Management Of Homozygous Familial Hypercholesterolemia Research Articles

Current treatments for the management of homozygous familial hypercholesterolemia: a systematic review and commentary.

Homozygous familial hypercholesterolemia (HoFH) is a rare disorder characterized by markedly elevated circulating low-density lipoprotein cholesterol (LDL-C) from birth. This review aimed to critically evaluate treatments for HoFH with respect to their efficacy, safety, accessibility, overall context and position within the treatment pathway. A mixed-methods review was undertaken to systematically identify and characterize primary interventional studies on HoFH, with a focus on LDL-C reduction as the primary outcome. Interventions assessed were ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), lomitapide, evinacumab, with or without LDL apheresis. Twenty-six seminal studies reporting unique patient data were identified. Four studies were randomized controlled trials (RCTs) with the remainder being single-arm trials or observational registries. Data extracted were heterogeneous and not suitable for meta-analyses. Two RCTs, assessed at being low risk of bias, demonstrated PCSK9i were safe and moderately effective. An RCT demonstrated evinacumab was safe and effective in all HoFH subgroups. Lomitapide was reported to be efficacious in a single-arm trial, but issues with adverse events, tolerability, and adherence were identified. An RCT on ezetimibe showed it was moderately effective when combined with a statin. LDL apheresis was reported as effective, but its evidence base was at very high risk of bias. All interventions lowered LDL-C, but the magnitude of this, and certainty in the supporting evidence, varied. In practice, multiple treatments are required to treat HoFH. The sequencing of these should be made on an individualized basis, with consideration made to the benefits of each intervention.

Contemporary lipid-lowering management and risk of cardiovascular events in homozygous familial hypercholesterolaemia: insights from the Italian LIPIGEN Registry.

The availability of novel lipid-lowering therapies (LLTs) has remarkably changed the clinical management of homozygous familial hypercholesterolaemia (HoFH). The impact of these advances was evaluated in a cohort of 139 HoFH patients followed in a real-world clinical setting. The clinical characteristics of 139 HoFH patients, along with information about LLTs and low-density lipoprotein cholesterol (LDL-C) levels at baseline and after a median follow-up of 5 years, were retrospectively retrieved from the records of patients enrolled in the LIPid transport disorders Italian GEnetic Network-Familial Hypercholesterolaemia (LIPIGEN-FH) Registry. The annual rates of major atherosclerotic cardiovascular events (MACE-plus) during follow-up were compared before and after baseline. Additionally, the lifelong survival free from MACE-plus was compared with that of the historical LIPIGEN HoFH cohort. At baseline, LDL-C level was 332 ± 138 mg/dL. During follow-up, the potency of LLTs was enhanced and, at the last visit, 15.8% of patients were taking quadruple therapy. Consistently, LDL-C decreased to an average value of 124 mg/dL corresponding to a 58.3% reduction (Pt < 0.001), with the lowest value (∼90 mg/dL) reached in patients receiving proprotein convertase subtilisin/kexin type 9 inhibitors and lomitapide and/or evinacumab as add-on therapies. The average annual MACE-plus rate in the 5-year follow-up was significantly lower than that observed during the 5 years before baseline visit (21.7 vs. 56.5 per 1000 patients/year; P = 0.0016). Our findings indicate that the combination of novel and conventional LLTs significantly improved LDL-C control with a signal of better cardiovascular prognosis in HoFH patients. Overall, these results advocate the use of intensive, multidrug LLTs to effectively manage HoFH.

Systematic review on the efficacy of current treatments for the management of homozygous familial hypercholesterolaemia

Systematic review on the efficacy of current treatments for the management of homozygous familial hypercholesterolaemia

Addressing Gaps in Management of Homozygous Familial Hypercholesterolemia: The Impacts of Continuing Medical Education that Includes Patients

Addressing Gaps in Management of Homozygous Familial Hypercholesterolemia: The Impacts of Continuing Medical Education that Includes Patients

Evaluation of the Real-World Effectiveness and Safety of Lomitapide in the Management of HoFH: The European Experience Study

Lead Author's Financial Disclosures L.D. has received consulting fees for Amryt. Study Funding Amryt Pharma. Background/Synopsis Homozygous familial hypercholesterolemia (HoFH) is characterized by severely elevated low-density lipoprotein-cholesterol (LDL-C) associated with extreme cardiovascular risk. Lomitapide is a lipid-lowering agent indicated as adjunct therapy for HoFH patients. This study aimed at evaluating the real-world long-term effectiveness and safety of lomitapide in the management of HoFH. Objective/Purpose The present analysis provides real world evidence on the effectiveness and safety of lomitapide in 75 HoFH patients treated in Europe for up to 9 years. Methods This multicenter European retrospective, observational cohort study collected clinical data from HoFH patients treated with lomitapide. LDL-C reduction versus baseline at 108 months was calculated. Adverse events (AEs), including major adverse cardiovascular events (MACE) and liver imaging were evaluated as safety outcomes. The study was conducted by the Italian and European Working Group on Lomitapide in HoFH. Results 75 HoFH patients from 9 countries were assessed (median age 44 yrs. [interquartile range; IQR 30.0-55.2], 60% with a previous major adverse cardiovascular event (MACE). Median baseline LDL-C was 280.5 mg/dL (IQR 191.8-405.0). At 108 months, median LDL-C decreased by 60% to 121.6 mg/dl (61.0-190.5). At baseline 38 (50.7%) patients received apheresis, after 108 months 14 (36.8%) discontinued apheresis, 32.0% achieved LDL-C ≤100mg/dL and 18.7% ≤70mg/dL. Incident MACE decreased from 28.8% within 2 yrs before lomitapide treatment, to 5.3% up to 2 yrs after treatment. At 3 months AEs were experienced by 33 (51.6%) patients, most frequently gastrointestinal, though these decreased from 37.5% to 6.1% at 24 months. Ten patients stopped treatment with lomitapide, 6 due to AEs. Liver tests did not change significantly during follow-up. In the subset of patients where ultrasound liver imaging data was available (n=45), a modest increase in hepatic steatosis was observed (at baseline 37.3% absent, 17.3% mild, 5.3% moderate vs 14.7% absent, 18.7% mild and 17.3% moderate at last visit) but hepatic stiffness measured by Fibroscan remained within the normal range, 3.4+/-2.3 kPa at baseline (n=15) vs 4.6+/-1.3 kPa at last visit (n=24). Conclusions Real-world experience in a large cohort of HoFH patients with long-term follow-up data showed that lomitapide is an effective treatment for reducing LDL-C in HoFH with an improved tolerability profile versus the phase 3 study. Liver imaging demonstrated a modest increase in hepatic fat but hepatic stiffness remained in the normal range. Additional data are needed to determine the potential impact of LDL-C reduction with lomitapide on major adverse cardiovascular events in HoFH. L.D. has received consulting fees for Amryt.

Evaluation of the real-world efficacy effectiveness and safety of lomitapide in the management of HoFH: The European experience study

Background and Aims: Background: Homozygous familial hypercholesterolemia (HoFH) is characterized by severely elevated low-density lipoprotein-cholesterol (LDL-C) associated with extreme cardiovascular risk. Lomitapide is a lipid-lowering agent indicated as adjunct therapy for HoFH patients. This study aimed at evaluating the real-world long-term efficacy and safety of lomitapide in the management of HoFH.

Integrated Guidance for Enhancing the Care of Familial Hypercholesterolaemia in Australia

Familial hypercholesterolaemia (FH) is a dominant and highly penetrant monogenic disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL)-cholesterol concentration and, if untreated, leads to premature atherosclerosis and coronary artery disease (CAD). There are approximately 100,000 people with FH in Australia. However, an overwhelming majority of those affected remain undetected and inadequately treated, consistent with FH being a leading challenge for public health genomics. To further address the unmet need, we provide an updated guidance, presented as a series of systematically collated recommendations, on the care of patients and families with FH. These recommendations have been informed by an exponential growth in published works and new evidence over the last 5 years and are compatible with a contemporary global call to action on FH. Recommendations are given on the detection, diagnosis, assessment and management of FH in adults and children. Recommendations are also made on genetic testing and risk notification of biological relatives who should undergo cascade testing for FH. Guidance on management is based on the concepts of risk re-stratification, adherence to heart healthy lifestyles, treatment of non-cholesterol risk factors, and safe and appropriate use of LDL-cholesterol lowering therapies, including statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors and lipoprotein apheresis. Broad recommendations are also provided for the organisation and development of health care services. Recommendations on best practice need to be underpinned by good clinical judgment and shared decision making with patients and families. Models of care for FH need to be adapted to local and regional health care needs and available resources. A comprehensive and realistic implementation strategy, informed by further research, including assessments of cost-benefit, will be required to ensure that this new guidance benefits all Australian families with or at risk of FH.

Homozygous familial hypercholesterolaemia: New hope for getting patients to goal?

Management of homozygous familial hypercholesterolaemia is challenging. What are the prospects for attaining low-density lipoprotein cholesterol (LDL-C) goal with novel therapies? This latest commentary discusses the new findings for evinacumab, an angiopoietin-like 3 protein (ANGPTL3) monoclonal antibody.

Clinical management, psychosocial characteristics, and quality of life in patients with homozygous familial hypercholesterolemia undergoing LDL-apheresis in Turkey: Results of a nationwide survey (A-HIT1 registry)

Homozygous familial hypercholesterolemia (HoFH) is a rare, life-threatening inherited disease leading to early-onset atherosclerosis and associated morbidity. Because of its rarity, longitudinal data on the management of HoFH in the real world are lacking, particularly on the impact the condition has on quality of life (QoL), including the impact of the extracorporeal lipid removal procedure apheresis (LA). The A-HIT1 study included 88 patients with HoFH aged ≥12years receiving regular LA in 19 centers in Turkey. Demographic and disease characteristics data were obtained. For patients aged ≥18years, additional data on psychosocial status were obtained via the SF-36 score, the Hospital Anxiety and Depression Scale, and a HoFH-specific questionnaire. There was no standardized approach to therapy between centers. Mean (±SD) frequency of LA sessions was every 19.9 (±14) days, with only 11.6% receiving LA weekly, and 85% of patients were not willing to increase LA frequency. The most common concerns of patients were disease prognosis (31%), and physical, aesthetic, and psychological problems (27.5%, 15.9%, and 11.6%, respectively). Lower age at diagnosis was associated with better QoL, lower anxiety, improved functioning, and greater emotional well-being compared to later diagnosis. These findings demonstrate that adult patients with HoFH undergoing LA, experience significant impairment of QoL with an increased risk of depression. From patients' point of view, LA is time-consuming, uncomfortable, and difficult to cope with. The speed of diagnosis and referral has a considerable impact on patient well-being.

Therapeutic Options for Homozygous Familial Hypercholesterolemia: The Role of Lomitapide.

Lomitapide (Juxtapid® in US and Lojuxta® in Europe) is the first developed inhibitor of the Microsomal Triglyceride Transfer Protein (MTP) approved as a novel drug for the management of Homozygous Familial Hypercholesterolemia (HoFH). It acts by binding directly and selectively to MTP thus decreasing the assembly and secretion of the apo-B containing lipoproteins both in the liver and in the intestine. The present review aims at summarizing the recent knowledge on lomitapide in the management of HoFH. The efficacy and safety of lomitapide have been evaluated in several trials and it has been shown a reduction of the plasma levels of Low-Density Lipoprotein Cholesterol (LDL-C) by an average of more than 50%. Although the most common side effects are gastrointestinal and liver events, lomitapide presents generally with a good tolerability and satisfactory patients compliance. Recently, in Europe, to evaluate the long-term safety and efficacy of lomitapide, the LOWER registry (ClinicalTrials.gov Identifier: NCT02135705) has been established in order to acquire informations on HoFH lomitapidetreated patients from "real life" clinical practice. Furthermore, the observation that lomitapide decreases triglyceride levels may be considered for patients affected by severe forms of hypertriglyceridemia who undergo recurrent episodes of pancreatitis and are poor responders to conventional treatment. Lomitapide represents an innovative and efficacious drug for the treatment of HoFH. Longterm safety data, treatment of pediatric and pregnant HoFH patients and management of severe hypertriglyceridemia still require further investigations.

HEART UK statement on the management of homozygous familial hypercholesterolaemia in the United Kingdom

This consensus statement addresses the current three main modalities of treatment of homozygous familial hypercholesterolaemia (HoFH): pharmacotherapy, lipoprotein (Lp) apheresis and liver transplantation. HoFH may cause very premature atheromatous arterial disease and death, despite treatment with Lp apheresis combined with statin, ezetimibe and bile acid sequestrants. Two new classes of drug, effective in lowering cholesterol in HoFH, are now licensed in the United Kingdom. Lomitapide is restricted to use in HoFH but, may cause fatty liver and is very expensive. PCSK9 inhibitors are quite effective in receptor defective HoFH, are safe and are less expensive. Lower treatment targets for lipid lowering in HoFH, in line with those for the general FH population, have been proposed to improve cardiovascular outcomes. HEART UK presents a strategy combining Lp apheresis with pharmacological treatment to achieve these targets in the United Kingdom (UK). Improved provision of Lp apheresis by use of existing infrastructure for extracorporeal treatments such as renal dialysis is promoted. The clinical management of adults and children with HoFH including advice on pregnancy and contraception are addressed. A premise of the HEART UK strategy is that the risk of early use of drug treatments beyond their licensed age restriction may be balanced against risks of liver transplantation or ineffective treatment in severely affected patients. This may be of interest beyond the UK.

Management of homozygous familial hypercholesterolemia in real-world clinical practice: A report of 7 Italian patients treated in Rome with lomitapide and lipoprotein apheresis

Homozygous familial hypercholesterolemia (HoFH) is a rare, genetically determined condition of highly elevated low-density lipoprotein cholesterol (LDLC) levels. If untreated, patients do not typically survive beyond the seconddecade of life. Traditional lipid-lowering therapies (statins and ezetimibe) are largely ineffective in HoFH patients, and extracorporeal lipoprotein apheresis (LA) forms the mainstay of treatment. Lomitapide is a microsomal triglyceride transfer protein inhibitor approved for the treatment of HoFH as an adjunct to LA. We undertook to examine the efficacy and safety of lomitapide in 7 HoFH patients treated with LA in the Lipid Clinic and Therapeutic Apheresis Unit in Rome, Italy outside a clinical trial setting. Seven patients with genetically determined HoFH were treated with lomitapide in the normal course of their therapy. All patients received LA either weekly or biweekly. Lomitapide was administered according to the approved European Union prescribing information. LDLC levels, liver enzymes, and hepatic fat were monitored. Length of follow-up varied between 12 and 50weeks. After titration, lomitapide doses ranged from 10 to 30mg/d for most (5/7) patients. One patient received lomitapide 60mg/d and another 5mg/d. Three patients achieved LDLC reductions of >50%. The patient on the lowest lomitapide dose did not gain significant benefit. Gastrointestinal adverse events (AEs) were managed via alterations to dietary fat intake. Lomitapide is an effective adjunct to LA in patients with HoFH. AEs are manageable; gastrointestinal AEs can be managed with a low-fat eating plan.

Premature Heart Attacks: Bad Lifestyle, Bad Luck, or Bad Genes?

Homozygous familial hypercholesterolaemia (HoFH), a rare inherited lipid disorder usually caused by bi-allelic defects in the LDLR gene, is characterised by marked elevation in low-density lipoprotein -cholesterol (LDL-C). Aggressive, early intervention with lipid-lowering therapy is warranted in patients with HoFH, and the recent introduction of new drug treatments including lomitapide and mipomersen has enabled physicians and their patients to achieve lower LDL-C levels than previously possible in this hard- to-treat condition. Understanding the overall impact of new interventions in HoFH requires a correct assessment of the true prevalence of the disease. Although it is rare, emerging studies suggest that HoFH may be more common than previously thought. We have reviewed data on the epidemiology and management of HoFH, with a focus on raising awareness on this condition so that clinicians can be made aware of the potential for genetic causes for presentation with premature cardiovascular disease. As classic clinical characteristics may be absent in HoFH patients, genetic status and/or family history should be part of the assessment of patients with significantly elevated LDL-C and premature atherosclerosis with a premature heart attack or clinical complications. As direct outcomes data for new treatments for HoFH are not yet available, intermediate phenotypes of arterial structure and function are being studied as endpoints in clinical trials. Novel therapies which enable lowering of LDL-C to levels that were, until recently, unachievable, have the potential to alter cardiovascular morbidity and mortality in this high-risk group of patients.

UK consensus position on the management of homozygous familial hypercholesterolaemia and the introduction of new agents

UK consensus position on the management of homozygous familial hypercholesterolaemia and the introduction of new agents

Lomitapide: A novel agent for the treatment of homozygous familial hypercholesterolemia

The pharmacology, pharmacokinetics, and clinical efficacy and safety of lomitapide in the management of homozygous familial hypercholesterolemia (HoFH) are reviewed. Lomitapide (Juxtapid, Aegerion Pharmaceuticals) is an oral microsomal triglyceride transfer protein (MTP) inhibitor indicated for the treatment of patients with HoFH, a rare form of hypercholesterolemia that can lead to premature atherosclerotic disease. In clinical trials, the use of lomitapide alone or in combination with other lipid-lowering modalities reduced plasma concentrations of low-density lipoprotein cholesterol (LDL-C) by a mean of more than 50%. Lomitapide is associated with significant gastrointestinal adverse effects and increases in hepatic fat levels. Lomitapide undergoes hepatic metabolism via cytochrome P-450 (CYP) isoenzyme 3A4 and interacts with CYP3A4 substrates including atorvastatin and simvastatin; dose adjustment is recommended when lomitapide is used concurrently with these agents. In patients receiving concomitant warfarin, the International Normalized Ratio (INR) should be closely monitored, as lomitapide use may increase INR values. The recommended initial dosage of lomitapide is 5 mg once daily, with subsequent upward dose adjustment at specified intervals according to tolerability. Lomitapide is contraindicated in patients with moderate-to-severe liver disease, patients with sustained abnormal liver function tests, patients taking strong or moderate CYP3A4 inhibitors, and pregnant patients. Lomitapide is an oral MTP inhibitor approved for the treatment of HoFH. This agent appears to be a realistic option for patients with HoFH who are unable to attain their LDL-C goal or cannot tolerate statin therapy.

Correction to "lomitapide for the management of homozygous familial hypercholesterolemia".

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Recent advances in the treatment of homozygous familial hypercholesterolaemia

To review publications in the English literature over the past 18 months relating to the management of homozygous familial hypercholesterolaemia. Experience with plasmapheresis has been summarized, guidelines are being introduced to enhance patient care and registries are under consideration to improve analysis of management in this rare but serious disorder. Liver transplantation has been reviewed for its biochemical efficacy, but still does not ensure freedom from vascular complications. For patients without access to plasmapheresis, there is now evidence that high-dose statins do improve the prognosis, but combination therapy with additional agents should still be considered for better outcome. Promising new agents that inhibit LDL production by limiting apolipoprotein B100 synthesis by means of antisense oligonucleotides (mipomersen) or by inhibition of microsomal triacylglycerol transfer protein (lomitapide) have made significant additional LDL reduction possible but are associated with hepatic fat accumulation and long-term safety data is still required. Several other lipid modulating agents and gene therapy are still being explored. The management of homozygous familial hypercholesterolaemia by pharmacological means is improving with agents that limit lipoprotein production but plasmapheresis, generally in combination with additional pharmacological treatment, remains the proven option. Liver transplantation is now less likely to be undertaken owing to improved pharmacological options and prognosis.

(15) Management of homozygous familial hypercholestero-laemia in pregnancy

Homozygous familial hypercholesterolaemia (FH), including compound heterozygotes, occurs in approximately one in a million births. If untreated, it can lead to the development of severe atherosclerosis in childhood, so early lowering of LDL cholesterol (LDL-c) is essential. The LDL receptors in this condition are minimally functional, if at all, and high doses of statins, often in combination with other medications, are only moderately effective in improving lipid levels. If drug therapy is unsuccessful at reducing LDL-c, lipoprotein apheresis should be used and started before 7 years of age.

Fatal myocardial infarction at 4.5 years in a case of homozygous familial hypercholesterolaemia.

Management of homozygous familial hypercholesterolaemia is notoriously difficult. For these patients, LDL apheresis is considered the treatment of choice. Treatment initiation is advocated generally from the age of seven years onwards (Thompson et al., Atherosclerosis 198:247-255, 2008). Here, we present the case of a young girl from a large inbred family of Turkish descent with homozygous familial hypercholesterolaemia and fatal outcome at the early age of 4½ years.In conclusion, this case suggests that management of homozygous familial hypercholesterolaemia may require earlier and more aggressive treatment, including LDL apheresis before the age of seven years.

The pivotal role of cholesterol absorption inhibitors in the management of dyslipidemia

Elevated low-density lipoprotein (LDL)-cholesterol is associated with a significantly increased risk of coronary heart disease. Ezetimibe is the first member of a new class of selective cholesterol absorption inhibitors. It impairs the intestinal reabsorption of both dietary and hepatically excreted biliary cholesterol. Ezetimibe is an effective and safe agent for lowering LDL-C and non HDL-C. Short term clinical trials have established the role of ezetimibe monotherapy and its use in combination with statins. Furthermore, ezetimibe and statin combination therapy increased the percentage of patients who achieved their LDL-C treatment goal.Studies using surrogate markers of atherosclerosis have suggested a possible role of ezetimibe in combating atherosclerosis. Ezetimibe provides an effective therapeutic strategy for the management of homozygous familial hypercholesterolemia (HoFH) and sitosterolemia. The lack of outcomes and long term safety data is attributed to the relatively recent introduction of this medication.