The eagerly awaited results of the CANVAS trial were just released yesterday at the American Diabetes Association Meeting, and published simultaneously in the New England Journal of Medicine.
The CANVAS program was a cardiovascular outcome trial of the SGLT2 inhibitor, canagliflozin (Invokana). This program enrolled 10,142 people with type 2 diabetes and high cardiovascular risk, and randomized them to receive either canagliflozin 100mg, canagliflozin 300mg, or placebo, in addition to their usual care.
After a mean of 3.6 years, they found that canagliflozin reduced the risk of a combination of cardiovascular death, non fatal heart attack and non fatal stroke by 14%, with the benefit being particular to those with established cardiovascular disease at baseline. The individual outcomes above were not significantly reduced when considered separately, but were significant when considered together. Canagliflozin also reduced the risk of hospitalization for congestive heart failure by 33%, reduced the risk of poor kidney outcomes by 40% (a composite of a sustained 40% reduction in GFR, need for renal replacement therapy, or death from renal causes), and reduced progression of albumin in the urine by 27%.
In terms of risks of canagliflozin, unexpectedly, there was an increase in the risk of amputation, with 3.3% of people on canagliflozin requiring an amputation (most commonly a toe or forefoot) during the course of the trial, vs 1.5% in the placebo group. There was also an increase in the risk of fracture, with 15.4 fractures per 1000 patient years on canagliflozin, vs 11.9 per 1000 patient years in the placebo group. There was an increased risk of genital yeast infection, as expected for this class of medications, but no increased risk of urinary tract infection.
The CANVAS program adds to our understanding of the SGLT2 class of medications. As the EMPA REG trial showed us that the SGLT2 inhibitor empagliflozin (Jardiance) also reduces CV events in people with type 2 diabetes and cardiovascular disease, this is looking more likely to be a ‘class effect’ of the SGLT2 inhibitors (we still await the DECLARE study of the SGLT2 inhibitor dapagliflozin (Forxiga) to be completed).
In terms of the risks seen in the CANVAS trial, much discussion is underway in the medical and scientific community, and more studies will need to be done to better understand these findings. As always, the benefit vs risk of any medication must be carefully considered in finding the best medications for each individual patient.
Disclaimer: I receive honoraria as as continuing medical education speaker and consultant from the makers of canagliflozin (Janssen), empagliflozin (Boehringer-Ingelheim and Lilly), and dapagliflozin (Astra Zeneca). I am involved in research of SGLT2 inhibitors as a treatment of diabetes.
