Homozygous familial hypercholesterolemia (HoFH) is a rare and severe genetic disease, caused by loss-of-function pathogenic variants in both alleles of the low-density lipoprotein receptor (LDLR) gene, involved in the receptor-mediated LDL particles uptake. Pathogenic variants in the apolipoprotein B (ApoB) and the proprotein convertase subtilisin/kexin type 9 (PCSK9) genes are also causative of HoFH, but are less frequently found [1]. Variants in the gene encoding LDL receptor adaptor protein 1 (LDLRAP1) produce a very rare condition known as autosomal recessive hypercholesterolemia (ARH) with a similar phenotypic expression than HoFH. Current prevalence of HoFH has been estimated in approximately one case in 300,000 to 400,000 persons in the general population [2]; therefore, it is expected to have 120 to 160 cases with HoFH in Spain.

Clinically, patients with HoFH have severe hypercholesterolemia since birth, cutaneous xanthomas and very early-onset of aortic valve stenosis and atherosclerotic coronary artery disease (ASCVD) can occur in adolescence [1,3,4]. Therefore, these patients should be treated early and intensively with statins, ezetimibe, and PCSK9 inhibitors (PCSK9i) that have shown some efficacy in some HoFH patients depending on their genetic background [1,5,6]. Due to the difficulty to control LDL-C levels specially those patients carrying more severe pathogenic variants, most of them will require therapies that decrease LDL-C levels irrespective of residual LDL receptor function as lomitapide or evinacumab, both drugs with a mechanism of action independent of the activity of LDLR, and/or LDL-apheresis if available, and exceptionally, a liver transplant [1,[7], [8], [9], [10], [11]]. In the last year, different cohorts have been published showing the difficulties in the diagnosis and management of this disorder [[12], [13], [14]].

Previous report of HoFH patients included in the SAFEHEART (Spanish Familial Hypercholesterolemia Cohort Study) with a median follow-up of 6.9 years showed that most patients do not attain the LDL-C treatment goals with high intensity statins plus ezetimibe. In addition, few patients were under lipoprotein-apheresis [3]. Since then, more patients have been included in this registry, and the availability of PCSK9i and Lomitapide in Spain with the indication of HoFH has allowed that patients may be treated more intensively.

Our aim in this study was to describe the clinical and genetic characteristics, changes in lipid-lowering treatments (LLT), LDL-C goals attainment and ASCVD outcomes over a longer period of follow-up in a well-defined HoFH population with genetic diagnosis.