Clinical potential of canagliflozin in cardiovascular risk reduction in patients with type 2 diabetes

Figures & data

Table 1 Study design and patient populations of studies evaluating canagliflozin and cardiovascular risk factors

Study	Design	Treatment	Population characteristics	Endpoints evaluated
CANVAS^Citation14	2 years, MC, DB, R, PCT	CAN 300 mg, 100 mg, or PBO daily	n=4,330 Mean age =63.5 years HbA1c =7%–10.5% Mean duration of T2DM =13.4 years >30 years of age with ASCVD history or >50 years of age with >2 CV risk factors	Primary: change in risk of CVD; safety and tolerability Secondary: change from baseline in beta-cell function, HbA1c, FPG, BW, BP, FPL, and side effects
CANVAS-R^Citation25	18 months, MC, DB, R, PCT	Initial: CAN 100 mg or PBO daily; Week 13 optional increase: CAN 300 mg or PBO daily	n=5,812 Mean age =64.0 years HbA1c =7%–10.5% Mean duration of T2DM =13.4 years eGFR >30 mL/min/1.72 m^2	Primary: progression of albuminuria Secondary: composite outcome of hospitalization for HF or CV death
CANTATA-M^Citation7	26 weeks, DB, PCT	CAN 300 mg, 100 mg, or PBO daily	n=678 Mean age =52.4 years HbA1c =7%–10% or >10%–12% Mean duration of T2DM =4.6 years	Primary: change from baseline in HbA1c Secondary: achievement of HbA1c <7.0%; change from baseline in FPG, SBP, BW, HDL-C
Townsend et al^Citation17	6 weeks, MC, DB, R, PCT	CAN 300 mg, 100 mg, or PBO daily	n=171 Mean age =58.6 years HbA1c >7%–10% Mean duration of T2DM =9 years HTN = SBP >130 mmHg, DBP >70 mmHg	Primary: change from baseline in the mean 24-hour SBP Secondary: change from baseline in mean 24-hour DBP, daytime SBP and DBP, FPG, and BW
Wilding et al^Citation25	26 weeks, R, DB, PCT	CAN 300 mg, 100 mg, or PBO daily	n=469 Mean age =56.8 years HbA1c =7%–10.5% Mean duration of T2DM = 9.6 years Receiving M ET >1,500 mg per day for >8 weeks	Primary: change from baseline in HbA1c by week 26 Secondary: change from baseline in HbA1c by week 52; achievement of HbA1c <7.0%; change from baseline in FPG, BW, HDL-C, and TG
Yale et al^Citation18	52 weeks, R, DB, PCT	CAN 300 mg, 100 mg, or PBO once daily	n=272 Mean age =68.5 years HbA1c 7%–10.5% Mean duration of T2DM =16.3 years CKD Stage 3 eGFR 30–50 mL/min/1.73 m^2	Primary: change from baseline in HbA1c by week 26 Secondary: achievement of HbA1c <7.0% by week 26; change from baseline in FPG, BP, BW, and FPL
Lavalle- Gonzalez et al^Citation21	26 week core study period with 26 weeks extension, R, DB, PBO, and active- controlled	CAN 300 mg, 100 mg, PBO, or SITA 100 mg once daily	n=1,284 Mean age =55.4 years HbA1c =7%–10.5% Mean duration of T2DM =6.9 years	Primary: change from baseline in HbA1c Secondary: achievement of proportion HbA1c <7.0%; change from baseline in FPG, SBP, BW, TG, and HDL-C
Schernthaner et al^Citation22	52 weeks, R, DB, active-controlled	CAN 300 mg or SITA 100 mg	n=756 Mean age =56.7 years HbA1c =7%–10.5% Receiving MET >1,500 mg per day for >8 weeks	Primary: change from baseline in HbA1c Secondary: achievement of HbA1c <7.0%; change from baseline in FPG, SBP, DBP, BW, TG, and HDL-C
Forst et al^Citation23	52 weeks, R, DB, PBO, and active- controlled trial	CAN 300 mg, 100 mg, PBO, or SITA 100 mg	n=342 Mean age =57.4 years HbA1c =7%–10.5% Mean duration of T2DM =10.5 years	Primary: change from baseline in HbA1c at week 26 Secondary: change from baseline in HbA1c at week 52; achievement of HbA1c <7.0%; change from baseline in FPG, SBP, beta-cell function; percent change in BW, HDL-C, and TG
Rosenstock et al^Citation24	12 weeks, MC, R, DB, PBO, and active-controlled	CAN 50 mg, 100 mg, 200 mg, 300 mg once daily or 300 mg twice daily, PBO, or SITA 100 mg	n=451 Mean age =52.9 years HbA1c 7%–10.5% Mean duration of T2DM = 6.0 years Receiving M ET >1,500 mg per day for >8 weeks	Primary: change from baseline in HbA1c Secondary: achievement of HbA1c <7.0%; change from baseline in FPG, BW, overnight urinary glucose to creatinine ratio
Patorno et al^Citation16	Retrospective cohort	CAN 300 mg, 100 mg, or active control of DPP4 inhibitor, GLP-agonist, or sulfonylurea	n=224,999 Mean age =56.4 years Mean HbA1c =8.8%	Primary: hospitalization for HF; composite CV endpoint (hospitalization for acute MI, ischemic stroke, hemorrhagic stroke) Secondary: unstable angina, coronary revascularization, and individual components of CV events
CVD-REAL^Citation15	Retrospective cohort	SGLT2 inhibitor (canagliflozin, empagliflozin, or dapagliflozin) or other oral or injectable glucose lowering agent	n=262,339 (including 132,572 canagliflozin) Mean age =57.0 years T2DM	Primary: hospitalization for HF Secondary: all-cause mortality; composite of hospitalization for HF
CANDLE^Citation49	24 week, MC, R, DB, active controlled	CAN 100 mg, or GLIM 0.5 mg to 6 mg	n=250 HbA1c =7%–10.5% CHF: NYHA class I to III	Primary: percent change from baseline in NT-proBNP Secondary: changes from baseline in HbA1c, SBP, DBP, BW, QoL, echocardiogram, and renal function

Abbreviations: ASCVD, Atherosclerotic Cardiovascular Disease; BP, blood pressure; BW, body weight; CAN, canagliflozin; CHF, chronic heart failure; CKD, chronic kidney disease; CV, cardiovascular; DB, double blind; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; FPL, fasting plasma lipid; GLIM, glimepiride; HDL-C, high-density lipoprotein cholesterol; HF, heart failure; HTN, hypertension; MC, multi-center; MET, metformin; MI, myocardial infarction; NT-proBNP, N-terminal pro-brain natriuretic peptide; NYHA, New York Heart Association; PBO, placebo; PCT, placebo-controlled trial; QoL, quality of life; R, randomized; SBP, systolic blood pressure; SITA, sitagliptin; T2DM, type 2 diabetes mellitus; TG, triglyceride.

Table 2 Reported cardiovascular clinical endpoint data

Study	Canagliflozin dose	Number of patients receiving canagliflozin	Change in SBP from baseline, mmHg	Change in DBP from baseline, mmHg	Orthostatic hypotension, n (%)	Change in HR from baseline, beats per minute	Change in BW from baseline, kg
CANVAS program^Citation14	100 mg or 300 mg once daily	5,795	−3.93±0.40	−1.39+0.30	26.0/1,000 pt-yr	NR	−1.60+0.10
CANTATA-M^Citation7	100 mg daily	195	−3.3+0.8	−1.7+0.5	0	−1.6	−2.5
	300 mg daily	197	−5.0±0.8	−2.1+0.5	0	−0.4	−3.4
Townsend et al^Citation17	100 mg daily	57	−3.3±3.4	−1.9±2.1	2 (3.8)	−0.6	−1.3
	300 mg daily	57	−4.9±3.4	−2.9+2.1	4 (7.1)	−0.4	−1.7
Wilding et al^Citation20	100 mg daily	157	−4.9±1.0	−2.9±0.6	1 (0.6)	0.9	−1.1
	300 mg daily	156	−4.3±1.0	−2.3±0.6	6 (3.8)	−1.2	−1.7
Yale et al^Citation18	100 mg daily	90	−6.1±1.5	−2.6±0.9	0	−1.9	−1.2
	300 mg daily	89	−6.4±1.5	−3.5±0.9	1 (1.1)	−1.1	−1.4
Lavalle-Gonzalez et al^Citation21	100 mg daily	368	−3.5±0.6	−1.8±0.4	0	−1.3	−3.3±0.2
	300 mg daily	367	−4.7±0.6	−1.8±0.4	1 (0.3)	−1.9	−3.7±0.2
Schernthaner et al^Citation22	300 mg daily	377	−5.9±1.7	−2.7±1.1	0	NR	−2.3
Forst et al^Citation23	100 mg daily	113	−5.3±1.0	−3.3±0.7	9 (8.0)	−0.3	−2.6
	300 mg daily	114	−4.7±1.0	−3.5±0.7	5 (4.4)	−1.3	−3.7
Rosenstock et al^Citation24	50 mg daily	64	NR	NR	0	NR	−2.3
	100 mg daily	64	NR	NR	4 (6)	NR	−2.6
	200 mg daily	65	NR	NR	3 (5)	NR	−2.7
	300 mg daily	64	NR	NR	1 (2)	NR	−3.4
	330 mg twice daily	64	NR	NR	1 (2)	NR	−3.4

Abbreviations: BW, body weight; DBP, diastolic blood pressure; HR, heart rate; NR, not reported; pt-yr, patient-years; SBP, systolic blood pressure.

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