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Plasma lipids affect dabigatran etexilate anticoagulation in rats with unbalanced diabetes mellitus
Alina Scridon1,2, Marcel Perian2, Alina MĂrginean2,3
1Laboratory of Functional Explorations, Center for Advanced Medical and Pharmaceutical Research, Tîrgu Mureş, Romania.
Insights
Diabetic rats showed a stronger anticoagulant response to dabigatran etexilate (DE). Plasma cholesterol levels, not just kidney function, significantly influenced this anticoagulation effect in diabetes.
Area of Science:
- Pharmacology
- Diabetology
- Nephrology
Background:
- Dabigatran etexilate (DE) offers similar stroke prevention in diabetic and non-diabetic patients.
- However, diabetic individuals do not experience the same reduction in major bleeding risk with DE.
- This necessitates an investigation into DE's anticoagulant response and its predictors in diabetes.
Purpose of the Study:
- To investigate the anticoagulant response to dabigatran etexilate (DE) in a diabetic rat model.
- To identify biological predictors of this response in diabetic conditions.
Main Methods:
- Experiments involved control and diabetic rats, with and without DE treatment.
- Dabigatran etexilate was administered daily for 12 weeks.
- Plasma glucose, lipids, creatinine, and diluted thrombin time (dTT) were measured.
Main Results:
- Diabetic rats exhibited significantly higher dTT, indicating intensified anticoagulation, even with similar DE intake.
- Creatinine clearance negatively correlated with dTT, while total cholesterol, LDL-C, and glucose positively correlated.
- Creatinine clearance, total cholesterol, and LDL-C were identified as independent predictors of dTT.
Conclusions:
- Diabetic rats show enhanced DE-induced anticoagulation, which is not solely due to kidney function changes.
- Plasma cholesterol levels significantly impact DE anticoagulation in diabetic settings.
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.
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