CLINICAL STUDY

Fluvastatin in the Treatment of Dyslipidemia Associated with Chronic KidneyFailure and Renal Transplantation

Alberto Corsini, Ph.D.Department of Pharmacological Sciences, University of Milan, Milan, Italy

Hallvard Holdaas, M.D.National Hospital, Oslo, Norway

Premature atherosclerotic coronary heart disease driven by

multiple risk factors is a major cause of morbidity and mortality

among the 6 million patients in the United States with chronic

renal failure. Consensus is that kidney failure and renal

transplantation patients should be treated aggressively for

dyslipidemia. Major medical literature databases were searched

for published information about fluvastatin, a HMG-CoA

reductase inhibitor, used in patients with impaired renal

function. This article characterizes the dyslipidemia observed

in these clinical settings and reviews the clinical experience with

fluvastatin.

Keywords atherosclerotic coronary heart disease, chronic

renal failure, renal transplantation, dyslipidemia,

fluvastatin

INTRODUCTION

Chronic kidney failure ranging from mild renal

insufficiency to end-stage disease is a common condition

that may affect as many as 6 million individuals in the

United States.[1] Premature atherosclerotic coronary heart

disease driven by multiple risk factors is a major cause of

morbidity and mortality among such patients. Data also

indicate that cardiovascular complications contribute to a

significant proportion of adverse outcomes in many of the

approximately 14,000 patients per year receiving kidney

transplants in the United States. Cardiovascular events

were responsible for 35% to 45% of deaths among renal

transplant recipients dying with a functioning graft.[2 – 4]

In both settings, atherogenic lipid abnormalities contrib-

ute to the accelerated atherosclerotic process and,

consequently, to the high prevalence of cardiovascular

disease observed in uremic patients and those who have

undergone renal transplantation.

Given the strong evidence of risk reduction and the

benefits of lipid-lowering treatment in the general

population, the emerging consensus is that kidney failure

and renal transplantation patients should be treated

aggressively for dyslipidemia.[5,6] This article character-

izes the dyslipidemia observed in these clinical settings

and reviews the clinical experience with fluvastatin, a

HMG-CoA reductase inhibitor, that may be particularly

suitable for use in kidney failure and renal transplanta-

tion patients.

LIPID DISORDERS IN KIDNEY FAILURE ANDRENAL TRANSPLANT PATIENTS

Dyslipidemia in Kidney Failure Patients

Abnormal lipid profiles vary according to the stage of

renal disease. During the asymptomatic stages of renal

insufficiency, dyslipidemia develops and becomes more

pronounced as renal failure advances. In patients with less

advanced renal insufficiency, the alteration is character-

ized more by its abnormal apolipoproteins rather than its

lipid profile.[7,8] With the progression of renal failure, the

prominent features of uremic dyslipidemia include an

increase in serum triglyceride (TG) levels (reflecting

increased production from free fatty acids and decreased

clearance of very low density lipoprotein [VLDL]

and intermediate-density lipoprotein [IDL]) and low

Address correspondence to Professor Alberto Corsini, Ph.D.,

Department of Pharmacological Sciences, University of Milan, Via

Balzretti 9, Milan 20133, Italy; E-mail: alberto.corsini@unimi.it

259

Renal Failure, 27:259–273, 2005

Copyright D 2005 Taylor & Francis Inc.

ISSN: 0886-022X print / 1525-6049 online

DOI: 10.1081/JDI-200056623

Order reprints of this article at www.copyright.rightslink.com

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high-density lipoprotein cholesterol (HDL-C). Low-den-

sity lipoprotein cholesterol (LDL-C) often is normal, but

the cholesterol may originate from the atherogenic small

and dense LDL subclass (sdLDL). The apolipoprotein B

(apoB100, the primary protein component of LDL, may

undergo enzymatic modifications contributing to im-

paired LDL receptor-mediated clearance from plasma

and to prolong its residence time in the circulation.[9] The

qualitative characteristics of renal dyslipoproteinemia are

not modified substantially by dialysis treatment.

The pathophysiologic links between the renal insuffi-

ciency and the abnormalities of lipoprotein transport are

still poorly defined, and the clinical significance of renal

dyslipidemia has not yet been clearly established. Never-

theless, it is believed that renal dyslipoproteinemia may

contribute to the development of atherosclerotic vascular

disease and progression of glomerular and tubular lesions

with subsequent deterioration of renal function.[10 – 12]

Dyslipidemia in Renal Transplantation

Patients who undergo renal transplantation often have

end stage renal disease (ESRD) for years and many of

them already have lipid derangement before transplanta-

tion. After successful renal transplant, though the renal

function returns to normal, the lipid profile is reported to

remain abnormal. The prevalence of posttransplant

hyperlipidemia ranges from 16%–78% of recipients,[13]

depending on at which time point posttransplantation

serum lipid levels were obtained. Hypercholesterolemia

occurs within 6 months in most patients (82%), whereas

the peak incidence of hypertriglyceridemia is at 12

months after transplantation.[14]

Significant elevations in total cholesterol (TC) levels

are typical, with most of the increase due to elevations in

LDL-C, although significant increases in VLDL-C and

VLDL-TG are also frequently seen.[15 – 17] In addition,

elevated apo B and lipoprotein (a) plasma levels have

been reported, and LDL oxidation may increase following

transplantation.[15,17 – 24] Changes in HDL-C posttrans-

plantation are more variable, with the literature reporting

no change, decreases, or increases.[15,25,26] Changes in

lipids may be seen as early as 3 weeks after transplan-

tation, but typically are observed during the first 3 to 6

months after transplantation, with initial changes persist-

ing over time.[27]

The causes of posttransplant hyperlipidemia (PTHL)

are complex and not fully understood, however several

classes of immunosuppressants including the cortico-

steroids,[14,28 – 30] calcineurin inhibitors (cyclospor-

ine),[31 – 34] (tacrolimus),[35 – 37] and (sirolimus)[38] appear

to play a role. Current data suggest that the discrepancies

in the relative incidence and severity of PTHL are largely

accounted for by this difference in corticosteroid dose.[39]

Posttransplant hyperlipidemia may not only contrib-

ute to increased cardiovascular morbidity and mortality in

the transplant population,[40 – 42] but also may be a factor

in the development and progression of chronic vascular

rejection and chronic graft dysfunction.[43 – 45]

ROLE OF FLUVASTATIN FOR DYSLIPIDEMIAIN THE KIDNEY FAILURE ANDRENAL TRANSPLANTATION

As a drug class, the six statins available in the United

States (atorvastatin, fluvastatin, lovastatin, pravastatin,

rosuvastatin, and simvastatin) all effectively lower LDL-

C. Yet, there are differences among them with respect to

1) pharmacokinetic properties; 2) effects on the entire

lipid profile; and 3) evidence for pleiotropic effects.

Evidence from experimental and clinical outcome trials

have shown that substantial benefits are associated with

treatment with fluvastatin in patients with chronic kidney

failure and following successful renal transplantation.

Pharmacokinetic Properties

The pharmacological features of fluvastatin make it

useful in the setting of kidney failure and renal

transplantation patients (Table 1). Cytochrome P450

(CYP) 2C9, not CYP3A4, is the major hepatic enzyme

responsible for fluvastatin metabolism.[46] Fluvastatin has

no detectable active circulating metabolites. After single

or multiple doses above 20 mg, fluvastatin exhibits

saturable first-pass metabolism resulting in higher-than-

expected plasma fluvastatin concentrations. This phe-

nomenon might be due to the saturation of CYP2C9

enzymes:[46,47] an effect totally prevented by the 80 mg

fluvastatin slow-release formulation.[48] Furthermore,

fluvastatin is not a substrate of p-glycoprotein.[46] Urinary

excretion accounts for just 6% of fluvastatin clearance,

while the fecal route is responsible for 90%.[47] The

pharmacokinetics (PK) of fluvastatin were assessed in

subjects with various degrees of renal impairment

including patients on hemodialysis and nephrotic syn-

drome by Appel-Dingemanse et al.[49] Renal impairment

did not affect the PK of fluvastatin after a single oral dose.

Patients with varying degrees of renal insufficiency,

as well as recipients of kidney transplants, are at high risk

for drug–drug interactions due to their need for multiple

medications. Drug interaction may cause the levels of

concomitant drugs to increase, and, thus, increase the risk

of side effects. Variability in pharmacokinetic properties

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among the statins results in some important differences

in their drug interaction potential. Most of the clinically

important drug interactions that occur with certain of

the statins are attributed to the co-administration of

the statins that are metabolized by Cytochrome P450

(CYP)3A4 and other agents that are potent inhibitors or

substrates of this enzyme. The CYP3A4 isoenzyme is

responsible for the metabolism of atorvastatin, lovastatin,

and simvastatin.[46] Three statins demonstrate only minor

metabolism by CYP3A4: fluvastatin, pravastatin, and

rosuvastatin.[46,47,50] Of particular concern is the potential

for pharmacokinetic interactions with other lipid-lowering

agents, such as fibrates and niacin, and with immunosup-

pressive agents, such as prednisone, tacrolimus, and cyclo-

sporine, which are used posttransplant. Interestingly, the

interaction between statins and fibrates appears to in-

volve more that a single mechanism and not CYP3A4

metabolism.[50 – 54]

Drug disposition can also be altered by mechanisms

independent of CYP-induced metabolism and thereby

may influence the interaction potential of statins. P-

glycoprotein (PGP) is a transmembrane drug-efflux pump

that transports many drugs across cells including those of

the liver and intestine. As such, PGP can be a locus

contributing to drug interactions.[55,56] That is, PGP can

often be the mechanism for significant pharmacokinetic

drug interactions when two or more drugs are competing

for the PGP transport site.

Statin and Cyclosporine Interactions

The interaction of cyclosporine and certain statins via

the CYP3A4 system is a major concern. Moreover, PGP is

responsible, at least in part, for the low and variable

bioavailability of cyclosporine, and the cyclosporine-

pravastatin interaction may occur at the PGP level.[57]

Cyclosporine increases the plasma levels of atorvastatin,

cerivastatin, lovastatin, pravastatin, simvastatin, and to a

very minor extent, that of fluvastatin (Table 2). Concom-

itant therapy with these statins has been reported to

greatly increase the risk of myopathy that may eventually

progress to rhabdomyolysis, and many cases of rhabdo-

myolysis have indeed occurred in transplant patients

taking cyclosporine together with statins.[57] There have

been no reports of rhabdomyolysis when fluvastatin is

Table 1

Clinical pharmacokinetics of HMG-CoA reductase inhibitors

Parameter Atorva Fluva Fluva XL Lova Prava Rosuva Simva

Tmax (h) 2–3 0.5–1 4 2–4 0.9–1.6 3 1.3–2.4

Cmax (ng/mL) 27–66 448 55 10–20 45–55 37 10–34

T1/2 (h) 15–30 0.5–2.3 4.7* 2.9 1.3–2.8 20.8 2–3

Bioavailability (%) 12 19–29 6 5 18 20 5

Protein binding (%) 80–90 >99 >99 >95 43–55 88 94–98

Metabolism CYP3A4 CYP2C9 CYP2C9 CYP3A4 Sulfation CYP2C9, 2C19 (minor) CYP3A4

Metabolites Active Inactive Inactive Active Inactive Active (minor) Active

P-glycoprotein substrate Yes No No Yes Yes No Yes

Urinary excretion (%) 2 6 6 10 20 10 13

Fecal excretion (%) 70 90 90 83 71 90 58

Atorva=atorvastatin; Fluva=fluvastatin; Lova=lovastatin; Prava=pravastatin; Rosuva=rosuvastatin; Simva=simvastatin. Based

in a 40-mg dose, with the exception of fluvastatin XL (80 mg).*Apparent half life.

Adapted from data in Refs. [47,50].

Table 2Effect of co-administered cyclosporine on

pharmacokinetic parameters of statins

AUC* Cmax*

Cerivastatin "�3.7 "�4.8

Fluvastatin "�1.9 "�1.3

Lovastatin "�20 —

Pravastatin "�5–23 "�8

Simvastatin "�3–8 —

Atorvastatin "�6 "�6

Rosuvastatin "�11 "�7

AUC, area under the plasma concentration-time curve; Cmax,

maximum plasma concentration.*Values shown are the changes relative to the statin alone.

Analytical procedures have been utilized for all statins with the

exception of atorvastatin where a bioassay (inhibition of HMG-

CoA reductase activity) has been employed.

Adapted from A. Corsini. Cardiovascular Drugs and Ther-

apy. 2003; Vol. 17, 257–277.

261Fluvastatin, Dyslipidemia, and Nephrotic Patients

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co-administered with cyclosporine. The reduced potential

for pharmacokinetic interaction between fluvastatin and

cyclosporine theoretically is due its predominant metab-

olism by CYP2C9, rather than CYP3A4, and its not being

a substrate for PGP. Recently, it has been reported that

cyclosporine also increased the plasma levels of rosuvas-

tatin (up to 11-fold, probably due to an interaction

between cyclosporine and rosuvastatin at the liver organic

anion transporting polypeptide (OATP-C).[58,59]

Thus, for fluvastatin, the likelihood for serious

metabolic drug interactions is expected to be minimal.[46]

Co-administration of fluvastatin with other lipid-lowering

agents has been shown to be without relevant drug inter-

actions.[60 – 62] In terms of its suitability for use in patients

with end-stage renal disease on maintenance hemodialy-

sis, plasma fluvastatin concentrations are not influenced

by the dialysis membrane, and it does not accumulate in

hemodialysis patients with hyperlipidemia.[63]

Effects on Lipid Profile

Considering that the lipid abnormalities associated

with accelerated atherosclerosis vary with the stage of

renal disease, it is desirable for a lipid lowering agent to

favorably affect abnormal apolipoproteins as well as

lipid levels. In one randomized, placebo-controlled trial

in the elderly (mean age, 75.5 years), fluvastatin XL

produced a mean LDL-C reduction of 31% after 6

months treatment.[64] Median decreases in triglycerides

levels, in another pooled analysis of 1674 patients with

primary hypercholesterolemia,[65] were 19%; and HDL-

C levels were increased by 8.7% overall. Favorable

changes in and apolipoprotein A-I and apolipoprotein B

levels also occurred.

The hypolipidemic potential of fluvastatin may be

greater than that expected from its effects on LDL-C and

TG alone. For example, fluvastatin 80 mg XL, once daily,

decreased total cholesterol and total LDL-C, but in

patients with atherogenic dLDL, absolute changes of

dLDL were most pronounced, emphasizing the value of

fluvastatin treatment in type 2 diabetes and other disease

conditions (including posttransplant dyslipidemia)[66]

characterized by these lipoprotein phenotypes.[67]

Pleiotropic Effects

Statins may have nonlipid-related (pleiotropic) prop-

erties that exert direct beneficial effects on the arterial

wall, interfering with the formation and progression of

atherosclerotic lesions. Evidence indicates that statins can

be differentiated in terms of their pleiotropic proper-

ties.[68 – 70] Preclinical studies of fluvastatin demonstrated

significantly altered leucocyte-endothelial cell adhesion

responses to platelet-activating factor and leukotriene

B4;[71] increased apoptosis in cardiac myocytes;[72]

reduced interleukin-6 levels;[73] inhibited proliferation of

vascular smooth muscle cells;[74] increased tissue plas-

minogen activator secretion;[75] reduced macrophage

accumulation in carotid lesions;[76] and direct antioxidant

effects on LDL-C.[77] Collectively, these actions suggest

that fluvastatin has the ability to decrease the thrombo-

genicity and instability of atheromatous plaques.[78,79]

CLINICAL EXPERIENCEWITH FLUVASTATIN

Kidney Failure/Maintenance Hemodialysis

The impact of atherosclerotic cardiovascular disease

in patients with renal insufficiency is well-documented;[6]

and there is a growing body of evidence documenting the

goals, efficacy, and safety of dyslipidemia treatment

among chronic renal insufficiency and dialysis patients. A

retrospective investigation of 3716 patients with ESRD

showed that statin use was independently associated with

a 36% reduction in the risk of cardiovascular mortality,[80]

and results of a post hoc subgroup analysis from the

recent CARE study showed pravastatin treatment reduced

the risk of major coronary events in patients with mild

chronic renal insufficiency.[81] Similar results have been

obtained with simvastatin in the Heart Protection Study

(HPS) trial.[82] With regard to fluvastatin, three stud-

ies[83 – 85] investigated the efficacy and safety of fluvas-

tatin in patients with various stages of chronic kidney

disease (CKD) and one small study[63] examined the ef-

fect of fluvastatin in hyperlipidemic hemodialysis

patients. Over the course of these studies, 90 patients

were treated with fluvastatin for durations ranging from

8 to 52 weeks (Table 3).

Each study reported significant reductions in TC,

LDL-C, and TG compared to baseline values, with two of

the studies[83,84] also demonstrating significant reductions

in these parameters compared to placebo. Total choles-

terol levels dropped 15% to 32% following fluvastatin

treatment, a trend mirrored by 21% to 31% reductions in

LDL-C and 7% to 19% reductions in TG. In one study

that compared the effects of fluvastatin in patients with or

without chronic kidney disease, the degree of renal

function (creatinine clearance levels 30 to 60 mL/min or

60 to 90 mL/min) did not appear to affect the lipid-

lowering effects of fluvastatin,[83] suggesting that patients

with any degree of renal impairment may benefit from

fluvastatin treatment. Another study noted significant

A. Corsini and H. Holdaas262

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irubin

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d

pla

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1fl

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tati

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pat

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dev

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myal

gia

.

[91]

182

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crit

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40

mg/d

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15%

�18%

a

(ver

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+2%

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of

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and

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num

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sof

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bet

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[92]

37

TC

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(ver

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pre

ssure

or

GF

Rbet

wee

nfl

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n

and

pla

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264

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onal

use

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y.

265

Ref

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Num

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n

Entr

ycr

iter

ia

(act

ive

trea

tmen

t)

Dura

tion

of

acti

ve

trea

tmen

t

Tre

atm

ent

regim

en

Eff

ects

on

lipid

s

Saf

ety

findin

gs

TC

LD

L-C

HD

L-C

TG

Tri

als

Com

par

ing

Post

-Tre

atm

ent

Eff

ects

toB

asel

ine

Val

ues

[94]

38

TC

>250

mg/d

L

LD

L-C

>150

mg/d

2yea

rs40

–80

mg/d

ay�

18%

b�

23%

b+

2%

�21%

bM

ild

and

tran

sien

tad

ver

seef

fect

sobse

rved

,

wit

hno

signif

ican

tvar

iati

on

inhep

atic

enzy

mes

,uri

cac

idor

CP

K.

[98]

21

(dia

bet

ic)

TC

255

–380

mg/d

L

TG

115

–352

mg/d

L

1yea

r20

mg/d

ay�

17%

b�

7%

b+

36%

b�

28%

bN

oad

ver

seev

ents

or

alte

rati

ons

in

hep

atic

enzy

mes

;sl

ight

and

signif

ican

tri

sein

CP

Kth

at

rem

ained

innorm

alre

fere

nce

range

[114]

20

TC

>251

mg/d

L1

yea

r20

–40

mg/d

ay�

18%

b

to�

21%

b

�27%

bto

�29%

b�

1%

to0%

�16%

to�

41%

Flu

vas

tati

ndis

conti

nued

in1

pat

ient

due

tonau

sea

and

vom

itin

g;

no

alte

rati

ons

inhep

atic

enzy

mes

or

CP

Kobse

rved

[115]

20

TC

>243

mg/d

L1

yea

r20

–40

mg/d

ay�

20%

b�

28%

b�

1%

�27%

2pat

ients

report

ednau

sea

(1dis

conti

nued

trea

tmen

t)an

d1

pat

ient

report

ed

tran

sien

tin

som

nia

[116]

30

‘‘N

on-r

esponsi

ve

todie

t’’

hyper

lipid

emia

6m

onth

s20

–40

mg/d

ay�

27%

to

�29%

b

�31%

bN

/Rz

N/R

zN

osi

gnif

ican

tef

fect

of

fluvas

tati

non

CP

K,

and

no

adver

seev

ents

rela

ted

tom

yoto

xic

ity

[117]

16

TC

>240

mg/d

L

LD

L-C

>130

mg/d

L

6m

onth

s20

–40

mg/d

ay�

16%

a,b

�29%

a,b

+6%

�11%

No

signif

ican

tef

fect

of

fluvas

tati

n

on

renal

and

liver

funct

ion

test

s

or

CP

Kle

vel

s;no

myal

gia

report

ed.

[95]

14

TC

>240

mg/d

L

TG

<440

mg/d

L

20

wee

ks

20

–40

mg/d

ay�

27%

b�

38%

b0%

�23%

bN

oad

ver

seev

ents

or

effe

cton

CP

Kobse

rved

.

[102]

20

LD

L-C

>160

mg/d

L

TG

<400

mg/d

L

14

wee

ks

20

mg/d

ay�

16%

b�

25%

b+

7%

�9%

Adver

seev

ents

gen

eral

lym

ild

and

tran

sien

t;no

evid

ence

of

myopat

hy,

rhab

dom

yoly

sis,

or

ophth

alm

olo

gic

abnorm

alit

ies

[118]

38

TC

>251

mg/d

L12

wee

ks

20

mg/d

ay�

23%

b�

30%

bN

/Rd

N/R

dA

dver

seef

fect

s(g

astr

icco

mpla

ints

,

myal

gia

)m

ild

and

tran

sien

tan

d

did

not

requir

etr

eatm

ent

dis

conti

nuat

ion;

no

signif

ican

t

elev

atio

ns

inhep

atic

enzy

mes

or

CP

K

[119]

17

TC

>240

mg/d

L

LD

L-C

>160

mg/d

L

12

wee

ks

20

mg/d

ay�

18%

b�

25%

b�

6%

�15%

No

stat

in-r

elat

edad

ver

seef

fect

s

report

ed,

and

no

chan

ges

inli

ver

enzy

mes

or

CP

K

[96]

12

TC

>220

mg/d

L

LD

L-C

>160

mg/d

L

12

wee

ks

20

mg/d

ay�

25%

b�

31%

b+

5%

�20%

bN

oad

ver

seev

ents

or

effe

cton

CP

Kobse

rved

[97]

21

(dia

bet

ic)

TC

>255

mg/d

L

TG

<354

mg/d

L

12

wee

ks

20

mg/d

ay�

17%

b�

3%

b+

36%

c�

7%

bN

oad

ver

seef

fect

sre

port

ed.

[120]

10

No

lipid

crit

eria

12

wee

ks

20

mg/d

ay�

17%

b�

28%

b+

4%

�11%

bN

osi

gnif

ican

tch

anges

inhep

atic

enzy

mes

or

CP

Kle

vel

sobse

rved

[121]

19

TC

>240

mg/d

L

LD

L-C

>130

mg/d

L

8w

eeks

40

mg/d

ay�

15%

b�

22%

b+

7%

�9%

No

effe

cton

hem

ost

atic

par

amet

ers.

[122]

20

(12

wit

h

pre

dnis

one

and

8w

ithout)

LD

L-C

>160

mg/d

Lor

TC

/HD

L-C

rati

o>

5.0

.

�26

wee

ks

20

mg/d

ay�

12%

ban

d

�13%

�12.%

ban

d

�16.%

b

No

chan

ge

No

chan

ge

Low

dosa

ges

of

fluvas

tati

nap

pea

r

tobe

safe

incy

closp

ori

ne-

trea

ted

renal

tran

spla

nt

reci

pie

nts

TC

=to

tal

chole

ster

ol;

LD

L-C

=lo

wden

sity

lipopro

tein

chole

ster

ol;

HD

L-C

=hig

hden

sity

lipopro

tein

chole

ster

ol;

TG

=tr

igly

ceri

des

.aS

ignif

ican

tly

low

erval

ues

than

those

achie

ved

wit

hpla

cebo

trea

tmen

t(

p<

0.0

5).

bS

ignif

ican

tly

low

erth

anbas

elin

eval

ues

(p

<0.0

5).

cS

ignif

ican

tly

hig

her

than

bas

elin

eval

ues

.dN

R=

not

report

ed;

spec

ific

val

ues

for

blo

od

lipid

par

amet

ers

not

report

ed.

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reductions in serum lipids within 2 months of the onset of

treatment, with effects persisting through 1 year.[85]

The largest study was conducted in 45 patients with

moderate-to-advanced renal insufficiency (i.e., stage 3 to

stage 5 CKD). In addition to the reductions in TC, LDL-

C, and TG noted in the other studies, this study also

reported beneficial changes in apolipoproteins and

lipoprotein particle profiles.[84] Following fluvastatin

treatment, the levels of TC, LDL-C, ApoB, and Lp(b)

returned to those seen in healthy, normolipidemic people,

while levels of TG, VLDL-C, apoCIII, and apoCIII-HP

were reduced less substantially.[84] Given the association

of abnormalities in these lipoproteins with the progression

of renal insufficiency,[86] the results of this study suggest

that fluvastatin treatment has the potential to attenuate the

progression of chronic kidney disease through its lipid-

lowering effects.

No serious adverse events were attributed to

fluvastatin treatment in any of the studies, with the most

common side effects being gastrointestinal complaints,

such as nausea or vomiting. While one study noted a

significant rise in serum creatinine levels, this was

attributed to decreased glomerular filtration, a character-

istic of the study population;[85] the other studies found no

such increase.

Together, these studies provide evidence that fluvas-

tatin can induce favorable changes in blood lipid

parameters; however, further studies must be conducted

to determine whether these alterations produce beneficial

outcomes with regard to the progression of chronic kidney

disease and the development of atherosclerotic processes

in patients with impaired renal function.

Renal Transplantation

Levels of TC, LDL-C, and HDL-C rise following

transplantation; a result of immunosuppressive therapy

and altered diet.[14,42,87] A total of 20 well-documented

studies have examined the lipid effects of fluvastatin in

patients who underwent successful renal transplantation

(Table 4). During the course of these studies, more than

1500 renal transplant recipients received fluvastatin for

durations ranging from 3 months to 6 years. Five of these

studies were placebo-controlled,[88 – 92] with the other

studies comparing the effects of fluvastatin to pretreat-

ment serum lipid values in patients with at least

moderately elevated TC (>200 mg/dL) or LDL-C (>130

mg/dL). Every study reported significant reductions in

LDL-C levels following fluvastatin treatment. In 11 of the

studies, LDL-C concentrations fell to levels 3% to 38%

below baseline values. With respect to the placebo-

controlled studies, LDL-C values observed in fluvastatin-

treated patients were consistently significantly lower than

those seen with placebo treatment.

Changes from baseline in the concentrations of TC

followed a similar pattern to that of LDL-C. With two

exceptions[91,92] the studies demonstrated declines in

serum levels of TC that ranged from 7% to 29% lower

than baseline values. With respect to these two studies, the

comparisons with placebo, however, did show significant

differences favoring fluvastatin (�10% and�18%, re-

spectively). Indeed, relative to placebo controls, the

fluvastatin-mediated changes in TC concentrations were

uniformly significant. Specifically, placebo-treated

patients completed the studies with TC values that were

more than 10% higher than were their fluvastatin-treated

counterparts. The reductions in TC and LDL-C occurred

within 1 month of initiating fluvastatin therapy[93,94] and

persisted for the duration of the treatment period, even in

those studies that exceeded 6 months[89,94] and persisted

for over 5 years in one study.[88] Most of the studies

reported numerical reductions in TG levels and increases

in HDL-C levels; however, these changes were found to

be statistically significant when compared to pretreatment

values only in certain studies.[94 – 98] Collectively these

studies demonstrate that fluvastatin exerts the same types

of lipid-lowering effects in renal transplant patients as it

produces in other study populations.[99,100]

Alert Trial

Whether the beneficial lipid effects described above

confer better outcomes for renal transplant patients has

been addressed in the ALERT (Assessment of Lescol1 in

Renal Transplantation) trial.[88] This multicenter trial

enrolled 2102 patients with functioning renal transplants

and mild-to-moderate elevations in serum cholesterol. All

patients received concomitant cyclosporine A and 81%

received steroid therapy. Nearly all patients also received

cardioprotective medications, including beta-blockers,

calcium channel antagonists, and aspirin.[88] Patients

were randomly assigned to receive fluvastatin at an initial

dose of 40 mg/day or placebo for a period of 5 to 6 years.

Two years into the study, the dosage of fluvastatin was

increased to 80 mg/day based on the more robust blood

lipid reductions noted at higher doses in other studies.[99]

The primary endpoint of the study was the first

occurrence of a major adverse cardiac event (MACE),

defined as cardiac death, nonfatal myocardial infarction

(MI), or coronary revascularization. In addition, the

ALERT trial investigated other combined and individual

cardiac and noncardiac endpoints as well as assessing

treatment effects on lipid concentrations and safety of the

study medication.

A. Corsini and H. Holdaas266

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After 6 weeks of treatment, fluvastatin therapy had

significantly lowered LDL-C concentrations by a mean of

25% compared with placebo, with these effects persisting

throughout the study. After a mean follow-up period of

5.1 years, fluvastatin had significantly lowered mean

LDL-C by 32% compared with placebo. Furthermore,

mean TC and mean TG levels decreased significantly in

the fluvastatin group compared with placebo.

Despite a 17% reduction in the incidence of MACE

in fluvastatin-treated patients, the decrease was not

significantly different than was that observed for placebo

( p=0.139). Treatment with fluvastatin reduced the risk

coronary heart disease, defined as cardiac death or

nonfatal MI by 35%, consistent with the beneficial effects

of statins in other populations. When these events were

assessed individually, fluvastatin treatment reduced the

risk of cardiac death and nonfatal MI by 38% and 32%,

respectively. These reductions were statistically signifi-

cant, and support the beneficial effects of fluvastatin in

this patient population.[88,101]

Safety of Fluvastatin in the Studies Overall

In all of the studies, among fluvastatin-treated pa-

tients compared with baseline or to placebo, no clinically

important alterations in laboratory tests of renal or hepatic

function were observed; likewise, in the placebo-con-

trolled studies, no differences in the frequency or severity

of adverse events were noted between those receiving

fluvastatin and those randomized to placebo. No cases of

fluvastatin-induced rhabdomyolysis were reported. Two

patients experienced myalgia but did not demonstrate

elevated levels of creatine kinase.[90,102] There was a

single patient with an isolated elevation in creatine kinase,

resolving even with continuing fluvastatin treatment.[102]

IMPACT OF FLUVASTATIN ONRENAL FUNCTION

Lipid abnormalities in renal disease are also associ-

ated with a progressive decline in renal function.

Experimental studies demonstrated that potentially ath-

erogenic lipoproteins, such LDL, are associated with renal

pathophysiological changes that result in progressive

glomerular and interstitial damage and an ultimate

reduction in renal function. Furthermore, clinical studies

show that renal function declines more rapidly among

patients with primary renal disease or diabetic nephrop-

athy who have hyperlipidemia.[103] The underlying

pathophysiological mechanisms of the relationship be-

tween dyslipidemia and progression of renal insufficiency

are not fully understood. However, fluvastatin and other

lipid-lowering agents can reduce renal lesions and

preserve renal function by virtue of their effect on lipid

abnormalities and also by influencing important intracel-

lular pathways that are involved in the inflammatory and

fibrogenic responses, which are common components of

many forms of progressive renal injury.[104] The later

effects are independent of plasma cholesterol lowering.

There is evidence that fluvastatin’s beneficial effects

on renal function, beyond reducing hyperlipidemia in

patients with kidney disease, involve a complex action on

several intracellular pathways mediating nitric oxide

formation,[105] inflammation[106] and oxidative process-

es,[107] mesangial cell proliferation,[108] macrophage

adhesion,[109] and fibrogensis.[110] Therefore, fluvastatin

appears to exhibit an antiproteinuric effect and preserve

creatinine clearance[111,112] due to both its lipid-lowering

activities and its direct pleiotropic actions on a number of

biologically important processes.

CONCLUSIONS

Although the National Cholesterol Education Pro-

gram Adult Treatment Panel III recommendations that

patients achieve a LDL-C less than 100 mg/dL, the

optimal extent of LDL-C lowering is even greater, based

on a recent statement.[113] Aggressive treatment that

lowers LDL-C below the currently recommended goal

may further reduce patients’ risk of cardiac death.

Recently reported trials in patients with proven coronary

heart disease suggest that intensive lipid-lowering treat-

ment was beneficial. (Cannon, 2003 #142; Nissen, 2004

#143; de Lemos, 2004 #457.) The rationale for such

treatment appears biologically and clinically plausible and

may be a relevant approach to the accelerated atheroscle-

rosis seen in renal insufficiency and kidney transplant

patients. Chronic kidney failure and renal transplantation

are characterized by abnormalities in lipoprotein metab-

olism, markedly increasing the risk of cardiovascular

disease and contributing to the progression of renal

disease. Therefore, preventive treatment is necessary in

these types of patients. There are no definitive guidelines

as to the best statin to use when renal function is impaired.

In this context, based on its pharmacokinetic properties

and its pleiotropic effects, fluvastatin is a good alternative

among the currently available statins for treatment of the

dyslipidemia in these high-risk populations. Fluvastatin’s

safely and effectively lowers cholesterol levels in patients

with renal disease, and management of dyslipidemia is

associated with beneficial effects on proteinuria and

creatinine clearance.

267Fluvastatin, Dyslipidemia, and Nephrotic Patients

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