Long-Term Evolocumab in Patients With Familial Hypercholesterolemia

Study Questions:

What are the long-term safety and efficacy data for evolocumab in patients with homozygous familial hypercholesterolemia (HoFH) and severe heterozygous FH (HeFH)?


This is an open-label, single-arm study, in which patients with HoFH or severe HeFH ≥12 years of age and on stable lipid-lowering therapy began subcutaneous evolocumab 420 mg monthly or 420 mg every 2 weeks if on lipoprotein apheresis. After 12 weeks, those not on apheresis could be up-titrated to 420 mg every 2 weeks. The primary endpoint was the incidence of treatment-emergent adverse events; secondary endpoints were changes in low-density lipoprotein cholesterol (LDL-C) and other lipids.


A total of 106 patients with HoFH (mean age 34 years including 14 <18 years of age at enrollment, 32% on LDL apheresis, mean LDL-C 330 mg/dl, 65% with atherosclerotic cardiovascular disease [ASCVD]) and 194 patients with HeFH (mean age 55 years, 14% on LDL apheresis, mean LDL-C 193 mg/dl, and 80% with ASCVD) received evolocumab for a median of 4.1 years. Adverse events occurred in 89.3% of patients, the most common of which were nasopharyngitis, influenza, upper respiratory tract infection, and headache. Mean change in LDL-C from baseline to week 12 was -21.2% (-59.8 mg/dl) in patients with HoFH and -54.9% (-104.4 mg/dl) in those with severe HeFH and was sustained over time. Of 48 patients with HoFH who were up-titrated, mean change in LDL-C improved from -19.6% at week 12 to -29.7% after 12 weeks of 420 mg every 2 weeks. The adjudicated cardiovascular event rate was 2.7% per year. Of 61 patients receiving apheresis at enrollment, 16 discontinued apheresis.


Evolocumab was well tolerated and effectively reduced plasma LDL-C levels in patients with HoFH and severe HeFH over a median of 4.1 years.


Once thought to be very rare, the worldwide prevalence of both HoFH and HeFH is much higher, ranging from 1 in 160,000-300,000 for HoFH and 1 in 12-250 for HeFH. Broader application of genetic testing has revealed greater phenotypic spectrum of FH, with lower LDL-C levels and lack of xanthomas in many. Of note, myalgias occurred in about 10% and creatine kinase >5x upper limit of normal in 5%, but only 2.7% withdrew from evolocumab. The 420 mg every 2 weeks is not approved in the United States. Clinical experience is that while the PCSK9 antibody class is very effective in HeFH, particularly with statins + ezetimide, the majority of HoFH patients require the very expensive lomitapide.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins

Keywords: Atherosclerosis, Cholesterol, LDL, Creatine Kinase, Dyslipidemias, Headache, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipoproteinemia Type II, Influenza, Human, Lipids, Myalgia, Nasopharyngitis, Primary Prevention, Proprotein Convertases, Xanthomatosis

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