Journal of Clinical Medicine Review Statins, Muscle Disease and Mitochondria Radha Ramachandran 1,2,* and Anthony S. Wierzbicki 1,3 1 Departments of Chemical Pathology/Metabolic Medicine, Guys and St Thomas’ Hospitals NHS Foundation Trust, London SE1 7EH, UK; [email protected] 2 Adult Inherited Metabolic Diseases, Centre for Inherited Metabolic Diseases, Evelina, Guys and St Thomas’ Hospitals NHS Foundation Trust, Lambeth Palace Road, London SE1 7EH, UK 3 King’s College, London SE1 7EH, UK * Correspondence: [email protected] Academic Editors: Iain P. Hargreaves and Jane Grant-Kels Received: 6 May 2017; Accepted: 12 July 2017; Published: 25 July 2017 Abstract: Cardiovascular disease (CVD) accounts for >17 million deaths globally every year, and this figure is predicted to rise to >23 million by 2030. Numerous studies have explored the relationship between cholesterol and CVD and there is now consensus that dyslipidaemia is a causal factor in the pathogenesis of atherosclerosis. Statins have become the cornerstone of the management of dyslipidaemia. Statins have proved to have a very good safety profile. The risk of adverse events is small compared to the benefits. Nevertheless, the potential risk of an adverse event occurring must be considered when prescribing and monitoring statin therapy to individual patients. Statin-associated muscle disease (SAMS) is by far the most studied and the most common reason for discontinuation of therapy. The reported incidence varies greatly, ranging between 5% and 29%. Milder disease is common and the more serious form, rhabdomyolysis is far rarer with an incidence of approximately 1 in 10,000. The pathophysiology of, and mechanisms leading to SAMS, are yet to be fully understood. Literature points towards statin-induced mitochondrial dysfunction as the most likely cause of SAMS. However, the exact processes leading to mitochondrial dysfunction are not yet fully understood. This paper details some of the different aetiological hypotheses put forward, focussing particularly on those related to mitochondrial dysfunction. Keywords: cardiovascular; statin; myopathy; muscle; mitochondria 1. Introduction Cardiovascular disease (CVD) accounts for >17 million deaths globally every year, and this figure is predicted to rise to >23 million by 2030 [1]. Numerous studies have explored the relationship between cholesterol and CVD and there is a consensus that low density lipoprotein cholesterol (LDL-C) is a causal factor in the pathogenesis of atherosclerosis [2,3]. The epidemiological studies underlying this concept have been aggregated and meta-analysed by the Emerging Risk Factors Collaboration [4]. These results provided the impetus for discovery of cholesterol lowering drugs starting with the use of high dose niacin and then proceeding through bile acid sequestrants, fibrates and eventually statins [5,6]. Statins have now become the cornerstone of the management of dyslipidaemia [7]. The first step in cholesterol synthesis involves formation of 2-Hydroxymethylglutaryl-coenzyme A (HMG-CoA) by condensation of acetyl CoA and aceto-acetylCoA; HMG-CoA is then converted to Mevalonate by the enzyme HMG-CoA reductase (Figure1). This is the rate-limiting step in cholesterol synthesis. HMG-CoA reductase was pursued as a viable target for cholesterol lowering drug development. This led to the development of HMG-CoA reductase inhibitors, known as “statins” [6]. Toxicity was limited as HMG-CoA, the immediate precursor before the block, is water soluble and can be metabolised via alternative metabolic pathways, thus preventing accumulation. Numerous J. Clin. Med. 2017, 6, 75; doi:10.3390/jcm6080075 www.mdpi.com/journal/jcm J. Clin. Med. 2017, 6, 75 2 of 13 J. Clin. Med. 2017, 6, 75 2 of 13 attemptsNumerous have attempts been made have tobeen inhibit made cholesterol to inhibit synthesis cholesterol at othersynthesis points at other but these points have but been these limited have eitherbeen limited by the knowledgeeither by the of inheritedknowledge errors of inherited of metabolism errors associatedof metabolism with associated defects at those with sitesdefects or byat toxicitythose sites of potentialor by toxicity drug of candidates, potential drug e.g., squalenecandidates, synthase e.g., squalene inhibition synthase [8]. inhibition [8]. Figure 1. Schematic representation of cholesterol and CoQ10 synthetic pathway. Dotted arrows are used where some of the intermediate products in the pathway have been omitted in the diagram. Site of Statin action is shown. Statin inhibits enzymes HMG CoA reductase which is written in bold italics. In September 1987, Lovastatin became the the first first statin to be given US Food and Drug Administration approval as a cholesterol lowering agent [[8].8]. Two further semi-syntheticsemi‐synthetic (pravastatin and simvastatin) and four synthetic statins (fluvastatin,(fluvastatin, pitavastatin, atorvastatin and rosuvastatin) of varying efficacyefficacy [[9]9] have been successfullysuccessfully introduced into the market since but cerivastatin was withdrawn duedue to to toxicity toxicity [10 ].[10]. 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Statins were initially received with some scepticism due to uncertainties regarding benefit and anxietiesStatins concerning were initially potential received adverse with effects some [ scepticism6]. These reservations due to uncertainties were dispelled regarding by the benefit results and of largeanxieties long-term concerning randomised potential controlled adverse trialseffects such [6]. as These the Scandinavian reservations were Simvastatin dispelled Survival by the Study results [12 of]. Thislarge studylong‐term provided randomised unequivocal controlled evidence trials for such reduction as the Scandinavian in all-cause mortalitySimvastatin (30%, Survivalp = 0.0003), Study coronary[12]. This arterystudy provided related deaths unequivocal (42%), major evidence coronary for reduction events (34%) in all‐ andcause revascularisation mortality (30%, proceduresp = 0.0003), (37%)coronary with artery statin related therapy. deaths The Heart (42%), Protection major coronary Study provided events (34%) further and evidence revascularisation for benefits procedures in women and(37%) in with patients statin with therapy. diabetes The and Heart previous Protection history Study of cerebrovascular provided further events evidence [13]. Moreover for benefits these in randomisedwomen and in controlled patients trialswith diabetes provided and reassurance previous thathistory there of wascerebrovascular no increase in events adverse [13]. effects Moreover such asthese cataracts, randomised previously controlled observed trials inprovided animal reassurance studies relating that tothere an earlierwas no cholesterol increase in loweringadverse effects drug candidatesuch as cataracts, triparanol previously [14], clinical observed liver diseasein animal [15 ]studies or cancer relating [16], althoughto an earlier some cholesterol concerns lowering continue todrug be raisedcandidate [17]. triparanol A later patient-based [14], clinical meta-analysis liver disease of [15] statin or trialscancer showed [16], although a 21% reduction some concerns in CVD eventscontinue and to anbe 11%raised[17]. reduction A later in CV patient mortality‐based for meta each‐analysis 1 mmol/LDL-C of statin trials reduction showed [18 a]. 21% Furthermore, reduction maintainingin CVD events a 2 and mmol/L an 11% reduction reduction in LDLin CV cholesterol mortality infor 10,000 each 1 patients mmol/LDL for 5‐C years reduction prevented [18]. approximatelyFurthermore, maintaining 1000 major a vascular 2 mmol/L events reduction in patients in LDL with cholesterol a high risk in 10,000 of coronary patients events for 5 [years7,18]. Hence,prevented with approximately good reason, statins1000 major are now vascular amongst events the in most patients widely with prescribed a high risk medications of coronary across events the globe.[7,18]. TheyHence, are with prescribed good reason, to roughly statins 30 millionare now people, amongst and the had most sales widely of $25 prescribed billion in 2005 medications [19]. acrossStatins the globe. have They proved are to prescribed have a very to roughly good safety 30 million profile people, [7,20]. Theand riskhad ofsales adverse of $25 events billion is in small 2005 compared[19]. to benefits. Nevertheless, the potential risk of an adverse event occurring must be considered whenStatins prescribing have proved and monitoring to have a very statin good therapy safety to profile individual [7,20]. patients. The risk Memory of adverse loss, events impairment is small ofcompared liver/kidney to benefits.