429
Atherosclerosis, 31 (1978) 429-433 Scientific Publishers, @ Elsevier/North-Holland
Ltd.
ONE-YEAR STUDY OF THE EFFECT OF BEZAFIBRATE ON SERUM LIPOPROTEIN CONCENTRATIONS IN HYPERLIPOPROTEINAEMIA
ANDERS
G. OLSSON
and P.D. LANG
King Gustaf V Research Institute and Department Stockholm (Sweden) (Received 7 June, 1978) (Revised, received 2 August, (Accepted 4 August, 1978)
of Medicine, Karolinska Hospital,
1978)
Summary
The effect of bezafibrate (2- {4-[ 2-(4chlorobenzamido)-ethyl] -phenoxy) -2methylpropionic acid) (450 mg daily) on serum lipoprotein concentrations was studied for 1 year in 14 subjects with hyperlipoproteinaemia (3 of type II A, 2 of type II B, 2 of type III and 7 of type IV). After 2 months serum cholesterol decreased from 7.12-6.08 mmoles/l (15%, P< O.Ol), triglycerides from 2.52-1.96 mmoles/l (22%, P < O.Ol), very low density lipoprotein triglycerides from 1.48-0.86 mmoles/l (42%, P< 0.01) and low density lipoprotein cholesWhile triglyceride concentraterol from 5.00-3.81 mmoles/l (24%, P < 0.01). tions of serum and lipoproteins remained constant for 1 year, serum and LDL cholesterol concentrations increased slightly after 6 and 12 months. The former rise was partly due also to a rise of the possibly beneficial high density lipoprotein cholesterol from 1.27-1.68 mmoles/l (32%, P < 0.01) after 6 months, making the effect on total cholesterol less pronounced. Subjective side-effects were nausea in one patient. No severe biochemical side-effects were noted. Key words:
Bezafibrate - Hyperlipoproteinaemia
-Serum
lipoprotein concentrations
Introduction
Bezafibrate (2- {4-[ 2-(4_chlorobenzamido)-ethyl] -phenoxy} -2-methylpropionic acid) effectively lowers increased concentrations of very low (VLDL) and low (LDL) density lipoproteins [l] and increases high density lipoprotein (HDL) concentrations [2]. The dose of 450 mg daily changes the lipoprotein
430
pattern almost maximally [ 21. In another study only minor additional effects on total serum lipids could be obtained by increasing the dose to 600 mg daily in type II B hyperlipoproteinaemia [ 31. Until now the effect of bezafibrate on serum lipoprotein concentrations has only been studied for a few months. However, in a study on total serum lipid concentrations Kaffarnik et al. found persistent effects on serum cholesterol and triglycerides (TG) during treatment for 1 year [4]. The purpose of the present study was to investigate the persistence of the effect of the drug on serum lipoprotein concentrations during treatment for 1 year. Materials and Methods Fifteen patients with primary hyperlipoproteinaemia were included in the study. Inclusion in the study followed the same requirements as given elsewhere [ 11. Drug treatment was preceded by dietary advice [ 11. Bezafibrate was given in a daily amount of 450 mg divided into 3 doses. Body weight, serum cholesterol [ 51 and TG [6], serum ASAT, ALAT, alkaline phosphatases and bilirubin as well as haemoglobin concentration and white blood-cell count were determined before treatment and after 2,4,6,9 and 12 months of bezafibrate. Non-lipid analyses were performed according to the hospital routine methods. Quantitative lipoprotein analysis [ 71 and typing of hyperlipoproteinaemia [S] was performed before treatment and after 2,6 and 12 months on the drug. The study was conducted as an open clinical trial which did not include a control group. This was not considered to be necessary in this case as clear evidence of the activity of bezafibrate had already been demonstrated [ 11. If the lipid-lowering effect decreases during the long observation time, it cannot be decided whether this is due to a diminishing drug effect and/or other factors. The statistical analysis is based on a comparison of the pre-treatment and treatment values (Wilcoxon signed-rank test). Results During the course of the study one patient had to stop treatment because of nausea caused by bezafibrate. Otherwise no subjective side-effects were noted. A decrease of mean serum alkaline phosphatases occurred (Table 1) during treatment. Mean body weight was constant throughout the study. Of the 14 patients who completed the study 3 had initially type II A, 2 type II B, 2 type III and 7 type IV hyperlipoproteinaemia. Mean serum cholesterol (Table 2) decreased on treatment by 15% after 2 months and then remained constant during the study. Mean serum TG fell by 22% during the first 2 months of treatment and then stayed low. Maximum reduction was 47% at 6 months. The decrease in serum cholesterol was due to decreases mainly in LDL cholesterol (Table 3) but also VLDL cholesterol decreased. After 6 and 12 months LDL cholesterol was slightly higher than after 2 months due to increasing LDL cholesterol concentrations in 2 subjects. HDL cholesterol increased significantly and stayed high throughout the study.
1
EFFECT
blood
a
Triglycerides
(rnInOI/l)
P < 0.05.
(mmoI/l)
b
(g/100
(450
+ 0.20
f. 0.35
vs we-treatment
2.52
7.12
II A,
4.2
2
0.24
0.05
0.04
0.4
+ 600
+_
f
f
i:
i:
-r
SERUM
1.96
6.08 C 0.18
+ 0.23
2 months
Bezafibrate
ON
concentrations.
mg/day)
concentrations.
6100
14.8
9
2.71
0.40
0.37
71.8
ON
b
b
LIPIDS
II B, 2 TYPE
(450mg/day)
2 TYPE
Pretreatment
(3 TYPE
BEZAFIBRATE
pretreatment
+ SEM)
P 4 0.01
MEAN
OF
vs pre-treatment
BEZAFIBRATE
P < 0.01
ml)
(tikat/l)
ceIIs/mm3
b
OF
IV:
2
Cholesterol
7 TYPE
EFFECT
TABLE
a P < 0.05.
(4000-9000)
White
(14.0-17.0)
Haemoglobin
(4-21)
(mmol/I)
phosphatase
(0.84.0)
BilirubIn
AIk.
(pkatil)
(0.10-0.70)
S-ALAT
(kg)
(pkatll)
weight
(0.20-0.70)
S-ASAT
Body
HYPERLIPOPROTEINAEMIA
LONG-TERM
TABLE
IN
6400
0.4b
1
0.12
0.04
0.04
PATIENTS
f 400
+_
+
+
+
f
1.66
6.10
f 0.17
f 0.25
4 months
14
14.1
8
1.82
0.36
0.37
h
b
b
WITH
+
? 300
?
i
f
+
t
4.1
0.3
1
0.17
0.06
0.09
1.34
6.42
f 0.09
+ 0.35
6 months
b
a
HYPERLIPOPROTEINAEMIA
6300
14.4
7
2.07
0.44
0.50
71.8
LABORATORY
71.4
f SEM)
SAFETY
6 months 4.1
AND MEAN
2 months +_
IV;
WEIGHT 7 TYPE
Bezafibrate
III.
BODY
a
b
1.41
6.42
? 0.13
? 0.30
8
b
b
IN
?
0.4
1
0.16
0.04
0.04
4.1
14
1.55
6.51
+ 0.19
2 0.30
b
a
III.
WITH
II B. 2 TYPE
b
a
b
PATIENTS
12 months
2 TYPE
t 600
*
?
f
+
f
II A,
1.96
0.46
0.44
14.4
(3 TYPE
9 months
months 72.0
6500
12
PARAMETERS
z
432 TABLE 3 LONG-TERM EFFECT OF BEZAFIBRATE (450 mg/day) ON SERUM LIPIDS AND LIPOPROTEINS IN 14 PATIENTS WITH HYPERLIPOPROTEINAEMIA (3 TYPE II A, 2 TYPE II B, 2 TYPE III, 7 TYPE IV; MEAN f SEM), Pretreatment
Bezafibrate 2 months
6 months
12 months
VLDL cholesterol triglycerides
0.91 + 0.13 1.48 + 0.26
0.44 k 0.05 b 0.86 ? 0.14 b
0.44 + 0.05 b 0.64 ? 0.10 b
0.59 ? 0.10 0.85 f 0.19
LDL cholesterol triglycerides
4.99 2 0.34 0.75 f 0.04
3.80 ? 0.18 b 0.55 ? 0.04 b
4.19 f 0.31 b 0.46 ? 0.03 b
4.24 f 0.21 a 0.46 ? 0.03 b
HDL cholesterol triglycerides
1.27 ? 0.10 0.23 + 0.01
1.50 + 0.13 b 0.17 f 0.01 b
1.68 ? 0.13 b 0.14 + 0.01 b
1.63 f 0.13 b 0.16 ? 0.01 b
a P Q 0.05. b P G 0.01.
The decrease of serum TG was due mainly to lower concentrations of VLDL TG, but also to lower levels of LDL and HDL TG. These effects all remained throughout the study. Discussion The present study confirms that bezafibrate is a well-tolerated drug which efficiently lowers elevated VLDL and LDL concentrations [ 1,2] at the dose of 450 mg daily. It also confirms a pronounced elevating effect on HDL cholesterol [2]. In most subjects the effects on the lipoprotein concentrations reached after 2 months stayed low throughout the 12 months. In 2 cases, however, increases were noted in LDL cholesterol, which was probably attributed to lack of adherence. It is concluded that the effects on lipoprotein concentrations by bezafibrate initially seen in short-term studies, i.e. decrease of VLDL, decrease of elevated LDL cholesterol and increases of HDL cholesterol concentrations, are maintained for 1 year in the majority of patients. If results of patients with types II A and II B were evaluated separately from type IV, reductions of LDL cholesterol were more pronounced in the former and of VLDL TG in the latter. The HDL cholesterol rise during bezafibrate treatment makes the decreasing effect on total serum cholesterol less. However, by studying lipoprotein concentrations it is clear that bezafibrate changes the lipoprotein pattern in a beneficial way. Elevated concentrations of the probably atherogenic lipoproteins VLDL and LDL decreases and HDL cholesterol, which might have a protecting effect against atherosclerosis [9], increases. References 1 Olsson, A.G.. Riissner. S.. WaIIdius, G., Carlson. L.A. and Lang. P.D., Effect of BM 15.075 on lipoprotein concentrations in different types of hyperlipoproteinaemia. Atherosclerosis. 27 (1977) 279-287.
4.73 2 Olsson, A.G. and Lang, P.D., Dose-response in hyperlipoproteinaemia, 3 Walhniiller, A., Adam,
study of bezafibrate
on serum lipoprotein
Atherosclerosis, 31 (1978) 421. 0.. Wolfram, C. and Zallner, N., Dosiswirkungsbeziehung
concentrations
van Bezafibrat
bei
Patienten mit Hypercholesterinfimie und Hypertriglyceridiimie, In preparation. 4 Kaffarnik. H., Schneider. J., Schubotz, R., Miihlfellner, 0.. Miihlfellner, G., Hausmann. L. and ZGfel. P.. Long-term results with bezafibrate, a new derivate of clofibrate. In: L.A. Carlson. R. Paoletti and G. Weber (Eds.), International Conference on Atherosclerosis, Milan. November 1977, Raven Press, New York, NY, 1978, p. 129. 5 Block, W.D., Jarrett. K.J. and Leoine, B., Use of a single color reagent to improve the automated
6 7 8 9
determination of serum total cholesterol. In: L.T. Skeggs (Ed.), Automation in Analytical Chemistry, Vol. 1, Mediad Inc., New York, NY, 1965, p. 345. Kessler, G. and Lederer. H., Fluorimetric measurements of triglycerides. In: L.T. Skeggs (Ed.), Automation in Analytical Chemistry, Vol. 1, Mediad Inc., New York, NY, 1965, p. 341. Carlson. K., Lipoprotein fractionation, J. Clin. Path., 26, Suppl. (Ass. Clin. Path.), 5 (1973) 32-37. Beaumont. J.-L., Carlson. L.A.. Cooper. G.R., Fejfar. Z., Fredrickson, D.S. and Strasser, T.. Classification of hyperlipidaemias and hyperlipoproteinaemias, Bull. Wld Hlth Org.. 43 (1970) 891. Miller, N.E. and Miller. G.J., High density lipoprotein and atherosclerosis, Lancet, 1 (1975) 1033.