Practical Implications of the CANVAS Trial

John Anderson, MD: In June of 2017 in San Diego, at the American Diabetes Association Scientific Sessions, the CANVAS trial results were released. Again, this was the second SGLT2 inhibitor to be studied in a large cardiovascular outcomes trial. This trial was a little different from EMPA-REG in that this trial had about 35% of patients who were just “at high risk”—maybe they had been over 50 or they had diabetes for more than 10 years—whereas 65% actually had a cardiovascular event. Now, to refresh memory, EMPA-REG had 100% of people who had some sort of cardiovascular event. The question was when you dilute that sample with people who are not quite as sick, would you get as good a result?

Well, there was still a 12% reduction in the primary MACE, those major adverse cardiovascular events, so it met the primary endpoint of its trial. This was driven by a reduction in cardiovascular death, a reduction in MI [myocardial infarction], and a reduction in stroke, none of which individually were statistically significant. But the overall numbers made it statistically significant. They did not have that same 38% reduction in cardiovascular death that you saw with EMPA-REG, but they did have another 35% reduction in hospitalization for heart failure. They also had the same decrease in progression to end-stage renal disease, renal replacement therapy, a doubling of creatinine, and all those measures of worsening renal function over the 6-and-a-half years of the trial.

The other thing that was pointed out by the FDA prior to the trial coming out was that there was this slight increased risk of amputation. The numbers went from 3 in 1000 patient-years to 6 in 1000 patient-years. So, statistically, it’s 0.3% to 0.6%. Most of those patients had already had an amputation and had evidence of peripheral vascular disease, but you can’t ignore that it was statistically significant. But, again, I think it’s helpful to know that these are small numbers and this is being looked at. We’ll have a lot of information, probably over the next year or year-and-a-half, looking at parsing those data, just like we’re going to have a lot of information over the next year or so looking at parsing some of the EMPA-REG OUTCOME data as well.

In the CANVAS trial, there was a 35% reduction in hospitalization for heart failure, very similar to EMPA-REG—eerily similar to the EMPA-REG trial and empagliflozin—as well as a marked decrease, some 45% to 50% decrease, in progression toward renal replacement therapy, death from end-stage renal disease, and a doubling of creatinine. In other words, with all those things that you measure as adverse renal endpoints, there was a marked reduction in the patients treated with canagliflozin.

One of the things I’d like to point out in the CANVAS trial is that those curves separated pretty early as well. It now seems that we have a second SGLT2 inhibitor that met that 3-point MACE, has a reduction in heart failure, and has those renal benefits. Now, you’re starting to think that this may be a real class effect. Dapagliflozin has the largest of the clinical trials, but it won’t report out until 2019. So, we’ll see if they meet the same endpoints, but most experts are now thinking this is a real class effect.