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

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.