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CANVAS Trial: Canagliflozin superior to placebo at preventing cardiovascular events


The CANVAS trial has shown that Canagliflozin ( Invokana ) was superior to placebo at preventing cardiovascular events.

The goal of the trial was to evaluate the sodium-glucose cotransporter 2 inhibitor Canagliflozin compared with placebo among patients with type 2 diabetes.
Patients with type 2 diabetes were randomized to Canagliflozin ( n = 5,795 ) versus placebo ( n = 4,347 ). Patients in the Canagliflozin arm received 300 mg daily or 100 mg daily.

Inclusion criteria were: patients with type 2 diabetes and high cardiovascular risk; greater than or equal to 30 years of age and history of symptomatic atherosclerotic cardiovascular disease, or greater than or equal to 50 years of age and 2+ of the following: diabetes duration more than10 years, systolic blood pressure more than140 mm Hg on antihypertensive therapy, current smoking, albuminuria, or high-density lipoprotein cholesterol less than 38.7 mg/dl.

Total number of enrollees was 10,142; mean patient age: 63 years; percentage female: 36%; percentage with diabetes: 100%; mean duration of diabetes: 13.5 years; 65.6% of participants had history of cardiovascular disease.

Duration of follow-up was 188 weeks.

The primary outcome, incidence of cardiovascular death, myocardial infarction, or stroke, occurred in 26.9 participants per 1,000 patient-years of the Canagliflozin group versus 31.5 participants per 1,000 patient-years of the placebo group ( p = 0.02 for superiority, p less than 0.001 for noninferiority ).

The benefit for Canagliflozin appeared to be similar for patients with heart failure with reduced ejection fraction ( HFrEF ) and those with heart failure with preserved ejection fraction ( HFpEF ).

Secondary outcomes, Canagliflozin versus placebo, were: amputation: 6.3 participants per 1,000 patient-years versus 3.4 participants per 1,000 patient-years ( p less than 0.05 ); progression of albuminuria: 89.4 participants per 1,000 patient-years versus 128.7 participants per 1,000 patient-years ( p less than 0.05 ).

Approximately 34% of the cohort was enrolled for primary prevention ( age greater than or equal to 50 years, no known coronary artery disease / cardiovascular disease / peripheral artery disease, at least two risk factors ). Event rates were higher in the secondary prevention subset.
Compared with placebo, Canagliflozin has reduced the primary endpoint ( p for interaction = 0.18 ), heart failure hospitalization ( p for interaction = 0.91 ), and progression to albuminuria ( p for interaction = 0.48 ) in both subgroups.
Canagliflozin has also increased lower extremity amputations ( p for interaction = 0.63 ) in both subgroups.

Reduction in cardiovascular death or hospitalization for heart failure appeared to be greater among those with a history of heart failure ( hazard ratio [ HR ] 0.61, 95% confidence interval [ CI ] 0.46-0.80 ), compared to those with no history of heart failure ( HR 0.87, 95% CI 0.72-1.06; p for interaction 0.021 ).

Cardiovascular death, myocardial infarction, or stroke was similar among those with chronic kidney disease ( estimated glomerular filtration rate [ eGFR ] greater than or equal to 30 to less than 60 ml/min/1.73 m2 ) ( HR 0.70, 95% CI 0.55-0.90 ), compared to those with normal renal function ( eGFR greater than or equal to 60 ml/min/1.73 m2 ) ( HR 0.92, 95% CI 0.79-1.07; p for heterogeneity 0.08 ).

N-terminal pro–B-type natriuretic peptide ( NT-proBNP ) greater than or equal to 125 pg/ml at baseline was substantially prognostic for subsequent heart failure hospitalization.
At 1 year, Canagliflozin was associated with a reduction in NT-proBNP, while placebo was associated with an increase in NT-proBNP.

In conclusion, among patients with type 2 diabetes, Canagliflozin was beneficial.
Canagliflozin compared with placebo was associated with a lower frequency of adverse cardiovascular events.
Canagliflozin was also associated with a lower rate of progression of albuminuria; however, amputation occurred more frequently.
Effects were similar among both primary and secondary prevention participants, with lower event rates among the primary prevention participants.
The benefit of Canagliflozin may be greater among those with a prior history of heart failure.
The benefit of Canagliflozin did not appear to be modified by baseline renal function. ( Xagena )

Source: American Heart Association ( AHA ) Annual Scientific Sessions, 2019

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