280 - Changes in oxidative RNA and DNA modifications following one-week treatment with sevelamer: two randomized, placebo-controlled trials

Abstract

Introduction Sevelamer is a phosphate-binding drug used in the treatment of chronic kidney disease. Studies have shown that sevelamer reduces oxidative stress measured as 8-isoprostanes. Oxidative RNA modifications are associated with increased cardiovascular as well as all-cause mortality in patients with type 2 diabetes (T2D) and the aim of this study was to evaluate the effect of sevelamer on oxidative RNA and DNA modifications in patients with T2D. Methods Two randomized, double-blinded, placebo-controlled trials were conducted evaluating changes in RNA and DNA oxidation, measured as urinary excretion of 8-oxo-7,8-dihydro-guanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2’-deoxyguanosine (8-oxodG), following one-week treatment with sevelamer (1.600 mg three times per day) in patients with T2D (n=20 (sevelamer) and n=10 (placebo)) and healthy subjects (n=12 (sevelamer) and n=8 (placebo)). Urine 8-oxoGuo and 8-oxodG were determined using ultra-performance liquid chromatography tandem mass spectrometry. Results Patients with T2D presented a tendency towards higher baseline levels of 8-oxoGuo/creatinine compared to healthy subjects (median (interquartile range): 1.59(1.35;1.78) vs. 1.33(1.20;1.55) nmol/mmol, P=0.05), but not 8-oxodG/creatinine. 8-oxoGuo/creatinine was significantly reduced by sevelamer treatment in T2D patients (1.53(1.34;1.82) vs. 1.33(1.26;1.62) nmol/mmol, P=0.02) and a similar tendency was seen for 8-oxodG/creatinine (1.00(0.82;1.35) vs. 0.95(0.80;1.16), P=0.09). Compared to placebo, a trend towards reduction in 8-oxoGuo/creatinine following treatment with sevelamer was observed in patients with T2D (Δ8-oxoGuo/creatinine: -0.04(-0.24; 0.01) vs. 0.02(-0.07;0.06) nmol/mmol, P=0.11), whereas no difference in 8-oxodG was evident. We found no significant changes in 8-oxoGuo or 8-oxodG within the group of healthy subjects. At baseline, a significant correlation between 8-oxoGuo and TNFα among patients with T2D was observed (r=0.49 (95% confidence interval: 0.16;0.72), P Conclusion One-week treatment with sevelamer reduced oxidative RNA modifications in a group of T2D patients. This combined with sevelamer’s glucose and low-density lipoprotein cholesterol-lowering effects may suggest a cardiovascular disease-reducing potential for sevelamer in patients with T2D.