Patients experiencing statin-induced myalgia exhibit a unique program of skeletal muscle gene expression following statin re-challenge

Abstract

Statins, the 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitors, are widely prescribed for treatment of hypercholesterolemia. Although statins are generally well tolerated, up to ten percent of statin-treated patients experience myalgia symptoms, defined as muscle pain without elevated creatinine phosphokinase (CPK) levels. Myalgia is the most frequent reason for discontinuation of statin therapy. The mechanisms underlying statin myalgia are not clearly understood. To elucidate changes in gene expression associated with statin myalgia, we compared profiles of gene expression in skeletal muscle biopsies from patients with statin myalgia who were undergoing statin re-challenge (cases) versus those of statin-tolerant controls. A robust separation of case and control cohorts was revealed by Principal Component Analysis of differentially expressed genes (DEGs). To identify putative gene expression and metabolic pathways that may be perturbed in skeletal muscles of patients with statin myalgia, we subjected DEGs to Ingenuity Pathways (IPA) and DAVID (Database for Annotation, Visualization and Integrated Discovery) analyses. The most prominent pathways altered by statins included cellular stress, apoptosis, cell senescence and DNA repair (TP53, BARD1, Mre11 and RAD51); activation of pro-inflammatory immune response (CXCL12, CST5, POU2F1); protein catabolism, cholesterol biosynthesis, protein prenylation and RAS-GTPase activation (FDFT1, LSS, TP53, UBD, ATF2, H-ras). Based on these data we tentatively conclude that persistent myalgia in response to statins may emanate from cellular stress underpinned by mechanisms of post-inflammatory repair and regeneration. We also posit that this subset of individuals is genetically predisposed to eliciting altered statin metabolism and/or increased end-organ susceptibility that lead to a range of statin-induced myopathies. This mechanistic scenario is further bolstered by the discovery that a number of single nucleotide polymorphisms (e.g., SLCO1B1, SLCO2B1 and RYR2) associated with statin myalgia and myositis were observed with increased frequency among patients with statin myalgia.

Statin-Related Myotoxicity: A Comprehensive Review of Pharmacokinetic, Pharmacogenomic and Muscle Components

“…This association between SVT myopathy and rs4149056 has been replicated [89,174] and confirmed in recent large meta-analyses [110,116]. Furthermore, rs4149056 has also been linked to milder adverse outcomes encompassing myalgia, prescription reductions and/or minor biochemical (e.g., CK) elevations indicative of SVT intolerance [69,85,113,175].…”

“…SRM constitutes the most commonly reported statin adverse event, comprising approximately two-thirds of all adverse events [68]. The most common muscular symptoms are pain, heaviness, stiffness and cramps with or without subjective weakness [58,69]. Symptoms involving leg muscles (thighs, calves) are most frequent, although back, neck, shoulder and generalised muscular symptoms have also been described [58,69].…”

“…SRM is most common during the first year of treatment [70] with a median time to onset of one month [51]; over 80% of patients report not experiencing similar symptoms before statin treatment [58]. The muscular symptoms in the majority of SRM cases (~70-80%) are sufficiently intense to disrupt everyday activities [58,69]; this includes statin persistence and so, can present as MACE. The rarer severe myopathies and rhabdomyolysis can directly lead to hospitalisation.…”

Suggested clinical approach for the diagnosis and management of ‘statin intolerance’ with an emphasis on muscle‐related side‐effects

“…Distinct molecular changes have been shown in patients with statin‐induced myalgia undergoing statin re‐challenge, such as mitochondrial stress, cell senescence and apoptosis, supporting a genetic susceptibility, although there are no routine tests . Furthermore, there is a rare autoimmune response to statins (antibodies develop to HMG‐CoA reductase): ‘statin‐induced necrotising autoimmune myopathy’ (see below), which we have also observed (including without large CK rises) in non‐statin‐exposed individuals. CK rises may be asymptomatic and muscle symptoms can occur without CK elevations .…”

“…In select cases, it is also important to identify autoantibodies to HMG‐CoA reductase as a cause of severe myositis and statin intolerance. Some patients may have necrotising autoimmune myositis, a recently identified rare (16 in 10 000 000 people) condition, necessitating specific specialist management, involving immunosuppression . Predisposing risk factors for statin‐induced myopathy and myositis, such as autoimmune conditions affecting muscle, carnitine palmitoyl transferase II (CPT‐II) deficiency, severe vitamin D deficiency and other causes of myopathy or CK elevations not due to lipid drugs need to be considered (Table ) …”