Background
Canagliflozin is a
sodium-glucose cotransporter 2 inhibitor that reduces glycemia as well as blood pressure,
body weight, and
albuminuria in people with diabetes. We report the effects of treatment with
canagliflozin on cardiovascular, renal, and safety outcomes. Methods The CANVAS Program integrated data from two trials involving a total of 10,142 participants with
type 2 diabetes and high cardiovascular risk. Participants in each trial were randomly assigned to receive
canagliflozin or placebo and were followed for a mean of 188.2 weeks. The primary outcome was a composite of death from cardiovascular causes, nonfatal
myocardial infarction, or nonfatal
stroke. Results The mean age of the participants was 63.3 years, 35.8% were women, the mean duration of diabetes was 13.5 years, and 65.6% had a history of
cardiovascular disease. The rate of the primary outcome was lower with
canagliflozin than with placebo (occurring in 26.9 vs. 31.5 participants per 1000 patient-years; hazard ratio, 0.86; 95% confidence interval [CI], 0.75 to 0.97; P<0.001 for noninferiority; P=0.02 for superiority). Although on the basis of the prespecified hypothesis testing sequence the renal outcomes are not viewed as statistically significant, the results showed a possible benefit of
canagliflozin with respect to the progression of
albuminuria (hazard ratio, 0.73; 95% CI, 0.67 to 0.79) and the composite outcome of a sustained 40% reduction in the estimated glomerular filtration rate, the need for
renal-replacement therapy, or death from renal causes (hazard ratio, 0.60; 95% CI, 0.47 to 0.77). Adverse reactions were consistent with the previously reported risks associated with
canagliflozin except for an increased risk of
amputation (6.3 vs. 3.4 participants per 1000 patient-years; hazard ratio, 1.97; 95% CI, 1.41 to 2.75);
amputations were primarily at the level of the toe or metatarsal. Conclusions In two trials involving patients with
type 2 diabetes and an elevated risk of
cardiovascular disease, patients treated with
canagliflozin had a lower risk of cardiovascular events than those who received placebo but a greater risk of
amputation, primarily at the level of the toe or metatarsal. (Funded by Janssen Research and Development; CANVAS and CANVAS-R ClinicalTrials.gov numbers, NCT01032629 and NCT01989754 , respectively.).