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

Abstract

Background and aims 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. Methods 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. Results 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. Conclusions 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.

Effect of evolocumab on fasting and post fat load lipids and lipoproteins in familial dysbetalipoproteinemia

“…A small observational non-randomized and unblinded study showed a reduction of 42% in fasting non-HDL-C and 44% in VLDL-C after PCSK9 mAbs for 12 weeks in 3 patients with FD. 29 This is line with our findings showing that PCSK9 mAbs are able to lower atherogenic lipids and lipoproteins in FD.…”

Imine Derivatives of Benzoxazole Attenuate High-Fat Diet-Induced Hyperlipidemia by Modulation of Lipid-Regulating Genes

“… 46 Therefore, PCSK9-inhibiting interventions are being employed to drastically reduce plasma LDL levels. 47 …”

“…PCSK9 acts as a catalyst and directs the endocytosis and lysosomal degradation of LDLR, hence decreasing LDLR recycling and its involvement in clearing plasma LDL . Therefore, PCSK9-inhibiting interventions are being employed to drastically reduce plasma LDL levels …”

Effect of PCSK9 inhibitors on remnant cholesterol and lipid residual risk: The LIPID‐REAL registry

“…Moreover, the effect of lipid ratios and TGGi was higher among patients who had cholesterol remnants above 30 mg/dl. A report of three patients with familial dysbetalipoproteinemia (type III hyperlipidemia), an uncommon form of mixed hyperlipidemia characterized by the accumulation of triglyceride‐ and cholesterol remnants, PCSK9 inhibition reduced VLDL‐cholesterol and the concentration of apoB containing lipoproteins throughout the whole density spectrum 31 ; interestingly, Lipoprotein(a) was decreased in all patient groups to a similar extent. Cholesterol remnants are not a recommended treatment target and no clinical trial has evaluated the outcomes related to their reduction but our results, at least, demonstrate an additional benefit of PCSK9 inhibitors.…”