Full text of DOI:10.2165/00002018-200124100-00004

Drug Safety 2001; 24 (10): 755-766
0114-5916/01/0010-0755/$22.00/0
REVIEW ARTICLE
© Adis International Limited. All rights reserved.
Calcineurin Inhibitors and
Post-Transplant Hyperlipidaemias
Richard Moore,1 Domingo Hernandez2 and Hannah Valantine3
1
2
3
University of Cardiff, Cardiff, Wales
Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
Department of Cardiac Transplantation, Stanford University Hospital, Stanford, California, USA
Contents
Abstract
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 755
1. Clinical Profile of Post-Transplant Hyperlipidaemia (PTHL) . . . . . . . . . . . . . . . . . . . . . . . . 756
1.1 Incidence and Prevalence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 756
2. Impact of PTHL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 757
2.1 Impact of Hyperlipidaemia on Cardiovascular Disease . . . . . . . . . . . . . . . . . . . . . . 757
2.2 Impact of Hyperlipidaemia on Chronic Rejection . . . . . . . . . . . . . . . . . . . . . . . . . 757
3. Aetiology of PTHL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 758
3.1 Immunosuppressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 758
3.1.1 Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 758
3.1.2 Calcineurin Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 758
3.1.3 Other Fungal-Derived Immunophilin-Binding Macrolides . . . . . . . . . . . . . . . . . 759
3.2 Direct Effects of Immunosuppressants on Atherosclerosis . . . . . . . . . . . . . . . . . . . . . 759
4. PTHL and the Calcineurin Inhibitors: Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . 760
4.1 Renal Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 760
4.2 Liver Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 760
4.3 Conversion Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 761
5. Treatment of PTHL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 761
5.1 Diet and Lifestyle Intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 761
5.2 Lipid-Lowering Agents in the Management of PTHL . . . . . . . . . . . . . . . . . . . . . . . . 761
5.3 Corticosteroid Withdrawal/Dose Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . 762
6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 763
Cardiovascular disease is now the leading cause of death in transplant recip-
Abstract
ients. This is due, in part, to the vulnerability of these patients to a complicated
set of conditions including hypertension, diabetes mellitus, and post-transplant
hyperlipidaemia (PTHL). PTHL is characterised by persistent elevations in total
serum cholesterol, low density lipoprotein cholesterol and triglyceride levels.
The causes of PTHL are complex and not fully understood, however several
classes of immunosuppressants including the corticosteroids, rapamycins and
calcineurin inhibitors, appear to play a role. PTHL has been observed in most
studies in which patients received calcineurin inhibitor–based regimens, and has
been observed with both tacrolimus and cyclosporin. Comparing these calcineu-
rin inhibitors with regard to the relative incidence or severity of PTHL occurring
during treatment is difficult because of the use of higher doses of corticosteroids

756
Moore et al.
in cyclosporin-based regimens, as compared with tacrolimus-based regimens.
However, current expert opinion suggests that the discrepancies in the relative
incidence and severity of PTHL are largely accounted for by this difference in
corticosteroid dose. At this point in time, evidence for potential differences is
scant and inconclusive. Further study is needed, not only to investigate differ-
ences in lipid profile, but also of the relative effects of these immunosuppressants
on long term graft function as well as on cardiovascular morbidity and mortality.
PTHL can be successfully managed with a combination of dietary manage-
ment, reduction and, if appropriate, withdrawal of corticosteroids, and the admin-
istration of lipid-lowering drugs. With this combination of therapeutic options,
the threats to long term health posed by PTHL may be effectively addressed.
The prevention of cardiovascular disease has
increased, and increases in triglyceride levels are
also common.[2,8-10] By contrast, high density lipo-
protein-cholesterol (HDL-C) levels vary.[2,10,11]
Other features of PTHL include increased levels of
apolipoprotein B and lipoprotein(a).[4] Addition-
ally, increased LDL oxidation may occur.
become a major challenge for transplantation med-
icine in the new century. Now the leading cause of
death, it accounts for more than 50% of all mortal-
ity in renal transplant recipients.[1]
The prevalence of ischemic heart disease is 6.4
times higher in transplant recipients without diabe-
tes mellitus than in the age-adjusted general popu-
lation, and in transplant recipients with diabetes mel-
litus, the prevalence is even higher – 20.8 times.[2]
Major contributors to this increased risk include
hypertension, diabetes mellitus, and post-trans-
plant hyperlipidaemia (PTHL).[3-6] All of these dis-
eases may have an impact on patient mortality and
graft loss. Moreover, they appear to be caused to
varying degrees by the immunosuppressive agents
used to prevent acute rejection. Agents include cor-
ticosteroids, sirolimus, and the calcineurin inhibi-
tors, tacrolimus and cyclosporin. This review will
focus on the role of the calcineurin inhibitors in
PTHL and on the complex relationship linking im-
munosuppression, hyperlipidaemia, and cardio-
vascular disease.
Threshold values commonly used in reporting
hyperlipidaemia are 240 mg/dl for total serum cho-
lesterol, 130mg for LDL-C, 200 mg/dl for triglyc-
erides and 30 mg/dl for lipoprotein(a).[12] The clin-
ical profile in individual patients may vary, but any
patient in whom just 1 lipid parameter exceeds its
threshold can be said to have PTHL.
PTHL typically develops 3 to 6 months after
transplantation. Following an initial steep rise in
lipid levels, there may be slight improvement. In
general, the levels then stabilise and remain ele-
vated at 12 months post transplantation.[13] In the
longer term, it is not yet clear whether lipid levels
return further towards baseline, or whether such
reductions simply reflect gradual reductions in the
doses of immunosuppressants used over time.
1.1 Incidence and Prevalence
1. Clinical Profile of Post-Transplant
Hyperlipidaemia (PTHL)
Estimates of the overall incidence of PTHL vary
widely, from 22 to 54%, with estimates varying
according to graft type, although some of this vari-
ation has been attributed to lack of standardisation
in the reporting of lipid levels.[5] PTHL is, how-
ever, well documented and has been observed re-
gardless of the type of organ received.
The most prominent feature of PTHL is an ele-
vation in total cholesterol, which increases in a
dose-dependent fashion with several classes of im-
munosuppressants.[4-10] Most of this increase is the
result of elevation of low density lipoprotein-cho-
lesterol (LDL-C) levels. Very low density lipopro-
tein-cholesterol (VLDL-C) levels are frequently
In kidney- and liver-graft–recipients, the preva-
lence of PTHL has been estimated at 40 to 50%.[14]
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Drug Safety 2001; 24 (10)

Calcineurin Inhibitors and PTHL
757
In a study by Jindal and colleagues,[15] 58% of liver
transplant recipients had evidence of hyperlipidae-
mia (importantly with respect to cardiovascular risk,
37% of patients also had diabetes mellitus). In a
study by Kasiske,[16] total serum cholesterol was
greater than 240 mg/dl in as many as 63% of renal
graft recipients with 60% having LDL-C levels
greater than 130 mg/dl. Triglyceride levels were
greater than 200 mg/dl in 36% of patients in this
study, and lipoprotein(a) levels were greater than 30
mg/dl in 23% of recipients. Pancreatic transplanta-
tion appears to be associated with a less abnormal
lipid profile, and combined kidney/pancreas trans-
plants are associated with a lower incidence of
PTHL in recipients than in patients who received
kidney transplantation alone.[17] However, in heart
transplant recipients, the prevalence of hyperlipi-
daemia may be as high as 80%. Even after dietary
modification, Ballantyne and colleagues[18] noted
LDL-C levels greater than 130 mg/dl in 64% of pat-
ients and triglyceride levels of 200 mg/dl or greater
in 41%.
ease burden in transplant patients even though the
exact relationship between PTHLand cardiovascu-
lar disease is not fully elucidated in this population.
For example, in renal transplant recipients, Aakhus
and colleagues[24] found total serum cholesterol
levels to be a predictor of ischaemic heart disease
but not of cerebrovascular or peripheral vascular
disease. In another multivariate analysis in renal
graft recipients, Kasiske[25] similarly found that to-
tal cholesterol (although not HDL-C or triglycer-
ide) levels were an independent risk factor for both
ischaemic heart disease and all vascular disease,
but not for cerebrovascular disease. In a later study,
Kasiske and colleagues found that HDL-C (but not
total or LDL-C) levels predicted ischaemic heart
disease.[26] Athird study, again by Kasiske and col-
leagues,[27] found that HDL-C and total cholesterol
levels independently predicted ischaemic heart
disease. There is still a need for further investiga-
tion.
2.2 Impact of Hyperlipidaemia on
Chronic Rejection
2. Impact of PTHL
In addition to contributing to cardiovascular
disease in transplant recipients, hyperlipidaemia
might also contribute to the development of chro-
nic allograft rejection. Worsening arteriosclerosis,
intimal thickening, and vascular lumenal oblitera-
tion, which have been described as characteristic
of chronic rejection, are also associated with hyper-
lipidaemia.[28] In vitro studies have shown that ox-
idised LDL has effects on endothelial cells, smooth
muscle cells, monocytes, and macrophages, which
could contribute to chronic rejection and acceler-
ated arteriosclerosis. LDL-C, particularly when
oxidised, also has been shown to stimulate the syn-
thesis of cytokines, growth factors, and extracellu-
lar matrix proteins in renal glomerular mesangial
cells.[29] Finally, on a clinical level, LDL oxidation
has been shown to be increased in transplant recip-
ients. Whether this translates into increased rates
of chronic rejection and graft loss remains to be
proven.[30-32]
Major trials in the general population have shown
the impact of hyperlipidaemia on cardiovascular
disease and mortality, and have demonstrated the
benefits of lowering lipid levels even in patients
with normal cholesterol levels.[19-21] Although less
well studied in transplant recipients, a similar im-
pact would be expected. Consistent with this expec-
tation is a study by Valantine and colleagues,[22] in
which they showed that high lipid levels predicted
mortality and post-transplant coronary artery dis-
ease in patients with heart transplants. In another
study, a 4 year prospective randomised trial, heart
transplant recipients taking simvastatin had both
an improved long term survival (88.6 vs 70.3%, p
= 0.05) and a decreased incidence of accelerated
graft disease (16.6 vs 42.3%, p = 0.045).[23]
2.1 Impact of Hyperlipidaemia on
Cardiovascular Disease
It is generally accepted that PTHL contributes
significantly to the increased cardiovascular dis-
In recipients of heart transplants, which are par-
ticularly prone to vasculopathy, McManus and col-
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Drug Safety 2001; 24 (10)

758
Moore et al.
leagues[33] reported greater lipid accumulation
within the coronary arteries of heart graft recipients
compared with age-matched control individuals. In
another study, Valantine[34] reported that increasing
intimal thickness correlated directly with blood
lipid levels.
been observed in patients with an E2 allele as com-
pared with other genotypes of apolipoprotein E.[44]
Renal insufficiency and overt proteinuria may also
contribute to PTHL as may certain antihypertensive
agents, e.g. β-adrenoceptor antagonists and diuret-
ics. In addition, several classes of immunosuppres-
sants, the subject of this review, play a causative
role.
Some studies in renal transplant patients have
also indicated that hyperlipidaemia is a risk factor
for chronic rejection. With respect to graft survival,
4 studies[26,34-36] in renal transplant recipients de-
monstrated no impact of hypercholesterolaemia,
possibly because appropriate therapy (e.g. with
lipid-lowering agents) prevented cardiovascular
complications. However, a study in younger pa-
tients showed that hypercholesterolaemia was link-
ed to early graft failure[37] and another study of
in male transplant recipients linked chronic rejec-
tion with hypercholesterolaemia.[38] Afurther study
showed LDL-C to be a predictor of renal graft out-
come; graft outcome was dependent on the level of
LDL-C.[39] Moreover, a study by Divakar and col-
leagues[9] showed lower LDL and increased HDL-
C levels to be independent correlates of improved
kidney graft survival.
3.1 Immunosuppressants
The immunosuppressants most associated with
PTHL are corticosteroids, calcineurin inhibitors,
and rapamycins. Although the association between
these agents and hyperlipidaemia has been shown
both clinically and in experimental models, the mo-
lecular mechanisms by which they cause PTHL are
still uncertain.
3.1.1 Corticosteroids
The major contributing role of corticosteroids in
PTHL has been well documented. Corticosteroids
promote insulin resistance, causing secondary hyp-
erinsulinaemia, with a reduction in lipoprotein li-
pase activity, overproduction of triglycerides, and
secretion of VLDL-C.[26,45] Clinical studies have
demonstrated a positive relationship between cor-
ticosteroid dose and hyperlipidaemia in renal trans-
plant patients,[46-48] and in liver graft recipients.[15]
Similarly, total serum cholesterol levels have been
shown to be higher in renal transplant patients
treated with cyclosporin and prednisone compared
with patients treated with cyclosporin and myco-
phenolate mofetil.[49] Interestingly, HDL-C levels
may be increased by corticosteroids, which may
account in part for the variability in HDL-C levels
observed in transplant patients.[50]
Elevated total and LDL-C and reduced HDL-C
are probably all valid independent predictors of ad-
verse outcomes in transplant recipients. Further-
more, elevated triglycerides are probably associ-
ated with an adverse outcome as well.
3. Aetiology of PTHL
The aetiology of PTHL is complex. Known risk
factors for high total cholesterol and LDL-C fol-
lowing transplantation include obesity, male gen-
der, and Black race.[40,41] The incidence of obesity,
a problem to which corticosteroids contribute, is
higher in transplant patients than in the general
population. Diet is a significant contributor to the
atherosclerotic process in the general population[42]
and is probably of equal importance in transplant
patients.
3.1.2 Calcineurin Inhibitors
It is generally accepted that calcineurin inhibi-
tor therapy (cyclosporin and tacrolimus) is associ-
ated with hyperlipidaemia. Postulated mechanisms
include inhibition of bile acid synthesis and bind-
ing of the drug to the LDL receptor with reduction
of its activity.[14] Neither mechanism is well estab-
lished and other mechanisms, including a decrease
in lipoprotein lipase activity and impairment of
Genetic variations may contribute to PTHL. In-
creased HDL levels have been associated with cer-
tain polymorphisms of the apolipoprotein A-I
gene,[43] and increased triglyceride levels have
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Drug Safety 2001; 24 (10)

Calcineurin Inhibitors and PTHL
759
LDL catabolism, may be involved.[51] Calcineurin
inhibitors additionally may increase the suscepti-
bility of LDLto oxidation and may increase plasma
homocysteine levels.[4] Transplant patients with a
history of ischaemic heart disease have also been
found to have reduced levels of antibodies against
oxidised LDL, a reduction that correlates with the
level of immunosuppression.[52]
3.1.3 Other Fungal-Derived
Immunophilin-Binding Macrolides
Like the calcineurin inhibitors, rapamycins are
fungal-derived immunophilin-binding macrolides.
However they have a different mode of action with-
in the cell. The rapamycins have been associated
with even greater hyperlipidaemia than cyclo-
sporin, producing significantly higher total choles-
terol and triglyceride levels.[58,59]
For tacrolimus, the incidence and severity of
PTHL is perceived within the transplant commu-
nity as less than that seen with cyclosporin. How-
ever, differences in the doses of corticosteroids
given to cyclosporin- and tacrolimus-treated pa-
tients prevent an objective comparison as does the
lack of long term clinical data in transplant patients
receiving tacrolimus. Cyclosporin has been more
extensively studied and much of the understanding
about the role of calcineurin inhibitors in PTHL
and cardiovascular morbidities has evolved from
studies of cyclosporin. An additional complicating
factor is that the database for cyclosporin is largely
based on an older formulation of cyclosporin (Sand-
immune®1), which was replaced by a microemul-
sion formulation (Neoral®) because of its more con-
sistent absorption. The impact of the formulation
change on PTHL is unknown, but differences in ex-
cipients may possibly result in selective metabolic
differences such as nitric oxidation.
In an open-label European multicentre study, the
incidence of hypercholesterolaemia was 44% and
the incidence of hypertriglyceridaemia was 51% in
patients who received sirolimus, compared with 14
and 12% respectively in the cyclosporin arm.[60] In
a separate US trial, patients who received sirolimus
2 or 5mg/day along with cyclosporin and pre-
dnisone experienced hypercholesterolaemia rates
of 33 and 37%, and hyperlipidaemia rates of 34
and 42% at 12 months.[61]
A phase I study of everolimus evaluated the ef-
fects of 0.75, 2.5, and 7.5 mg/day of everolimus
when given in combination with cyclosporin and
prednisone. Patients receiving everolimus 0.75
mg/day had similarly increased levels of total se-
rum cholesterol and triglycerides.[62] However the
patient groups receiving everolimus 2.5 and 7.5
mg/day had increases of 89.5 and 54.9% respec-
tively in serum cholesterol, and 459 and 159% re-
spectively in triglycerides.
Studies with cyclosporin monotherapy have
confirmed the hyperlipidaemic effects of the calci-
neurin inhibitors.[2,53-55] However, the addition of
corticosteroids to cyclosporin therapy appears to
account for much of the problem of hyperlipidae-
mia seen in clinical practice. In renal transplant
patients, Locsey and colleagues[56] reported PTHL
in only 3 of 17 patients given cyclosporin mono-
therapy, compared with 30 of 55 patients treated
with combination cyclosporin/corticosteroid ther-
apy. Similarly, in a parallel group study in kidney
transplant recipients, Hricik and colleagues[57]
found that discontinuation of corticosteroids re-
duced total cholesterol levels by over 1 mmol/L in
cyclosporin-treated patients.
3.2 Direct Effects of Immunosuppressants
on Atherosclerosis
In addition to contributing to PTHL, immuno-
suppressants may also directly affect the develop-
ment of atherosclerosis. Although immune cells
present in atherosclerotic plaques have been thought
to contribute to atherogenesis, there is emerging
evidence that both cellular and humoral immune
responses may actually protect against atherogen-
esis, an effect that immunosuppression may atten-
uate. In class I major histocompatibility complex
(MHC)-deficient mice for example, atherosclero-
sis develops at an accelerated rate.[63] In rabbits,
immunisation against oxidised or native LDL has
been shown to decrease atherosclerosis.[64] There-
1
Use of tradenames is for product identification purposes
only and does not imply endorsement.
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Drug Safety 2001; 24 (10)

760
Moore et al.
fore, reduced immunologic function may contrib-
ute to cardiovascular disease independent of the
major metabolic and rheological risk factors asso-
ciated with immunosuppressive therapy.
steroid regimen post-transplant (including a main-
tenance dosage of 10 mg/day prednisone). Interest-
ingly, the authors of this study also noted that there
was no significant difference in cardiovascular
deaths between treatment groups at 1 year. How-
ever, they stated that 1 year follow-up may not be
long enough to assess the long term risks of the
differences in lipid levels.
4. PTHL and the Calcineurin Inhibitors:
Clinical Studies
A large number of studies have compared the
relative effects of cyclosporin and tacrolimus on
lipid profiles in transplant recipients. However, the
use of higher doses of corticosteroids in the major-
ity of cyclosporin studies introduced a bias. Results
of several such studies in patients with renal and
kidney grafts will be discussed. Although not dis-
cussed here, similar results have been obtained in
heart transplant recipients, including children.
4.2 Liver Transplantation
An objective comparison of the effects of cyclo-
sporin and tacrolimus on the lipid profile in liver
transplant patients is similarly difficult because of
differences in corticosteroid dose. In a study of
lipid metabolism 2 years after transplantation, lev-
els of total serum cholesterol or triglycerides did
not significantly differ between treatment groups
although LDL-C and apolipoprotein B levels were
significantly greater in patients receiving cyclo-
sporin compared with tacrolimus.[69] The mean
dosages of corticosteroids in this study were 5.77
mg/day in the cyclosporin group and 4.66 mg/day
in the tacrolimus group. Likewise, in a major US
trial comparing tacrolimus with the Sandimmune®
formulation of cyclosporin, total serum and LDL-C
levels were higher at 6 months and 1 year in the
cyclosporin group.[70] The authors noted that the
difference in corticosteroid dose could account for
some or all of the observed differences in lipid pro-
files. In the equivalent European trial, similar lipo-
protein metabolism results were obtained from
substudies of the population.[71]
In a small study in liver transplant recipients
who were matched for corticosteroid dose, there
were no significant differences between groups at
1 year post-transplant in levels of total cholesterol,
triglycerides, LDL-C or HDL-C.[71] In another
study, gender-specific differences in lipid profile
were observed even after corticosteroid with-
drawal. However, the number of patients not taking
corticosteroids was small, and cholesterol and tri-
glyceride level elevations not exceeding hyper-
lipidaemia threshold values occurred with both
cyclosporin and tacrolimus treatment.[72] Finally,
results of another small study by Fernandez-
4.1 Renal Transplantation
Hohage and colleagues[65] investigated the com-
parative effects of tacrolimus and cyclosporin in
kidney transplant patients. After a median of 6
months post-transplant, there were no significant
differences in levels of total cholesterol, triglycer-
ides, or HDL-C between the cyclosporin and tac-
rolimus groups. Mean LDL-C, lipoprotein(a), and
fibrinogen levels were lower in the tacrolimus
group, however the corticosteroid dosage was 11.0
mg/day in the tacrolimus group compared with
19.0 mg/day in the cyclosporin group. Vela and col-
leagues[66] reported that tacrolimus prevented the
increase in total cholesterol and apolipoprotein B
levels seen in renal transplant patients with cyclo-
sporin, but noted that this also could have been a
result of the use of lower dosages of corticosteroids
in patients receiving tacrolimus. In the major US
trial comparing tacrolimus with the Sandimmune®
formulation of cyclosporin, hypercholesterolaemia
was more common in the cyclosporin group, but
again corticosteroid use was greater.[67] By con-
trast, in a smaller study evaluating the Neoral® for-
mulation, elevations in total serum cholesterol as
well as LDL-C were not as great at 6 months in
patients treated with tacrolimus compared with
those treated with cyclosporin.[68] This was despite
the fact that all patients received a similar cortico-
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Drug Safety 2001; 24 (10)

Calcineurin Inhibitors and PTHL
761
Miranda[73] determined corticosteroid therapy to
be the major determinant of increased cholesterol
levels, as did a 4-year long term study by Charco
and colleagues,[74] which showed that cholesterol
levels were similar in patients treated with cyclo-
sporin or tacrolimus once corticosteroids were
stopped.
5.1 Diet and Lifestyle Intervention
All transplant recipients should be encouraged
to control bodyweight and reduce the intake of un-
saturated fat and cholesterol. Regular exercise and
nonsmoking should also be encouraged. Diets rich
in fish oils[77] containing omega-3 fatty acids have
been reported to improve renal haemodynamics
and serum lipid levels,[5] decrease production of
interleukin-1 and tumour necrosis factor,[78] and
reduce post-transplant hypertension and chronic
rejection. Soya protein has also been reported to
reduce serum cholesterol levels.[79] However, these
findings need to be confirmed in larger, multi-
centre studies.
4.3 Conversion Studies
Switching from cyclosporin to tacrolimus ther-
apy has been reported to reduce levels of total cho-
lesterol by 10 to 15%, and LDL-C by 20 to 25%.
McCune and colleagues,[75] for example, reported
a 23% reduction of LDL-C levels in kidney graft
recipients who were switched from cyclosporin to
tacrolimus. However, in many of these studies,
there was also a concomitant reduction in cortico-
steroid dose. Furthermore, some trials have failed
to show any improvement in cholesterol levels.[76]
Pratschke and colleagues[76] found no reduction in
total serum cholesterol levels after l year despite a
switch to tacrolimus. Althoughtriglyceridesfellfrom
212 to 172 mg/dl the number of patients receiving
corticosteroids also decreased, which may have
impacted the improvement in triglyceride levels.
5.2 Lipid-Lowering Agents in the
Management of PTHL
Several lipid-lowering agents are available, but
not all are appropriate for use in transplant recip-
ients. Cholestyramine, for instance, may interfere
with cyclosporin absorption, and nicotinic acid
(niacin) may cause glucose intolerance, hyper-
uricaemia, and hepatotoxicity, as well as flush-
ing.[5] Fibric acid derivatives, such as gemfibrozil,
have been shown to improve the LDL/HDL ratio
in renal transplant patients and may have a role in
recipients with hypertriglyceridaemia. However,
they may not be suitable for use in liver graft re-
cipients because of the potential to increase the in-
cidence of gallstones.[80]
Hydroxymethylglutaryl coenzyme A (HMG CoA)
reductase inhibitors, more commonly known as
statins, have been widely and successfully used to
treat PTHL. The major HMG CoAreductase inhib-
itors (table I) are effective in lowering LDL-C lev-
els and also have good safety profiles. However,
competition between certain HMG CoA reductase
inhibitors (atorvastatin, cerivastatin, lovastatin, and
simvastatin) and calcineurin inhibitors for the
same hepatic metabolising enzymes (these HMG
CoA reductase inhibitors are predominantly meta-
bolised by the cytochrome P450 3A4 isoenzyme)
can increase blood concentrations of the calci-
neurin inhibitors.[81] Fluvastatin has several meta-
5. Treatment of PTHL
There is still some lack of consensus as to the
threshold for intervention with lipid-lowering
agents in the transplant population and whether to
follow the same guidelines as those used for the
general population. Factors to be considered in-
clude age, gender, the presence of other cardiovas-
cular risk factors, past history of cardiovascular
disease, and costs of intervention. However, re-
gardless of the threshold that is chosen for inter-
vention, pharmacological therapy must be accom-
panied by diet and lifestyle modification. An
additional consideration in transplant patients is
the possible interaction of immunosuppressants
with drugs used to lower serum lipids.
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Drug Safety 2001; 24 (10)

762
Moore et al.
bolic pathways available[82] and pravastatin is not
significantly metabolised by this enzyme. There-
fore, fluvastatin and pravastatin are considered to
be the HMG CoA reductase inhibitors of choice in
patients receiving calcineurin inhibitors.
In studies in renal transplant recipients, flu-
vastatin has been shown to reduce levels of total cho-
lesterol by 13 to 27%, LDL-C by 22 to 38%, and
apolipoprotein B by 13%.[82-84] Similarly, in a com-
bined study of cardiac and renal transplant recipi-
ents, Schrama and colleagues[83] found that fluva-
statin 20 to 40 mg/day reduced levels of total serum
cholesterol by 20%, LDL-C by 30% and HDL2-C
by 35% without causing any subclinical muscle pa-
thology.
Table I. Hydroxymethylglutaryl coenzyme A reductase inhibitors
(‘statins’)
Drug
Potential competition with CNI
metabolism
Atorvastatin
Yes
Yes
No
Cerivastatin
Fluvastatin
Lovastatin
Yes
No
Pravastatin
Simvastatin
Yes
CNI = calcineurin inhibitors.
cytotoxicity as well as a suppression of natural kill-
er cell function.[93]
5.3 Corticosteroid Withdrawal/Dose
Reduction
Pravastatin has also been shown to effectively
reduce total or total and LDL-C in patients with renal
or heart transplants[85-87] without adversely affecting
graft function or creatinine kinase levels. Addition-
ally, it has been reported to reduce the number of
rejection episodes in heart transplant recipients.
Lovastatin, simvastatin, and atorvastatin have all
been used to successfully treat PTHL.[88-90] Lova-
statin has been reported to produce sustained re-
ductions of total cholesterol in renal graft recipi-
ents; however, an unusually high incidence of
rhadomyolysis has been reported in patients with
heart transplants administered lovastatin.[89] The
use of simvastatin has been reported to increase
survival in heart transplant recipients.[23] Atorva-
statin also has been reported to significantly reduce
triglyceride levels in transplant patients.[91]
HMG CoA reductase inhibitors are thus effec-
tive in reducing total cholesterol and LDL-C levels
with a good safety profile. A meta-analysis of 154
studies involving over 3000 transplant recipients
receiving HMG CoA reductase inhibitors recently
confirmed these findings.[92] Most transplant pat-
ients with PTHL will benefit from HMG CoAreduc-
tase inhibitor therapy, but fibric acid derivatives
may be considered in those with hypertriglyceridae-
mia.[5] An additional benefit of HMG CoA reductase
inhibitors is that they appear to have antirejection
effects involving a decrease in antibody-dependent
Many centres have placed growing emphasis on
the tapering or even discontinuation of corticoste-
roid therapy in recent years, particularly in patients
given tacrolimus as a primary immunosuppres-
sant.[94] However, cyclosporin regimens have also
been evolving towards a reduced reliance on corti-
costeroids.
The benefits of corticosteroid withdrawal on the
lipid profile of kidney graft recipients receiving
cyclosporin-based therapy was recently studied by
De Carlis and colleagues.[95] Triglyceride and total
cholesterol levels were both significantly reduced
in patients in whom corticosteroids were discon-
tinued at 6 months, 1 year, and 2 years after ran-
domisation. After 2 years, levels of total choles-
terol, LDL-C, and triglycerides were 25.2, 32.7,
and 26.6% lower and HDL-C levels were 18.6%
higher in these patients compared with those who
continued corticosteroids. Although a study by
Hollander and colleagues[96] showed no differ-
ences in lipid profile despite successful corticoste-
roid withdrawal, this may have reflected differ-
ences between groups in the use of lipid-lowering
therapies. Additionally, in a study by Ratcliffe and
colleagues,[97] there was a sustained fall in the level
of total serum cholesterol of more than 1 mmol/L
with corticosteroid discontinuation.
Corticosteroid withdrawal has also been achiev-
ed in patients with stable liver transplants, receiv-
© Adis International Limited. All rights reserved.
Drug Safety 2001; 24 (10)

Calcineurin Inhibitors and PTHL
763
ing cyclosporin. Gomez and colleagues success-
fully discontinued corticosteroids in patients who
were taking cyclosporin and azathioprine.[98] Fast-
ing total cholesterol levels fell from 211 to 196 mg/dl.
A reduction in triglyceride levels also occurred but
was not significant.
as aggressively as the nontransplant patient for
whom secondary prevention is needed. Finally a
greater commitment to screening for cardiovascu-
lar risk factors prior to transplantation may ensure
a more comprehensive management programme for
the patient.
In patients with stable grafts at least 1 year post-
transplant, corticosteroid reduction and even with-
drawal can be achieved in the majority of patients
with a resultant improvement in lipid profiles.
However graft function must be monitored care-
fully to avoid the danger of acute rejection. If com-
plete withdrawal is inappropriate, a reduction to as
little as 0.1 mg/kg/day would be expected to have
a significant effect on PTHL and should be at-
tempted if possible.
The mainstays of treatment for PTHL should be
diet and lifestyle modification, reduction, or if ap-
propriate, withdrawal of corticosteroids, and the
use of lipid-lowering drugs. Pharmacological in-
tervention should be primarily based on HMG CoA
reductase inhibitors, which can provide an effec-
tive and well tolerated therapy for reducing lipid
levels. Fluvastatin and pravastatin do not affect
cyclosporin or tacrolimus blood concentrations
and are preferred choices in transplant recipients
taking calcineurin inhibitors. When hypertrigly-
ceridaemia is a significant component of PTHL,
atorvastatin or other therapies such as fibric acid
derivatives may be appropriate. Additionally other
medications capable of interfering with cholesterol
metabolism should be administered with care and
switched if appropriate.
In some patients, a normal lipid profile is not
achieved despite the use of dietary measures, cor-
ticosteroid dose reduction (if possible), and lipid-
lowering agents, and switching from one calci-
neurin inhibitor to another may be appropriate.
With the current therapeutic options and aggres-
sive intervention, PTHL can be successfully treat-
ed in the majority of patients. And, if the manage-
ment of cardiovascular risk in transplant patients
generally can achieve the high standards that are
now emerging for PTHL therapy, the benefit for
long term patient survival may ultimately come to
rival that achieved by antirejection drugs.
6. Conclusions
Although there currently is no consensus as to
the correlation between PTHL and mortality or
graft loss in the transplant recipient, there is wide-
spread opinion that lipid abnormalities should be
treated using guidelines similar to those used to the
general population.
The calcineurin inhibitors, cyclosporin and
tacrolimus are both associated with PTHL. Much
of the purported difference between the 2 immuno-
suppressants as to the degree of hyperlipidaemia
they cause appears to be the result of differences in
doses of concomitantly used corticosteroids. More-
over in long term maintenance therapy, the lipid
profiles seen with these 2 agents are indistinguish-
able. Overall, studies comparing the incidence and
severity of PTHL between tacrolimus and cyclo-
sporin have been based largely on single-centre
and small-study population data, and have pro-
duced inconclusive results. Both tacrolimus- and
cyclosporin-treated patients are at risk of PTHL,
and should be treated when PTHL does occur.
The goal of treatment in transplant patients
should be to restore a normal lipid profile. Given
the magnitude of the problem posed by cardiovas-
cular disease in these patients, more aggressive in-
tervention is required and serious consideration
should be given to treating the transplant recipient
Acknowledgements
The authors would like to thank Novartis Pharmaceutical
for their support in the preparation of this article.
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Correspondence and offprints: Dr Richard Moore, Renal
Offices, University Hospital of Wales, Heath Park, Cardiff
CF14 4XW, United Kingdom.
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E-mail: Richard.Moore@UHW-TR.wales.nhs.uk
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