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Statinintolerance: Some Practical Hints
Statinintolerance: Some Practical Hints
KEYWORDS
Adverse effects Cardiovascular disease Statins Statin-associated muscle symptoms
Therapy
KEY POINTS
Statin intolerance is a worldwide problem concerning the inability to tolerate a dose of statin
required to sufficiently reduce cardiovascular risk.
Muscle symptoms are the most common statin-associated adverse effects.
New therapies with the proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors and
bempedoic acid might be an effective response.
Disclosure: M. Banach is on the Speakers Bureau for Abbott/Mylan, Abbott Vascular, Actavis, Akcea, Amgen, Biofarm,
KRKA, MSD, Sanofi-Aventis, and Valeant; is a consultant to Abbott Vascular, Akcea, Amgen, Daichii Sankyo, Esperion,
Lilly, MSD, Pfizer, Resverlogix, and Sanofi-Aventis; and receives grants from Sanofi-Aventis and Valeant. D.P. Mikhailidis
has given talks and attended conferences sponsored by MSD, AstraZeneca, and Libytec.
cardiology.theclinics.com
a
Department of Hypertension, WAM University Hospital in Lodz, Medical University of Lodz (MUL), 113 Zer-
omskiego Street, Lodz 90-549, Poland; b Polish Mother’s Memorial Hospital Research Institute (PMMHRI),
281/289 Rzgowska Street, Lodz 93-338, Poland; c Cardiovascular Research Centre, University of Zielona Gora,
28 Zyty Street, Zielona Gora 65-046, Poland; d Department of Clinical Biochemistry, Royal Free Campus, Univer-
sity College London Medical School, University College London (UCL), Pond Street, London NW3 2QG, UK
* Corresponding author. Department of Hypertension, Medical University of Lodz, Zeromskiego 113, Lodz 90-549,
Poland.
E-mail address: maciejbanach@aol.co.uk
subjects (usually 1%–3%).6 The principal approach this phenomenon) as the appearance of statin-
should be to try not to discontinue statin therapy. related side effects caused by patients’ knowledge
This is a real challenge for lipidologists and those (eg, from media, Internet) and expectations and not
taking care of patients with dyslipidemia. Not dis- by statin therapy.1 The first strong data on the exis-
continuing treatment is especially important for tence of this phenomenon are based on the recent
those with a high and very high CV risk. Statin subanalysis of the Anglo-Scandinavian Cardiac
discontinuation, which might concern even 50% Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA)
to 60% of patients on statins after 2 years, is one trial. In the nonrandomized phase there was a
reason why these patients often do not achieve their 41% significant increase of the rate of SAMS in pa-
recommended goals of therapy (Box 1).7–9 tients treated with atorvastatin in comparison with
the blinded phase, where there was no significant
SYMPTOMS AND CAUSALITY difference between groups.13
SAMS, statin-related new-onset diabetes, and
SAMS are the most common adverse effects alanine aminotransferase (ALT) elevation are the
observed in patients on statins.5 They might range only side effects with confirmed causality.1,2 There
from muscle weakness, muscle aches, soreness, are also several other possible side effects after
stiffness, tenderness, and muscle cramps (but statin therapy, including highly debatable neuro-
not nocturnal cramping; not necessarily with crea- cognitive disorders14 or erectile dysfunction2 or
tine kinase [CK] increase) to muscle myositis (with sleep disorders, for which the causality has not
CK increase) and rhabdomyolysis (very rare at 1.6 been confirmed so far; there are also data that
per 100,000 patient-years), which is usually asso- suggest a lack of such associations.15
ciated with genetic predisposition or other risk fac- From the clinical point of view it is important to
tors present during statin therapy (eg, kidney or clearly present the current recommendations on
liver disease, extensive exercise, or concomitant the association between statin therapy and liver
medication).10,11 diseases. First of all it is crucial to remember that
It needs to be emphasized that one should always ALT elevation greater than three times the upper
ask patients about the tolerability of muscle symp- limit of normal (ULN) occurs in less than 0.5% for
toms. If patients can tolerate the symptoms (with moderate-dose statins and rosuvastatin at all
lack or slight CK increase) one should continue the doses, and about 1% for 80 mg of atorvastatin or
treatment because the symptoms may be tempo- simvastatin (usually <3% all together),2 and usually
rary and resolve after 2 to 4 weeks.2 However, close returns to normal after a dose reduction without the
follow-up should be maintained in case the symp- need for statin discontinuation; in most cases it is
toms and biochemical changes are progressive. It possible to return to the initial doses of statins after
is important that patients should be fully aware 2 to 4 weeks.2,10 Because of this most of the cur-
about all the benefits of statin therapy and the CV rent recommendations suggest ALT measurement
risk increase caused by statin discontinuation or only before statin therapy and thereafter in case of
not taking a suitable statin dose.8,9 Unfortunately, side effects occurrence (without necessity of regu-
most patients usually know much more about lar monitoring).2,16,17 Finally, the risk of statin-
SAAEs than the benefits associated with statin ther- related serious liver disease is 1 per 1,000,000
apy. According to available data, there is several with the number needed to harm at 1 million. In
times more information on the Internet regarding comparison, use of statins prevents about 33%
side effects than on the benefits of statin use.12 of major CV disease events when compared with
Because of this there are more and more patients placebo; the number needed to treat is 3. Unfortu-
with so-called nocebo effect, which is defined nately the percentage of patients who fail to receive
(despite completely different original definition of statins because of fear of hepatotoxicity ranges
between 10% and 30%.2,18 Furthermore, available
Box 1 studies indicate that statin therapy should be
Practical hints on definition and prevalence of continued and benefits are achieved in all patients
statin intolerance with chronic liver diseases, and therapy should be
More than 90% of patients with statin intol-
stopped only in case of acute conditions.2 The
erance might be treated with statins and available data suggest that even in patients with
complete statin intolerance only concerns hepatitis B and C viruses, although not in acute
less than 5% of subjects. and active forms of the disease, statins significant
The principal approach to patients with statin
decrease the risk of hepatocellular carcinoma (by
intolerance should be to try not to discon- <30%) and reduce in the incidence of hepatitis C
tinue statin therapy. virus in the blood by inhibiting its replication.2,19
They might also be beneficial in patients with
Statin Intolerance 3
primary biliary cirrhosis in terms of improved antibiotics; human immunodeficiency virus pro-
course of the disease but primarily in terms of CV tease inhibitors; calcium antagonists; and such
risk reduction, and even greater therapeutic bene- drugs as cyclosporine, danazol, amiodarone,
fits is noted in patients with nonalcoholic fatty liver and ranolazine), and (5) family history (genetic
disease and nonalcoholic steatohepatitis (almost predisposition).1,2,6,17,22
30% higher CV morbidity reduction in comparison 3. Exclude nocebo effect and confirm whether
with those with nonalcoholic fatty liver disease muscle symptoms are caused by statin therapy.
without statin therapy) (Box 2).2,20,21 It is crucial to perform a detailed subjective and
objective patient examination with special
attention to the character of muscle pain.
FOUR-STEP DIAGNOSIS SAMS manifest with large muscle symmetric
(eg, bilateral) aches or bilateral aches of the
There are doubts as to whether there are suitable
smaller distal or proximal musculature,
and effective tools to diagnose statin intolerance
whereas nonstatin-related myalgia is associ-
(Box 3). The step-by-step approach to diagnosis
ated with more diverse symptoms, such as
(and then to treatment) is probably a suitable solu-
whole-body fatigue and groin pain.2,6,23 To
tion.6 Described next are some useful tools on how
confirm whether muscle pain is statin-related
to diagnose patients with statin intolerance:
one should use the SAMS-Clinical Index.6,24
1. Ask when statin therapy was initiated or 4. Ask about the tolerability of the symptoms and
whether there was a dose increase in the last always clearly emphasize the benefits of statin
several weeks. It is important because most of therapy and the risk on statin discontinuation.
the symptoms (>75%) usually appear within Check for CK (no other predictors have been
the first 12 weeks and almost 90% in the first confirmed to be effective and possible to use
6 months, so it is less likely to have statin intol- in every-day clinical practice),25 and remember
erance in patients on statin therapy for a few the following principal rules based on recent
years (unless a new external factor might be guidelines5,16,17: (1) if the patient reports mus-
the cause).2,10 cle pain at CK greater than or equal to 4 ULN,
2. Obtain a family history and check for conditions statin treatment should be discontinued for 4
that might increase statin intolerance risk. There to 6 weeks until the regression of pain and CK
are five important conditions/risk factors that normalization; (2) if the patient reports tolerable
might cause SAMS: (1) new intensive exercise muscle pain at CK less than 4 ULN, a reduction
(eg, with the initiation of statin therapy when in statin dose and treatment continuation with
there is also a recommendation for lifestyle close monitoring of CK may be considered; if
changes), (2) hypothyroidism/hyperthyroidism clinical symptoms are exacerbated and/or the
(mainly hypothyroidism), (3) vitamin D defi- CK concentration is increased, statin treatment
ciency (especially in countries with limited sun should be discontinued for 4 to 6 weeks until
access annually), (4) concomitant therapy the regression of pain and CK normalization;
(especially with some antifungal medications; and (3) if the patient reports intolerable muscle
pain at CK less than 4 ULN, statin treatment
Box 2 should be discontinued for 2 to 4 weeks until
Practical hints on statin intolerance symptoms the regression of pain and CK normalization.
and causality
ALT elevation after statin therapy is rare Obtain a family history and check for condi-
(<3%) and ALT usually returns to normal tions that might increase statin intolerance
without the need for statin discontinuation; risk.
in most cases, it is possible to return to the Exclude nocebo effect and confirm whether
initial doses of statins after 2 to 4 weeks. muscle symptoms are caused by statin therapy.
Statin therapy is effective and safe and should Ask about the tolerability of the symptoms and
be continued in all patients with chronic liver always clearly emphasize the benefits of statin
diseases. therapy and the risk of statin discontinuation.
4 Banach & Mikhailidis
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