Introduction: Evolocumab (AMG 145), a fully human monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9), can reduce LDL-C to very low levels, particularly when administered with statins. We analyzed data from two recent 52-week studies of monthly evolocumab to assess the safety and tolerability of lowering LDL-C to<40 mg/dL.

Methods: We compared adverse events and lab abnormality rates in 1012 patients who ever achieved LDL-C <40 mg/dL (1005 [99.3%] treated with evolocumab) with 1187 patients who never achieved LDL-C <40 mg/dL (462 [38.9%] of whom were treated with evolocumab) in the DESCARTES and OSLER-1 studies. DESCARTES patients received background lipid regulating therapy based on NCEP risk and were then randomized 2:1 to blinded evolocumab 420 mg monthly or placebo. OSLER-1 randomized patients completing Phase 2 evolocumab studies to either standard of care (SoC) plus open-label evolocumab 420 mg administered monthly or SoC (followed-up quarterly) (2:1). Both studies evaluated patients over 52 weeks.

Results: Overall, patients who achieved very low (<40 mg/dL) as compared to higher (≥40 mg/dL) LDL-C levels had comparable rates of at least one AE: 77.8% vs 78.2% (Table). The occurrence of common AEs was balanced between very low and higher LDL-C groups. Analysis of laboratory abnormalities showed a higher rate of isolated elevated total bilirubin above 2x normal (0.9% vs 0.2%) in the very low vs higher LDL-C group, but less frequent elevation of transaminases above 3x normal in very low vs higher LDL-C treated patients (0.8% vs 1.9%). The overall event rates did not appear to be influenced by the use of intensive background statin therapy.

Conclusion: In two recent 52-week trials with evolocumab, patients who achieved very low LDL-C levels (<40 mg/dL) demonstrated comparable safety and tolerability vs patients with higher LDL-C levels (≥40 mg/dL) over one year of treatment.