Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management

Abstract

Statin-associated muscle symptoms (SAMS) are one of the principal reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. This European Atherosclerosis Society (EAS) Consensus Panel overviews current understanding of the pathophysiology of statin-associated myopathy, and provides guidance for diagnosis and management of SAMS. Statin-associated myopathy, with significant elevation of serum creatine kinase (CK), is a rare but serious side effect of statins, affecting 1 per 1000 to 1 per 10 000 people on standard statin doses. Statin-associated muscle symptoms cover a broader range of clinical presentations, usually with normal or minimally elevated CK levels, with a prevalence of 7-29% in registries and observational studies. Preclinical studies show that statins decrease mitochondrial function, attenuate energy production, and alter muscle protein degradation, thereby providing a potential link between statins and muscle symptoms; controlled mechanistic and genetic studies in humans are necessary to further understanding. The Panel proposes to identify SAMS by symptoms typical of statin myalgia (i.e. muscle pain or aching) and their temporal association with discontinuation and response to repetitive statin re-challenge. In people with SAMS, the Panel recommends the use of a maximally tolerated statin dose combined with non-statin lipid-lowering therapies to attain recommended low-density lipoprotein cholesterol targets. The Panel recommends a structured work-up to identify individuals with clinically relevant SAMS generally to at least three different statins, so that they can be offered therapeutic regimens to satisfactorily address their cardiovascular risk. Further research into the underlying pathophysiological mechanisms may offer future therapeutic potential.

Keywords: Cholesterol; Consensus statement; Lipids; Mitochondrial; Muscle symptoms; Myalgia; Myopathy; Statin; Statin intolerance.

Figure 1

Trends in statin use (upper panel) and statin non-adherence/discontinuation (lower panel) in adults ≥40 years, in Denmark over the period 1995–2010. Statin use from 1 January 1995 to 31 December 2010 was classified according to the Anatomical Therapeutic Classification of Drugs code C10AA, as registered in the national Danish Registry of Medicinal Products Statistics, recording information on all prescribed drugs dispensed at all Danish pharmacies from 1995 onwards (for details see references^,). The percentage of the Danish population aged ≥40 years on statins increased from <1% in 1995 to 11% in 2010. Correspondingly, non-adherence or discontinuation (defined as the percentage of patients starting statins who only redeemed one prescription) increased from 2% in 1995 to 13% in 2010. Figure designed by Dr Sune F. Nielsen and Prof Børge G. Nordestgaard.

Figure 2

Therapeutic flow-chart for management of patients with statin-associated muscle symptoms.

Figure 3

Effects potentially involved in statin-related muscle injury/symptoms (Reproduced with permission from Needham and Mastaglia 2014). 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.^– Statin-induced depletion of myocellular ubiquinone, an essential coenzyme which participates in electron transport during oxidative phosphorylation, 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.