CREDENCE: Early Change in Albuminuria with Canagliflozin Predicts Kidney and CV Outcomes in Patient with T2DM and CKD

29 Oct, 20

Introduction

Most of the evidence on the association between early changes in albuminuria and kidney and cardiovascular (CV) events in patients with type-2 diabetes mellitus (T2DM) is primarily based on trials of renin-angiotensin aldosterone system (RAAS) blockade. It is currently not known whether sodium-glucose co-transporter 2 (SGLT2) inhibition would impact this association.

Aim

To determine whether the early change in albuminuria due to canagliflozin treatment would be associated with long-term CV and kidney outcomes and to determine whether this association would be independent of the early change in other CV risk factors.

Patient Profile

Patients with T2DM (age ≥ 30 years), glycated hemoglobin (HbA1c) 6.5%-12.0%, eGFR of 30–<90 ml/min per 1.73 m², urinary albumin-creatinine ratio (UACR) >300–5000 mg/g (n=4401)
All patients were treated with stable maximum labeled or tolerated dose of RAAS inhibitors for ≥4 weeks before randomization

Methods

Study Design

Post hoc analysis of the CREDENCE trial
CREDENCE was a randomized, double-blind, placebo-controlled, multicenter clinical trial

Treatment Strategy

Patients underwent 2-week single-blind placebo run-in period before randomization
Based on the baseline eGFR, patients were stratified into categories of 30 to <45, 45 to <60, and 60 to <90 ml/min per 1.73 m²
Patients were randomized to canagliflozin (100 mg) or placebo
The use of background therapy for glycemic management and control of CV risk factors was recommended as per local guidelines

Outcomes

Primary Kidney Outcome

Composite of end-stage kidney disease (ESKD; defined as dialysis for ≥30 days, kidney transplantation, or an eGFR of <15 ml/min/1.73 m² sustained for ≥30 days), doubling of the serum creatinine level from baseline (average of randomization and pre-randomization values) sustained for ≥30 days, or kidney death

Primary Cardiac Outcomes

Major adverse cardiovascular events [MACE; defined as a composite of CV death, nonfatal myocardial infarction, or nonfatal stroke, and a composite of hospitalization for HF (HHF)/or CV death].

Results

Median follow-up period for the study was 2.2 years.
Compared with placebo, canagliflozin lowered UACR by 31% [95% confidence interval (95% CI), 27% to 36%] at week 26. Patients on canagliflozin were approximately 2.5 times more likely to achieve a 30% reduction in UACR [odds ratio (OR): 2.69; 95% CI: 2.35 to 3.07] and had decreased odds of increase in UACR of ≥30% (OR: 0.41; 95% CI: 0.36 to 0.48; P<0.001) vs. placebo at 26 weeks.
Canagliflozin reduced the risk of progression of albuminuria vs. placebo (OR: 0.52; 95% CI: 0.41 to 0.66) and resulted in approximately 2 times increased likelihood of regression in stage of albuminuria vs. placebo (OR: 1.85; 95%CI: 1.55 to 2.22) at 26 weeks.
This early reduction in albuminuria at 26 weeks was independently associated with 29% reduced risk of primary renal outcome (composite of ESKD, doubling of serum creatinine or renal death) [p<0.001], 8% reduced risk of MACE (p<0.001) and 14% reduced risk of CV death or HHF (p<0.001) with canagliflozin vs. placebo.
Residual albuminuria level at week 26 was a robust independent risk factor for kidney and CV events, overall and in each treatment arm.

Conclusions

In patients with T2DM and CKD, use of canagliflozin resulted in early, sustained reductions in albuminuria that were independently associated with lower incidence long-term kidney and CV outcomes.
Monitoring albuminuria during treatment with canagliflozin is important to track kidney and CV prognosis.

J Am Soc Nephrol. 2020 Sep 30 (Published Ahead of Print); doi: 10.1681/ASN.2020050723.