The CANVAS Program identified the effect of
canagliflozin on major adverse cardiovascular events (
MACE) differed according to whether participants were using
diuretics at study commencement. We sought to further evaluate this finding related to baseline differences, treatment effects, safety, and risk factor changes.
METHODS AND RESULTS: The CANVAS Program enrolled 10 142 participants with
type 2 diabetes mellitus and high cardiovascular risk. Participants were randomized to
canagliflozin or placebo and followed for a mean of 188 weeks. The primary outcome was major cardiovascular events, a composite of cardiovascular death, nonfatal
myocardial infarction, or nonfatal
stroke. Secondary outcomes included multiple cardiovascular, renal, and safety events. In this post hoc subgroup analysis, participants were categorized according to baseline use of any
diuretic. The effect on outcomes was compared using Cox proportional hazards models, while risk factor changes were compared using mixed-effect models. At baseline, 4490 (44.3%) participants were using a
diuretic. Compared with those not using a
diuretic, participants using a
diuretic were more likely to be older (mean age ± standard deviation, 64.3 ± 8.0 vs. 62.5 ± 8.3), be female (38.9% vs. 33.4%), and have
heart failure (19.6% vs. 10.3%) (all Pdifference < 0.0001). The effect of
canagliflozin on major cardiovascular events was greater for those using
diuretic at baseline than for those who were not [adjusted hazard ratio 0.65 (95% confidence interval 0.54-0.78) vs. adjusted hazard ratio 1.13 (95% confidence interval 0.93-1.36), Pheterogeneity < 0.0001]. Changes in most risk factors, including blood pressure,
body weight, and urine
albumin-to-
creatinine ratio, were similar between groups (all Pdifference > 0.11), although the effect of
canagliflozin on haemoglobin A1c reduction was slightly weaker in participants using compared with not using
diuretics at baseline (-0.52% vs. -0.64%, Pheterogeneity = 0.0007). Overall serious adverse events and key safety outcomes, including adverse renal events, were also similar (all Pheterogeneity > 0.07).
CONCLUSIONS: