Apparent Nonresponse to PCSK9 Inhibition in a Patient With Heterozygous Familial Hypercholesterolemia Due to PCSK9...

Heterozygous familial hypercholesterolemia is a genetic disorder characterized by persistently elevated low-density lipoprotein (LDL-C) levels and increased cardiovascular risk. Management includes statins as well as nonstatin lipid-lowering agents, such as ezetimibe, bempedoic acid, and inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9). Although PCSK9 inhibition is a potent mechanism to reduce levels of LDL-C, a small percentage of patients respond poorly for reasons that are not fully understood.

A 52-year-old woman presented with persistently elevated LDL-C and a history of atherosclerotic cardiovascular disease. Her LDL-C levels remained elevated despite high-intensity statin therapy and ezetimibe. She was treated with various inhibitors of PCSK9 but displayed little or no reduction in LDL-C levels. Genetic testing identified a duplication of the PCSK9 gene. Treatment with a higher dose of evolocumab (420 mg every 2 weeks) led to a more pronounced reduction in LDL-C levels.

This case identifies PCSK9 gene duplication as a potential mechanism underlying nonresponse to PCSK9 inhibition and suggests that higher dosing of PCSK9 inhibitors may overcome nonresponse in some patients.