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Abstract: TH-PO170

Canagliflozin Treatment Impact on Collagen Type III Turnover Is Associated with a Reduced Mortality Risk in CANVAS

Session Information

Category: Diabetic Kidney Disease

  • 702 Diabetic Kidney Disease: Clinical

Authors

  • Genovese, Federica, Nordic Bioscience, Herlev, Herlev , Denmark
  • Rasmussen, Daniel Guldager Kring, Nordic Bioscience, Herlev, Herlev , Denmark
  • Neal, Bruce, The George Institute for Global Health, Sydney, New South Wales, Australia
  • Karsdal, Morten Asser, Nordic Bioscience, Herlev, Herlev , Denmark
  • Hansen, Michael K., Janssen Research and Development LLC, Spring House, Pennsylvania, United States
Background

The precise mechanism underlying the beneficial effects of SGLT2 inhibition remains uncertain; however, it has been suggested that it may be related to a decrease in inflammation and tissue fibrosis. Collagen type III (COL III) is one of the major constituents of the extracellular matrix in different organs and is markedly upregulated in fibrotic conditions. In this study, we examined the effect of canagliflozin treatment on biomarkers of COL III turnover in the CANVAS trial.

Methods

Fragments reflecting COL III formation (PRO-C3) and degradation fragments of both cross-linked (CTX-III) or non-cross-linked COL III (C3M) were assessed with ELISA in plasma (n=2141, 1549, 2155, respectively). The change in biomarker levels from baseline to year 3 were investigated in plasma samples from both placebo (PBO)- and canagliflozin (CANA)-treated patients using a linear model. Investigated outcomes included all-cause mortality (n=116). Hazard ratios (HR) with 95% CI represent a comparison of the 75th percentile versus 25th percentile. The p-values presented are derived from a Wald test.

Results

At follow-up,PRO-C3 was significantly lower (p<0.0001; Figure 1A) and CTX-III was significantly higher in CANA-treated patients compared to PBO-treated patients (p=0.0002; Figure 1B). There was no impact on C3M (p=0.06, not shown).
In the entire cohort, an increase in PRO-C3 was significantly associated with all-cause mortality (HR [95% CI] = 1.07 [1.05-1.10], p<0.0001). The prognostic ability of an increase in PRO-C3 to predict all-cause mortalitywas significantly higher in the PBO-treated patients than in the CANA-treated patients (1.28 [1.11-1.47] vs 1.07 [1.04-1.10], p=0.04).

Conclusion

The observed decrease in fragments reflecting COL III formation, as well as the increase in cross-linked COL III degradation fragments following canagliflozin treatment may reflect the anticipated potential anti-fibrotic effect of the treatment. An increase in COL III formation was associated to an increase in the risk of all-cause mortality.

Funding

  • Commercial Support – Janssen and Nordic Bioscience