The CANVAS Program: implications of canagliflozin on reducing cardiovascular risk in patients with type 2 diabetes mellitus

Carbone, Salvatore; Dixon, Dave L.

doi:10.1186/s12933-019-0869-2

Cardiovascular Diabetology

Table 1 Key information for CVOTs of glucose-lowering agents with demonstrated CV benefit in patients with type 2 diabetes mellitus [16,17,18,19, 66, 76]

From: The CANVAS Program: implications of canagliflozin on reducing cardiovascular risk in patients with type 2 diabetes mellitus

Class	Study name	Intervention	N of patients and median (max) follow-up	Inclusion criteria	Primary outcome(s)	Secondary findings
SGLT2 inhibitors	CANVAS Program (2017)	Canagliflozin 100 mg or 300 mg daily vs placebo	10,142 3.6 (6.5) years	≥ 30 years with established CVD (66%) or ≥ 50 years and ≥ 2 CV risk factors (34%)^a	MACE^b: Met criteria for noninferiority and superiority 14% RRR (overall) 18% RRR (secondary cohort)	33% ↓ HF hospitalizations No difference in ACM, CV death, or nonfatal stroke
	EMPA-REG OUTCOME (2015)	Empagliflozin 10 mg or 25 mg once daily vs placebo	7020 3.1 (4.0) years	≥ 18 years and established CVD (100%)^c	MACE^b: Met criteria for noninferiority and superiority 14% RRR	32% ↓ ACM 38% ↓ CV death 35% ↓ HF hospitalizations
	DECLARE-TIMI 58 (2018)	Dapagliflozin 10 mg daily vs placebo	17,160 4.2 years	≥ 40 years with established CVD (41%) or men ≥ 55 years and women ≥ 60 years with ≥ 1 CV risk factor (59%)^d	MACE^b: Met criteria for noninferiority but not superiority	27% ↓ HF hospitalizations No difference in CV death, nonfatal MI, nonfatal stroke, or ACM
	DECLARE-TIMI 58 (2018)	Dapagliflozin 10 mg daily vs placebo	17,160 4.2 years		CV death and hospitalization for HF: Met criteria for noninferiority and superiority 14% RRR
GLP-1 receptor agonists	LEADER (2016)	Liraglutide target dose of 1.8 mg daily vs placebo	9340 3.8 (4.5) years	≥ 50 years and established CVD (72.4%) or ≥ 60 years and ≥ 1 CV risk factor (27.6%)^e	MACE^b: Met criteria for noninferiority and superiority 13% RRR	15% ↓ ACM 22% ↓ CV death No difference in HF hospitalization
	SUSTAIN-6 (2016)	Semaglutide 0.5 mg, 1 mg once weekly vs placebo	3297 2.1 years	≥ 50 years and established CVD (83.0%) or ≥ 60 years and ≥ 1 CV risk factor (17.0%)^e	MACE^b: Met criteria for noninferiority and superiority 26% RRR	26% ↓ in nonfatal stroke No difference in ACM, CV death, or HF hospitalization
	Harmony Outcomes (2018)	Albiglutide 30–50 mg once weekly vs placebo	9463 1.6 (2.6) years	≥ 40 years and established CVD (100%)^f	MACE^b: Met criteria for noninferiority and superiority 22% RRR	22% ↓ in MACE and urgent coronary revascularization 25% ↓ in MI No difference in CV death, stroke, ACM, or CV death and hospitalization for HF

CVOT, cardiovascular outcomes trial; CV, cardiovascular; SGLT2, sodium glucose co-transporter-2; GLP-1, glucagon-like peptide-1; CVD, cardiovascular disease; MACE, major adverse cardiovascular event; RRR, relative risk reduction; HF, heart failure; ACM, all-cause mortality; MI, myocardial infarction; PVD, peripheral vascular disease; CAD, coronary artery disease; CKD, chronic kidney disease
^aIncludes patients with history of symptomatic atherosclerotic vascular disease (coronary, cerebrovascular, or peripheral), including stroke, MI, hospital admission for unstable angina, coronary artery bypass graft, percutaneous coronary intervention (with or without stenting), peripheral revascularization (angioplasty or surgery), symptomatic with documented hemodynamically-significant carotid or peripheral vascular disease, or amputation secondary to vascular disease. Risk factors include: duration of diabetes ≥ 10 years, systolic blood pressure > 140 mm Hg while receiving ≥ 1 antihypertensive agent, current smoking, microalbuminuria or macroalbuminuria, or high-density lipoprotein cholesterol levels of < 38.7 mg/dL (1 mmol/L)
^bComposite outcome of CV death, nonfatal MI, or nonfatal stroke
^cIncludes patients with ≥ 1 of the following: history of MI or evidence of multivessel CAD (drug-naïve patients) or presence of significant stenosis; previous revascularization; combination of revascularization in 1 coronary artery and significant stenosis in another major coronary artery; evidence of single vessel CAD, ≥ 50% luminal narrowing during angiopathy not subsequently successfully revascularized with positive noninvasive stress test for ischemia and/or hospital discharge for unstable angina; unstable angina with evidence of single- or multi-vessel CAD; history of stroke; or occlusive peripheral artery disease documented by limb angioplasty, stenting, or bypass surgery, limb or foot amputation due to circulatory insufficiency, evidence of significant peripheral artery stenosis in 1 limb, or ankle brachial index < 0.9 in ≥ 1 ankle (patients on background therapy)
^dIncludes patients with clinically evident ischemic heart disease (documented MI, percutaneous coronary intervention, coronary artery bypass grafting, objective findings of coronary stenosis [≥ 50%] in ≥ 2 coronary artery territories [i.e., left anterior descending, ramus intermedius, left circumflex, right coronary artery] involving the main vessel, a major branch, or a bypass graft), cerebrovascular disease (documented ischemic stroke [known transient ischemic attack, primary intracerebral hemorrhage or sub-arachnoid hemorrhage do not qualify], carotid stenting, or endarterectomy), or peripheral artery disease (peripheral arterial intervention, stenting, or surgical revascularization; lower-extremity amputation as a result of peripheral arterial obstructive disease; or current symptoms of intermittent claudication and ankle/brachial index < 0.90 documented within last 12 months). Risk factors include: hypertension (blood pressure > 140/90 mm Hg at enrollment visit; patient must have both elevated systolic and diastolic blood pressure on both measurements), dyslipidemia (defined as low-density lipoprotein cholesterol levels > 130 mg/dL [3.36 mmol/L] or the use of lipid lower therapies), or the use of tobacco
^eWith ≥ 1 CV coexisting condition (coronary heart disease, cerebrovascular disease, PVD, CKD of stage 3 or greater or chronic HF of the New York Heart Association class II or III)
^fIncludes established disease of the coronary (MI, ≥ 50% stenosis in ≥ 1 coronary artery, or previous coronary revascularization), cerebrovascular (ischemic stroke, ≥ 50% carotid artery stenosis, or a previous carotid vascular procedure), or peripheral arterial circulation (intermittent claudication and an ankle to brachial index < 0.9, nontraumatic amputation, or a previous peripheral vascular procedure)

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