PMID- 35635326
OWN - NLM
STAT- MEDLINE
DCOM- 20220908
LR  - 20221015
IS  - 1463-1326 (Electronic)
IS  - 1462-8902 (Print)
IS  - 1462-8902 (Linking)
VI  - 24
IP  - 10
DP  - 2022 Oct
TI  - 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.
PG  - 1950-1956
LID - 10.1111/dom.14779 [doi]
AB  - 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.
CI  - (c) 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & 
      Sons Ltd.
FAU - Sen, Taha
AU  - Sen T
AUID- ORCID: 0000-0001-6359-2945
AD  - Department of Clinical Pharmacy and Pharmacology, University of Groningen, 
      University Medical Centre Groningen, Groningen, The Netherlands.
FAU - Koshino, Akihiko
AU  - Koshino A
AUID- ORCID: 0000-0002-9432-2427
AD  - Department of Clinical Pharmacy and Pharmacology, University of Groningen, 
      University Medical Centre Groningen, Groningen, The Netherlands.
AD  - Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, 
      Japan.
FAU - Neal, Bruce
AU  - Neal B
AUID- ORCID: 0000-0002-0490-7465
AD  - The George Institute for Global Health, UNSW Sydney, Sydney, New South Wales, 
      Australia.
FAU - Bijlsma, Maarten J
AU  - Bijlsma MJ
AUID- ORCID: 0000-0002-7330-6006
AD  - Unit PharmacoTherapy, Epidemiology, and Economics (PTEE), Groningen Research 
      Institute of Pharmacy, University of Groningen, Groningen, The Netherlands.
FAU - Arnott, Clare
AU  - Arnott C
AUID- ORCID: 0000-0001-9370-9913
AD  - The George Institute for Global Health, UNSW Sydney, Sydney, New South Wales, 
      Australia.
FAU - Li, Jingwei
AU  - Li J
AUID- ORCID: 0000-0003-1638-2317
AD  - The George Institute for Global Health, UNSW Sydney, Sydney, New South Wales, 
      Australia.
FAU - Hansen, Michael K
AU  - Hansen MK
AD  - Janssen Research & Development, LLC, Spring House, Pennsylvania, USA.
FAU - Ix, Joachim H
AU  - Ix JH
AUID- ORCID: 0000-0002-8084-9869
AD  - Nephrology Section, Veterans Affairs San Diego Healthcare System, La Jolla, 
      California, USA.
AD  - Division of Nephrology-Hypertension, Department of Medicine, University of 
      California San Diego, San Diego, California, USA.
FAU - Heerspink, Hiddo J L
AU  - Heerspink HJL
AUID- ORCID: 0000-0002-3126-3730
AD  - Department of Clinical Pharmacy and Pharmacology, University of Groningen, 
      University Medical Centre Groningen, Groningen, The Netherlands.
AD  - The George Institute for Global Health, UNSW Sydney, Sydney, New South Wales, 
      Australia.
LA  - eng
PT  - Clinical Trial
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220628
PL  - England
TA  - Diabetes Obes Metab
JT  - Diabetes, obesity & metabolism
JID - 100883645
RN  - 0 (Albumins)
RN  - 0 (Sodium-Glucose Transporter 2)
RN  - 0 (Sodium-Glucose Transporter 2 Inhibitors)
RN  - 0SAC974Z85 (Canagliflozin)
RN  - 9NEZ333N27 (Sodium)
RN  - AYI8EX34EU (Creatinine)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Albumins
MH  - Canagliflozin/therapeutic use
MH  - Creatinine/urine
MH  - *Diabetes Mellitus, Type 2/chemically induced/complications/drug therapy
MH  - Glucose/therapeutic use
MH  - Humans
MH  - Inflammation/chemically induced/drug therapy
MH  - Mediation Analysis
MH  - Sodium
MH  - Sodium-Glucose Transporter 2
MH  - *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use
PMC - PMC9546391
OTO - NOTNLM
OT  - CANVAS
OT  - KIM-1
OT  - MCP-1
OT  - albuminuria
OT  - canagliflozin
OT  - type 2 diabetes
COIS- T. Sen, A. Koshino, M.J. Bijlsma and J. Li have nothing to disclose. B. Neal is 
      an employee of the George Institute for Global Health and is supported by a 
      National Health and Medical Research Council Investigator Grant. His institution 
      has received fees for his roles in advisory boards, steering committees or 
      scientific presentations from AstraZeneca, Janssen, Merck and Mundipharma. C. 
      Arnott is an employee of the George Institute for Global Health and is supported 
      by an NSW Health Early- and Mid-Career Researcher Grant and a Medical Research 
      Future Fund Investigator Grant. M.K. Hansen is an employee of Janssen Research & 
      Development, LLC. J.H. Ix is serving on the National Academy of Medicine panel 
      "Review of the Dietary Reference Intakes for Sodium and Potassium" and is 
      receiving research grant support from the National Institute of Diabetes and 
      Digestive and Kidney Diseases, the National Heart, Lung, and Blood Institute, and 
      the American Heart Association. H.J.L. Heerspink has served as a consultant for 
      AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, CSL Behring, Dimerix, 
      Eli-Lilly, Gilead, Goldfinch, Janssen, Merck, Novo Nordisk and Travere 
      Pharmaceuticals, and has received grant support from AbbVie, AstraZeneca, 
      Boehringer Ingelheim, Janssen and Novo Nordisk.
EDAT- 2022/06/01 06:00
MHDA- 2022/09/09 06:00
PMCR- 2022/10/07
CRDT- 2022/05/31 12:24
PHST- 2022/05/09 00:00 [revised]
PHST- 2022/03/16 00:00 [received]
PHST- 2022/05/25 00:00 [accepted]
PHST- 2022/06/01 06:00 [pubmed]
PHST- 2022/09/09 06:00 [medline]
PHST- 2022/05/31 12:24 [entrez]
PHST- 2022/10/07 00:00 [pmc-release]
AID - DOM14779 [pii]
AID - 10.1111/dom.14779 [doi]
PST - ppublish
SO  - Diabetes Obes Metab. 2022 Oct;24(10):1950-1956. doi: 10.1111/dom.14779. Epub 2022 
      Jun 28.