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Cited by 130Chronic Kidney Disease and DiabetesDiabetes Treatment and ManagementAcute Kidney Injury Research

The DOI matches its Crossref record; 41 of the 41 references it cites were found in a registry or an index.

Mediators of the effects of canagliflozin on kidney protection in patients with type 2 diabetes

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Li, JingWei, Neal, Bruce, Perkovic, Vlado, de Zeeuw, Dick, Neuen, Brendon L., Arnott, Clare, Simpson, Roger, Oh, Richard, Mahaffey, Kenneth W., Heerspink, Hiddo J.L.·2020·Kidney International
DOI 10.1016/j.kint.2020.04.051
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Abstract

Canagliflozin reduced kidney disease progression in participants with type 2 diabetes in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. This analysis explored potential mediators of the effects of canagliflozin on kidney outcomes. The percent mediating effect of 18 biomarkers indicative of disease was determined by comparing the hazard ratios for the effect of randomized treatment from an unadjusted model and from a model adjusting for the average post-randomization level of each biomarker. Multivariable analyses assessed the joint effects of biomarkers that mediated most strongly in univariable analyses. The kidney outcome was defined as a composite of 40% estimated glomerular filtration rate decline, end-stage kidney disease, or death due to kidney disease. Nine biomarkers (systolic blood pressure [8.9% of effect explained], urinary albumin:creatinine ratio [UACR; 23.9%], gamma glutamyltransferase [4.1%], hematocrit [51.1%], hemoglobin [41.3%], serum albumin [19.5%], erythrocytes [56.7%], serum urate [35.4%], and urine pH [7.5%]) individually mediated the effect of canagliflozin on the kidney outcome. In a parsimonious multivariable model, erythrocyte concentration, serum urate, and systolic blood pressure maximized cumulative mediation (115%). Mediating effects of UACR, but not other mediators, were highly dependent upon the baseline level of UACR: UACR mediated 42% and 7% of the effect in those with baseline UACR 30 mg/g or more and under 30 mg/g, respectively. The identified mediators support existing hypothesized mechanisms for the prevention of kidney outcomes with sodium glucose co-transporter 2 inhibitors. Thus, the disparity in mediating effects across baseline UACR subgroups suggests that the mechanism for kidney protection with canagliflozin may vary across patient subgroups.

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Authors
Li, J., Neal, B., Perkovic, V., de Zeeuw, D., Neuen, B. L., Arnott, C., Simpson, R., Oh, R., Mahaffey, K. W., & Heerspink, H. J. L.
Affiliations
  • Army Medical University (CN)
  • The George Institute for Global Health (GB)
  • UNSW Sydney (AU)
  • University Medical Center Groningen (NL)
  • Royal Prince Alfred Hospital (AU)
  • Janssen Research & Development (United States) (US)
  • Stanford Medicine (US)
Corresponding author
Heerspink, Hiddo J.L.
ORCID
Venue
Kidney International
Publisher
Elsevier BV
Published
2020-09
Volume
98
Issue
3
Pages
769-777
ISSN
0085-2538 (ISSN-L)
DOI
10.1016/j.kint.2020.04.051
OpenAlex
W3029576443
Cited by
130
References
41
Citations by year
2026: 8 · 2025: 30 · 2024: 25 · 2023: 21 · 2022: 22 · 2021: 21 · 2020: 3
FWCI
10.52
Type
journal article
Language
en
Open access
Licence
Locations
  • Kidney International (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, cc-by)
  • UNSWorks (UNSW Sydney) (submittedVersion, cc-by-nc-nd)
  • Spiral (Imperial College London) (submittedVersion, other-oa)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
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, type 2 diabetes, renal protection, kidney disease progression, SGLT2 inhibitors, mediation analysis, urinary albumin-creatinine ratio, erythrocyte concentration, serum uric acid, systolic blood pressure, estimated glomerular filtration rate decline, end-stage renal disease, CANVAS trial
MeSH terms
Canagliflozin, Sodium-Glucose Transporter 2 Inhibitors, Diabetes Mellitus, Type 2, Glomerular Filtration Rate, Humans, Kidney

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