Effect of Canagliflozin on Total Cardiovascular Burden in Patients With Diabetes and Chronic Kidney Disease: A Post Hoc Analysis From the CREDENCE Trial

Abstract

Background The sodium-glucose cotransporter 2 inhibitor canagliflozin reduced the risk of first cardiovascular composite events in the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial. In this post hoc analysis, we evaluated the effect of canagliflozin on total (first and recurrent) cardiovascular events. Methods and Results The CREDENCE trial compared canagliflozin or matching placebo in 4401 patients with type 2 diabetes, albuminuria, and estimated glomerular filtration rate of 30 to <90 mL/min per 1.73 m², over a median of 2.6 years. The primary outcome was analyzed as a composite of any cardiovascular event including myocardial infarction, stroke, hospitalization for heart failure, hospitalization for unstable angina, and cardiovascular death. Negative binomial regression models were used to assess the effect of canagliflozin on the net burden of cardiovascular events. During the trial, 634 patients had 883 cardiovascular events, of whom 472 (74%) had just 1 cardiovascular event and 162 (26%) had multiple cardiovascular events. Canagliflozin reduced first cardiovascular events by 26% (hazard ratio, 0.74 [95% CI, 0.63-0.86]; P<0.001) and total cardiovascular events by 29% (incidence rate ratio, 0.71 [95% CI, 0.59-0.86]; P<0.001). The absolute risk difference per 1000 patients treated over 2.5 years was -44 (95% CI, -67 to -21) first cardiovascular events and -73 (95% CI, -114 to -33) total events. Conclusions Canagliflozin reduced cardiovascular events, with a larger absolute benefit for total cardiovascular than first cardiovascular events. These findings provide further support for the benefit of continuing canagliflozin therapy after an initial event to prevent recurrent cardiovascular events. Registration Information URL: https://www.clinicaltrials.gov; Unique Identifier: NCT02065791.

Keywords: canagliflozin; chronic kidney disease; diabetes; recurrent cardiovascular event.

Figure 1. Cumulative rate of total (first and subsequent) cardiovascular events and time to cardiovascular composite outcomes.

CV indicates cardiovascular.

Figure 2. Total primary end point events by randomized therapy.

P value was produced by negative binomial regression.

Figure 3. Forest plot of total cardiovascular composite end points and individual component end points.

CV indicates cardiovascular; HF, heart failure; HR, hazard ratio; IRR, incidence rate ratio; MI, myocardial infarction; and UA, unstable angina.

Figure 4. Sankey diagram for illustration of cardiovascular disease spectrum interface.

The Sankey plot depicts event transitions from the first to third events. Longer indicates more events. CV indicates cardiovascular; HF, heart failure; MI, myocardial infarction; and UA, unstable angina.