According to recent prospective studies, hypofibrinolysis due to elevated plasma plasminogen activator inhibitor 1 levels appears to be an independent risk factor for myocardial reinfarction in men, and hyperinsulinaemia, a major indicator of insulin resistance is considered as a risk factor for coronary disease. It has recently been shown that insulin resistance is accompanied by an increased plasma plasminogen activator inhibitor 1 concentration: A significant correlation coefficient was demonstrated between plasminogen activator inhibitor 1 and fasting plasma insulin in the normal population, in obese subjects, in Type 2 (non-insulin-dependent) diabetic patients and in angina pectoris. Attempts to decrease insulin resistance such as fasting, diet, or administration of an oral anti-diabetic drug such as Metformin induced a parallel decrease in plasma insulin and plasminogen activator inhibitor 1 levels. This inhibitor is produced by endothelial cells and by hepatocytes in culture. Plasminogen activator inhibitor 1 synthesis by hepatocytes in culture was stimulated by an increasing insulin concentration, or low density lipoproteins, whereas the endothelial cell synthesis was stimulated by very low density lipoproteins especially when they were obtained from hypertriglyceridaemic patients. Therefore, a direct effect of insulin or lipoprotein changes on the cells which synthesize plasminogen activator inhibitor 1 could be responsible for its increased plasma concentration in insulin resistance states. The increase in plasma plasminogen activator inhibitor 1 levels linked to hyperinsulinaemia is a tempting partial explanation for the association between insulin resistance and coronary disease.

Plasma clearance of active TPA was faster than clearance of TPA/PAI-1 complex. High levels of active PAI-1 converted more TPA into TPA/PAI-1 complex, effectively slowing the clearance of total TPA antigen and explaining in part why high levels of PAI-1 activity are associated with increases in total TPA antigen.

In long-term basal-bolus therapy, insulin detemir with insulin aspart as mealtime insulin is well tolerated and reduces the risks of nocturnal hypoglycaemia and weight gain compared to NPH insulin.

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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.

The fibrinolytic activity of blood depends on the balance between the circulating level of tissue-type plasminogen activator (t-PA), which is secreted by endothelial cells, and plasminogen activator inhibitor-1 (PAI-1), 3 which is secreted by endothelial cells and hepatocytes and is also released by platelets. 4 Patients with coronary artery disease, either before or after myocardial infarction, have an increased plasma level of PAI activity, 5 -8 which may predispose to infarction. Received September 13, 1988; revision accepted December 13, 1988. stand the mechanisms that regulate PAI-1 production in patients at risk for myocardial infarction. Methods PatientsSixty-seven consecutive patients undergoing coronary angiography (51 men, mean age [SD] 61 [6], range 43 to 77) were studied; 22 had angina on exertion, 17 had angina at rest, four had mixed angina, and 24, unstable angina. Electrocardiographs (ECG) changes at rest were noted in 40 patients (ST segment depression of at least 1 mm or T wave inversion). Seven patients had ECG changes during painful episodes only. The other 20 had a normal ECG at rest. Of 44 patients, 31 had an abnormal exercise ECG. Previous myocardial infarction (more than 3 months before blood sampling) had occurred in 13 men and two women, and three patients had previous deep venous thrombosis. Patients received Ca ++ -antagonists (40 patients), ^-blocking agents (22 patients), nitrates (18 patients), heparin (18 patients), oral anticoagulants (three patients), or platelet aggregation inhibitors (13 patients).Body mass index (BMI) defined as body weight (kg) divided by the square of height (m), was (mean±SD): for men, 25±2.7, range 22 to 28 (normal value, 23); and for women, 24±3.6, range 21 to 28 (normal value, 21). The prevalence of risk factors is reported in Table 1.Coronary angiograms were performed with the femoral or brachial approach. The severity of coronary disease 362 Downloaded from http://ahajournals.org by on April 1, 2019

SummaryWe have previously observed a positive correlation between Plasminogen Activator Inhibition capacity (PA Inhibition), Body Mass Index (BMI) and plasma insulin levels in a population of non diabetic subjects. The anti diabetic biguanide Metformin which decreases insulin resistance has been reported to increase the blood fibrinolytic activity. Therefore we have studied the effect of Metformin on PA Inhibition levels in obese subjects with normal glucose tolerance. Eighteen obese women (O) (BMI: 31.4 ± 1.13, m ± S.E.M.) were compared to age matched controls (C) (BMI: 20.2 ± 0.8) and randomized to a 15 days treatment by Metformin (M) (1.7 g/day) or placebo (P) in a double blind study while on a weight maintaining diet. O compared to C had higher levels (m ± S.E.M.) of PA Inhibition (9 ± 1.8 IU/ml, versus 2.88 ± 0.29 p <0.01), lower euglobulin fibrinolytic activity (EFA) (4.95 ±1.17 mm versus 9 ± 0.29 p <0.05), higher plasma insulin (24.1 ±2.1. uU/ml), versus 12 ± 1 p <0.01) and triglyceride (1.32 ± 0.16 mmol/1, versus 0.8 ± 0.08 p <0.05). After 15 days of treatment, in group M a significant decrease in PA Inhibition (5.51 ± 1.4, versus 9.48 ±2.1 p <0.05) in plasma insulin (18.5 ±0.1, versus 24.5 ± 3.5, p <0.05) and plasma triglyceride (1.08 ± 0.1, versus 1.47 ± 0.3 p <0.05) and an increase in EFA (6.50 ± 0.28, versus 5.25 ± 0.35 p <0.05) were observed. No significant variation was observed in group P.

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