Key result
Alirocumab plus ezetimibe yields ~57% maximal LDL-C reduction, outperforming alirocumab alone.
Why the study?
Does alirocumab 150 mg every 4 weeks added to ezetimibe or fenofibrate improve LDL-C reduction compared to alirocumab plus placebo in subjects with LDL-C >130 mg/dL?
RCT (n=72)
Does alirocumab 150 mg every 4 weeks added to ezetimibe or fenofibrate improve LDL-C reduction compared to alirocumab plus placebo in subjects with LDL-C >130 mg/dL?
Absolute Event Rate: 56.6% vs 47.4%
Alirocumab 150 mg every 4 weeks produces significant LDL-C reductions when combined with ezetimibe or fenofibrate, and the modest increase in PCSK9 levels and alirocumab clearance caused by these oral therapies does not preclude their concomitant use.
Supports concomitant alirocumab use with ezetimibe or fenofibrate; extends evidence for flexible combination LDL-C lowering in hypercholesterolemia.
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. CLINICAL TRIAL REGISTRATION: URL: http://www.Clinicaltrials.gov. Unique identifier: NCT01723735.
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Rey et al. (2016) conducted an RCT in Elevated LDL-C (n=72). Alirocumab plus ezetimibe or fenofibrate vs. Alirocumab plus placebo was evaluated on Maximal mean LDL-C reduction at day 71. Alirocumab 150 mg every 4 weeks produced maximal LDL-C reductions of 47.4% with placebo, 56.6% with ezetimibe, and 54.3% with fenofibrate at day 71.
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