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

Abstract

Statins are a cornerstone in the pharmacological prevention of cardiovascular disease. Although generally well tolerated, a small subset of patients experience statin-related myotoxicity (SRM). SRM is heterogeneous in presentation; phenotypes include the relatively more common myalgias, infrequent myopathies, and rare rhabdomyolysis. Very rarely, statins induce an anti-HMGCR positive immune-mediated necrotizing myopathy. Diagnosing SRM in clinical practice can be challenging, particularly for mild SRM that is frequently due to alternative aetiologies and the nocebo effect. Nevertheless, SRM can directly harm patients and lead to statin discontinuation/non-adherence, which increases the risk of cardiovascular events. Several factors increase systemic statin exposure and predispose to SRM, including advanced age, concomitant medications, and the nonsynonymous variant, rs4149056, in SLCO1B1, which encodes the hepatic sinusoidal transporter, OATP1B1. Increased exposure of skeletal muscle to statins increases the risk of mitochondrial dysfunction, calcium signalling disruption, reduced prenylation, atrogin-1 mediated atrophy and pro-apoptotic signalling. Rare variants in several metabolic myopathy genes including CACNA1S, CPT2, LPIN1, PYGM and RYR1 increase myopathy/rhabdomyolysis risk following statin exposure. The immune system is implicated in both conventional statin intolerance/myotoxicity via LILRB5 rs12975366, and a strong association exists between HLA-DRB1*11:01 and anti-HMGCR positive myopathy. Epigenetic factors (miR-499-5p, miR-145) have also been implicated in statin myotoxicity. SRM remains a challenge to the safe and effective use of statins, although consensus strategies to manage SRM have been proposed. Further research is required, including stringent phenotyping of mild SRM through N-of-1 trials coupled to systems pharmacology omics- approaches to identify novel risk factors and provide mechanistic insight.

Fatal Rhabdomyolysis in a COVID-19 Patient on Rosuvastatin

“…Although rhabdomyolysis is a reported event in patients on statin therapy, including rosuvastatin, this continues to be a very rare event, with an incidence of about 1.1/10,000 person-years [ 8 ]. It is generally believed that statin-induced myopathic toxicity is associated with mitochondrial dysfunction, calcium signaling disruption, and pro-apoptotic signaling [ 7 ]. Aging and concomitant infection will further predispose to rhabdomyolysis.…”

“…Myopathy is a known side effect of statin class medication [ 6 ]. Its mechanism is believed to be associated with mitochondrial dysfunction and calcium signaling disruption [ 7 ]. COVID-19 may have enhanced and exaggerated an otherwise non-fatal muscular pathology with statin use.…”

Considerations for Statin Therapy in Patients with COVID‐19

“…Rhabdomyolysis can cause acute kidney injury. 23 Myalgia, increased creatine phosphokinase, rhabdomyolysis, and acute kidney injury occur in patients with COVID-19 as well. 2 In addition, some risk factors such as advanced age and liver and kidney impairments are common between statininduced myopathies and infection with SARS-CoV-2.…”

Pathophysiological mechanisms of statin‐associated myopathies: possible role of the ubiquitin‐proteasome system

“…The mechanisms seem to be interdependent: an increased statin systemic exposure which increases skeletal muscle exposure leads to an intracellular skeletal myocyte susceptibility and perturbation of muscle function. 59 Studies suggest multiple hypotheses ( Table 1). First of all, structural abnormalities appeared in the biopsy of skeletal muscle of statins-treated patients, even in asymptomatic subjects.…”