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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.
Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Lomitapide selectively inhibits the microsomal triglyceride transfer protein (MTP) located in the ER of hepatocytes and enterocytes where it is responsible for transferring triglycerides, cholesterolesters, and phospholipids onto newly synthesized plasma lipoproteins associated Apo B leading to the formation of VLDL, IDL, LDL, chylomicrons. Inhibition of MTP results in a reduction of chylomicrons secretionintheintestineandthatof VLDL in the liver which leads to decreased levels of LDL, apolipoprotein B, triglycerides, non-HDL cholesterol, and Lp(a). Lomitapide causes side effects in the gastrointestinal tract (diarrhea, nausea, vomiting) and in the liver, where the reduction of VLDL production goes along with fatty liver formation and enhanced liver enzymes (Feingold and Grunfeld, 2016, and literature cited therein).
Evinacumab: a new option in the treatment of homozygous familial hypercholesterolemia
Published in Expert Opinion on Biological Therapy, 2022
Angela Pirillo, Alberico L. Catapano
Abetalipoproteinemia is a rare autosomal recessive disorder characterized by the lack of plasma apoB-containing lipoproteins and is caused by mutations in the gene encoding the microsomal triglyceride transfer protein (MTP); MTP plays a crucial role in the assembly of apoB-containing lipoproteins in both the liver (VLDL) and intestine (chylomicrons) [23]. Lomitapide inhibits the activity of MTP and lowers LDL-C levels by approximately 45% in an LDLR-independent way (Table 1) [24,25]. Based on its mechanism of action, lomitapide is approved for the treatment of adult HoFH as an adjunct to a low-fat diet and other lipid-lowering drugs with or without lipoprotein apheresis. Patients must comply with a low-fat diet to reduce gastrointestinal adverse events, which represent the major cause of drug discontinuation. A phase 3 trial and its open-label extension study have reported elevations in the hepatic fat content in patients treated with lomitapide, although no overt liver disease has been observed [25,26]. A modeling analysis has suggested that a lifelong lomitapide therapy started early in life (18 years of age) would increase life expectancy by 11.2 years and delay the time to the first MACE by 5.7 years in HoFH [27]. Gastrointestinal side effects and hepatic fat accumulation may limit the tolerability of this drug. The ongoing LOWER registry will evaluate the long-term safety and efficacy of lomitapide in real-life clinical practice [28].
Safety and efficacy of therapies for chylomicronemia
Published in Expert Review of Clinical Pharmacology, 2022
Isabel Shamsudeen, Robert A. Hegele
Lomitapide is a microsomal TG transfer protein (MTTP) inhibitor that lowers TG levels by preventing the transfer of TG to nascent apo B-containing lipoproteins, including chylomicrons [49–51]. It is approved in North America and Europe for the treatment of homozygous familial hypercholesterolemia (HoFH) but not FCS 1,52]. A case study of a FCS patient with recurrent severe pancreatitis episodes annually for decades who was treated with lomitapide showed a reduction in TG levels by 60–70% with no further episodes of pancreatitis while on treatment [50], although the patient eventually developed hepatic fibrosis. Common mechanism-related side effects of lomitapide include nausea, vomiting, and diarrhea, though these can be mitigated by gradual dose escalation [49,50,52]. Patients taking lomitapide are instructed to follow a low-fat diet, which can help to reduce gastrointestinal side effects [52]. A more serious side effect of lomitapide is a fatty liver with transaminase elevation, although this is reversible with dose de-escalation or cessation [49,50,52]. Widespread use of lomitapide has been limited by its cost and adverse gastrointestinal and hepatic effects.
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.