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Mediators of the effects of canagliflozin on kidney protection in patients with type 2 diabetes
Open accessAbstract
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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“Reduction in albuminuria is also important to evaluate the efficacy of medications prescribed for kidney protection, as both SGLT2 inhibitors and finerenone have shown that the majority of their beneficial effect is mediated by reduction in albuminuria (42,43).”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [43]
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Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes
Neal, B., Perkovic, V., Mahaffey, K. W., de Zeeuw, D., Fulcher, G., Erondu, N., Shaw, W., Law, G., Desai, M., & Matthews, D. R. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1611925 · Cited by 7,830
Self-citationCanagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy
Perkovic, V., Jardine, M. J., Neal, B., Bompoint, S., Heerspink, H. J. L., Charytan, D. M., Edwards, R., Agarwal, R., Bakris, G., Bull, S., et al. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1811744 · Cited by 6,189
Self-citationMacKinnon, D. P., Fairchild, A. J., & Fritz, M. S. (2007) · Annual Review of Psychology · doi:10.1146/annurev.psych.58.110405.085542 · Cited by 5,688
Introduction to Statistical Mediation Analysis
MacKinnon, D. P. (2012) · doi:10.4324/9780203809556 · Cited by 5,618
Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
Wanner, C., Inzucchi, S. E., Lachin, J. M., Fitchett, D., von Eynatten, M., Mattheus, M., Johansen, O. E., Woerle, H. J., Broedl, U. C., & Zinman, B. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1515920 · Cited by 3,655
Zelniker, T. A., Wiviott, S. D., Raz, I., Im, K., Goodrich, E. L., Bonaca, M. P., Mosenzon, O., Kato, E. T., Cahn, A., Furtado, R. H. M., et al. (2019) · The Lancet · doi:10.1016/s0140-6736(18)32590-x · Cited by 2,845 · cited 1×
“T he CANagliflozin cardioVascular Assessment Study (CANVAS) Program reported that the sodium glucose cotransporter 2 (SGLT2) inhibitor canagliflozin reduces the risk of clinically important kidney outcomes in patients with type 2 diabetes with established cardiovascular disease or those at high cardiovascular risk.(1)…”
BackgroundSurrogate End Points in Clinical Trials: Are We Being Misled?
Fleming, T. R., & DeMets, D. L. (1996) · Annals of Internal Medicine · doi:10.7326/0003-4819-125-7-199610010-00011 · Cited by 1,651
Heerspink, H. J. L., Perkins, B. A., Fitchett, D. H., Husain, M., & Cherney, D. Z. I. (2016) · Circulation · doi:10.1161/circulationaha.116.021887 · Cited by 1,376
Self-citationPathophysiology of Progressive Nephropathies
Remuzzi, G., & Bertani, T. (1998) · New England Journal of Medicine · doi:10.1056/nejm199811123392007 · Cited by 1,258
CV Protection in the EMPA-REG OUTCOME Trial: A “Thrifty Substrate” Hypothesis
Ferrannini, E., Mark, M., & Mayoux, E. (2016) · Diabetes Care · doi:10.2337/dc16-0330 · Cited by 975
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Effects of SGLT2 Inhibitors on Kidney and Cardiovascular Function
Vallon, V., & Verma, S. (2020) · Annual Review of Physiology · doi:10.1146/annurev-physiol-031620-095920 · Cited by 556
Finerenone with empagliflozin in chronic kidney disease and type 2 diabetes
Agarwal, R., Green, J. B., Heerspink, H. J. L., Mann, J. F. E., McGill, J. B., Mottl, A. K., Rosenstock, J., Rossing, P., Vaduganathan, M., Brinker, M., et al. (2025) · New England Journal of Medicine · doi:10.1056/nejmoa2410659 · Cited by 319
Self-citationZannad, F. M., Ferreira, J. P., Butler, J., Filippatos, G. S., Januzzi, J. L., Sumin, M., Zwick, M., Saadati, M., Pocock, S., Sattar, N. A., et al. (2022) · European Heart Journal · doi:10.1093/eurheartj/ehac495 · Cited by 202
Apperloo, E. M., Neuen, B. L., Fletcher, R. A., Jongs, N., Anker, S. D., Bhatt, D. L., Butler, J., Cherney, D. Z. I., Herrington, W. G., Inzucchi, S. E., et al. (2024) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(24)00155-4 · Cited by 180
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Metadata
- 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)
- 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
- hybrid
- doi.org
- 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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