An evidence-based practice-oriented review focusing on canagliflozin in the management of type 2 diabetes

Figures & data

Figure 1 Timeline for milestones in the development of drugs to manage diabetes.

Abbreviations: AGI, alpha-glucosidase inhibitor; GLP, glucagon-like polypeptide; SGLT2, sodium–glucose-linked transporter type 2.

Figure 2 The chemical structures of phlorizin, glucose, and canagliflozin.

Table 1 Representative clinical trials of glucose control and body weight changes with canagliflozin

Study	Therapy	Treatment arms (n)	Baseline A1C% at baseline (mean ± SD)	Change in A1C%	Baseline body weight (kg; mean ± SD)	Change in body weight (kg)
Stenlof et al^Citation20	Mono-Rx, 26 weeks	CANA 100 mg (195)	8.1±1.0	−0.77 (P<0.001)	85.8±21.4	−2.5 (P<0.001)
		CANA 300 mg (197)	8.0±1.0	−1.03 (P<0.001)	86.9±20.5	−3.4 (P<0.001)
		PBO (192)	8.0±1.0	0.14	87.6±19.5	−0.5
Wilding et al^Citation25	Combo-Rx, MET + SU, 26 weeks	CANA 100 mg (157)	8.1±0.9	−0.85 (P<0.001)	93.8±22.6	−1.9 (P<0.001)
		CANA 300 mg (156)	8.1±0.9	−1.06 (P<0.001)	93.5±22.0	−2.5 (P<0.001)
		PBO (156)	8.1±0.9	−0.13	91.2±22.6	−0.8
Lavalle-Gonzalez et al^Citation23	Combo-Rx + MET, 26 weeks	CANA 100 mg (368)	7.9±0.9	−0.79 (P<0.001)	88.8±22.2	−3.3 (P<0.001)
		CANA 300 mg (367)	7.9±0.9	−0.94 (P<0.001)	85.4±20.9	−3.6 (P<0.001)
		SITA 100 mg (366)	7.9±0.9	−0.82	87.7±21.6	−1.1
				NA		NT
		PBO (183)	8.0±0.9	−0.17	86.6±22.4	−1.1
Cefalu et al^Citation26	Combo-Rx + MET, 52 weeks	CANA 100 mg (483)	7.8±0.8	−0.82	86.9±20.1	−3.7 (P<0.0001)
				NA
		CANA 300 mg (485)	7.8±0.8	−0.93	86.6±19.5	−4.0 (P<0.001)
				NA
		GLIM 6–8 mg (484)	7.8±0.8	−0.81	86.5±19.8	0.7
Schernthaner et al^Citation28	Combo-Rx MET + SU, 52 weeks	CANA 300 mg (378)	8.1±0.9	−1.03	87.4±23.2	−2.3 (P<0.001)
				NA
		SITA 100 mg (378)	8.1±0.9	−0.66	89.1±23.2	0.1
				NA
Inagaki et al^Citation21	Mono-Rx, 24 weeks	CANA 100 mg (90)	7.98±0.73	−0.74 (P<0.001)	69.1±14.5	−3.8 (P<0.001)
		PBO (93)	8.04±0.7	0.29	68.6±15.2	−0.8
Forst et al^Citation22	Combo-Rx, MET + PIO, 26 weeks	CANA 100 mg (113)	8.0±0.9	−0.89 (P<0.001)	94.2±22.2	−2.6 (P<0.001)
		CANA 300 mg (114)	7.9±0.9	−1.03 (P<0.001)	94.4±25.9	−3.7 (P<0.001)
		PBO/SITA 100 mg (115)	8.0±1.0	−0.26	93.8±22.4	−0.2

Note: Sodium-glucose cotransporter 2 inhibitors: an evidence-based practice approach to their use in the natural history of type 2 diabetes, Schwartz SS, Ahmed I, Curr Med Res Opin, 2016;32(5):907–919, reprinted by permission of the publisher (Taylor & Francis Ltd, http://www.tandfonline.com).⁷⁰

Abbreviations: CANA, canagliflozin; GLIM, glimepiride; PBO, placebo; SITA, sitagliptin; MET, metformin; SU, sulfonylurea; NA, not applicable; NT, not tested; PIO, pioglitazone; A1C%, Hemoglobin A1C concentration.

Table 2 Major ongoing trials using canagliflozin

Age (years)	Treatment armsa	Baseline CV risk	Enrolled (n)	Primary outcome	Anticipated end point	Study name
≥30	PBO, 100, 300	H/O CV event or >50 years old with high CV risk	4331	MACE	April 2017	CANVAS^Citation24
≥30	PBO, 100	Not applicable	Estimated at 4200	ESKD; doubling serum creatinine; renal or CV death	January 2020	CREDENCE^Citation69

Notes:

a Arms are placebo once daily, 100 mg canagliflozin daily, and 300 mg canagliflozin daily; MACE, including death, nonfatal myocardial infarction, and nonfatal stroke.

Abbreviations: CANVAS, Canagliflozin Cardiovascular Assessment Study; CREDENCE, Canagliflozin on Renal and Cardiovascular Outcomes in Participants with Diabetic Nephropathy; CV, cardiovascular; ESKD, end-stage kidney disease; H/O, history of; MACE, major adverse CV events; PBO, placebo.

StenlofKCefaluWTKimKAEfficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exerciseDiabetes Obes Metab201315437238223279307

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WildingJPCharpentierGHollanderPEfficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trialInt J Clin Pract201367121267128224118688

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Lavalle-GonzalezFJJanuszewiczADavidsonJEfficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trialDiabetologia201356122582259224026211

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CefaluWTLeiterLAYoonKHEfficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trialLancet2013382989694195023850055

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SchernthanerGGrossJLRosenstockJCanagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week randomized trialDiabetes Care20133692508251523564919

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InagakiNKondoKYoshinariTTakahashiNSusutaYKukiHEfficacy 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 studyExpert Opin Pharmacother201415111501151525010793

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ForstTGuthrieRGoldenbergREfficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes on background metformin and pioglitazoneDiabetes Obes Metab201416546747724528605

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SchwartzSSAhmedISodium-glucose cotransporter 2 inhibitors: an evidence-based practice approach to their use in the natural history of type 2 diabetesCurr Med Res Opin201632590791926854518

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NealBPerkovicVde ZeeuwDRationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS) – a randomized placebo-controlled trialAm Heart J20131662217223.e1123895803

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Janssen Research and Development, LLCEvaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE) Available from: https://clinicaltrials.gov/ct2/show/NCT02065791. NLM identifier: NCT02065791Accessed November 29, 2016

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