Early Change in Albuminuria with Canagliflozin Predicts Kidney and Cardiovascular Outcomes: A PostHoc Analysis from the CREDENCE Trial

Abstract

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.

Keywords: SGLT2 inhibitor; albuminuria; canagliflozin; kidney and cardiovascular outcomes.

Graphical abstract

Figure 1.

By week 26, canagliflozin lowered the odds of progression to nephrotic range albuminuria (Panel A) and increased the odds of regression of albuminuria (Panel B). Canaglifozin decreased the odds of a ≥30% increase in albuminuria (OR, 0.41; 95% CI, 0.36 to 0.48; P<0.001) and increased the odds of experiencing a >30% reduction in albuminuria (OR, 2.69; 95% CI, 2.35 to 3.07; P<0.001).

Figure 2.

Canagliflozin lowered albuminuria by 31% (95% CI, 27% to 36%) at week 26. At an individual level, however, there was large variation in early change in albuminuria, both in canagliflozin- and placebo-treated participants.

Figure 3.

Early change in albuminuria at week 26 was independently associated with risk of (A) kidney composite outcome, (B) MACE, and (C) HHF/CV death. The numbers above each circle represent the event rates for each change in UACR category. Adjusted for baseline covariates (including age, sex, race or ethnic group, current smoking, history of hypertension, history of heart failure, duration of diabetes, history of cardiovascular disease, body mass index, systolic BP, HbA1c, eGFR, HDL cholesterol, LDL cholesterol, log-transformed triglycerides, diuretic use, RAAS inhibitor use, randomized treatment [canagliflozin or placebo], and log-transformed UACR) and percentage changes in HbA1c, body weight, systolic BP, and eGFR at week 26.

Figure 4.

Early progression to nephrotic range albuminuria was associated with increased risk of the kidney outcome and HHF/CV death, while early regression of albuminuria was associated with a decreased risk of MACE and HHF/CV death. Early progression or regression of albuminuria is defined as the development of progression or regression of albuminuria before UACR measurements at week 26. Adjusted for baseline covariates (including age, sex, race or ethnic group, current smoking, history of hypertension, history of heart failure, duration of diabetes, history of cardiovascular disease, body mass index, systolic BP, HbA1c, eGFR, HDL cholesterol, LDL cholesterol, log-transformed triglycerides, diuretic use, RAAS inhibitor use, randomized treatment [canagliflozin or placebo], and log-transformed UACR) and percentage changes in HbA1c, body weight, systolic BP, and eGFR at week 26.

Figure 5.

More participants treated with canagliozin, compared with placebo, were categorized into lower UACR categories at week 26. Number of participants in each category at baseline and month 6 are provided at the bottom.

Figure 6.

Residual albuminuria at week 26 was strongly associated with kidney and cardiovascular outcomes and was present irrespective of randomized treatment allocation. Associations of residual albuminuria at week 26 with (A) kidney composite outcome, (B) MACE outcome, and (C) HHF/CV death outcome in the canagliflozin and placebo groups. Adjusted for baseline covariates, including age, sex, race or ethnic group, current smoking, history of hypertension, history of heart failure, duration of diabetes, history of cardiovascular disease, body mass index, systolic BP, HbA1c, eGFR, HDL cholesterol, LDL cholesterol, log-transformed triglycerides, diuretic use, RAAS inhibitor use, randomized treatment (canagliflozin or placebo), and log-transformed UACR.