INVOKANA® (canagliflozin) Significantly Reduces the Combined Risk of Cardiovascular Death, Myocardial Infarction, and Stroke in the CANVAS Program

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Results from the landmark CANVAS Program showed
INVOKANA®
(canagliflozin) significantly reduced the combined risk of cardiovascular (CV)
death, myocardial infarction (MI), and nonfatal stroke, versus placebo in patients with type 2
diabetes mellitus (T2DM) at risk for or with a history of CV disease. The results also showed
canagliflozin treatment was associated with a reduced risk for hospitalization for heart failure
(HHF) and demonstrated potential renal protective effects. These data from the integrated
analysis of the CANVAS and CANVAS-R trials were published in the New England Journal of
Medicine, and presented in a special symposium at the American Diabetes Association 77th
Scientific Sessions on Monday, June 12, in San Diego, CA.
Canagliflozin was studied in the longest, largest and broadest completed CV outcomes program
of any sodium glucose cotransporter-2 (SGLT2) inhibitor. The CANVAS Program is the first
program to assess the efficacy, safety and durability of canagliflozin in more than 10,000
patients with T2DM, who had either a prior history of CV disease, or at least two CV risk factors.
Canagliflozin achieved a 14% reduction in the risk of the composite primary endpoint of CV
mortality, nonfatal MI, or nonfatal stroke (HR: 0.86; 95% CI: 0.75 to 0.97), and demonstrated the
CV safety of canagliflozin (p<0.0001 for non-inferiority) and superiority compared to placebo Page 2 of 8 (p=0.0158). Each component evenly contributed to this risk reduction, including nonfatal MI by 15% (HR: 0.85; 95% CI: 0.69 to 1.05), CV death by 13% (HR: 0.87; 95% CI: 0.72 to 1.06), and nonfatal stroke by 10% (HR: 0.90; 95% CI: 0.71 to 1.15). These outcomes were broadly consistent across various patient subgroups, and across the individual composite primary endpoint. Additional analysis further revealed canagliflozin lowered the risk of HHF by 33% (HR: 0.67; 95% CI: 0.52 to 0.87), and provided sustained positive effects on glycemic and blood pressure control, as well as weight reduction, demonstrating wide-ranging durability. In addition, canagliflozin showed potential renal protective effects, delaying progression of albuminuria and reducing the risk of clinically important renal composite outcomes (such as renal death, renal replacement therapy, and 40% reduction of eGFR) by 40% (HR: 0.60; 95% CI: 0.47 to 0.77).The ongoing, fully enrolled CREDENCE study, the first dedicated SGLT2 inhibitor renal outcome trial in patients with T2DM and kidney disease, is further evaluating the effects of canagliflozin on renal and CV outcomes. “The CANVAS results are important because they clearly demonstrate the benefit of canagliflozin over current standard-of-care treatments,” said Dr. Vincent Woo, CANVAS Program investigator and endocrinologist at the Diabetes Research Group, University of Manitoba. “The CANVAS Program demonstrated consistent reductions across all components of the primary study outcome, which were cardiovascular death, myocardial infarction and stroke. These results confirm the efficacy of canagliflozin for CV risks that patients living with type-2 diabetes are most likely to experience.” Overall adverse events seen in the CANVAS Program were consistent with previous findings. An increased risk of amputation with canagliflozin was seen in both the completed CANVAS study and in the CANVAS-R study. This is consistent with the observation made by the study’s Independent Data Monitoring Committee (IDMC) in 2016, and interim data from the CANVAS study shared with Health Canada in March 2016 and reflected in the current Product Monograph. In the completed CANVAS Program, there was an increased risk of amputation (6.3 vs. 3.4/1000 patient-years in the canagliflozin vs. the placebo arm) corresponding to a hazard ratio (HR) of 1.97. The highest absolute risk of amputation occurred in patients with a prior history of amputation or peripheral vascular disease, but the relative risk for amputation with canagliflozin was comparable across these subgroups. Separately, while an increased risk of adjudicated low trauma fracture was identified in the CANVAS study and reflected in the Canadian Product Monograph, no increase was observed in the CANVAS-R study. A full assessment is ongoing to provide a complete safety review of these results.

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