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Mechanisms of action of the sodium‐glucose cotransporter‐2 (SGLT2) inhibitor canagliflozin on tubular inflammation and damage: A post hoc mediation analysis of the CANVAS trial

AIMS: To test the hypothesis that the reduction in urinary kidney injury molecule‐1 (KIM‐1) observed with the sodium‐glucose cotransporter‐2 (SGLT2) inhibitor canagliflozin is mediated through its effects on urine albumin to creatinine ratio (UACR) and monocyte chemoattractant protein‐1 (MCP‐1) by a...

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Autores principales: Sen, Taha, Koshino, Akihiko, Neal, Bruce, Bijlsma, Maarten J., Arnott, Clare, Li, Jingwei, Hansen, Michael K., Ix, Joachim H., Heerspink, Hiddo J. L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Blackwell Publishing Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9546391/
https://www.ncbi.nlm.nih.gov/pubmed/35635326
http://dx.doi.org/10.1111/dom.14779
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author Sen, Taha
Koshino, Akihiko
Neal, Bruce
Bijlsma, Maarten J.
Arnott, Clare
Li, Jingwei
Hansen, Michael K.
Ix, Joachim H.
Heerspink, Hiddo J. L.
author_facet Sen, Taha
Koshino, Akihiko
Neal, Bruce
Bijlsma, Maarten J.
Arnott, Clare
Li, Jingwei
Hansen, Michael K.
Ix, Joachim H.
Heerspink, Hiddo J. L.
author_sort Sen, Taha
collection PubMed
description AIMS: To test the hypothesis that the reduction in urinary kidney injury molecule‐1 (KIM‐1) observed with the sodium‐glucose cotransporter‐2 (SGLT2) inhibitor canagliflozin is mediated through its effects on urine albumin to creatinine ratio (UACR) and monocyte chemoattractant protein‐1 (MCP‐1) by assessing the proportion of the effect of canagliflozin on KIM‐1 that is mediated through its effects on MCP‐1 and UACR in patients with type 2 diabetes and albuminuric kidney disease. MATERIAL AND METHODS: We measured KIM‐1 and MCP‐1 levels in urine samples from the CANVAS trial at baseline and Week 52 with the Mesoscale QuickPlex SQ 120 platform. KIM‐1 and MCP‐1 were standardized by urinary creatinine (Cr). The proportion of the effect of canagliflozin that is mediated through UACR and MCP‐1/Cr on KIM‐1/Cr was estimated with G‐computation. RESULTS: In total, 763 patients with micro‐ or macroalbuminuria (17.6% of the total cohort) were included. Baseline characteristics were well balanced between the canagliflozin and placebo group. At Year 1, canagliflozin compared to placebo reduced UACR, MCP‐1/Cr and KIM‐1/Cr by 40.4% (95% CI 31.0, 48.4), 18.1% (95% CI 8.9, 26.4) and 30.9% (95% CI 23.0, 38.0), respectively. The proportion of the effect of canagliflozin on KIM‐1/Cr mediated by its effect on UACR and in turn on MCP‐1/Cr was 15.2% (95% CI 9.4, 24.5). CONCLUSION: Canagliflozin reduces urinary KIM‐1, suggesting decreased tubular damage. This effect was partly mediated through a reduction in MCP‐1, indicative of reduced tubular inflammation, which was in turn mediated by a reduction in UACR. This post hoc analysis suggests that urinary albumin leakage may lead to tubular inflammation and induction of injury, and provide mechanistic insight for how canagliflozin may ameliorate tubular damage, but further research is required to confirm these findings.
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spelling pubmed-95463912022-10-14 Mechanisms of action of the sodium‐glucose cotransporter‐2 (SGLT2) inhibitor canagliflozin on tubular inflammation and damage: A post hoc mediation analysis of the CANVAS trial Sen, Taha Koshino, Akihiko Neal, Bruce Bijlsma, Maarten J. Arnott, Clare Li, Jingwei Hansen, Michael K. Ix, Joachim H. Heerspink, Hiddo J. L. Diabetes Obes Metab Original Articles AIMS: To test the hypothesis that the reduction in urinary kidney injury molecule‐1 (KIM‐1) observed with the sodium‐glucose cotransporter‐2 (SGLT2) inhibitor canagliflozin is mediated through its effects on urine albumin to creatinine ratio (UACR) and monocyte chemoattractant protein‐1 (MCP‐1) by assessing the proportion of the effect of canagliflozin on KIM‐1 that is mediated through its effects on MCP‐1 and UACR in patients with type 2 diabetes and albuminuric kidney disease. MATERIAL AND METHODS: We measured KIM‐1 and MCP‐1 levels in urine samples from the CANVAS trial at baseline and Week 52 with the Mesoscale QuickPlex SQ 120 platform. KIM‐1 and MCP‐1 were standardized by urinary creatinine (Cr). The proportion of the effect of canagliflozin that is mediated through UACR and MCP‐1/Cr on KIM‐1/Cr was estimated with G‐computation. RESULTS: In total, 763 patients with micro‐ or macroalbuminuria (17.6% of the total cohort) were included. Baseline characteristics were well balanced between the canagliflozin and placebo group. At Year 1, canagliflozin compared to placebo reduced UACR, MCP‐1/Cr and KIM‐1/Cr by 40.4% (95% CI 31.0, 48.4), 18.1% (95% CI 8.9, 26.4) and 30.9% (95% CI 23.0, 38.0), respectively. The proportion of the effect of canagliflozin on KIM‐1/Cr mediated by its effect on UACR and in turn on MCP‐1/Cr was 15.2% (95% CI 9.4, 24.5). CONCLUSION: Canagliflozin reduces urinary KIM‐1, suggesting decreased tubular damage. This effect was partly mediated through a reduction in MCP‐1, indicative of reduced tubular inflammation, which was in turn mediated by a reduction in UACR. This post hoc analysis suggests that urinary albumin leakage may lead to tubular inflammation and induction of injury, and provide mechanistic insight for how canagliflozin may ameliorate tubular damage, but further research is required to confirm these findings. Blackwell Publishing Ltd 2022-06-28 2022-10 /pmc/articles/PMC9546391/ /pubmed/35635326 http://dx.doi.org/10.1111/dom.14779 Text en © 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Articles
Sen, Taha
Koshino, Akihiko
Neal, Bruce
Bijlsma, Maarten J.
Arnott, Clare
Li, Jingwei
Hansen, Michael K.
Ix, Joachim H.
Heerspink, Hiddo J. L.
Mechanisms of action of the sodium‐glucose cotransporter‐2 (SGLT2) inhibitor canagliflozin on tubular inflammation and damage: A post hoc mediation analysis of the CANVAS trial
title Mechanisms of action of the sodium‐glucose cotransporter‐2 (SGLT2) inhibitor canagliflozin on tubular inflammation and damage: A post hoc mediation analysis of the CANVAS trial
title_full Mechanisms of action of the sodium‐glucose cotransporter‐2 (SGLT2) inhibitor canagliflozin on tubular inflammation and damage: A post hoc mediation analysis of the CANVAS trial
title_fullStr Mechanisms of action of the sodium‐glucose cotransporter‐2 (SGLT2) inhibitor canagliflozin on tubular inflammation and damage: A post hoc mediation analysis of the CANVAS trial
title_full_unstemmed Mechanisms of action of the sodium‐glucose cotransporter‐2 (SGLT2) inhibitor canagliflozin on tubular inflammation and damage: A post hoc mediation analysis of the CANVAS trial
title_short Mechanisms of action of the sodium‐glucose cotransporter‐2 (SGLT2) inhibitor canagliflozin on tubular inflammation and damage: A post hoc mediation analysis of the CANVAS trial
title_sort mechanisms of action of the sodium‐glucose cotransporter‐2 (sglt2) inhibitor canagliflozin on tubular inflammation and damage: a post hoc mediation analysis of the canvas trial
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9546391/
https://www.ncbi.nlm.nih.gov/pubmed/35635326
http://dx.doi.org/10.1111/dom.14779
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