Retrospective cohort study of the efficacy and safety of dabigatran: real-life dabigatran use including very low-dose 75 mg twice daily administration.

BACKGROUND: Dabigatran is a direct thrombin inhibitor and an anticoagulant that is prescribed to prevent ischemic stroke and systemic embolism in non-valvular atrial fibrillation. Dabigatran (150 mg twice daily) is non-inferior to warfarin for the prevention of stroke and systemic embolism. A dose reduction to 110 mg twice daily should be considered for patients with decreased renal function, elderly patients, and those with a history of gastrointestinal bleeding. A small number of patients are prescribed 75 mg twice daily; however, excessive dose reduction below that indicated on the package insert may decrease the effectiveness of dabigatran. In this study, we investigated the incidence of thromboembolic events and hemorrhagic complications in patients receiving different doses of dabigatran, including patients receiving the very low-dose of 75 mg twice daily. METHODS: Five hospitals in Meguro and Setagaya areas of Tokyo were included in this study. The subjects were patients receiving dabigatran in the hospitals from March 2011 to February 2014. Thromboembolic events (stroke, systemic embolism, and transient cerebral ischemic attack) and hemorrhagic complications occurring before December 2014 were retrospectively evaluated. RESULTS: A total of 701 subjects received dabigatran during the study period: 187 patients (26.7%) received 150 mg twice daily (normal dose), 488 patients (69.6%) received 110 mg twice daily (low-dose), and 26 patients (3.7%) received 75 mg twice daily (very low-dose). Thromboembolism occurred in 4 (2.1%), 11 (2.3%), and 3 patients (11.5%), in the normal dose, low-dose, and very low-dose groups, respectively. The odds ratio of the 75 mg dose to the 150 and 110 mg doses was 5.73 (95% CI, 1.55-21.2; p = 0.009), and the incidence with the 75 mg dose was higher than that with the other doses. Although the number of events was limited, it should be noted that 3 patients in the very low-dose group had thromboembolic events. CONCLUSIONS: The results suggest that sufficient anticoagulation efficacy may not be maintained when the dabigatran dose is excessively reduced to 75 mg twice daily.

Green and black tea suppress hyperglycemia and insulin resistance by retaining the expression of glucose transporter 4 in muscle of high-fat diet-fed C57BL/6J mice.

To investigate the preventive effects of tea on hyperglycemia and insulin resistance, male C57BL/6J mice were given a high-fat diet containing 29% lard and also green or black tea ad libitum for 14 weeks. Both teas suppressed body weight gain and deposition of white adipose tissue caused by the diet. In addition, they improved hyperglycemia and glucose intolerance by stimulating glucose uptake activity accompanied by the translocation of glucose transporter (GLUT) 4 to the plasma membrane in muscle. Long-term consumption of the high-fat diet reduced levels of insulin receptor ß-subunit, GLUT4 and AMP-activated protein kinase α in muscle, and green and black tea suppressed these decreases. The results strongly suggest that green and black tea suppress high-fat diet-evoked hyperglycemia and insulin resistance by retaining the level of GLUT4 and increasing the level of GLUT4 on the plasma membrane in muscle.

Tea catechins modulate the glucose transport system in 3T3-L1 adipocytes.

In this study, we investigated the effects of tea catechins on the translocation of glucose transporter (GLUT) 4 in 3T3-L1 adipocytes. We found that the ethyl acetate fraction of green tea extract, containing abundant catechins, most decreased insulin-induced glucose uptake activity in 3T3-L1 cells. When the cells were treated with 50 µM catechins in the absence or presence of insulin for 30 min, nongallate-type catechins increased glucose uptake activity without insulin, whereas gallate-type catechins decreased insulin-induced glucose uptake activity. (-)-Epicatechin (EC) and (-)-epigallocatechin (EGC), nongallate-type catechins, increased glucose uptake activity in the dose- and time-dependent manner, whereas (-)-catechin 3-gallate (Cg) and (-)-epigallocatechin 3-gallate (EGCg), gallate-type catechins, decreased insulin-induced glucose uptake activity in the dose- and time-dependent manner. When the cells were treated with 50 µM catechins for 30 min, EC and EGC promoted GLUT4 translocation, whereas Cg and EGCg decreased the insulin-induced translocation in the cells. EC and EGC increased phosphorylation of PKCλ/ζ without phosphorylation of insulin receptor (IR) and Akt. Wortmannin and LY294002, inhibitors for phosphatidylinositol 3'-kinase (PI3K), decreased EC- and EGC-induced glucose uptake activity in the cells. Cg and EGCg decreased phosphorylation of PKCλ/ζ in the presence of insulin without affecting insulin-induced phosphorylation of IR, and Akt. Therefore, EC and EGC promote the translocation of GLUT4 through activation of PI3K, and Cg and EGCg inhibit insulin-induced translocation of GLUT4 by the insulin signaling pathway in 3T3-L1 cells.

Tea catechin suppresses adipocyte differentiation accompanied by down-regulation of PPARgamma2 and C/EBPalpha in 3T3-L1 cells.

Obesity is a serious health problem, and its prevention is promoted through life style including diet and exercise. In this study, we investigated the suppressive effects of tea catechin on the differentiation of 3T3-L1 preadipocytes to adipocytes. (-)-Catechin 3-gallate (CG), (-)-epigallocatechin (EGC), (-)-epicatechin 3-gallate, and (-)-epigallocatechin 3-gallate at 5 muM suppressed intracellular lipid accumulation. The suppressive effects of CG and EGC were stronger than the others, and CG and EGC also suppressed the activity of glycerol-3-phosphate dehydrogenase as a differentiation marker. These catechins inhibited the expression of peroxisome proliferator-activated receptor (PPAR) gamma2 and CCAAT/enhancer-binding protein (C/EBP) alpha, both of which act as key transcription factors at an early stage of differentiation, followed by the expression of glucose transporter (GLUT) 4 at a later stage. In addition, the catechins did not affect the phosphorylation status of the insulin signal pathway. Thus, catechin suppressed adipocyte differentiation accompanied by the down-regulation of PPARgamma2, C/EBPalpha, and GLUT4. These results suggest that tea catechin prevents obesity through the suppression of adipocyte differentiation.