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.
Highlights
Statins are oral hypolipidaemic drugs and amongst the most widely prescribed medications worldwide [1]; in the United Kingdom (UK) alone, ~7 million patients take a statin [2]
Metabolism is responsible for the clearance of 70% of the top 200 used drugs [142], a subset of 12 of the 57 putatively functional cytochrome P450 (CYP) within the human CYP superfamily carry out 75% of drug biotransformations [143], and CYP3A metabolises the largest number of different drugs [142]
A robust separation in skeletal muscle differentially expressed genes was found that highlighted the roles of mitochondrial stress, cell senescence and apoptosis, localised activation of a pro-inflammatory immune response, and altered cell and calcium signalling mediated by protein prenylation and Ras-GTPase activation, in statin myalgia [69]
Summary
Statins are oral hypolipidaemic drugs and amongst the most widely prescribed medications worldwide [1]; in the United Kingdom (UK) alone, ~7 million patients take a statin [2]. Large meta-analyses of statin high-density lipoprotein-cholesterol (HDL-C) (~5%) to a modest extent [10]. Statins have been associated with a range of beneficial pleiotropic effects including anti-inflammatory, antioxidant and immunomodulatory effects, inhibition of effects including anti-inflammatory, antioxidant and immunomodulatory effects, inhibition of platelet platelet activation, regulation of pyroptosis, and increased plaque stability [12,13,14]. Can versus be sub-divided into: (i) those administered the FVT, inactive lactone those administered as active acid statinas(ATV, therapeutically inactive lactone (LVT, SVT). Versus those administered as active acid statin (ATV, PVT, PIT, RVT); (ii) those that undergo extensive metabolism by the phase I cytochrome P450 (CYP). FVT, LVT, SVT) versus those excreted predominantly unchanged
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