EFFECTS OF 2 DIFFERENT FIBRIC ACID-DERIVATIVES ON LIPOPROTEINS, CHOLESTERYL ESTER TRANSFER, FIBRINOGEN, PLASMINOGEN-ACTIVATOR INHIBITOR ANDPARAOXONASE ACTIVITY IN TYPE IIB HYPERLIPOPROTEINEMIA

Citation
Pn. Durrington et al., EFFECTS OF 2 DIFFERENT FIBRIC ACID-DERIVATIVES ON LIPOPROTEINS, CHOLESTERYL ESTER TRANSFER, FIBRINOGEN, PLASMINOGEN-ACTIVATOR INHIBITOR ANDPARAOXONASE ACTIVITY IN TYPE IIB HYPERLIPOPROTEINEMIA, Atherosclerosis, 138(1), 1998, pp. 217-225
Citations number
42
Categorie Soggetti
Peripheal Vascular Diseas
Journal title
ISSN journal
00219150
Volume
138
Issue
1
Year of publication
1998
Pages
217 - 225
Database
ISI
SICI code
0021-9150(1998)138:1<217:EO2DFA>2.0.ZU;2-F
Abstract
We have investigated the effects of two fibric acid derivatives, bezaf ibrate mono (400 mg daily) and gemfibrozil (600 mg b.d.), in 29 patien ts with type IIb hyperlipoproteinaemia. All patients received placebo and each drug for 8 weeks in randomised order in a double-blind, cross -over study designed to evaluate any different effects of the drugs on serum lipoproteins, cholesteryl ester transfer protein (CETP), choles teryl eater transfer activity (CETA), plasma fibrinogen, plasminogen a ctivator inhibitor-I (PAI-1) or paraoxonase. Serum cholesterol decreas ed (P < 0.05) with gemfibrozil, but the effect of bezafibrate on serum cholesterol did not achieve statistical significance (placebo 8.34 +/ - 1.05 (mean +/- S.D.), gemfibrozil 7.70 +/- 1.23 and bezafibrate 7.8 + 1.37 mmol/l). Both drugs decreased the serum triglyceride concentrat ion (both P < 0.001) (placebo 4.39 (3.13-5.75) (median (interquartile range)), bezafibrate 2.26 (1.89-3.89) and gemfibrozil 2.00 (1.30-3.30) mmol/l) and very low density lipoprotein (VLDL) cholesterol (both P < 0.001) (placebo 1.18 (0.74-2.30), bezafibrate 0.59 (0.34-0.85) and ge mfibrozil 0.48 (0.34-0.68) mmol/l). Discontinuous gradient ultracentri fugation (DGU) revealed that Sf 60-400 (large VLDL) decreased by more than 50% and Sf 20-60 (small VLDL) by more than 30% with each of the d rugs (both P < 0.001), neither of which affected the composition of th ese lipoproteins. Gemfibrozil decreased the concentration of Sf 12-20 lipoprotein (intermediate density lipoprotein; IDL) by 23% (P < 0.01), whereas the effect of bezafibrate on this lipoprotein did not achieve statistical significance. Neither drug altered the concentration of a polipoprotein B or of total Sf 0-12 lipoproteins (low density lipoprot ein, (LDL)). Both, however, significantly increased the quantity of fr ee cholesterol in Sf 0-12 lipoproteins (P < 0.05). Overall the concent ration of triglycerides decreased significantly in all lipoproteins is olated by DGU (Sf 0-12, Sf 12-20, Sf 20-60, Sf 60-400) on gemfibrozil treatment, but only in Sf 20-60 and Sf 60-400 on bezafibrate tall P < 0.05). Both drugs also increased serum high density lipoprotein (HDL) cholesterol (placebo 1.15 +/- 0.29, bezafibrate 1.27 +/- 0.38 (P < 0.0 1) and gemfibrozil 1.26 +/- 0.49 (P < 0.05) mmol/l) and HDL, cholester ol concentration (placebo 0.59 +/- 0.12, bezafibrate 0.72 +/- 0.23 (P < 0.001) and gemfibrozil 0.70 +/- 0.24 (P < 0.01) mmol/l). Serum apoli poprotein Al (apo Al) was increased (P < 0.05) by bezafibrate compared to gemfibrozil (placebo 103 +/- 26, bezafibrate 111 +/- 28 and gemfib rozil 102 +/- 25 mg/dl) and CETA from HDL to VLDL and LDL was decrease d (P < 0.05) by bezafibrate compared to placebo, but the apparent decr ease with gemfibrozil did not achieve statistical significance (placeb o 39.6 +/- 17.7, bezafibrate 32.3 +/- 14.7 and gemfibrozil 33.8 +/- 15 .0 nmol/ml/h). Neither drug affected the circulating concentration of CETP. Plasma fibrinogen was increased (P < 0.05) by gemfibrozil (place bo 4.16 (3.38-4.71) and gemfibrozil 4.65 (4.05-5.77) g/l) and was sign ificantly lower (P<0.001) on bezafibrate (3.60 (3.18-4.54) g/l) than o n gemfibrozil treatment. There was a significant (P < 0.05) increase i n PAI-1 activity with bezafibrate and a similar trend with gemfibrozil (placebo 41.2 (25.6-64.5), bezafibrate 50.5 (35.1-73.9) and gemfibroz il 48.5 (31.5-5.4 U/l). Neither fibrate influenced plasma concentratio ns of PAI-1 nor were the activities of lecithin:cholesterol acyl trans ferase or paraoxonase affected. The major difference in the action of the two drugs on lipoprotein metabolism was the greater effect of gemf ibrozil in decreasing the overall serum concentration of Sf 12-20 lipo proteins and the triglycerides in Sf 12-20 and 0-12 lipoproteins. Beza fibrate, however, increased serum apo Al concentration and significant ly decreased CETA. The two drugs also had different effects on the pla sma fibrinogen levels, which increased with gemfibrozil and tended to decrease with bezafibrate. These differences may be of importance in t he interpretation of trials with clinical end-points. The effect of fi bric acid derivatives on CETA in type IIb hyperlipoproteinaemia may be less than previously reported in type IV hyperlipoproteinaemia. (C) 1 998 Elsevier Science Ireland Ltd. All rights reserved.