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