Plasma lipids affect dabigatran etexilate anticoagulation in rats with unbalanced diabetes mellitus

Background Dabigatran etexilate (DE) has similar stroke prevention efficacy in patients with and without diabetes mellitus (DM). However, the benefit of reducing major bleeding was not seen in diabetics. Thus, this study investigated anticoagulant responses to DE and the biological predictors of this response in a DM model. Methods Experiments were performed in six control (C), eight DE‐treated control (CD), five diabetic (D), and eight DE‐treated diabetic (DD) rats. Dabigatran etexilate (50 mg/kg/day) was administered in chow for 12 weeks. At the end of the study, plasma glucose, triglycerides, total cholesterol (TC), high‐density lipoprotein cholesterol, low‐density lipoprotein cholesterol (LDL‐C), and plasma creatinine were measured. Correlations were ascertained with the diluted thrombin time (dTT). Results When corrected for similar DE intake, dTT was significantly higher in DD than CD rats (P < 0.001). There was a significant negative correlation between creatinine clearance (CCr) and dTT (r = −0.91, P < 0.01) in DD rats. In addition, dTT was positively correlated with TC (r = 0.96, P < 0.01), LDL‐C (r = 0.75, P = 0.04), and glucose (r = 0.83, P = 0.02). In multiple regression analysis, CCr (r = −0.81, P = 0.01), TC (r = 0.93, P < 0.001), and LDL‐C (r = 0.74, P < 0.01) remained the only independent predictors of dTT. Conclusions The results show a significantly more intense DE‐induced anticoagulation in diabetic rats that does not seem to be solely related to altered kidney function, and demonstrate that plasma cholesterol can significantly affect DE anticoagulation in this setting. 摘要 背景 无论患者是否合并糖尿病(DM), 达比加群酯(Dabigatran etexilate, DE)预防脑卒中的疗效都相似。然而, 目前在糖尿病患者中还没有看到具有减少大出血的获益。因此, 这项研究在一个DM模型中调查了使用DE后的抗凝反应以及这种反应的生物学预测因子。 方法 这项实验将大鼠分为以下几组:对照组(control, C)6只、使用DE治疗的对照组8只(DE‐treated control, CD)、糖尿病组5只(diabetic, D)、使用DE治疗的糖尿病组8只(DE‐treated diabetic, DD)。大鼠使用混入DE(50 mg/kg/日)的饲料饲养了12周。研究结束时, 测定了血糖、甘油三酯、总胆固醇(total cholesterol, TC)、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇(low‐density lipoprotein cholesterol, LDL‐C)以及血浆肌酐。使用稀释凝血酶时间法(diluted thrombin time, dTT)来确定相关性。 结果 在校正相似的DE摄入量之后, 发现DD组大鼠的dTT显著高于CD组大鼠(P < 0.001)。在DD组大鼠中肌酐清除率(creatinine clearance, CCr)与dTT之间具有显著的负相关关系(r = −0.91, P < 0.01)。另外, dTT与TC(r = 0.96, P < 0.01)、LDL‐C(r = 0.75, P = 0.04)以及血糖(r = 0.83, P = 0.02)之间具有显著的正相关关系。多元回归分析后发现, 只有CCr(r = −0.81, P = 0.01)、TC(r = 0.93, P < 0.001)以及LDL‐C(r = 0.74, P < 0.01)仍然是dTT的独立预测因子。 结论 这项研究结果表明, 糖尿病大鼠使用DE诱导后出现了显著更强的抗凝作用, 这种结果看来似乎并不仅仅与肾功能的改变有关, 并且这项研究结果还证实了在这种环境下血浆胆固醇能够显著