PCSK9 Inhibitors
Several new medical therapies are being evaluated in clinical trials for the treatment of FH. The most promising of which are the PCSK9 inhibitors, a completely novel class of medications. PCSK9 is a serine protease that is involved with the degradation of LDL receptors leading to higher circulating plasma LDL-C levels. PCSK9 inhibitors are injectable monoclonal antibodies that bind to PCSK9, thereby decreasing the turnover of LDL receptors, which in turn leads to a decrease in circulating LDL-C levels. Two of the most promising medications in this novel class are evolocumab and alirocumab. Both of these medications have undergone extensive phase II trials and are in the process of completing phases III trials. The DESCARTES phase III trial recently presented 52-week follow up data that compared evolocumab and placebo in patients already treated with standard lipid lowering therapies.51 The investigators’ data show a 57 % reduction in LDL-C in the evolocumab group compared to placebo.
Further supporting this class of medications is the ODYSSEY trial, which randomised heterozygous FH patients on standard lipidlowering therapy to receive alirocumab or placebo.52 The results of this trial showed that alirocumab decreased LDL-C by 49 % from baseline while the placebo group had a 9 % increase in LDL-C. Impressively, in this traditionally very difficult to treat FH population, the percentage of patients reaching goal LDL-C was 70–80 %. Moreover, the post hoc analysis of a separate ODYSSEY Long Term trial was notable for a 54 % reduction in major adverse cardiovascular events in the alirocumab group versus placebo.53 This result was statistically significant.
There are several other medications being evaluated for the treatment of FH but none seem to be as promising as the PCSK9 inhibitors. The MODE trial is a phase II examination of recombinant ApoA1 milano infusions in homozygous FH patients.54 Finally, anacetrapib, a CETP-inhibitor is being studied in homozygous FH patients in a phase III trial.54
Lipoprotein Apheresis
When lifestyle modifications prove inadequate and pharmaceutical interventions are either not tolerated or lack adequate response, lipoprotein apheresis (LA) can be used to remove circulating LDL along with other atherogenic particles. All apheresis processes require the removal of blood from a vein (typically the antecubital) and typically involve the separation of that blood into cellular and plasma components. LA sessions typically last three hours and are performed on average every two weeks for HeFH patients and 7–10 days. Hyperlipidaemia HoFH patients.55
Once the blood is removed, several strategies can be employed to remove atherogenic compounds from the plasma including immunoadsorption, plasmapheresis, direct adsorption, dextran sulfate adsorption, and heparin extracorporeal LDL apheresis. Plasmapheresis was one of the original methods used to remove LDL from serum. During this process, plasma is separated from the cellular components of the blood and is removed from the body and replaced by albumin infusions. This process was non-selective and removed helpful plasma protein including HDL and immunoglobulins. Immunoadsorption is more selective for the atherogenic particles. In immunoadsorption, the plasma is passed over membranes coated with polyclonal sheep antibodies against apolipoprotein B100 and apolipoprotein B containing lipoproteins thereby removing LDL, VLDL and lipoprotein(a).
Not requiring separation of the plasma and cells, direct lipoprotein adsorption employs polyacrylamide beads within a filter. These beads contain pores of a particular diameter that allows only certain particles to enter and thus be removed from the patient’s serum. Based on the width of the pore, the filters can be more or less selective which is typically determined by disease severity. Typically, these columns can remove LDL, lipoprotein(a) and triglycerides but can also remove fibrinogen in the more non-selective columns.
Dextran sulfate adsorption (DSA) involves separated plasma being passed over two cellulose-bead columns, which contain dextran sulfate. This interaction leads to electrostatic binding of (apolipoprotein- B)-containing particles and their removal from circulation. This process, similar to the above-mentioned immunoadsorption, is specific to apolipoprotein-B and does not remove HDL or albumin from circulation. DSA is the most efficient method to remove atherogenic particles from circulation given the quantity of plasma it can filter in a given session. Patients receiving DSA must be anticoagulated with heparin during the session, making heparin hypersensitivity a contraindication to DSA.
The last filtration process, heparin extracorporeal LDL apheresis (HELP), involves the heparinisation and acidification of the patient’s plasma, causing heparin to carry a negative charge and LDL to carry a positive charge. These opposite charges lead to heparin-LDL complex formation, precipitation and eventual filtration. Via this method 60–64 % of LDL, 65–75 % of VLDL and 60-70 % of lipoprotein(a) is removed.55–57
Given the relatively low numbers of patients receiving LA, few randomised clinical trials have been performed to examine its effectiveness.56 The Familial Hypercholesterolaemia Regression Study examined 39 patients randomised to LA and simvastatin or simvastatin and colestipol and found biweekly LA and simvastatin decreased LDL cholesterol levels by 31 % more than the medication only group.58 Similarly, the LDLApheresis Atherosclerosis Regression Study (LAARS) found reductions in the LDL levels of their 42 study subjects randomised to LA.59 Neither study showed a significant difference in coronary atherosclerosis as determined by coronary angiography.55,58,59 Other randomised studies have shown reductions in circulating inflammatory biomarkers such as CRP and lipoprotein-associated phospholipase A2.60,61
Given its association with improved LDL control, LA is approved in the United States for HoFH patients with LDL ≥ 500 mg/dL or HeFH patients with LDL ≥ 300 mg/dL or ≥ 200 mg/dL with documented coronary artery disease.55
Liver Transplantation
Orthotopic Liver transplantation (OLT) remains the only curative option for patients with homozygous FH that cannot achieve optimal LDL levels after pharmacological treatment and for those unable to tolerate lipid apheresis.19,50 Liver transplantation replaces dysfunctional hepatic LDL in receptors patients, allowing near normalisation of lipoprotein metabolism.62 While lipid apheresis can reduce or maintain LDL levels at acceptable ranges, it does not prevent development of atherosclerosis.63 The first liver and heart transplant64 for homozygous FH occurred in 1984 in a six-year-old female with severe coronary artery disease. The patient showed significantly improved and sustained lower LDL levels postoperatively, but ultimately died due to cardiac allograft rejection. Since then, over 30 cases with patients ranging from 2–46 years of age have been reported.64–67 The long-term outcomes of OLT are unknown due to paucity of donors, high-risk postsurgical outcomes, and the concern for life-long immunosuppressive therapy. However, a recent update has shown the five-year survival rates after OLT in paediatric patients approaches 90 % in the United States.68 Case reports have shown patients free of coronary artery disease 20 years after transplant, while others have had post-operative complications, immediate organ rejection, and complications from immunosuppressant therapy.62,63,65 Patients who are considered for OLT usually have severe coronary artery disease and valvular insufficiency, which requires simultaneous heart and liver transplant, further increasing postoperative risks and complications. Recent literature supports transplantation in a younger population before the onset of significant coronary artery disease to preclude the need for cardiac transplantation.66–67 Patients with homozygous FH who fail medical therapy and apheresis should be considered candidates for OLT.
Special Populations
While statins are the most effective therapy for those with FH, the use of statins is contraindicated during pregnancy. Animal studies have demonstrated conflicting evidence on the teratogenicity of statins during pregnancy.69 There have been studies that have found the lipophilic class of statins (lovastatin, cerivastatin, and fluvastatin) to be associated with skeletal malformations. Atorvastatin and lovastatin have also been associated with developmental toxicity and skeletal defects, but only at supratherapeutic doses that also caused maternal toxicity.69
There is limited data on the teratogenicity of other lipid-lowering agents in humans. Ezetimibe, nicotinic acid, and fibrates have all been associated with teratogenic effects in animal studies.69 Therefore, the only medications currently acceptable to use during pregnancy are the bile acid binding resins, cholestyramine and colsevelam, as these medications do not pass into the systemic circulation and have not been shown to have any adverse effects thus far.70,71
The National Institute of Clinical Excellence (NICE) guidelines recommend that all women stop taking statins three months prior to attempting to conceive.72 Women who become pregnant while taking a statin or other systemically absorbed lipid-modifying agent, should be instructed to stop treatment immediately and be referred to an obstetrician for urgent fetal assessment.73 Women should not resume statin therapy until after they have completed lactation.72