Sex differences in statin-associated adverse event reporting: a disproportionality analysis of 348,856 reports to the FDA Adverse Event Reporting System

Abstract

Statin-associated muscle symptoms are among the most common reasons for statin discontinuation, and women are widely believed to be more susceptible. Whether this belief reflects a genuine excess of muscle injury in women, or an excess of muscle symptoms, has not been established at scale. Case/non-case disproportionality analysis of the FDA Adverse Event Reporting System (FAERS) via the openFDA database. All reports listing an HMG-CoA reductase inhibitor with a recorded patient sex were included. Comparisons were made within the statin cohort, holding drug exposure constant so that only sex varied. Reporting odds ratios (RORs) for women versus men were calculated for pre-specified muscle, renal and cardiovascular outcomes, with Benjamini-Hochberg control of the false discovery rate. 348,856 statin reports were analysed (180,392 from women, 168,464 from men). A severity gradient was evident within a single organ system. Women disproportionately reported subjective muscle complaints: pain in extremity (ROR 1.49, 95% CI 1.43-1.55) and muscle spasms (1.36, 1.30-1.43). Men disproportionately reported objectively verifiable injury: rhabdomyolysis (0.58, 0.55-0.61), death (0.61, 0.58-0.64), myocardial infarction (0.63, 0.60-0.66) and acute kidney injury (0.86, 0.83-0.90). Myalgia (0.99, 0.95-1.03) and muscular weakness (1.02, 0.97-1.08), which lie between these poles, showed no sex difference. Within statin reports, women predominantly report muscle symptoms and men predominantly report muscle destruction. The assumption that women experience more statin muscle toxicity conflates these phenomena. If confirmed in cohort data, a man reporting statin-associated muscle pain may warrant a lower threshold for creatine kinase measurement than a woman with identical symptoms.