Early Change in Albuminuria with Canagliflozin Predicts Kidney and Cardiovascular Outcomes: A Post Hoc Analysis from the CREDENCE Trial
Authors: Oshima Megumi , Neuen Brendon L. , Li JingWei , Perkovic Vlado , Charytan David M. , de Zeeuw Dick , Edwards Robert , Greene Tom , Levin Adeera , Mahaffey Kenneth W. , De Nicola Luca , Pollock Carol , Rosenthal Norman , Wheeler David C. , Jardine Meg J. , Heerspink Hiddo J.L. 
Published: September 2020

Significance Statement
Studies of renin-angiotensin system inhibitors have consistently shown that the magnitude of albuminuria reduction during the first months of treatment is associated with risk reduction for kidney and cardiovascular outcomes. Whether or not the association between early changes in albuminuria and these outcomes also occurs with sodium-glucose cotransporter 2 (SGLT2) inhibition is unclear. This post hoc analysis of the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial demonstrated that, in people with type 2 diabetes and CKD, treatment with the SGLT2 inhibitor canagliflozin results in an early and sustained reduction in albuminuria. It also shows that early changes in albuminuria were independently associated with long-term kidney and cardiovascular outcomes. These findings highlight the importance of monitoring albuminuria during canagliflozin treatment to assess kidney and cardiovascular prognosis.

Background
The association between early changes in albuminuria and kidney and cardiovascular events is primarily based on trials of renin-angiotensin system blockade. It is unclear whether this association occurs with sodium-glucose cotransporter 2 inhibition.

Methods
The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial enrolled 4401 patients with type 2 diabetes and CKD (urinary albumin-creatinine ratio [UACR] >300 mg/g). This post hoc analysis assessed canagliflozin’s effect on albuminuria and how early change in albuminuria (baseline to week 26) is associated with the primary kidney outcome (ESKD, doubling of serum creatinine, or kidney death), major adverse cardiovascular events, and hospitalization for heart failure or cardiovascular death.

Results
Complete data for early change in albuminuria and other covariates were available for 3836 (87.2%) participants in the CREDENCE trial. Compared with placebo, canagliflozin lowered UACR by 31% (95% confidence interval [95% CI], 27% to 36%) at week 26, and significantly increased the likelihood of achieving a 30% reduction in UACR (odds ratio, 2.69; 95% CI, 2.35 to 3.07). Each 30% decrease in UACR over the first 26 weeks was independently associated with a lower hazard for the primary kidney outcome (hazard ratio [HR], 0.71; 95% CI, 0.67 to 0.76; P<0.001), major adverse cardiovascular events (HR, 0.92; 95% CI, 0.88 to 0.96; P<0.001), and hospitalization for heart failure or cardiovascular death (HR, 0.86; 95% CI, 0.81 to 0.90; P<0.001). Residual albuminuria levels at week 26 remained a strong independent risk factor for kidney and cardiovascular events, overall and in each treatment arm.

Conclusions
In people with type 2 diabetes and CKD, use of canagliflozin results in early, sustained reductions in albuminuria, which were independently associated with long-term kidney and cardiovascular outcomes.