Current Medical Research and Opinion
ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: http://www.tandfonline.com/loi/icmo20
Additional therapy for cholesterol lowering in
ezetimibe-treated, statin-intolerant patients in
clinical practice: results from an internal audit of a
university lipid clinic.
Arrigo F.G. Cicero, Martino Morbini, Marilisa Bove, Sergio D’Addato, Federica
Fogacci, Martina Rosticci & Claudio Borghi
To cite this article: Arrigo F.G. Cicero, Martino Morbini, Marilisa Bove, Sergio D’Addato,
Federica Fogacci, Martina Rosticci & Claudio Borghi (2016): Additional therapy for cholesterol
lowering in ezetimibe-treated, statin-intolerant patients in clinical practice: results from
an internal audit of a university lipid clinic., Current Medical Research and Opinion, DOI:
10.1080/03007995.2016.1190326
To link to this article: http://dx.doi.org/10.1080/03007995.2016.1190326
Accepted author version posted online: 13
May 2016.
Published online: 13 May 2016.
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Date: 08 June 2016, At: 02:27
ORIGINAL ARTICLE
Additional therapy for cholesterol lowering in ezetimibe-treated, statin-intolerant patients in
clinical practice: results from an internal audit of a university lipid clinic.
Arrigo F.G. Cicero, Martino Morbini, Marilisa Bove, Sergio D’Addato, Federica Fogacci, Martina
Rosticci, Claudio Borghi
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Address for correspondence: Arrigo F.G. Cicero, MD, PhD, S. Orsola-Malpighi University
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Hospital, Via Albertoni, 15, 40138 Bologna, Italy. Tel. ++39 512142224; Fax ++ 39 516826125;
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[email protected]
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Key words: Hypercholesterolemia, Statin-intolerance, Nutraceuticals, Ezetimibe
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[Short title: Managing statin-related myalgia in clinical practice]
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S. Orsola-Malpighi University Hospital, Lipid Clinic, Bologna, Italy
Abstract
Objective: The aim of our study was to evaluate the tolerability and efficacy of alternative
approaches to improve cholesterolemia control in patients with statin-related myalgia treated with
ezetimibe.
Research Design and Methods: We retrospectively evaluated 3534 Clinical Report Forms (CRFs)
filled in the period June 2012-June 2015 for first visits to the lipid clinic of the University of
Bologna. For this study, we selected 252 CRFs based on the following criteria: statin-related
ezetimibe. Then, the following lipid-lowering treatments were added in order to improve the
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ezetimibe Low Density Lipoprotein Cholesterol (LDL-C)-lowering efficacy, based on clinical
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judgment: fenofibrate 145 mg, rosuvastatin 5 mg 1 tablet/week, rosuvastatin 5 mg 2 tablets/week,
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red yeast rice (standardized in Monacolin K 3 mg) + berberine 500 mg, berberine 500 mg b.i.d.,
phytosterols 900 mg+psyllium fiber 3.5 g b.i.d. Patients continuing to claim a tolerable myalgia
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were then treated with coenzyme Q10 nanoemulsions 200 mg/day.
Results: The treatment with standard lipid-lowering diet plus ezetimibe alone was associated with a
mean LDL-C reduction of 17±2%. The additive LDL-lowering effect with the various tested
treatment was: -16±2% with fenofibrate 145 mg/day, -13±1% with rosuvastatin 5 mg 1
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tablet/week, -17±3% with rosuvastatin 5 mg 2 tablets/week, -19±4% with red yeast rice +
berberine, -17±4% with berberine b.i.d. and -10±3% with phytosterols + psyllium b.i.d. 11% of
the patients treated with fenofibrate required treatment modification because of myalgia recurrence,
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myalgia, previous failed treatment with at least two low-dosed statins, well-tolerated treatment with
while the percentage was negligible for the other tested treatments. In patients with residual
tolerable myalgia, treatment with coenzyme Q10 for 8 weeks was associated with a mean
improvement of the graduated myalgia score from 4.8±1.9 to 2.9±1.3 (p= 0.013).
Conclusions: Some alternative treatments seems to be effective and well tolerated, thus improving
the ezetimibe effect on cholesterolemia.
1. Introduction
Statin treatments carried on in order to reduce cholesterol levels and with the final target of
preventing cardiovascular morbidity and mortality are extensively used by hundreds of millions of
patients, mainly with success1,2. However, the interruption of statin treatment due to some adverse
effects is not a rare event3,4. Myotoxicity is currently the main issue, ranging from simple myalgia
to rhabdomyolysis5. While events like rhabdomyolysis or severe myositis with very high creatine
kinase (CK) levels (> 10 times above normal levels) are quite rare6,7. mild to moderate myalgia,
studies8,9. Furthermore, clinical practice surveys usually show even larger percentages of reported
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to difference in the definition applied to this condition.12,13.
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muscular side effects.10,11 The difficulty to define a prevalence of statin-intolerance is also related
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A mild association between new-onset type 2 diabetes and high statin doses in patients with risk
factors for diabetes has been confirmed by at least two recent meta-analyses14,15. However, in
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patients with moderate to high cardiovascular risk the benefits from statin therapy overcome the
slightly increased risk of type 2 diabetes incidence16.
The effects of statin treatments on cognitive functions have been debated with conflicting results,
however some studies and reviews pointed out the absence of a definitive association between statin
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treatment and incident cognitive impairment17,18, and the dominant thought is that, globally, the
positive cardiovascular effects prevail on the uncertain cognitive ones19.
However, as discussed above, the main concern in clinical practice is the relatively wide number of
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with or without CK elevation, occurs in approximately 5 to 15% of the participants in observational
statin intolerant patients because of muscular adverse effects. There are suggestions regarding
options for treating these patients. Intermittent treatment (i.e. taking statins every other day) seems
to be effective in some patients intolerant to full doses of statins, allowing a sufficient therapeutic
effect on LDL-C levels while reducing the incidence of side effects, but larger and more complete
studies are needed on this matter20,21. Ezetimibe per se is usually well-tolerated by statin-intolerant
subjects, but its use is associated with a minimal risk to develop myalgia22 and this risk increases
when it is associated with statins, even when given at low dose23. Other approaches are empirical.
For example, red yeast rice is often well tolerated, but containing small amounts of statins, its use
could also related to myalgia24. However, the main aim in these patients is to reach as much as
possible the LDL-C target foreseen for their category of cardiovascular risk.
The main aim of our study was to evaluate the tolerability and efficacy of alternative approaches to
reduce hypercholesterolemia in patients with statin-related myalgia. A secondary aim was to
evaluate if supplementation with coenzyme Q10 can improve residual myalgia after therapy
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2. Materials and Methods
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The lipid clinic of the University of Bologna is the largest of the Emilia-Romagna region and one of
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the largest in Italy. The clinical team usually carries out around 3000 visits/year. For this study, we
retrospectively evaluated the 3534 standard Lipid Clinic Clinical Report Forms (CRFs) filled in the
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period June 2012 – June 2015 for first visits.
For this study, we selected the CRFs based on the following criteria.
Inclusion criteria:
- Age between 18 and 85
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- Hypercholesterolemia requiring pharmacological treatment (off target after at least 3 months of
adequate life-style improvement)
- General Practitioner (GP) diagnosis of statin intolerance because of intolerable myalgia (beyond
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stabilization.
serum CK level)
- Previous failed treatment with at least 2 statins at low dosage (for example, pravastatin 20 mg 1
tablet/day, rosuvastatin 5 mg 1 tablet/day)
Exclusion criteria:
-
Myalgia unrelated to statin-treatment (e.g. pre-existing to statin treatment and not worsened by
statin treatment)
-
Known organic myopathies or rheumatic diseases
-
Severe vitamin D deficiency
-
Uncontrolled thyroid disease
In particular, myalgia unrelated to statin-treatment or joint pain related to rheumatic diseases are
frequent causes of misdiagnosed statin-intolerance, and consequently they are systematically
considered in our center.
Finally, we selected 252 patient CRFs (M: 114, F: 138). We stratified their risk on the basis of the
<100 mg/dL, and low-to-moderate risk ones an LDL-C <115 mg/dL.
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accordingly: very high risk patients had to reach an LDL-C <70 mg/dL, high risk ones an LDL-C
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As per internal routine, all these patients were initially treated with ezetimibe, one 10 mg tablet/day,
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and during the whole observation the patients were given standard behavioral and qualitative
dietary suggestions to correct unhealthy habits. Standard diet advice was given by a dietitian and/or
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specialist doctor. Dietitian and/or specialist doctor periodically provided instruction on dietary
intake recording procedures as part of a behavior modification program and then later used the
subject’s food diaries for counselling. In particular subjects were instructed to follow general
indication of a Mediterranean diet, avoiding excessive intake of dairy products and red meat derived
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products during the study, maintaining overall constant dietary habits. Individuals were also
encouraged to increase their physical activity by walking briskly for 20 to 30 min, 3 to 5 times per
week, or by cycling.
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European Guidelines for dyslipidemia management25 and their LDL-C targets attributed
Once ezetimibe tolerability was established, the following lipid-lowering treatments were added in
order to improve the LDL-C-lowering efficacy. The first treatment was decided based on clinical
judgment (mainly considering the previous report to intolerance and patient preference):
-
Fenofibrate 145 mg (n = 27)
-
Rosuvastatin 5 mg, 1 tablet/week (n = 45)
-
Rosuvastatin 5 mg, 2 tablets/week (n = 38)
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Red Yeast Rice (standardized in Monacolin K 3 mg) + berberine 500 mg (n = 57) (Meda
SpA, Monza, Italy)
-
Berberine 500 mg b.i.d. (n = 53) (Pharmextracta Srl, Pontenure, Italy)
-
Phytosterols 900 mg + psyllium fiber 3.5 gr b.i.d. (n = 32) (Innovares Srl, Sant’Ilario d’Enza,
Italy)
The main rule for the treatment choice was based on the previous treatment attempts by the patient
GPs, avoiding re-testing similar approaches. For example, if a patient experienced myalgia with
was not attempted. On the other hand, if a patient experienced intestinal side effect with berberine,
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it was not prescribed as first choice.
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As for the dietary supplements, the choice was based on the most well studied available commercial
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products in Italy. Patients taking different drugs or drug-dietary supplement association were
excluded from our analysis because their numbers were small.
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The final reported result is the one obtained with the first proposed alternative treatment in
association with ezetimibe 10 mg.
Patients continuing to claim a tolerable myalgia (not causing therapy interruption) were then treated
with coenzyme 10 nanoemulsions 200 mg/day (Pharmextracta Srl, Pontenure, Italy). A simple
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graduated score of myalgia tolerability was administered at baseline and after 8 weeks of treatment
(1 = disappeared and 10 = strongly increased).
The data were sampled and encoded in a specific database, then statistically analyzed using SPSS
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standard statins and also with a minimal dose of Monacolin K (3 mg), treatment with another statin
21.0, version for Window (IBM, Chicago, USA). The data have been mainly reported as absolute
numbers and percentage. LDL-C was reported as mean ± standard deviation. Changes in LDL-C
were compared by ANOVA followed by Bonferroni correction. Percentages were compared by
Chi-square. A two-sided p<0.05 was considered significant.
3. Results
The main characteristics of the evaluated patients at the baseline are summarized in table 1.
Concomitant medication by patient subgroups have been listed in an appendix. Patients
experiencing statin-associated myalgia were mainly women (p<0.05). A large part of these patients
experienced myalgia with >3 statins assumed at different dosages. The cohort of patients also
included subjects at high or very high cardiovascular disease risk because of previous
cardiovascular events, type 2 diabetes or chronic kidney disease, for whom an intensive LDL-C
ezetimibe alone was associated with a mean LDL-C reduction of 17±2%, without significant
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differences among the considered subgroups (P>0.05).
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Patients previously intolerant to other lipid-lowering treatments than statins or previously
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experiencing other lipid-lowering treatment adverse event other than myalgia were treated more
often with nutraceuticals selectively acting on bowel cholesterol absorption (p<0.05 vs other
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treatments).
Rechallenge with rosuvastatin 5 mg 2 tablets/week was more frequently tried in patients with higher
cardiovascular risk or CKD (p<0.05 vs other treatments).
The mean effect of the different tested treatments was similar, beyond the one based on phytosterols
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and fibers, that was significantly lower (p<0.05) (Table 2).
The reached LDL-C values and the percentage of subjects that achieved the desired LDL-C target
with the different proposed treatments in association with ezetimibe 10 mg are shown in table 2.
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reduction was a compelling requirement. The treatment with standard lipid-lowering diet plus
About 50% of the patients treated with micronized fenofibrate 145 mg/day, rosuvastatin 5 mg 2
tablets/week, red yeast rice (Monacolin K 3 mg) + berberine 500 mg, and berberine 500 mg b.i.d.
associated to ezetimibe reached the LDL-C target foreseen for their class of cardiovascular disease
risk, while the percentage was much lower for those treated with rosuvastatin 5 mg once a week or
with phytosterols 900 mg + psyllium fiber 3.5 g b.i.d.
The percentage of subjects that accepted the proposed treatment and of those needed to change
treatment protocol because of myalgia reappraisal or the appearance of other adverse events than
myalgia are also reported in table 2.
Fenofibrate and rosuvastatin treated subjects did not experienced any further need to change
treatment because of adverse events other than myalgia. One subject treated with red yeast
rice+berberine (2%), two treated with berberine 500 mg b.i.d. (4%), and one treated with
phytosterols + psyllium (3%) experienced moderate to intense gastrointestinal discomfort causing
All the tested protocols were overall well tolerated. Eleven percent of the patients treated with
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fenofibrate required to change treatment because of myalgia reappraisal, while the percentage was
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negligible with the other tested treatments.
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In patients with residual tolerable myalgia (n = 52), the treatment with coenzyme Q10 for 8 weeks
was associated with a mean improvement of the graduated myalgia score from 4.8±1.9 to 2.9±1.3
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(p= 0.013), without significant difference among different lipid-lowering drug groups, with myalgia
disappearance in 18 of 52 subjects.
4. Discussion
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In a relatively large cohort of statin intolerant subjects, we have observed that the application of an
empirical protocol has led to a high rate of lipid-lowering therapy tolerability and acceptance and to
a relatively good control of cholesterolemia, often near to the LDL-C target suggested by
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treatment interruption.
guidelines25.
Overall, our data are in agreement with the available literature on the management of statinintolerant patients. In particular, a number of trials have clearly shown that the use of alternate-day
low-dose rosuvastatin administration is usually well tolerated and it mildly but significantly
improves cholesterolemia26,27. Theoretically, we could also have used atorvastatin 10 mg twice a
week28, but atorvastatin had already been used at low dosage or alternate day administration before
the patients were referred to our Lipid Clinic without positive effects in term of tolerability, in
agreement with what reported by other Lipid Clinic audits29,30. However, the LDL-C reduction
achieved with the tested approaches based on low-dosed statin is similar to the one obtained with
daily pravastatin in the MEGA trial, where a significant reduction in cardiovascular risk has been
achieved31. Full dosed red yeast rice has also shown to reduce cardiovascular disease risk, at least in
secondary prevention32, while a large amount of data have confirmed its efficacy and safety
profile33. The main concern about red yeast rice extracts is related to their degree of purification that
low doses of red yeast rice added to berberine is also well-tolerated in previously statin-intolerant
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patients35,36. Relatively off-label is the use of fenofibrate in order to manage hypercholesterolemia,
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but its moderate cholesterol lowering effect achieved by mechanisms different from that of statins is
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also clearly known37. The use of full dosed berberine has already been tested and described in a
recent meta-analysis, showing that berberine treatment alone reduced LDL-C levels as well as
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statins, and it additionally seemed to lower triglycerides levels and raise high-density lipoprotein
cholesterol levels better than statins did38. This could have a pharmacological background, since
berberine does not inhibit the 3-hydroxy-3-methyl-coenzyme A reductase, as statins do, while it
inhibits the proprotein convertase subtilisin/kexin type 9 (PCSK9) activity39. We are aware that the
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tested approaches could have quantitatively different lipid-lowering effects, but our aim was to
detect in clinical practice condition, which ones were the most tolerated rather than efficacious.
Obviously, long-term randomized clinical trials are needed to test whether these alternative ways to
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could be largely different among various formulation34. Other studies have proved that the use of
manage LDL-C are associated with an improvement in cardiovascular disease risk, in particular as
it regards the use of berberine and phytosterols that is not supported by direct evidence of a positive
effects on outcomes. However, the old results on cholestyramine 40 and fibrates41 and the recent
results derived from the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial
(IMPROVE-IT) trial with ezetimibe42 and the highly preliminary (and yet grossly underpowered)
ones from phase 3 long-term trials with PCSK9 inhibitors43,44 suggest that wherever cholesterol
levels are decreased there is a gain in terms of cardiovascular disease risk reduction. Moreover, the
literature shows that low adherence to statin therapy (and the consequent rise in LDL-C level) is
associated with an increase in the risk of developing cardiovascular disease45,46, so that any
tolerated and safe treatment protocol that is able to maintain an acceptable LDL-C level appears to
be better than no treatment at all.
Our findings on coenzyme Q10 administration and residual myalgia are partly in contrast with the
negative results reported in a meta-analysis of controlled trials47 and by a recent well-designed
other causes of myalgia were a priori excluded and with mild residual myalgia. Moreover, we used
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to improve drug bioavailability, and consequently its efficacy49.
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a high dosage of coenzyme Q10 administered as nanoemulsions, a delivery system that is supposed
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Our study has several limitations. First, it is a retrospective analysis and not a randomized clinical
trial. Consequently, the groups are numerically unbalanced limiting a deep statistical comparison.
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However, its main aim was to evaluate how the empirical approaches applied in clinical practice
were tolerated and how efficacious they were in a large cohort of patients with statin-associated
myalgia, with different baseline characteristics and history of drug intolerance. Second, the
treatments were not randomly assigned but based on the previous history of intolerance and with the
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will of the patients to try a different kind of proposed treatment. However, this is a picture of the
way these kind of patients are currently managed in a specialized Lipid Clinic. Third, the
psychological aspects of statin-intolerance have not been specifically and systematically
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randomized clinical trial48. However, our tests were carried out on strongly selected patients, where
investigated in our patients. Probably, some patients were lost to follow-up because they did not
tolerate the proposed treatment and therefore lost confidence in the lipid clinic team. However,
there is a similar possibility that other subjects had a good experience with the proposed treatment
and did not find necessary repeating the visit in the hospital setting. It was also difficult to
analytically report and compare the effects of different treatment protocols, when sequentially
modified because of reappraisal of myalgia. One more limitation is related to the lack of specific
data on compliance to therapy, since it was just derived from the patient reported data. Then,
contrarily to what reported in other surveys, we were not able to determine the risk factors for the
statin-intolerance incidence, because our patients were largely heterogeneous as regards age,
gender, medical history, and concomitant therapy and all data have been not prospectively and
systematically sampled, since it is a retrospective study. Finally, the data on coenzyme Q10 are
quite anedoctal and need larger confirmation: the high dose of a more available formulation has
been used in an empirical way, and it is not yet supported by the results a randomized clinical trial.
alternative to daily statin treatment in order to manage hypercholesterolemia, in the setting of
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everyday clinical practice in a large lipid clinic.
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5. Conclusions
We found that patients interrupting statin treatment because of myalgia are largely heterogeneous in
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term of their response to alternative treatments, but some low-dosed drugs or nutraceuticals seems
to be both effective and well tolerated, thus improving the ezetimibe effect on cholesterolemia.
Moreover, coenzyme Q10 nanoemulsions seem to increase the tolerability of residual myalgia.
Long-term randomized clinical trials are needed in order to evaluate the effects of these kinds of
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approach on cardiovascular disease events.
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To the best of our knowledge, this is a rare report on the efficacy and tolerability of therapies
Transparency
Declaration of funding:
The study was carried out with the support of institutional funding of the University of Bologna
(ex-RFO 2014).
Declaration of financial/other relationships:
The Authors and CMRO Peer Reviewers on this manuscript have no relevant financial relationships
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Author contributions:
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AC and SD planned the study, FF, MB and MR sampled and encoded the data, AC statistically
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analyzed data, AC and MM wrote the paper, MB revised the paper, CB coordinates the research
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team. All the authors read and revised the paper contributing to the data discussion.
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to disclose. .
27 (13/14)
4
45 (21/24)
4
38 (16/22)
3.5
57 (26/31)
3.5
N. of
subjects
previousl
y
experienc
ing
adverse
event
other
than
myalgia
N. of
smokers
N. of
patien
ts
with
3-5
stage
CKD
N. of
patient
s with
high/v
ery
high
CVD
risk
Mean
(SD)
LDL-C
after
ezetimi
be
treatm
ent
(mg/dL)
1/27
(3.7%)
3/45
(6.6%)
4/27(14.
8%)
5/45
(11.1%)
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Fenofibra
te 145 mg
Rosuvast
atin 5 mg,
1
tablet/we
ek
Rosuvast
atin 5 mg,
2
tablets/we
ek
RYR
(Monacol
in K 3
mg) +
berberine
500 mg
Berberine
500 mg
b.i.d.
Phytoster
ols 900
mg +
psyllium
fiber 3.5
g b.i.d.
N. of
subjects
previous
ly
intolera
nts to
lipidlowering
treatme
nts
other
than
statins
1/27
(3.7%)
2/45
(4.4%)
1/27
(3.7%)
3/45
(6.6%)
2/27
(7.4%)
5/45
(11.1%
)
145
(17)
149
(16)
2/38
(5.2%)
2/38
(5.2%)
5/38
(13.2%)
4/38
(10.4
%)
6/38
(15.6%
)
155
(19)
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Median
N. of
statin
treatme
nts
tested
before
referral
to the
lipid
clinic
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N. of
patients
(Men/Wom
en)
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First
prescribe
d
treatmen
t
3/57
(5.3%)
4/57
(7.0%)
7/57
(12.3%)
6/57
(10.6
%)
3/57
(5.3%)
142
(13)
53 (23/30)
4
3/53
(5.7%)
4/53
(7.5%)
6/53
(11.4%)
5/53
(9.4%)
3/53
(5.7%)
141
(14)
32 (15/17)
4.5
5/32
(15.6%)
4/32
(12.5%)
3/32
(9.4%)
4/32
(12.5
%)
3/32
(9.4%)
139
(12)
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Table 1 – Baseline characteristics of the considered patients with statin-associated myalgia by prescribed
treatment in addition to ezetimibe 10 mg.
CKD, chronic kidney disease; CVD, cardiovascular disease; LDL-C, low density lipoprotein-cholesterol; RYR, red yeast
rice; b.i.d., twice daily
Table 2 – Efficacy and tolerability of the firstly proposed treatments in association to ezetimibe 10 mg.
First prescribed
% of overall
% need to
% need to change
LDL-C
% of LDL
treatment
treatment
change
treatment because
reached
target
acceptability
treatment
of adverse events
(mg/dL)
reached
because of
other than myalgia
117 (13)
14/27
myalgia
Fenofibrate 145
22/27 (81%)
3/27 (11%)
0/27 (0%)
(52%)
41/45 (91%)
1/45 (2%)
0/45 (0%)
30/38 (79%)
2/38 (5%)
tablets/week
52/57 (91%)
K 3 mg) +
berberine 500 mg
mg b.i.d.
Phytosterols 900
50/53 (94%)
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Berberine 500
1/57 (2%)
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RYR (Monacolin
31/32 (97%)
0/38 (0%)
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mg, 2
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mg, 1 tablet/week
Rosuvastatin 5
135 (15)
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Rosuvastatin 5
0/53 (0%)
1/57 (2%)
139 (16)
13/45
(29%)
18/38
(47%)
114 (14)
33/57
(58%)
2/53 (4%)
116 (11)
27/53
(51%)
0/32 (0%)
1/32 (3%)
123 (13)
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mg
mg + psyllium
fiber 3.5 g b.i.d.
LDL-C, low density lipoprotein-cholesterol; LDL, low density lipoprotein; RYR, red yeast rice; b.i.d., twice daily
5/32
(16%)
Appendix Table 1 – Concomitant medication by study group
First prescribed treatment
Fenofibrate 145 mg (n = 27)
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RYR (Monacolin K 3 mg) + Berberine 500 mg (n = 57)
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Rosuvastatin 5 mg 2 tablets/week (n = 38)
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Berberine 500 mg b.i.d. (n = 53)
Phytosterols 900 mg + Psyllium fiber 3.5 g b.i.d. (n = 32)
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Rosuvastatin 5 mg 1 tablet/week (n = 45)
Concomitant medication
Beta-blockers: n=1
RAS-blockers: n=4
Calcium-antagonists: n=2
Diuretics: n=2
Anti-platelets: n=2
Oral antidiabetics: n=1
Other drugs: n=1
Beta-blockers: n=2
RAS-blockers: n=7
Calcium-antagonists: n=3
Diuretics: n=2
Anti-platelets: n=3
Oral antidiabetics: n=2
Other drugs: n=5
Beta-blockers: n=2
RAS-blockers: n=5
Calcium-antagonists: n=3
Diuretics: n=2
Anti-platelets: n=3
Oral antidiabetic: n=1
Other drugs: n=3
Beta-blockers: n=4
RAS-blockers: n=5
Calcium-antagonists: n=4
Diuretics: n=3
Anti-platelets: n=4
Oral antidiabetics: n=2
Other drugs: n=4
Beta-blockers: n=3
RAS-blockers: n=6
Calcium-antagonists: n=4
Diuretics: n=2
Anti-platelets: n=3
Oral antidiabetics: n=2
Other drugs: n=3
Beta-blockers: n=1
RAS-blockers: n=4
Calcium-antagonists: n=3
Diuretics: n=2
Anti-platelets: n=2
Oral antidiabetics: n=1
Other drugs: n=2
RAS-blockers, renin-angiotension system-blockers; RYR, red yeast rice; b.i.d., twice daily
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Figure legends:
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Figure 1 – Flow-chart resuming patient case report forms selection.