05.05.2021 | ISSUE #15
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USE OF EVINACUMAB IN PATIENTS WITH REFRACTORY HYPERCHOLESTEROLEMIA
INTRODUCTION Heterozygous familial hypercholesterolemia, an autosomal dominant genetic disorder, can lead to elevated plasma LDL cholesterol level due to the mutation in the LDL receptor gene. Elevated low-density lipoprotein (LDL) cholesterol levels may expose patients at higher risk for atherosclerotic cardiovascular disease. According to a meta-analysis involving 11 million adults, the estimate prevalence of heterozygous familial hypercholesterolemia is 0.32% worldwide, and they are associated with 10, 20, and 23 times risk for atherosclerotic cardiovascular disease, premature atherosclerotic cardiovascular disease, and severe hypercholesterolemia, as compared to general population. Despite standard treatment with lipid-lowering therapies at maximum tolerated doses, including statin, ezetimibe, and a PCSK9 inhibitors, some patients with heterozygous familial hypercholesterolemia are unable achieve the target LDL cholesterol level due to high baseline LDL level, and adverse events with standard therapies, including statinassociated muscle symptoms. Angiopoietin-like 3 (ANGPLT3) has important role in regulating the lipid metabolism by inhibiting the lipoprotein lipase and endothelial lipase. In a recent Phase 2 proof-ofconcept study and Phase 3 ELIPSE HoFH tiral, evinacumab , a fully human monoclonal antibody against ANGPLT3, was shown to be effective in lowering the LDL cholesterol level.
METHODS
WHO -Dutch Lipid Clinic Network criteria with score of 8 point or higher.
In a double-blind, placebo-controlled, Phase 2 trials, patients were enrolled if they have refractory hypercholesterolemia with or without heterozygous familial hypercholesterolemia. Refractory hypercholesterolemia was defined as LDL cholesterol level ≥ 70mg per deciliter with clinical atherosclerosis or LDL cholesterol level ≥ 100 mg per deciliter without clinical atherosclerosis. Heterozygous familial hypercholesterolemia was diagnosed based on genotyping or clinical criteria according to Simon Broome criteria or
272 patients were randomly assigned to received subcutaneous evinacumab at dose of 450mg weekly (N=40), 300mg weekly (N=43), or 300mg every 2 weeks (N=39) or placebo (N=41); or IV evinacumab at dose of 15mg/kg every 4 week (N=39), 5mg/kg every 4 week (N=36), or placebo (N=34). The primary endpoint was the percentage change of LDL cholesterol level from baseline at Week 16 with subcutaneous or IV evinacumab as compared with placebo. (continued)
RESULTS
RESULTS
(CONT'D)
The difference in the least-squares mean change from baseline in the LDL with subcutaneous evinacumab at dose of 450mg weekly, 300mg weekly, or 300mg every 2 weeks and the placebo group were as following: -56%, -52.9%, and -38.5% (P<0.001). The least-squares mean difference from the baseline in the LDL with IV evinacumab at dose 15mg/kg and 5mg/kg and placebo group were as following: -50.5% and -24.2% (P<0.001)
CONCLUSION This study found that the use of evinacumab reduced the LDL cholesterol level and atherogenic lipoprotein in patients with refractory hypercholesterolemia. According to this study, the addition of evinacumab to standard lipid-lowering therapies may potentially benefit patients in achieving the guideline-defined target LDL level, and thereby reduce the risk of cardiovascular events and overall mortality rate.
CITATION All credit for the scientific information is held by the authors who worked in the creation of the scientific article!
https://www-nejm-org.libproxy.lib.unc.edu/doi/pdf/10.1056/NEJMoa2031049? articleTools=true Rosenson, R. S., Burgess, L. J., Ebenbichler, C. F., Baum, S. J., Stroes, E., Ali, S., Khilla, N., Hamlin, R., Pordy, R., Dong, Y., Son, V., & Gaudet, D. (2020). Evinacumab in Patients with Refractory Hypercholesterolemia. The New England Journal of Medicine , 383 (24), 2307–2319. https://doi.org/10.1056/NEJMoa2031049
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