Renal, Cardiovascular, and Safety Outcomes of Canagliflozin by Baseline Kidney Function: A Secondary Analysis of the CREDENCE Randomized Trial
Authors: Jardine Meg J. , Zhou Zien , Mahaffey Kenneth W. , Oshima Megumi , Agarwal Rajiv , Bakris George , Bajaj Harpreet S. , Bull Scott , Cannon Christopher P. , Charytan David M. , de Zeeuw Dick , Di Tanna Gian Luca , Greene Tom , Heerspink Hiddo J.L. , Levin Adeera , Neal Bruce , Pollock Carol , Qiu Rose , Sun Tao , Wheeler David C. , Zhang Hong , Zinman Bernard , Rosenthal Norman , Perkovic Vlado ,   on behalf of the CREDENCE Study Investigators
Published: April 2020

Significance Statement
The CREDENCE randomized trial demonstrated that canagliflozin reduces risk of cardiovascular and renal events in people with type 2 diabetes and substantial albuminuria. The authors analyzed CREDENCE data to assess whether canagliflozin’s benefits are safely preserved in people with reduced eGFR, finding that the relative benefits for renal and cardiovascular outcomes appeared consistent among subgroups with initial eGFR ranging from 30 to <90 ml/min per 1.73 m2. Absolute benefit for renal outcomes was greater in subgroups with an initial eGFR of <60 ml/min per 1.73 m2. Safety outcomes were generally consistent among eGFR subgroups. Canagliflozin led to an acute eGFR drop, followed by relative stabilization of eGFR loss across subgroups. Canagliflozin’s benefits and safety are apparent across the eGFR range, including among those initiating treatment with eGFR as low as 30 ml/min per 1.73 m2.

Background
Canagliflozin reduced renal and cardiovascular events in people with type 2 diabetes in the CREDENCE trial. We assessed efficacy and safety of canagliflozin by initial estimated glomerular filtration rate (eGFR).

Methods
CREDENCE randomly assigned 4401 participants with an eGFR of 30 to <90 ml/min per 1.73 m2 and substantial albuminuria to canagliflozin 100 mg or placebo. We used Cox proportional hazards regression to analyze effects on renal and cardiovascular efficacy and safety outcomes within screening eGFR subgroups (30 to <45, 45 to <60, and 60 to <90 ml/min per 1.73 m2) and linear mixed effects models to analyze the effects on eGFR slope.

Results
At screening, 1313 (30%), 1279 (29%), and 1809 (41%) participants had an eGFR of 30 to <45, 45 to <60, and 60 to <90 ml/min per 1.73 m2, respectively. The relative benefits of canagliflozin for renal and cardiovascular outcomes appeared consistent among eGFR subgroups (all P interaction >0.11). Subgroups with lower eGFRs, who were at greater risk, exhibited larger absolute benefits for renal outcomes. Canagliflozin’s lack of effect on serious adverse events, amputations, and fractures appeared consistent among eGFR subgroups. In all subgroups, canagliflozin use led to an acute eGFR drop followed by relative stabilization of eGFR loss. Among those with an eGFR of 30 to <45 ml/min per 1.73 m2, canagliflozin led to an initial drop of 2.03 ml/min per 1.73 m2. Thereafter, decline in eGFR was slower in the canagliflozin versus placebo group (–1.72 versus –4.33 ml/min per 1.73 m2; between-group difference 2.61 ml/min per 1.73 m2).

Conclusions
Canagliflozin safely reduced the risk of renal and cardiovascular events, with consistent results across eGFR subgroups, including the subgroup initiating treatment with an eGFR of 30 to <45 ml/min per 1.73 m2. Absolute benefits for renal outcomes were greatest in subgroups with lower eGFR.

Clinical Trial registry name and registration number
Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE), NCT02065791.