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Dyslipidemia
Published in Jahangir Moini, Matthew Adams, Anthony LoGalbo, Complications of Diabetes Mellitus, 2022
Jahangir Moini, Matthew Adams, Anthony LoGalbo
There are dietary supplements that lower LDL, including fiber, margarines, and other products that contain the plant sterols called campesterol and sitosterol, or that contain stanols. Fiber supplements reduce cholesterol by decreasing its absorption and increasing its excretion. The fiber supplements based on oats can provide up to 18% total cholesterol decrease. The plant sterols and stanols displace cholesterol from the intestinal micelles, and may reduce LDL by up to 10%, with no effect upon HDL or total triglycerides. For homozygous familial hypercholesterolemia, medications include lomitapide and mipomersen. Lomitapide inhibitors the microsomal triglyceride transfer protein that interfere with secretion of total triglycerides rich lipoproteins in the intestine and liver. Doses start low and are titrated gradually, every 2 weeks. The patient must eat a diet with fewer than 20% of calories from fat. Adverse effects of lomitapide include diarrhea, elevated liver enzymes, and increased fat in the liver. Mipomersen is an apo B antisense oligonucleotide. It decreases apo B synthesis in the liver, while decreasing levels of LDL, apo B, and Lp(α). Mipomersen is injected subcutaneously. Adverse effects include injection site reactions, increased fat in the liver, enzyme elevations, and flu-like symptoms.
Atherosclerosis
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
In Tangier disease, the spleen enlargement is connected with the accumulation of cholesteryl esters within reticuloendothelial cells.193 The disease is characterized by extremely low plasma HDL cholesterol and HDL apoproteins. In this disease, the primary defect is the abnormality in apoA-I structure, leading to a binding failure with HDL lipids and increased clearance.12,193,194,560 The susceptibility to atherosclerosis is increased in Tangier disease, but not to the extent shown by the epidemiological relationship between ischemic heart disease and HDL cholesterol in the general population.561 There are other genetic conditions where low HDL concentrations are connected with enhanced atherogenesis. Genetically determined familial hyperalphalipoproteinemia with high plasma HDL levels is rarely accompanied with clinical complications of atherosclerosis.226 Abnormalities have been reported recently in HDL in homozygous familial hypercholesterolemia.227 Also, high HDL cholesterol levels have been associated with increased mortality from carcinoma,333,701 but this possibility was not supported by a comprehensive study.96,280,284,286
Therapeutic Apheresis in Children
Published in James L. MacPherson, Duke O. Kasprisin, Therapeutic Hemapheresis, 2019
The treatment of homozygous familial hypercholesterolemia by PE, has been frequently reported in children.22–28 In most cases, a marked reduction in serum cholesterol levels could be obtained, usually with a proportionately greater decrease in LDL cholesterol yielding an improved LDL/HDL ratio. Clinically, xanthomata usually decrease in size rapidly, which suggests that cholesterol is mobilized and tissue levels can be reduced. However, the value of PE in this disease must be measured by whether it can improve the overall survival of these patients.
An update on emerging drugs for the treatment of hypercholesterolemia
Published in Expert Opinion on Emerging Drugs, 2021
Adam J Nelson, Kristen Bubb, Stephen J Nicholls
Angiopoietin-like 3 (ANGPTL3) plays an important role primarily in the regulation of metabolism of triglyceride rich lipoproteins (TRLs). This family of ANGPTL proteins are endogenous inhibitors of lipoprotein lipase, the major factor within the circulation responsible for hydrolysis of TRLs [59]. Loss of function ANGPTL3 variants are associated with lower levels of both triglyceride and LDL cholesterol and a 41% lower risk of coronary heart disease [60]. In patients with homozygous familial hypercholesterolemia, administration of intravenous evinacumab, an ANGPTL3 monoclonal antibody, every 4 weeks produced a 49% reduction in LDL cholesterol levels compared with placebo after 24 weeks. Evinacumab was well tolerated by the patients [61]. This provides an additional therapeutic strategy for the management of patients with homozygous familial hypercholesterolemia
Hepatoprotective effects of Cassia semen ethanol extract on non-alcoholic fatty liver disease in experimental rat
Published in Pharmaceutical Biology, 2019
Yuanyuan Meng, Yong Liu, Ningning Fang, Yongmin Guo
In the study, we also detected the levels of LDL-R mRNA in liver tissue. Increasing evidence indicates that NAFLD may be in part caused by malfunction of low density lipoprotein (LDL) secretion (Yu et al. 2017). Liver expression of the LDL-R is a major factor in regulation of plasma levels of LDL cholesterol (LDL-C) (Ivaturi et al. 2014). Human patients with loss-of-function LDL-R could develop to familial hypercholesterolemia (Usifo et al. 2012), and the homozygous familial hypercholesterolemia patients could develop to advanced atherosclerotic lesions at an early age (López et al. 2018; Tada et al. 2018). Thus, LDL-R could cause the metabolism outlet of all kinds of lipoprotein, and regulate the content of plasma lipoprotein (Go 2015; Toldo et al. 2017). In the present study, the levels of LDL-R mRNA in HFD-induce NAFLD model group was significantly decreased compared with the control group. However, Cs treatment groups (0.5, 1, and 2 g/kg) markedly up-regulated the levels of LDL-R mRNA in a dose-dependent manner, which further confirmed the protective effects of Cs ethanol extract.
Mipomersen and its use in familial hypercholesterolemia
Published in Expert Opinion on Pharmacotherapy, 2019
Johnathon Seth Parham, Anne Carol Goldberg
The treatment of severe hypercholesterolemia including familial hypercholesterolemia will continue moving forward with the development of new treatment modalities that use a variety of methodologies including further generations of antisense nucleotides, monoclonal antibodies to various targets, and RNA silencing. The ultimate goal in the treatment of familial hypercholesterolemia is to be able to lower LDL-C levels significantly with few side effects given the lifelong nature of the treatment. Treatment of homozygous FH can be particularly difficult, and the need is great in these patients to lower LDL-C from an early age. The viability of mipomersen, an early generation antisense oligonucleotide, with its cutaneous and systemic reactions as well as the concerns about hepatic fat is questionable. Outcomes trials in patients with homozygous familial hypercholesterolemia are probably not feasible given the low numbers of these patients. For those HoFH patients with some LDL receptor activity, the PCSK9 monoclonal antibodies can offer some benefit. Newer therapies including those involving other targets probably hold more promise for the future treatment of HoFH than mipomersen. Although mipomersen did show efficacy in treatment of heterozygous FH, it has not been marketed for use in the HeFH population and has clearly been superseded by the currently marketed alirocumab and evolocumab with their ease of use, every two-week dosing, and fewer side effects. These PCSK9 monoclonal antibodies have also been shown to reduce cardiovascular events in randomized cardiovascular outcomes trials, although the trials were not specifically done in patients with familial hypercholesterolemia.