EJINME-02778; No of Pages 1 European Journal of Internal Medicine xxx (2014) xxx

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Letter to the Editor Debate on adverse effects of statins Keywords: Statin Side effects Cardiovascular disease

Dear Editor, An interesting debate on statin side effects has been recently raised at the British Medical Journal (BMJ), when Abramson, a medical researcher in Cambridge, declared, in a published article, the breakdown of the strategy adopted by the National Institute for Health and Care Experience (NICE), which plans to extend the use of the cholesterol-lowering drugs for primary prevention in patients with a low risk of cardiovascular disease (CVD) [1]. According to the authors, the reanalysis of data from the Cholesterol Treatment Trialists' (CTT) Collaboration [2] did not register any significant reduction in mortality of statin-treated patients who, instead, experienced an 18% forced relinquishment of therapy because of intolerable side effects onset [3]. As reported by the epidemiologist Rory Collins, subsequently acknowledged and withdrew by the authors themselves, the indicated rate of side effects was mistaken, due to a misreading of an observational study by Zhang and colleagues [4]. An independent panel of experts has been proposed, through an Editorial, by Fiona Godlee, the BMJ Editor in Chief, to establish whether a retraction of the article is suitable to discontinue the controversy into the scientific community and the hesitations in public opinion [5]. The balance between risk/benefit in statin taking for primary prevention is actually an opened question. As previously reported [6] and discussed in our recent review, indeed, statins induce several side effects: the most important include liver toxicity, acute hepatic failure and episodes of myalgia, which can progress to rhabdomyolysis, a severe clinical condition characterized by rupture of muscle mass, myoglobinuria and acute renal failure. Adverse effects are commonly due to an excessive dosage of statins or drug interactions that reduce their metabolism [6,7] and are suggested to be partially overcome through coenzyme Q10 supplementation [8]. The uncertainty concerning the rate of side effects rises from the inability of randomized-clinical trials (RCT) to provide entirely unambiguous results. As Fiona Godlee claimed, the generalization to a larger population is complex and has to take into account several factors that can affect its success, including patient age, presence of co-morbidities, and potential drug interactions. This may explain, at least in part, the discrepancy between data on adverse events obtained from CTT and those from observational studies (9), which, according to the Food and Drug Administration (FDA), represent the “gold standard”

for detection. In our opinion, besides this concern, the most important issue regards the efficacy of statins as primary prevention tools for CVD. A recent update of a 2011 review (10) demonstrates that primary prevention with statins was cost-effective in reducing all-cause mortality, major vascular events and revascularizations (11), but this matter remains to be discussed and unanimously elucidated. A “medicalization” of life, without proven health benefits, would be something far away medical practice, especially if the alternative to maintain a state of good health could be an improvement in lifestyle. According to us, the professionalism of Fiona Godlee has been laudable, since the acceptance of a public debate has confirmed the independence of the journal and a “scientific spirit of open source” and created the chance for a constructive exchange of views on statin safety for an improvement of public health [6]. Conflict of interest I wish to confirm that there are no known conflict of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. References [1] NICE. Draft for consultation. Lipid modification. Cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. Clinical Guideline Appendices; February 2014. [2] Cholesterol Treatment Trialists' Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012;380:581–90. [3] Abramson JD, Rosenberg HG, Jewell N, Wright JM. Should people at low risk of cardiovascular disease take a statin? BMJ 2013;347:f6123. [4] Zhang H, Plutzky J, Skentzos S, Morrison F, Mar P, Shubina M, et al. Discontinuation of statins in routine care settings. Ann Intern Med 2013;158:526–34. [5] Godlee F. Adverse effects of statins. BMJ 2014;348:g3306. [6] Bifulco M. Re: adverse effects of statins. Rapid response to BMJ 2014;348:g3306 [published 25 May 2014, http://www.bmj.com/content/348/bmj.g3306/rr/699462]. [7] Gazzerro P, Proto MC, Gangemi G, Malfitano AM, Ciaglia E, Pisanti S, et al. Pharmacological actions of statins: a critical appraisal in the management of cancer. Pharmacol Rev 2012;64(1):102–46. [8] Golomb BA, Evans MA. Statin adverse effects: a review of the literature and evidence for a mitochondrial mechanism. Am J Cardiovasc Drugs 2008;8(6):373–418.

Maurizio Bifulco Presidente Facoltà di Farmacia e Medicina, Università di Salerno, 84084 Baronissi, Salerno, Italy Corresponding author. Tel.: +39 089 96 9742; fax: +39 089 96 9602. E-mail address: [email protected]. 30 July 2014 Available online xxxx

http://dx.doi.org/10.1016/j.ejim.2014.08.006 0953-6205/© 2014 Published by Elsevier B.V. on behalf of European Federation of Internal Medicine.

Please cite this article as: Bifulco M, Debate on adverse effects of statins, Eur J Intern Med (2014), http://dx.doi.org/10.1016/j.ejim.2014.08.006

Debate on adverse effects of statins.

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