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. Submit your article to this journal
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Date: 26 May 2016, At: 08:47
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
S. Orsola-Malpighi University Hospital, Lipid Clinic, Bologna, Italy
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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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Rosticci, Claudio Borghi
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
myalgia, previous failed treatment with at least two low-dosed statins, well-tolerated treatment with 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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Bologna. For this study, we selected 252 CRFs based on the following criteria: statin-related
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
with or without CK elevation, occurs in approximately 5 to 15% of the participants in observational 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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kinase (CK) levels (> 10 times above normal levels) are quite rare6,7. mild to moderate myalgia,
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
stabilization.
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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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evaluate if supplementation with coenzyme Q10 can improve residual myalgia after therapy
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)
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Known organic myopathies or rheumatic diseases
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Severe vitamin D deficiency
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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.
European Guidelines for dyslipidemia management25 and their LDL-C targets attributed
