Statin Intolerance: the Clinician’s Perspective
Curr Atheroscler Rep
Statin Intolerance: the Clinician's Perspective
Tomáš Stulc 0 1 2
Richard Ceška 0 1 2
Antonio M. Gotto Jr. 0 1 2
0 Weill Cornell Medical College , New York, 1305 York Avenue, Y-807, New York, NY 10021 , USA
1 3rd Department of Internal Medicine, 1st Faculty of Medicine, Charles University , U Nemocnice 1, CZ 128 21 Praha 2 / Prague , Czech Republic
2 On Behalf of the ScreenPro FH Project Dan GA (Romania) , Djuric D (Serbia), Ezhov MV (Russia), Fras Z (Slovenia), Freiberger T (Czech Republic), Gaita D (Romania), Goudev A (Bulgaria), Harangi M (Hungary), Kayikcioglu M (Turkey), Latkovskis G (Latvia), Mark L (Hungary), Mirrakhimov EM (Kyrgyzstan), Mitchenko E (Ukraine), Murataliev TM (Kyrgyzstan), Paragh G (Hungary), Petrulioniene Z (Lithuania), Pojskic B (Bosnia and Herzegovina), Raslova K (Slovakia), Reiner Z (Croatia), Rynkiewicz A (Poland), Susekov AV (Russia), Tasic N (Serbia), Tokgozoglu L (Turkey), Tselepis A (Greece), Vohnout B , Slovakia
Muscle problems and other adverse symptoms associated with statin use are frequent reasons for nonadherence and discontinuation of statin therapy, which results in inadequate control of hyperlipidemia and increased cardiovascular risk. However, most patients who experience adverse symptoms during statin use are able to tolerate at least some degree of statin therapy. Given the profound cardiovascular benefits derived from statins, an adequate practical approach to statin intolerance is, therefore, of great clinical importance. Statin intolerance can be defined as the occurrence of myalgia or other adverse symptoms that are attributed to statin therapy and that lead to its discontinuation. In reality, these symptoms are actually unrelated to statin use in many patients, especially in those with atypical presentations following long periods of treatment. Thus, the first step in approaching patients with adverse symptoms during the course of statin therapy is identification of those patients for whom true statin intolerance is unlikely, since most of these patients would probably be capable of tolerating adequate statin therapy. In patients with statin intolerance, an altered dosing regimen of very low doses of statins should be attempted and, if tolerated, should gradually be increased to achieve the highest tolerable doses. In addition, other lipid-lowering drugs may be needed, either in combination with statins, or alone, if statins are not tolerated at all. Stringent control of other risk factors can aid in reducing cardiovascular risk if attaining lipid treatment goals proves difficult.
Statin; Statin intolerance; Muscle side effects; Myalgia; Low-dose statin therapy
Statins effectively decrease cardiovascular risk, and
cholesterol lowering with statins has become a cornerstone of
cardiovascular disease prevention for a wide range of patients .
Despite this, adequate use of statins is limited by adverse
symptoms in many patients [2–4], which leads to statin
discontinuation in some patients, and low adherence to therapy in
others. The issue of statin intolerance is, therefore, of great
Despite the existence of statin intolerance having been
widely acknowledged, a large degree of variability remains
as to what is considered to be statin intolerance. In addition,
there is significant uncertainty regarding the actual incidence,
and there is insufficient knowledge concerning the best
therapeutic approaches to the problem. Most cases of statin
intolerance are related to muscle complaints [5–7], with increased
liver or muscle enzymes , various neurological symptoms
 and other problems being much less frequent. The
glycemic effects of statins are occasionally included as a symptom
of statin intolerance; although, they are undesired side effects
rather than serious findings necessitating discontinuation of
therapy in individual cases. Moreover, as we have previously
discussed elsewhere , the diabetogenic effects of statins
are generally overestimated.
It should be noted that all of the mentioned symptoms can
stem from a number of different causes and are often unrelated
to actual statin use. However, even among patients with true
statin-related symptoms, many can tolerate lower doses of the
same statin, or perhaps a different statin. Establishing a
diagnosis of statin intolerance is therefore less straightforward than
it might appear, and an adequate therapeutic approach is more
complex than simple discontinuation of statin therapy.
As a result of these complexities, statin intolerance is
currently gaining increased attention and several guidelines [5,
11, 12] and review papers [13–16] have recently been
published, thereby providing an in-depth discussion of this
complicated, and often controversial, topic. Practicing physicians,
however, may find the aforementioned recommendations
somewhat lengthy and difficult to implement in their daily
practice. In this review, we propose a practical definition of
statin intolerance and outline a therapeutic approach to
patients with this condition.
Definition of Statin Intolerance
In general terms, statin intolerance can be defined as the
occurrence of (1) adverse symptoms perceived by the patient to
be unacceptable, and/or (2) laboratory abnormalities
suggesting undue risk, which are attributed to statin therapy and lead
to its discontinuation. For practical purposes, descriptions
regarding acceptability of symptoms, attributability to statin
therapy, and the degree of intolerance, need to be better
Most cases of statin intolerance are related to patient
complaints; the discontinuation of therapy due to laboratory
abnormalities is far less common. Thus, in most cases, decisions
pertaining to statin intolerance are patient decisions. In this
context, it is important to note that some degree of adverse
symptoms might be tolerated by patients and it does not
necessarily imply intolerance of therapy. Statin intolerance is not
simply the occurrence of symptoms in general, but rather
those symptoms that are perceived to be unacceptable.
Hence, the patient’s subjective assessment of perceived risks
and inconveniences, versus the benefits of therapy, are at the
core of an effective approach to the issue of statin intolerance.
When experienced during the course of statin therapy,
myalgia and other adverse symptoms are often unrelated to
treatment, and most patients with a history involving episodes of
these symptoms are able to tolerate adequate statin therapy
[17, 18]. Identifying true cases of statin intolerance is,
therefore, of great practical importance in order to avoid
unnecessary discontinuation of statins from patients who would
otherwise benefit from them. However, evaluating the
likelihood that the adverse symptoms are causally related to statins
is often a difficult task (Table 1). Close temporal association to
statin therapy is an important feature that suggests causality.
Symptoms are more likely to be attributable to statins if they
appear within the first month of statin therapy, improve upon
discontinuation, and reoccur after readministration [3, 4].
Consequently, dechallenge–rechallenge testing is an
important evaluation tool when assessing statin intolerance.
Similarly, regional distribution and the type of pain/
complaints are important for assessing their association with
statin therapy. A causal relation to statins is more likely
in cases of symmetrical involvement of large muscle
groups (especially proximal lower limbs) or in cases
with widespread involvement; a causal relationship is
less likely when symptoms are asymmetrical or involve
small isolated regions. Typical complaints involve
muscle pain, tenderness or cramps, and weakness during
exertion, while joint or tendon pain, muscle tingling
and twitching, or shooting pain, suggest causes other
than statin therapy. In addition, factors known to be
associated with increased risk of statin intolerance, as
well as contributing factors that may precipitate
symptom manifestation, such as hypothyroidism , drug
interactions, and vitamin D deficiency , should be
carefully evaluated (Table 2). It is also important to rule
out conditions that are associated with symptoms that
mimic statin intolerance (musculoskeletal disorders, in
particular). The American College of Cardiology has
recently developed an ACC Statin Intolerance App to
aid clinicians in evaluating and managing patients who
report muscle symptoms while on a statin (available at
Given the specifications mentioned above, we propose the
following definition of statin intolerance for use in clinical
Statin intolerance is the occurrence of (1) adverse
symptoms perceived by the patient to be unacceptable,
and/or (2) laboratory abnormalities suggesting undue
risk, which are attributed to statin therapy and lead to
To be attributed to statins:
symptoms or abnormalities should be temporally
associated with the initiation of statin therapy, improve upon
discontinuation, and reoccur after the readministration of
known precipitating factors and conditions with similar
presentations should first be excluded. These primarily
include musculoskeletal diseases, hypothyroidism,
vitamin D deficiency, strenuous exercise, intercurrent illness,
or drug interactions (e.g., azole antifungals, macrolide
Regarding the degree of statin intolerance, it can be
classified as partial or complete (additional information provided
Mild symptoms should not be considered intolerance,
provided they are deemed acceptable by the patient.
Among patients presenting with statin intolerance,
there is great variability regarding the number and doses
of statins they are unable to tolerate. Some patients are
intolerant of virtually all statins, even in low doses;
others only experience adverse symptoms with a
particular statin, or only with the highest doses of particular
statins. With this in mind, we propose two degrees of
statin intolerance for consideration:
complete statin intolerance: the inability to tolerate a
minimum of three statins at their usual lowest daily starting
partial statin intolerance: the inability to tolerate statin
therapy in the form and dosages required to achieve
treatment goals (including the highest doses of potent statins, if
For the purposes of this definition, the lowest daily starting
doses of statins are proposed as rosuvastatin 5 mg, atorvastatin
10 mg, simvastatin 20 mg, lovastatin 20 mg, pravastatin
40 mg, fluvastatin 40 mg, and pitavastatin 2 mg.
Partial intolerance is pragmatically defined with respect to
the therapeutic needs of individual patients. Inability to
tolerate some statins, or some doses, should not be considered as
statin intolerance, provided it does not interfere with the
achievement of treatment goals.
Factors associated with increased risk of statin intolerance
Therapeutic Approach to Statin Intolerance
Most patients who experience adverse symptoms when using
statins are able to tolerate at least one statin, albeit sometimes
only when administered in an altered dosing regimen. Given
the profound cardiovascular benefits of statins, statin therapy
remains the mainstay of lipid-lowering treatment for most of
these patients (Fig. 1).
In many patients, adverse symptoms are unrelated to statin
usage, especially in those with atypical and intermittent
presentations following long periods of treatment. The first step
in approaching patients who experience adverse symptoms
during the course of statin therapy is therefore to assess
whether the symptoms are likely attributable to statins. This
includes obtaining a complete history of symptoms, evaluation
of risk factors for statin intolerance (Table 2), temporary
withdrawal of statins followed by a rechallenge, as well as seeking
other causes of the symptoms . If statin intolerance appears
Evaluating the likelihood of an association between muscle complaints and statin therapy
Causal relation of symptoms to statin therapy
to statin therapy
Adapted from [3, 4, 6]
widespread or large muscle groups involvement (proximal
lower limbs, calves, proximal upper limbs)
muscle pain, tenderness, cramps, stiffness
muscle weakness or heaviness during exertion
small isolated regions
Try very low doses of statin using non-daily
dosing, preferably atorvastatin or rosuvastatin
this step may be repeated in case of intolerance
Initiate non-statin therapy
Search for potential provoking factors and correct
Perform de-challenge/re-challenge testing
Continue with therapy or gradually increase the
doses, if appropriate, to achieve the highest
Try another statin at the lowest starting dose,
including re-challenge testing if appropriate
this step may be repeated in case of intolerance
Continue with therapy or gradually increase the
doses, if appropriate, to achieve the highest
Patient with muscle complaints on his/her first statin
Discuss with the patient the issue of statin muscle side effects and explain the need for trying another statin(s)
Try another statin at the lowest starting dose
Fig. 1 Flowchart for evaluation and management of patients with statin-associated muscle complaints
unlikely, the patient can probably tolerate adequate therapy
with the same, or alternative, statin.
Likewise, potential provoking factors such as
hypothyroidism, vitamin D deficiency, or drug interactions should also be
evaluated, as correcting these problems may improve statin
In patients with statin intolerance, very low doses of statins
administered via an altered dosing regimen should be
attempted and, if tolerated, should be gradually increased to
achieve the highest tolerable doses. With this cautious
approach, the majority of patients are able to tolerate at least
some degree of statin therapy. In addition, other
lipid-lowering drugs may be needed to achieve the appropriate targets.
The principles of lipid-lowering therapy in cases of statin
intolerance are discussed in the following sections.
Lifestyle interventions reduce blood cholesterol levels and
improve other cardiovascular risk factors, but adherence to
these measures is low among the general patient population.
Encouraging and motivating patients to improve adherence to
lifestyle measures may aid in the attainment of treatment goals
in cases where the possibility of using lipid-lowering drugs is
The ultimate goal of lipid-lowering treatment is to decrease
cardiovascular risk, which depends upon the interplay of
multiple risk factors. Control of other risk factors—especially
those of hypertension and smoking—effectively reduces
cardiovascular risk, which may move the patient to a lower risk
category with less stringent, and more easily attainable, lipid
Coenzyme Q10 (CoQ10) supplementation is frequently
used for statin myalgia, but the evidence in support of its use
has, thus far, been contradictory. Recently, a well-designed
trial , in conjunction with a meta-analysis of previous
smaller trials , consistently failed to demonstrate a
Continue with therapy or gradually increase the
doses if appropriate to achieve the highest
difference between CoQ10 and placebo, demonstrating that
the beneficial effect of CoQ10 supplementation in patients
with statin-induced myalgia is quite unlikely.
In patients with partial statin intolerance (i.e., those who
require, but are unable to tolerate, moderate or high doses of
potent statins), lower doses, or less potent statins, should be
For patients unable to tolerate any statin at the usual
starting daily dose, there is emerging agreement that
very low doses, and/or less-than-daily dosing, should
be attempted [7, 13]. Since the association between
statin dose and low-density cholesterol (LDL-C) is
logarithmic, reducing the usual dose of a statin to one-half (or
even to one-quarter) still provides a reasonable degree
of lipid lowering (ultimately, this approach is simply
applying the notorious Brule of six^ in the reverse
direction). Multiple studies of patients with
hypercholesterolemia have demonstrated that rosuvastatin 5–10 mg
or atorvastatin 10–20 mg given every other day
produced LDL-C reduction of 20–40 % . In patients
with previous statin intolerance, rosuvastatin
administered once or twice weekly (at a mean dose of 10 mg
per week) achieved an LDL-C reduction of 23–29 %
and was well tolerated by 74–80 % [23–25] of patients.
In a recent review report from a specialized lipid clinic,
90 % of patients referred for intolerance to multiple
statins were actually able to tolerate statin therapy,
although the majority was at a reduced dose and
lessthan-daily dosing . Obviously, the efficacy of
nonlicensed dosing regimens in terms of reducing
cardiovascular risk has not been studied. On the other hand,
most statin effects are mediated through the lowering of
LDL-C; therefore, it would seem reasonable to assume
that the cardiovascular risk reduction achieved with
alternate statin dosing regimens would be proportionate to
their LDL-lowering effects.
In terms of a practical approach to statin intolerance,
listening to the patient’s complaints and fears is crucial to encourage
greater receptivity and willingness to try various statins and
dosing schedules, some of which may be associated with
adverse symptoms [5, 26]. These patients need to understand
that (i) while these symptoms may be bothersome, they are
rarely dangerous, and (ii) they are free to discontinue the drug
at any time. It is equally important that physicians
emphatically explain the beneficial effects of therapy in terms of
cardiovascular event reduction.
In order to prevent unnecessarily intense symptoms
of statin intolerance and improve patient adherence to
statin therapy in the general population, it may be wise
to initiate statin therapy in statin-naive patients with low
or moderate (rather than high) doses in the majority of
cases, except for patients at highest cardiovascular risk.
Patients who previously tolerated lower doses are much
more willing to return to them in cases where they
experienced problems with higher doses, compared to
those who were intolerant to a higher starting dose. It
is also advisable to perform both creatine kinase and
liver tests prior to commencing statin therapy in order
to establish reference baseline values in case the patient
develops elevations in these tests during therapy.
Non-statin Lipid-Lowering Drugs
Other lipid-lowering drugs may be needed to achieve
appropriate targets, either in combination with statins,
or alone, if statins are not tolerated at all. A
combination of these drugs and low-dose statin therapy can
provide reductions in LDL-C similar to those obtained with
high doses of statins.
Ezetimibe decreases LDL-C by 15–20 % (either in
combination with statins or as monotherapy) and is widely used in
patients with statin intolerance. Ezetimibe is well tolerated,
but the evidence of cardiovascular benefit is limited to one
trial that demonstrated a modest 6 % reduction of
cardiovascular events .
Fibrates are primarily used to lower triglycerides and
increase high-density cholesterol; they also decrease LDL-C
levels, but to a lesser extent. The effect on LDL-C is more
pronounced in patients with hypertriglyceridemia.
Accordingly, the reduction of cardiovascular risk with fibrates
is only 10 % in unselected patient population, but is
substantially greater (≈30 %) in patients with hypertriglyceridemia
. As such, fibrates represent a reasonable option in these
patients. However, caution must be exercised when
combining fibrates with statins, as the combination may increase the
risk of myalgia.
Bile acid sequestrants (resins) provide LDL-C reduction
that is comparable to that observed with ezetimibe, and they
have been proven to reduce cardiovascular events. Resins are
safe, but poorly tolerated, due to gastrointestinal side effects.
The recently developed colesevelam has fewer side effects
and better patient compliance.
Niacin is similar to fibrates relative to its effect on blood
lipids, but its use in clinical practice has dropped substantially
after two clinical-endpoint trials failed to demonstrate
cardiovascular benefits of niacin therapy [29, 30].
PCSK9 inhibitors are a novel class of lipid-lowering drugs;
they were approved quite recently in the USA and Europe.
They reduce LDL-C levels by≈50 %. Meta-analyses of phase
2 and 3 trials demonstrated a >50 % reduction of
cardiovascular events with evolocumab and alirocumab [31, 32], and
the results of major clinical trials are eagerly awaited by
clinicians. Statin intolerance is one of the approved indications
for use of PCSK9 inhibitors.
Muscle problems and other adverse symptoms associated with
statin use are relatively frequent reasons for non-adherence
and discontinuation of statin therapy, which can contribute
to adverse cardiovascular outcomes. However, most patients
who experience objectionable symptoms during statin use are
still able to tolerate at least some degree of statin therapy. The
clinician’s challenge is therefore to help their patients find
their way back to statins.
In essence, this task comprises only a few steps: First,
identify patients with unlikely statin intolerance, and who can
therefore probably continue with some type of adequate statin
therapy. A pragmatic definition of statin intolerance, as
outlined above, may be useful in this respect. Second, in cases
with statin intolerance, consider very low doses of statins and/
or altered dosing regimens. In addition, other lipid-lowering
drugs may be needed, in conjunction with changes in lifestyle
and better control of other cardiovascular risk factors. With this
cautious and multifactorial approach, reasonable improvement
in blood lipid levels, as well as a marked reduction in global
cardiovascular risk score, can be achieved in most patients.
As simple this approach may appear, it may prove difficult
in practice. Listening to patients’ complaints and fears,
explaining the benefits of therapy, and motivating patients to
try various therapeutic schedules (some of which may be
associated with adverse symptoms) are often difficult and
timeconsuming tasks. From a clinician’s perspective, a successful
approach to statin intolerance primarily entails the art of
successful communication with the patient.
Acknowledgments This article was supported by the grant project IGA
MZCR NT 12217-5/2011.
Compliance with Ethical Standards
Conflict of Interest Tomáš Štulc and Richard Češka declare that they
have no conflict of interest.
Antonio M. Gotto Jr. declares personal fees from Aegerion
Pharmaceuticals, Arisaph Pharmaceuticals, DuPont, Esperion
Therapeutics, KOWA, Merck, Roche, Vatera Capital, and ISIS
Pharmaceuticals for various boards of directors, advisory boards,
consultancies, and data safety monitoring board duties.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
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