Reducing cardiovascular risk in patients with familial hypercholesterolemia: Risk prediction and lipid management

Familial hypercholesterolemia (FH) is a frequent genetic disorder characterized by elevated low-density lipoprotein (LDL)-cholesterol (LDL-C) levels and early onset of atherosclerotic cardiovascular disease. FH is caused by mutations in genes that regulate LDL catabolism, mainly the LDL receptor (LDLR), apolipoprotein B (APOB) and gain of function of proprotein convertase subtilisin kexin type 9 (PCSK9). However, the phenotype may be encountered in individuals not carrying the latter monogenic defects, in approximately 20% of these effects of polygenes predominate, and in many individuals no molecular defects are encountered at all. These so-called FH phenocopy individuals have an elevated atherosclerotic cardiovascular disease risk in comparison with normolipidemic individuals but this risk is lower than in those with monogenic disease. Individuals with FH are exposed to elevated LDL-C levels since birth and this explains the high cardiovascular, mainly coronary heart disease, burden of these subjects. However, recent studies show that this risk is heterogenous and depends not only on high LDL-C levels but also on presence of previous cardiovascular disease, a monogenic cause, male sex, smoking, hypertension, diabetes, low HDL-cholesterol, obesity and elevated lipoprotein(a). This heterogeneity in risk can be captured by risk equations like one from the SAFEHEART cohort and by detection of subclinical coronary atherosclerosis. High dose high potency statins are the main stain for LDL-C lowering in FH, however, in most situations these medications are not powered enough to reduce cholesterol to adequate levels. Ezetimibe and PCSK9 inhibitors should also be used in order to better treat LDL-C in FH patients.