New algorithms for treating homozygous familial hypercholesterolemia

Abstract

Purpose of reviewWe reviewed current and future therapeutic options for patients with homozygous familial hypercholesterolemia (HoFH) and place this evidence in context of an adaptable treatment algorithm. Recent findingsLowering LDL-C levels to normal in patients with HoFH is challenging, but a combination of multiple lipidlowering therapies (LLT) is key. Patients with (near) absence of LDL receptor expression are most severely affected and frequently require regular lipoprotein apheresis on top of combined pharmacologic LLT. Therapies acting independently of the LDL receptor pathway, such as lomitapide and evinacumab, are considered game changers for many patients with HoFH, and may reduce the need for lipoprotein apheresis in future. Liver transplantation is to be considered a treatment option of last resort. Headway is being made in gene therapy strategies, either aiming to permanently replace or knock out key lipid-related genes, with first translational steps into humans being made. Cardiovascular disease risk management beyond LDL-C, such as residual Lp(a) or inflammatory risk, should be evaluated and addressed accordingly in HoFH.

Genetic Heterogeneity of Familial Hypercholesterolemia: Repercussions for Molecular Diagnosis

“…Since in case of biallelic pathogenic variants in the LDLR gene, only a very low residual activity of the LDLR is present, novel and effective therapies for HoFH are independent of the LDLR activity. These therapies include lomitapide for the inhibition of microsomal triglyceride transfer protein (MTTP), leading to a decreased production of VLDLs by the liver [ 37 , 38 ] or monoclonal antibodies for the inhibition of the Angiopoietin-Like Protein 3 (ANGPTL3), which was proved to increase IDL and LDL clearance by LDLR independent pathways [ 39 ]. Bempedoic acid is another drug acting independently of LDLR used in HeFH patients; it is an inhibitor of the ATP citrate lyase, the enzyme transforming citrate into acetyl-CoA molecules used for fatty acid synthesis [ 40 ].…”

Atherogenic Dyslipidemias: Unmet Needs and the Therapeutic Potential of Emerging and Novel Approaches and Drugs

“…In fact, these patients had to undergo, on top of SCLT, LDL-apheresis weekly or every other week or, as a last resource, liver transplantation [ 45 ]. These therapies are still valid options for contexts where the innovative PCSK-9 inhibitors, lomitapide and/or evinacumab, are not available or cannot be afforded [ 49 ].…”

Current Treatment Options in Homozygous Familial Hypercholesterolemia

“…The treatment algorithm and its goals in patients with HoFH should be handled like other patients with high or very high risk [ 10 ]. Lifestyle changes and combatting other risk factors should be started as soon as these patients are diagnosed [ 3 ].…”

“…Moreover, the semi-invasive, time consuming, and the chronic nature of lipid apheresis significantly contributes to the high refusal and low adherence rates [ 7 , 8 , 9 , 33 ]. Hence, a structured approach, including standardized protocols for apheresis therapy, with regular cardiovascular follow-up by an experienced multidisciplinary team, is warranted [ 10 , 33 ]. Another important aspect of the management of HoFH patients on apheresis therapy is the need for a close follow up of LDL-C levels with time-averaged LDL-C. Of note, the Kroon formula calculates the time-averaged LDL-C between two apheresis procedures, adjusting for the non-linear rebound of LDL-C.…”