Effect of PCSK9 inhibition with evolocumab on lipoprotein subfractions in familial dysbetalipoproteinemia (type III hyperlipidemia)

by Elisa Waldmann, Liya Wu, Kristina Busygina, Julia Altenhofer, Kerstin Henze, Alexander Folwaczny, Klaus G. Parhofer

Familial dysbetalipoproteinemia (FDBL) is a rare inborn lipid disorder characterized by the formation of abnormal triglyceride- and cholesterol-rich lipoproteins (remnant particles). Patients with FDBL have a high risk for atherosclerotic disease. The effect of PCSK9 inhibition on lipoproteins and its subfractions has not been evaluated in FDBL.

Three patients (65±7 years, 23±3 kg/m², 2 females) with FDBL (diagnosed by isoelectrofocusing) and atherosclerosis (coronary and/or cerebro-vascular and/or peripheral arterial disease) resistant or intolerant to statin and fibrate therapy received evolocumab (140mg every 14 days). In addition to a fasting lipid profile (preparative ultracentrifugation), apoB and cholesterol concentrations were determined in 15 lipoprotein-subfractions (density gradient ultracentrifugation; d 1.006–1.21g/ml) before and after 12 weeks of evolocumab treatment. Patients with LDL-hypercholesterolemia (n = 8, 56±8 years, 31±7 kg/m²) and mixed hyperlipidemia (n = 5, 68±12 years, 30±1 kg/m²) also receiving evolocumab for 12 weeks were used for comparison.

All patients tolerated PCSK9 inhibition well. PCSK9 inhibitors reduced cholesterol (29–37%), non-HDL-cholesterol (36–50%) and apoB (40–52%) in all patient groups including FDBL. In FDBL, PCSK9 inhibition reduced VLDL-cholesterol and the concentration of apoB containing lipoproteins throughout the whole density spectrum (VLDL, IDL, remnants, LDL). Lipoprotein(a) was decreased in all patient groups to a similar extent.

This indicates that the dominant fraction of apoB-containing lipoproteins is reduced with PCSK9 inhibition, i.e. LDL in hypercholesterolemia and mixed hyperlipidemia, and cholesterol-rich VLDL, remnants and LDL in FDBL. PCSK9 inhibition may be a treatment option in patients with FDBL resistant or intolerant to statin and/or fibrate therapy.