COMMENTARY

CANVAS Proves CV Safety and Metabolic Value of Canagliflozin

Clifford J. Bailey, PhD, FRCP (Edin), FRCPath; Videographer: Mark Harmel, MPH

Disclosures

June 30, 2017

The CANVAS program[1] combined the CANVAS[2] and CANVAS-R[3] studies as part of the postmarketing cardiovascular outcomes studies for canagliflozin. These studies were originally designed to confirm the cardiovascular safety of canagliflozin.

Combining the data from the two CANVAS studies resulted in a 14% reduction in the major adverse cardiac events: cardiovascular death, myocardial infarction, and stroke. There also was a considerable reduction in hospitalizations for heart failure. In that sense, the CANVAS program more than achieved what was required for demonstrating cardiovascular safety from the perspective of the US Food and Drug Administration.

The study also looked at renal outcomes and showed quite clearly a reduction in albuminuria and in progression of albuminuria. Thus, it found evidence of renal protection and also some evidence of the possibility for some remission of kidney problems.

What About Adverse Events?

At the same time, we must not forget adverse events. The CANVAS program found a small increase in diabetic ketoacidosis. This is uncommon in patients with type 2 diabetes but it can occur with underinsulinization.

The occurrence of ketoacidosis essentially revealed that some patients in the trial probably were patients with type 1 diabetes. Thus, we must make sure that patients who take an SGLT2 inhibitor maintain their insulin.

This gives us an indication of which patients should not receive canagliflozin.

The study also found some heterogeneity among the bone fractures between CANVAS and CANVAS-R, [with more fractures in the patients who received canagliflozin than placebo,] but we do not see a definite signal there.

There was an increase in amputations, however. This was a small increase, was largely associated with foot and metatarsal amputations, and occurred predominantly in patients who had a previous amputation or who have significant peripheral vascular disease. This gives us an indication of which patients should not receive canagliflozin, to avoid that particular problem.

Comparing CANVAS With EMPA-REG

CANVAS showed positive superior major adverse cardiac events (MACE) outcomes, which enables it to be compared with the EMPA-REG study.[4] EMPA-REG also showed a similar reduction in MACE, but we need to compare the two trial populations. EMPA-REG included essentially all patients who previously had evidence of cardiovascular disease, whereas in CANVAS, only 65% of patients had evidence of cardiovascular disease before the trial. About one third of patients in the CANVAS trial had risk factors but would be considered a primary prevention population. Thus, the population in the CANVAS trial probably reflects the routine practice population of patients with type 2 patients that we see.

Looking at the outcomes, we see reductions in each of the main components of MACE in each of the trials, with the exception of stroke in the EMPA-REG study. The majority of patients who had a stroke in the EMPA-REG study actually had it after the drug had been stopped at the end of the study, during the follow-up period and not during the study period.[5] By comparison, the CANVAS program study shows a gentle reduction in stroke throughout.

The population in the CANVAS trial probably reflects the routine practice population of patients with type 2 patients.

In addition, if one looks at the graphic depiction of adverse event outcomes, in EMPA-REG we see a very early divergence in the rate of cardiovascular events, with reductions in events in those patients taking empagliflozin. This early divergence coincides with the time when the other agents in the so-called placebo arm were being titrated up in an attempt to gain glycemic equipoise.

Therefore, we cannot be sure how much of that very early effect is related to a population of patients who have much more cardiovascular disease than those in the CANVAS trial, the combination of agents that are used in the placebo arm, or the agent itself. We can say that there is a very quick divergence with the EMPA-REG study, whereas with the CANVAS study, one sees a rather more gradual separation in the occurrence of MACE. It is possible that having a larger primary prevention population means that there is a slower separation of the lines because of a slower rate of events.

Studies with other SGLT2 inhibitors, and indeed other studies that have been conducted with canagliflozin, have not revealed a problem with amputation, so this outcome remains to be looked at in some detail.

At this time, we can say that we have new agents that are able to reduce cardiovascular risk in patients with type 2 diabetes in addition to providing metabolic value. We have an opportunity, while reducing glucose levels, to also reduce weight, assist in the reduction of blood pressure, and offer cardiovascular and renal protective benefits.

Thank you very much.

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