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Review article
Dyslipidemia after allogeneic hematopoietic stem cell transplantation: evaluation
and management
Michelle L. Griffith,1,2 Bipin N. Savani,2,3 and Jeffrey B. Boord2,4
1Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University School of Medicine, Nashville, TN; 2Veterans
Administration Tennessee Valley Health System, Nashville; 3Long-Term Follow-up Transplant Clinic, Hematology and Stem Cell Transplantation Section,
Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN; and 4Vanderbilt Heart and Vascular Institute,
Nashville, TN
Currently, approximately 15 000 to 20 000
patients undergo allogeneic hematopoietic stem cell transplantation (HSCT) annually throughout the world, with the number of long-term survivors increasing
rapidly. In long-term follow-up after transplantation, the focus of care moves beyond cure of the original disease to the
identification and treatment of late effects after HSCT. One of the more serious complications is therapy-related
cardiovascular disease. Long-term survivors after HSCT probably have an
increased risk of premature cardiovascular events. Cardiovascular complications related to dyslipidemia and other
risk factors account for a significant
proportion of late nonrelapse morbidity
and mortality. This review addresses
the risk and causes of dyslipidemia
and impact on cardiovascular complications after HSCT. Immunosuppressive
therapy, chronic graft-versus-host disease, and other long-term complications influence the management of dyslipidemia. There are currently no
established guidelines for evaluation
and management of dyslipidemia in
HSCT patients; in this review, we have
summarized our suggested approach in
the HSCT population. (Blood. 2010;116(8):
1197-1204)
Introduction
Allogeneic hematopoietic stem cell transplantation (HSCT) is recognized as an effective treatment for hematologic malignancies and some
nonmalignant diseases. Advances in transplantation techniques and
supportive care have resulted in a significant improvement in survival,
such that long-term survival has now become an expected outcome for
patients undergoing HSCT. The list of late complications is increasing,
with longer follow-up times and improved knowledge of late effects; in
theory, any organ can be the target of a late event. Therefore, knowledge
about late complications after HSCT has become increasingly important, particularly because there has been liberalization in the indications
for transplantation with respect to the age of the patient, the type of the
donor, and the indication for the transplantation.
In the general population, without history of HSCT, cardiovascular disease remains the leading cause of mortality in the United
States1 and the United Kingdom.2 Lipid abnormalities, including
elevated low-density lipoprotein cholesterol (LDL-C) as well as
elevated triglycerides and reduced levels of high-density lipoprotein cholesterol (HDL-C), contribute to cardiovascular risk.3 Other
significant risk factors include age, hypertension, diabetes, smoking, family history, and markers of inflammation, including highsensitivity C-reactive protein (hs-CRP). Multiple studies have
shown increased prevalence of cardiovascular risk factors in
survivors of allogeneic HSCT, and investigators have begun to
examine cardiovascular outcomes in this population. As postHSCT survival has increased, management of cardiovascular risk
and other long-term sequelae of HSCT are becoming ever more
important. In this review, we summarize the current knowledge of
cardiovascular risk factors and outcomes in HSCT patients, and we
focus on the evaluation and management of dyslipidemia in the
HSCT patient.
Submitted March 30, 2010; accepted April 28, 2010. Prepublished online as
Blood First Edition paper, May 3, 2010; DOI 10.1182/blood-2010-03-276576.
BLOOD, 26 AUGUST 2010 䡠 VOLUME 116, NUMBER 8
Cardiovascular outcomes in HSCT patients
Among patients who survive at least 2 years after transplantation,
approximately 70% of autologous HSCT and 80% of allogeneic
HSCT patients are expected to become long-term survivors.4 After
2 years of posttransplantation survival, relative mortality rates
decrease over time but still remain elevated at 15 years after
transplantation with a standardized mortality ratio of 2.9 at
15 years.5 In allogeneic HSCT patients followed for an average of
9.5 years from transplantation, relapse of primary disease and
chronic graft-versus-host disease (GVHD) remained the first and
second most frequent causes of late death, with 3% of observed
deaths resulting from cardiac causes. The risk of premature death
resulting from cardiac complications was 2.3-fold higher compared
with the United States general population.5 A recent long-term
outcome study after allogeneic HSCT found a coronary artery
disease (CAD) incidence of 2.2% and a peripheral vascular disease
incidence of 1.9% among 369 patients who survived at least 2 years
disease-free, from an original cohort of 429 patients.6 CAD was the
cause of death for 5% of the 60 patients who died in the study
population.6
In a retrospective multicenter study, Tichelli et al assessed the
frequency of cardiovascular events after a minimum one-year
survival from allogeneic HSCT and reported a cumulative incidence of combined first arterial thrombotic events of 6% at 15 years
after transplantation.7 When patients were further stratified by
number of cardiovascular risk factors (defined as hypertension,
diabetes, dyslipidemia, increased body mass index, physical inactivity, smoking), cumulative cardiovascular event incidence was
© 2010 by The American Society of Hematology
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1198
GRIFFITH et al
17% for those with more than or equal to 3 risk factors versus
4% for those with less than or equal to 2 risk factors.7 A separate
retrospective cohort study compared incidence and risk factors for
cardiovascular events between cohorts of patients after allogeneic
versus autologous HSCT.8 The cumulative incidence of cardiovascular events (CAD, stroke, or peripheral vascular disease) 15 years
after allogeneic HSCT was 7.5% compared with 2.3% after
autologous HSCT. Adjusting for age, allogeneic HSCT recipients
had an almost 7-fold increased relative risk for cardiovascular
events compared with autologous recipients.8 Age at transplantation for allogeneic HCST was also an important factor, with a
20-year cardiovascular event rate of 8.7% for patients transplanted
at less than 20 years of age, 20.2% for patients 20 to 40 years of
age, and 50.1% for patients 40 to 60 years of age.8
Taken together, these studies indicate that allogeneic transplantation patients are at increased risk for cardiovascular complications, and traditional cardiovascular risk factors remain important
in their overall risk assessment. In addition to established cardiovascular risk factors, the increased cardiovascular event rates in
allogeneic HSCT patients may be related to the effects for GVHD
on the artery wall.7 Although further exploration of this area is
needed, potential causative links between GVHD and vascular
damage could include increased inflammatory cytokines, such as
tumor necrosis factor-␣ and interleukin-6, or prolonged treatment
of GVHD with calcineurin inhibitors and steroids.4 These agents
can promote myocardial hypertrophy and increase risk for hypertension, diabetes, dyslipidemia, and renal disease.4 Endothelial cell
damage is thought to contribute to microvascular damage in the
post-HSCT setting. Markers of endothelial damage, including
plasminogen-activator inhibitor, cell adhesion molecules, and thrombomodulin, are altered after HSCT.9 Prolonged endothelial injury
could promote atherosclerosis and contribute to more cardiovascular events in long-term survivors after allogeneic HSCT. Long-term
survivors after allogeneic HSCT are likely to have an increased risk
of premature cardiovascular events irrespective of heterogeneity
based on the underlying reason for HSCT. Many patients with
hematologic malignancy have been treated with anthracyclines or
received chest irradiation before or during HSCT, both of which are
known to cause cardiovascular damage. These patients are at added
cardiovascular risk after HSCT.
Dyslipidemia and other cardiovascular risk
factors in HSCT patients
A cohort analysis based on the Bone Marrow Transplant Survivor
Study showed a 3.65-fold higher prevalence of diabetes and
2.06-fold higher prevalence of hypertension compared with a group
of siblings, matched for age, sex, race, and body mass index.10
Allogeneic HSCT recipients were also more likely to develop
hypertension (odds ratio ⫽ 2.31) compared with autologous recipients.10 In the aforementioned retrospective cohort study of allogeneic and autologous HSCT patients, the allogeneic group had
significantly higher risk of new-onset dyslipidemia (relative
risk ⫽ 2.31) and hypertension (relative risk ⫽ 2.5) compared with
the autologous group.8 The metabolic syndrome is a clustering of
cardiovascular risk factors characterized by abdominal obesity,
dyslipidemia, hypertension, and elevated fasting glucose.11 A recent
cross-sectional study of 86 adult allogeneic HSCT patients showed a
49% prevalence of metabolic syndrome, a 2.2-fold increase compared
with a group of 258 age- and sex-matched controls.12
BLOOD, 26 AUGUST 2010 䡠 VOLUME 116, NUMBER 8
Estimates of dyslipidemia in different cohorts who survived at
least one year after allogeneic HSCT range from 8.9% in a
Canadian group6 to 56% of patients in a United States cohort, 71%
of whom remained on immunosuppressive therapy (IST).13 Taskinen et al reported that hypertriglyceridemia was present in 39% of a
small group of 23 survivors of childhood allogeneic HSCT in
Finland, excluding patients on active steroid therapy.14 This was
compared with the prevalence of 8% of patients in a group of
13 survivors of acute lymphoblastic leukemia who were treated
with chemotherapy but no HSCT. An Italian cohort of 85 survivors
of autologous or allogeneic HSCT in complete remission at 5 years
demonstrated 34% prevalence of metabolic syndrome; this contrasts with the general population prevalence of approximately
15%.15 Twenty-four of the 29 patients with metabolic syndrome
had hypertriglyceridemia, and 18 had low HDL-C.15 Many of the
aforementioned studies and others have also found clinically and
statistically significant increases in glucose dysmetabolism among
minimum 1- to 2-year HSCT survivors compared with controls
with prior chemotherapy exposure without HSCT14 or sibling
controls. Prevalence of hypertension ranges from 15%7 to 48.7%15
of long-term posttransplantation survivors and has been reported to
be as high as 70% at one year after HSCT.16
The presence or absence of ongoing IST in allogeneic HSCT
patients may account for some of the differences in reported risk
factor incidence. In an attempt to isolate transplantation- or
conditioning-related etiologies for cardiovascular risk factors,
some studies exclude patients on ongoing steroid or other IST.10,14,15
Although this will help clarify disease mechanisms, it also may
lead to underestimation of the clinical burden of dyslipidemia and
other metabolic complications in this patient population.
Causes of dyslipidemia in transplantation
patients
Common causes of dyslipidemia, such as obesity, and the more
common primary genetic lipid disorders, such as familial combined
hyperlipidemia (occurring in ⬃ 1 of 200 adults) or familial
hypercholesterolemia (occurring in ⬃ 1 of 500 adults), can also be
present in HSCT patients.3 Significant alcohol intake can raise
serum triglycerides and should be assessed in patients with
dyslipidemia.3 Uncontrolled diabetes mellitus can cause marked
elevations in cholesterol and triglycerides and make dyslipidemia
refractory to drug therapy. Complications of the primary disease,
treatment, or transplantation can worsen dyslipidemia. Hypogonadism is common in patients treated in childhood17,18 and ovulatory
failure common in adult female HSCT patients.17 Hypogonadism
and growth hormone deficiency may predispose to insulin resistance, the metabolic syndrome, and related lipid abnormalities.18
Hypothyroidism occurs in up to 45% of post-HSCT patients and
can promote diastolic hypertension and dyslipidemia.19 Nephrotic
syndrome can also cause significant dyslipidemia or worsen a
preexisting genetic lipid disorder.
Chronic GVHD of the liver, when it results in severe cholestatic
liver disease, has also been associated with severe hypercholesterolemia in adult and pediatric allogeneic HSCT patients. These
patients can have marked elevations in serum cholesterol levels,
thought to be caused by intrahepatic cholestasis, reflux of bile
lipoproteins into the bloodstream, and subsequent formation of
lipoprotein X, an abnormal lipoprotein seen in cholestatic liver
disease.20-22 Complications of extreme hypercholesterolemia (total
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BLOOD, 26 AUGUST 2010 䡠 VOLUME 116, NUMBER 8
cholesterol ⬎ 1000 mg/dL) in this setting can include retinal
cholesterol thromboembolism and pulmonary cholesteroloma.20
Drugs used to treat GVHD are also important causes of dyslipidemia. Dyslipidemia occurs in 45% to 80% of solid-organ transplantation
patients on immunosuppressive therapy.23 Among solid-organ transplantation patients, risk factors for dyslipidemia include age, proteinuria,
obesity, antihypertensive medication use, dosage of glucocorticoids
(with increasing risk related to increasing cumulative dose), use of
cyclosporine, and use of sirolimus.23 Glucocorticoids can directly affect
lipid metabolism pathways and also may indirectly increase lipid levels
by promoting weight gain and hyperglycemia.23 Changes in the lipid
profile can include increased VLDL, total cholesterol, and triglyceride
levels and decreased HDL-C levels.24-26
Cyclosporine is thought to inhibit bile acid synthesis, bind to
and block the LDL receptor, and reduce activity of lipoprotein
lipase while increasing activity of hepatic lipase, all of which can
promote increases in LDL-C.26,27 Nontransplantation subjects
receiving cyclosporine for other indications exhibit increased
LDL-C.27 It has been shown to raise total cholesterol and LDL-C in
recent study of renal transplantation patients with stable renal
function28 and to increase lipoprotein (a) levels in renal transplantation recipients.27 Cyclosporine can also inhibit prednisone metabolism and exacerbate the glucocorticoid effects in patients treated
with both agents.27
FK506 (tacrolimus) has been associated with increased lipid
levels when given with a corticosteroid; FK506 has shown less
frequent and milder effects on lipids compared with cyclosporine27,28 and can allow reduction of steroid dose in combined
therapy.23 In solid organ patients, sirolimus has been shown to raise
total cholesterol and triglyceride levels, with delay of 4 weeks in
return to baseline levels after discontinuation of the drug.23 As
many as 49% of liver transplantation and 40% of renal transplantation patients on sirolimus develop hyperlipidemia.27 Mycophenolate mofetil has not been shown to have any direct effects on
lipoprotein metabolism or induce hyperlipidemia independent of
other agents.23 There is also no apparent adverse effect of
azathioprine on lipids.27 Steroids and cyclosporine can also exacerbate other cardiovascular risk factors, such as hypertension and
glucose dysmetabolism. Tacrolimus and sirolimus can also have
significant detrimental effects on glucose metabolism.27 Interactions between lipid-lowering drugs and immunosuppressants must
be carefully considered in the therapeutic approach. Marked
hypertriglyceridemia in particular is also associated with risk of
pancreatitis. A total of 1% to 4% of pancreatitis cases in the United
States are the result of hypertriglyceridemia, usually with serum
levels more than 1000 mg/dL.29
In summary, complications of HSCT, such as chronic GVHD,
can contribute directly to dyslipidemia by the mechanisms discussed in this section. It is not yet known whether other features
inherent to HSCT cause dyslipidemia. In our clinical experience,
immunosuppressant agents are the most common cause of significant secondary dyslipidemia in the HSCT population, followed by
uncontrolled diabetes. Primary genetic dyslipidemias are also
common and can be identified by medical history and review of
pre-HSCT lipoprotein profiles. Considering and addressing the
factors discussed in this section can also facilitate treatment,
particularly in refractory dyslipidemia cases.
Lipid and cardiovascular risk assessment in
the transplantation patient
Joint recommendations for monitoring long-term survivors of
HSCT by the European Group for Blood and Marrow Transplanta-
DYSLIPIDEMIA AFTER TRANSPLANTATION
1199
tion/Center for International Blood and Marrow Transplant Research/American Society for Blood and Marrow Transplantation
suggested that, at a minimum, cholesterol and HDL-C levels
should be checked at least every 5 years for men starting by age
35 and women starting by age 45. It was further recommended that
screening should start at age 20 in smokers, patients with diabetes,
or patients with a family history of heart disease. Abnormalities
(total cholesterol ⬎ 200 mg/dL or HDL-C ⬍ 40 mg/dL) should be
followed up with a full fasting lipoprotein profile.30 However, these
recommendations were published in 2006, before several important
papers on late cardiovascular events as reviewed in “Cardiovascular outcomes in HSCT patients,” and should be updated to reflect
the new data. Our recommendations based on our clinical experience are summarized in Table 3.
Dyslipidemia should be assessed with a lipid profile after a 9- to
12-hour fast. Traditionally, LDL-C has been estimated using
the Friedwald formula (LDL-C ⫽ total cholesterol ⫺ HDL-C ⫺
(triglycerides/5)). However, this formula is inaccurate when triglycerides are more than 400 mg/dL. Direct LDL-C measurement is
now available in many laboratories and is unaffected by elevations
in serum triglycerides. If a direct LDL measurement is not
available, clinicians can use non-HDL cholesterol as an alternative
measure. Non-HDL cholesterol equals total cholesterol minus
HDL-C and estimates the burden of atherogenic apoprotein Bcontaining lipoproteins. Generally, advanced lipoprotein testing,
such as LDL particle number or lipoprotein subfractions, is not
required for dyslipidemia assessment in HSCT patients. Given the
increased risk of cholesterol and triglyceride increases on immunosuppressive therapy, periodic monitoring for dyslipidemia should
be performed, particularly during the acute posttransplantation
phase for patients on IST. Patients with preexisting lipid abnormalities or cardiovascular disease (CVD) risk who undergo HSCT
should have a fasting lipid profile before transplantation and
regularly thereafter, particularly with initiation of IST.
Decisions about using lipid-lowering therapy should incorporate the patient’s overall cardiovascular risk, other comorbidities,
type and severity of dyslipidemia, and potential drug interactions.
The patient’s proximity to transplantation and use of immunosuppressants should also be considered. HSCT patients can develop
dyslipidemia related to IST and other factors in the early posttransplantation phase but can also develop dyslipidemia later, even if
IST has been discontinued. Dyslipidemia in both the early and late
phases after HSCT may contribute to long-term cardiovascular
risk. The most widely used and recommended risk assessment tool
is based on data from the Framingham Heart Study and estimates
10-year risk of hard cardiovascular events (myocardial infarction
and coronary death). This 10-year CVD risk calculator is accessible
from the National Heart, Lung, and Blood Institute website
(www.nhlbi.nih.gov) and incorporates age, sex, total cholesterol,
HDL-C, current smoking status, systolic blood pressure, diabetes
status, and hypertension treatment status.31 The current National
Cholesterol Education Program Adult Treatment Panel guidelines
(ATP-III, updated in 2004) stratify LDL treatment recommendations based on the patient’s 10-year cardiovascular risk (Table 1).
Threshold levels to initiate therapeutic lifestyle changes and
pharmacologic therapy vary for the different levels of risk. LDL-C
is the primary therapeutic target, with HDL-C and triglycerides as
the secondary targets per ATP-III recommendations. As noted
above in this section, non-HDL cholesterol can be used as an
alternative target when a calculated LDL-C is not available; the
non-HDL cholesterol goal is 30 points higher than the recommended LDL-C goal. Patients with known coronary heart disease
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BLOOD, 26 AUGUST 2010 䡠 VOLUME 116, NUMBER 8
GRIFFITH et al
Table 1. Summary of ATP-III LDL cholesterol and triglyceride goals by risk category
Risk category
Threshold to initiate TLC
Threshold to consider drug therapy
High risk: goal LDL-C < 100 mg/dL (optional < 70)
CHD or CHD risk equivalents* (10-year risk ⬎ 20%)
ⱖ 100 mg/dL
ⱖ 100 mg/dL (⬍ 100 mg/dL: consider drug)
ⱖ 130 mg/dL
ⱖ 130 mg/dL (100-129 mg/dL: consider drug)
ⱖ 130 mg/dL
ⱖ 160 mg/dL
ⱖ 160 mg/dL
ⱖ 190 mg/dL (160-189 mg/dL: drug optional)
⬎ 500 mg/dL
⬎ 500 mg/dL
⬎ 200 mg/dL
Consider modifying therapy to reach secondary non-HDL
Moderately high risk: goal LDL-C < 130 mg/dL (optional < 100)
2 or more risk factors† (10-year risk 10%-20%)
Moderate risk: goal LDL-C < 130 mg/dL
2 or more risk factors (risk ⬍ 10%)
Lower risk: Goal LDL-C < 160 mg/dL
0 or 1 risk factor
Severe hypertriglyceridemia (⬎ 500 mg/dL): triglyceride goal
⬍ 500 mg/dL
Moderate hypertriglyceridemia (200-500 mg/dL): triglyceride goal
⬍ 200 mg/dL
cholesterol‡ goal (only after LDL goal reached)
al.31
Adapted from Grundy et
TLC indicates therapeutic lifestyle change.
*Equivalents: abdominal aortic aneurysm, carotid stenosis, peripheral arterial disease, diabetes, or 2 or more risk factors with 10-year risk ⬎ 20%.
†Risk factors: smoking, hypertension, low HDL (⬍ 40 mg/dL), family history of premature CHD, and age (men ⱖ 45 years, women ⱖ 55 years).
‡Non-HDL cholesterol ⫽ total cholesterol-HDL; goal is 30 points higher than LDL goal (ie, non-HDL cholesterol goal ⬍ 130 mg/dL for LDL goal of ⬍ 100 mg/dL).
(CHD) or who have one or more “CHD risk-equivalents” (diabetes
mellitus, abdominal aortic aneurysm, carotid stenosis, and peripheral arterial disease) are automatically considered to have high risk.
Otherwise, patients should have their 10-year risk calculated to
determine their risk category (low, moderate, moderately high, or
high risk). When using the risk assessment tool, it is preferable to
use a baseline lipoprotein profile before initiation of IST after
transplantation because drug-induced dyslipidemia can cause an
overestimation of 10-year CHD risk. For patients with severe
hypertriglyceridemia (⬎ 500 mg/dL), the goal is to reduce triglyceride levels to less than 500 mg/dL to avoid risk of pancreatitis.
Although the Framingham risk score has not been validated
specifically in the HSCT population, it does provide a useful means
to estimate cardiovascular risk and guide therapy. Atherosclerosis
is a very chronic process and can be present as a subclinical disease
in many patients with preexisting risk factors before HSCT. In
long-term HSCT survivors, conventional risk factors, such as
diabetes, dyslipidemia, and hypertension, are associated with
higher risk of cardiovascular events.8
There have been other methods used to estimate CHD risk in
patients, including measurement of hs-CRP and coronary artery
calcium scoring by computed tomography. Although hs-CRP
has been shown to add prognostic value for CHD risk assessment in the general population, it has not been validated in
HSCT.32 In the HSCT population, assessment of hs-CRP may be
confounded by several factors, including infection, IST, or
GVHD. Therefore, hs-CRP measurement should not be used
after HSCT for CHD risk stratification. Likewise, although
coronary artery calcium scoring can have use in specific clinical
situations, it has not been studied in the HSCT population; thus,
its clinical value is uncertain.33
No large study has yet been able to define the influence of
HSCT on long-term CVD risk. Longer-term lipid treatment will
also depend on weighing the possible benefits for CHD risk
reduction against their risk of mortality from malignancy or
other diseases after HSCT. If long-term recurrence of the
underlying disease is thought to be likely within a few years or
the patient has reduced life expectancy resulting from complications after HSCT, then higher lipid levels might be tolerated.
However, if 5 to 10 years or more life expectancy is anticipated,
then management of cardiovascular risk as would be performed
for a general population is likely warranted to reduce morbidity
and mortality from cardiovascular disease. Although more study
is needed, we think the current available evidence suggests that
allogeneic HSCT patients over age 40 with one or more risk
factors should be considered to have high CHD risk (10-year
risk ⬎ 20%).
Management of dyslipidemia in the HSCT
patient
There are only 2 treatment goals for lipid-lowering therapy: (1) to
reduce risk of future CVD events and (2) to prevent risk of
pancreatitis in patients with severe hypertriglyceridemia. There are
few published data on management of dyslipidemia in HSCT.
However, there are more data in the solid organ transplantation
literature, and many issues regarding lipid therapy, including
drug-drug interactions, are common between HSCT and solid
organ transplantation patients. Although there is robust evidence
for improved CVD outcomes in patients treated with lipid-lowering
therapy (particularly HMG-CoA reductase inhibitors, or statins) in
the general population, the evidence of clinical outcome benefits in
transplantation patients is more limited. There are prospective
randomized clinical trials showing improved CVD outcomes and
good safety with statin therapy in both renal and cardiac transplantation recipients.34,35
After fasting lipids are measured, the patient’s cardiovascular
risk should be assessed as indicated in “Lipid and cardiovascular
risk assessment in the transplantation patient.” If LDL-C exceeds
the goal as defined by National Cholesterol Education Program
ATP-III, therapeutic lifestyle change (TLC) should be initiated, and
any secondary causes of lipid abnormalities should be addressed.
The American Heart Association TLC guidelines recommend less
than 7% total calories from saturated fat and less than 200 mg of
daily dietary cholesterol. Lifestyle change should also include
minimization of trans-fatty acid intake, increased physical activity,
and consideration of increased soluble fiber intake (10-25 g/day).36
Patients who develop dyslipidemia in an early or intermediate
posttransplantation period may still have increased risk of cardiovascular events over the long term. In these patients who are still
taking IST, consideration should be given to whether IST medications can be safely reduced in dose or changed to modify their
effects on lipids.3 In patients with low or moderate CHD risk and
moderate dyslipidemia, a trial of TLC alone can be used as initial
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BLOOD, 26 AUGUST 2010 䡠 VOLUME 116, NUMBER 8
DYSLIPIDEMIA AFTER TRANSPLANTATION
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Table 2. Lipid-lowering agents and considerations in the post-HSCT population
Predominant
dyslipidemia/drug class
Agent/daily dose range*
Expected effect
Major side effects
Important interactions
Elevated LDL-C predominant
HMG-CoA reductase inhibitors
Pravastatin, lovastatin,† or
2 LDL-C 30%-45%;
Myopathy; elevated liver tests
Increased myopathy risk with
atorvastatin†/10-80 mg;
2 triglycerides 7%-30%;
renal dysfunction and
fluvastatin/20-80 mg;
1 HDL-C up to 10% (variable
cyclosporine; fibrates;
simvastatin†/5-80 mg;
by agent)
CYP3A4 inhibitors
rosuvastatin/5-40 mg
Cholesterol absorption inhibitor
Ezetimibe/10 mg
2 LDL-C 17%
Gastrointestinal upset, elevated
No major drug interactions
liver tests, myalgias (rare)
Bile acid sequestrants
Colesevelam‡/2400-3750 mg
2 LDL-C 15%-30%; can raise
Constipation, dyspepsia
Monitor drug levels in IST
Gastrointestinal upset, diarrhea
No major drug interactions
Myopathy, elevated liver tests,
Use with caution in
triglycerides
Hypertriglyceridemia
predominant
Omega-3 fatty acids
Omega-3-acid ethyl esters/2-4 g
daily divided bid
Fibric acid derivatives
Fenofibrate, fenofibric acid/45200 mg daily; gemfibrozil/600-
2 triglycerides 35%-45%,
1 HDL-C 3%, 1 LDL-C 5%
2 triglycerides 20%-50%,
1 HDL-C 10%-20%
1200 mg daily divided bid
gallstones, rash; renal
combination with statins
dysfunction (fenofibrate)
and cyclosporine.
Mixed hyperlipidemia
Niacin
Niacin/500-2000 mg
2 LDL-C 20%-30%,
Dyspepsia, flushing, elevated
2 triglycerides 35%-55%,
liver tests, 1 glucose, 1 uric
1 HDL-C 20%-35%
acid
No major drug interactions
*We recommend submaximal statin dosing in patients on IST agents that may alter metabolism of the statin agents. In general, patients gain only 6% additional LDL-C
lowering with each doubling of statin dose.
†Metabolized by CYP3A4.
‡Older bile acid sequestrants (cholestyramine and colestipol) should be avoided in patients on IST or those with complex medication regimens because of the potential
inhibition of drug absorption.
management. If lipid levels remain above goal for a patient’s risk
category, then pharmacologic therapy should be considered with
attention to drug interactions. In patients who are no longer on IST
and have stabilized in the longer term after transplantation, TLC
may be used initially for low to moderate CHD risk and moderate
dyslipidemia; however, if response is inadequate, then intensification of therapy should not be delayed. In the absence of ongoing
IST or GVHD, treatment of lipids is similar to that of any patient
with dyslipidemia.
Pharmacologic agents for dyslipidemia are summarized in
Table 2. Statins are the most widely used class of agent, but
proper selection of statin preparation and dose is important.
Cyclosporine’s metabolism by the cytochrome P450 3A4 is a
key factor in drug-drug interactions, as it can raise levels of
statins also metabolized by this pathway (lovastatin, simvastatin, and atorvastatin) and thus risk for myopathy.37,38 FK506 and
sirolimus also appear to be metabolized by this pathway.23
However, cyclosporine also can increase statin drug levels
through effects on the cell membrane transporter multidrugresistant protein 2; thus, cyclosporine can potentially increase
risk for toxicity of any statin.39,40 Other inhibitors of CYP3A4
that may be used in HSCT patients include azole antifungals,
nondihydropyridine calcium channel blockers (verapamil and
diltiazem), and macrolide antibiotics. Pravastatin, rosuvastatin,
and fluvastatin are metabolized by alternate pathways and thus
are better choices for patients requiring coadministration of
CYP3A4-inhibiting agents. Pravastatin has been safely used as
preemptive treatment for hypercholesterolemia in children receiving renal transplantations.41 Atorvastatin has also had demonstrated safety at low doses (10-20 mg/day) in cardiac transplantation patients and has been suggested as an alternative statin in
cardiac transplantation patients when dyslipidemia is not controlled after titration of pravastatin up to 40 mg/day.40 Rare but
clinically important side effects of statins can include elevated
transaminases, myositis, and rhabdomyolysis. Transaminase
measurement is recommended at baseline and within 8 to
12 weeks of initiating statin therapy in a general population.
Closer monitoring within 2 to 4 weeks is warranted in patients
on IST or with potential for active liver GVHD. Although no
large prospective clinical trials of statin therapy have been done
in HSCT patients with GVHD, several studies have demonstrated that statins can be safely used in patients with stable
chronic liver disease, particularly in nonalcoholic fatty liver
disease.42 Interestingly, the immunomodulatory effects of statins
may potentially be beneficial in suppressing acute GVHD.43,44 In
patients with mild elevations in transaminases (ie, ⬍ 3⫻ upper
limit of normal), statins can generally be used with appropriate
clinical monitoring. Statins should be avoided in patients with
severe elevations in liver enzymes, decompensated cirrhosis, or
acute liver failure.
Bile acid sequestrants tend to be less well tolerated, have
relatively modest LDL-C–lowering capability (15%–30%), and
may have important effects on decreasing absorption of other
drugs, including cyclosporine.45 Older bile sequestrants (colestipol and cholestyramine) should not be used for patients on IST.
Colesevelam, a newer agent in this class, binds bile acids more
specifically and can be safely coadministered with immunosuppressive drugs,46 but drug levels should be monitored. Bile acid
sequestrants can raise triglyceride levels and are contraindicated
in patients with hypertriglyceridemia. Ezetimibe was previously
reported to interact with cyclosporine to cause 12-fold elevations in ezetimibe levels.40 However, safe use of this agent has
been reported in solid organ transplantation patients.47,48 It is
less potent than the statins and does not have proven benefit in
CHD outcomes, so it is considered a second-line agent for LDL
reduction.
In patients with hypertriglyceridemia, other agents may be
needed. Statins may reduce triglycerides in the range of 7% to
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
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BLOOD, 26 AUGUST 2010 䡠 VOLUME 116, NUMBER 8
GRIFFITH et al
Table 3. Suggested approach to lipid management in HSCT patients
Evaluation
Obtain fasting lipid profile before transplantation
Evaluate CHD risk
1. If patient has CHD or CHD risk equivalent, then manage as high risk with appropriate therapy to reach LDL goal
a. Option to consider allogeneic HSCT patients 40 years of age or older as high risk
2. Otherwise, calculate 10-year risk with online risk assessment tool (hp2010.nhlbihin.net/atpiii/calculator.asp?usertype⫽prof) and manage LDL per ATP-III guidelines
Monitor lipid profiles after HSCT
1. Check lipid profile within 4 weeks after HSCT and then at least every 3 months for patients on IST
2. For patients at treatment goal on stable therapy every 6 to 12 months as indicated, or after significant change in IST regimen in patients with dyslipidemia
3. If patients develop significant dyslipidemia after HSCT compared with baseline, consider secondary causes of dyslipidemia (IST, diabetes, and hypothyroidism)
4. Even patients without dyslipidemia should have lipids monitored every 1 to 2 years after allogeneic HSCT given increased CV risk
Management
If patient has high CHD risk (⬎20% 10-year risk), treat dyslipidemia with appropriate agent(s) to meet LDL goal, but monitor clinically if on IST or renal dysfunction
In patients with low (⬍10%) or moderate CHD risk (10%–20%), consider drug treatment based upon severity of dyslipidemia, estimated prognosis after HSCT, and risks
of lipid drug therapy (if on long-term IST for GVHD)
1. In patients with low CHD risk that develop moderate secondary dyslipidemia on IST, this can be managed conservatively if IST will be tapered off
2. Patients with low to moderate CHD risk that develop severe hypertriglyceridemia (⬎ 500 mg/dL) should be treated to prevent pancreatitis
Consider referral to a lipid specialist for the following:
1. Severe dyslipidemia (total cholesterol ⬎ 300 or LDL ⬎ 180, triglycerides ⬎ 500-1000)
2. Patients with dyslipidemia refractory to treatment and not meeting goals
3. Patients with intolerance or contraindications to lipid-lowering therapy
4. Patients requiring combination lipid therapy, particularly in the setting of IST
5. Patients needing individualized cardiovascular risk assessment because of strong family history of premature CHD or other factors
30% of initial levels and so may be an option for relatively mild
hypertriglyceridemia (eg, ⬍ 400 mg/dL). For moderate to severe
hypertriglyceridemia, omega-3 fatty acids and niacin should be
considered. Niacin can lower LDL-C by approximately 16%, lower
triglyceride levels by approximately 38%, and raise HDL-C by
approximately 22%.40 It has no significant interactions with
cyclosporine40 or other IST. Niacin can mildly exacerbate hyperglycemia and hyperuricemia in some patients and cause side effects of
flushing and gastrointestinal intolerance. Only extended release
preparations of niacin should be used because of improved
tolerability. Niacin should be considered in patients with elevations
in both cholesterol and triglycerides. Omega-3 fatty acids have
been successfully used to treat sirolimus-induced hypertriglyceridemia49 and have been safely used in a variety of other settings.
Omega-3 fatty acids reduce hepatic production of triglycerides and
can reduce triglycerides by 35% to 45% at 4 g/day dosing.50 They
have minor effects on HDL-C and LDL-C but have good tolerability and excellent safety. These agents can impair platelet aggregation, but they have not been shown to have clinically significant
bleeding problems in patients without hematologic disease.51
Omega-3 fatty acids have also been shown to be safe in patients on
dual antiplatelet therapy with aspirin and clopidogrel, with no
clinically significant increase in bleeding.52 In patients with
hypertriglyceridemia, uncontrolled diabetes and hyperglycemia
can markedly worsen triglyceride levels, so treatment of diabetes
should be intensified.
Fibrates reduce triglycerides 20% to 50% and are generally
used for severe hypertriglyceridemia (triglycerides ⬎ 500 mg/
dL).3 Potential side effects include cholelithiasis, gastrointestinal upset, and myopathy. Risk of myopathy is increased when
fibrates are given with statins, particularly in patients with
impaired renal function or those on cyclosporine. Thus, statinfibrate therapy should be used with great caution in patients on
IST or with renal dysfunction. Gemfibrozil has been shown to
increase statin levels 1.9- to 5.7-fold by inhibition of glucuronidation, making fenofibrate a better choice if a fibrate must be
added to a statin.47,48 However, fenofibrate can cause a reversible increase in serum creatinine levels and has been associated
with reversible renal allograft dysfunction in some renal transplantation patients.40,45,53
Summary and recommendations
Dyslipidemia and other cardiovascular risk factors are increased in
allogeneic HSCT patients. The risk for allogeneic transplantation
exceeds that for autologous transplantation, even when autologous
transplantation patients are older; some of the increased risk is
related to IST, but other, unknown mechanisms may also contribute. As post-HSCT survival improves, prevention and treatment of
longer-term morbidities such as cardiovascular disease is gaining
importance, and management of dyslipidemia is an important
factor in managing cardiovascular risk. LDL-C is the primary focus
for cardiovascular risk reduction, although treatment should
also be initiated for severe hypertriglyceridemia (⬎ 500 mg/
day) to reduce the risk of pancreatitis. There are currently no
established guidelines for evaluation and management of dyslipidemia in HSCT patients, so we have summarized our suggested
approach in the HSCT population based on our clinical experience (Table 3). Recommendations from a National Heart, Lung,
and Blood Institute clinical advisory on the use and safety of
statins provides useful guidelines for monitoring statin therapy.54
Although creatine phosphokinase (CPK) levels should be checked
at baseline, routine monitoring of CPK in asymptomatic patients
on statins is not recommended because mild elevations in CPK
are often not clinically significant. However, patients should be
asked about muscle symptoms at follow-up, and a CPK should
be checked if the patient has symptoms concerning for myopathy. Aspartate aminotransferase and alanine transaminase should
be monitored at baseline and within 12 weeks of starting
therapy. Generally, transaminase elevations less than 3 times the
upper limit of normal do not represent a contraindication to
statin therapy. Because mild transaminase elevations are common in patients after HSCT, these can simply be monitored and
therapy continued as long as they are not progressively
increasing.
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
BLOOD, 26 AUGUST 2010 䡠 VOLUME 116, NUMBER 8
DYSLIPIDEMIA AFTER TRANSPLANTATION
At this time, it is unclear how HSCT influences CVD risk, so
other comorbidities should be taken into account to determine
LDL-C goals using the National Cholesterol Education Program
ATP-III guidelines. Patients who are still on IST are more likely to
have dyslipidemia and also are at risk for drug interactions. Statin
therapy is first-line treatment for LDL-C–predominant dyslipidemia. Given their established role in cardiovascular risk reduction in
the general population, they should be considered first-line therapy
for dyslipidemia in HSCT patients. Selection of the appropriate
statin preparation and dose are important to minimize side effect
risk. Niacin, ezetimibe, or colesevelam may be considered as
second-line agents if LDL-C goals are not met. For mild to
moderate hypertriglyceridemia, we favor omega-3 fatty acids
because of their excellent safety and tolerability. Fibrates should be
reserved for more severe hypertriglyceridemia in patients on IST
1203
and used with caution in patients requiring statin therapy or with
renal dysfunction. Niacin may be considered as a second agent with
statins or for treatment of elevated triglycerides and low HDL in
patients with mixed hyperlipidemia.
Authorship
Contribution: B.N.S. planned the review; and M.L.G., B.N.S., and
J.B.B. contributed to the writing of the manuscript.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Correspondence: Jeffrey B. Boord, Vanderbilt Heart and Vascular Institute, 5209 MCE South Tower, 1215 21st Ave S, Nashville,
TN 37232-8802; e-mail: [email protected].
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2010 116: 1197-1204
doi:10.1182/blood-2010-03-276576 originally published
online May 3, 2010
Dyslipidemia after allogeneic hematopoietic stem cell transplantation:
evaluation and management
Michelle L. Griffith, Bipin N. Savani and Jeffrey B. Boord
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