FAMILIAL HYPERCHOLESTEROLEMIA: ADVANCES IN MOLECULAR PATHOGENESIS, CLINICAL DIAGNOSIS, AND EMERGING LIPID-LOWERING THERAPIES

Abstract

Familial hypercholesterolemia (FH) is an autosomal dominant disorder of lipoprotein metabolism, primarily driven by pathogenic mutations in the LDLR, APOB, or PCSK9 genes, leading to severely elevated low-density lipoprotein cholesterol (LDL-C) from birth. The hallmark of FH is, accelerated atherosclerosis, culminating in premature coronary artery disease if untreated. While heterozygous FH (HeFH) affects approximately 1 in 200-250 individuals, the rarer homozygous form (HoFH) presents with more extreme lipid elevations and cardiovascular events in early childhood. This review examines the shift from traditional lipid-lowering therapies such as statins and ezetimibe, toward a new generation of biologics. These include monoclonal antibodies targeting PCSK9 (alirocumab, evolocumab), the small interfering RNA agent inclisiran, and the ANGPTL3 inhibitor evinacumab, the latter offering an LDL receptor-independent pathway. With the advent of these agents, a substantial proportion of FH patients can now achieve recommended LDL-C targets, ushering in an era of precision management for this once-formidable genetic condition.