Homozygous familial hypercholesterolemia and its treatment by inclisiran

ABSTRACT Introduction Homozygous familial hypercholesterolemia (hoFH), a genetic disorder characterized by markedly impaired hepatic clearance of LDL and LDL cholesterol concentration exceeding 12 mmol/L, causes coronary artery and aortic valve disease before adulthood. The hoFH phenotype is mostly due to bi-allelic mutations in the LDL receptor gene. Areas covered HoFH as a clinical phenotype has distinct genetic causes which may affect response to treatment. The role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in lipoprotein metabolism and other physiologic processes including inflammation and sepsis. Strategies that may lower plasma PCSK9 activity so that uptake of plasma LDL into the liver is improved. Inclisiran, a synthetic oligonucleotide, specifically targets the liver to limit production of PCSK9. Adverse effects due to oligonucleotides in general and specific to low PCSK9 concentration are considered. Expert opinion HoFH requires expert diagnostic work-up for best management and prediction of response to treatment, including inclisiran. Though most hoFH patients will not reach the ideal LDL cholesterol concentration target by adding agents that lower PCSK9 activity to treatment with statins and ezetimibe, additional benefit is expected. Some patients may not respond. The safety to date appears good but patients with hoFH require treatment from childhood and long-term safety remains to be established.