Atorvastatin-associated neurological adverse events: a disproportionality analysis with adjustment for confounding by...

Atorvastatin, a widely prescribed HMG-CoA reductase inhibitor, is associated with neurological adverse events (NAEs) beyond its well-known myopathy; however, comprehensive evaluations accounting for confounding by indication remain limited.

A disproportionality analysis was performed using the FDA Adverse Event Reporting System (FAERS) database (Q1 2004-Q3 2025) with three signal detection algorithms (PRR, BCPNN, and MGPS). Signal criteria were: PRR ≥ 2, χ² ≥ 4, EBGM₀₅ > 2, IC₀₂₅ > 0. To minimize confounding by indication, reports with indications for hypercholesterolemia or coronary artery disease (i.e., the approved label indications of atorvastatin) were excluded.

Of 50 NAE signals identified for atorvastatin, 32 remained significant after exclusion. The strongest signals clustered into three clinically meaningful categories: neuromuscular junction disorders (myasthenia gravis: PRR = 5.65, χ² = 748.22, EBGM₀₅ = 4.82), peripheral neuropathies (axonal neuropathy: PRR = 6.15, χ² = 117.78, EBGM₀₅ = 4.14; peripheral sensory neuropathy: PRR = 3.42, χ² = 182.34, EBGM₀₅ = 2.80), and central nervous system and cognitive disorders (encephalitis toxic: PRR = 7.76, χ² = 17.11, EBGM₀₅ = 2.39; brain fog: PRR = 2.94, χ² = 168.76, EBGM₀₅ = 2.46). Additionally, exceptionally strong signals without detailed published case support included acute necrotising myelitis (PRR = 832.92, EBGM₀₅ = 38.61), vibration syndrome (PRR = 37.02, EBGM₀₅ = 14.51), and radiculitis brachial (PRR = 26.03, EBGM₀₅ = 13.57).

This study identified multiple strong neurological safety signals associated with atorvastatin using a rigorous disproportionality analysis with adjustment for confounding by indication. These findings provide valuable real-world evidence to guide clinical monitoring and warrant further validation.