Relationship between low-density lipoprotein cholesterol,free proprotein convertase subtilisin/kexin type 9,and alirocumab levels after different lipid-lowering strategies

Background-alirocumab undergoes target-mediated clearance via binding of proprotein convertase subtilisin/kexin type 9 (pcsk9). statins increase pcsk9 levels; the effects of nonstatin lipid-lowering therapies are unclear. every-4-weeks dosing of alirocumab may be appropriate for some patients in absence of background statin but is not yet approved. methods and results-low-density lipoprotein cholesterol (ldl-c),pcsk9,and alirocumab levels were assessed in subjects (ldl-c > 130 mg/dl,n=24/group) after a 4-week run-in taking oral ezetimibe,fenofibrate,or ezetimibe placebo,when alirocumab 150 mg every 4 weeks (days 1,29,and 57) was added. maximal mean ldl-c reductions from day -1 baseline (prealirocumab) occurred on day 71 in all groups: alirocumab plus placebo,47.4%; alirocumab plus ezetimibe,56.6%; and alirocumab plus fenofibrate,54.3%. ldl-c reductions were sustained through day 85 with alirocumab plus placebo (47.0%); the duration of effect was slightly diminished at day 85 versus day 71 with ezetimibe (49.6%) or fenofibrate combinations (43.2%). free pcsk9 concentrations were lowest at day 71 in all groups,then increased over time; by day 85,free pcsk9 concentrations were higher,and alirocumab levels lower,with alirocumab plus fenofibrate,and to a lesser extent alirocumab plus ezetimibe,versus alirocumab plus placebo. conclusions-alirocumab 150 mg every 4 weeks produced maximal ldl-c reductions of 47% in combination with placebo and 54% to 57% in combination with ezetimibe or fenofibrate. the oral lipid-lowering therapies appear to increase pcsk9 levels,leading to increased alirocumab clearance. although the duration of effect was modestly diminished with alirocumab plus ezetimibe/fenofibrate versus placebo,the effect was less than observed in trials with background statins,and it would not preclude the use of alirocumab every 4 weeks in patients taking these nonstatin lipid-lowering therapies concomitantly. © 2016 the authors.