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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.
Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Despite many challenges and skepticism from market analysts, in January 2013, 24 years after the formation of Isis Pharmaceuticals, the FDA announced the approval of mipomersen (KynamroTM), the second antisense agent to be commercialized. This agent was developed for the treatment of homozygous familial hypercholesterolemia (HoFH), a rare genetic disease that causes extremely high cholesterol levels and heart attacks at a young age. Although invented by Isis, this agent was marketed by Genzyme Inc, the rare-disease specialty unit of Sanofi. Mipomersen is a so-called “second generation” antisense oligonucleotide, with the nucleotides linked with phosphorothioate linkages rather than the phosphodiester linkages of RNA and DNA, and with deoxyribose sugar moieties in the middle part of the molecule and 2′-O-methoxyethyl-modified ribose units at the two ends. These modifications provide resistance to degradation by nucleases, thus allowing it to be administered by weekly intravenous injection. However, the success of this agent again highlights the delivery problems associated with antisense agents in that it is fortuitous that mipomersen accumulates in the liver, where the target apolipoprotein B predominantly acts.
Familial hypercholesterolemia
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
Mipomersen, an oligonucleotide antisense inhibitor directed against apoB mRNA, has been studied in patients with heterozygous FH also receiving conventional lipid-lowering therapy. Significant reduction of LDL cholesterol of 21 and 34 percent were encountered in a dose-related fashion. Levels of APOB were also reduced [106].
Will evinacumab become the standard treatment for homozygous familial hypercholesterolemia?
Published in Expert Opinion on Biological Therapy, 2021
To be effective in the treatment of HoFH, medicines must bypass the LDL receptor, and this is the case for the two medicines that have been licensed to treat HoFH in the US; lomitapide and mipomersen. Lomitapide is an inhibitor of microsomal triglyceride transfer protein, which transfers triglycerides to triglyceride-rich proteins, such as chylomicrons in the intestine, VLDL cholesterol in the liver, and consequently lowers LDL cholesterol. Although lomitapide can lower LDL cholesterol by 50% in subjects with HoFH, its use is associated with gastrointestinal disturbances and liver toxicity. Mipomersen is an antisense oligonucleotide to liver apoB100 mRNA, which like lomitapide, reduces VLDL in the liver. Mipomersen lowered LDL cholesterol by 26% in HoFH. Its use was associated with injection site reactions, flu-like symptoms, hepatic steatosis, and elevated liver enzymes [3], which led to it being discontinued by its manufacturer. Thus, medicines that are more effective and less toxic are required for the treatment of HoFH.
Efficacy and safety of add on therapies in patients with hypercholesterolemia undergoing statin therapy
Published in Expert Opinion on Pharmacotherapy, 2020
Brian Tomlinson, Paul Chan, Yuzhen Zhang, Christopher Wai Kei Lam
Some lipid-modifying treatments have very limited indications and others have been withdrawn or have restricted availability and these will not be included in this review. Lomitapide and mipomersen have been used for the very rare condition of homozygous familial hypercholesterolemia (HoFH). These drugs are quite effective in lowering LDL-C but they have considerable safety issues [14]. Probucol was withdrawn in western countries but is still used in Japan and some other Asian countries in high-risk patients such as those with severe familial hypercholesterolemia (FH) [15]. It reduces high-density lipoprotein cholesterol (HDL-C), which was thought to be a disadvantage, but it may actually improve HDL function, and it did show a benefit in a recent trial in Asian patients with ischemic stroke [16].
Safety and tolerability of injectable lipid-lowering drugs: an update of clinical data
Published in Expert Opinion on Drug Safety, 2019
Larysa Strilchuck, Federica Fogacci, Arrigo Fg Cicero
Mipomersen should not be used in severe renal impairment or hepatic dysfunction [95]. As the secretion of very low-density lipoproteins cholesterol (VLDL-C) particles takes part in maintaining triglyceride (TG) balance in liver, mipomersen therapy can potentially lead to hepatic steatosis [96]. In 2012, the Committee for Medicinal Products for Human Use recommended the refusal of the marketing authorization of mipomersen and confirmed this decision after the re-examination in 2013. The Committee explained this negative decision by the potential of fat build-up in liver with its consecutive damage and own cardiovascular risk of mipomersen intake [97]. Nevertheless, evaluation of liver histopathology in 7 patients treated with mipomersen for 23–159 weeks showed that mipomersen-induced steatosis is not associated with liver cell injury [98]. In long-term trials the investigators observed a plateau and further progressive decrease of liver fat with continued dosing, suggesting a kind of liver adaptation [99]. The same tendency was noted for ISRs [100].