Effect of Troglitazone on Fibrinolysis and Activated Coagulation in Patients With Non–Insulin-Dependent Diabetes Mellitus

doi:10.1016/S1056-8727(97)00109-8

Journal of Diabetes and its Complications

Volume 12, Issue 4, July–August 1998, Pages 181-186

https://doi.org/10.1016/S1056-8727(97)00109-8 Get rights and content

Abstract

The objective of this study was to determine if treatment of non–insulin-dependent diabetes mellitus (NIDDM) patients with the “insulin sensitizer” troglitazone, both as monotherapy and in combination with insulin, corrects the impaired fibrinolysis and activated coagulation associated with NIDDM. Patients participating in two clinical trials comparing troglitazone and placebo in patients with NIDDM were studied at the time of randomization and after 26 weeks of treatment. Eighteen patients were treated with troglitazone (ten in combination with insulin and eight as monotherapy) and eight were treated with placebo (four in each trial). Plasma concentrations of plasminogen activator inhibitor (PAI-1), prothrombin fragment F1+2, fibrinogen, and von Willebrand Factor (vWF) activity were measured. Plasma PAI-1 concentrations fell significantly from a mean of 68.8 ± 32.3 ng/mL to 40.4 ± 20.4 in the troglitazone treated group, but did not change significantly in the placebo treated group. Plasma PAI-1 concentrations were elevated in 15 patients treated with troglitazone and fell to normal in eight of them. There was no significant change in plasma F1+2, vWF, and fibrinogen, but plasma C-peptide and triglyceride concentrations fell significantly with troglitazone. This study demonstrates that troglitazone treatment is associated with a significant fall in plasma PAI-1 antigen concentrations in patients with NIDDM and, therefore, may have a beneficial effect on fibrinolysis.

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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Insulin is a pleiotropic hormone that exerts a multitude of effects on metabolism and various cellular processes in the body. The main metabolic actions of insulin are to stimulate glucose uptake in skeletal muscle and the heart and to suppress the production of glucose and very-low-density lipoprotein in the liver. Other metabolic effects of insulin include inhibition of glucose release from the liver, inhibition of the release of free fatty acids (FFAs) from adipose tissue, and stimulation of the process by which amino acids are incorporated into protein. Insulin resistance (IR) is a condition in which defects in the action of insulin are such that normal levels of insulin do not trigger the signal for glucose absorption. An excess of FFAs is implicated in the pathogenesis of IR. The effects of this condition can have profound pathophysiologic effects on various organs and tissues of the body. For example, IR is associated with impaired insulin signaling, impaired fibrinolysis, and inflammation. The clinical consequences include hyperglycemia-induced tissue damage, hypertension, dyslipidemia, metabolic syndrome, and cardiovascular disease. Pharmacotherapies that target IR include metformin and the thiazolidinediones. Fndocannabinoid antagonists, agents that target obesity and associated cardiovascular and metabolic risk factors, are currently being developed.
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Cardiovascular events in patients with type 2 diabetes mellitus are a major problem in clinical practice, and patients with diabetes have derived less benefit from advances in preventive and interventional cardiology. Tighter goals for metabolic management and attention to nontraditional risk factors may be needed in this patient group. Insulin resistance rather than hyperinsulinemia is thought to underlie cardiovascular disease in patients with diabetes. Insulin resistance is associated with cardiovascular events and a wide range of traditional and nontraditional risk factors for cardiovascular disease (e.g., endothelial dysfunction, dyslipidemia, inflammation, vascular wall abnormalities). Therapy with lifestyle modifications, metformin, or thiazolidinediones (TZDs) corrects many of the abnormalities associated with diabetes in addition to lowering blood glucose and correcting diabetic dyslipidemia. TZDs, acting via the peroxisome proliferator-activated receptor–γ, affect a number of mediators involved in the development of the cardiovascular complications of diabetes, including lipid profiles, vascular changes, and inflammatory mediators. TZDs decrease plasminogen activator–1 and C-reactive protein levels. They also reduce the extent of thickening of the carotid artery and reduce hyperplasia after coronary stent implantation. Insulin-sensitizing therapy with TZDs is a promising intervention for patients with diabetes at risk for adverse cardiovascular outcomes.
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Citation 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.
The epidemic of type 2 diabetes mellitus (T2DM) continues unabated and unless urgent steps are taken to prevent the onset of, or at the least, ameliorate the macrovascular complications, the medical as well as the socio-economic costs to the people will be insurmountable.
Insulin resistance and decreased insulin secretory capacity of the beta cells are central to the onset of dysglycemia seen in T2DM. The thiazolinediones (glitazones) are a relatively new group of drugs which have been shown to help in correcting the dysglycemia by lowering the insulin resistance levels.
Adequate attention has not been paid to the pleiotropic effects of these group of drugs. Leaving aside the controversy about whether insulin resistance leads to beta cell dysfunction or whether the beta cells are genetically prone to failure, the glitazones have a significant capacity to alleviate the beta cell failure and allow them to continue secreting insulin to meet the higher requirements imposed by the resistant state. Although the precise mechanisms are still being investigated, glitazones have been shown to significantly lessen the effects of glucotoxicity and lipotoxicity on the beta cell function and apoptosis.
Moreover, in the present days, diabetes means much more than just glucose control. One has to take measures to prevent the cardiovascular complications and sequelae. The glitazones have a salutary effect on many of the traditional as well as the new risk factors and can help in preventing or lessening the impact of the cardiovascular consequences. They have been shown to lower the levels of atherogenic dyslipidemia, lower the blood pressure and lessen microalbuminuria, lower visceral obesity, lessen the levels of the proinflammatory and prothrombotic cytokines and adipokines as well as increase the levels of the antiatherogenic adinopectin. It decreases levels of PAI-1 and fibrinogen thereby lowering the procoagulant state and has a salutary effect on endothelial function.
All these actions allow the glitazones to play a much larger role in our efforts to lower the vascular risks. Unfortunately, these beneficial actions are not widely recognized and reports of edema propensity, weight gain and hepatic toxicity do not allow the wider use of glitazones in our therapeutic armamentarium.
This brief review discusses the pleiotropic effects of the glitazones and one would sincerely feel that they should be used early, in contrast to their present use as the third oral agent to be used in our management.
Metabolic consequences of hyperglycemia and insulin resistance
2007, Clinical Cornerstone
Insulin is a pleiotropic hormone that exerts a multitude of effects on metabolism and various cellular processes in the body. The main metabolic actions of insulin are to stimulate glucose uptake in skeletal muscle and the heart and to suppress the production of glucose and very-low-density lipoprotein in the liver. Other metabolic effects of insulin include inhibition of glucose release from the liver, inhibition of the release of free fatty acids (FFAs) from adipose tissue, and stimulation of the process by which amino acids are incorporated into protein. Insulin resistance (IR) is a condition in which defects in the action of insulin are such that normal levels of insulin do not trigger the signal for glucose absorption. An excess of FFAs is implicated in the pathogenesis of IR. The effects of this condition can have profound pathophysiologic effects on various organs and tissues of the body. For example, IR is associated with impaired insulin signaling, impaired fibrinolysis, and inflammation. The clinical consequences include hyperglycemia-induced tissue damage, hypertension, dyslipidemia, metabolic syndrome, and cardiovascular disease. Pharmacotherapies that target IR include metformin and the thiazolidinediones. Endocannabinoid antagonists, agents that target obesity and associated cardiovascular and metabolic risk factors, are currently being developed.
Tumor necrosis factor-α-induced production of plasminogen activator inhibitor 1 and its regulation by pioglitazone and cerivastatin in a nonmalignant human hepatocyte cell line
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Plasminogen activator inhibitor 1 (PAI-1) is an important mediator of atherosclerosis and liver fibrosis in insulin resistance. Circulating levels of PAI-1 are elevated in obese individuals, and PAI-1 messenger RNA is significantly higher in the livers of obese type 2 diabetic individuals than in nonobese type 2 diabetic individuals. To address the mechanism underlying the up-regulation of hepatic PAI-1 in obesity, we tested the effects of tumor necrosis factor α (TNF-α), an important link between obesity and insulin resistance, on PAI-1 production in the nonmalignant human hepatocyte cell line, THLE-5b. Incubation of THLE-5b cells with TNF-α stimulated PAI-1 production via protein kinase C–, mitogen-activated protein kinase–, protein tyrosine kinase–, and nuclear factor-κB–dependent pathways. A thiazolidinedione, pioglitazone, reduced TNF-α–induced PAI-1 production by 32%, via protein kinase C– and nuclear factor-κB–dependent pathways. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor cerivastatin inhibited TNF-α–induced PAI-1 production by 59%, which was reversed by coincubation with mevalonic acid. In conclusion, obesity and TNF-α up-regulation of PAI-1 expression in human hepatocytes may contribute to the impairment of the fibrinolytic system, leading to the development of atherosclerosis and liver fibrosis in insulin-resistant individuals. A thiazolidinedione and a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor may thus be candidate drugs to inhibit obesity-associated hepatic PAI-1 production.
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ORIGINAL ARTICLEEffect of Troglitazone on Fibrinolysis and Activated Coagulation in Patients With Non–Insulin-Dependent Diabetes Mellitus

Abstract

Introduction

Section snippets

Methods

Monotherapy Study

Results

Discussion

Thromb Res

Lancet

Factors responsible for impaired fibrinolysis in obese subjects and NIDDM patients

Diabetes

Hyperfibrinogenemiaan important risk factor for vascular complications in diabetes

Diabetes Care

Increased prothrombin fragment 1+2 in type I diabetic patients

Haemostasis

Plasminogen activator inhibitor 1 and atherothrombosis

Thromb Haemost

Insulin therapy in type 2 diabetic subjects suppresses plasminogen activator inhibitor (PAI-1) activity and proinsulin-like molecules independently of glycaemic control

Diabetic Med

Plasminogen activator inhibitorA risk factor for myocardial infarction in diabetic patients

Br Heart J

Enzymatic evidence of impaired reperfusion in diabetic patients after thrombolytic therapy for acute myocardial infarctionA role for plasminogen activator inhibitor?

Br Heart J

Coagulation activation in diabetes mellitusThe role of hyperglycaemia and therapeutic prospects

Diabetologia

Prothrombin fragment 1.2.3, a major product of prothrombin activation in human plasma

J Biol Chem

Hyperglycemia-induced thrombin formation in diabetes; the possible role of oxidative stress

Diabetes

Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone

N Engl J Med

ORIGINAL ARTICLE
Effect of Troglitazone on Fibrinolysis and Activated Coagulation in Patients With Non–Insulin-Dependent Diabetes Mellitus