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Clinical Research
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Different eGFR Decline Thresholds and Renal Effects of Canagliflozin: Data from the CANVAS Program

Megumi Oshima, Bruce Neal, Tadashi Toyama, Toshiaki Ohkuma, Qiang Li, Dick de Zeeuw, Hiddo J.L. Heerspink, Kenneth W. Mahaffey, Gregory Fulcher, William Canovatchel, David R. Matthews and Vlado Perkovic
JASN October 2020, 31 (10) 2446-2456; DOI: https://doi.org/10.1681/ASN.2019121312
Megumi Oshima
1Department of Renal and Metabolic, The George Institute for Global Health, University of New South Wales Sydney, Sydney, New South Wales, Australia
2Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
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  • ORCID record for Megumi Oshima
Bruce Neal
1Department of Renal and Metabolic, The George Institute for Global Health, University of New South Wales Sydney, Sydney, New South Wales, Australia
3The Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia
4Imperial College London, London, United Kingdom
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Tadashi Toyama
2Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
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Toshiaki Ohkuma
1Department of Renal and Metabolic, The George Institute for Global Health, University of New South Wales Sydney, Sydney, New South Wales, Australia
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Qiang Li
1Department of Renal and Metabolic, The George Institute for Global Health, University of New South Wales Sydney, Sydney, New South Wales, Australia
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Dick de Zeeuw
5Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Hiddo J.L. Heerspink
1Department of Renal and Metabolic, The George Institute for Global Health, University of New South Wales Sydney, Sydney, New South Wales, Australia
5Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Kenneth W. Mahaffey
6Stanford University School of Medicine, Stanford, California
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Gregory Fulcher
7Royal North Shore Hospital, Sydney, New South Wales, Australia
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William Canovatchel
8Janssen Global Services, LLC, Raritan, New Jersey
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David R. Matthews
9Harris Manchester College, University of Oxford, Oxford, United Kingdom
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Vlado Perkovic
1Department of Renal and Metabolic, The George Institute for Global Health, University of New South Wales Sydney, Sydney, New South Wales, Australia
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Significance Statement

Traditionally, clinical trials studying effects of new therapies on renal outcome use the doubling of serum creatinine (equivalent to a 57% eGFR reduction) as an end point, requiring large sample sizes. Use of lesser eGFR reductions has been proposed, but few studies have evaluated their reliability. In this post hoc study of two multicenter, randomized trials, a greater number of observed events resulted from use of 50%, 40%, and 30% eGFR reductions compared with a 57% eGFR reduction. Observed effect sizes for canagliflozin versus placebo were attenuated when lesser eGFR reductions were used, likely because of canagliflozin’s acute effect on eGFR. However, if analyses control for this acute effect, lesser eGFR decline thresholds may be preferred to identify renoprotective effects of potential therapies because much smaller sample sizes can be used.

Abstract

Background Traditionally, clinical trials evaluating effects of a new therapy with creatinine-based renal end points use doubling of serum creatinine (equivalent to a 57% eGFR reduction), requiring large sample sizes.

Methods To assess whether eGFR declines <57% could detect canagliflozin’s effects on renal outcomes, we conducted a post hoc study comparing effects of canagliflozin versus placebo on composite renal outcomes using sustained 57%, 50%, 40%, or 30% eGFR reductions in conjunction with ESKD and renal death. Because canagliflozin causes an acute reversible hemodynamic decline in eGFR, we made estimates using all eGFR values as well as estimates that excluded early measures of eGFR influenced by the acute hemodynamic effect.

Results Among the 10,142 participants, 93 (0.9%), 161 (1.6%), 352 (3.5%), and 800 (7.9%) participants recorded renal outcomes on the basis of 57%, 50%, 40%, or 30% eGFR reduction, respectively, during a mean follow-up of 188 weeks. Compared with a 57% eGFR reduction (risk ratio [RR], 0.51; 95% confidence interval [95% CI], 0.34 to 0.77), the effect sizes were progressively attenuated when using 50% (RR, 0.61; 95% CI, 0.45 to 0.83), 40% (RR, 0.70; 95% CI, 0.57 to 0.86), or 30% (RR, 0.81; 95% CI, 0.71 to 0.93) eGFR reductions. In analyses that controlled for the acute hemodynamic fall in eGFR, effect sizes were comparable, regardless of whether a 57%, 50%, 40%, or 30% eGFR reduction was used. Estimated sample sizes for studies on the basis of lesser eGFR reductions were much reduced by controlling for this early hemodynamic effect.

Conclusions Declines in eGFR <57% may provide robust estimates of canagliflozin’s effects on renal outcomes if the analysis controls for the drug’s acute hemodynamic effect.

Clinical Trial registry name and registration number: CANagliflozin cardioVascular Assessment Study (CANVAS), NCT01032629 and CANVAS-R, NCT01989754.

  • Type 2 diabetes
  • eGFR decline
  • canagliflozin
  • SGLT2 inhibitors
  • Copyright © 2020 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 31 (10)
Journal of the American Society of Nephrology
Vol. 31, Issue 10
October 2020
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Different eGFR Decline Thresholds and Renal Effects of Canagliflozin: Data from the CANVAS Program
Megumi Oshima, Bruce Neal, Tadashi Toyama, Toshiaki Ohkuma, Qiang Li, Dick de Zeeuw, Hiddo J.L. Heerspink, Kenneth W. Mahaffey, Gregory Fulcher, William Canovatchel, David R. Matthews, Vlado Perkovic
JASN Oct 2020, 31 (10) 2446-2456; DOI: 10.1681/ASN.2019121312

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Different eGFR Decline Thresholds and Renal Effects of Canagliflozin: Data from the CANVAS Program
Megumi Oshima, Bruce Neal, Tadashi Toyama, Toshiaki Ohkuma, Qiang Li, Dick de Zeeuw, Hiddo J.L. Heerspink, Kenneth W. Mahaffey, Gregory Fulcher, William Canovatchel, David R. Matthews, Vlado Perkovic
JASN Oct 2020, 31 (10) 2446-2456; DOI: 10.1681/ASN.2019121312
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