Marc S. Sabatine, MD, MPH, Brigham and Women’s Hospital, Boston, Massachusetts, USA, presented data on the OSLER studies [Sabatine MS et al. N Engl J Med. 2015], 2 open-label, randomized extension studies of evolocumab phase 2 and phase 3 trials. OSLER showed that evolocumab, a proprotein convertase subtilisinkexin type 9 (PCSK9) inhibitor, effectively decreased low-density lipoprotein cholesterol (LDL-C) levels and reduced cardiovascular (CV) outcomes. The drug was well tolerated, with no gradient of adverse events (AEs) across all levels of minimum achieved LDL-C.

Available data on evolocumab, a fully human monoclonal antibody against PCSK9, demonstrate its ability to lower LDL-C by about 60% on top of statin therapy; additionally, the drug has been well tolerated by patients [Raal FJ et al. Lancet. 2015; Robinson JG et al. JAMA. 2014; Stein EA et al. Eur Heart J. 2014]. However, the effect of evolocumab on CV outcomes of patients was previously undefined.

Patients were randomized in a 2:1 ratio to receive evolocumab plus standard of care (n = 2976) or standard of care alone (n = 1489). Evolocumab was administered by subcutaneous injections of either 140 mg every 2 weeks or 420 mg once monthly. Median follow-up was 11.1 months (interquartile range, 11.0 to 12.8); the vast majority of patients (96%) completed follow-up and 7% discontinued evolocumab early. The primary end point was the incidence of AEs, and the secondary outcome was the percent change in LDL-C levels. A prespecified, exploratory analysis of adjudicated CV clinical outcomes was performed.

Baseline characteristics were similar between treatment arms. The average age was 58 years, 80% of patients had at least 1 CV risk factor, and 25% had known vascular disease. A majority (70%) of patients were receiving statins, mostly (62%) of high or moderate intensity.

Treatment with evolocumab resulted in a 61% reduction in LDL-C at 12 weeks (95% CI, 59% to 63%; P < .001) as compared to standard therapy. The absolute reduction in LDL-C was 73 mg/dL (95% CI, 71 to 76), with a median achieved LDL-C of 48 mg/dL. All lipid parameters were significantly affected, including decreased non-high-density lipoprotein cholesterol (HDL-C), apolipoprotein B, lipoprotein(a), and triglycerides, and increased HDL-C and apolipoprotein A1 (P < .001 for all).

Using a composite CV end point, including death, coronary events, cerebrovascular events, and heart failure requiring hospitalization, the Kaplan-Meier 1-year rates of CV events were 0.95% for patients receiving evolocumab and 2.18% for patients receiving standard of care alone (HR, 0.47; 95% CI, 0.28 to 0.78; P = .003). Separation of the Kaplan-Meier plots was evident after 2 to 3 months of follow-up.

This decrease in CV end points was consistent across all types of CV outcomes and was consistent across all patient subgroups with no heterogeneity of effect. Rates of AEs were balanced between treatment arms, except for neurocognitive AEs, which were higher in the evolocumab arm although they were low in both arms (< 1%). Notably, these events did not appear related to achieved LDL-C.

Further study on evolocumab is underway with the FOURIER trial, for which results are expected in 2017. Dr Sabatine concluded that in the interim, the OSLER data support the potential for PCSK9 inhibition with evolocumab to reduce the risk of CV outcomes through lowered LDL-C levels.