Official Publication of the National Lipid Association
LipidSpin
Theme:
Statin Intolerance—
Facing Adversity
Also in this issue: Evidence-Based Approach to the Use of CoQ10 to Deal with Statin Intolerance
Vitamin D Deficiency and Statin Intolerance
This issue sponsored by the Southeast Lipid Association
Volume 11 Issue 4 Fall 2013
visit www.lipid.org
MORE THAN A
MEETING IN MAUI
Join us for the opening session of the 2014 Clinical Lipid Update Meeting
as world renowned thought leaders discuss Lipid Management and Metabolic Syndrome
in various populations from around the world.
W. Virgil Brown, MD, FNLA
Yuji Matsuzawa, MD, PhD
Cesare R. Sirtori, MD, PhD
GeraldWatts, DSc, MB, BS, PhD
This meeting features evidence-based sessions that include:
A debate from John Brunzell, MD and Sekar Kathiresan, MD
How Close are we to Personalizing CVD Prevention with Genetics?
Other key sessions include:
HDL Analytics & Functionality
Benjamin Ansell, MD, FNLA
Cardiovascular Risk in Asians
and Pacific Islanders
Beatriz Rodriguez, MD, PhD
Keawe’aimoku Kaholokula, PhD
Nathan Wong, PhD
Latha Palaniappan, MD, MPH
See you in Maui!
Visit www.lipid.org/springclu to register now.
To book your room, call 800-888-6100 and ask for the
National Lipid Association room rate.
Get the NLA room rate starting at $235/night plus tax if you
book your room by February 11, 2014.
Delta Airlines discount code: NMGR6
WALDORF ASTORIA GRAND WAILEA HOTEL
WAILEA, MAUI, HAWAII
CME Credit provided by the National Lipid Association
This activity has been approved for AMA PRA Category 1 Credit™
This activity is eligible for CDR credit
CE credit provided by Postgraduate Institute for Medicine
This activity is eligible for ACPE and ANCC credit
See final activity program for specific details
Debate: Is it time to Stop using
Fibrates Combined with Statins?
Jocelyne R. Benatar, MD, MBChB
Eliot Brinton, MD, FNLA
Dietary Issues and Supplements
Kathleen Wyne, MD, PhD, FNLA
Terry Jacobson, MD, FNLA
Forrest Batz, PharmD
Geeta Sikand, RD, FNLA
In This Issue: Fall 2013 (Volume 11, Issue 4)
Editors
JAMES A. UNDERBERG, MD, MS, FACPM, FACP, FNLA*
Preventive CV Medicine, Lipidology and Hypertension
Clinical Assistant Professor of Medicine
NYU Medical School and Center for CV Prevention
New York, NY
ROBERT A. WILD, MD, PhD, MPH, FNLA*
Clinical Epidemiology and Biostatistics and
Clinical Lipidology Professor
Oklahoma University Health Sciences Center
Oklahoma City, OK
Managing Editor
EMILY T. PARKER, MA
National Lipid Association
Executive Director
CHRISTOPHER R. SEYMOUR, MBA
National Lipid Association
Contributing Editor
KEVIN C. MAKI, PhD, CLS, FNLA
Associate Editor for Patient Education
VANESSA L. MILNE, MS, NP, CLS
Cardiac Vascular Nurse and Family Nurse Practitioner
Bellevue Hospital Lipid Clinic
New York, NY
Lipid Spin is published quarterly by the
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Copyright ©2013 by the NLA.
All rights reserved.
Visit us on the web at www.lipid.org.
The National Lipid Association makes every effort to
provide accurate information in the Lipid Spin at the
time of publication; however, circumstances may alter
certain details, such as dates or locations of events.
Any changes will be denoted as soon as possible.
The NLA invites members and guest authors to
provide scientific and medical opinion, which do not
necessarily reflect the policy of the Association.
2 From the NLA President
Spreading the Word
—Matthew K. Ito, PharmD, CLS, FNLA
3PastFrom
the SELA President and Immediate
President
Look for the NLA Community logo to discuss
articles online at www.lipid.org
Statin Intolerance
—Ralph La Forge, MSc, CLS, FNLA
—Paul E. Ziajka, MD, PhD, FNLA*
4 Letter from the Lipid Spin Editors
21 Practical Pearls
—Robert A. Wild, MD, PhD, MPH, FNLA*
—Debra A. Friedrich, DNP, ARNP, FNP-BC,
FNLA
NLA CME: A Culture of Policing
Ourselves
5 Clinical Feature
An Update on Statin Safety with an
Emphasis on Differences
—Demir Baykal, MD, FACC, FASE, CCT*
9 Guest Editorial
Managing the Statin-Intolerant
Patient: Low-Dose/Low-Frequency
Treatment Regimens
—Mary Honkanen, MD, ABIM, FNLA*
13 EBM Tools for Practice
Evidence-Based Approach to the
Use of CoQ10 to Deal with Statin
Intolerance
—Jennifer M. Welding, PharmD, CTTS
—Bishoy Ragheb, PharmD, BCACP, CDE, CTTS
16 Lipid Luminations
Vitamin D Deficiency and Statin
Intolerance
23 Case Study
Muscle-Related Statin Intolerance
—Nicole Gaskins Greyshock, MD*
—John R. Guyton, MD, FNLA*
26 Member Spotlight:
Barbara Wiggins, PharmD
27 Education, News and Notes
28 Foundation Update
29 References
32 Events Calendar
33 Provider Tear Sheet
Lowering LDL Using Non-Statin
Regimens
­—Casey Elkins, DNP, NP-C, CLS
19 Specialty Corner
Tolerability of Statin Therapy in
Children
*indicates ABCL Diplomate status
­—Jessica Lilley, MD
1
From the NLA President: Spreading the Word
Matthew K. Ito, PharmD, CLS, FNLA
National Lipid Association President
Professor of Pharmacy Practice
Oregon State University/Oregon Health and Science University
Portland, OR
Diplomate, Accreditation Council for Clinical Lipidology
during National Cholesterol Education
Month this September.
Discuss this article at
www.lipid.org/lipidspin
As a teen, I did all the things other
14-year-old boys did: played sports,
hung out with friends, and raced dirt
bikes. But around that time I learned I
inherited a genetic disorder called Familial
Hypercholesterolemia (FH).
When I was diagnosed with FH in 1974,
the medical community didn’t have ideal
guidance or treatment for it, especially for
children and teens. In fact, I wasn’t treated
for FH until my late 20s, just after statins
were introduced. The only thing standing
between me and a life-changing—or lifeending—heart attack was a semi-strict diet
and exercise.
That is why I was pleased to help
spread the word, along with so many
of my colleagues, about FH and other
dyslipidemias and cholesterol disorders
2
As a Doctor of Pharmacy and President
of the National Lipid Association (NLA)
this year, I am committed to raising
awareness about this disorder. I want
both patients and health care providers to
know exactly how important early diagnosis
and aggressive treatment is—from my
personal—and life-threatening--experience.
I encourage you to continue to educate
your patients about FH through the
many resources the National Lipid
Association offers, including lipid.org,
lipidfoundation.org and
learnyourlipids.com.
It is important to know that although
not curable, FH and other dyslipidemias
are treatable. The aim of treatment is to
reduce your cholesterol to an acceptable
level, thereby preventing or delaying
ischemic vascular disease. As a lipidologist,
you can implement cascade screening in
all first-degree relatives of the FH index
case to help facilitate early detection and
treatment, develop the best treatment plan
between you and your patient, provide
optimal patient education to ensure patient
adherence and persistence to therapeutic
lifestyle changes and pharmacotherapy,
and continue to assess for subclinical
atherosclerosis to further guide the
intensity of therapy. In the near future,
if emergent therapies in clinical trials
are approved, these therapies added to
maximum tolerated statin combination
therapy could provide important reductions
in cardiovascular risk to our FH patients.
In addition, please spread the word about
the FH Foundation’s new patient registry.
You can find more information at
www.thefhfoundation.org.
I hope to see you at one of our upcoming
meetings. Best wishes to you and your
families this holiday season. n
LipidSpin
From the Chapter President and Immediate Past-President:
Statin Intolerance
RALPH LA FORGE, MSc, CLS, FNLA
President, Southeast Lipid Association
Durham, NC
Diplomate, Accreditation Council for Clinical Lipidology
PAUL E. ZIAJKA, MD, PhD, FNLA
Immediate Past-President, Southeast Lipid Association
Director, Florida Lipid Institute
Winter Park, FL
Diplomate, American Board of Clinical Lipidology
The SELA board decided to devote this
issue of Lipid Spin to the problem of statin
intolerance. In formal clinical trials statin
intolerance is reported in 2 to 3 percent
of study subjects, but longer term follow
up studies report a more realistic rate of
15 to 20 percent. In an informal survey of
the past-president’s (PZ) private practice
lipid clinic 24 of the most recent 30 new
patients were referred because of statin
intolerance.
The most common problems reported
by statin intolerant patients are muscle
complaints (about 80%), but the full
spectrum of statin intolerance includes
increased liver enzymes, allergic reaction,
headache, neuropathy, alopecia, memory
disturbances, glucose intolerance,
gastrointestinal disturbances, insomnia,
arthralgias, exercise intolerance,
depression and dizziness.
Also, patients with statin intolerance are
at a clinical and economic disadvantage. In
patients with a history of coronary heart
disease statin intolerance is associated
with an 80 percent relative risk increase
for myocardial infarctions and a 53
percent relative risk increase for all cause
mortality compared to similar patients
able to tolerate statins. Dyslipidemic
patients unable to take statins have been
reported to incur a $400 to $900 greater
total health care cost over an 18 month
observation period compared to similar
patients able to tolerate statin therapy.
Discuss this article at
www.lipid.org/lipidspin
This issue of Lipid Spin will examine some
of the clinical strategies used to deal with
statin intolerance, including switching to
statins with a better tolerability profile,
use of very low dose - low frequency statin
administration, vitamin D supplementation,
CoQ10 supplementation and the use of
non-statin lipid lowering regimens. n
Official Publication of the National Lipid Association
3
Letter From the Lipid Spin Editors: NLA CME: A Culture of Policing Ourselves
ROBERT A. WILD, MD, PhD, MPH, FNLA
Clinical Epidemiology and Biostatistics and
Clinical Lipidology Professor
Oklahoma University Health Sciences Center
Oklahoma City, OK
Diplomate, American Board of Clinical Lipidology
lowest form of evidence. Often the stronger
the opinion the least amount of data behind
the opinion!
Discuss this article at
www.lipid.org/lipidspin
Lipid Spin is but one NLA educational
offering. As editors we are pleased to bring
these issues to clinicians on a regular basis.
Lipid Spin is peer reviewed. The subject
matter is always trying to address how we
can better take care of the patients/clients
we serve. Our focus is prevention. Because
we are always trying to prevent ravages
of CVD for everyone, by definition some
of what we offer will always be useful for
some and not useful for others. We need
to remind everyone from time to time that
many of the articles here provide clinical
opinions. Peer review is not a perfect
process. There is always an element of
subjectivity involved. However it is the
best way we have to try to avoid conflicts
of interest. We strive to bring you useful
information from a clinical perspective.
Always be aware that articles presented
are opinions of the authors and as such do
not imply NLA endorsement. One of my
favorite maxims is that strong opinion is the
4
The educational efforts of the NLA are
undergoing a massive structural change
for peer review to deal with issues of
subjectivity and/or potential conflicts of
interest. We recognize that all of us have
‘bias’. We all have our likes, dislikes and
each of us has a relatively limited view
of the world of science around us given
the massive differences, experiences and
individuality as we apply the information we
learn about.
As a professional educational organization
we are guided by governing bodies that try
to assure that all professional organizations
do their best to avoid conflicts of interest.
In short we have national guidelines
that we adhere to as we strive to make
our educational efforts second to none.
The NLA has many educational offerings
and the process of peer review requires
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that this is a priority for the NLA. As you
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please be aware that presenters are given
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presentations are reviewed for compliance.
We ask that everyone help in this effort. If
a potential conflict of interest arises, real
or perceived, for any of our educational
offerings, let us know so that we can look
into it.
We feel strongly as an educational
organization that we all benefit from
this effort to strive to be the premier
organization for the clinician in the practice
of Clinical Lipidology. Help us all by doing
your part. Help us move to clarity and
give us feedback. Not until we know how
we can help you can we learn how best
to provide what is useful and meaningful
to each of you. We welcome your input.
Be part of this culture. Let your regional
president know if you have any concerns,
and most importantly, you have suggestions
regarding how best to improve our efforts.
There are a number of considerations
that we have to deal with: logistics, costs,
feasibility, relevance, timeliness, etc. Rest
assured however that our hearts are in the
right place. Help us move to excellence.
We hope that you enjoy this publication and
recognize that it has a place. Also recognize
that helping us by giving us feedback in the
long run will allow us to serve you better. n
LipidSpin
Clinical Feature:
An Update on Statin Safety with an Emphasis on Differences
DEMIR BAYKAL, MD, FACC, FASE, CCT
Gwinnett Consultants in Cardiology
Medical Software LLC
Diplomate, American Board of Clinical Lipidology
Abbreviations
ULN = upper-limit normal
CAD = coronary artery disease
MMSE = Mini-Mental State Examination
LFT = liver function test
Statin drugs have been studied in
numerous controlled trials involving
hundreds of thousands of study
participants. Their use has resulted in
reduced coronary artery disease (CAD)
mortality, morbidity and, in several
studies, all-cause mortality. Even though
clinical trial evidence and clinical practice
experience have demonstrated extremely
low incidence of adverse effects, safety
concerns have existed, mostly on the basis
of case reports and data from clinical trials.
The U.S. Food and Drug Administration
(FDA) provided updates on statin labels
regarding side effects in 2011 and 2012.
Clinical trial assessment of muscle
adversities
No conclusive comparative evidence exists
to indicate that currently available statins
differ in regard to their risks of myopathy,
defined as otherwise unexplained marked
creatine kinase (CK) elevation >x10
the upper-limit normal (ULN) associated
with myalgia or rhabdomyolysis. The
incidence of myopathy was (0.1%) for
lovastatin 40mg/day and (0.2%) for
lovastatin 80mg/day in the Evaluation of
Xience Prime™ versus Coronary Artery
Bypass Surgery for Effectiveness of Left
Main Revascularization (EXCEL) trial.¹
There were no cases of myopathy or
rhabdomyolysis in three major pravastatin
trials.² None of the three cases of
rhabdomyolysisin patients on 10mg/day
dose or the two cases on 80mg/day dose of
atorvastatin in the Treating to New Targets
(TNT) trial was felt by investigators to
be casually related to atorvastatin.³ In an
analysis of 27 Phase 2/3 controlled clinical
trials of rosuvastatin, CK elevation>10X
ULN occurred in 0.02% to 0.04% in a
dose-independent manner. No cases of
rhabdomyolysis was reported.4
The incidence of CK elevations is reported
as 0.03% on 40mg/day fluvastatin and
0.00% on fluvastatin 80mg/day and
there have been no reported cases of
rhabdomyolysis. Therefore, fluvastatin
may have the least propensity to cause
myotoxicity.6 On the other hand, 10
Official Publication of the National Lipid Association
Discuss this article at
www.lipid.org/lipidspin
patients – nine of them on simvastatin
80mg/day – developed myopathy in the
high-risk-CAD A to Z trial.7 The highest
incidence of statin-related myopathy
was encountered in the seven-year,
randomized, double-blind SEARCH study.
Fifty-two patients (0.9%) in the 80mg
group versus one patient (0.02%) in the
20mg group developed myopathy, defined
as unexplained muscle weakness or pain
with a serum CK >10 times ULN.8 This
was higher than the labeled risk (based on
clinical trial data) of 0.53%. Twenty-two
patients (0.4%) in the 80mg group versus
no patient in the 20mg group developed
rhabdomyolysis. The risks for myopathy
and rhabdomyolysis with simvastatin 80mg
were highest in the first 12 months of
treatment; older age and female gender
both increased the risk of myopathy.
In SEARCH, the risk of myopathy was
approximately doubled in patients taking
5
a calcium channel blocker, in particular
diltiazem.8
The findings from the SEARCH trial
are supported by analyses of the FDA’s
Adverse Event Reporting System (AERS)
database, which show that the level
of reporting of fatal rhabdomyolysis
associated with the 80mg dose of
simvastatin has been higher in comparison
with lower doses of simvastatin or most
other statins, leading to a recommendation
to limit the initiation of an 80mg/day dose.
The incidence
of statin-related
myopathy varies
little between
different statins,
except the highest
incidence is seen
with the initiation
of simvastatin 80mg
daily and lowest
(none reported) with
fluvastatin 80mg daily.
Drug interactions and metabolic pathways
are major considerations. Because they
are not metabolized significantly via
the cytochrome P450 (CYP) pathway,
pravastatin and rosuvastatin may be
administered in a safer fashion if given
concomitantly with drugs known to be CYP
inhibitors.
Potential liver adversities
Overall, statin trials have demonstrated
that the incidence of significant
6
elevations41 in liver injury tests (defined
as > 3 X ULN) is between 0.5% and 5%;
and liver enzyme elevations are dose
dependent. There is little relationship
between the magnitude of low-density
lipoprotein (LDL) reduction and the
degree of enzyme elevation at lower
doses; in other words, there are no
differences between more potent statins
and less potent ones. Instead, when a
statin dose is doubled from the second
highest to maximum allowed dose, blood
transaminase levels increase. In one
comparative head-to-head, six-week study
involving 2,431 participants, there were
only five cases of two consecutive-visit
aspartate transaminase (AST) elevations
on atorvastatin 80mg (n=1), atorvastatin
20mg (n=2), simvastatin 40mg (n=1),
simvastatin 80mg (n=1), and none on
rosuvastatin 40mg daily dose.9 The clinical
significance of these often transient,
self-limited elevations is unclear. The
baseline measurements of liver function
tests are useful for future comparisons.
Pretreatment liver enzyme levels have not
been predictive of clinically meaningful
acute hepatocellular reactions. Therefore,
routine continued monitoring of liver
enzymes at lower doses of statins is
not necessary except for patients on
concomitant medications, with co-morbid
conditions or otherwise felt to be at high
risk. On Feb. 28, 2012, the FDA approved
crucial changes to the safety label for
statins, removing the recommendation
for periodic monitoring of liver enzymes.
According to the new labels, the FDA
recommends that such tests be conducted
before starting therapy and as clinically
indicated thereafter.
Adverse renal experiences
Preclinical animal studies have
demonstrated renal tubular toxicities
related to high-dose statin intake.
Mild proteinuria seen clinically is the
result of impairment of renal tubular
protein absorption by receptor-mediated
Clinical hepatotoxicity
is exceedingly rare,
mild to moderately
elevated LFT
abnormalities
are higher-dose
dependent and almost
always self-limited.
endocytosis and is physiological because
of HMG-CoA reductase inhibition.
Hematuria seen with statin use in clinical
trials commonly has other explanations.
To address the question of whether
urinary abnormalities with statin use
are detrimental to long-term renal
function, an open-label atorvastatin study
was conducted. It was concluded that
atorvastatin reduced the proteinuria and
progression of chronic kidney disease
(CKD) additive to angiotensin-convertingenzyme (ACE) Is or angiotensin-receptor
blockers (ARBs). This particular beneficial
or safety profile of atorvastatin may be
contributed by minimal renal excretion,
<2% as opposed to 10% with rosuvastatin,
13% with simvastatin and 20% with
pravastatin. In the atorvastatin-based Die
Deutsche Diabetes Dialyse (4D) study, no
case of rhabdomyolysis was reported in
619 hemodialysis patients.¹¹
Potential neurological adverse
experiences
The level of evidence supporting potential
neurological adverse effects of statins is
listed in Table 1.
Case reports and clinical trials have
suggested that statins may impair cognitive
function, which may be of safety concern,
LipidSpin
Level of Evidence
Potential Statin-Adverse Experience
A
Statins reduce the risk of ischemic stroke12
B
A decrease in cognition or memory 13,14,15
F
Statins may worsen dementia, Alzheimer’s disease16
B
Statins may improve dementia, Alzheimer’s disease17
U
Some statins are safer than others in regard to adverse neurological events
C
Peripheral neuropathy is a potential adverse effect18,19
Table 1.
particularly in older individuals.
In a double-blind study of 209 generally
healthy hypercholesterolemic adults,
randomly assigned to six-month
treatment with lovastatin 20 mg or
a placebo, lovastatin did not cause
psychological distress or substantially
alter cognitive function, but it did result
in small performance decrements on
neuropsychological tests of attention
and psychomotor speed, which were
concluded to be of uncertain clinical
importance. In a similar follow-up study
of 308 adults with hypercholesterolemia,
a randomized, double-blind, placebocontrolled trial of simvastatin 10mg or
40mg for six months provided partial
support for minor decrements in cognitive
functioning with statins. In the Pravastatin
in Elderly Individuals at Risk of Vascular
Disease (PROSPER) trial, the largest statin
The incidence of new
diabetes development
appears to be a class
effect and appears
to be more common
with moderate or
higher doses, but a
causal relationship is
unproven.
trial conducted specifically in older study
participants, 5,804 men and women ages
70 to 82 years with a history of or risk
factors for vascular disease were evaluated
for mental changes. After an average
of 3.2 years, pravastatin 40mg/day was
found to have no significant effect on
cognitive function or disability compared
with a placebo, as assessed by diagnostic
instruments such as the Mini-Mental
State Examination (MMSE). With specific
regard to dementia (which may include
Alzheimer’s disease), nested case-control
designed studies revealed that individuals
who were prescribed statins actually had
a substantially lowered risk of developing
dementia. However, a meta-analysis based
on the Cochrane database review (pooling
the studies providing a change in MMSE
from baseline) of the effect of statins on
dementia concluded that, while there was
insufficient evidence to recommend statins
for the treatment of dementia, statins were
not detrimental to cognitive function.
An FDA review concluded that data from
the observational studies and clinical
trials did not suggest that cognitive
changes associated with statin use were
common or led to clinically significant
cognitive decline, but information about
the potential for generally non-serious and
reversible cognitive side effects (memory
loss, confusion, etc.) was added to the
statin labels.
Peripheral nervous system
In case reports, and in a small number
of case-control and cohort studies it is
suggested that statins may be associated
Official Publication of the National Lipid Association
with peripheral nervous system adverse
experiences. However, from a review of
the literature, it is reasonable to conclude
that any potential risk of peripheral
neuropathy with statin use is very small.
A stepwise approach to the patient with
a potential statin-related peripheral
neuropathy adverse experience may be to,
first, ensure that other secondary causes
have been evaluated; second, to perform
a neurologic physical examination and
attempt to objectively quantify abnormal
neurologic physical findings; and third, to
obtain appropriate diagnostic neurologic
studies; and, fourth, to stop administering
the statin. If objective abnormalities
Neurotoxicity
seems to originate
from idiosyncratic
reaction, reversible
upon discontinuation
with little difference
between different
statins.
are found on physical examination and
diagnostic neurologic testing, and if the
neuropathic symptoms resolve upon
discontinuing the statin, then it may be
useful to repeat the objective evaluations
to see whether the resolution of symptoms
correlates with the resolution of objective
neurologic findings. If resolution of
symptoms or objective neurologic testing
does not occur after withdrawal of statin
therapy, then the diagnosis of idiopathic
peripheral neuropathy unrelated to statin
use should be considered. Conversely, if
symptoms and objective neurologic testing
resolve, then the clinician can best decide
7
whether the benefits of a re-challenge of a
statin drug exceeds the potential risks.
Increases in glycosylated hemoglobin
(HbA1c) and fasting plasma glucose
In the FDA’s review of the results from
the Justification for the Use of Statins in
Primary Prevention: an Intervention Trial
Evaluating Rosuvastatin (JUPITER) trial, it
was reported that there was a 27% increase
in investigator-reported diabetes mellitus
in rosuvastatin-treated patients compared
to placebo-treated patients. High-dose
atorvastatin also has been associated
with worsening glycemic control in the
Pravastatin or Atorvastatin Evaluation
and Infection Therapy – Thrombolysis in
Myocardial Infarction 22 Investigators
(PROVE-IT TIMI 22) substudy. A meta-
8
analysis by Sattar, et al., reported that
statin therapy was associated with a 9%
increased risk for incident diabetes (odds
ratio [OR] 1.09[1.02-1.17]), with little
heterogeneity (I2=11%) between trials.19 A
meta-analysis by Rajpathak also reported a
small increase in diabetes risk (relative risk
[RR] 1.13[1.03-1.23]) with no evidence
of heterogeneity across trials.²¹ A recent
study by Culver, et al., using data from
the Women’s Health Initiative, reported
that statin use conveys an increased risk
of new-onset diabetes in postmenopausal
women and noted that the effect appears
to be a medication-class effect, unrelated
to potency or to individual statin type²²
contrary to the findings of Carter.²³ In this
14-year observational study, a relationship
between the potency (and duration)
of statin therapy and the incidence of
diabetes development was observed.
However, the selection bias of a higher-risk
population requiring more intense statin
therapy could not be excluded.²³
Based on clinical trial meta-analyses and
epidemiological data from the published
literature, information concerning an
effect of statins on incident diabetes and
increases in HbA1c and/or fasting plasma
glucose was added to statin labels. n
Disclosure statement: Dr. Baykal has received consulting
fees from Actelion Pharmaceuticals Ltd.
References are listed on page 29.
LipidSpin
Guest Editorial:
Managing the Statin-Intolerant Patient:
Low-Dose/Low-Frequency Treatment Regimens
MARY HONKANEN, MD, ABIM, FNLA
Director of The Cholesterol and Lipid Treatment Center
Mobile Diagnostic Center
Providence Hospital
Mobile, AL
Diplomate, American Board of Clinical Lipidology
A patient recently told me the story of her
statin-intolerant sister, who was referred to
a cardiologist she had seen for chest pain
a few years earlier. When he entered the
room, she explained that she could hardly
walk or even get out of bed on atorvastatin.
The doctor simply stated there was nothing
he could do for her and walked out,
leaving her confused and hurt. We can do
something for these patients and it starts
with listening.
Statin clinical trials suggest an incidence
of adverse muscular events of ~ 1.5 - 3%,
but the true incidence of statin intolerance
(SI) is likely between 10% and 15%.1, 2
In a recent one-month chart review of
393 patients seen in our lipid clinic, 185
(47%) were originally seen for statinrelated adverse events, and 145 (37%) of
these had a history of SI related solely to
musculoskeletal complaints.
So, what can we do for these patients? Of
the 145 SI patients from our review, 90%
(129 patients) are actually on a statin today
– 14% on a statin alone and 83% on statins
dosed at very low doses and/or dosed 2-4
times weekly, in combination with other
lipid lowering medications. The average
low-density lipoprotein (LDL) reduction
in these patients was 50.8%. So the crux
of therapy for our statin-intolerant
patients is STATIN, but often dosed
in an unconventional manner in unusual
combinations with other lipid-lowering
agents.
Following is our approach to the SI patient.
First, listen to the patient. Just listening
with a compassionate ear will make the
patient more receptive to at least try
another statin at a very low dose.
Second, educate the patient on the
benefits of statin therapy. The patient’s
perception of these drugs often comes
from the evening news, a friend’s report
of some statin horror story or the hungry
lawyer ads on T.V. They rarely hear the
good news. A favorite “one-liner” for this
purpose: “For every one high-risk person
on statin who has died from an adverse
muscle event, 1,188 people DIDN’T
DIE because they took their statin,” a
calculation based on the incidence of fatal
rhabdomyolysis of 0.3/100,000 person-
Official Publication of the National Lipid Association
Discuss this article at
www.lipid.org/lipidspin
years of statin therapy3 compared to the
360 lives saved per 100,000 personyears of statin therapy in 17 secondary
prevention trials. A little pain is worth a lot
of gain.
Third, rule out other causes of
myopathy and evaluate potential
exacerbating factors by checking a
TSH, B12, vitamin D level. A baseline
CK should be established and monitored
with symptoms as recommended by the
National Lipid Association Statin Safety
Task Force.3
Finally, we initiate drug therapy by:
(1) Switching to another statin, one with
a different metabolism or to an extendedrelease preparation (fluvastatinXL or
lovastatin XR-Altoprev).
(2) Initiating very low doses (Ld) of
9
triglyceride monitoring, niacin for LDLs
not at goal and NOT for those with severe
expressions of metabolic syndrome,
monitoring platelets and symptoms of
ulcers and gout.
Myalgia
Check CK
Rule out other causes of myopathy.
Address exacerbating factors.
Tolerable pain
CK<10xULNa
Tolerable pain
CK>10xULNa
Continue statin.
Reduce dose/ change
statin as symptoms
dictate
Rhabdomyolysis
CK>10,000 or
>10XULN+ Cr
Intolerable pain
Without elevated CK
requiring medical
attention
Discontinue statin until symptoms resolve
•
•
•
Carefully reconsider
risk/ benefit of statin
therapy
Rechallenge with
Same statin at reduced dose
Statin with different metabolism
Extended release statinb
OR
If symptoms recur, consider:
• Very low doses of potent statin
(rosuva 2.5-5mg or atorva 5-10mg QD)
• Low-dose / low-frequency (Ld/Lf) long half -life statins
rosuva 5-10 mg or atorva 10-20mg 1-4x/week (i.e. M, MF, MWF, QOD)
pitavastatin 1-2mg QOD
• Combination of ezetimibe (also at low dose QD or QOD) with very low doses
of weaker statins or Ld/Lf regimens
i.e.pravastatin 10-20mg + ezetimibe 5-10mg QD
rosuva 2.5-5mg or atorva 5-10mg 3x/week – QOD (MWF), alternating
with ezetimibe 5-10mg (Tues/ Thurs/ Sat)
Tolerable symptoms, but
symptoms present and
lipids not at goal, consider
adding non-statin
medications: BAS, fibrate,
niacin, ezetimibe
Very few symptoms and
lipids not at goal, slowly
advance statin dose.
Increase the dose, not the
frequency in Ld/Lf
regimens
If symptoms recur: try
non-statin drugs: BAS,
fibrate, niacin, ezetimibe
in varying combinations
Figure 1: Algorithm for managing statin-intolerant patients*
Adapted from Arca and Pigna15and NLA Task Force3
a NLA taskforce recommends 10xULN; some clinicians use 5xULN
b fluvastatinXL (Lescol) or lovastatinXR (Altoprev)
*This protocol is not the recommendation of the NLA but the personal protocol of the author
long half-life statins at a low frequency
(Lf), i.e. once a week to every other day
(QOD), using primarily rosuvastatin (19
hours) and atorvastatin (14 hours) or
pitavastatin (11 hours) QOD.
(3) Combining very low daily doses of
weaker statins or alternate-day dosing
of long half-life statins with ezetimibe
– also used at a low-dose/low-frequency
(5-10mg daily, QOD or 3 times weekly)
– for reduced symptoms, lower cost or if
10
full doses cause a reduction in high-density
lipoprotein (HDL).
(4) Combining the above (statin
+/- ezetimibe) or ezetimibe alone
with other non-statin lipid-lowering
medications (BAS, niacin, fibrates) with
an intense effort to choose a drug that
has some clinical trial evidence of benefit
for that individual patient, i.e. fibrate for
triglycerides>200mg/dl and HDL<40mg/
dl, colesevelam for diabetics with close
Since most patients referred to lipid clinics
have already failed multiple attempts with
multiple statins, proceeding directly to
options 2 and 3 above is reasonable. We
almost always start with rosuvastatin 2.5mg
-5mg, taken on Mondays, Wednesdays
and Fridays (MWF), with directions
to add ezetimibe 5mg (1/2 10mg pill)
on Tuesdays, Thursdays and Saturdays
(TuThSa). Providing samples for this first
cycle definitely improves compliance.
A normal week’s supply lasts a month
with the pill splitting and QOD dosing.
We repeat labs after six weeks. Once
the patients see the usually significant
improvements, they are encouraged
enough to continue and even increase the
medications. We advance the statin very
gradually, as tolerated, by increasing the
dose first, not the frequency. For insurance
purposes, we often switch to atorvastatin
5-10mg dosed at the same frequency or
change to very low doses of weaker statins
(i.e. pravastatin 10-20mg) daily. From
there, it’s a slow process of tweaking,
determined by other lipid abnormalities,
comorbidities and cost.
Following is a summary of studies
evaluating the efficacy and tolerability
of low-dose/low-frequency (Ld/Lf)
dosing strategies with statins:
(1) Piamsomboon et al.4—In 61 patients
treated with atorvastatin 10mg QOD,
LDL was reduced 30%.
(2) Juszczyk et al.5—In 25 patients treated
with atorvastatin QOD (mean dose
18.8mg) or rosuvastatin QOD (mean dose
9.7mg), LDL reductions were 43% and
28%, respectively.
(3) Wongwiwatthanaukit et al.6—In 81
patients treated with rosuvastatin 10mg
LipidSpin
qd vs. QOD, LDLs were reduced 48%
and 39%, respectively, and 85% vs 70%
achieved NCEP targets, neither statistically
significantly different.
(4) Jafari et al.7—In 54 patients, there
were no statistically significant differences
in LDL reductions between atorvastatin
dosed at 10mg qd, 10mg QOD or 20mg
QOD after 6 weeks of treatment; all
tolerated treatment.
(5) Keles et al.8—In 61 patients treated
with atorvastatin 20mg qd vs QOD,
there was no significant differences in
the reductions of LDL or hsCRP after 3
months.
Similar trials performed in STATIN
INTOLERANT patients include:
(1) Backes, et al.9—In 51 patients treated
with rosuvastatin 2.5-10mg QOD,
(mean dose 5.6mg), LDL was reduced
34.5%, 50% achieved National Cholesterol
Education Program goals and 72.5%
tolerated therapy.
(2) Gardala, et al.10—In 40 lipid patients
receiving rosuvastatin 5-10mg twice
weekly (Mondays and Thursdays); LDLs
were reduced 26% and 80% tolerated
treatment.
(3) Rusinger, et al.11—50 patients receiving
rosuvastatin 2.5-20mg once a week;
LDLs were reduced 23%, 74% tolerated
treatment, but only 27% reached their
NCEP goal.
Studies evaluating Ld/Lf or extendedrelease statin therapy in SI patients in
combination with ezetimibe include:
(1) Athyros, et al.12—In 54 patients
receiving ezetimibe 10mg QD for three
months and subsequently receiving
atorvastatin 10mg twice weekly
for three months, LDLs were reduced
34%, 84% achieved LDL goals vs. only
9% on ezetimibe alone, and only one
patient could not tolerate the addition of
atorvastatin.
Lipid-Lowering Agent
No. of patients
on medications
%a
129
19
44
49
20
29
90
14
29
35
14
21
Ezetimibe (5-10mg)
Non-daily dosing d
90
48
64
35
Fibrate e
63
48
27
15
45
34
19
11
ER Niacin
14
10
BAS (Welchol)
5
3.5
Statins b
Single- agent
+ ezetimibe alone
+ ezetimibe + other agents (below)
+ other agents (no ezetimibe)
Non-daily dosing (low-dose/ low-frequency) c
Fenofibrate
1/3-2/3 max dose
Gemfibrozil
Table 1. Usage of Lipid-Lowering Medications in 140 Patients with Myalgia-Related Statin Intolerance; A OneMonth Chart Review.
a 145 of 393 patients were SI; 2 had stopped all medications, 3 had no results following initial visits; the denominator
used to calculate percentages was 140.
b Statins used: rosuvastatin 48% (average dose: 7.4mg/d); atorvastatin 27% (average dose: 13.5mg/d); pravastatin 14%
(average dose: 35mg/d); pitvastatin 3% (average dose: 2mg/d); fluvastatin XL 2% (average dose: 80mg/d); simvastatin
3.5% (average dose: 24mg/d); lovastatin 0.7% (average dose: 40mg/d).
c Statins used for non-daily dosing: rosuvastatin 2.5mg (7pts), 5mg (13pts), 10mg (4pts) and 20mg (2pts) dosed twice
weekly (M&F), MWF, MWF p.m. + Sun a.m.; atorvastatin 5mg (5pts), 10mg (1pt), 20mg (4pts) dosed M:F, MWF or QOD
d Ezetimibe was used at 5-10mg, dosed 2-4 times/week (Tues/Sat, Tues/Thurs/Sat or Tues/Thurs/Sat/Sun) usually
alternating with statin MWF
e 75% of 393 lipid patients reviewed had TG>200; 22% had TG>500mg/dl. Gemfibrozil was used only with very low
doses of rosuvastatin and pravastatin in very carefully selected patients who were educated extensively on the signs/
symptoms of rhabdomyolysis
(2) Reddy, et al.13—In 23 patients
intolerant of atorvastatin or rosuvastatin
receiving the same drug dosed twice
weekly plus ezetimibe twice weekly
plus colesevalam 6 pills a day, LDLs
were maintained at the level produced by
daily dosing, but 87% of patients tolerated
treatment, and HDLs went up in the
rosuvastatin patients.
(3) Stein, et al.14—In patients receiving
daily fluvastatin XL 80mg, ezetimibe
10mg or both, LDLs were reduced 33%,
16% and 41%, NCEP targets were achieved
in 59%, 29% and 84%, and muscle-related
side effects occurred in 17%, 24% and 14%,
respectively.
Results from our chart review are
consistent with the above reports: 29
of 140 SI patients were on non-daily
Official Publication of the National Lipid Association
doses of statins, and 44 were on statin
in combination with ezetimibe alone
with an average LDL reduction of 52%.
Many of these were on non-daily low
doses of ezetimibe (5mg 2-4 times per
week). An additional 33 patients were
on statin+ezetimibe+other non-statin
drugs and had an average LDL reduction of
62%. Coincidentally, 62% of the patients
were below the more aggressive NCEP
targets; 79% of those not at goal had
>40% LDL reductions.
Following statins and ezetimibe, fibrates
were the drugs used at the next highest
frequency. This is not surprising, because
295 of 393 (75%) of our patients had TGs
>200, and 22% were referred with severe
hypertrigyceridemia (TG>500). Even so,
less than half of these patients were on
full-dose fenofibrate. Fenofibrate can help
11
lower the LDL further and often results in
a dramatic LDL reduction when combined
with ezetimibe alone, a very consistent
finding in the completely statin-intolerant
patient. If fenofibrate lowers HDL and
increases creatinine, especially enough to
preclude the use of metformin, we reduce
the dose or stop it. Table 1 summarizes
the drugs used and Table 2 the lipid values
achieved with various drug combinations.
Only 20% of the patients were on a Ld/
Lf statin-dosing schedule, but most were
originally started on rosuvastatin (2.5mg)
three days a week. Most patients tolerate
a very gradual increase in the statin dose –
to a point. The art is knowing when to
stop.
While all of these results of alternate-day
statin dosing, especially in combination
with other lipid drugs, are quite
remarkable and encouraging, these are
non-approved strategies and no clinical trial
evidence for cardiovascular risk reduction
exists. Therefore, these strategies should
be reserved for those patients who have
failed recurrent attempts of conventionally
dosed statins. Designing a clinical trial
to evaluate these kinds of treatments
in SI patients would be a monumental
task. However, if one were designed so
medications were meticulously tailored for
the individual patient – the way most of us
treat these SI patients – compared to those
treated with statin alone, these patients
just might come out ahead – or at least
they could get out of a chair! n
Treatment
% of patients
on regimen
% LDL
reduction
% HDLc
increase
% TG c
reduction
Statin alone
13.7
42
28
30
Statin + Ezetimibe
29.5
53
29
44
Statin + Ezetimibe + Fenofibrate
17.3
52
26
60
Statin + Ezetimibe + Gemfibrozil
6.5
57
41
68
Statin + Ezetimibe + ER+ Niacin
5.5
60
56
44
1.4
60
21
34
Statin + Ezetimibe + Fenofibrate + ER
Niacin
1.4
72
34
73
Statin + Ezetimibe + Fenofibrate + BAS
2.9
62
41
68
Statin + Ezetimibe + BAS+
d
Statin + Gemfibrozil
4.3
46
44
72
Statin + Fenofibrate e
5.8
48
21
69
Statin + Fenofibrate + ER Niacin
0.7
37
63
31
Statin + ER Niacin + BAS
0.7
49
9
47
Statin + ER Niacin
2.2
36
48
41
Statin + ER Niacin + BAS
0.7
51
47
55
Ezetimibe Alone
0.7
11
0
-2
Ezetimibe + Fenofibrate
5.0
41
72
58
Ezetimibe + Fenofibrate + BAS
0.7
58
22
45
Table 2. Efficacy of Various Treatment Regimens Used in Statin-Intolerant Patients; A Chart Review of 140
Patients a,b
a Results were calculated by comparing the most recent lipid values to the worst corresponding lipid value on record. For
example, LDLs were compared to the highest LDL observed after correcting chylomicronemia. Some baseline values
were not available, because patients often were referred while on some lipid therapy
b 62% of patients achieved the more aggressive NCEP/ADA LDL target, i.e. <70mg/dl with documented disease or DM +
1 risk factor. Of the 38% not at goal, 79% had LDL reductions > 40%.
c Triglyceride and HDL responses were likely confounded by changes in other medications (i.e. addition of pioglitazone,
other diabetic agents and omega-3 fatty acids [10 pts] or discontinuation of thiazides, atenolol etc.) and significant
lifestyle modifications.
d BAS bile acid sequestrant
e 4 of 8 patients also were started on high-dose omega-3 fatty acids in the fenofibrate group, none in the gemfibrozill
group.
Disclosure statement: Dr. Honkanen is on the speaker’s
bureau for Merck & Co., Inc., Astra-Zeneca and Amarin
Pharma, Inc.
References are listed on page 29.
12
LipidSpin
EBM Tools for Practice:
Evidence-Based Approach to the Use of CoQ10 to Deal
with Statin Intolerance
JENNIFER M. WELDING, PharmD, CTTS
Clinical Pharmacist
PharMerica
Fort Lauderdale, FL
BISHOY RAGHEB, PharmD, BCACP, CDE, CTTS
Clinical Pharmacy Specialist
Residency Coordinator
Veterans Affairs Health Systems
Tallahassee, FL
Statins reportedly are the most effective
of the lipid-modifying drugs in primary
and secondary prevention of coronary
heart disease.1-6 Yet, many patients are
deprived of the benefits of statins because
of their associated complications. The
most common statin-related complication
is myopathy, which was underreported
in clinical trials because of the exclusion
of patients with a previous history of
myalgia.1,7,8 Studies specifically designed
to assess the rate of statin-related
myalgia have estimated muscle-related
complications occur in between 9% and
22% of patients – or 1.5 million people –
each year.9-12 This ultimately leads to the
discontinuation of statins in between 5%
and 10% of patients.11 Practitioners have
been searching for strategies capable of
alleviating statin-induced myopathy to
facilitate the continued use of statins.
The most prevalent of these strategies is
CoQ10 supplementation.9
Statins, CoQ10 and Myopathies
CoQ10 is essential in cellular
bioenergetics, because it participates
in the electron transport chain during
oxidative physphorylation, leading to
adenosine triphosphate (ATP) production.13
Depletion of CoQ10 is known to result
in mitochondrial dysfunction, which is
theorized to result in myopathy.10,14
The theory of CoQ10 depletion
involvement in statin-induced myopathy
was first proposed in the late 1980s.14
CoQ10 is an end-product of the
mevalonate pathway. Statins are believed
to reduce CoQ10 biosynthesis and
cause myopathy by interfering with this
pathway via the inhibition 3-hydroxy3-methylglutaryl coenzyme A [HMGCoA].7,10,14,16
CoQ10 Depletion Studies
The theory of statin-induced CoQ10
depletion was supported by Ghirlandaio
Official Publication of the National Lipid Association
Discuss this article at
www.lipid.org/lipidspin
et al., who published the first doubleblind study assessing the effect of statins
on plasma CoQ10 levels. Since then, the
relationship of statins and reduced
CoQ10 plasma levels has been well
documented. 8,10,12,17-36
Conventional wisdom would suggest that,
given the role of CoQ10 in muscle-energy
production, reversing CoQ10 depletion via
supplementation would resolve cases of
statin-induced myopathy. The evidence to
date has been, at best, controversial.10
13
CoQ10 Outcomes
The two most widely cited studies, by
Young et al. and Caso et al., have produced
equivocal results. In a double-blind
placebo-controlled pilot study, Young et
al. concluded that, despite a significant
increase in plasma CoQ10 levels,
supplementation with 200mg/day CoQ10
did not improve statin tolerance and
myalgia after 12 weeks in patients with
prior statin-induced myalgia.37
Caso et al. performed a double-blind,
randomized pilot study assessing the effect
of 100mg/day CoQ10 versus 400IU/day
Vitamin E on the degree of muscle pain
and its interference with daily activities.
After 30 days, pain intensity decreased
significantly from baseline in the CoQ10
group. Those in the Vitamin E group did
not experience a significant difference in
pain.38
Adding to the dilemma, more recent
studies – such as those by Bookstaver et al.,
Zlatohlavk et al., and Fedacko et al. – also
failed to produce consistent results.39-41
Several clinical reviews have assessed
these studies and have been unable to
definitively conclude that CoQ10 improves
statin-induced myopathy. 8,9,42-44
Rethinking Plasma CoQ10
Inconsistencies in the research data
have led some to call into question the
significance of reduced plasma CoQ10
levels on myalgia.
Researchers suggest that, rather than
indicating a true inhibition of CoQ10
synthesis, a reduction in plasma CoQ10
levels should be expected because of
the statin-induced reduction of lowdensity lipoprotein (LDL) particles,
the primary transporter of CoQ10 in
plasma.8 Additionally, while the statininduced depletion of CoQ10 is well
documented, research has not established
a firm association between statin use
14
and mitochondrial myopathy, because
intramuscular CoQ10 levels have not
consistently decreased with statins.7,10,42,45
Two studies observed intramuscular
CoQ10 increases of 46% and 9% in statintreated patients.46,47
CoQ10 should be
considered in statinintolerant patients,
even if only to induce
a placebo effect,
arguing minimal risk
with possible benefit.
Where do we go from here?
Because of inconsistent results, the
National Lipid Association (NLA) has
not endorsed the use of CoQ10 for
prophylaxis to reduce statin-induced
myalgias.48 However, some researchers
have suggested that CoQ10 may still
have a place in treating statin-induced
myalgia, particularly in the setting of
CoQ10-depleting conditions such as
advanced age, multisystem diseases,
multisystem inherited metabolic disease,
mitochondrial encephalomyopathies and
certain movement disorders, including
Parkinson’s disease and some cerbebellar
ataxias.7,45 There also is research to suggest
the benefits of CoQ10 in patients with
cancer. 49,50
up to 600mg/day.8,10,12,45,54 There is strong
evidence based on the observed safety
level of CoQ10 that doses up to 1,200mg/
dl are very safe.53 Based on the safety data
alone, several authors have suggested
CoQ10 should be considered in statinintolerant patients, even if only to induce
a placebo effect, arguing minimal risk with
possible benefit.10,12,45
Conclusion
To date, there is inconclusive evidence to
prove if CoQ10 can reduce statin-induced
myopathy in all patients. Some research,
however, suggests that it may provide
some benefit in certain patients who have
CoQ10-depleting conditions. Additionally,
the remarkable safety profile makes
CoQ10 an attractive low-risk option for
practitioners who are aggressively trying
to maintain statin use in their patients.
More data are needed to determine if
CoQ10 is an effective treatment in statininduced myopathy. Many are eagerly
anticipating the release of the Parker et al.
trial later this year in the Journal of Clinical
Lipidology, hoping it will shed more light
on this ongoing debate.55 n
Disclosure statement: Dr. Welding has no disclosures to
report. Dr. Ragheb has no disclosures to report.
References are listed on page 29-30.
Additionally, CoQ10 may be beneficial
in patients who have a genetic or
neuromuscular predisposition to statininduced myopathies.51,52
The use of CoQ10 may be considered
because of its remarkable safety record,
because there are no known risks in doses
LipidSpin
Updated and Revised
September 2013
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1 The Science of Lipidology: Lipid Metabolism, Pathogenesis of
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and Management of Patients at Risk
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Lipid Luminations: Lowering LDL Using Non-Statin Regimens
CASEY ELKINS, DNP, NP-C, CLS
Assistant Professor
University of South Alabama, College of Nursing
Mobile, AL
Director/Founder
The Lipid Center at Cooper Family Med Center
Pascagoula, MS
Diplomate, Accreditation Council for Clinical Lipidology
Discuss this article at
www.lipid.org/lipidspin
Although statin therapy is a cornerstone
of cardiovascular disease prevention,
and although it achieves the largest
reduction of low-density lipoprotein (LDLC),1 and has one of the safest overall
side-effect profiles among lipid-lowering
medications, some patients are unable to
tolerate statins because of one or more
side effects. When this clinical scenario
is present, alternative risk-reduction
strategies are needed to achieve target
LDL-C goals. Clinicians should be familiar
with alternative pharmacological therapies,
non-pharmacologic therapy and intensive
therapeutic lifestyle modifications that
reduce atherosclerosis progression when
statin therapy is not an option.
Bile acid Sequestrants
Bile acid sequestrants – colestipol,
cholestyramine and colesevelam – bind
16
to bile acid in the intestines and prevent
recirculation of cholesterol-decreasing
LDL-C by 15%-26%,2,3 achieving maximal
LDL-C reductions within two weeks.
Colesevelam has a higher specificity for
bile acids than the two older bile acid
sequestrants, and consequently there are
fewer gastrointestinal side effects and
drug interactions.2 Colesevelam has been
noted to decrease hemoglobin A1C by
about 0.5%,3,4 and is more frequently being
used in diabetic patients. Because bile acid
sequestrants are not absorbed systemically,
large doses are required. They do not have
any systemic drug interactions but they
can interfere with drug absorption.2, 5 This
requires constant vigilance, monitoring and
adjustments to ensure therapeutic levels of
concomitant medications are maintained to
improve outcomes.
Nicotinic acid
Although recent clinical trials have
shown no benefit from nicotinic acid
when LDL cholesterol is therapeutically
low, there are many research studies
demonstrating LDL-C reduction.5 The
Coronary Drug Project found significantly
fewer cardiovascular events and decreased
mortality with niacin, and these benefits
persisted for up to 15 years after induction
or therapy.6 Niacin reduces LDL-C by 25%,
increases high-density lipoprotein (HDL-C)
by 15%-30% and decreases triglycerides
by 35%-50%3 with more pronounced
benefits in patients with metabolic
syndrome. Some clinicians erroneously
eliminate niacin from dyslipidemia
treatment options because of results of
several recent randomized clinical trials
without an overall understanding of
aggregate literature. In addition to the
lipoprotein changes associated with niacin
administration, there are several other
pleotropic effects, including associated
anti-oxidative and anti-inflammatory
properties, improved endothelial function,
reduced high-sensitivity C-reactive protein,
and regression of carotid intima-media
thickness. This makes niacin a more
compelling option.1, 7
Cholesterol-absorption inhibitors
Ezetimibe, a cholesterol-absorption
inhibitor, can be used alone or in
combination with other medications to
LipidSpin
reduce LDL-C (by 15%-20%).3,8,9 This
amount of reduction in LDL-C does not
meet the 30% reduction proven to reduce
cardiovascular events, and routinely
clinicians use ezetimibe in combination
with other medications. Based on the
available data, ezetimibe appears to be
safe but has not been proven to provide
significant long-term cardiovascular
benefit.3,9,10 Ezetimibe and colesevelam
combination therapy has been noted to
provide a 30%-40% reduction in LDL-C.11
Alternative therapies
Red yeast rice is a traditional Chinese
supplement that is procured after red
yeast is grown on rice. It combines
monounsaturated fatty acids, sterols,
isoflavones, Monacolin K (a form of
lovastatin) and other ingredients, whereby
it is reported to lower LDL-C by 10%-20%
in several small population studies.3,12
This level of LDL-C reduction does not
equal the potency of the weakest statin,
and long-term safety and decreased
cardiovascular mortality are not clearly
documented, leading some clinicians to
object to its use. It has been used for
centuries in China and it does lower
LDL-C to some degree, and therefore
remains non-statin option to reduce LDLC, primarily in combination with other
therapies.
Plant sterols occur naturally and have
a similar structure to cholesterol. Plant
stanols are “saturated sterols” and do not
have double bonds. Between 150-400
mg/d of sterols and stanols are provided
by the typical Western diet. However,
much higher intakes (1-3 g/d) are needed
to decrease atherogenic lipoprotein
properties. Plant sterols and stanols
are underutilized in the treatment of
dyslipidemia. At doses of 2 grams per
day, they can lower LDL-C by about 10%15%; and these benefits are often additive
to lifestyle modifications.13-14 There are
several commercially available forms of
sterols and stanols, including margarine
spreads, juices, smoothies, and chews.
All patients receiving
lipid-lowering
medications should
be counseled
on the benefits
and importance
of aggressive
therapeutic lifestyle
modifications.
Lifestyle modifications
All patients receiving lipid-lowering
medications should be counseled on the
benefits and importance of aggressive
therapeutic lifestyle modifications.3
In general however, knowledge and
implementation of these lifestyle
modifications are under-used or underutilized in clinical practice. The current
ACSM guidelines for exercise and
dyslipidemia are: Aerobic exercise, 40-75%
of aerobic capacity, for 5-7 days a week,
for 30-60 minutes per day or ≥ 2000 kcal/
week of leisure-time physical activity.15
Therapeutic lifestyle changes have the
best chance of reducing LDL-C when both
physical activity and dietary changes are
made together. A 4.5kg weight loss has
been documented to reduce LDL-C by 5%8%.3 Decreasing the intake of cholesterol,
saturated fat, trans-saturated fat, and using
dietary adjuncts aids in LDL-C reduction.3,9
forming a viscous matrix and trapping
cholesterol and bile acids. National
Cholesterol Education Program Adult
Treatment Panel III (NCEP ATP III)
recommends a daily intake of 10-25 g/day
of viscous fiber. Grains, prunes, apples
and legumes are natural sources of viscous
fiber. Psyllium-containing products are
supplemental sources of viscous fiber
that provide patients with a convenient
method to increase daily fiber intake. It is
important to instruct patients to gradually
increase their daily dosage of fiber to
promote gastrointestinal tolerance and to
increase adherence. Combining decreased
saturated fat and dietary cholesterol with
weight reduction and increased levels of
viscous fiber and plant sterols/ stanols can
provide a cumulative LDL-C reduction of
20%-30%.16
Conclusion
Statin therapy is first line pharmacologic
interventions for patients with increased
LDL-C; however, some patients experience
untoward side effects and are unable to
continually adhere to this therapy. As
clinicians we need to be familiar with
effective strategies that lead to better
lifestyle modifications and we need to be
able to employ alternative pharmacologic
and non-pharmacologic therapies to
reduce cardiovascular risk and to improve
healthcare outcomes in our patients in
need of CVD risk reduction. n
Disclosure statement: Dr. Elkins is a member of the
speakers bureau for LipoScience Inc.
References are listed on page 30.
Increasing viscous fiber to at least 5%-10
grams per day can lower LDL-C by 6%13%9. Water-soluble viscous fiber acts by
Official Publication of the National Lipid Association
17
Lipid Academy Online is a user-friendly, tech-savvy
adaptation of the NLA’s live training course.
This series of seven interactive modules provides a
comprehensive indoctrination to lipid science and
essential information for the systematic management
of dyslipidemia and the metabolic syndrome.
Introducing an Interactive
Online Training Program in Clinical
Lipid Management
An iPad-friendly version of Lipid Academy Online will be available soon.
This activity has been approved for AMA PRA CATEGORY 1 CREDIT™
CME credit provided by the National Lipid Association
This activity is Co-provided by Postgraduate Institute for Medicine
This activity is eligible for ACPE, ANCC and CDR credit; see final CE activity for specific
details. Full accreditation information is available online at nlalipidacademy.com/
For more information, visit www.nlalipidacademy.com
18
LipidSpin
Specialty Corner:
Tolerability of Statin Therapy in Children
JESSICA LILLEY, MD
Assistant Professor of Pediatrics
Blair Batson Children’s Hospital
University of Mississippi Medical Center
Jackson, MS
Acknowledgements: Written with the mentorship and guidance of
Sergio Fazio, MD, PhD, Vanderbilt University School of Medicine.
The National Heart, Lung and Blood
Institute (NHLBI) recommends universal
pediatric lipid screening to identify
and treat children with serious genetic
dyslipidemias.1 Primary care providers
should certainly identify children who
will be candidates for statin therapy. One
in 500 people are heterozygous for the
autosomal co-dominant mutations causing
familial hypercholesterolemia2 (FH),
making it one of the most common genetic
diseases in Western populations. Still, a
very low number of the children tested
will reach the threshold for treatment.3
Statin therapy is recommended for
otherwise healthy children older than
10 years with low-density lipoprotein
cholesterol (LDL-C) > 190 mg/dL;
this high cutpoint include only those
with severe dyslipidemias such as FH.1
Regardless of the low number of children
who will require treatment, obstacles
remain for these pediatric patients.
Medications commonly associated with
grandparents and secondary prevention of
further cardiovascular disease may seem
out of place in a child’s medicine cabinet.
Even for willing prescribers, pediatricians
historically have had little training in the
management of lipid disorders, particularly
pharmacotherapy.
Hesitation to use this class of drugs is
unfortunate, because statins have proven
highly effective and safe in adult primary
and secondary prevention trials4,5 and
improve carotid medial thickness in
children with FH.6 Furthermore, a recent
meta-analysis of 135 studies involving
~250,000 adult patients showed that
side effects of statins were rare.7 They are
far more palatable and more effective at
Official Publication of the National Lipid Association
Statins are well
tolerated in children
when prescribed
by specialists as
recommended by
the conservative
guidelines given by
the NHLBI.
Discuss this article at
www.lipid.org/lipidspin
lowering LDL-C than the prior mainstay
of pediatric treatment, bile-acid-binding
resins.
Regardless of the agent used, reducing
cholesterol in the pediatric population
has caused concerns about decreasing
the available substrate to form hormones
that orchestrate pubertal development,
and initiating a low-fat diet in at-risk
children has been questioned because
of the necessity of fats for healthy brain
development. These concerns remain
theoretical; a well-designed meta-analysis
of six studies examining a total of 798
children showed no pubertal or growth
concerns in children treated with statins.8
Smaller studies showed efficacy and safety
of other agents, though none was powered
to detect rare events.9-12 Reversible
elevations in transaminases were reported
19
in from 1% to 5% of children in trials of
simvastatin or atorvastatin, but none had
clinical signs of liver injury.11,12
Infrequent but significant adverse effects
of statin therapy have been reported,
including severe muscle injury leading
to rhabdomyolysis. However, the more
common issue in practice is statin
intolerance, an inability to stay on the
medication because of muscle complaints
without objective signs or blood marker
changes. Furthermore, recent studies
showing a slight but statistically significant
increase in risk for new onset diabetes
have given many prescribers pause about
statin use in patients of all ages.7,13 Acute
kidney injury with high doses,14 increased
muscle injury and strains,15 reversible
memory problems16 and decreased exercise
tolerance17also have been reported.
Furthermore, the possible cumulative
effect of statins is unknown. Young
patients who start statin therapy for FH
will likely take a pill for the rest of their
lives. Statins are classified as a Category X
medication for their potential teratogenic
effects18 and should be used carefully in
women of childbearing age, including
teenage girls.
In the Vanderbilt University Medical
Center pediatric lipid program, we first
present lifestyle measures for lowering
LDL-C and improving overall cardiovascular
health, and each family meets with our
dietitian. Following six months of optimal
lifestyle efforts, we offer low-dose statin
therapy and transparently discuss the
risks and benefits of pharmacotherapy if
LDL-C remains above the recommended
threshold and continue close follow-up in
our clinic. Only one patient in our practice,
an obese but active girl, discontinued
simvastatin based on complaints of muscle
pain while performing ballet. There was
no evidence of serious muscle injury, and
a creatine phosphokinase level was normal
at 114 IU/L (normal 26-140); following a
20
brief medication holiday, she has had no
complaints with rosuvastatin treatment for
years now. A survey of our colleagues at
three other pediatric lipid clinics at tertiary
academic referral centers similarly revealed
no knowledge of adverse effects requiring
discontinuation of statin therapy.
Recent studies
showing a slight but
statistically significant
increase in risk for
new onset diabetes
have given many
prescribers pause
about statin use in
patients of all ages.
disease later in life. Routine clinic
visits with appropriate screening and
counseling regarding adverse drug effects
are necessary, but the knowledge of
these potential rare complications should
not limit the use of these powerful
and effective lipid-lowering agents in
appropriate patients. n
Disclosure statement: Dr. Lilley has no disclosures to
report.
References are listed on page 30-31.
One potential explanation for low rates of
adverse effects in young patients is that
children are generally healthy, without
concomitant kidney or muscle disease.
Furthermore, children are not usually
taking other medications known to cause
serious interactions, including gemfibrozil
and digoxin.19 Polypharmacy increases the
risk of toxicity because of competition
with other cytochrome P450 isoform 3A4metabolized substances.19 Lipid specialists
also treat to less aggressive goals in
children and use lower doses than for highrisk adult patients, and lower doses are
associated with fewer adverse effects.7
In summary, statins are well tolerated in
children when prescribed by specialists
as recommended by the conservative
guidelines given by the NHLBI. Early
identification and treatment of serious
dyslipidemias provide an important
opportunity to prevent atherosclerotic
LipidSpin
Practical Pearls:
Vitamin D Deficiency and Statin Intolerance
DEBRA A. FRIEDRICH, DNP, ARNP, FNP-BC, FNLA
Director, West Florida Lipidology
Assistant Professor, University of South Florida
Tampa, FL
Diplomate, Accreditation Council for Clinical Lipidology
Studies specifically designed to evaluate
prevalence of statin-related myalgia
have shown that approximately 22% of
patients on statins have some degree
of musculoskeletal pain.1 As clinicians,
we know it is difficult for patients to
discern between pain related to statin
intolerance and that associated with aging,
osteoarthritis or autoimmune disorders.
Many patients with these symptoms
discontinue their statin medication
without consulting their primary care
provider. This likely leads to increased
cardiovascular disease (CVD) risk related
to medication non-compliance.
Low serum concentrations of
25-hydroxyvitamin D (< 20 ng/ml) are
independently associated with myalgia2,3
and there is a possible connection
between statin intolerance and vitamin D
deficiency. Bioactive vitamin D, or
calcitriol (1, 25-(OH) 2D3), is a steroid
hormone that has an essential role in
bone mineralization. However, recent
data shows that vitamin D receptors
have been identified in a wide variety of
cells, demonstrating that this hormone’s
biological involvement may well extend
beyond mineral metabolism.4 The function
of vitamin D at the cellular and genomic
levels may explain the hormone’s possible
role in diseases such as multiple sclerosis,
depression, tuberculosis, CVD, asthma
and cancer.5,6 It is reported that vitamin
D deficiency is more prevalent than
previously recognized and may be present
in 50% of the adult population.7
Vitamin D
insufficiency may
potentiate statininduced myalgia
and/or statins
themselves may
contribute to vitamin
D deficiency.
In my own clinical practice dealing
with lipid disorder patients, I began
seeing an association between vitamin
D deficiency and reported intolerance to
statins. Vitamin D levels were measured
Official Publication of the National Lipid Association
Discuss this article at
www.lipid.org/lipidspin
as part of a retrospective chart review
of lipid outcomes in patients seen in my
lipid clinic. This allowed me to track my
presumption that an association may exist
between a deficiency in vitamin D and
intolerance to statin medications. This
association led to a review of the literature
and a closer look of patients already
enrolled in a six-month pilot study within
my practice.
From this literature review there appears
to be different concepts related to the
potential mechanisms by which vitamin D
and statins may be connected to patient
intolerance. Vitamin D insufficiency may
potentiate statin-induced myalgia and/
or statins themselves may contribute to
vitamin D deficiency. As of this review,
there have been several non-blinded
studies that support the concept that
vitamin D deficiency may be directly
21
47 (44%)
Number of vitamin D deficient patients in pilot study
28 (59%)
Number of vitamin D deficient patients intolerant to statins
18 (64%)
Number of deficient and intolerant patients who tolerated a statin
re-challenge after vitamin D levels were normalized
patients who are already at increased CVD
risk. Statins are the cornerstone for the
prevention and treatment of coronary
heart disease. Strategies to improve
tolerance of and compliance with these
medications are essential; thus, supporting
the suggestion that vitamin D may be is an
excellent option for this statin intolerant
patients with inadequate Vitamin D, thus,
supporting the suggestion that vitamin
D may be an excellent option for statin
intolerant patients with inadequate
vitamin D. n
Disclosure statement: Debra Friedrich has received
honoraria from Amarin Corporation.
References are listed on page 31.
Figure 1. Vitamin D Levels Related to Statin Tolerance.
related to statin-induced myalgia. Ahmed
et al.8 reported in 2009 the resolution of
statin-induced myalgia in 92% of vitamin
D-deficient patients after vitamin D
supplementation. In a small case series
published in 2010 by Dr. David Bell,9 four
of six patients with statin-induced myalgia
and vitamin D deficiency who were rechallenged with the same statin dosage
after the correction of vitamin D levels
tolerated the statin for at least six months.
In a review, Lee et al.10 also highlighted
the association of vitamin D insufficiency
with statin-induced myalgia, demonstrating
successful re-introduction of statin
therapy in a subgroup of patients following
appropriate repletion of vitamin D levels.
Literature also reports that insufficient
cytochrome P450 (CYP) enzyme activity
related to vitamin D deficiency may be
responsible for inactivity and increased
toxicity of CYP-metabolized statins in
some patients, leading to the need for
possible statin dose adjustments.11
Reviewing the data from my own sixmonth pilot study (Figure 1), I found
that 106 (70%) of 151 lipid patients had
vitamin D levels assessed as part of their
initial workup. Of these patients, 47 (44%)
22
had vitamin D levels of less than 30 ng/
dl. The number of vitamin D-insufficient
patients intolerant to statins was 28 (59%).
Most notably, the number of vitamin
D-deficient and -intolerant patients who
– after achieving normal vitamin D levels
with supplementation – were able to
tolerate the re-challenge of a statin for at
least six months was 18 (64%).
The data are certainly evolving related to
vitamin D deficiency and it relationship to
CVD risk as a whole. Vitamin D deficiency
potentially is associated with hypertension,
diabetes and the metabolic syndrome,
left ventricular hypertrophy, congestive
heart failure and chronic vascular
inflammation.12,13 In a recent meta-analysis
of 18 randomized controlled trials of
57,000 subjects, a vitamin D intake of >
500 IU/day was associated with lower allcause mortality, in part by association with
fewer CV deaths.14
This information, along with the small
non-blinded studies and anecdotal
observations that repletion of 25 (OH) D
levels predictably improves or resolves
statin-related myalgia, certainly warrants
a further look at how we treat our lipid
LipidSpin
Case Study:
Case Study: Muscle-Related Statin Intolerance
NICOLE GASKINS GREYSHOCK, MD
Endocrinology Fellow
Division of Endocrinology, Metabolism and Nutrition
Duke University Medical Center
Durham, NC
Diplomate, American Board of Clinical Lipidology
JOHN R. GUYTON, MD
Associate Professor of Medicine
Division of Endocrinology, Metabolism and Nutrition
Duke University Medical Center
Durham, NC
Diplomate, American Board of Clinical Lipidology
Our patient is a 67-year-old African
American female referred to the Duke
Lipid Clinic for hypercholesterolemia
and elevated creatine kinase (CK). She
has a history of coronary heart disease
with a prior non ST-elevation myocardial
infarction (NSTEMI) and stent placement.
She has a former 40-packs-a-year smoking
history, hypertension, lumbar degenerative
disk disease and constipation. She
had lower extremity muscle pain with
atorvastatin with elevated CK in the low
300s (reference 20-200 U/L). Her mild
CK elevation persisted when she was off of
statin therapy. She was unable to tolerate
a statin re-challenge with pravastatin
because of lower extremity muscle
cramping that started within a few weeks
of beginning statin therapy and stopped
after statin discontinuation. CK levels
never rose above her baseline of 290-330
U/L on statin therapy. However, her quality
of life was impaired to the point of being
unable to perform her activities of daily
living (ADLs). At her initial visit, when
she was off all lipid medications, her lipid
profile results were: total cholesterol 287
mg/dL, low-density lipoprotein cholesterol
(LDL-C) 209 mg/dL, triglycerides 108 mg/
dL; her high-density lipoprotein (HDL) was
56 mg/dL.
How common are statin-related muscle
complaints?
There is little doubt that Statins are highly
effective for cholesterol lowering. Clinical
trials have demonstrated that they reduce
the risk of ischemic heart disease events,
coronary procedures and stroke by about
one third.1 Clinical trials and experience
have demonstrated that statin therapy is
generally safe and well tolerated. However,
muscle symptoms and associated myopathy
can limit their use in clinical practice.
While the incidence of severe myopathy
is low, occurring in less than 0.1% of
Official Publication of the National Lipid Association
Discuss this article at
www.lipid.org/lipidspin
patients who receive statin therapy,2 mild
to moderate muscular symptoms are quite
common. The Prediction of Muscular
Risk in Observational conditions (PRIMO)
study, a large observational study of
primary care patients on high-dose statin
therapy, demonstrated that 10.5% of study
patients had mild to moderate muscular
symptoms.3
What are risk factors for muscular
symptoms?
The PRIMO study highlights certain
patient characteristics that are likely to be
associated with muscle side effects from
statin therapy. In PRIMO, the strongest
23
independent risk factor for muscular
symptoms was a personal history of muscle
pain with another lipid-lowering therapy
(statins or fibrates).This prior history
was associated with a 10-fold increase
in the risk of muscular symptoms. Other
significant, independent risk factors in the
PRIMO study were unexplained cramps
(odds ratio [OR] 4.14), a history of CK
elevation (OR 2.04), a family history
of muscular symptoms (OR 1.89) and
hypothyroidism (OR 1.71). Treatment with
statins for more than three months and
concomitant antidepressant medication use
were associated with a significantly lower
prevalence of muscular symptoms (OR
0.28 and 0.51, respectively). Importantly,
no greater prevalence was found amongst
patients with impaired kidney function or
older age. Patients with muscle symptoms
were more physically active and the
incidence of muscle pain increased with
the level of physical activity.
Clinical features of statin-induced
myalgia
Usual Statin-related muscular pains are
proximal, symmetric muscle weaknesses
and soreness. In the PRIMO study,
pains were most commonly described as
heaviness, stiffness or cramps. However,
weakness, loss of strength during exertion
and tendon-associated pain were also
frequently reported. Symptoms were
most commonly in the lower extremities;
however, upper extremity, truncal and
diffuse pain also were also found.3 On
physical exam, patients may have muscle
tenderness and impairment in motor
function, such as difficulty rising from a
seated position or raising arms above the
head. Most patients have no elevation – or
only minor elevation – in serum CK.4
How do you evaluate a patient with
statin intolerance?
Our approach to patients with statin
intolerance because of muscle side effects
consists of a detailed history, physical
24
exam, medicine reconciliation and focused
laboratory evaluation. Our history focuses
on the timing of muscle effects related to
statin initiation or dose titration, unusual
physical activity or concurrent illness,
as well as historical features that would
point to a secondary cause of muscle pain
(hypothyroidism, vitamin D deficiency,
and family history of autoimmune or
neuromuscular disease, symptoms of
systemic illness). Medication reconciliation
particularly focuses on drugs that inhibit
cytochrome P450 3A4, fibrate therapy,
drugs independently considered a risk
factor for myopathy (i.e. glucocorticoids,
cyclosporine, daptomycin, zidovudine)
and diet history (daily consumption
of grapefruit juice). During physical
examination, we look for signs of systemic
illness or inflammatory myositis (rash,
joint effusions, fever, muscle redness or
edema) as well as muscle weakness and
pain. In a younger person, the ability to do
six deep knee bends without using arms
and hands to assist the legs is reassuring
that proximal motor weakness is absent;
in an older person, the ability to rise from
a chair without using arms and hands is
reassuring. A standard laboratory workup
includes renal and liver function tests,
and measurement of CK and thyroidstimulating hormone (TSH). Based on
the history and physical examination,
serum calcium, albumin, phosphorus,
25-hydroxyvitamin D, CBC, erythrocyte
sedimentation rate (ESR), autoantibodies
(such as antinuclear antibodies [ANA] for
suspected lupus, rheumatoid factor [RF]
for suspected rheumatoid arthritis, etc.),
electromyogram or possibly muscle biopsy
may be obtained.
Let’s get back to our patient. At her initial
appointment, off statin therapy for several
months, she had intermittent, chronic low
back pain. She denied systemic complaints
other than severe constipation. She rode
a stationary bike for 30 minutes three
times weekly without difficulty. She ate
a low-fat, low-glycemic-index diet. Her
medications consisted of Tylenol, tramadol,
aspirin, carvedilol, lisinopril and a bowel
regimen. Her blood pressure was 133/58,
her body mass index (BMI) was 27 kg/m,2
and her physical examination was within
normal limits, including the ability to
rise from a chair without using her arms.
There was no other muscle weakness or
pain. Her basic metabolic profile, albumin,
phosphorus, liver function and TSH
were all within normal limits. She had
an erythrocyte sedimentation rate (ESR)
of 22 mm/h and CK 305 U/L off of statin
therapy.
Rosuvastatin 2.5 mg twice weekly was
prescribed5 but, within three weeks, she
developed crampy lower-extremity pain
and weakness that made it difficult for
her to walk up the stairs in her home and
take care of her other ADLs. Symptoms
resolved several weeks after discontinuing
rosuvastatin.
Based on National Cholesterol Education
Program Adult Treatment Panel III (NCEP
ATP III), our patient’s LDL-C goal is less
than 100mg/dL. Given her intolerance of
low-dose pravastatin and even low-dose
rosuvastatin twice weekly with symptoms
that interfered with her ability to carry out
ADLs, she was felt to be statin intolerant.
Other medication possibilities include
fibrates, bile acid sequestrants, niacin
and cholesterol-absorption inhibitors.
Given her severe constipation, bile acid
sequestrants were not an option. She
was counseled on therapeutic lifestyle
changes and started on ezetimibe 10mg
daily with immediate-release niacin titrated
up to 1,000 mg twice daily. A mortality
benefit from niacin was suggested from
the follow-up of the Coronary Drug Project
which demonstrated an 11% decrease in
mortality in patients who received niacin
after a myocardial infarction.6 Ezetimibe
has been demonstrated to reduce LDL-C by
25% when added to niacin therapy.7
LipidSpin
Over a period of about nine months, our
patient lost weight, reaching a BMI of 25
kg/m2 and increasing her exercise to an
hour five times weekly. She tolerated her
medications and had no medical event.
She recently had the following lipid profile:
total cholesterol, 198; LDL-C, 102; HDL-C,
89; triglyceride, 36 mg/dL. The decrement
in her LDL-C is surprisingly large for
niacin-ezetimibe combination therapy;
however, individual patient responses
are variable. During a period of active
weight loss, LDL-C can drop transiently
for several months, and we warned her
that long-term results may not sustained
at this level.8 She is not at her NCEP ATP
III goal; nevertheless, she has had vast
improvement and, for the next six months,
we will continue current medications. We
suggest that adding psyllium to her bowel
regimen may reduce LDL-C further.9 n
Disclosure statement: Dr. Greyshock has no disclosures
to report. Dr. Guyton has received consulting fees from
Merck & Co. Inc. and research grants from Merck &
Co. Inc., Abbott Laboratories, GlaxoSmithKline, Amarin
Corporation, Regeneron Pharmaceuticals, Inc., Amgen
Inc., and Genzyme Corporation, A Sanofi Company. He
is a stockholder in Eli Lilly and Company.
References are listed on page 31.
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25
Member Spotlight:
Barbara S. Wiggins, PharmD
BARBARA S. WIGGINS, PharmD, BCPS, CLS, FNLA, FCCP, FAHA, AACC
Clinical Pharmacy Specialist Cardiology
Medical University of South Carolina
Adjunct Associate Professor
South Carolina College of Pharmacy
Charleston, SC
Diplomate, Accreditation Council for Clinical Lipidology
development of what is now known as the
ACCL.
Discuss this article at
www.lipid.org/lipidspin
For Barbara Wiggins, PharmD, a typical
work day involves working up patients,
managing medication reconciliation,
verifying doses, compliance, and
completing rounds as a member of an
interdisciplinary health care team. Her
spare time is divided into providing input
on patient management, counseling and
teaching.
“I think it is easy to just think of lipidology
in terms of HDL, LDL, triglycerides, etc.,”
Dr. Wiggins said, “through my involvement
with the NLA and the ACCL, I have
acquired a greater depth of knowledge
regarding the various aspects of lipid
management that I incorporate into my
everyday practice.”
She has gradually become more involved
with the NLA, starting first with
involvement with the ACCL and then
moving on to serve on the NLA and
Southeast Lipid Association (SELA) boards.
Before she became a clinical pharmacy
specialist in cardiology, Dr. Wiggins had
deferred going into clinical practice and
served in the United states Navy for 6
years. She then continued her education
by obtaining her PharmD, and made the
transition to clinical practice. She enjoys
all aspects of patient care.
In the future, Dr. Wiggins would like to
see lipid management focus on methods
to increase medication compliance,
particularly with statin therapy, and
she would also like to someday see a
breakthrough on HDL-raising agents that
show reduced cardiovascular outcomes.
Dr. Wiggins first became interested in
Clinical Lipidology through a colleague
who invited her to get involved with
the National Lipid Association where
she participated in the naming and
Outside of the office, Dr. Wiggins likes to
spend time with her husband, her three
children, three dogs, and loves running.
Something surprising that most people
don’t know about Dr. Wiggins is that
she is a former professional runner who
26
competed in the Olympic trials in the
marathon, and was at one time nationally
ranked for the 5 and 10 kilometer
distances. She continues to race and is
looking forward to running in the U.S.
Army 10- miler in Washington, D.C., this
October. n
LipidSpin
Education and Meeting News and Notes
Save the Date! NLA Clinical Lipid Update
in Maui: March 13-16, 2014
Save the date for breathtaking Maui!
The NLA’s Spring CLU is scheduled for
March 13-16, 2014 at the Grand Wailea
Hotel in Maui, HI. Be there as world
renowned thought leaders discuss lipid
management and metabolic syndrome in
various populations from around the world.
Other sessions include HDL analytics &
functionality and cardiovascular risk in
Asians in Pacific Islanders. You can earn 18.5
CME/CE credits for attending. Please check
www.lipid.org/springclu for the latest
details.
Adherence Toolkit Available
This issue of Lipid Spin includes a
supplemental Clinician’s Toolkit: A Guide
to Medication and Lifestyle Adherence. The
goals of the toolkit are to define adherence
and the various types of non-adherence,
identify common barriers to adherence
and predictors of non-adherence, describe
the role of all health care professionals in
the identification and management of nonadherence, summarize current methods
used to assess adherence and review
evidence-based, innovative strategies to
improve adherence. Access this toolkit
online and let us know how it has helped
you in your practice: www.lipid.org/
practicetools/tools/adherence.
New Patient Registry Available for
Patients with High Triglycerides
As a professional organization, the National
Lipid Association’s mission has been to
reduce the morbidity and mortality from
cardiovascular disease by increasing the
understanding of the pathophysiology, and
detection and optimal treatment of lipid
disorders. Developing patient registries is
crucial to this mission by pooling patient
data concerning more rare dyslipidemias so
that epidemiologic and/or clinical research
can be more focused. Your participation
in this specific patient registry will assist
researchers in the planning of clinical trials
that will assess the efficacy of new therapies.
The NLA and the Foundation of the NLA
are pleased to announce the formation
of this new registry specific patients with
hypertriglyceridemia. For information on
the registry and how to get patients added,
go to www.connect.patientcrossroads.
org/?org=fnla
Introducing the Clinical Lipidology
Resource Center
The Clinical Lipidology Resource Center is
now available. This resource center aims
to support lipidologists and other health
care professionals through its expert
provision of peer-reviewed, evidence-based
educational content from the Journal of
Clinical Lipidology and the National Lipid
Association. You can access the resource
center directly from the NLA website or by
visiting this link: www.nlaresourcecenter.
lipidjournal.com
Abstracts now Invited for NLA Annual
Scientific Sessions May 1-4, 2014
The National Lipid Association is now
accepting abstracts for the Scientific
Sessions in Orlando, FL May 1 – 4, 2014.
This is your opportunity to submit your
science for inclusion in the NLA’s 2014
Poster Hall. Visit lipid.org/abstracts to
submit. The NLA Poster Hall will cover
a vast array of topics in 16 categories,
including clinical applications of biomarkers,
epidemiology of cardiovascular disease,
Official Publication of the National Lipid Association
management of statin intolerance, and
imaging in atherosclerosis. Submit your
abstract using the online abstract submission
system. All accepted poster abstracts will
also be published in the 2014 Annual
Scientific Sessions edition of the Journal of
Clinical Lipidology.
Thank you Dr. Swartz
The Lipid Spin co-editors wish to thank
ToniMarie Swartz, PharmD, for her work
supplying keywords so each issue of Lipid
Spin is conveniently accessible in the search
function on www.lipid.org.
Pediatric Dyslipidemia Questionnaire
As a member of the NLA, your expertise
and knowledge of dyslipidemia is a valued
opinion for a pediatric dyslipidemia survey.
Please follow the link to the questionnaire
on the homepage of www.lipid.org. Your
participation is voluntary and all responses
are anonymous. Even though you may
not screen or medically manage pediatric
populations, but your participation is still
valued.
Research Study Request from University
of Pennsylvania
We are looking for patients with HDL-C
levels consistent with a confirmed or
suspected genetic cause (apoA-I, ABCA1,
LCAT, CETP deficiency) interested in
participating in a study assessing reverse
cholesterol transport using a radiotracer
technique developed by our team at the
University of Pennsylvania. Subjects are
required to have one overnight stay in our
research unit. Travel and lodging costs are
covered. If you are interested in receiving
more information, please contact Marina
Cuchel, MD, PhD at 215-746-2834;
mcuchel@mail.med.upenn.edu.
27
Foundation Update
ANNE C. GOLDBERG, MD, FNLA
President, Foundation of the National Lipid Association
Associate Professor of Medicine
Washington University School of Medicine
St. Louis, MO
Diplomate, American Board of Clinical Lipidology
Discuss this article at
www.lipid.org/lipidspin
lipidjournal.com), FH specialist member
highlights on lipid.org, and public relations
outreach to local and regional media
affiliates.
Other Foundation highlights include:
•
September is National Cholesterol
Education Month. In recognition of this,
the Foundation of the NLA has supported
an important campaign called “ARE YOU
THE ONE?” To help call attention to
familial hypercholesterolemia (FH), the
Foundation has provided two copies
of a poster and handout to all NLA
members and more than 40,000 members
of the American Academy of Family
Physicians. This campaign furthers one
of our priorities: to educate clinicians—
especially primary care providers—on
FH and other cholesterol disorders to
facilitate proper diagnosis and treatment
of patients.
Additional FH awareness efforts for
National Cholesterol Education Month
include a series of FH-themed broadcasts
on ReachMD, an FH content area on the
newly created Clinical Lipidology Resource
Center (http://nlaresourcecenter.
28
•
Hosting a food tour in the historic
Fell’s Point Neighborhood of
Baltimore at our Fall Clinical
Lipid Update in Baltimore, MD.
Thank you to everyone who
supported the Foundation of the
NLA through this event. Please
stay tuned for more information
about the Foundation event in
Maui, which will be inspired by
the traditional luau, perfect for
our Pacific location during this
meeting!
Lifetime Membership has been a
successful membership campaign
and it is not over yet! Remind
your colleagues that Lifetime
Membership to the NLA is only
available through December
2013. To show your support,
please visit lipid.org/membership/
lifemember and register today!
•
Foundation members assisted
with a patient survey to launch
a new registry for patients with
high triglycerides. Go to http://
connect.patientcrossroads.
org/?org=fnla for more
information on the registry.
As always, we are extremely grateful for
your support of the Foundation!
Two new patient registries:
Hypertriglyceridemia patient
registry, visit:
http://connect.patientrcrossroads.
org/?org=fnla
Familial Hypercholesterolemia
patient registry, visit:
www.thefhfoundation.org
LipidSpin
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30
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Lipid Luminiations
1. Chapman MJ, Redfern JS, McGovern ME, Giral P. Niacin and
fibrates in atherogenic dyslipidemia: Pharmacotherapy to reduce
cardiovascular risk. Pharma & Thera. 2010;126:314-345.
2. Insull W. Clinical utility of bile acid sequestrants in the treatment
5. Tenenbaum A, Fisman EZ, Motro M, Adler Y. Atherogenic dyslipidemia in metabolic syndrome type 2 diabetes: Therapeutic options
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inflammatory markers in patients with the metabolic syndrome. Int J
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of randomized controlled trials. J Intern Med. 2009;265:568-580.
9. Skoumas I. Dyslipidemia: Treatment in statin-intolerant patients.
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10.Kastelein JJP, Akdim F, Stroes ESG, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia (ENHANCE). New
Eng J Med. 2008;358:1431-1433.
11.Bays H, Rhyne J, Abby S, et al. Lipid-lowering effects of colesevelam HCl in combination with ezetimibe. Curr Med Res Opin.
2006;22:2191-2200.
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14.Demonty I, et al. J Nutr. 2009;139:271-284.
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Specialty Corner
1. Expert panel on integrated guidelines for cardiovascular health and
risk reduction in children and adolescents: summary report. Pediatrics. 2011;128 Suppl 5:S213-56.
2. Brown MS, Goldstein JL. Familial hypercholesterolemia: A genetic
defect in the low-density lipoprotein receptor. N Engl J Med.
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3. Ford ES, Li C, Zhao G, Mokdad AH. Concentrations of low-density
lipoprotein cholesterol and total cholesterol among children and
adolescents in the United States. Circulation. 2009;119:1108-15.
4. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of
cholesterol-lowering treatment: prospective meta-analysis of data
from 90,056 participants in 14 randomised trials of statins. Lancet.
2005;366:1267-78.
5. Cholesterol Treatment Trialists C, Mihaylova B, Emberson J, et al.
The effects of lowering LDL cholesterol with statin therapy in people
at low risk of vascular disease: meta-analysis of individual data from
27 randomised trials. Lancet. 2012;380:581-90.
6. Rodenburg J, Vissers MN, Wiegman A, et al. Statin treatment in
children with familial hypercholesterolemia: the younger, the better.
Circulation. 2007;116:664-8.
7. Naci H, Brugts J, Ades T. Comparative Tolerability and Harms of
Individual Statins: A Study-Level Network Meta-Analysis of 246,955
LipidSpin
Participants From 135 Randomized Controlled Trials. Circulation
Cardiovascular quality and outcomes 2013.
8. Avis HJ, Vissers MN, Stein EA, et al. A systematic review and metaanalysis of statin therapy in children with familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2007;27:1803-10.
9. Stein EA, Illingworth DR, Kwiterovich PO, Jr., et al. Efficacy and
safety of lovastatin in adolescent males with heterozygous familial hypercholesterolemia: a randomized controlled trial. JAMA.
1999;281:137-44.
10.McCrindle BW, Helden E, Cullen-Dean G, Conner WT. A randomized crossover trial of combination pharmacologic therapy
in children with familial hyperlipidemia. Pediatric Research.
2002;51:715-21.
11.de Jongh S, Ose L, Szamosi T, et al. Efficacy and safety of statin
therapy in children with familial hypercholesterolemia: a randomized, double-blind, placebo-controlled trial with simvastatin. Circulation. 2002;106:2231-7.
12.McCrindle BW, Ose L, Marais AD. Efficacy and safety of atorvastatin in children and adolescents with familial hypercholesterolemia
or severe hyperlipidemia: a multicenter, randomized, placebocontrolled trial. The Journal of Pediatrics. 2003;143:74-80.
13.Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident
diabetes: a collaborative meta-analysis of randomised statin trials.
Lancet. 2010;375:735-42.
14.Dormuth CR, Hemmelgarn BR, Paterson JM, et al. Use of highpotency statins and rates of admission for acute kidney injury:
multicenter, retrospective observational analysis of administrative
databases. BMJ. 2013;346:f880.
15.Mansi IA, Mortensen EM, Pugh MJ, Wegner M, Frei CR. Incidence
of musculoskeletal and neoplastic diseases in patients on statin
therapy: results of a retrospective cohort analysis. The American
Journal of the Medical Sciences 2013;345:343-8.
16.Rojas-Fernandez CH, Cameron JC. Is statin-associated cognitive
impairment clinically relevant? A narrative review and clinical recommendations. The Annals of Pharmacotherapy. 2012;46:549-57.
17.Golomb BA, Evans MA, Dimsdale JE, White HL. Effects of statins
on energy and fatigue with exertion: results from a randomized
controlled trial. Archives of Internal Medicine. 2012;172:1180-2.
18.Godfrey LM, Erramouspe J, Cleveland KW. Teratogenic risk
of statins in pregnancy. The Annals of Pharmacotherapy.
2012;46:1419-24.
19.Florentin M, Elisaf MS. Simvastatin interactions with other drugs.
Expert Opin Drug Saf. 2012;11:439-44.
Practical Pearls
1. Buettner C, Davis RB, Levelle SG, et al. Prevalence of
musculoskeletal pain and statin use. J Gen Inter Med. 2008;
23:1182-6.
2. Reddy KJ, Singh M., Batsell RR, et al. Efficacy of combination drug
pulse therapy in maintaining lipid levels in patients intolerant of
daily statin use. J Clin Hypertens. 2009; 11:766-8.
3. Plotnikoff GA, Quigley JM. Prevalence of severe hypovitaminosis
D in patients with persistent, nonspecific musculoskeletal pain.
Mayo Clinic Proc. 2003;78:1463-70.
4. Demay M. Muscle: A nontraditional 1,25-dihydroxyvitamin D target
tissue exhibiting classic hormone-dependent vitamin D receptor
actions. Endocrinology 2003;144:5135-7.
5. Ross AC, Taylor CL, Yaktine AL, Del Valle HB, eds.; Institute of
Medicine (U.S.) Committee. Dietary reference intakes for calcium
and vitamin D. Washington DC: National Academies Press, 2011.
6. Nussey S, Whitehead S, eds. Endocrinology: an integrated
approach. Oxford: BIOS Scientific Publishers, 2001.
8. Ahmed W, Khan N, Glueck C, et al. Low serum 25 (OH) vitamin D
levels (,32 ng/mL) are associated with reversible myositis-myalgia in
statin-treated patients. Translational Research 2009;153:11-16.
9. Bell D. Resolution of statin-induced myalgias by correcting vitamin
D deficiency. Southern Medical Journal. 2010;103:690-3.
10.Lee JH, O’Keefe JH, Bell D, Hensrud D, Holick M. Vitamin
D deficiency: An important, common and easily treatable
cardiovascular risk factor? JACC 2008;50:1949-56.
11.Bhattacharyya S, Bhattacharyya K, Maitra A. Possible mechanisms
of interaction between statins and vitamin D. Q J Med.
2012;105:487-491.
12.Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266-81.
13.Zitterman A. Vitamin D and disease prevention with special
reference to cardiovascular disease. Prog BiophysMol Biol.
2006;92:39-48.
14.Autier P, Gandini S. Vitamin D supplementation and total mortality:
A meta-analysis of randomized controlled trials. Arch Intern Med.
2007;167:1730-7.
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patients with previous muscular adverse effects. Am J Health-Syst
Pharm 2012;69:291-300.
16.Gupta A, Thompson P. The relationship of vitamin D deficiency to
statin myopathy. Atherosclerosis 2011;215:23-29.
17.Haines S, Park S. Vitamin D supplementation: What’s known, what
to do, and what’s needed. Pharmacotherapy 2012;32:354-382.
18.Glueck C, Abuchaibe C, Wang P. Symptomatic myositis-myalgia
in hypercholesterolemic statin- treated patients with concurrent
vitamin D deficiency leading to statin intolerance may reflect a
reversible interaction between vitamin D deficiency and statins on
skeletal muscle. Medical Hypothesis 2011;77:658-661.
Case Study
1. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult
Treatment Panel III). JAMA. 2001;285:2486-2497.
2. Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis. N Engl J Med. 2002;346:539-540.
3. Bruckert E, Hayem G, Dejager S, et al. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic
patients – the PRIMO study. Cardiovasc Drugs Ther. 2005;19:403414.
4. McKenney JM, Davidson M, Jacobson TA, Guyton JR. Final conclusions and recommendations of the National Lipid Association Statin
Safety Assessment Task Force. Am J Cardiol. 2006;97:89C-94C.
5. Keating AJ, Campbell KB, Guyton JR. Intermittent Nondaily Dosing
Strategies in Patients with Previous Statin-Induced Myopathy. Ann
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Tolerability of Adding Ezetimibe to Niacin-Based Regimens for Primary Hyperlipidemia. Endoc Pract. 2006;12:159-166.
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1992;56:320-328.
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7. Tangpricha V, Pearce EN, Chen TC, Holick MF. Vitamin D
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2002;112:659-62.
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LipidSpin
This information is intended for providers. Always assess risk/benefit of statin therapy.
Author: Paul E. Ziajka, MD, PhD, FNLA
Strategies to Deal with Muscle-Related Statin Intolerance
1. Switch statins
• if muscle symptoms developed on a lipophyllic statin, switch to a hydrophyllic one (see hydrophyllic vs. lipophyllic listing below)
• if muscle symptoms developed on CYP3A4 metabolized statin, switch to one metabolized by a different pathway (see metabolic pathways in table below)
• if muscle symptoms developed on a long half-life statin, switch to a short half-life statin and vice versa
(see half lives in table below)
• if statin therapy is thought to objectively and consistently interfere with exercise tolerance (e.g., compromised
exercise capacity, extended recovery and/or muscle pain) consider another statin with different pharmacokinetics
2. Use a statin at a dose and/or frequency that is below the FDA approved lowest dose
• try half of the lowest FDA approved dose every day and then consider every other day or 2 to 3 times a week
3. Consider checking for 25 (OH) vitamin D deficiency
• if the level is less than 30 ng/ml, hold the statin until vitamin D has been replaced to greater than 30 ng/ml,
then rechallenge
Replacement Protocol #1:
• 50,000 IUs of prescription vitamin D2 qweek for 8 weeks, then recheck the 25(OH) vitamin D level
• repeat as needed until 25(OH) vitamin D is greater than 30 ng/ml
• then switch to over-the-counter vitamin D3 at 2000 IUs daily
Replacement Protocol #2:
• 5000 IUs of vitamin D3 for 8 weeks, then recheck the 25(OH) vitamin D level
• repeat as needed until 25(OH) vitamin D is greater than 30 ng/ml
• then switch to vitamin D2 at 2000 IUs daily
4. Consider supplement with 200 mg of CoQ10 daily, although randomized trials
haven’t been uniformly supportive
5. Lower the LDL to goal using a non-statin treatment regimen
• especially in patients with the SLCO1B1 Val/Ala or Ala/Ala variations
Generic Name
lovastatin
pravastatin simvastatinfluvastatin atorvastatin rosuvastatin
Brand Name
Mevacor
Pravachol
Zocor
Lescol
Lipitor
CrestorLivalo
Year Introduced
1987
1991
1991
1993
1997
2003
pitavastatin
2010
Generic Available
Yes
Yes
Yes
Yes
Yes
NoNo
FDA approved dose range (mg/day)
10 to 80
10 to 80
10 to 40
20 to 80
10 to 80
5 to 40
1 to 4
LDL reduction range (%) 24 to 40
18 to 37
27 to 47
14 to 35
35 to 60
52 to 63
31 to 44
1
Hydrophyllic/Lipophyllic
Lipo
Hydro
Lipo
Hydro
Lipo
HydroLipo
Primary mode of metabolism2
CYP3A4
nonCYP
CYP3A4
CYP2C9
CYP3A4
nonCYP
nonCYP
Half-life (hours)3
2 to 3
1
2 to 3
0.5
13 to 16
19
12
(1) per FDA approved package labelling
(2) lists the primary mode of metabolism; most statins have alternate modes as well
(3) lists half life of the active drug, not metabolites
Definitions:
Myalgias: muscle pain without an increase in CPK
levels or with an increase that is less than 10 times
the upper limit of normal
Myositis/myopathy: muscle pain with a CPK
increase equal to or greater than 10 times the
upper limit of normal
Rhabdomyolysis: myopathy (as defined above)
with renal compromise (i.e. increase in serum
creatinine)
Hydrophyllic statin: a statin that is primarily
soluble in water (i.e. the oil/water separation
coefficient is less than 1.0). Includes: pravastatin,
rosuvastatin and fluvastatin
Lipophyllic statin: a statin that is primarily soluble
in oil (i.e. the oil/water separation coefficient
is greater than 1.0). In order of most to least
lipophyllic: simvastatin > lovastatin > atorvastatin
> pitavastatin
SLCO1B1 174 Ala variant – single nucleotide
polymorphism associated with statin induced
muscle side effects
Cytochrome p450 3A4 (CYP3A4): primary mode
of metabolism of lovastatin, simvastatin and
atorvastatin
Organic Anion Transport Polypeptide 1B1
(OATP1B1): the main transporter responsible for
extracting all statins from the portal circulation into
the hepatocyte. Many of muscle statin side effects
are related to the concomitant use of drugs that
inhibit CYP3A4 and/or OATP1B1
CYP3A4 inhibitors: itraconazole, ketoconazole,
posaconazole, voriconazole, erythromycin,
clarithromycin, telithromycin, HIV protease
inhibitors, cyclosporine, danazol, verapamil,
diltiazem, dronedarone, amiodarone, amlodipine,
ranolazine
OATB1B1 inhibitors: rifampin, clarithromycin,
indinavir, ritonavir, cyclosporine, nelfinavir,
erythromycin, atazanir
Health Care Providers—access this tear sheet at www.learnyourlipids.com
Disclaimer: The information contained in this tear sheet is not the formal policy or position of the National Lipid Association.
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