Statin-associated Muscle Symptoms: Impact on Statin Therapy—European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management

Erik S. Stroes; Paul D. Thompson; Alberto Corsini; Georgirene D. Vladutiu; Frederick J. Raal; Kausik K. Ray; Michael Roden; Evan Stein; Lale Tokgözoğlu; Børge G. Nordestgaard; Eric Bruckert; Guy De Backer; Ronald M. Krauss; Ulrich Laufs; Raul D. Santos; Robert A. Hegele; G. Kees Hovingh; Lawrence A. Leiter; Francois Mach; Winfried März; Connie B. Newman; Olov Wiklund; Terry A. Jacobson; Alberico L. Catapano; M. John Chapman; Henry N. Ginsberg

Disclosures

Eur Heart J. 2015;36(17):1012-1022. 

In This Article

Overview of the Pathophysiology of Statin-induced Myopathy

Our understanding of the pathophysiology of SAMS and statin-induced myopathy remains elusive, although several mechanisms have been proposed (see Figure 3, Supplementary material online, Table S3 http://eurheartj.oxfordjournals.org/content/suppl/2015/02/18/ehv043.DC1).[79] Interest has focused primarily on altered cellular energy utilization and mitochondrial function (Figure 4, Box 4).[80–95] Abnormal mitochondrial function with depletion of CoQ10 have been reported during statin therapy, even in asymptomatic statin users. Some argue that this may be unmasking previously undiagnosed mitochondrial pathology (see Supplementary material online, Table S4 http://eurheartj.oxfordjournals.org/content/suppl/2015/02/18/ehv043.DC1).[96] Notably, insulin-resistant obese individuals, or those with a family history of, or with overt type 2 diabetes, frequently exhibit reduction in both muscle ATP turnover and oxidative capacity.[97,98] The effects of statins on muscle mitochondria have been detected by various methods ranging from morphometry to in vivo magnetic response spectroscopy, all of which test different features of mitochondrial function.[96]

Figure 3.

Effects potentially involved in statin-related muscle injury/symptoms (Reproduced with permission from Needham and Mastaglia 2014).79 A number of statin-mediated effects have been proposed including reduced levels of non-cholesterol end-products of the mevalonate pathway; reduced sarcolemmal and/or sarcoplasmic reticular cholesterol; increased myocellular fat and/or sterols; inhibition of production of prenylated proteins or guanosine triphosphate (GTP)ases; alterations in muscle protein catabolism; decreased myocellular creatine; changes in calcium homeostasis; immune-mediated effects of statins and effects on mitochondrial function—see Figure 4 and Box 4. Ca2+ATPase, calcium ATPase; HMG CoA, 3-hydroxy-3-methyl-glutaryl-CoA; PP, pyrophosphate.

Figure 4.

Possible targets of statins in the mitochondrion with deleterious effects on muscle function. The interaction of statins with muscle mitochondria can involve (i) reduced production of prenylated proteins including the mitochondrial electron transport chain (ETC) protein, ubiquinone (coenzyme Q10), (ii) subnormal levels of farnesyl pyrophosphate and geranylgeranyl pyrophosphate leading to impaired cell growth and autophagy, (iii) low membrane cholesterol content affecting membrane fluidity and ion channels, and (iv) the triggered calcium release from the sarcoplasmic reticulum via ryanodine receptors, resulting in impaired calcium signalling.92–94 Statin-induced depletion of myocellular ubiquinone, an essential coenzyme which participates in electron transport during oxidative phosphorylation,95 may attenuate electron transfer between complexes I, III, and II of ETC. ADP, adenosine diphosphate; ATP, adenosine triphosphate; Cyt C, cytochrome C; FAD, flavin adenine dinucleotide; FADH2, flavin adenine dinucleotide reduced; MPT, mitochondrial permeability transition; MtDNA, mitochondrial DNA; NAD, nicotinamide adenine dinucleotide; NADH, nicotinamide adenine dinucleotide; ROS, reactive oxidative species; TCA cycle, tricarboxylic acid cycle.

Based on these observations, it is likely that statins decrease mitochondrial function, attenuate energy production, and alter muscle protein degradation, each of which may contribute to the onset of muscle symptoms.[99] However, progress has been hampered by the fact that myopathy has been difficult to induce with statin treatment in preclinical models.[100–103] Only recently, mice with genetically induced deficiency of lipin-1, a phosphatidic acid phosphatase, were shown to develop myopathy/myositis that was associated with impaired autophagy and the presence of abnormal mitochondria.[104] In this model, myopathy/myositis could be aggravated by co-administration of statins, whereas both lipin-1 deficiency and statins were found to attenuate autolysosome maturation.

In patients, persistent myopathy has been suggested to reflect structural muscle damage.[81] Muscle biopsy studies in a limited number of patients with SAMS and normal CK levels suggested a role for abnormal mitochondrial function.[80,81] Conversely, other studies in patients with statin-induced SAMS with CK elevations were unable to demonstrate structural abnormalities in muscle cells.[82] Although rare, it has also been suggested that statins may trigger idiopathic inflammatory myositis or immune-mediated necrotizing myopathy. Thus, statins increase the risk for development of anti-HMG-CoA-reductase antibodies, dependent upon statin exposure, male gender, diabetes, and genetic background.[35,105] Overall, notwithstanding promising preclinical data, it is still not clear what the underlying pathophysiological mechanism(s) is in patients with SAMS.

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