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Cited by 142Chronic Kidney Disease and DiabetesDiabetes Treatment and ManagementAcute Kidney Injury Research

Effects of Canagliflozin in Patients with Baseline eGFR <30 ml/min per 1.73 m2: Subgroup Analysis of the Randomized CREDENCE Trial

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Bakris, George, Oshima, Megumi, Mahaffey, Kenneth W., Agarwal, Rajiv, Cannon, Christopher P., Capuano, George, Charytan, David M., de Zeeuw, Dick +13 more·2020·Clinical Journal of the American Society of Nephrology
DOI 10.2215/cjn.10140620PMC PMC7769025
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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 m 2 . 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 m 2 at screening. This post hoc analysis evaluated participants with eGFR <30 ml/min per 1.73 m 2 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 m 2 (mean [SD] eGFR, 26 [3] ml/min per 1.73 m 2 ). 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 m 2 per year; difference, −2.54 ml/min per 1.73 m 2 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 m 2 (all P interaction >0.20). The estimate for kidney failure in participants with eGFR <30 ml/min per 1.73 m 2 (hazard ratio, 0.67; 95% CI, 0.35 to 1.27) was similar to those with eGFR ≥30 ml/min per 1.73 m 2 (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 m 2 (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 m 2 .

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  • Post hoc analyses of CREDENCE and DAPA-CKD demonstrated that participants who met eGFR eligibility at screening but subsequently had lower baseline eGFR prior to randomization experienced similar kidney benefits as those with baseline eGFR above eligibility thresholds.

    “In addition, post hoc analyses of CREDENCE and DAPA-CKD demonstrated that participants who met eGFR eligibility at screening but subsequently had lower baseline eGFR prior to randomization ( &lt; 30 ml/min per 1.73 m 2 and &lt; 25 ml/min per 1.73 m 2 , respectively) experienced similar kidney bene fi ts as those with baseline eGFR above eligibility thresholds.”

    From KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease (2022) · cites this paper as [140]

    The Study Design and Patients sections describe CREDENCE participants whose eGFR met the screening threshold but fell below 30 ml/min per 1.73 m² by randomization. The Discussion says their kidney outcomes appeared consistent with those of participants whose eGFR remained at or above 30. The paper mentions DAPA-CKD participants with eGFR down to 25, but does not report a post hoc analysis of participants below 25 at randomization or the claimed comparison for that trial. Page numbers are unavailable in our copy. (LLM, conf=0.90)

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  • Subgroup analyses of participants in CREDENCE and DAPA-CKD with baseline eGFR <30 mL/min/1.73 m2 provide additional support for SGLT2 inhibitor use.

    “Additional support comes from subgroup analyses of participants in the CREDENCE and DAPA-CKD trials with baseline eGFR <30 mL/min/1.73 m2 (59,60).”

    From Diabetes management in chronic kidney disease: a consensus report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO) (2022) · cites this paper as [59]

  • Subgroup analyses of individual trials and meta-analyses have consistently demonstrated kidney and cardiovascular benefits of SGLT2i across eGFR categories, including participants with eGFR <30 ml/min per 1.73 m2 and participants without albuminuria.

    “Subgroup analyses of individual trials and meta-analyses have consistently demonstrated kidney and cardiovascular benefits across eGFR categories, including participants with eGFR <30 ml/min per 1.73 m 2 and participants without albuminuria.16,17”

    From Executive summary of the KDIGO 2022 clinical practice guideline for diabetes management in chronic kidney disease: an update based on rapidly emerging new evidence (2022) · cites this paper as [16]

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Authors
Bakris, G., Oshima, M., Mahaffey, K. W., Agarwal, R., Cannon, C. P., Capuano, G., Charytan, D. M., de Zeeuw, D., Edwards, R., Greene, T., Heerspink, H. J. L., Levin, A., Neal, B., Oh, R., Pollock, C., Rosenthal, N., Wheeler, D. C., Zhang, H., Zinman, B., Jardine, M. J., & Perkovic, V.
Affiliations
  • University of Chicago (US)
  • Kanazawa University (JP)
  • Stanford Medicine (US)
  • Richard L. Roudebush VA Medical Center (US)
  • Brigham and Women's Hospital (US)
  • Janssen Research & Development (United States) (US)
  • NYU Langone Health (US)
  • Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
  • University of Utah (US)
  • University Medical Center Groningen (NL)
  • University of British Columbia (CA)
  • The University of Sydney (AU)
  • UNSW Sydney (AU)
  • Peking University First Hospital (CN)
  • Mount Sinai Hospital (CA)
  • Concord Repatriation General Hospital (AU)
  • Royal North Shore Hospital (AU)
ORCID
Venue
Clinical Journal of the American Society of Nephrology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2020-11-19
Volume
15
Issue
12
Pages
1705-1714
ISSN
  • 1555-9041 (ISSN-L)
  • 1555-905X
DOI
10.2215/cjn.10140620
PMC
PMC7769025
OpenAlex
W3101633024
Cited by
142
References
19
Citations by year
2026: 14 · 2025: 15 · 2024: 24 · 2023: 25 · 2022: 42 · 2021: 21 · 2020: 1
FWCI
13.89
Type
journal article
Language
en
Open access
Licence
public-domain
Locations
  • Clinical Journal of the American Society of Nephrology (publishedVersion, public-domain)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, other-oa)
  • UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by-nc-nd)
  • IUScholarWorks (Indiana University) (submittedVersion)
  • Purdue University Indianapolis (Indiana University) (submittedVersion)
  • Spiral (Imperial College London) (submittedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
Funders
Janssen Research & Development
Topics
  • Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
Keywords
canagliflozin, SGLT2 inhibitors, end-stage renal disease, renal failure, estimated glomerular filtration rate decline, type 2 diabetes, chronic kidney disease, CREDENCE trial, cardiovascular events, mortality, renal safety, albuminuria, eGFR slope, post hoc analysis
MeSH terms
Canagliflozin, Sodium-Glucose Transporter 2 Inhibitors, Aged, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Double-Blind Method, Female, Glomerular Filtration Rate, Humans, Kidney, Male, Middle Aged, Risk Factors, Time Factors, Treatment Outcome, Disease Progression, Acute Kidney Injury

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