What are the mechanisms behind statin (HMG-CoA reductase inhibitors)-induced myopathy or myalgia?

From the Guidelines

Statin-induced myopathy or myalgia is primarily caused by the inhibition of coenzyme Q10 production, disruption of muscle cell membranes, and immune-mediated inflammatory responses, with genetic factors and high doses of statins increasing the risk of these side effects. The mechanisms behind statin-induced myopathy or myalgia are complex and multifactorial. According to the 2022 ACC expert consensus decision pathway 1, statin-associated muscle symptoms (SAMS) may occur in 5% to 20% of patients, and true complete statin intolerance is uncommon. The primary mechanism involves statins inhibiting the production of coenzyme Q10 (CoQ10), an essential component for mitochondrial energy production in muscle cells, leading to mitochondrial dysfunction and reduced energy availability. Statins also disrupt muscle cell membranes by reducing cholesterol content, affecting membrane stability and function. Additionally, they can trigger an immune-mediated inflammatory response in some individuals, causing muscle inflammation. Genetic factors play a role too, with variations in genes like SLCO1B1 affecting statin metabolism and increasing risk of muscle symptoms.

Some key points to consider in the management of SAMS include:

• A thorough assessment of symptoms is recommended, in addition to evaluation for nonstatin etiologies, assessment of predisposing factors, and a physical exam 1
• Objective muscle weakness (myopathy) and associated significant increase in CK (myositis) are rare but require prompt statin cessation and evaluation for reversible causes 1
• Rhabdomyolysis (CK >10 times upper limit of normal, with evidence of renal injury) is exceedingly rare and usually encountered in the setting of a patient with several predisposing comorbidities and concomitant high-risk medications 1
• Management options include dose reduction, switching to a different statin (pravastatin and fluvastatin typically cause fewer muscle issues), or adding CoQ10 supplements (typically 100-200 mg daily) 1
• For severe cases, temporary discontinuation followed by rechallenge at a lower dose or alternative dosing regimen (e.g., every other day) may help 1

It is essential to note that nonstatin therapies are not considered to be an alternative to evidence-based statin therapy unless SASEs have been systematically and rigorously evaluated and documented 1. In patients with clinical ASCVD and possible SASEs who have failed at least 2 (and preferably 3) statins, including a trial of 1 attempt at the lowest approved dose or using alternative statin dosing, or who still have not achieved adequate reduction in LDL-C or non–HDL-C on maximally tolerated statin therapy, a trial of ezetimibe or a PCSK9 mAb may be considered as first-line nonstatin therapy 1.

From the FDA Drug Label

The major biotransformation pathways for pravastatin are: (a) isomerization to 6-epi pravastatin and the 3α-hydroxy isomer of pravastatin (SQ 31,906) and (b) enzymatic ring hydroxylation to SQ 31,945. Pitavastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, a rate-limiting step in the biosynthetic pathway for cholesterol.

The mechanisms behind statin (HMG-CoA reductase inhibitors)-induced myopathy or myalgia are not directly explained in the provided drug labels. However, the labels do mention that advanced age (≥65 years) and renal impairment are risk factors for myopathy and rhabdomyolysis.

• Risk factors for myopathy include:
  • Advanced age (≥65 years)
  • Renal impairment
• The labels also describe the pharmacokinetics and mechanism of action of the statins, but do not provide a direct explanation for the mechanisms behind statin-induced myopathy or myalgia 2 3.

From the Research

Mechanisms of Statin-Induced Myopathy

The mechanisms behind statin-induced myopathy or myalgia are complex and multifactorial. Some possible mechanisms include:

• Depletion of isoprenoids and interference with intracellular calcium signaling 4
• Mitochondrial dysfunction, which can lead to reduced ATP production, increased ROS production, and induction of apoptosis 5
• Impairment of the Akt/mTOR pathway, leading to increased skeletal muscle protein degradation, impaired protein synthesis, and stimulation of apoptosis 5
• Inhibition of coenzyme Q10 (CoQ10) production, which can contribute to muscle symptoms 6, 7

Risk Factors for Statin-Induced Myopathy

Certain patient and drug characteristics can increase the risk of statin-induced myopathy, including:

• Higher statin doses 4
• Statin cytochrome metabolism 4
• Polypharmacy 4
• Genetic risk factors, such as a single nucleotide polymorphism of SLCO1B1 4

Management of Statin-Induced Myopathy

Management of statin-induced myopathy can include:

• CoQ10 supplementation, which has been shown to ameliorate statin-associated muscle symptoms 6, 7
• Reduction of statin dose or use of alternate-day dosing 4
• Use of twice-weekly dosing with longer half-life statins 4
• Exchange of statin, which may be beneficial in some cases 8