bms201038 and Atherosclerosis

In the last 50 years, several clinical and epidemiological studies during have shown that increased levels of low-density lipoprotein cholesterol (LDLc) are associated with the development and progression of atherosclerotic lesions. The discovery of β-Hydroxy β-methylglutaryl-CoA reductase inhibitors (statins), that possess LDLc-lowering effects, lead to a true revolution in the prevention and treatment of cardiovascular diseases. Statins remain the cornerstone of LDLc-lowering therapy. Lipid-lowering drugs, such as ezetimibe and bile acid sequestrants, are prescribed either in combination with statins or in monotherapy (in the setting of statin intolerance or contraindications to statins). Microsomal triglyceride transfer protein inhibitors and protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are other drug classes which have been investigated for their potential to decrease LDLc. PCSK9 have been approved for the treatment of hypercholesterolemia and for the secondary prevention of cardiovascular events. The present narrative review discusses the latest (2019) guidelines of the European Atherosclerosis Society/European Society of Cardiology for the management of dyslipidemia, focusing on LDLc-lowering drugs that are either already available on the market or under development. We also consider "whom, when and how" do we treat in terms of LDLc reduction in the daily clinical practice.

Topics: Antibodies, Monoclonal, Humanized; Anticholesteremic Agents; Atherosclerosis; Benzimidazoles; Bile Acids and Salts; Carrier Proteins; Cholesterol, LDL; Dicarboxylic Acids; Europe; Ezetimibe; Fatty Acids; Gene Expression; Guidelines as Topic; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; PCSK9 Inhibitors; Proprotein Convertase 9; RNA, Small Interfering

Homozygous familial hypercholesterolemia (HoFH) is a serious rare inherited condition that leads to extremely elevated levels of low density lipoprotein cholesterol (LDL-C), and predisposes affected individuals to high risk of atherosclerotic vascular disease. Traditional therapies are largely ineffective in managing the hypercholesterolemia in these patients; diet and regular LDL-apheresis are the mainstays of management. Lomitapide is an inhibitor of microsomal triglyceride transfer protein (MTP) that blocks the assembly of metabolic precursors of LDL particles. Lomitapide has been approved for use in the HoFH population. Areas covered: This article explores the basic properties of lomitapide, including its pharmacodynamic, pharmacokinetic and metabolic profiles. It also reports the current market status of lomitapide and its close competitors. Trials of lomitapide are also briefly reviewed as well as the safety and tolerability of the drug. Expert opinion: Lomitapide has been recently approved for use in HoFH, a population that has been traditionally very difficult to effectively manage. While lomitapide has some safety concerns, including gastrointestinal symptoms and potential hepatotoxicity, and has yet to prove long term efficacy on hard cardiovascular endpoints, it does represent an attractive treatment option for a small group of patients who, until now, had very limited available effective therapies.

Topics: Anticholesteremic Agents; Atherosclerosis; Benzimidazoles; Carrier Proteins; Cholesterol, LDL; Clinical Trials as Topic; Genotype; Humans; Hypercholesterolemia

Homozygous familial hypercholesterolaemia (HoFH) is characterised by extremely elevated levels of low-density lipoprotein cholesterol (LDL-C) and results from multiple mutations in genes affecting the LDL receptor pathway. Patients are at risk of premature atherosclerotic cardiovascular disease (ASCVD) and premature death. Lomitapide is a microsomal triglyceride transfer protein inhibitor developed to treat HoFH, but cardiovascular outcome data are lacking.. We evaluated detailed data from five HoFH patients and one patient with heterozygous FH (HeFH) and a very severe phenotype. We also analysed confirmatory data from a further 8 HoFH cases. In total, we analysed data from patients in seven global centres in six countries who were all treated with lomitapide with long-term follow-up. Carotid intima-media thickness (CIMT) imaging was recorded on an ad hoc basis to monitor ASCVD in HoFH.. Lomitapide resulted in marked decreases in LDL-C of 56.8-93.9% [77.7-93.9% in the 6 initial cases (mean nadir 64.8 ± 30.1 mg/dL); 56.8-86.0% in the 8 confirmatory cases (mean nadir 131.4 ± 38.2 mg/dL)]. CIMT regressed in 50% of cases (mean follow-up 5.0 ± 3.1 years in initial six cases, and 4.4 ± 1.4 years in confirmatory cases). In the remaining patients, CIMT showed little further change. In patients where assessments of plaque area were available, regression or stabilisation in CIMT was accompanied by clinically significant regression of plaque area.. Lomitapide reduces LDL-C levels in patients with HoFH and severe LDL-C phenotypes, and results in stabilisation and/or regression of CIMT, which is an established marker of ASCVD risk. Additional data are needed to determine if this confers a survival benefit in these very high-risk patients.

Topics: Anticholesteremic Agents; Atherosclerosis; Benzimidazoles; Carotid Intima-Media Thickness; Cholesterol, LDL; Homozygote; Homozygous Familial Hypercholesterolemia; Humans; Hyperlipoproteinemia Type II

Homozygous familial hypercholesterolemia (HoFH) is a genetic dyslipidemia characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C) and accelerated atherosclerosis. Frequently, traditional lipid-lowering therapy is ineffective in these patients, and lipoprotein apheresis is required. Lomitapide has been recently approved for HoFH. We reported our experience in HoFH patients treated with lomitapide, evaluating its efficacy and safety profile.. Probands suspected for familial hypercholesterolemia were extrapolated from the registry of patients admitted to our cardiology department. Dutch Lipid Clinic Network (DLCN) criteria were adopted to diagnose familial hypercholesterolemia clinically. Individuals receiving a definite or probable diagnosis of familial hypercholesterolemia underwent family cascade screening and genetic test. Patients with a genetic diagnosis of HoFH were treated with lomitapide and monitored with serial follow-up visits.. Within 1 year of screening, from a population of 3250 patients admitted to our cardiology department, seven probands were selected with a DLCN score greater than 5. A total of two patients resulted genetically homozygotes for familial hypercholesterolemia and started lomitapide. A marked reduction in LDL-C occurred in both patients on lomitapide (78% reduction in patient 1 and 86% in patient 2 already on lipoprotein apheresis, compared with baseline LDL-C), allowing the apheresis treatment to be stopped in the second case. Lomitapide was well tolerated, and both patients experienced only mild gastrointestinal events.. Lomitapide is an effective and well tolerated cholesterol-lowering drug approved for the treatment of HoFH patients. It would be useful to administer it early in these patients to reduce LDL-C and avoid the development of fatal cardiovascular complications.

Topics: Anticholesteremic Agents; Atherosclerosis; Benzimidazoles; Cholesterol, LDL; Humans; Hyperlipoproteinemia Type II; Male; Middle Aged; Treatment Outcome

Lomitapide reduces low-density lipoprotein-cholesterol (LDL-C) but also high-density lipoprotein-cholesterol (HDL-C) levels. The latter may reduce the clinical efficacy of lomitapide. We investigated the effect of lomitapide on HDL-C levels and on cholesterol efflux capacity (CEC) of HDL in patients with homozygous familial hypercholesterolemia (HoFH).. Four HoFH patients were treated with increasing dosages of lomitapide. Lomitapide decreased LDL-C (range -34 to -89%). Total HDL-C levels decreased (range -16 to -34%) with a shift to buoyant HDL. ABCA1-mediated CEC decreased in all patients (range -39 to -99%). The changes of total, ABCG1- and SR-BI-mediated CEC were less consistent.. Lomitapide decreased LDL-C and HDL-C levels. Our report raises the hypothesis that the anti-atherogenic potential of HDL seems to be unaffected as total CEC did not seem to change consistently. Combined with the reduction of atherogenic lipoproteins, the net effect of lomitapide appears to be beneficial in HoFH patients.

Topics: Adult; Atherosclerosis; ATP Binding Cassette Transporter 1; Benzimidazoles; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Female; Homozygote; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipoproteinemia Type II; Lipoproteins, HDL; Male; Phenotype; Treatment Outcome; Young Adult

1. Insulin-resistant states are commonly associated with a significantly higher risk of atherosclerosis. Insulin resistance has also been correlated with enhanced very low-density lipoprotein (VLDL) production, which is exacerbated by increased intestinal lipid synthesis and insulin-stimulated de novo lipogenesis. Microsomal triglyceride transfer protein (MTP) catalyses the critical step in the synthesis and secretion of VLDL and chylomicrons. The purpose of the present study was to test the hypothesis that chronic inhibition of MTP with a small molecule inhibitor would improve insulin sensitivity and reduce atherogenic risk in a genetic model of diabetic dyslipidaemia. 2. The in vivo activity of BMS-201038, a potent inhibitor of MTP, was evaluated in a model of hypertriglyceridemia induced by Triton WR1339 and corn oil in Zucker fatty rats. Triglyceride secretion rate was significantly reduced by a single dose of BMS-201038 by 35% at 0.3 mg/kg and 47% at 1 mg/kg, respectively. 3. Another group of Zucker fatty rats was dosed orally with BMS-201038 (0.3 and 1 mg/kg) for 14 days. Serum levels of triglycerides were reduced by 71% and 87%, non-esterified free fatty acids were reduced by 33% and 40%, and low-density lipoproteins by 26% and 29%, by 0.3 mg/kg and 1 mg/kg dose of BMS-201038, respectively. These serum lipid changes were accompanied by significant improvements in glucose tolerance and insulin sensitivity. In addition, lipid peroxidation in liver was reduced by 59% and 61%, and superoxide dismutase activity was increased by 11% and 45% by 0.3 mg/kg and 1 mg/kg dose of BMS-201038, respectively. Similar beneficial changes were found in aorta as well. 4. The present study provides evidence that inhibition of MTP with a small molecule inhibitor significantly improves dyslipidaemia associated with insulin resistance and reduces the atherosclerotic risk.

Topics: Animals; Anticholesteremic Agents; Atherosclerosis; Benzimidazoles; Blood Glucose; Carrier Proteins; Dose-Response Relationship, Drug; Down-Regulation; Drug Evaluation, Preclinical; Insulin Resistance; Lipid Metabolism; Male; Metabolism; Obesity; Rats; Rats, Zucker; Risk Factors