Patients with type 2 diabetes and an elevated risk of cardiovascular disease (CVD) who were treated with canagliflozin had a lower risk of CV events compared to those receiving placebo, but a greater risk of amputation. This according to 2 clinical trials (CANVAS and CANVAS-R) that included a total of 10,142 participants (mean age 63.3 years, 35.8% women) with T2D and a history of CVD. Participants in each trial were randomly assigned to receive canagliflozin or placebo and were followed for a mean of 188 weeks. Primary outcome was composite of death from CV causes, nonfatal myocardial infarction, or nonfatal stroke. Researchers found:
- The rate of primary outcomes was lower with canagliflozin vs placebo (occurring in 26.9 vs 31.5 participants per 1,000 patient-years; HR, 0.86).
- Due to the prespecified hypothesis testing sequence, the renal outcomes are not considered statistically significant. The results did show a possible benefit of canagliflozin on progression of albuminuria (HR, 0.73; 95% CI, 0.67 to 0.79), the composite of a sustained 40% reduction in the estimated glomerular filtration rate, the need for renal-replacement therapy, or death from renal causes (HR, 0.60; 95% CI, 0.47 to 0.77).
- Adverse reactions were consistent with previously reported risks associated with canagliflozin use except for the increased risk of amputation (6.3 vs. 3.4 participants per 1000 patient-years; HR, 1.97).
Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. [Published online ahead of print June 12, 2017]. N Engl J Med. doi:10.1056/NEJMoa1611925.
Canagliflozin is now the second SGLT-2 to show beneficial cardiovascular outcomes. Previously, empagliflozine showed positive cardiovascular outcomes in a population of patients with diabetes and existent CV disease.1 In that trial, the primary outcome of 3-point MACE (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) showed a 14% reduction in the empagliflozin group. Death from cardiovascular causes had a 38% relative risk reduction, hospitalization for heart failure had a 35% relative risk reduction, and death from any cause had a 32% relative risk reduction. The CANVAS trial shows that the CV benefit applies as well to canagliflozin, which means that it may be a class effect. Also notable, however, was the increase in the rate of amputation in the treated group, which recently led the FDA to issue a caution about canagliflozin regarding this issue. Whether the differences in the level of effect on cardiovascular outcomes were due to differences in the population studied or differences in the actual effect of the 2 compounds is not clear. What is clear, though, is that 2 medications in each of both the SGLT-2 class and the GLP-1 receptor agonist class have evidence of positive cardiovascular outcomes in patients with diabetes with existent and/or at high-risk for CV disease. —Neil Skolnik, MD
- Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-28. doi:10.1056/NEJMoa1504720.