Effect of weight change and metformin on fibrinolysis and the von Willebrand factor in obese nondiabetic subjects: the BIGPRO1 Study. Biguanides and the Prevention of the Risk of Obesity

OBJECTIVE: Insulin resistance is associated with hypofibrinolysis. Metformin has been shown to improve insulin sensitivity and fibrinolysis. Its action on fibrinolysis and the von Willebrand factor was evaluated in the Biguanides and the Prevention of the Risk of Obesity (BIGPRO)1 trial in nondiabetic men (n = 151) and women (n = 306) aged between 34 and 65 years with a central fat distribution and a mean BMI of 32.5 kg/m2. RESEARCH DESIGN AND METHODS: The subjects were randomly allocated to a 1-year treatment with metformin (850 mg b.i.d.) or placebo, in addition to diet and exercise recommendations. RESULTS: Plasminogen activator inhibitor 1 (PAI-1) activity and antigen decreased significantly but similarly by 30 and 40%, respectively, in both the placebo and the metformin groups. This decrease occurred mainly in subjects who lost weight. Metformin did not have any significant additional effect on PAI-1. In contrast to the results for PAI-1, there was a significantly greater decrease in tissue-type plasminogen activator (tPA) antigen in the metformin than in the placebo group (mean+/-SD: -1.1+/-3.1 vs. 0.2+/-3.2 ng/ml, P < 0.02). The von Willebrand factor (vWF) also decreased significantly more in the metformin group (-0.17+/-0.42 vs. -0.05+/-0.38 U/I, P < 0.02). CONCLUSIONS: Weight loss was the main factor associated with the decrease in PAI-1, in accordance with the recent demonstration of production of PAI-1 by adipocytes. Metformin had a significant effect on two factors, tPA antigen and vWF, mainly secreted by the endothelial cells, which suggests an effect of the drug on the production or the metabolism of these two hemostatic proteins.