impact of the nocebo effect on discontinuation of statin therapy due to myopathy in patients with cardiovascular disease – a review

Abstract

Introduction and purpose of review: Statins are widely used drugs in the prevention of cardiovascular diseases, yet many patients experience side effects of statin use, mainly muscle symptoms, such as myopathy, which often lead to discontinuation of treatment. The aim of this literature review is to assess the role of the nocebo effect in reported muscle symptoms and its impact on statin discontinuation in patients with cardiovascular diseases. Methods: The review analysed the results of several studies, including key publications such as the N-of-1 trial by Wood et al.[1] and the work of Collins et al.[2] on the safety and efficacy of statin therapy. The review covered articles published between 2000 and 2023 that examined the impact of the nocebo effect on statin discontinuation[3-10]. Results: The collected data indicate that the nocebo effect plays a significant role in the reported muscle symptoms during statin use. The study by Wood et al.[1] showed no significant differences in reported symptoms between the groups taking statins, placebo, or receiving no treatment, suggesting that a substantial portion of the symptoms results from the nocebo effect. Similar findings were obtained in the study conducted by the StatinWISE group[4], where patients taking statins and placebo reported a comparable frequency of muscle symptoms. An analysis conducted by Collins et al.[2] indicates that the actual incidence of myopathy associated with statin therapy is much lower than commonly reported. Conclusions: The nocebo effect significantly influences the perceived adverse effects of statins, which may lead to the unjustified discontinuation of these drugs by patients with cardiovascular diseases. Further research is needed to better understand the psychological mechanisms affecting statin tolerance and to develop educational and clinical strategies aimed at minimizing the nocebo effect and improving long-term adherence to therapy.

Full text

STANEK, Jakub, SORNEK, Patrycja, IZDEBSKA, Wiktoria, BORKOWSKA, Agata, CIESIELSKI, Radosław, KAŹMIERCZAK,
Anna, KIEŁB, Anna, MICH, Anna, PERKOWSKA, Klaudia and PAWLAK, Igor. The impact of the nocebo effect on discontinuation
of statin therapy due to myopathy in patients with cardiovascular disease – a review. Quality in Sport. 2024;31:55769. eISSN 2450-
3118.
https://dx.doi.org/10.12775/QS.2024.31.55769
https://apcz.umk.pl/QS/article/view/55769
The journal has been 20 points in the Ministry of Higher Education and Science of Poland parametric evaluation. Annex to the announcement
of the Minister of Higher Education and Science of 05.01.2024. No. 32553.
Has a Journal's Unique Identifier: 201398. Scientific disciplines assig589 ned: Economics and finance (Field of social sciences); Management
and Quality Sciences (Field of social sciences).
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© The Authors 2024;
This article is published with open access at Licensee Open Journal Systems of Nicolaus Copernicus University in Torun, Poland
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Received: 22.10.2024. Revised: 13.11.2024. Accepted: 18.11.2024. Published: 18.11.2024.
1
The impact of the nocebo effect on discontinuation of statin therapy
due to myopathy in patients with cardiovascular disease – a review
Jakub Stanek,
Medical University of Lodz, al. Tadeusza Kosciuszki 4, 90-419 Lodz, Poland
Orcid: https://orcid.org/0000-0002-9450-7261
E-mail: jakubstanek22@gmail.com
Patrycja Sornek,
Military Medical Academy Memorial Teaching Hospital- Central Veteran Hospital ul. Stefana
Żeromskiego 113, 90-549 Lodz, Poland
Orcid: https://orcid.org/0009-0003-9630-055X
E-mail: sornekpatrycja5@gmail.com
Wiktoria Izdebska,
J. Gromkowski Regional Specialist Hospital in Wroclaw, Koszarowa 5, 51-149 Wroclaw,
Poland
Orcid: https://orcid.org/0009-0005-0242-141X
E-mail: wiktoriaxizdebska@gmail.com
Agata Borkowska,
Military Institute of Aviation Medicine, ul. Zygmunta Krasińskiego 54/56, 01-755 Warsaw,
PL
Orcid: https://orcid.org/0009-0008-7347-7762
E-mail: agata.borkowska.ab@wp.pl
Radosław Ciesielski,
Independent Public Hospital in Mińsk Mazowiecki, ul. Szpitalna 37, 05-300 Mińsk
Mazowiecki
Orcid: https://orcid.org/0000-0002-3458-2024
E-mail: radoslaw.ciesielski@yahoo.com

2
Anna Kaźmierczak,
4th Military Clinical Hospital in Wroclaw, Weigla 5, 53-114 Wroclaw, Poland
Orcid: https://orcid.org/0009-0000-8435-6685
E-mail: a.kazmierczak.1998@o2.pl
Anna Kiełb,
5th Military Clinical Hospital in Krakow, ul. Wrocławska 1-3, 30-901 Krakow, Poland
Orcid: https://orcid.org/0009-0005-3152-5429
E-mail: akielb97@gmail.com
Anna Mich,
Independent Public Hospital in Mińsk Mazowiecki, ul. Szpitalna 37, 05-300 Mińsk
Mazowiecki
Orcid: https://orcid.org/0009-0004-6299-5506
E-mail: aniamich97@icloud.com
Klaudia Perkowska,
Military Medical Institute, Szaserów 128, 04-349 Warsaw, Poland
Orcid: https://orcid.org/0009-0001-7362-4995
E-mail: dr.kperkowska@gmail.com
Igor Pawlak,
Independent Public Hospital in Mińsk Mazowiecki, ul. Szpitalna 37, 05-300 Mińsk
Mazowiecki
Orcid: https://orcid.org/0009-0003-1942-9296
E-mail: igor.a.pawlak@gmail.com
Abstract
Introduction and purpose of review: Statins are widely used drugs in the prevention of
cardiovascular diseases, yet many patients experience side effects of statin use, mainly muscle
symptoms, such as myopathy, which often lead to discontinuation of treatment. The aim of this
literature review is to assess the role of the nocebo effect in reported muscle symptoms and its
impact on statin discontinuation in patients with cardiovascular diseases.
Methods: The review analysed the results of several studies, including key publications such
as the N-of-1 trial by Wood et al. [1] and the work of Collins et al. [2] on the safety and efficacy
of statin therapy. The review covered articles published between 2000 and 2023 that examined
the impact of the nocebo effect on statin discontinuation [3-10].
Results: The collected data indicate that the nocebo effect plays a significant role in the reported
muscle symptoms during statin use. The study by Wood et al. [1] showed no significant
differences in reported symptoms between the groups taking statins, placebo, or receiving no
treatment, suggesting that a substantial portion of the symptoms results from the nocebo effect.
Similar findings were obtained in the study conducted by the StatinWISE group [4], where

3
patients taking statins and placebo reported a comparable frequency of muscle symptoms . An
analysis conducted by Collins et al. [2] indicates that the actual incidence of myopathy
associated with statin therapy is much lower than commonly reported.
Conclusions: The nocebo effect significantly influences the perceived adverse effects of statins,
which may lead to the unjustified discontinuation of these drugs by patients with cardiovascular
diseases. Further research is needed to better understand the psychological mechanisms
affecting statin tolerance and to develop educational and clinical strategies aimed at minimizing
the nocebo effect and improving long-term adherence to therapy.
Keywords: statins, nocebo effect, myopathy, cardiovascular diseases, dyslipidemia,
hypercholesterolemia, literature review, drug discontinuation.
Background
Statins are a class of pharmacological agents that play a pivotal role in lowering blood
cholesterol levels, which is crucial for the prevention of cardiovascular diseases. Their
mechanism of action is based on the competitive inhibition of the enzyme HMG-CoA reductase
(3-hydroxy-3-methylglutaryl-coenzyme A reductase), a key enzyme in the cholesterol
biosynthesis pathway in the liver. HMG-CoA reductase catalyzes the conversion of HMG-CoA
to mevalonate, an early and rate-limiting step in cholesterol synthesis. The inhibition of this
enzyme by statins results in a reduction of intracellular cholesterol production.
In response to the decreased intracellular cholesterol levels within hepatocytes, there is an
upregulation of low-density lipoprotein receptors (LDLR) on the surface of these liver cells.
The increased number of LDL receptors enhances the clearance of LDL-C (low-density
lipoprotein cholesterol) from the bloodstream. Consequently, there is a reduction in circulating
LDL-C levels, as well as other apolipoprotein B-containing lipoproteins, including triglyceride-
rich lipoproteins (TG) [11].
The use of statins may reduce the risk of atherosclerotic cardiovascular diseases up to
55% [11, 12]. Adverse effects of drugs are very difficult to assess and identify. The
interpretation of some side effects of statins is incorrect, and the adverse effects attributed to
them are related to the occurrence of separate diseases, risk factors, the use of other drugs, or

4
the patient's clinical condition [13]. Potential side effects associated with the use of statins are
still the main reason for non-compliance with recommendations or discontinuation of their use
[10, 14, 15, Praca]. Non-adherence to statin treatment may be as high as 60% after 24 months
of treatment and is associated with a 70% increase in the risk of cardiovascular events [16].
When taking statins, patients especially complain of myopathies [2]. Patients' knowledge of
side effects of medications makes them susceptible to the nocebo effect —a psychological
phenomenon in which the patient experiences negative side effects that are not actually related
to the medication, but rather to their expectations [1].
Studies on the impact of the nocebo effect on statin therapy have shown that many symptoms
of myopathy reported by patients may be associated with their expectations and beliefs about
potential side effects, rather than with the treatment itself [1, 17]. A study conducted by Wood
et al. [1] demonstrated that patients receiving statins, placebo, or no treatment reported similar
symptoms, suggesting a significant influence of the nocebo effect on patient experiences.
Similar findings were observed in the StatinWISE trial, where muscle symptoms were reported
with suchlike frequency in both the statin and placebo groups [5].
Knowledge about the possibility of myopathy in patients taking statins causes some patients to
discontinue treatment, which inevitably leads to cardiovascular complications. Recent papers
shows that myopathies do not affect many patients [1, 18]. In last years, some studies have
completely denied the existence of a link between myopathy and statin use [5, 18, 19].
Analyses conducted by Collins et al. [2] and Thavendiranathan et al. [6] indicate that the actual
incidence of statin-induced myopathy is significantly lower than suggested by patients’ reports.
In fact, many of these symptoms may result from the nocebo effect rather than the
pharmacological action of the drug itself [10]. Studies on the risks and benefits of statin
therapy, such as those by Kashani et al. [7] and Zhang et al. [9], have noted that misconceptions
about risk can affect adherence to therapy and its effectiveness [7, 9].
In the context of global research on statin therapy, understanding the role of the nocebo effect
and developing strategies to minimize its impact, are crucial for improving treatment adherence
and achieving better health outcomes [8,13]. Therefore, further research is needed to explore
the psychological mechanisms influencing statin tolerance and to develop effective clinical
interventions.
Review of selected original publications
The study conducted by Wood FA, Howard JP, Finegold JA, and Nowbar AN [1],
examined whether statin-induced myopathy is a nocebo effect. The study involved 60 patients

5
(from June 2016 to March 2019) who discontinued statins use due to side effects occurring after
2 weeks of taking the drug. Patients were enrolled in a randomized, double-blind study (n-of-1
trials) to see whether their symptoms would be induced by a statin or a placebo. Participants
were given 12 1- month bottles: four bottles of atorvastatin 20 mg, four bottles of placebo and
four empty bottles. Each bottle was intended to be used for a period of 1 month in random
order. Patients rated the severity of side effects daily on a scale from 0 (no symptoms) to 100
(worst imaginable symptoms), including muscle pain. They used a smartphone application for
this purpose. If the patient experienced very severe side effects, he could stop taking the tablets
for a month. The analysis of the primary endpoint showed a nocebo ratio of 2.2 (95% confidence
interval [CI], -62.3 to 66.7). This value was high and had a wide confidence interval because in
some patients the difference in symptom severity scores with statins and symptom severity
scores without statins or placebo was unexpectedly small or negative. The mean symptom
intensity among all 60 patients, was 8,0 for no-tablet months (95% CI, 4,7 to 11,3), 15,4 for
placebo months (95% CI, 12,1 to 18,7; P<0,001when comparing with no-tablet months) and
16,3 for statin months (95% CI, 13,0 to 19,6; p<0,001 when comparing with no-tablet months
and P=0.39 when comparing with placebo months) [1].
Six months after the end of the study, 30 patients (50%) had successfully resumed taking statins,
4 planned to do so, and 1 could not be contacted. The remaining 25 patients were not receiving
statins and did not plan to be re-treated with statins for the following reasons: side effects in 18,
spontaneous improvement in cholesterol in 4 (patients no longer believed that statins caused
side effects), recall that their cholesterol was not lowered by statins in 1, new diagnosis of
progressive neurodegenerative disorder in 1, the feeling of being "too old" in 1. In patients who
discontinued statin therapy due to side effects, 90% of the severity of symptoms induced by
statin challenge was also elicited by placebo [1].
A series of randomized, double-blind studies by Emily Herrett, Elizabeth Williamson,
Kieran Brack et al. [4] examined the overall effect of atorvastatin on muscle symptoms. The
study was carried out in 50 general practitioners centers in the UK between December 2016
and April 2018. The study included 200 participants who had recently stopped or were
considering stopping statin treatment due to muscle symptoms.
The study lasted for 12 months. Participants were randomly assigned to six two-month study
periods. Three of the two-month periods, consisted of treatment with atorvastatin 20 mg. During
other months, participants were given a placebo. Both parts of the study were double-blind.
Patients and researchers did not know when the participant was receiving a statin. At the end

6
of each treatment period, participants rated their muscle symptoms on a visual analog scale
(from 0 to 10). The analysis compared symptom scores during the statin and placebo periods.
151 participants provided symptom scores for at least one statin period and one placebo period,
and were included in the analysis (Table 1).
No (%) of participants
Statin periods
Placebo periods
Muscle symptoms
248/397 (62.5)
239/388 (61.6)
Muscle symptoms, not attributed to
other causes
216/397 (54.4)
200/388 (51.6)
Table 1. Estimated effects for secondary outcomes comparing statin with placebo periods (from
participant questionnaire; n=152) - table based on [4].
There were few participants who withdrew from the study due to health complications. Eighteen
of two hundred participants (9%) withdrew during the statin treatment period and 13 (7%)
withdrew during the placebo period. A small group of participants in this study had previously
experienced side effects from taking statins that were severe enough for them to discontinue
treatment. Therefore, they knew the side effects of statins and may have been susceptible to the
nocebo effect [1, 17]. Researchers found no differences in the frequency or severity of muscle
symptoms between the periods of satin and placebo. In this series of studies, discontinuations
due to symptom intolerance were rare and the excess compared with ststins and placebo was
2%. Of those who participated in the study, almost two-thirds reported that they intended to
resume statin treatment. The researchers emphasize the consistency of their study with the
ODYSSEY ALTERNATIVE study [20] and the GAUSS-3 study [21], which proved that only
a small proportion of statin-intolerant patients developed intolerable muscle symptoms while
taking statins compared to placebo. Observational studies have shown a negative effect of
statins on muscles [2, 22] and the occurrence of muscle symptoms during therapy with these
drugs in clinical practice often prompts patients to discontinue treatment [9, 10, 14, 15]. Various
explanations have been proposed for this phenomenon, including the nocebo effect, in which
waiting for the occurrence of side effects may cause patients to attribute muscle ailments to the
statins they are taking [9, 10, 23]. Additionally, muscle pain is a common symptom in the
elderly population, which often takes statins, which may lead to these ailments being wrongly
attributed to the use of statins [13, 3]. The lack of randomization and blinding in observational

7
studies means that in the case of subjective symptoms, such as muscle pain, the association with
statins may not be causal [8, 13]. The significant proportion of participants in our studies who
intended to resume statin therapy after study completion is consistent with observational data
suggesting that reinitiation of statin therapy is tolerable in most patients [24 , 25].
An article by Gupta et al. published in the Lancet in 2017 is an important study on the
side effects of statins [3]. The aim of the study was to determine the true incidence of statin-
related adverse events, including myopathy (Table 2).
Empty Cell Blinded randomised
phase (ASCOT-LLA)
Non-blinded non-randomised phase
Empty Cell
Placebo
(n=5079)
Atorvastatin
(n=5101)
Atorvastatin
non-user
(n=3490)
Atorvastatin
user
(n=6409)
Muscle related
Patients (n)
283
298
124
161
AE rate (% per
annum)
2·00%
2·03%
1·00%
1·26%
HR (95% CI)
1
1·03 (0·88–
1·21)
1
1·41 (1·10–
1·79)
p value
..
0·72
..
0·006
Table 2. Risk of adverse events of interest - table based on [3].
Study participants of the Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes
Trial (ASCOT-LLA) [3], were recruited from various clinics and hospitals, which ensured
population diversity and increased the representativeness of the results.
The subjects had not previously taken statins or fibrates. Patients were assigned to atorvastatin
10 mg daily or placebo, respectively. Investigators compared the reporting rate of adverse
events during statin treatment in the blinded, randomized, and unblinded, nonrandomized
phases (Table 3).

8
In the blinded randomised phase
Rate (% per annum)
HR (95 % Cl)
P value
Placebo
Atorvastatin
Musculoskeletal
and connective
tissue disorders
6·91%
7·19%
1·04 (0·96–
1·11)
0·33
In the non-blinded non-randomised phase
Rate (% per annum)
HR (95 % Cl)
P value
Atorvastatin non-user
Atorvastatin user
Musculoskeletal
and connective
tissue disorders.
7·45%
8·69%
1·17 (1·06–
1·29)
0·001
Table 3. Rates of all adverse events, in the blinded randomised phase nad in the non-blinded
non-randomised phase - table based on [3].
The study found that in the blinded phase, when participants did not know whether they were
taking statins, there were no excess reports of muscle problems. However, after it was revealed
that patients were taking statins in the unblinded phase, reports of such problems increased
significantly. This observation suggests a nocebo effect [17].
Gupta A et al., draw attention to non-randomized observational studies on the use of statins in
everyday health care, where every fifth patient reports that they do not tolerate statins [26, 27].
However, these studies, unlike the study by Gupta et al., are not blinded. Both the patient and
the doctor know what drug is being used for therapy and that the treatment has specific side
effects. The ASCOT-LLA example illustrates how lack of blinding can lead to overreporting
of adverse events. This article is an important source of knowledge on the impact of statin
therapy on patient safety and provides a starting point for further analysis, especially in the
context of the nocebo effect.

9
In 2008, a JUPITER study was published, in which 17,802 people without hyperlipemia
were selected. It was randomized, double-blind, placebo-controlled, multicenter study,
conducted in 1,315 centers in 26 countries [28]. During the study, the number of reported
adverse events was similar in the group receiving rosuvastatin 20 mg and placebo. The number
of patients reporting muscle symptoms (muscle weakness, stiffness, or pain) was 1,421 for
rosuvastatin group and 1,375 for placebo group (Table 4). There were no significant differences
between the two study groups in terms of adverse events on muscles during the study.
Event
Rosuvastatin
(N=8091)
Placebo
(N=8901)
P Value
Muscular weakness, stiffess, or pain – no. (%)
1421 (16.0)
1375 (15.4)
0.34
Myoparthy – no. (%)
10 (0.1)
9 (0.1)
0.82
Rhabdomyolysis – no. (%)
1 (<0.1)
0
-
Creatinine, >100% increase from baseline – no.
(%)
16 (0.2)
10 (0.1)
0.24
Table 4. Monitored Adverse Events Reported Events of Interest during the Follow-up Period.
Tabela na podstawie badania; „Rosuvastatin to Prevent Vascular Events in Men and Women
with Elevated C-Reactive Protein - table based on [28].
.An increase in adverse events with long-term statin use cannot be excluded. The median
follow-up time for patients was 1.9 years. However, there was no increase in adverse events in
the analysis of participants who continued treatment for 4 or more years. The rates of first major
cardiovascular event and all-cause death were significantly lower in participants receiving
rosuvastatin than in those receiving placebo. There were 142 major cardiovascular events in the
rosuvastatin group and 251 in the placebo group.
This study showed that rosuvastatin therapy significantly reduced the number of cardiovascular
events. The study was double-blind, meaning that neither patients nor investigators knew which
treatment was assigned to each participant. This method helps eliminate the influence of patient

10
and investigator expectations on the results, allowing for more reliable data on the efficacy and
safety of the treatment.
In a study conducted as part of the Integrated Systematic Care for Older Persons
(ISCOPE) study in the Netherlands [29], patients with a well-documented medical history and
a history of statin treatment were selected. The screening questionnaire asked: “What health
problems currently limit you most in your daily life?” [30, 31]. No muscle-related adverse
events were suggested.
The study included a representative group of 4355 patients. During the observation period, there
was no difference in the frequency of muscle-related complaints in statin users (3.3%) and non-
users (2.5%)(p=0.18) (Fig.1).
Fig 1. Prevalence of self-reported complaints according to statin use and non-statin use - chart
based on [29].
The study examined whether the use of statins is associated with self-reported muscle
symptoms that impair daily living. No significant difference was found in the frequency of self-
reported muscle symptoms between individuals using statins and those not using statins [10,
32]. The researchers draw attention to the frequently discussed topic in public discourse
regarding muscle symptoms related to statin use, which may lead to negative patient
expectations towards statins. The unpleasant effects experienced are not always necessarily a
result of statin use [23, 33]. Furthermore, physicians may be inclined to incorrectly attribute
muscle symptoms to statin therapy [5].
3,3
10,3
2,5
10
0
2
4
6
8
10
12
muscle complaints muscloskeletal complaints
Prevalence (%)
Self-reported complaints
Statin use non-statin use

11
The Heart Protection Study is one of the largest clinical trials evaluating the effect of
statins on the prevention of cardiovascular disease [34]. The primary objective of the study was
to determine whether the use of statins can reduce the risk of death and cardiovascular events
in patients at various risk of cardiovascular disease, regardless of baseline cholesterol levels. A
total of 20,536 patients took part in the study, the average duration of follow-up was 5 years.
At each follow-up, approximately 6% of participants reported unexplained muscle pain or
weakness, but there was no significant difference between the simvastatin and placebo groups.
These symptoms occurred at least once in 32.9% of participants taking simvastatin and 33.2%
of participants taking placebo. Similarly, there was no significant difference in the number of
participants who discontinued treatment because of muscle symptoms (49 in the statin group
vs. 50 in the placebo group). Creatine kinase levels were measured in every participant who
reported muscle symptoms. Only a few patients taking a statin had elevated creatinine levels
(Table 5).
Simvastatin-allocated
(n=10269)
Placebo-allocated (n=10267)
Elevated CK
4−10×ULN
19 (0·19%)
13 (0·13%)
>10×ULN*
11 (0·11%)
6 (0·06%)
Myopathy
No rhabdomyolysis
5 (0·05%)
1 (0·01%)
Rhabdomyolysis
5 (0·05%)
3 (0·03%)
CK=creatine kinase; ULN=upper limit of normal for laboratory.
*
Among those with CK >10×ULN, 1 vs2 were asymptomatic.
Table 5. Numbers of participants with elevated liver or muscle enzymes during follow-up -
based on [34].
Myopathy, defined as the occurrence of muscle symptoms and a creatine kinase increase of
more than 10 times the upper limit of normal (ULN), was diagnosed in a small number of
participants taking simvastatin, but the difference was not statistically significant (p=0.2).
The Heart Protection Study found no significant difference in the incidence of unexplained
muscle pain or weakness between simvastatin and placebo. The study results suggest that statin
therapy provides a clear health benefit that may prevent serious vascular events in about 70 to
100 people per 1,000 treated for 5 years, even with a moderate incidence of muscle-related side

12
effects. Long-term statin therapy appears to be valuable for many high-risk patients, especially
because the therapy is well tolerated and safe.
Conclusions
This review discusses issues related to statin therapy, particularly with regard to the
incidence of adverse events and the impact of the nocebo effect on reported symptoms [35].
Recent studies suggest that the true incidence of statin-related myopathy is much lower than
that reported by patients [2,6, 28, 29, 34]. That is why it is important to understand the role of
the nocebo effect and develop strategies to minimize its impact on treatment.. The results of the
studies by Wood et al. [1] and Herrett et al. [4] indicate a significant influence of the nocebo
effect on the reported muscle symptoms in patients taking statins. Both studies used
randomized, double-blind, placebo-controlled protocols, which allowed for the assessment of
the true association between statin use and the occurrence of symptoms. The results of these
studies indicate that patient-reported symptoms were as common in the placebo group as in the
statin group, strongly suggesting that the nocebo effect plays a significant role in the perception
of adverse effects by patients. Similar conclusions can be drawn from the study by Gupta et al.
[3], which showed that there was no excess reporting of muscle problems during the blinded
phase, but after revealing that patients were taking statins, the number of such reports increased
significantly. This observation also suggests the influence of the nocebo effect on the subjective
experiences of patients. Observational studies have shown that patients taking statins are more
likely to report muscle symptoms, which often leads to treatment discontinuation [9, 10, 14,
15]. However, the lack of randomization and blinding in these studies means that the association
between statin use and muscle symptoms may not be causal [8, 13]. The evidence confirms that
the actual incidence of statin-induced myopathy is significantly lower than suggested by patient
reports [2, 28, 29, 34, 36, 37]. These data underscore the importance of the nocebo effect in
statin therapy. Patients who are aware of the potential side effects may be more susceptible to
the nocebo effect, which may lead to higher adverse event reporting rates and more frequent
discontinuation of therapy. Unfortunately this may lead to worse health outcomes, as statins
play a key role in preventing cardiovascular disease [38, 39, 40].
Disclosure
Author's contribution
Conceptualization: Jakub Stanek and Patrycja Sornek; Methodology: Wiktoria Izdebska;
Software: Klaudia Perkowska; Check: Anna Kaźmierczak; Formal analysis: Jakub Stanek;
Investigation: Jakub Stanek, Patrycja Sornek; Resources: Radosław Ciesielski; Data
curation: Igor Pawlak and Wiktoria Izdebska; Writing- rough preparation: Agata Borkowska;

13
Writing- review and editing: Anna Mich; Visualization: Anna Kiełb Project administration:
Jakub Stanek
All authors have read and agreed to the published version of the manuscript.
Funding statement
This research received no external funding.
The Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
Not applicable.
Informed Consent Statement
Not applicable.
Conflict of interest
The authors deny any conflict of interest.
References
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treatment to assess side effects." New England Journal of Medicine. 2020; 383:2182-
2184.
2. Collins R, Armitage J, Parish S, et al. "Interpretation of the evidence for the efficacy
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