Pharmacological Research Communications, Vol. 18, No. 5, 1986 471

LONG TERM-EFFECT OF FENOFIBRATE ON LIPOPROTEIN LEVEL AND

COMPOSITION IN DIFFERENT TYPES OF GENETIC HYPERLIPIDEMIAS

G. Baggio, A. Gasparotto, G. C i u f f e t t i * , G. Valer io,

R. Fe l l i n , U. Senin*, C. Gabel l i , G. Crepaldi

Department of Internal Medicine-Universi ty of Padua-Pol icl inico Univers i tar io

Via G ius t in ian i , 2 - 35128 PADOVA - I t a l y

* Cl in ica Medica-Universit~ di Perugia-Pol ic l in ico Monteluce-Perugia- l ta ly

Received in final form 21 March 1986

SUMMARY

Fenofibrate e f fec t on plasma l ip ids and l ipoprote ins was studied in 23

pat ients with primary hyperlipoproteinemias (HLP): 12 with fami l ia l

hypercholesterolemia (FH), 5 wi th combined HLP and 6 with Type I I I HLP. Tr ia l

lasted from 8 to 10 months.

Cholesterol and t r i g l yce r ides were s i gn i f i can t l y reduced in a l l pat ients

as fo l lows: cholesterol dropped 26% in FH (p<O. O01), 32% in combined HLP and

48% in type I I I HLP; t r i g l yce r ides dropped 29%, 64% and 72% respect ively.

This drop involved LDL in FH, VLDL and LDL in combined HLP and ~-VLDL in

type I I I HLP pat ients. In FH and combined HLP patients we observed a +10%

(p<O.01) and a +9% (n.s . ) increase of HDL, respect ive ly .

Two patients had a mild SGOT and SGPT increase and three had a vescicular

cutaneous erythema.

INTRODUCTION

Fenofibrate is very valuable among l i p i d lowering drugs since i t was

shown to be e f f i c i e n t in reducing atherogenic l ipoprote ins (VLDL, LDL and

~-VLDL) and increasing HDL in d i f f e ren t types of hyperl ipoproteinemia (HLP)

(1-8).

However, i t s long range e f fec t have not yet been studied and only one

0031-6989/86/050471-10/$03.00/0 © 1986 The Italian Pharmacological Society

472 Pharmaco~g~alResearch Commun~ation~VoL 1~ No. ~ 1986

publication reports on i ts ef fect on type I I I HLP (4)° This is why we'studied

for a period of 8-10 months fenofibrate ef fect and i ts tolerance with a dosage

of I00x3 mg/die in various types of primary hyperlipoproteinemia (HLP):

fami l ia l hypercholesterolemia (FH), combined HLP and fami l ia l type I I I HLP.

MATERIALS AND METHODS

I) Case Report

23 patients affected by fami l ia l hypercholesterolemia (HLP) were studied:

12 (7 females and 5 males) with fami l ia l hypercholesterolemia (FH), 5 (2

females and 3 males) with combined HLP and 6 (I female and 5 males) with type

I I I HLP. The patients have been informed about the treatment plan and gave

the i r consent to i t . Anthropometric parameters and cholesterol and

t r ig lycer ide basal levels are reported in Tab. I .

Familial HLP phenotypes were established on the basis of WHO c r i t e r i a (9):

cholesterol and t r ig lycer ides levels of plasma, and of LDL, VLDL and HDL

fractions obtained by preparative u l t racentr i fugat ion plus polyanions

precip i tat ion (11-12), agarose l ipoprotein electrophoresis, c l in ica l features

and fami l ia l h is tory. For type I I I HLP diagnosis, the VLDL cholesterol/Serum

Triglycerides ra t io was evaluated (always >O.30).Apo E2/E2 phenotype was

confirmed with isoelectr icfocusing (10) af ter the t r i a l in four of these

patients (patient No. 3-4-5-6). As regard the other two patients: patient No.

I died for myocardial in farct ion (he had severe CVD, PAD and CHD as well as

al l typical cutaneous features of type I I I hyperlipoproteinemia), patient No.

2 did not attend our l i p id c l i n i c af ter the end of the t r i a l . Renal, thyroid,

l i ve r function were normal; other causes of secondary hyperlipidemia were

excluded.

2) Treatment Plan

300 mg fenofibrate were administered in three dai ly doses (100mgx3) for 8

months to combined and type ] I I HLP, and for 10 months to FH patients. Two

months before and during the whole t r i a l the patients followed a standard

isocaloric diet (20% protein, 45% carbohydrates, 35% f a t ) , containing 300 mg

cholesterol per day, a P/S ra t io of 1.8, and 12-15 gr f ibre per day. FH

patients af ter 10 months treatment were studied for another 4 weeks only under

Pharmacological Research Communications, Vol. 18, No. 5, 1986 4?3

Table I

ANTHROPOMETRIC PARAMETERS AND SERUM CHOLESTEROL AND TRIGLYCERIDES BASAL LEVELS

(mg/dl) OF 12 PATIENTS AFFECTED BY FAMILIAL HYPERCHOLESTEROLEMIA, 5 PATIENTS

BY COMBINED HYPERLIPOPROTEINEMIA AND 6 PATIENTS BY TYPE I I I HYPERLIPOPROTEINEMIA

Patients Sex Age BMI Cholesterol Tr ig lycer ides (years) (mg/1OOml) (mg/1OOml)

FAMILIAL HYPERCHOLESTEROLEMIA I) Lo. R. M 39 24.4 285 145 2) Ci. A. F 56 23.1 275 130 3) Ma. A. M 51 23.8 270 100 4) Br. A. M 58 22.5 345 138 5) An. ML. F 59 24.6 329 148 6) Cu. M. F 40 24.8 385 72 7) Ha. J. F 50 22.4 377 138 8) Gi. F. M 32 23.6 386 142 9) Ha. A. F 40 24.0 375 131

10) Pa. C. F 46 23.1 348 178 11) Ma. G. F 52 22.4 340 147 12) Ci. M. M 41 23.8 248 130

• +S.E.M. 47_+2 23.5_+0.24 333±12 133_+8

Serum CH/TG

I . 96 2.11 2.70 2.50 2.22 5.34 2.75 2.71 2.86 I. 96 2.31 2.18

2.63_+0.26

COMBINED HYPERLIPOPROTEINEMIA I) Fe. A. M 65 26.9 420 374 2) Fa. A. M 52 25.9 288 210 3) Fao L. M 34 27.1 292 234 4) Ca. G. F 70 23.8 328 485 5) Gi. F. F 51 21.3 600 816

_+S.E.M. 54_+6 25_+I 385_+59 424_+110

TYPE I I I HYPERLIPOPROTEINEMIA I) Tr. M. M 52 32.9 320 505 2) Se. A. M 58 31.9 356 405 3) R.G.F. M 44 34.9 414 582 4) Ze. C. F 49 36.7 468 522 5) Ze. P. M 51 30.4 581 790 6) Ze. V. M 44 30.2 480 830

_+S.E.M. 50_+2 33_+I 437_+38 606_+69

VLDL-CH/Serum-TG

0.15 0. I I 0.12 0.19 0.21

0.16_+0.02

0.34 0.35 0.35 0.50 0.46 0.39

0.40_+0.03

474 Pharmacological Research Communications, VoI. 18, No. 5, 1986

diet . Plasma cholesterol and t r ig lycer ides and l ipoprotein fract ions were

evaluated monthly. Al l safety parameters (hepatic and renal function, blood

sugar, uricemia, alkal ine phosphatase, hematology, CPK, LDH, iron, urine

analysis) were control led before and af ter 4 and 8 months t r i a l s .

Every month al l patients underwent c l in ica l examination. Compliance to

d iet and to drug therapy was control led by dietary enquires and p i l l s count.

Patients were not taking other drugs during the study. Any other

pharmacological hypolipidemic treatment was suspended 3 months before the

fenofibrate t r i a l .

3) L_iipoprotein isolat ion and chemical analysis

Lipoprotein fract ions were isolated by a combination of preparative

u l t racentr i fugat ion and polyanions precip i tat ion (11,12). Cholesterol and

t r ig lycer ides were measured by enzymatic methods (13,14).

Lipoprotein electrophoresis in agarose was done according to Seidel et al.

(15).

4) S ta t is t i ca l analysis

Sta t is t i ca l analysis for the evaluation of results was made with the

Student two ta i l s t test only for data of FH patients (16).

Due to a low number of patients studied, 5 with combined HLP and 6 with

type I I I HLP, the i r s ta t i s t i ca l evaluation was not possible. Only variat ions of

percentages are reported.

RESULTS

Table I reports serum cholesterol and t r ig lycer ides basal levels of a l l

patients. As can be seen in Fig. I , in FH cholesterol decrease ( ~ mg%) is

always highly s ign i f icant with a maximal decrease of 26% (p<O.O01) af ter 4

months of treatment. This drop stabi l ized i t s e l f at 17% af ter 7 months. Also

t r ig lycer ides are s ign i f i can t l y reduced with a maximal decrease of 29% (p

<0.001) at the 7th month. In 5 combined HLP patients the percentage decrease

of cholesterol reached 32% at the 7th month at which time t r ig lycer ides drop

was 64%. In type I I I HLP pat ients, l i p id decrease was shown to be more

consistent, cholesterol decrease was 48% and t r ig lycer ide 72% af ter 7 months.

PharmacologicalResearch Communications, VoL 18, No. 5, 1986

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476 Pharmacological Research Communications, VoL 18, No. 5, 1986

Fig. 2 shows that in FH pat ients , LDL cholesterol has a decrease s imi lar

to that of serum (-31% at the 4th month, p<O.O01; -20% at the 10th month,

p<O.01). However, HDL cholesterol increased s i g n i f i c a n t l y a f te r 6 months

treatment, reaching a 10% increment at the 7th month (p<0.01).

In combined HLP (Fig. 3) the most important var ia t ions occurred wi th in

VLDL f rac t ions : at the 8th month -73% t r i g l yce r i de and -87% cholestero l . LDL

cholesterol also showed a decrease during the whole t r i a l reaching -22% at the

7th month. HDL cholesterol had a tendency to increase reaching a +9% at the

end of the t r i a l . In type I I I HLP disappearance of ~-VLDL occurred as noted

from the reduction of t r i g l yce r i des : cholesterol ra t io in the f rac t ion with

d<I.006 g/ml from 0.48 to 0.10 (Table 2).

TABLE 2

VLDL-CHOLESTEROL (CH)/TRIGLYCERIDES (TG) AND VLDL-CH/SERUM-TG RATIOS

DURING TREATMENT WITH FENOFIBRATE IN TYPE I I I HYPERLIPOPROTEINEMIA

Months -I 0 +4 +8

VLDL CH m ± 0.57± 0.48± 0.35± 0.01± TG S.E.M. 0.08 0.03 0.10 0.06

VLDL-CH m ± 0.39± 0.40± 0.21± 0.14± Serum-TG S.E.M. 0.06 0.03 0.12 0.04

LDL cholesterol (Fig. 4) demonstrates var iat ions during the whole t r i a l

even i f i t remained wi th in normal range.

Also HDL cholesterol presented mild var iat ions ranging from 40 to 46

mg/dl.

Lipid and l ipoprote in levels in FH pat ients reached normal basal values

a f te r 4 weeks of wash-out.

Body weight was kept stable in FH and type I I I HLP pat ients , whereas i t

increased on the 4th and 6th month in combined HLP pat ients.

SIDE EFFECTS

Two FH patients suspended t r i a l due to SGOT and SGPT increase to about

100 U/L (normal value <40 U/L). The SGOT and SGPT levels decreased wi th in

Pharmacological Research Communications, Vol. 18, No. 5, 1986

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478 PharmacologicalResearch Communications, Vol. 18, No. 5, 1986

normal range in few days a f te r the drug suspension.

Three pat ients (I with combined HLP and 2 with t y p e l l l HLP) during f ina l

stage of t r i a l had a cutaneous vescicular erythema which disappeared a f te r drug

treatment.

DISCUSSION

Results of our study are in agreement with those of other authors ( I -8 ) .

Fenofibrate was very e f f i c i e n t in reducing both cholesterol and t r i g l yce r i de

levels in hyperlipidemias with d i f f e ren t pathogenesis.

In FH i t reduces LDL, in combined HLP both LDL and VLDL, in type I I I HLP

i t causes the disappearance of B-VLDL. These data seems to indicate that th is

drug acts on various steps of the l ipoprote in catabol ic cascade.

Treatment of combined HLP with other drugs resul ts in a decrease of VLDL

but in an increase of LDL (17,18). As well the disappearance of ~-VLDL should

resu l t in an increase of LDL. This phenomenon was not seen under fenof ibrate

treatment. We think that fenof ibrate acts on catabolism of VLDL and B-VLDL as

well as of LDL with the same strength and ve loc i ty .

Concerning HDL behavior under fenof ibrate treatment data are

contradictory. In our study we observed an HDL cholesterol increase both in FH

and combined HLP. No var ia t ion of HDL cholesterol was observed in type I I I HLP

patients as was instead reported by R6ssner et al . (4).

Drug e f f icacy remained stable during t r i a l as was already reported by

others (4). I ts tolerance was good during the whole t r i a l .

These resul ts underl ine the important e f f icacy of fenof ibrate on d i f f e ren t

types of genetic hyperlipidemias and makes fenof ibrate nowadays one of the

f i r s t choice l i p i d lowering drugs.

AKNOWLEDGEMENTS

This study was supported in part by grants from Progetto Final izzato CNR:

Ingegneria Genetica e Basi Molecolari del le Malat t ie Ered i tar ie ; Sottoprogetto

Basi Molecolari del le Malat t ie Ered i tar ie .

Pharmacological Research Communications, Vol. 18, No. 5, 1986 479

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480 Pharmacological Research Communications, VoL 18, No. 5, 1986

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