Plasma CAF22, a Biomarker of Neuromuscular Junction Integrity, is Associated with Risk and Earlier Onset of Statin-Associated Muscle Symptoms

Background Statin-associated muscle symptoms (SAMS) are a major limitation to effective lipid-lowering therapy. C-terminal agrin fragment 22 (CAF22) is a biomarker of neuromuscular junction degradation, but its role in predicting SAMS remains unclear. Methods In this prospective cohort study, 383 adults aged 40–60 years initiating statin therapy were followed for 12 months. Baseline plasma CAF22 was measured prior to statin initiation. Statin intolerance was defined as clinically significant muscle symptoms leading to dose modification, discontinuation, or switching. Logistic regression and Cox proportional hazards models were used to assess associations with the occurrence and timing of statin intolerance, respectively. Results Statin intolerance occurred in 17% of participants. Higher baseline CAF22 was associated with increased odds of statin intolerance (adjusted OR: 1.32, 95% CI: 1.08–1.61, p = 0.006) and earlier onset (adjusted HR: 1.38, 95% CI: 1.15–1.63, p < 0.001). The association was consistent across unadjusted and age- and sex-adjusted models. Higher handgrip strength was associated with reduced odds (OR 0.82, 95% CI 0.74–0.97, p = 0.018) and delayed onset (HR 0.80, 95% CI 0.66–0.95, p = 0.011) of intolerance. Diabetes mellitus was independently associated with both increased odds and earlier onset, while lipophilic and high-intensity statin use were associated with earlier intolerance. Other demographic and biochemical variables were not significant predictors. Conclusions Baseline CAF22 is independently associated with the risk and timing of statin intolerance. These findings support a role for neuromuscular junction integrity in SAMS and suggest that CAF22 may represent a potential biomarker of vulnerability.