Therapeutic Low-Density Lipoprotein Cholesterol-Lowering in a Patient With Familial Hyperlipidemia Refractory to PCSK9 Monoclonal Antibody (Evolocumab)

Abstract

Patients with heterozygous familial hypercholesterolemia if untreated are at increased risk for atherosclerotic cardiovascular disease events by age 40 years. Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) is a demonstrated potent approach to low-density lipoprotein cholesterol (LDL-C)-lowering in this population. We describe a 67-year-old patient with heterozygous familial hypercholesterolemia who developed a paradoxical increase in LDL-C while on a PCSK9 monoclonal antibody but had a subsequent reduction in LDL-C when started on inclisiran, a PCSK9-directed oligonucleotide. The overall mechanism of monoclonal antibody refractoriness remains to be determined, but it indicates that PCSK9 as a target is still a viable option using a different mechanism.