Novel treatment options for the management of heterozygous familial hypercholesterolemia

Abstract

Even though statins represent the mainstay of treatment of heterozygous familial hypercholesterolemia (FH), their low-density lipoprotein cholesterol (LDL-C) lowering efficacy is finite and most patients with FH will not achieve LDL-C targets with statin monotherapy. Addition of ezetimibe with or without bile acid sequestrants will also not lead to treatment goals in many of these patients, particularly in those with established cardiovascular disease. In this selected subgroup of the FH population, proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors provide substantial reductions in LDL-C levels, reduce cardiovascular morbidity and appear to be safe. Mipomersen, an antisense single-strand oligonucleotide that inhibits the production of apoB by binding to the mRNA that encodes the synthesis of apoB, and lomitapide, an inhibitor of microsomal triglyceride transfer protein, also reduce LDL-C levels but are currently indicated only for the management of homozygous FH. Areas covered: In the present review, the role of PCSK9 inhibitors, mipomersen and lomitapide in the management of FH is briefly discussed. Other LDL-C-lowering agents under evaluation include inclisiran, a small interference RNA molecule that induces long-term inhibition of PSCK9 synthesis, anacetrapib, a cholesterol ester-transfer protein inhibitor, ETC-1002 (bempedoic acid), an inhibitor of adenosine triphosphate citrate lyase, and gemcabene, which reduces hepatic apolipoprotein C-III mRNA. The safety and efficacy of these agents are also reviewed. Expert Commentary: Even though several novel treatment options for heterozygous FH are under development, it remains to be shown whether these treatments will also reduce cardiovascular morbidity in these high-risk patients.

Cobomarsen, an oligonucleotide inhibitor of miR‐155, co‐ordinately regulates multiple survival pathways to reduce cellular proliferation and survival in cutaneous T‐cell lymphoma

“…In this study, we developed cobomarsen, a synthetic locked nucleic acid‐modified oligonucleotide inhibitor of miR‐155. Oligonucleotides have been proven to be viable antisense therapies for several drug targets (Janssen et al , ; Polychronopoulos & Tziomalos, ). Cobomarsen, which has base‐pairing complementarity to miR‐155, was chosen from a panel of miR‐155 inhibitors for its superiority in de‐repression of miR‐155 direct targets (Fig A, B and Figure S2) and unfacilitated uptake (Fig D).…”

Treatment Strategy for Dyslipidemia in Cardiovascular Disease Prevention: Focus on Old and New Drugs

“…Other currently available lipid-lowering agents for the management of FH are mipomersen, an antisense single-strand oligonucleotide that inhibits the production of apoB, and Lomitapide, which inhibits the enzyme that transfers triglycerides onto apoB. However, these specialized therapies may be needed to control LDL-C in patients with atherosclerotic cardiovascular disease risk, baseline LDL-C > 190 mg/dL, and/or phenotypic HoFH, who have an inadequate response to statins with or without ezetimibe and PCSK9 inhibitors [ 58 ]. Mipomersen and lomitapide are only indicated for HoFH and may be prescribed at the discretion of lipid specialists.…”

“…It is a selective inhibitor of the microsomal transport protein of triglycerides (MTP), an intracellular protein found in the endoplasmic reticulum of liver and intestine cells which plays a role in the assembly of fats, such as cholesterol and triglycerides, in lipoproteins, and their subsequent release into the blood. The inhibition of MTP reduces the production of chylomicrons in enterocytes and increases production of very low-density lipoprotein (VLDL) cholesterol in hepatocytes independently of the LDL receptor ( Figure 1 ) [ 58 ].…”

Hiperkolesterolemia Familiarra: patofisiologia, diagnostikoa eta tratamendua

“…Mipomersen, berriz, APOB100 mRNArekin batzen diren oligonukleotidoz osatuta dago eta horiek gibeleko LDL eta VLDL sorrera murrizten dute. Aipatutako bi farmakoek hainbat albo-kalte eragiten dituzte eta HoHF edo arrisku kardiobaskular handiko kasuetan bakarrik gomendatzen dira (43).…”