Effects of the SGLT2 inhibitor canagliflozin on plasma biomarkers TNFR-1, TNFR-2 and KIM-1 in the CANVAS trial.

Details

• Personal Author:
  Arnott C ; Coca SG ; Hansen MK ; Heerspink HJL ; Li J ; Mahaffey KW ; Neal B ; Neuen BL ; Parikh CR ; Perkovic V ; Rosenthal N ; Sen T ; Yavin Y
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Biomarkers Blood Drug Therapy Hematologic Diseases Occupational Health Safety
• Keywords:
  Author Keywords: Canagliflozin; Kidney And Cardiovascular Outcomes; KIM-1; SGLT2 Inhibitor; TNFR-1; TNFR-2 Kidney Disorders; Kidneys; Biomarkers; Blood Sugar Disorders; Pharmacodynamics; Immunoassays; Medicinal Chemicals; Drug Therapy;
• ISSN:
  0012-186X
• Document Type:
  Text
• Funding:
  Cooperative Agreement
• Genre:
  Journal Article
• Place as Subject:
  California ; Maryland ; New York ; OSHA Region 2 ; OSHA Region 3 ; OSHA Region 9 ; Pennsylvania
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  64
• Issue:
  10
• NIOSHTIC Number:
  nn:20064790
• Citation:
  Diabetologia 2021 Oct; 64(10):2147-2158
• Contact Point Address:
  Hiddo J. L. Heerspink, Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, the Netherlands
• Email:
  h.j.lambers.heerspink@umcg.nl
• CAS Registry Number:
  Canagliflozin (CAS RN 842133-18-0)
• Federal Fiscal Year:
  2022
• Performing Organization:
  Icahn School of Medicine at Mount Sinai, New York
• Peer Reviewed:
  True
• Start Date:
  20170701
• Source Full Name:
  Diabetologia
• End Date:
  20200630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:263c4773207c83bf010deeb9a11c18e9a6021246412e5340bcce0b89bc4d14c18184754583f83dac880b6d02eef1965f09320eb24d8867f643dbff535b0d4bba
• Download URL:
  https://stacks.cdc.gov/view/cdc/249238/cdc_249238_DS1.pdf
• File Type:
  [PDF - 780.96 KB ]