TY - JOUR
T1 - Effects of the SGLT2 inhibitor canagliflozin on plasma biomarkers TNFR-1, TNFR-2 and KIM-1 in the CANVAS trial
AU - Sen, Taha
AU - Li, Jingwei
AU - Neuen, Brendon L.
AU - Neal, Bruce
AU - Arnott, Clare
AU - Parikh, Chirag R.
AU - Coca, Steven G.
AU - Perkovic, Vlado
AU - Mahaffey, Kenneth W.
AU - Yavin, Yshai
AU - Rosenthal, Norman
AU - Hansen, Michael K.
AU - Heerspink, Hiddo J.L.
N1 - Funding Information:
SGC has received fees for advisory boards or steering committee roles for RenalytixAI, CHF Solutions, Bayer, Boehringer Ingelheim, Takeda, Relypsa, Quark, inRegen and Akebia; owns equity in RenalytixAI; and receives salary and research support from RenalytixAI and inRegen, and from the following grants from the NIH: U01DK106962, R01DK115562, R01HL85757, R01DK112258, U01OH011326 and R01DK126477.
Funding Information:
The CANVAS trial and biomarker measurements were funded by Janssen Research & Development. The CANVAS trial was done as a collaboration between the funder, an academic steering committee and an academic research organisation (George Clinical). The funder was involved in the study design, data collection, data analysis, data interpretation and writing of the report.
Funding Information:
BLN is supported by an Australian National Health and Medical Research Council (NHMRC) Postgraduate Scholarship and a University Postgraduate Award from the University of New South Wales. He has received travel support from Janssen and consultancy fees from Bayer with all honoraria paid to his institution.
Funding Information:
HJLH is supported by a VIDI (917.15.306) grant from the Netherlands Organisation for Scientific Research and has served as a consultant for AbbVie, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, CSL Pharma, Fresenius, Gilead, Janssen, Merck, Mundipharma, Mitsubishi Tanabe and Retrophin; and has received grant support from AbbVie, AstraZeneca, Boehringer Ingelheim and Janssen.
Funding Information:
CA is an employee of the George Institute for Global Health and is supported by an NSW Health EMCR Grant and an MRFF Investigator Grant.
Funding Information:
CRP is on the advisory board for RenalytixAI, the DSMB committee for Genfit, and is supported by National Institutes of Health (NIH) grants R01HL85757, U01DK106962 and UH3DK114866.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/10
Y1 - 2021/10
N2 - Aims/hypothesis: Higher plasma concentrations of tumour necrosis factor receptor (TNFR)-1, TNFR-2 and kidney injury molecule-1 (KIM-1) have been found to be associated with higher risk of kidney failure in individuals with type 2 diabetes in previous studies. Whether drugs can reduce these biomarkers is not well established. We measured these biomarkers in samples of the CANVAS study and examined the effect of the sodium–glucose cotransporter 2 inhibitor canagliflozin on these biomarkers and assessed whether the early change in these biomarkers predict cardiovascular and kidney outcomes in individuals with type 2 diabetes in the CANagliflozin cardioVascular Assessment Study (CANVAS). Methods: Biomarkers were measured with immunoassays (proprietary multiplex assay performed by RenalytixAI, New York, NY, USA) at baseline and years 1, 3 and 6. Mixed-effects models for repeated measures assessed the effect of canagliflozin vs placebo on the biomarkers. Associations of baseline levels and the early change (baseline to year 1) for each biomarker with the kidney outcome were assessed using multivariable-adjusted Cox regression. Results: In total, 3523/4330 (81.4%) of the CANVAS participants had available samples at baseline. Each doubling in baseline TNFR-1, TNFR-2 and KIM-1 was associated with a higher risk of kidney outcomes, with corresponding HRs of 3.7 (95% CI 2.3, 6.1; p < 0.01), 2.7 (95% CI 2.0, 3.6; p < 0.01) and 1.5 (95% CI 1.2, 1.8; p < 0.01), respectively. Canagliflozin reduced the level of the plasma biomarkers with differences in TNFR-1, TNFR-2 and KIM-1 between canagliflozin and placebo during follow-up of 2.8% (95% CI 3.4%, 1.3%; p < 0.01), 1.9% (95% CI 3.5%, 0.2%; p = 0.03) and 26.7% (95% CI 30.7%, 22.7%; p < 0.01), respectively. Within the canagliflozin treatment group, each 10% reduction in TNFR-1 and TNFR-2 at year 1 was associated with a lower risk of the kidney outcome (HR 0.8 [95% CI 0.7, 1.0; p = 0.02] and 0.9 [95% CI 0.9, 1.0; p < 0.01] respectively), independent of other patient characteristics. The baseline and 1 year change in biomarkers did not associate with cardiovascular or heart failure outcomes. Conclusions/interpretation: Canagliflozin decreased KIM-1 and modestly reduced TNFR-1 and TNFR-2 compared with placebo in individuals with type 2 diabetes in CANVAS. Early decreases in TNFR-1 and TNFR-2 during canagliflozin treatment were independently associated with a lower risk of kidney disease progression, suggesting that TNFR-1 and TNFR-2 have the potential to be pharmacodynamic markers of response to canagliflozin. Graphical abstract: [Figure not available: see fulltext.]
AB - Aims/hypothesis: Higher plasma concentrations of tumour necrosis factor receptor (TNFR)-1, TNFR-2 and kidney injury molecule-1 (KIM-1) have been found to be associated with higher risk of kidney failure in individuals with type 2 diabetes in previous studies. Whether drugs can reduce these biomarkers is not well established. We measured these biomarkers in samples of the CANVAS study and examined the effect of the sodium–glucose cotransporter 2 inhibitor canagliflozin on these biomarkers and assessed whether the early change in these biomarkers predict cardiovascular and kidney outcomes in individuals with type 2 diabetes in the CANagliflozin cardioVascular Assessment Study (CANVAS). Methods: Biomarkers were measured with immunoassays (proprietary multiplex assay performed by RenalytixAI, New York, NY, USA) at baseline and years 1, 3 and 6. Mixed-effects models for repeated measures assessed the effect of canagliflozin vs placebo on the biomarkers. Associations of baseline levels and the early change (baseline to year 1) for each biomarker with the kidney outcome were assessed using multivariable-adjusted Cox regression. Results: In total, 3523/4330 (81.4%) of the CANVAS participants had available samples at baseline. Each doubling in baseline TNFR-1, TNFR-2 and KIM-1 was associated with a higher risk of kidney outcomes, with corresponding HRs of 3.7 (95% CI 2.3, 6.1; p < 0.01), 2.7 (95% CI 2.0, 3.6; p < 0.01) and 1.5 (95% CI 1.2, 1.8; p < 0.01), respectively. Canagliflozin reduced the level of the plasma biomarkers with differences in TNFR-1, TNFR-2 and KIM-1 between canagliflozin and placebo during follow-up of 2.8% (95% CI 3.4%, 1.3%; p < 0.01), 1.9% (95% CI 3.5%, 0.2%; p = 0.03) and 26.7% (95% CI 30.7%, 22.7%; p < 0.01), respectively. Within the canagliflozin treatment group, each 10% reduction in TNFR-1 and TNFR-2 at year 1 was associated with a lower risk of the kidney outcome (HR 0.8 [95% CI 0.7, 1.0; p = 0.02] and 0.9 [95% CI 0.9, 1.0; p < 0.01] respectively), independent of other patient characteristics. The baseline and 1 year change in biomarkers did not associate with cardiovascular or heart failure outcomes. Conclusions/interpretation: Canagliflozin decreased KIM-1 and modestly reduced TNFR-1 and TNFR-2 compared with placebo in individuals with type 2 diabetes in CANVAS. Early decreases in TNFR-1 and TNFR-2 during canagliflozin treatment were independently associated with a lower risk of kidney disease progression, suggesting that TNFR-1 and TNFR-2 have the potential to be pharmacodynamic markers of response to canagliflozin. Graphical abstract: [Figure not available: see fulltext.]
KW - Canagliflozin
KW - KIM-1
KW - Kidney and cardiovascular outcomes
KW - SGLT2 inhibitor
KW - TNFR-1
KW - TNFR-2
UR - http://www.scopus.com/inward/record.url?scp=85113144633&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85113144633&partnerID=8YFLogxK
U2 - 10.1007/s00125-021-05512-5
DO - 10.1007/s00125-021-05512-5
M3 - Article
C2 - 34415356
AN - SCOPUS:85113144633
SN - 0012-186X
VL - 64
SP - 2147
EP - 2158
JO - Diabetologia
JF - Diabetologia
IS - 10
ER -