John B. Buse, MD, PhD: The CANVAS trial involved canagliflozin, another SGLT2 inhibitor. In the CANVAS trial, patients were randomized to a placebo or canagliflozin in a cardiovascular outcome study, and then, also randomized to a canagliflozin or placebo in a renal outcome study. The 2 studies were merged to look at cardiovascular outcomes.
One thing that’s different with this trial from the other trials is that there was an interim unbinding of the CANVAS trial itself, which was used to support the cardiovascular safety of canagliflozin before marketing. And then, events were accumulated and the final study was released in June of 2017. In the CANVAS trial, for the primary endpoint—which was the first occurrence of heart attack, stroke, or cardiovascular death—there was a 14% reduction in the cardiovascular outcome, which was highly statistically significant for noninferiority and statistically significant for superiority. There were trends toward benefits on the other subanalyses—so cardiovascular death, heart attacks, strokes, and total mortality—as well as a statistically significant reduction in kidney endpoints, specifically albuminuria.
The CANVAS trial really looks very much like the EMPA-REG trial with regards to the types of benefits that are seen. One thing that seems apparent is that the relative reduction of each of the components of the composite endpoint in the CANVAS trial are more similar. In the EMPA-REG trial, there were greater differences with dramatic reductions in death and no benefit on stroke. And here, there’s more consistency with the CANVAS trial.
The one surprise in the CANVAS trial was really around amputations. So, there was demonstrated a statistically significant, approximate doubling in the risk of amputations seen with canagliflozin in the CANVAS trial. This was evident in both parts of the trial: in the CANVAS cardiovascular trial and in the CANVAS renal trial. Most of these amputations were so-called minor amputations: toes or less than toes. The minority were leg, below the knee, or above the knee, amputations.