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Original ArticlesDiabetes and the Kidney
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Effects of Canagliflozin in Patients with Baseline eGFR <30 ml/min per 1.73 m2

Subgroup Analysis of the Randomized CREDENCE Trial

George Bakris, Megumi Oshima, Kenneth W. Mahaffey, Rajiv Agarwal, Christopher P. Cannon, George Capuano, David M. Charytan, Dick de Zeeuw, Robert Edwards, Tom Greene, Hiddo J.L. Heerspink, Adeera Levin, Bruce Neal, Richard Oh, Carol Pollock, Norman Rosenthal, David C. Wheeler, Hong Zhang, Bernard Zinman, Meg J. Jardine and Vlado Perkovic
CJASN December 2020, 15 (12) 1705-1714; DOI: https://doi.org/10.2215/CJN.10140620
George Bakris
1Department of Medicine, University of Chicago Medicine, Chicago, Illinois
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Megumi Oshima
2The George Institute for Global Health, University of New South Wales Sydney, Sydney, Australia
3Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
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Kenneth W. Mahaffey
4Department of Medicine, Stanford Center for Clinical Research, Stanford University School of Medicine, Stanford, California
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Rajiv Agarwal
5Indiana University School of Medicine and Veterans Affairs Medical Center, Indianapolis, Indiana
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Christopher P. Cannon
6Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts
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George Capuano
7Janssen Research & Development, LLC, Raritan, New Jersey
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David M. Charytan
8Nephrology Division, New York University School of Medicine and New York University Langone Medical Center, New York, New York
9Baim Institute for Clinical Research, Boston, Massachusetts
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Dick de Zeeuw
10Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Robert Edwards
7Janssen Research & Development, LLC, Raritan, New Jersey
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Tom Greene
11Division of Biostatistics, Department of Population Health Sciences, University of Utah, Salt Lake City, Utah
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Hiddo J.L. Heerspink
2The George Institute for Global Health, University of New South Wales Sydney, Sydney, Australia
10Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Adeera Levin
12Division of Nephrology, University of British Columbia, Vancouver, British Columbia, Canada
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Bruce Neal
2The George Institute for Global Health, University of New South Wales Sydney, Sydney, Australia
13Charles Perkins Centre, University of Sydney, Sydney, Australia
14Imperial College London, London, United Kingdom
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Richard Oh
7Janssen Research & Development, LLC, Raritan, New Jersey
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Carol Pollock
15Kolling Institute of Medical Research, Sydney Medical School, University of Sydney, Royal North Shore Hospital, St Leonards, New South Wales, Australia
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Norman Rosenthal
7Janssen Research & Development, LLC, Raritan, New Jersey
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David C. Wheeler
2The George Institute for Global Health, University of New South Wales Sydney, Sydney, Australia
16Department of Renal Medicine, University College London Medical School, London, United Kingdom
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Hong Zhang
17Renal Division, Peking University First Hospital, Beijing, China
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Bernard Zinman
18Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
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Meg J. Jardine
2The George Institute for Global Health, University of New South Wales Sydney, Sydney, Australia
19Concord Repatriation General Hospital, Sydney, Australia
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Vlado Perkovic
2The George Institute for Global Health, University of New South Wales Sydney, Sydney, Australia
20Royal North Shore Hospital, Sydney, Australia
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Abstract

Background and objectives The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial demonstrated that the sodium glucose cotransporter 2 (SGLT2) inhibitor canagliflozin reduced the risk of kidney failure and cardiovascular events in participants with type 2 diabetes mellitus and CKD. Little is known about the use of SGLT2 inhibitors in patients with eGFR <30 ml/min per 1.73 m2. The participants in the CREDENCE study had type 2 diabetes mellitus, a urinary albumin-creatinine ratio >300–5000 mg/g, and an eGFR of 30 to <90 ml/min per 1.73 m2 at screening. This post hoc analysis evaluated participants with eGFR <30 ml/min per 1.73 m2 at randomization.

Design, setting, participants, & measurements Effects of eGFR slope through week 130 were analyzed using a piecewise, linear, mixed-effects model. Efficacy was analyzed in the intention-to-treat population, on the basis of Cox proportional hazard models, and safety was analyzed in the on-treatment population. At randomization (an average of 29 days after screening), 174 of 4401 (4%) participants had an eGFR <30 ml/min per 1.73 m2 (mean [SD] eGFR, 26 [3] ml/min per 1.73 m2).

Results From weeks 3 to 130, there was a 66% difference in the mean rate of eGFR decline with canagliflozin versus placebo (mean slopes, −1.30 versus −3.83 ml/min per 1.73 m2 per year; difference, −2.54 ml/min per 1.73 m2 per year; 95% confidence interval [CI], 0.90 to 4.17). Effects of canagliflozin on kidney, cardiovascular, and mortality outcomes were consistent for those with eGFR <30 and ≥30 ml/min per 1.73 m2 (all P interaction >0.20). The estimate for kidney failure in participants with eGFR <30 ml/min per 1.73 m2 (hazard ratio, 0.67; 95% CI, 0.35 to 1.27) was similar to those with eGFR ≥30 ml/min per 1.73 m2 (hazard ratio, 0.70; 95% CI, 0.54 to 0.91; P interaction=0.80). There was no imbalance in the rate of kidney-related adverse events or AKI associated with canagliflozin between participants with eGFR <30 and ≥30 ml/min per 1.73 m2 (all P interaction >0.12).

Conclusions This post hoc analysis suggests canagliflozin slowed progression of kidney disease, without increasing AKI, even in participants with eGFR <30 ml/min per 1.73 m2.

  • chronic kidney disease
  • diabetes
  • diabetic nephropathy
  • canagliflozin
  • Received June 22, 2020.
  • Accepted October 8, 2020.
  • Copyright © 2020 by the American Society of Nephrology
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Clinical Journal of the American Society of Nephrology: 15 (12)
Clinical Journal of the American Society of Nephrology
Vol. 15, Issue 12
December 07, 2020
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Effects of Canagliflozin in Patients with Baseline eGFR <30 ml/min per 1.73 m2
George Bakris, Megumi Oshima, Kenneth W. Mahaffey, Rajiv Agarwal, Christopher P. Cannon, George Capuano, David M. Charytan, Dick de Zeeuw, Robert Edwards, Tom Greene, Hiddo J.L. Heerspink, Adeera Levin, Bruce Neal, Richard Oh, Carol Pollock, Norman Rosenthal, David C. Wheeler, Hong Zhang, Bernard Zinman, Meg J. Jardine, Vlado Perkovic
CJASN Dec 2020, 15 (12) 1705-1714; DOI: 10.2215/CJN.10140620

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Effects of Canagliflozin in Patients with Baseline eGFR <30 ml/min per 1.73 m2
George Bakris, Megumi Oshima, Kenneth W. Mahaffey, Rajiv Agarwal, Christopher P. Cannon, George Capuano, David M. Charytan, Dick de Zeeuw, Robert Edwards, Tom Greene, Hiddo J.L. Heerspink, Adeera Levin, Bruce Neal, Richard Oh, Carol Pollock, Norman Rosenthal, David C. Wheeler, Hong Zhang, Bernard Zinman, Meg J. Jardine, Vlado Perkovic
CJASN Dec 2020, 15 (12) 1705-1714; DOI: 10.2215/CJN.10140620
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  • canagliflozin

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