Management of familial hypercholesterolemias in adult patients: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia.

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Management of Familial Hypercholesterolemias in
adult patients: Recommendations from the National
Lipid Association Expert Panel on Familial
Hypercholesterolemia
Matthew K. Ito, PharmD, FNLA*, Mary P. McGowan, MD, FNLA, Patrick M. Moriarty, MD
Oregon State University/Oregon Health & Science University, Portland, OR, USA (Dr. Ito); Cholesterol Treatment Center,
Concord Hospital, Concord, NH, USA (Dr. McGowan); and The University of Kansas Hospital, Kansas City,
KS, USA (Dr. Moriarty)
Introduction
Cardiovascular disease is the leading cause of morbidity
and mortality in the United States.1Hypercholesterolemia,
specifically elevated level of low-density lipoprotein (LDL)
cholesterol, is a major coronary heart disease (CHD) risk
factor.2Whileenvironmentalfactorssuchasdietandphysical
activity have important roles in determining an individual’s
levelofcirculatingcholesterol,thereisalsoageneticcompo-
nent. The familial hypercholesterolemias (FH)are a group of
inherited genetic defects resulting in severely elevated serum
cholesterol concentrations. The genetic defects in FH arise
from mutations affecting the LDL receptor,3apolipoprotein
(Apo) B4or proprotein convertase subtilisin kexin type 9
(PCSK9; an enzyme involved in LDL receptor degradation)5.
Heterozygous FH is a common genetic defect affecting
approximately one of every 500 persons in the United States,
although this ratio is much higher in certain subpopulations
in the U.S. Homozygous FH is quite rare, affecting one of
everyonemillionindividualsintheUnitedStates.6–9Through-
outthisdocument,thetermFHreferstotheheterozygousform
of FH, unless otherwise indicated.
FH is associated with a high risk for premature coronary
heart disease (.50% risk in men by age 50 and .30% in
women by age 60).8,9In untreated individuals, symptoms of
coronary disease may manifest in men in their 40s and in
women 10 to 15 years later. There is a substantial body
of evidence from large-scale clinical trials supporting the
benefit of lowering LDL cholesterol with statins to reduce
cardiovascular disease morbidity and mortality.2,10Al-
though no randomized placebo-controlled outcome trials
of statin therapy have been conducted in FH cohorts (for
ethical reasons) due to their high LDL cholesterol levels
and associated cardiovascular disease risk, observational
studies provide compelling evidence that statins alter the
clinical course of the disease.11Thus, aggressive lipid man-
agement in men and women with FH is vital in order to pre-
vent or slow the progression of coronary atherosclerosis.
This document provides the rationale for the consensus
reached by the National Lipid Association Familial Hyper-
cholesterolemia Panel with regards to recommendations for
the treatment of FH in adult patients.
National Lipid Association Expert Panel on Familial Hypercholes-
terolemia: Anne C. Goldberg, MD, FNLA, Chair, Paul N. Hopkins, MD,
MSPH, Peter P. Toth, MD, PhD, FNLA, Christie M. Ballantyne, MD,
FNLA, Daniel J. Rader, MD, FNLA, Jennifer G. Robinson, MD, MPH,
FNLA, Stephen R. Daniels, MD, PhD, Samuel S. Gidding, MD, Sarah
D. de Ferranti, MD, MPH, Matthew K. Ito, PharmD, FNLA, Mary P.
McGowan, MD, FNLA, Patrick M. Moriarty, MD, William C. Cromwell,
MD, FNLA, Joyce L. Ross, MSN, CRNP, FNLA, Paul E. Ziajka, MD,
PhD, FNLA.
* Corresponding author: Matthew K. Ito, PharmD, FNLA, Professor of
Pharmacy Practice, Oregon State University/Oregon Health & Science Uni-
versity, College of Pharmacy Portland Campus at OHSU, Tel: 503-494-
3657.
E-mail address: itom@ohsu.edu
Submitted March 31, 2011. Accepted for publication April 4, 2011.
1933-2874/$ - see front matter ? 2011 National Lipid Association. All rights reserved.
doi:10.1016/j.jacl.2011.04.001
Journal of Clinical Lipidology (2011) 5, S38–S45

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Summary Recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia
Lifestyle Modifications
? Patients with familial hypercholesterolemias (FH) should be counseled regarding the following lifestyle modifications:
B Therapeutic Lifestyle Changes and dietary adjuncts.
- Reduced intakes of saturated fats and cholesterol: total fat 25-35% of energy intake, saturated fatty acids ,7% of
energy intake, dietary cholesterol ,200 mg/d.
- Use of plant stanol or sterol esters 2 g/d.
- Use of soluble fiber 10-20 g/d.
B Physical activity and caloric intake to achieve and maintain a healthy body weight.
B Limitation of alcohol consumption.
B Emphatic recommendation to avoid use of any tobacco products.
? Clinicians are encouraged to refer patients to registered dietitians or other qualified nutritionists for medical nutrition
therapy.
Drug Treatment of FH
? For adult FH patients, initial treatment is the use of moderate to high doses of high-potency statins titrated to achieve
low-density lipoprotein (LDL) cholesterol reduction $50% from baseline. Low potency statins are generally inadequate
for FH patients.
? If the initial statin is not tolerated, consider changing to an alternative statin, or every-other-day statin therapy.
? If initial statin therapy is contraindicated or poorly tolerated, ezetimibe, a bile acid sequestrant (colesevelam) or niacin
may be considered.
? For patients who cannot use a statin, most will require combination drug therapy.
Additional Treatment Considerations
? If the patient is not at LDL cholesterol treatment goal with the maximum available and tolerable dose of statin, then
combine with ezetimibe, niacin, or a bile acid sequestrant (colesevelam preferred).
? Decisions regarding selection of additional drug combinations should be based on concomitant risk factors for myop-
athy, concomitant medications, and the presence of other disease conditions and lipid abnormalities.
Candidates for LDL Apheresis
? LDL apheresis is a U.S. Food and Drug Administration approved medical therapy for patients who are not at LDL cho-
lesterol treatment goal or who have ongoing symptomatic disease.
? In patients who, after six months, do not have an adequate response to maximum tolerated drug therapy, LDL apheresis
is indicated according to these guidelines:
B Functional homozygous FH patients with LDL cholesterol $300 mg/dL (or non-HDL cholesterol $ 330 mg/dL).
B Functional heterozygous FH patients with LDL cholesterol $300 mg/dL (or non-HDL cholesterol $330 mg/dL)
and 0-1 risk factors.
B Functional heterozygous FH patients with LDL cholesterol $200 mg/dL (or non-HDL cholesterol $230 mg/dL)
and high risk characteristics such as $2 risk factors or high lipoprotein (a) $50 mg/dL using an isoform insensitive
assay.
B Functional heterozygotes with LDL cholesterol $160 mg/dL (or non-HDL cholesterol $190 mg/dL) and very high-
risk characteristics (established CHD, other cardiovascular disease, or diabetes).
LDL Apheresis Referrals
? Healthcare practitioners should refer candidates for LDL apheresis to qualified sites. Self-referrals are also possible. A
listing of sites qualified to perform LDL apheresis is in development and will be posted on the National Lipid Asso-
ciation website (www.lipid.org).
Women of Childbearing Age
? Women with FH should receive pre-pregnancy counseling and instructions to stop statins, ezetimibe, and niacin at least
four weeks before discontinuing contraception and should not use them during pregnancy and lactation.
? Consultation with her healthcare practitioner regarding continuation of any other lipid medications is recommended.
? In case of unintended pregnancy, a woman with FH should discontinue statins, ezetimibe, and niacin immediately and
should consult with her healthcare practitioner promptly.
Ito et alManagement of FH in adults S39

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Lifestyle modifications
The goal of treatment for patients with FH is to achieve
an LDL cholesterol reduction of at least 50% from base-
line.8,9In patients with FH, lifestyle modifications should
always be instituted, but usually these changes alone are in-
sufficient to achieve the LDL cholesterol treatment
goal.12,13The degree of LDL cholesterol reduction with di-
etary and lifestyle changes is quite variable, depending on
the patient’s original diet, compliance, and genetic respon-
siveness. A decrease of 10 to 15% is achievable in many
individuals.13,14
Clinicians are encouraged to refer FH patients to regis-
tered dietitians or other qualified nutritionists for medical
nutrition therapy and counseling in order to achieve the
maximum possible diet-mediated reduction in LDL cho-
lesterol. The National Cholesterol Education Program
(NCEP) Third Adult Treatment Panel (ATP III) Therapeutic
Lifestyle Changes (TLC) diet, which restricts intakes of
total fat (25 to 35% of energy intake), saturated fatty acids
(,7% of energy intake), and cholesterol (,200 mg/d) is
recommended for patients with FH.2Patients should also be
instructed to incorporate dietary adjuncts including 2 g/d of
plant stanol or sterol esters and 10 to 20 g/d of soluble fiber,
both of which decrease cholesterol absorption.2,15,16
In addition to following the TLC diet, patients with FH
should be encouraged to achieve and maintain a healthy
body weight through physical activity and appropriate
caloric intake.2If an individual is overweight or obese, sig-
nificant weight loss will improve lipid levels. Each kilo-
gram of weight loss produces a reduction of about 0.8
mg/dL in the LDL cholesterol concentration.17Limiting al-
cohol consumption and avoiding or stopping tobacco use
(smoking cessation has been shown to increase HDL cho-
lesterol levels18) is recommended in order to reduce the
burden of additional cardiovascular risk factors among
FH patients who are already at high risk by virtue of their
severe hypercholesterolemia. Assistance in stopping smok-
ing should be offered.
Dietary modifications should not be discounted in FH
patients undergoing pharmacological therapy, because the
effects on LDL cholesterol reduction are directly additive
to those of lipid-lowering medications.19–22The importance
of complying with dietary management of hypercholester-
olemia should be strongly emphasized during counseling
of patients with FH, and the added negative effects of
smoking should be thoroughly explained.
Drug treatment of FH
Management of FH in women of childbearing potential
and in breastfeeding women requires specific guidance, due
to the risks to the child of certain types of drug therapies
during pregnancy and breastfeeding (see sections below for
Women of Childbearing Age and Treatment During Preg-
nancy). The recommendations for drug treatment of FH in
the present section refer to women who are using contra-
ception or who are not of childbearing potential.
After a confirmatory diagnosis of FH (excluding sec-
ondary causes of hypercholesterolemia), adult FH patients
should receive initial treatment with higher potency statins
(atorvastatin, rosuvastatin, pitavastatin, simvastatin) titrated
to achieve an LDL cholesterol reduction $50% from
baseline (pitavastatin and simvastatin have lower probabil-
ity of achieving a 50% reduction from baseline).8,9,23Low
potency statins (fluvastatin, lovastatin, pravastatin) are gen-
erally inappropriate as initial therapy for FH patients. Stat-
ins inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG
CoA) reductase, the rate-limiting enzyme in cholesterol
synthesis, causing a reduction in hepatic cholesterol and
leading to upregulation of hepatic LDL receptors. Increased
LDL receptor activity results in a reduction in circulating
LDL cholesterol concentration. With 50% functional LDL
receptors, heterozygous FH patients typically have an ex-
cellent response to statins. Even some FH homozygotes
who have LDL receptor defective mutations have sufficient
LDL receptor activity to respond favorably to statin ther-
apy, although generally to a degree insufficient to achieve
their LDL cholesterol goal.24,25In individuals with hyper-
cholesterolemia (not necessarily FH), statins have been
shown to reduce LDL cholesterol concentrations by 50
to 60% at their maximum approved doses.26–29Many ran-
domized, placebo-controlled trials have demonstrated that
lowering LDL cholesterol with statins reduces coronary
morbidity and mortality.2,10
Treatment Options During Pregnancy
? Statins, ezetimibe, and niacin should not be used during pregnancy. Use of other lipid lowering medications (e.g.,
colesevelam) may be considered under the guidance of the healthcare practitioner.
? Consider LDL apheresis during pregnancy if there is significant atherosclerotic disease or if the patient has homozygous
FH.
Hard to Manage Patients
? If other treatment options are inadequate or the FH patient cannot tolerate pharmacotherapy or LDL apheresis, other
treatment options include ileal bypass and liver transplantation (both are used rarely), and, potentially, new drugs in
development.
S40Journal of Clinical Lipidology, Vol 5, No 3S, June 2011

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Statins are generally well tolerated and have an excellent
safety profile.30–32The potential adverse effects of statins
in FH patients are the same as in other treated patients, no-
tably myopathy and elevated liver enzymes. Certain low
potency statins, such as fluvastatin and pravastatin, may
be less likely to cause severe myopathy,32but they are
not the preferred choice for patients with FH due to their
lower ability to reduce LDL cholesterol levels.27,28,33
Some patients do not tolerate statin therapy. In these
cases, possible alternatives include changing to a different
statin, instituting every-other-day statin therapy, or using
very low dose statin therapy in combination with other
LDL cholesterol lowering medications. Alternative lipid-
lowering medications to consider, if initial statin therapy is
either contraindicated or poorly tolerated, include ezeti-
mibe (cholesterol absorption inhibitor), a bile acid seques-
trant, most often colesevelam, or niacin.8,9,29For patients
who cannot use a statin, combination therapy of these other
LDL cholesterol lowering agents will likely be required.
Even among patients who tolerate the maximum doses of
the higher efficacy statins, the addition of one or more
non-statin cholesterol-lowering medications is often neces-
sary to achieve the recommended LDL cholesterol reduc-
tion of $50%.
Ezetimibe specifically inhibits cholesterol and phytoste-
rol absorption by binding to intestinal enterocytes and
interfering with the activity of the Niemann-Pick C1-Like
1 sterol transporter. The reduced flow of cholesterol from
the intestine to the liver leads to a compensatory increase in
the hepatic LDL receptor resulting in increased uptake of
circulating LDL and other lipoprotein particles. Ezetimibe
reduces LDL cholesterol by approximately 15 to 20% when
given alone or when combined with a statin. It can be
administered in combination with other lipid medications in
FH patients who do not tolerate statins.34–39
Bile acid sequestrants (colesevelam, cholestyramine,
colestipol) are anion-exchange compounds that prevent
reabsorption of bile acids in the intestine. They have been
shown to decrease LDL cholesterol concentrations by up to
20%40and can be added to statin therapy in FH patients re-
quiring additional LDL cholesterol lowering.41Because
they are not absorbed systemically, they are generally con-
sidered safer than other lipid-lowering drugs. Cholestyra-
mine and colestipol are associated with significant
adverse gastrointestinal side effects, particularly constipa-
tion and multiple drug-drug interactions; and patient com-
pliance is often an issue. The newest bile acid sequestrant
on the market is colesevelam, a polymer available as a tab-
let or as a powder for oral suspension. Compared with cho-
lestyramineandcolestipol,
gastrointestinal side effects and drug-drug interactions
and is effective at a lower dose. Its use may be associated
with improved adherence compared with cholestyramine
and colestipol. Colesevelam is also approved by the U. S.
Food and Drug Administration for improving glycemic
control in patients with type 2 diabetes mellitus. Coleseve-
lam is therefore the recommended bile acid sequestrant for
colesevelam has fewer
use in patients with FH. Colesevelam can produce up to
20% further LDL cholesterol reductions when added to a
statin.41
Niacin or nicotinic acid is available in immediate-
release, extended-release, and sustained-release forms. The
extended-release prescription product is preferred and most
sustained-release non-prescription forms are not recom-
mended due to increased potential for liver toxicity. Niacin
is a water-soluble B vitamin which lowers very low-density
lipoprotein and LDL cholesterol while raising HDL
cholesterol, but its use is typically associated with trouble-
some side effects of flushing or hot flashes due to vasodi-
latation.42–44Extended-release niacin, dosing not to exceed
2 g/d, when added to a stable dose of statin therapy has been
shown to be effective in lowering LDL cholesterol.45–46
Fibric acid derivatives (gemfibrozil, fenofibric acid, and
fenofibrate) primarily act to lower triglycerides and raise
HDL cholesterol, but do not reliably lower LDL choles-
terol. Furthermore, fibrates (particularly gemfibrozil) may
increase the risk of statin-induced myositis.47Therefore,
fibrates should be used with caution. However, fenofibric
acid is FDA approved for use in combination with low to
moderate doses of statins. Prescription omega-3 fatty acid
esters can also be used if concurrent high triglyceride levels
are present.
Additional treatment considerations
As described above, if an individual with FH is not at
LDL cholesterol treatment goal with the maximum avail-
able and tolerable dose of statin, then the statin should be
combined with ezetimibe, niacin, or a bile acid sequestrant
(colesevelam preferred). The risk for myopathy with statin
therapy appears to be positively associated with the dose
and potency of the statin.32Because doubling the dose of a
statin further lowers LDL cholesterol by only 6 to 7%,28ad-
dition of another agent (such as ezetimibe, niacin, or cole-
sevelam) is often necessary to achieve the amount of LDL
cholesterol reduction required in FH patients. However, the
risk for myopathy is also increased by certain drug combi-
nations, such as that of a fibrate (particularly gemfibrozil)
with a statin.32,47Decisions regarding the selection of
drug combinations should be based on concomitant risk
factors for myopathy. Polypill forms of simvastatin com-
bined with extended-release niacin (Simcor) and simvasta-
tin combined with ezetimibe (Vytorin) are attractive
options for patients with FH, reducing the number of pills
required, which lowers cost and may improve adherence.
Another important factor to consider in the selection
of combination drug therapies is potential concomitant
medication interactions. Drug interactions with statins
are primarily related to cytochrome P450 metabolism,
drug transporters, and glucuronidation. Thus, caution
should be used with a statin in combination with fibrates
(mainly gemfibrozil), antifungals (except terbinafine which
canbeused withastatin),macrolide antibiotics,
Ito et alManagement of FH in adultsS41

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antiarrythmics, cyclosporine, protease inhibitors, or in
patients who routinely drink grapefruit juice. Because it
is not metabolized by cytochrome 3A4, rosuvastatin, unlike
atorvastatin and simvastatin, may be less likely to produce
interactions with other medications. Bile acid sequestrants
may decrease the absorption of some medications, and the
timing of dosing in conjunction with other medications is
important, particularly with cholestyramine and colestipol.
Ezetimibe, on the other hand, has a specific mechanism of
action to inhibit cholesterol absorption, and therefore does
not interfere with the absorption of other drugs.
Other major considerations when selecting drug combi-
nations for treating FH are the presence of additional lipid
abnormalities and other disease conditions, particularly hy-
pertension, diabetes (type 1 or 2), and obesity, which also
increase CHD risk. In addition to treating hypercholesterol-
emia, other cardiovascular risk factors should be identified
andtreatedaggressivelyinpatientswithFH.Theprognosisof
FH patients depends heavily on the amount of LDL choles-
terol reduction that can be achieved, but treatment of other
modifiable risk factors such as hypertension, diabetes, and
smoking, further decreases the risk of heart disease.
Candidates for LDL apheresis
In patients where LDL cholesterol reduction has been
inadequate despite diet and maximum drug therapy (after 6
months), or if drug therapy is not tolerated or contra-
indicated, LDL apheresis may be considered for the
following individuals: 1) functional homozygous FH pa-
tients with LDL cholesterol $300 mg/dL (or non-HDL
cholesterol $330 mg/dL), 2) functional heterozygous FH
patients with LDL cholesterol $300 mg/dL (or non-HDL
cholesterol $330 mg/dL) and 0-1 risk factors, 3) functional
heterozygous FH patients with LDL cholesterol $200 mg/
dL (or non-HDL cholesterol $230 mg/dL) and high risk
characteristics such as $2 risk factors or high lipoprotein
(a) $50 mg/dL using an isoform insensitive assay, and 4)
functional heterozygotes with LDL cholesterol $160 mg/
dL (or non-HDL cholesterol $190 mg/dL) and very high
risk characteristics (established CHD, other cardiovascular
disease, or diabetes).
LDL apheresis is a U.S. FDA-approved process of
selectively removing Apo B-containing particles from the
circulation through extracorporeal precipitation with either
dextran sulphate cellulose or heparin.48–51The procedure
must be repeated every 1 to 2 weeks. In a single procedure,
LDL apheresis typically removes at least 60% of the Apo
B-containing lipoproteins.50Higher baseline lipid levels ap-
pear to exhibit a greater response to LDL apheresis treat-
ment. Due to the cyclical nature of Apo B synthesis and
circulation, recurrent hypercholesterolemia occurs in ap-
proximately 12 to 13 days with a rebound to pre-treatment
levels of Apo B particles.52Concomitant treatment with a
statin enhances the efficacy of LDL apheresis.53Long-
term therapy has been shown to result in a 20 to 40%
reduction in LDL cholesterol from pre-treatment levels.54,55
Few adverse effects are associated with LDL apheresis,
mostly noncritical episodes of hypotension.
Several clinical trials have confirmed the benefits of
LDL apheresis for prevention and slowing the progression
of cardiovascular disease,50,56–62and for other cardiovascu-
lar effects such as improvements in endothelial function,63
coronary vasodilation,64microvascular flow,65and myocar-
dial perfusion.66LDL apheresis has also been shown to pro-
mote regression of xanthomas50and modify a number of
markers associated with vascular disease, including lipo-
protein (a), an atherothrombotic marker.67LDL apheresis
is the only treatment shown to consistently reduce lipopro-
tein (a) levels by more than 50%.68Although LDL apheresis
is effective for retarding the development of atherosclero-
sis, and is often the only viable option for certain patients
such as those with homozygous FH, the procedure is time
consuming (more than 3 hours every 1 to 2 weeks) and
expensive.62,69
LDL apheresis referrals
Physicians should refer candidates for LDL apheresis to
qualified sites. Self-referrals are also possible. A listing of
sites qualified to perform LDL apheresis is in development
and will be posted on the National Lipid Association
website (www.lipid.org). Currently, there are more than
400 patients in North America receiving LDL apheresis
therapy at more than 40 centers. While new facilities are
added regularly, there is a significant gap between the num-
ber of patients receiving LDL apheresis therapy and the
number that, according to FDA guidelines,70may qualify
for LDL apheresis.
Women of childbearing age
Statins, ezetimibe, and niacin are not approved for use by
pregnant or breastfeeding women. Women with FH should
receive pre-pregnancy counseling and instructions to stop
use of statins, ezetimibe, and niacin at least four weeks prior
to discontinuing contraception, and should not use these
drugs during pregnancy and lactation. It is recommended
that a woman of childbearing age consult her physician
regarding continuation of any other lipid medications. In
cases of unintended pregnancy, a woman with FH should
discontinue statins, ezetimibe, and niacin immediately, and
she should consult with her physician promptly.
Treatment options during pregnancy
LDL cholesterol concentrations increase during the
course of pregnancy due to hormonal changes.71–73This
is considered beneficial in non-FH patients because choles-
terol is necessary for embryonic and fetal nervous system
development. However, in women with FH, the hormonal
S42Journal of Clinical Lipidology, Vol 5, No 3S, June 2011