ORIGINAL ARTICLEEffect of Troglitazone on Fibrinolysis and Activated Coagulation in Patients With Non–Insulin-Dependent Diabetes Mellitus
Introduction
Cardiovascular disease is the leading cause of death in patients with non–insulin-dependent diabetes mellitus (NIDDM). While the exact cause of this accelerated vascular disease is not known, contributory factors include impaired fibrinolysis,1 elevated fibrinogen,2 elevated von Willebrand factor (vWF) activity,3 and activated coagulation.4
Impaired fibrinolytic activity is well recognized in patients with NIDDM1 and may accelerate atherosclerosis by exposing vascular luminal wall surfaces to persistent recurrent thrombi and clot associated mitogens. Evidence for impaired fibrinolysis in NIDDM and insulin resistance (IR) include elevations in plasma plasminogen activator inhibitor (PAI-1) antigen and activity.5 Jain et al.6 have demonstrated that treatment with exogenous insulin may decrease plasma PAI-1. However, PAI-1 concentrations remain elevated in most patients with NIDDM treated with insulin.
PAI-1 has a molecular weight of 50,000 and is produced by endothelial cells and hepatocytes, and is found in inactive form in platelets. High plasma PAI-1 activity constitutes an independent risk factor for myocardial infarction.7 Diabetic patients have higher PAI-1 antigen and activity both on admission with a myocardial infarction (MI) and up to one year later, when compared to nondiabetics.8 Raised PAI-1 may predispose diabetics to an MI and may impair myocardial reperfusion, contributing to the poor outcome in these patients.9
Several hemostatic abnormalities resulting in a mild hypercoagulable state also occur in NIDDM. The existence of a direct link between abnormal glucose levels and increased activity of the coagulation system has been demonstrated.10 Prothrombin fragment 1+2 (F1+2) is a reliable marker of the amount of thrombin released in the circulation.11 Increased plasma F1+2 concentrations have been demonstrated in diabetes.4 These concentrations rise following a glucose load and subsequent hyperglycemia, and this rise is attenuated by treatment with the antioxidant glutathione.12
Thiazolidinediones are a new class of orally active drugs that enhance the action of insulin. These agents reduce insulin resistance by increasing insulin-dependent glucose uptake and reducing hepatic glucose output.13, 14 Troglitazone is a thiazolidinedione that has recently undergone clinical trials for the treatment of NIDDM. Troglitazone was synthesized with an alpha tocopherol substitution in an effort to produce a bifunctional drug that might also inhibit lipid peroxidation.14
Because of its dual effect on lowering insulin resistance and acting as an antioxidant, we proposed that troglitazone would have a beneficial effect on the elevations in PAI-1 and activated coagulation associated with NIDDM.
Section snippets
Methods
Patients participating in two clinical trials of troglitazone in patients with NIDDM (one as monotherapy and one in combination with insulin) were included in our study, after informed consent. Both trials were approved by our institution’s Human Research Advisory Committee. The diagnosis of NIDDM was based on the criteria of the National Diabetes Data Group.15 The patient demographics and characteristics are summarized in Table 1. There were no significant differences between the two groups at
Monotherapy Study
Patients with NIDDM with a fasting C-peptide concentration greater than 1.5 ng/mL, and not under adequate glycemic control (fasting glucose > 140 mg/dL) following two weeks of diet therapy were randomized to receive either 100, 200, 400, or 600 mg troglitazone, once daily, or placebo for 6 months. All patients in our center had previously been on sulfonylurea drugs that were discontinued at the start of the study (2 weeks prior to randomization). As 100 mg/day of troglitazone was subsequently
Results
The results of our study are summarized in Table 2. Plasma PAI-1 concentrations fell significantly from a mean (±SD) of 68.8 ± 32.3 ng/mL to 40.4 ± 20.4 (p < 0.01) in the troglitazone treated group as illustrated in Figure 1. In the placebo treated group there was a modest fall from 72.6 to 54.9 ng/mL, which was not statistically significant. Plasma PAI-1 concentrations were elevated above the upper limit of the normal range (<40 ng/mL) in 15 patients and fell to less than 40 ng/mL in eight of
Discussion
Our data demonstrate that treatment with troglitazone lowers plasma PAI-1 concentrations in patients with NIDDM. This very significant fall in PAI-1 occurred when troglitazone was used as monotherapy as well as in combination with insulin. This fall in plasma PAI-1 appears to be independent of glycemic control, but may relate to an improvement in “insulin resistance,” as evidenced by a fall in plasma C-peptide and triglyceride concentrations.
Insulin resistance is associated with a cluster of
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2007, Diabetes and Metabolic Syndrome: Clinical Research and ReviewsCitation Excerpt :Elevated PAI-1 and fibrinogen levels show a positive correlation with other criteria for the metabolic syndrome. Studies have shown that glitazones can lead to a significant decrease in the PAI-1 levels as well as the raised fibrinogen levels not only in people with diabetes [76–78] but also in nondiabetics with insulin resistant state [79,80]. The effect is thought to be a class action of the glitazone group of drugs acting on the vessel wall by way of the activation of PPAR-ɣ and subsequent suppression of PAI-1.
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