Plasma Lipoproteins to Low-dose Simvastatin in Nine Turkish Men

A Preliminary Report on the Sensitivity of

Plasma Lipoproteins to Low-dose Simvastatin in Nine Turkish Men

Thomas. P. BERSOT, Robert W. MAHLEY

Gladstone Rescm·ch Laboratory, Koç American Hospital, İstanbul, Turkey,

and Gladstone Institute ofCardiovascular Disease, University ofCalifornia, San Francisco, CA

DÜŞÜK DOZ SİMVASTATİNE 9 TÜRK ERKEGİNDE PLAZMA

LİPOPROTEİNLERİNİN DUYARLIGINA İLİŞKİN ÖNBİLDİRİ

ÖZET

Düşük

dansiteli lipoprotein kolesterolün (LDL-K) yüksek (>160 mgldl) ve yüksek dansiteli lipoprotein kolesterolün (HDL-K) alçak plazma düzeyleri ( <35 mg! d!) erken

yaşta

koroner kalp

hastalrğr

riskini yükseltir. Türk

halkı,

belki genetik köken

sonııcu,

mutad olmayan ölçüde

düşük

HDL- K düzeylerine sahip görünmektedir. Üstelik, kenstsel alanlarda

yaşayan

refahlr Türk erkeklerinin

birçoğunun

kolesterol ile LDL-K düzeyleri yüksek olup 5'i

aşan

tah- ripkar total kolesterol/HDL-K oranmr

barrndırmaktadrr.

Eldeki pilot

çalışma düşük

doz simvastatin'in bu oram düze/tip

düzeltemeyeceği

amaciyle

yapı/dr.

HDL-K >35 mg/d! ve total kolesterol/HDL-K >5.5 olan 9 Türk

erkeği

8 hafta süreyle günde 10 mg simvaslatin ile tedavi edildi. LDL-K düzeyleri, tipik olarak ilacrn daha yüksek dozlannda rastlanan dramatik biçimde, yani %42 oranmda

düşürüldü.

Ayrrca, HDL-K düzeyleri, beklenenin ötesinde ve stalin tedavisinin herhangi bir dozu için atipik

sayılacak şekilde

%23

oranında

artll. Bu çok arzu edilen etkiler total kolesterol/HDL-K oramnr %43 mertebesinde, yani

başlangrçtaki

7.5'ten, 8

haftalık

ilaç tedavisi sonunda 4.3'e indirdi. Bu sonuçlar Türklerde alçak doz simvasta- tin'in özellikle etkin

olduğunu düşündürmektedir.

Anahtar kelime/er: Plazma lipoproteinleri, simvastatin , total kolesterol/HDL-K

oranı

T hough the T urk ish Risk Factor Study of the Turk- ish Society of Cardiology (1) has demonstrated that the T urk ish pop ulation generally has low levels of total plasma cholesterol compared to Europeans and Americans, nevertheless, one out of every ten adults has cholesterol val ues

~229

mg/dL. In addi tion, the T urkish Heart Study (2) revealed that many affluent T urkish men and women living in urban areas have Received November 12, 1997

Correspondence to: Robert W. Mahley, M.D., Ph.D.

Gladstone Institute of Cardiovascular Disease P.O. Box 419100 San Francisco, CA 94141-9100

Telephone: (415) 826-7500 Fax : (4 1 5) 285-5632

unacceptably high total cholesterol and ancllow clen- sity lipoprotein cholesterol (LDL-C) levels similar to those seen in populations at high risk of cleveloping eoronary heart disease (CHD). For example, -20%

of Turkish men living in Istanbul and 20% of men residing in the United States have total cholestcrol levels in excess of 240 mg/ciL (2.3). However, as shown in the Turkish Heart Study, Turks may be at even greater CHD risk than is indicated by their total cholesterollevel beccause their levels of high clensi - ty lipoprotein cholesterol (HDL-C) are 10-15 mg/ciL Iower than those in other populations

(2).

Approxi- mately 53% of Turkish men and 26% of Turkis h women have HDL-C levels less than 35 mg/ciL, a value below which CHD risk rises sharply in other populations (2,4). By comparison, only about 15% of men and 5% of women in the United States and Eu- rope have HDL-C levels below 35 mg/ciL

(5).

In combination, elevated cholesterol and LDL-C levels and reduced HDL-C levels are likely to be very de t- rimental with respeet to CHD risk (6,7).

T he low HDL-C appears to represent a

ınajor

popu- lation difference and may, in part, be genetic in ori- gin. Turks surveyeel in six different regions of Tur- key with very different diets had

siınilarly

low HDL - C levels

(2)_

Likewise, Turks living in

Gerınany

(8) and the United States (T.P. Bersot and R .W. Mahley, unpublished o bservations) also have low HDL-C.

Specifica lly, the Turks have low levels of lipopro- te in AI (LpAI), a subfraction of HDL

sinıilar

to

HDLı

(T.P. Bersot and R.W. Mahley, unpublishcd observations). The

HDLı

subelass is considercd to be most protective against the development of CHD(9), whereas low levels of

HDLı

appear to be detrimental.

Studies in progress indicate that the Turks have sig-

nificantly higher levels of hepa tic li pase than United

T.P.Bersot and

R.W.Malıley:

A Preliminar y Report

ontlıe

Sensitivity of Plasma Lipoproteins to Low-dose

Simı·astmin

in Ni m? Turkish

ıli! c•

n

States age-and sex-matched controls (T.P. Bersot and R .W. Mahley, unpublished observations). He- patic lipase is a triglyceride hydrolase and a phos- pholipase that converts HDLı to HDL3 (10-12), and high levels would be expected to reduce both total HDL-C, as well as the

HDLı

subelass. Transgenic animal s expressing high levels of hepatic lipase have markedly low HDL levels ^(13-15), anda deficiency of hepatic lipase in humans (16) and animal models

(17,1 8) is associated with elevated HDL levels, espe- cially

HDLı.

The high levels of hepatic lipase in the Turkish population may be a major factor causing low HDL levels.

In other populations, the total cholesterol to HDL-C ratio (TC/HDL-C) predicts CHD risk irrespective of the etiology of the low HDL-C level. In fact, various studies suggest that a TC/HDL-C ratio >4.5 is asso- ciated with increased ri sk of cardiovascular disease

(7).

Because of the prevalence of lo w HDL-C levels, many Turkish have TC/HDL-C ratios >5 and might profit from decreasing total cholesterol of increasing HDL-C. However, it is po ssible that Turks, with their unique genetic background, might respond dif- ferently to hypolipidemic drug therapy compared to th e response seen in other populations.

The statins are inhibitors of HMG-CoA reductase, a rate-limiting enzyme in cellular cholesterol synthe- sis. Treatment with statin decreases hepatic cho leste- rol content, which increases expression of the LDL receptor gene and leads to increased receptor synthe- sis, enhanced elearance of LDL, and reduced plasma LDL-C and cholesterollevels (19). Simvastatin, one of the

sıaıins

widely usedin Turkey, is highly effec- tive in reducing total cholesterol, LDL-C, and very low dens ity lipoprotein cholesterol (VLDL-C) (20).

In addition, numerous studies in Europe and the United States have shown that simvaslatin reduces triglycerides moderately and slightly increases HDL- C levels by about 10%. The Scandinavian Simvasta-

tİn

Survival Study (4S) has established the safety and effectiveness of simvaslatin at doses of 20-40 mg/day over the 5.4 years of study of this elinical trial (21), In various studies at doses of 5, 10, 20, and 40 mg/day, simvaslatin reduced LDL-C I evels by 24%, 30%, 35%, and 40%, respectively ^(22-25). The purpose of the present study was to determine the ef- fectiveness of simvaslatin in lowering LDL-C and

total cholesterol levels in Turkish subjects and to ob- serve the efects on HDL-C leve ls in an

^attenıpt

to improve the TC/HDL-C ratio in th is population characterized by low HDL-C levels.

Methods Patients

Healthy adult Turkish men

liviııg

in Istanbul. Tu rkey, who had plasma lipid

determiııatioııs

after a 12-h fas t as part of an annual health survey returned to the Koç American Hospital for a second phlebotomy to confirm thcir eligi bil- ity based on the lipid eriteria d eseribed bclow. Subjccts who had fasting triglycerides <300 mg/dL. HDL-C $35 mg/dL, and TC/ HDL-C>5.5 were invitcd to

parıicipate

in the study. Patients using hypolipidemic drugs.

~-blockers,

or thiazide diuretics were excludcd. All subjccts wcre screened by appropria te testing to exeJude secondary caus- es of hyerlipidemia, such as diabetes

melliıus

and thyroid.

renal, or live r disease. All subjects were requesteel to

nıaintain

their usual dietand l ife-style.

Upon accoptance into the trial the patients were

givcıı

4- week supplies of

sinıvastatin,

10 mg (Zocor. MSD-Tur- key) and instructed to take one tabJet daily at

bedtinıe.

At the enel of 4 and 8 weeks, plasma lipid mensurement s were repcated. Compliance was assessed by pill counts a t each

visiı.

All nine patie nts included in this repo rt had > 90%

compliance.

Laboratory Procedures

The plasma cholesterol, triglyceride, and HDL-C

conceıı­

trations were measurcd by enzymatic tcchniqucs in the lip- id diagnostic laboratory of the Koç American Hospital.

İstanbul, Turkey, a certified lipid refcrcnce laboratory

!2>.

The coneentrations of the HDL

subfractioııs

LpAl and LpAI/II were determined by

electroiınınunoassay <2~J.

Re- sults in the tables are

nıean

± SO. Student's

1

test was used to compare changes in

meaıı

values. A probabilit y of 0 .05 or below was considered

significanı.

Results

This is a preliminary report of the data from nine healthy Turkish men who

coınplcted

a

ıhcrapcutic

8- week trial with 10 mg/day of sim vaslatin takcn at bedtime. All subjects enrolled in th e study had an HDL-C

~35

mg/dL, a TC/HDL-C ratio >5.5, and tri- glycerides <300 mg/dL. As shown in Table

ı,

two subjects (A.T. and A.

Şeh)

were obcse (BMI >27 kg/m2). The weight of the

paticnıs

did not vary by more than 1 kg during the 8-week study.

The effect of 10 mg of simvaslatin on vario us plas- ma lipid values at 8 weeks is summarized in Tablc 2.

The individual data on plasma cholesterol, LDL-C,

~••••••~u•~••J.,..."~""''"'"''$'"'"''-"•-""' '"" ...

Tab le 1. Characteristics of the mal e patients

Age (years) Height (m) Weight (kg) BMI(kg/ml)

A.A. 54 1.72 75 25.4

H.A. 40 1.67 70 25.1

Şeh.A.

48 1.69 91 31.9

Şev.A.

36 1.59 68 26.9

F.B. 49 1.75 70 22.9

I.

B. 51 1.80 77 23.8

M.B. 38 1.73 67 22.4

C. E. 45 1.79 77 24.0

A.T. 53 1.75 88 28.7

BM!, body mass index.

Table 2. Effects of

sinıvastalin

(10 mg/day) on

plasnıa

lipid levels in n ine Turkish men

Baseline• 8 Weeks*

(mg/dL) (mg/dL) %change p value

Cholesterol 225±36 160±25 ! 29% <0.001

LDL-C 161±34 94±25 !42% <0.001

HDL-C 30±3 37±3 f23% 0.002

Triglyccrides 166±36 146±36 ! 12% N.S.

*mean ± SD. t

Tab le 3. Effects of

sinıvastalin

(lO

ıng/day)

on HDL subfrac- tion and apo-Al levels.

Week O* Week 8* %change p value

LpAI 32±3 28±3 ! 9% N.S.

LpAI/AII 68±7 102±14 f50% <0.001

Apo-Al 100±8 129±14 tJO% <0.001

*mg apo-AlldL

HDL-C, and triglycerides areshownin Figures 1-4, respectively. The m ean total cholesterol !eve! de- clined by 29% (range, 15-50%) from 225±36 to 160±25 mg/dL (p<O.OO

ı;

Tab le 2 and Fig. 1 ). The mean LDL-C !eve! decreased by 42% (range, 24- 62%) from 16

ı

±34 to 94 ± 25 mg/dL (p<OOO 1; Ta- ble 2 and Fig. 2). The mean HDL-C value increased by 23% (range, 2-40%) from 30±3 to 37±3 mg/dL (p=0.002, Tab1e 2 and Fig. 3). Although the mean

!eve! of plasma triglycerides declined from 166±36 to 146 ± 45 mg/dL, this difference did not achieve statistical significance (Tab le 2 and Fig. 4 ). The mean TC/HDL-C ratio decreased by 43% from 7.5 to 4.3 compareel to the baseline mean value.

The 23% increase in HDL-C levels reflects the im-

pact of s imvaslatin therapy on total HDL cholcstcrol levels, but does not reveal the impact of this treat- ment on the different HDL subfractions, wh ich elif- fer structurally and metabolically. Accordingly, the samples of baseline HDL and those after the 8-week treatment were separated into two major subfra c- tions, LpAI and LpAI/AII (Table 3). Total

plasnıa

apolipoprotein (apo-) AI levels were also measurcd (Table 3). Plasma apo-AI levels inercaseel s ignifi- cantly (30%) from

ıoo

± 8 to 129 ± 14 mg/ciL (p<O.OOI). This increase in the mean apo-AI lcvcl was due to an increase in the mean LpAI/AII con- centration from 68 ± 7 to 102 ± 14 mg/ciL (p<O.OO I) on treatment. Therefore, the !eve! of apo-AT was sig- nificantly affected by s imvaslatin

tlıerapy,

but the LpAI fraction was not.

D iscussion

This study shows that low-close simvaslatin thcrapy markedly decreased LDL-C and inercaseel HDL-C, resulting in a very s ignificant clecrease in the TC/HDL-C ratio. Because only nine subjects wc re studiecl, these substantial bencficial effccts mu st be confirmed by studies with add itional su bj ccts. How- ever, the

effecıs

on LDL-C and HDL-C are unprccc- dented and for this reason we are reporting the m

here . Why Turks respond so favorably to low closcs

of simvaslatin compareel with

subjecıs sıucliccl

in western Europe and the United States is unclcar and requires further study.

The

sıriking

42% reduction in the mean LDL-C in Turks treated w ith

ı

O mg of

sinıvastalin

is equiva- lent to the effect of 40 mg of s imvaslatin reporteel in the Scandinavian Simvaslatin Survival Study (4S) and other elinical trials conducted in wcstcrn Europc and in the United States (21-23,25). These Turkish pa- tients also had substantially greater reductions in LDL-C levels (42% vers us - 31 %) than paticnts with

comparabıy

low HDL-C le ve ls trcated in the United States with 20 mg lovastatin, a close cquiva- lent to

-ı

O mg of simvastari n

(27).

Even more striking was the mark eel

effccı

of low-

dose simvaslatin on the mean HDL-C lcvcl. which

increased by 23%. In virtually al l of the elinical

trials of s tatins, inciueling simvastatin. conducted

outside of Turkey, mean HDL-C leve ls increased

only 3-12%, irrespective of basel ine HDL-C lcvc ls

T.P.Bersor and

R.W.Malıley:

A Preliminary Report

onrlıe

Sensiril'iry of Plasma Lipoproreins ro Low-dose Simmsrarin in Nine Turkish l'vfen

--.. 300

:o ²⁸⁰ _o

aı E ²⁶⁰

- ö ...

Q)

²⁴⁰ ₂₂₀

Q)

^{- i O}

c:ı-20

-

^{Cl) Q)}

^{200 c} _ro

o

_ıso

6-30

.r;;

<.>

160

^~

ro

^o

-40

E ₁₄₀

Cl)

ro _-50

c: ¹²⁰

100 -o o

o 4 8 o 4 8

Weeks Weeks

Figure 1.

A.

Plasma cholesterollevels at baseline and after 8 weeks of

simvasıaıin ıherapy

(10 mg/day). B. Percent change in

ıoıal cholesıe­

rol from baseline.

240

.-220 o

~

_0'1

²⁰⁰

-1 0

.§, 180

e ^{160 ~-20}

ı::

Q)

140 _~ -30

-

^{Cl) Q)}

120 u

ö _cJ100 * ^-40

- 50 ..J o 80

..J 60

^~o

40 -70

o 4 8 o 4 8

Week s Weeks

Figure 2. A. LDL

cholesıerollevels

ar baseline and

afıer

8 week s of simvaslatin

ıherapy

( 10 mg/ day). B. Percent change in LDL

cholcsıcrol

from baseline.

or the dose of statin employed (21,27-30). It is possi- ble that the effects of simvaslatin in Turks who have low HDL-C may be a function of the spec ific genet- ic trait(s) that mediates low HDL-C in this popula-

ıion.

Specifically, in the context of high levels of he- patic lipase, simvaslatin may be especially effective in elevating HDL levels.

The increase in HDL-C was associated with a 30%

increase in mean apo-AI levels. The HDL subfrac- tion affected was the LpAI/AII subfraction, which increased by 50%. Although it is the concentration of the LpAI subfraction of HDL that correlates best with CHD risk, there are few data on the effects of various treatmenis (diet, drug, or exercise) on LpAI

or LpAI/AII

concenırations

in patients with lo w HDL-C levels. In the Monitored Athcrosclcrosis Rc- gression Study (MARS), hypercholesterolemic pa- tients with normal HDL-C levels trcatcd

witlı

lovas-

ıatin

(80 mg/day) experienced no statistically signifi- cant change in HDL-C, LpAI, or LpAI/ AII lcvel s (31 ). In a study of hypercholesterolemic

paticnıs

with

nomıal

HDL-C levels treated with s imvastari n (20 or 40 mg), LpAI levels increased slightly (5.69), but

ttıere

was no effect on LpAI/AII lcvcls (32). Howcv-

er, pravastat in , in a study of

subjccıs

wi th nonnal

HDL-C levels, increased LpAI/AII levels signifi-

cantly (33%) and also had a significant cffect on

LpAI levels (33). The variable

cffccıs

of statins on

-···---··-··..~~--~······~-

.. - ^...

^{-~. ·~}

^...

45 50

,...

=ti 40

o, ₄₀

- E o ... ₃₅

^{O) Q1}

_c: ³⁰

.!

<U

ı.n •ıo

Q)

u

ö ₃₀

_-;:;!!..

• ^o

()

10

-1 c ₂₅

:ı:

o

20 o 4 8 o 4 a

Weeks Weeks

Figure 3. A. HDL

cholesıerollevels

at baseline and

afıer

8 weeks of simvastat in

ıherapy

( 10

ıng/day).

B. Percent change in HDL

clıolesıe­

rol from baseline.

,...280 so

~ ²⁶⁰

Ol

so

E 240

-

^(/1 _Q)

220 40

~ (1)

·.: 200

_cı

20

(1) ı::

§!. 180

nı

~ ^{160 .:::.}

()

o

ı= 140 "#-

<U

-20

E 120

(/1

<U

-4{)

c: ¹⁰⁰

80 -ôO

o 4 8 o 4 8

Weeks Week s

Figure

.ı.

A. Triglyccridc

lcvel~ at

baseline and

afıer

8 wccks of

siıııva~ıaıin ıhcrapy

( 10 mg/day). B. Percent change in

ıriglyccridc' frcıııı ba~cline.

LpAI and LpAI/AII levels reported in these studies suggcsts that further work is necded to deterrnine the specific e ffec ts of th ese drugs on HDL subfractions and their metabolis m. Similarly, further study of Turkish patients with low HDL-C levels is necessary to confirm the e ffec ts of simvastatin on specific HDL subfractions.

In our study, the beneficial effects of simvaslatin in- creasing HDL-C and decreasing LDL-C, decreased the TC/HDL-C ratio by 43% from 7.5 to 4.3. Epi- demiologic data s uggest that TC/HDL-C val ues greater than 4.5 to 6.0 are associated with substantial increases in risk o f devetoping CHD (6,34,35). From

all that we know, a rat io of 7.5 (the

ıncan

for our Turkish patients at baseline) is ccrtainly a high ris k ratio, and low-dose simvaslati n therapy dramatically reduced this ratio and apparently the associatcd risk.

In both observational and intervcn tion trials, CHD risk has decreased by 2-3% for cac h I

ıng/ciL

in- crease in HDL-C (34.36). In our Turkis h subjccts, the

ınean

HDL-C level increased by 7 mg/dL, which

ınight

be expected to produce a 14-21 % dccrcasc in CHD ri s k in these subjects due to the

inıprovcd

HDL-C levels alone. An even greatcr reduction in CHD risk might be expected from the

addiıional

benefit associated with the 42% reduction in the

mean LDL-C leve1 in our subjccts.

T.P.Bersor and R.

W.Malıley:

A

Prelinıinary

Report on

rlıe

Sensiriviry of

Plasnıa

Lipoproreins ro Low-dose Simmswrin in N ine Turkish Men

In summary, we have made a preliminary observa- tion that a lo w dose of simvaslatin (1 O mg) reduced LDL-C by 42% and increased HDL-C by 23% in a small group of Turkish men who had low HDL-C lcvels and high-risk TC/HDL-C ratios. If confinned,

ıhese

results suggest that low-do se statin therapy may have a unique therapeutic effect in Turks that could substantially reduce CHD risk in this popula- tion.

Acknowledgments

We are indebted to Drs.

İlyas Tokatlı, Durmuş

Sevinç, Or- ya! Gökdemir, and Sinan

Özbayrakçı

for their assistance in recruiting the patients at the Koç American Hospital, Is- tanbul. We also thank Dr. K. Erhan

Palaoğlu

for coordi- nating and overseeing the lipid and

biocheınical

analyses in the Clinical

Laboratoı·y

at the Koç American Hospital.

The exeelieni technical assistance of Judy Pepin. Willard

Freenıan,

Timur

Arslanoğlu,

Sarah Kim, and Hülya Onat is gratefully acknowledgecl. For exeelieni help in

ınanu­

script preparation, we thank Ellen Serman and Sylvia Richmond, for editorial assistance we than k Stephen Ord- way and Gary Howard, and for graphics we thank Sylvia Richmond. We also wish to acknowledge the generous

sııpport

of the Koç American Hospital, the J. David Olad- stone

Institııtes,

and Merck

Slıarp

and

Dohnıe,

Turkey.

REFERENCES

1. Onat A, Şurdum- Avcı G, Şenocak M, Örnek E, Gözükara Y:

Plasına

lipids and their interrelationship in Turkish adults. J. Epidemiol.

Conınıunity

Health I 992; 46:

470-476

2. Mahley RW,

Palaoğlu

KE, Atak Z. et al: Turki sh Heart Study: Lipid s, lipoproteins, and apolipoproteins. J.

Lipid Res.

ı

995; 36: 839-859

3.

Seınpos

CT,

Cleeınan

JI, Carroll MD, et al: Preva- lcnce of high blood cho lesterol among US adults. An up- date based on guidelines from the second report of the Na- tional Cholesterol Education

Progranı

Adul t Treatment Panel. J.

Anı.

Med. Assoc. 1993; 269: 3009-3014

4. NIH Consensus Development Panel Triglyceride, high- density

lipoproıein.

and coronary heart disease. J Am Med Assoc 1 993; 269: 505-51 O

5. National Cholesterol Education Program. Second report of the Expert Panel on Detection, Evaluation, and Treat- ment of High Blood Cholesterol in Adults (Adult Treat- ment Panel Il). Circulation 1994; 89: 1329-1445

6. Castelli WP, Garriso RJ, Wilson PWF, Abbout RD, Kalousdian S, Kannel WB: Ineidence of coronary heart disease and lipoprotein cholesterol levels. The

Fraıning­

hanı

Study. J

Anı

Med Assoc 1 986; 256: 2835-2838

7. Gordon T, Castelli WP, Hjortland MC, Kannel, WB, Dawber TR: High adensity lipoprotein asa

proıec­

tive factor against coronary heart disease. The

Framiııg­

hanı

Study.

Anı

J Med I 997; 62: 707-714

8.

Lüttınann

S, von Eckardstein A, W ei W, et al:

Eıec­

trophoretic screening for genetic

varitıtion

i n apolipopro- tein C-III: ldentification of a novel apoC-lll variant. apoC- III(Asp45Asn) ina Turkish patient. J. Lipid Res. 1994: 35:

1431 - 1440

9. von Eckardstein A, Huang Y, Assmann G: Physi- ological role and elinical

reıevance

o f hig h-

deıısity

lipoprotein subclasses. Curr Opin Lipid ol 1994; 5: 404- 416

10. Hayden R , Ma Y, Brunzell J, Henderson HE: Ge- netic variants affecting hurınan lipoprotein and lı epat ic li- pases. Curr Opin Lipidol 1991; 2: 104-109

ll. Jackson RL: Lipoprotein

ıipase

and hepatic

ıipase.

In The Enzymes. 3rd ed. Vol. 16, P. D. Boyer,

ediıoı·s.

Aca-

denıic

Pre ss, New York 1983; 14 1-181.

12. Olivecrona T, Bengtsson -O livecrona G: Li popro- tein lipase and hepatic lipase. Curr Opin Lipiclol 1993: 4 : 187-196

13. Fan J, Wang J, Bensadoun A:

Ovcrcxprcssioıı

of he- pa tic lipase in

transgeııic

rabbits leads to a markeel reduc- tion of plasma hi gh

deıısity

lipoproteins and

internıcdiaıc

density lipoproteins. Proc N ati Acad Sc i USA I 994; 9 1:

8724-8728

14. Busch SJ,

Barıılıart

RL, Martin GA, et al: Human hepatic triglyceridc lipase expressian rccluces high clensity lipoprotein and aortic cholesterol in

choıesterol-fccl tnıns­

genic

nıice.

J Biol

Chenı

1994; 269: 16376-16382 15. Applebaum-Bowden D, Kobayashi .J, KashyapVS, et al: Hepatic lipase gene therapy in hcpatic lipase-clefi- cient

ın

ice.

Aclcnovirus-ıııediated rcplacenıcnt

of a

ıipoıyı­

ic

enzyıne

to the vascular

endotheliunı.

J

Cı

in l nvest 1996;

97: 799-805

16. Hegele RA , Little JA, Vezina C, Maguire ct al: Hc- patic lipase deficiency. Clinical.

biocheınical.

and

nıolecu­

lar genetic charactcristics. Arterioscler

Throıııb

1993: 13:

720-728

17. Daggy BP, Bensadoun A:

Enrichıneııt

of apolipopro- tein B-48 in the LDL

deıısity

class

fotıowing

in vivo

inlıi­

bition of hepatic lipase.

Biochiın

Biophys Acta

ı

9R6: R77:

252-261

18. Kuusi T, Kinnunen PK.J, Nikkilii EA: Hepat ic en- dothelial lipase antiserum influences rat

pıasıııa

low and high density lipoproteins in v ivo. FEB S Le tt 1979:

ı

04:

384-388

19. Brown MS, Golclstein .JI. 1986. A

receptor-nıediated

pathway for

choıcsterol homeosıasis. Scieııcc

232: 34-47 20. Todcl PA, Goa KL:

Simvastatiıı.

A revicw of its phar- macological properties and therapeuti c

poıenıial

in hy per- cholesterolaemia. Drugs

ı

990; 40: 583-607

21. Scandinavian Simvaslatin Survival Study Group.

Randemised trial of cholesterol lowering in 4444

paıicnıs

with coronary heart disease : The Scandinavian Simvasla- tin Survival Study (4S) . Laneel 1994; 344: 1383-1 389 22. Mo! MJT M , E rkelens DW, Gevers Leuven JA, Schouten JA, Sta lenhoef AFH: S imvaslatin (MK-733):

A poteni cholesterol synthesis inhibitor in heterozygous familial hypercholesterolemia. Atherosclerosis 1 988; 69:

13 1-137

23. P rihoda JS, lllingworth DR: Drug thearpy of hyper- lipidemia. Curr Probl Cardiol 1 992; I 7: 545-605

24 . Bruckert E, De Gennes JL, Malbecq W, Baigts F:

Comparison of the efficacy of simvaslatin and standard

fı­

brate therapy in the treatment of primary hypereholestero- lemia and

coınbined

hyperlipidemia. C lin Cardiol 1 995;

ı

8: 62

ı

-629

25. Stcin EA, Davidson MH, Dujovnc CA, et al: Effi ca- cy and to lerability of low-dose simvaslatin and niacin, alone and in

coınbination,

in

patienıs wiıh

combined hy- perl ipidemia: A prospective trial. J Cardiovase Pharrnacol Ther 1996; 1: 107-11 6

26. Par ra HJ , Mezdour H, G halim N, Bard J M, Fru- chart JC: Differential

electroiınmunoassay

of hum an LpA-I lipoprotein partides on ready-to-use plates. Clin Chem 1990; 36: 1431-1435

27. Vega G L, G rundy SM : Lipoprotein respanses to treatment wi th lovastatin, gemfibrozil, and nicotin ic acid in

nornıolipidemic

patients with hypoalphalipoproteine- mia.

Arclı

Intern Med 1994; 154: 73-82

28. Sh epher d J , Cobbe SM, F ord I , et al: Provention of coronary heart disease

wiıh

pravastatin in men

wiıh

hyper-

cholesıerolenıia.

N Engl J Med 1995; 333: 130 1 - 1307 29. Nawroeki , JW, Weiss SR, Davidson MH, et al: Re- d uctio n of LDL cholesterol by 25% to 60% in

paıients

with primary hypercholesterolemia by

atorvasıaıin.

a new HMG-CoA

reducıase

inh ibi tor.

Arıerioscler Tlıronıb.

Vasc. Biol. 1995; 15: 678-682

30. Davidson MH: Fluvastatin

Long-ternı Exıension

Trial (FLUENT): Summary of efficacy and safety.

Anı

J Med 1994; 96 (Suppl. 6A): 41S-44S.

3l. Alaupovic P, Hodis HN, K night-Gibson C, et al: Ef- fects of lovastatin on apoA- and apoB-containing lipopro- teins. Familics in a subpopulation of

paıienıs parıicipaıing

in the Moni tored Atheroselerosis Regressio n Study (MARS). Arterioscler Thromb Vasc. Biol 1 994: 14: 1906- 1914

32. Bard J -M, Parra H-J, Camare R, et al: A

ıııulticeıı­

ıer

comparison of the effects of simvaslatin and

ferıofi­

braıe

th erapy in severe

priınaı·y lıyperclıolesıeroleıııia. wiılı

partic ular emphasis on

lipoproıeiııs defiııed

by

ılıeir

apo- lipoprotein

conıposition.

Metabol i sm 1992: 4 1: 498-503 33. Bard JM, Parra HJ , Do uste-Biazy P,

Fruchıırt

.JC : Effect of pravastatin, an HMG CoA reduc tase

inlıibiıor.

and cholestyramine, a bile acid

sequesıranı.

on

ıipoproıein

partides

defıned

by th eir

apoıipoproıeiıı coıııposiıioıı.

Me-

taboıism

1990; 39: 269-273

34. Castelli W P, Ab bott RD ,

McMaıııara

PM:

Suııı­

nıary

estimates of

cholesteroı

used to

predicı

coronary heart disease. Circulation 1983: 67: 730-734

35. Castelli WP: The folly of questioning the benefi

ıs

of

choıesıeroı

reduction. Am

Faııı Physiciaıı ı

994; 49: 567- 574

36. Lipid Research Clinics

Programı.

19X4. The Lipid Re- search

Cıinics

Coronary Primary

Preveııtion Triaı

results:

II. The

reıaıionship

of reduct ion in ineidence of

coroııary

heart disease to

choıesıeroı ıowering.

J

Anı

Med Assoc

25

ı:

365-374