bms201038 and Cardiovascular-Diseases

The goal of this review is to evaluate the role of inhibiting the synthesis of lipoproteins when there is no or little residual LDL-receptor function as in patients with homozygous familial hypercholesterolaemia. Lomitapide is administered orally once a day while mipomersen is given by subcutaneous injection once a week. Lomitapide inhibits microsomal triglyceride transfer protein while mipomersen is an antisense oligonucleotide directed against apoB100.. The pivotal registration trials for lomitapide and mipomersen were published in 2013 and 2010, respectively. More recently published data from extension trials and cohort studies provides additional information on long-term safety and efficacy. The mean LDL cholesterol reduction was 50% with lomitapide in its single-arm open-label registration trial. Mipomersen reduced LDL cholesterol by approximately 25% in its double-blind, placebo-controlled registration study. Both lomitapide and mipomersen therapy are associated with variable increases in hepatic fat content. The long-term safety of increased hepatic fat content in patients receiving these therapies is uncertain and requires further study. Both drugs may cause elevated transaminase in some patients, but no cases of severe liver injury have been reported. Lomitapide may also cause gastrointestinal discomfort and diarrhoea, especially if patients consume high-fat meals and patients are advised to follow a low-fat diet supplemented with essential fatty acids and fat-soluble vitamins. Mipomersen may cause injection-site and influenza-like reactions. The effect of lomitapide and mipomersen on cardiovascular outcomes has not been studied, but circumstantial evidence suggests that the LDL cholesterol lowering achieved with these two agents may reduce cardiovascular event rates.

Topics: Anticholesteremic Agents; Apolipoprotein B-100; Benzimidazoles; Cardiovascular Diseases; Carrier Proteins; Humans; Hyperlipoproteinemia Type II; Microsomes; Oligonucleotides

Control of lipid levels is one of the most effective strategies for cardiovascular (CV) event prevention. In fact, many clinical trials have clearly demonstrated that low-density lipoprotein cholesterol (LDL-C) lowering, primarily with statins, reduces major CV events and mortality. The evidence from these trials has been useful in designing the cholesterol treatment guidelines, which are mainly aimed at preventing and managing cardiovascular disease (CVD). However, available data indicate that a large proportion of patients fail to achieve lipid goals, and this is particularly frequent in patients at high or very high CV risk. Furthermore, owing to side effects, a significant percentage of patients cannot tolerate statin treatment. Hence, researchers have focused their attention on novel LDL-C-lowering agents that act via mechanisms distinct from that of statins. Among the new compounds under investigation, the monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (PCSK9) seem particularly promising, having recently been shown to be well tolerated and highly effective at lowering LDL-C, with a possible effect on the occurrence of CV events. Currently, alirocumab is approved by the US Food and Drug Administration (FDA) as an adjunct to diet and maximally tolerated statin therapy for use in adults with heterozygous familial hypercholesterolemia (FH) or those with atherosclerotic CV disease who require additional LDL-C lowering; it has also been recently approved by the European Medicines Agency (EMA) for use in patients with heterozygous FH, non-familial hypercholesterolemia or mixed dyslipidemia in whom statins are ineffective or not tolerated. Evolocumab is approved by the FDA as an adjunct to diet and maximally tolerated statins for adults with hetero- and homozygous FH and those with atherosclerotic CV disease who require additional lowering of LDL-C, and by the EMA in adults with primary hypercholesterolemia or mixed dyslipidemia, as an adjunct to diet, in combination with a statin or a statin with other lipid lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin; alone or in combination with other lipid lowering therapies in patients who are statin-intolerant, or those for whom a statin is contraindicated. Evolocumab is also indicated in adults and adolescents aged 12 years and over with homozygous familial hypercholesterolemia in combination with other lipid-lowering therapies.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Anticholesteremic Agents; Apolipoprotein B-100; Benzimidazoles; Biomarkers; Cardiovascular Diseases; Carrier Proteins; Cholesterol, LDL; Drug Therapy, Combination; Humans; Hypercholesterolemia; Molecular Targeted Therapy; Oligonucleotides; PCSK9 Inhibitors; Proprotein Convertase 9; Risk Factors; Treatment Outcome

Although many clinical trials and meta-analyses have demonstrated that lower serum low-density lipoprotein cholesterol (LDL-C) levels are associated with proportionately greater reductions in the risk of cardiovascular disease events, not all patients with hypercholesterolemia are able to attain risk-stratified LDL-C goals with statin monotherapy. Elucidation of the pathophysiology of genetic disorders of lipid metabolism (e.g., familial hypercholesterolemia) has led to the development of several novel lipid-lowering strategies, including blocking the degradation of hepatic LDL-C receptors that are important in LDL-C clearance, or the inhibition of apoprotein synthesis and lipidation. Mipomersen and lomitapide are highly efficacious new agents available for the treatment of patients with homozygous familial hypercholesterolemia. The recent introduction of PCSK9 inhibitors (alirocumab and evolocumab) have made it possible for many patients to achieve very low LDL-C concentrations (e.g., <40 mg/dl) that are usually not attainable with statin monotherapy. Ongoing clinical trials are examining the impact of very low LDL-C levels on cardiovascular disease event rates and the long-term safety of this approach.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Anticholesteremic Agents; Benzimidazoles; Cardiovascular Diseases; Cholesterol, LDL; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Oligonucleotides; Practice Guidelines as Topic; Risk Assessment; Risk Factors

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.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Anticholesteremic Agents; Benzimidazoles; Biomarkers; Blood Component Removal; Cardiovascular Diseases; Cholesterol; Combined Modality Therapy; Consensus; Genetic Predisposition to Disease; Homozygote; Humans; Hyperlipoproteinemia Type II; Mutation; PCSK9 Inhibitors; Phenotype; Proprotein Convertase 9; Risk Assessment; Risk Factors; Treatment Outcome; United Kingdom

Familial hypercholesterolemia is an inherited disorder associated with early accelerated atherosclerosis with morbidity and mortality resulting from premature cardiovascular disease. Affected individuals have extreme elevations in low-density lipoprotein cholesterol levels. Patients usually do not achieve target reductions in cholesterol levels with conventional antihyperlipidemic pharmacotherapy. This unmet need has resulted in the recent development and approval of novel therapies targeting different cholesterol pathways. This article briefly summarizes familial hypercholesterolemia and then discusses the newer pharmacotherapies available in the management of familial hypercholesterolemia.

Topics: Animals; Anticholesteremic Agents; Benzimidazoles; Cardiovascular Diseases; Cholesterol, LDL; Humans; Hyperlipoproteinemia Type II; Oligonucleotides

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder of low-density lipoprotein cholesterol (LDL-C) metabolism resulting in extremely elevated serum levels of LDL-C and premature atherosclerotic cardiovascular disease. Treatment typically involves multiple pharmacologic agents, as well as mechanical filtration using weekly or biweekly LDL apheresis. Despite combination lipid-lowering therapy, LDL-C levels and cardiovascular morbidity and mortality remain unacceptably high in HoFH patients. The European Commission and the US Food and Drug Administration approved the use of lomitapide, a novel medication designed to address this significant unmet need. Lomitapide is an orally administered inhibitor of microsomal triglyceride transfer protein that is indicated as an adjunct to a low-fat diet and other lipid-lowering treatments, including LDL apheresis where available for the reduction of LDL-C, total cholesterol, apolipoprotein B, and non-high-density lipoprotein cholesterol in adult patients with HoFH. The risks of transaminase elevations, hepatic steatosis, and gastrointestinal side effects, and the potential for drug interactions, require vigilant examination of the clinical and laboratory data and patient counseling prior to initiation of lomitapide, as well as regular monitoring during follow-up care. This article highlights important practical considerations for the use of lomitapide in the context of the evaluation and management of a HoFH patient case.

Topics: Anticholesteremic Agents; Benzimidazoles; Biomarkers; Cardiovascular Diseases; Carrier Proteins; Cholesterol, LDL; Drug Interactions; Genetic Predisposition to Disease; Homozygote; Humans; Hyperlipoproteinemia Type II; Male; Middle Aged; Phenotype; Risk Factors; Treatment Outcome

Although the past 4 decades have been the most productive in transitioning from an low-density lipoprotein cholesterol (LDL-C) hypothesis to demonstration of clinical benefit, cardiovascular disease remains a major cause of mortality and morbidity. It is fortunate that most of the effective lipid-lowering drugs, the statins, have become generic and inexpensive. However, there remains a large unmet medical need for new and effective agents that are also well tolerated and safe, especially for patients unable to either tolerate statins or achieve optimal LDL-C on current therapies. It is likely that the agents discussed in this review will fill that need.

Topics: Anticholesteremic Agents; Benzimidazoles; Cardiovascular Diseases; Cholesterol, LDL; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Oligonucleotides

Cardiovascular disease (CVD) is a significant cause of death in Europe. In addition to patients with proven CVD, those with type 2 diabetes (T2D) are at a particularly high-risk of CVD and associated mortality. Treatment for dyslipidaemia, a principal risk factor for CVD, remains a healthcare priority; evidence supports the reduction of low-density lipoprotein cholesterol (LDL-C) as the primary objective of dyslipidaemia management. While statins are the treatment of choice for lowering LDL-C in the majority of patients, including those with T2D, many patients retain a high CVD risk despite achieving the recommended LDL-C targets with statins. This 'residual risk' is mainly due to elevated triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) levels. Following statin therapy optimisation additional pharmacotherapy should be considered as part of a multifaceted approach to risk reduction. Fibrates (especially fenofibrate) are the principal agents recommended for add-on therapy to treat elevated TG or low HDL-C levels. Currently, the strongest evidence of benefit is for the addition of fenofibrate to statin treatment in high-risk patients with T2D and dyslipidaemia. An alternative approach is the addition of agents to reduce LDL-C beyond the levels attainable with statin monotherapy. Here, addition of fibrates and niacin to statin therapy is discussed, and novel approaches being developed for HDL-C and TG management, including cholesteryl ester transfer protein inhibitors, Apo A-1 analogues, mipomersen, lomitapide and monoclonal antibodies against PCSK9, are reviewed.

Topics: Antibodies, Monoclonal; Anticholesteremic Agents; Apolipoprotein A-I; Benzimidazoles; Cardiovascular Diseases; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Diabetes Mellitus, Type 2; Dyslipidemias; Fibric Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Niacin; Oligonucleotides; Proprotein Convertase 9; Proprotein Convertases; Risk Factors; Serine Endopeptidases; Triglycerides

Background Patients with homozygous familial hypercholesterolemia are at high risk of cardiovascular disease due to high low-density lipoprotein (LDL)-cholesterol levels. Cardiovascular disease outcome studies are impossible to conduct, due to the rarity of homozygous familial hypercholesterolemia. We modelled the potential efficacy of lomitapide, a microsomal transfer protein inhibitor, on major adverse cardiovascular events (MACEs) and survival. Design We calculated the effect on cardiovascular outcomes of a 38% plasma LDL-cholesterol reduction induced by lomitapide. Methods Age-dependent hazards and treatment-dependent hazard ratios for mortality and time to first MACE were calculated from an observational study of 149 South African homozygous familial hypercholesterolemia patients. Cardiovascular-related mortality hazards were derived by adjusting for general population non-cardiovascular-related mortality. For every mmol/L LDL-cholesterol reduction, a relative risk reductions of 23% (mortality) and 15% (major adverse cardiovascular events) were observed. Results For the most robust model, baseline median survival with current treatments (LDL-cholesterol 8.7 mmol/L) was 48 years. In the survival benefit analysis, starting lomitapide at age 18 years and reducing LDL-cholesterol by 3.3 mmol/L from baseline would increase life expectancy by 11.2 years and delay the time to first MACE by 5.7 years. Analysis suggested lifetime lomitapide treatment could increase median life expectancy by 11.7 years and time to first MACE by 6.7 years. Conclusion Our modelling analyses show that additional LDL-cholesterol lowering by lomitapide may increase life expectancy in patients with homozygous familial hypercholesterolemia. Further clinical studies are warranted to determine the cardiovascular morbidity and mortality benefits of lomitapide.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticholesteremic Agents; Benzimidazoles; Biomarkers; Cardiovascular Diseases; Child; Child, Preschool; Cholesterol, LDL; Disease-Free Survival; Down-Regulation; Female; Genetic Predisposition to Disease; Homozygote; Humans; Hyperlipoproteinemia Type II; Infant; Infant, Newborn; Life Expectancy; Male; Middle Aged; Models, Statistical; Phenotype; Risk Assessment; Risk Factors; South Africa; Time Factors; Treatment Outcome; Young Adult

Topics: Anticholesteremic Agents; Benzimidazoles; Cardiovascular Diseases; Homozygote; Humans; Hyperlipoproteinemia Type II; Prognosis

Familial hypercholesterolemias are a group of genetic disorders that cause high levels of low-density lipoprotein (LDL) cholesterol, which can lead to atherosclerosis and premature coronary heart disease. Heart disease is the leading cause of death in U.S. women. A major goal in prevention of cardiovascular disease is identification and modification of risk factors. Lomitapide and mipomersen are two new pharmacologic options for treatment of familial hypercholesterolemia. Both are indicated as an adjunct for the management of homozygous familial hypercholesterolemia, along with lipid-lowering medications and diet modification.

Topics: Anticholesteremic Agents; Benzimidazoles; Cardiovascular Diseases; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Hyperlipoproteinemia Type II; Oligonucleotides; Patient Education as Topic; Pregnancy; Pregnancy Complications; Risk Factors; Risk Management; Risk Reduction Behavior; United States; Women's Health

Topics: Benzimidazoles; Cardiovascular Diseases; Dyslipidemias; Humans; Lipoproteins, HDL; Niacin; Propionates; Triazoles