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• W4213306883 abstract "The CANVAS trial investigated the effects of canagliflozin in patients with type 2 diabetes 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. Canagliflozin treatment has shown promising findings in both patients with and without diabetes, indicating that it has beneficial effects besides lowering circulating glucose levels. One of the beneficial effects of canagliflozin is proposed to be through reducing inflammation and fibrosis. In the current study, we investigated the impact of canagliflozin treatment on the disease activity biomarkers of COL III formation (PRO-C3) and degradation (CTX-III) in the CANVAS trial. 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 CTX-III ELISA, detecting a cross-linked fragment released during degradation. The analysis included patients who had paired baseline and year 3 plasma samples available from the CANVAS study (PRO-C3 n=2160, CTX-III n=2136). Ordinary least squares models with restricted cubic splines (with 3 knots) were used to describe a potential non-linear relationship between baseline levels and follow-up levels of the biomarkers. The models included treatment interactions, allowing the curves to differ in level and shape between treatments. Treatment contrast by baseline levels were estimated and plotted with 95% CI. Using likelihood ratio tests (LRT) the interaction models were compared to simpler models specifying only a level shift in follow-up measurement between the treatment arms. The analysis was performed in R (R Core Team (2020)). When looking at the effect of treatment on PRO-C3 and CTX-III conditional on the baseline levels of the biomarkers, we found that treatment with canagliflozin significantly impacted the levels of both biomarkers. The effect became more pronounced with increasing biomarker levels at baseline both for PRO-C3 (LRT = 88.2, p<0.0001; Figure A) and CTX-III (LRT = 195.1, p<0.0001; Figure B). To identify patients who on average had a decrease in biomarker levels, we found the baseline level at which the confidence interval of the curves for the canagliflozin and placebo arm no longer overlapped. For PRO-C3 the cut-point was 15.9 ng/mL, and for CTX-III the cut-point was 13.6 ng/mL. We observed a marked impact of canagliflozin treatment on levels of both PRO-C3 and CTX-III, indicating that canagliflozin affects COL III turnover. The impact of treatment increased with increasing levels of biomarker levels at baseline, indicating that the biomarkers identify patients with high disease activity where the potential anti-fibrotic effect of canagliflozin becomes more prominent. Further research is necessary to understand the mechanism for canagliflozin’s effects on fibrosis." @default.
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• W4213306883 date "2022-02-01" @default.
• W4213306883 modified "2023-09-28" @default.
• W4213306883 title "POS-392 CANAGLIFLOZIN TREATMENT IMPACTS COLLAGEN TYPE III DEGRADATION AND FORMATION IN THE CANAGLIFLOZIN CARDIOVASCULAR ASSESSMENT STUDY (CANVAS)" @default.
• W4213306883 doi "https://doi.org/10.1016/j.ekir.2022.01.414" @default.
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