Effects of Gemfibrozil and Ciprofibrate on Plasma Levels of Tissue-type Plasminogen Activator, Plasminogen Activator Inhibitor-1 and Fibrinogen in Hyperlipidaemic Patients

Abstract

SummaryEvaluation of fibrate treatment in humans has focused primarily on its anti-lipidaemic effects. A potentially favourable haemostasis-modulating activity of fibrates has also been recognized but the data are not consistent. We sought to learn more about this variability by examining the effects of gemfibrozil and ciprofibrate on plasma levels of tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) and fibrinogen in primary hyperlipidaemic patients after six and twelve weeks of treatment using different assay systems for PAI-1 and fibrinogen. Although both fibrates effectively lowered triglyceride and cholesterol levels, no effect on the elevated baseline antigen levels of t-PA and PAI-1 was observed after fibrate treatment. However, both fibrates influenced plasma fibrinogen levels, albeit in a different way. Fibrinogen antigen levels were elevated by 17.6% (p <0.05) and 24.3% (p <0.001) with gemfibrozil after six and twelve weeks, respectively, whereas with ciprofibrate there was no effect. Using a Clauss functional assay with either a mechanical end point or a turbidity-based end point, no significant change in fibrinogen levels was seen after six weeks of gemfibrozil treatment. However, after twelve weeks, gemfibrozil enhanced functional fibrinogen levels by 7.2% (p <0.05) as assessed by the Clauss mechanical assay, but decreased functional fibrinogen levels by 12.5% (p <0.0001) when a Clauss assay based on turbidity was used. After six or twelve weeks of ciprofibrate treatment, functional fibrinogen levels were decreased by 10.1% (p <0.001) and 10.5% (p <0.0001), respectively on the basis of Clauss mechanical and by 14.2% (p <0.001) and 28.2% (p <0.0001), respectively with the Clauss turbidimetric assay. A remarkable and consistent finding with both fibrates was the decrease in functionality of fibrinogen as assessed by the ratio of functional fibrinogen (determined by either of the two Clauss assays) to fibrinogen antigen.Taken together, our results indicate that at least part of the variability in the effects of fibrates on haemostatic parameters can be explained by intrinsic differences between various fibrates, by differences in treatment period and/or by the different outcomes of various assay systems. Interestingly, the two fibrates tested both reduced the functionality of fibrinogen.

Effects of Fibrate Compounds on Expression of Plasminogen Activator Inhibitor-1 by Cultured Endothelial Cells

“…4,6 However, clinical trials have demonstrated that fibrates producing a comparable triglyceride lowering have widely different effects on plasma PAI-1 activity. [7][8][9][10][11] This finding in vivo along with previous cell biological studies 12,13 and the present in vitro data from ECs strongly indicate that any fibrate effects on plasma PAI-1 activity in humans are at least partly a result of direct effects of the drug on PAI-1 synthesis in liver cells and/or ECs. The question then arises as to whether the diverse fibrate effects on PAI-1 expression in ECs observed in the present study could explain some of the discrepancies between the previous clinical trials.…”

“…However, the results with respect to lowering of plasma PAI-1 activity have been discrepant: an overall significant effect, 7 an effect detectable on subgroup analysis only, 8,9 or no effect. 10,11 In comparison, studies of the effect of fibrates on PAI-1 synthesis in liver cells in culture have been more conclusive. Gemfibrozil suppresses PAI-1 synthesis in HepG2 cells, 12 and a range of fibrate compounds have been demonstrated to suppress PAI-1 synthesis in cultured cynomolgus monkey hepatocytes.…”

“…Furthermore, a consistent fibrate effect on PAI-1 synthesis in liver cells in vitro, as has been seen with gemfibrozil, 12,13 is not accompanied by a consistent lowering of plasma PAI-1 activity in vivo in humans. [7][8][9][10][11] The observations made so far in vitro and in clinical trials with fibrates may be interpreted in different ways. Liver cells may not be a significant source of PAI-1 in vivo in humans.…”

“…This, in turn, could account for the heterogeneous PAI-1 responses in clinical trials. [7][8][9][10][11] Against this background, we examined the effects of several fibrate compounds on PAI-1 expression and secretion by cultured ECs.…”

Impact of Fibrinogen Levels on Angiographic Progression and 12-Year Survival in the Armed Forces Regression Study

“…This may not be surprising given that treatment with at least one of the agents studied, gemfibrozil, has previously been shown not to affect fibrinogen levels. 23 In summary, these data support the notion that fibrinogen is an independent risk factor for both all-cause mortality and CV death. This is also, to our knowledge, the first demonstration that elevated baseline fibrinogen predicts angiographic progression of existing CHD.…”