Early Change in Albuminuria with Canagliflozin Predicts... : Journal of the American Society of Nephrology (original) (raw)

Clinical Research

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

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.

1The George Institute for Global Health, University of New South Wales Sydney, Sydney, Australia

2Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan

3Nephrology Division, School of Medicine and Langone Medical Center, New York University, New York, New York

4Baim Institute for Clinical Research, Boston, Massachusetts

5Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

6Janssen Research & Development, LLC, Raritan, New Jersey

7Division of Biostatistics, Department of Population Health Sciences, University of Utah, Salt Lake City, Utah

8Division of Nephrology, University of British Columbia, Vancouver, Canada

9Stanford Center for Clinical Research, Department of Medicine, Stanford University School of Medicine, Stanford, California

10Department of Advanced Medical and Surgical Sciences, Nephrology and Dialysis Unit, University Vanvitelli, Naples, Italy

11Kolling Institute of Medical Research, Sydney Medical School, University of Sydney, Royal North Shore Hospital, St Leonards, Australia

12Department of Renal Medicine, University College London Medical School, London, United Kingdom

13Concord Repatriation General Hospital, Sydney, Australia

Correspondence: Dr. Hiddo J.L. Heerspink, Department of Clinical Pharmacy and Pharmacology, Faculty of Medical Sciences, University of Groningen, University Medical Center, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. Email: [email protected]

M.O. and B.L.N. contributed equally to this work.

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Abstract

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.

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