DPP-4, dipeptidyl peptidase-4 inhibitor.

Table 3. Efficacy summary of pivotal study data about the effects of canagliflozin 100 mg on cardiometabolic parameters.

Patient parameter	TA-7284–05 (24 weeks) [52,60] Placebo difference (SE)	p	TA-7284–06 pooled analysis (52 weeks) [57,58] Baseline difference (SD)	P
HbA1c (%)	−1.03 (0.10)	<0.001	−0.94 (0.77)	<0.001
FPG (mg/dL)	−35.3 (3.90)	<0.001	−29.7 (34.2)	<0.001
Body weight (% change)	−3.00 (0.49)	<0.001	−3.85 (3.38)	<0.001
SBP (mmHg)	−5.16 (1.51)	<0.001	−4.76 (11.43)	<0.001
DBP (mmHg)	−2.61 (1.03)	<0.05	−2.87 (7.49)	<0.001
HDL-C (mg/dL)			4.3 (7.8)	<0.001
(% change)	7.11 (1.83)	<0.001
LDL-C (mg/dL)			−1.2 (22.9)	NS
(% change)	4.89 (2.27)	<0.05
LDL/HDL	−0.084 (0.068)	NS	−0.182 (0.567)	<0.001
TG (mg/dL)			−11.7 (103.7)	0.007
(% change)	−14.70 (8.20)	NS
Proinsulin/C-peptide ratio	−0.0091 (0.0014)	<0.001
HOMA2-%B (%)	15.54 (2.08)	<0.001
OGTT
AUCglucose, mg·h/dL	−126.7311 (11.1880)	<0.001
IAUCglucose, mg·h/dl	−62.4848 (7.7724)	<0.001
IAUCC-peptide/IAUCglucose	0.0119 (0.0027)	<0.001

AUC, area under the curve; DBP, diastolic blood pressure; FPG, fasting plasma glucose; HbA1c, hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol; HOMA, homeostatic model assessment; IAUC, incremental area under the curve; LDL-C, low-density lipoprotein cholesterol; OGTT, oral glucose tolerance test; SBP, systolic blood pressure; SD, standard deviation; SE, standard error; TG, triglyceride.

Table 4. Summary of safety data (number, % of events) for canagliflozin 100 mg.

	Double-blind studies				Long-term studies
	Pooled analysis (TA-7284–04, 05) [51,52,60]		TA-7284–11 [54]		Pooled analysis (TA-7284–06) [53,57,58,60]	TA-7284–12 [56]	TA-7284–13 [55]
	PBO N = 168	CAN N = 164	PBO N = 71	CAN N = 75	52 weeks N = 584	52 weeks N = 71	36 weeks N = 67	52 weeks N = 75
All AEs	81 (48.2)	93 (56.7)	46 (64.8)	51 (68.0)	478 (81.8)	51 (71.8)	57 (85.1)	69 (92.0)
ADRs	17 (10.1)	38 (23.2)	16 (22.5)	30 (40.0)	187 (32.0)	23 (32.4)	33 (49.3)	41 (54.7)
Serious AEs	2 (1.2)	1 (0.6)	1 (1.4)	3 (4.0)	30 (5.1)	5 (7.0)	7 (10.4)	7 (9.3)
AEs leading to discontinuation	2 (1.2)	3 (1.8)	0 (0.0)	1 (1.3)	20 (3.4)	4 (5.6)	4 (6.0)	4 (5.3)
All hypoglycemia	3 (1.8)	9 (5.5)	21 (29.6)	30 (40.0)		7 (9.9)	29 (43.3)	41 (54.7)
Symptomatic	1 (0.6)	4 (2.4)	15 (21.1)	19 (25.3)	44 (7.5)	7 (9.9)	20 (29.9)	28 (37.3)
Asymptomatic	2 (1.2)	5 (3.0)	11(15.5)	20 (26.7)	54 (9.2)	0 (0.0)	16 (23.9)	29 (38.7)
Volume depletion	1 (0.6)	1 (0.6)	0 (0.0)	0 (0.0)	7 (1.2)	1 (1.4)	0 (0.0)	1 (1.3)
Genital infections
Male	1/114 (0.9)	0 (0.0)	0 (0.0)	0 (0.0)	3/421 (0.7)	0 (0.0)	0/46 (0.0)	1/44 (2.3)
Female	0 (0.0)	3/53 (5.7)	0 (0.0)	1 (3.2)	14/163 (8.6)	2/28 (7.1)	3/21 (14.3)	2/31 (6.5)
Urinary tract infections	1 (0.6)	1 (0.6)	0 (0.0)	1 (1.3)	19 (3.3)	1 (1.4)	1 (1.5)	1 (1.3)
Osmotic diuresis	3 (1.8)	6 (3.7)	2 (2.8)	4 (5.3)	35 (6.0)	9 (12.7)	6 (9.0)	5 (6.7)
Blood ketone bodies increased	4 (2.4)	8 (4.9)	2 (2.8)	3 (4.0)	12 (2.1)	3 (4.2)	1 (1.5)	3 (4.0)
Fracture	2 (1.2)	0 (0.0)	1 (1.4)	0 (0.0)	7 (1.2)	1 (1.4)	2 (3.0)	1 (1.3)
Skin and subcutaneous tissue disorder	12 (7.1)	10 (6.1)	0 (0.0)	2 (2.7)	76 (13.0)	6 (8.5)	4 (6.0)	7 (9.3)

AE, adverse event; ADR: adverse drug reaction, PBO, placebo; CAN, canagliflozin.

MedDRA/J version 13.0–18.1.

Figure 4. Effect of canagliflozin on (a) HbA1c and (b) body weight as add-on therapy to teneligliptin in Japanese patients with type 2 diabetes. Grey bars represent placebo, blue bars are CAN 100 mg.

Data shown are mean ± standard deviation (MT-2412-J03); or mean ± 95% confidence interval (MT-2412-J01). Bars at the end of treatment represent last observation carried forward. HbA1c, hemoglobin A1c; CAN, canagliflozin; PBO, placebo.

Table 5. Effect of canagliflozin in overseas studies in non-Japanese patients (for comparison).

	Canagliflozin 100 mg	Canagliflozin 300 mg
	Change (placebo difference) Mean (95% CI)	Change (placebo difference) Mean (95% CI)	Treatment period	Type of study	Study reference
HbA1c (%)	−0.91 (−1.1, −0.7)	−1.16 (−1.3, −1.0)	26 weeks	Monotherapy	[67]
	−0.63 (−0.77, −0.49)	−0.80 (−0.98, −0.62)	26 weeks	Meta-analysis	[68]
	−0.60 (−0.67, −0.54)	−0.76 (−0.84, −0.68)	12–52 weeks	Meta-analysis	[69]
Body weight (% change)	−2.2 (−2.9, −1.6)	−3.3 (−4.0, −2.6)	26 weeks	Monotherapy	[67]
	−2.23 (−2.56, −1.91)	−3.00 (−3.54, −2.46)	26 weeks	Meta-analysis	[68]
	−2.53 (−2.89, −2.17)	−2.91 (−3.63, −2.19)	12–52 weeks	Meta-analysis	[69]
SBP (mmHg)	−3.7 (−5.9, −1.6)	−5.4 (−7.6, −3.3)	26 weeks	Monotherapy	[67]
	−4.26 (−5.31, −3.21)	−5.18 (−6.96, −3.39)	26 weeks	Meta-analysis	[68]
DBP (mmHg)	−1.6 (−2.0, −0.2)	−2.0 (−3.4, −0.7)	26 weeks	Monotherapy	[67]
	−1.76 (−2.56, −0.96)	−1.96 (−2.68, −1.24)	26 weeks	Meta-analysis	[68]

CI, confidence interval; DBP, diastolic blood pressure; HbA1c, hemoglobin A1c; SBP, systolic blood pressure.

Figure 5. Results from the CANagliflozin CardioVascular ASsessment (CANVAS) program. Reprinted from [30] with permission of the Massachusetts Medical Society.

Iijima H, Kifuji T, Maruyama N, et al. Pharmacokinetics, pharmacodynamics, and safety of canagliflozin in Japanese patients with type 2 diabetes mellitus. Adv Ther. 2015;32:768–782.

 PubMed Web of Science ®Google Scholar

Inagaki N, Kondo K, Yoshinari T, et al. Pharmacokinetic and pharmacodynamic profiles of canagliflozin in Japanese patients with type 2 diabetes mellitus and moderate renal impairment. Clin Drug Invest. 2014;34:731–742.

 PubMed Web of Science ®Google Scholar

Inagaki N, Kondo K, Yoshinari T, et al. Efficacy and safety of canagliflozin in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, 12-week study. Diabetes Obes Metab. 2013;15:1136–1145.

 PubMed Web of Science ®Google Scholar

Inagaki N, Kondo K, Yoshinari T, et al. Efficacy and safety of canagliflozin monotherapy in Japanese patients with type 2 diabetes inadequately controlled with diet and exercise: a 24-week, randomized, double-blind, placebo-controlled, Phase III study. Expert Opin Pharmacother. 2014;15:1501–1515.

 PubMed Web of Science ®Google Scholar

Inagaki N, Kondo K, Yoshinari T, et al. Efficacy and safety of canagliflozin alone or as add-on to other oral antihyperglycemic drugs in Japanese patients with type 2 diabetes: A 52-week open-label study. J Diabetes Investig. 2015;6:210–218.

 PubMed Web of Science ®Google Scholar

Inagaki N, Harashima S, Maruyama N, et al. Efficacy and safety of canagliflozin in combination with insulin: a double-blind, randomized, placebo-controlled study in Japanese patients with type 2 diabetes mellitus. Cardiovasc Diabetol. 2016;15:89.

 PubMed Web of Science ®Google Scholar

Harashima S, Inagaki N, Kondo K, et al. Efficacy and safety of canagliflozin as add-on therapy to a glucagon-like peptide-1 receptor agonist in Japanese patients with type 2 diabetes mellitus: a 52-week, open-label, phase IV study. Diabetes Obes Metab. 2018 Feb 23. DOI:10.1111/dom.13267

 Web of Science ®Google Scholar

Inagaki N, Harashima S, Kaku K, et al. Long-term efficacy and safety of canagliflozin in combination with insulin in Japanese type 2 diabetes mellitus patients. Diabetes Obes Metab. 2018;20:812–820.

 PubMed Web of Science ®Google Scholar

Kinoshita S, Kondo K. Evaluation of pharmacokinetic and pharmacodynamic interactions of canagliflozin and teneligliptin in Japanese healthy male volunteers. Expert Opin Drug Metab Toxicol. 2015;11:7–14.

 PubMed Web of Science ®Google Scholar

Kadowaki T, Inagaki N, Kondo K, et al. Efficacy and safety of canagliflozin as add-on therapy to teneligliptin in Japanese patients with type 2 diabetes mellitus: results of a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2017;19:874–882.

 PubMed Web of Science ®Google Scholar

Kadowaki T, Inagaki N, Kondo K, et al. Long-term safety and efficacy of canagliflozin as add-on therapy to teneligliptin in Japanese patients with type 2 diabetes. Diabetes Obes Metab. 2018;20:77–84.

 PubMed Web of Science ®Google Scholar

Devineni D, Polidori D. Clinical pharmacokinetic, pharmacodynamic, and drug-drug interaction profile of canagliflozin, a sodium-glucose co-transporter 2 inhibitor. Clin Pharmacokinet. 2015;54:1027–1041.

 PubMed Web of Science ®Google Scholar

Devineni D, Curtin CR, Polidori D, et al. Pharmacokinetics and pharmacodynamics of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in subjects with type 2 diabetes mellitus. J Clin Pharmacol. 2013;53:601–610.

 PubMed Web of Science ®Google Scholar

CANAGLU® (canagliflozin), Common Technical Document. 2014 [cited 2017 Nov 2] Available from: http://www.pmda.go.jp/drugs/2014/P201400070/400315000_22600AMX00744_K102_1.pdf

 Google Scholar

Inagaki N, Goda M, Yokota S, et al. Safety and efficacy of canagliflozin in Japanese patients with type 2 diabetes mellitus: post hoc subgroup analyses according to body mass index in a 52-week open-label study. Expert Opin Pharmacother. 2015;16:1577–1591.

 PubMed Web of Science ®Google Scholar

Inagaki N, Goda M, Yokota S, et al. Effects of baseline blood pressure and low-density lipoprotein cholesterol on safety and efficacy of canagliflozin in Japanese patients with type 2 diabetes mellitus. Adv Ther. 2015;32:1085–1103.

 PubMed Web of Science ®Google Scholar

Stenlöf 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.

 PubMed Web of Science ®Google Scholar

Xiong W, Xiao MY, Zhang M, et al. Efficacy and safety of canagliflozin in patients with type 2 diabetes: A meta-analysis of randomized controlled trials. Medicine (Baltimore). 2016;95:e5473.

 PubMed Web of Science ®Google Scholar

Meng Q, Shen Y, Liu D, et al. Efficacy of canagliflozin combined with antidiabetic drugs in treating type 2 diabetes mellitus: meta-analysis of randomized control trials. J Diabetes Investig. 2016;7:359–365.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar