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Abstract: PO1003

Canagliflozin Treatment Reduces Formation and Increases Degradation of Collagen Type III in the Canagliflozin Cardiovascular Assessment Study (CANVAS)

Session Information

Category: Diabetic Kidney Disease

  • 602 Diabetic Kidney Disease: Clinical

Authors

  • Rasmussen, Daniel Guldager Kring, Nordic Bioscience, Herlev, Denmark
  • Jatkoe, Timothy, Janssen Research & Development, LLC., Raritan, New Jersey, United States
  • Sparding, Nadja, Nordic Bioscience, Herlev, Denmark
  • Møller, Alexandra L., Nordic Bioscience, Herlev, Denmark
  • Karsdal, Morten Asser, Nordic Bioscience, Herlev, Denmark
  • Rosenthal, Norm, Janssen Research & Development, LLC., Raritan, New Jersey, United States
  • Gutstein, David E., Janssen Research & Development, LLC., Spring House, Pennsylvania, United States
  • Neal, Bruce, The George Institute for Global Health, Sydney, Australia
  • Perkovic, Vlado, The George Institute for Global Health, Sydney, New South Wales, Australia
  • Mahaffey, Kenneth W., Stanford Center for Clinical Research, Department of Medicine, Stanford University School of Medicine, Stanford, California, United States
  • Genovese, Federica, Nordic Bioscience, Herlev, Denmark
  • Hansen, Michael K., Janssen Research & Development, LLC., Spring House, Pennsylvania, United States
Background

The CANVAS trial investigated the effects of canagliflozin in T2D patients at high risk of cardiovascular (CV) disease. Collagen type III (COL III) is one of the main components of the interstitial extracellular matrix that is significantly upregulated in fibrosis. In the current study, we investigated the impact of canagliflozin treatment on biomarkers of COL III formation (PRO-C3) and degradation (C3M) in the CANVAS trial.

Methods

COL III formation was assessed with the PRO-C3 enzyme-linked immunosorbent assay (ELISA), detecting the cleaved pro-peptide released upon deposition in the extracellular matrix. COL III degradation was assessed with the C3M ELISA, detecting a neo-epitope fragment released after MMP-9 mediated degradation. The change in biomarker measurements at year 3 from baseline were compared between placebo and canagliflozin in plasma (n=2156) and urine (n=2137) samples using a linear model to assess whether biomarker levels were significantly affected by treatment. Urine biomarker levels were corrected for urine creatinine.

Results

Treatment with canagliflozin compared to placebo resulted in significantly lower plasma PRO-C3 levels -0.52 ng/mL (p=0.0054; 95% CI: -0.88, -0.15), with mean levels rising in the placebo group (0.48 ng/mL) but remaining stable in the intervention group (-0.04 ng/mL). Urinary PRO-C3 levels were increased 293.19 ng/mmol (p<0.001; 95% CI: 158.87, 427.51), with mean levels increasing 24.23 ng/mmol in the placebo group and 317.42 ng/mmol in the intervention group. Urinary C3M levels were increased 833.01 ng/mmol (p<0.001; 95% CI: 481.27, 1184.74), with mean levels decreasing -337.71 ng/mmol in placebo and increasing 495.30 ng/mmol on treatment. There was no correlation between the change in plasma and urine PRO-C3 (r=0.07).

Conclusion

The reduction in PRO-C3 levels in plasma and the increase in urine C3M levels following treatment with canagliflozin suggest an anti-fibrotic effect of canagliflozin. Further research is necessary to understand the mechanism for canagliflozin’s effects on fibrosis.

Funding

  • Commercial Support